Curcumin downregulates Smad pathways and reduces hepatic stellate cells activation in experimental fibrosis

array:24 ["pii" => "S166526812030065X" "issn" => "16652681" "doi" => "10.1016/j.aohep.2020.05.006" "estado" => "S300" "fechaPublicacion" => "2020-09-01" "aid" => "218" "copyright" => "Fundación Clínica Médica Sur, A.C." "copyrightAnyo" => "2020" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2020;19:497-506" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:19 [ "pii" => "S1665268120300569" "issn" => "16652681" "doi" => "10.1016/j.aohep.2020.06.002" "estado" => "S300" "fechaPublicacion" => "2020-09-01" "aid" => "215" "copyright" => "Fundación Clínica Médica Sur, A.C." "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2020;19:507-15" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Identification of mutations in the S gene of hepatitis B virus in HIV positive Mexican patients with occult hepatitis B virus infection" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "507" "paginaFinal" => "515" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 4131 "Ancho" => 2175 "Tamanyo" => 356162 ] ] "descripcion" => array:1 [ "en" => "Phylogenetic tree constructed by the Maximum Likelihood analysis of the S region of hepatitis B virus (HBV) isolates from 18 patients with occult HBV infection (filled circle) and including 23 GenBank sequences of genotypes A–H (GenBank accession number and HBV genotype indicated, genotype H unfilled circle). The bootstrap values are indicated for the major nodes as a percentage of the data obtained from 1000 replicates." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Karina Enriquez-Navarro, Angelica Maldonado-Rodriguez, Othon Rojas-Montes, Rocio Torres-Ibarra, Leticia Bucio-Ortiz, Miguel A. De la Cruz, Jesus Torres-Flores, Beatriz Xoconostle-Cazares, Rosalia Lira" "autores" => array:9 [ 0 => array:2 [ "nombre" => "Karina" "apellidos" => "Enriquez-Navarro" ] 1 => array:2 [ "nombre" => "Angelica" "apellidos" => "Maldonado-Rodriguez" ] 2 => array:2 [ "nombre" => "Othon" "apellidos" => "Rojas-Montes" ] 3 => array:2 [ "nombre" => "Rocio" "apellidos" => "Torres-Ibarra" ] 4 => array:2 [ "nombre" => "Leticia" "apellidos" => "Bucio-Ortiz" ] 5 => array:2 [ "nombre" => "Miguel A." "apellidos" => "De la Cruz" ] 6 => array:2 [ "nombre" => "Jesus" "apellidos" => "Torres-Flores" ] 7 => array:2 [ "nombre" => "Beatriz" "apellidos" => "Xoconostle-Cazares" ] 8 => array:2 [ "nombre" => "Rosalia" "apellidos" => "Lira" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268120300569?idApp=UINPBA00004N" "url" => "/16652681/0000001900000005/v5_202012011817/S1665268120300569/v5_202012011817/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1665268120300661" "issn" => "16652681" "doi" => "10.1016/j.aohep.2020.06.005" "estado" => "S300" "fechaPublicacion" => "2020-09-01" "aid" => "219" "copyright" => "Fundación Clínica Médica Sur, A.C." "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2020;19:489-96" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Mediterranean-like mix of fatty acids induces cellular protection on lipid-overloaded hepatocytes from western diet fed mice" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "489" "paginaFinal" => "496" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1607 "Ancho" => 2421 "Tamanyo" => 146433 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Cellular functionality by MTT assay. Control and western cells were treated or not with high mono and polyunsaturated fatty acids (HMPFA) or high saturated fatty acids (HSFA) according <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, for 24 h. Each bar represents the mean ± SEM in at least four mice, *p < 0.05 vs control cells, # p < 0.05 vs western cells." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Lyssia Castellanos-Tapia, María Elizabeth Tejero-Barrera, Soraya Salas-Silva, Arturo Simoni-Nieves, Alejandro Escobedo-Calvario, Luis E. Gomez-Quiroz" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Lyssia" "apellidos" => "Castellanos-Tapia" ] 1 => array:2 [ "nombre" => "María Elizabeth" "apellidos" => "Tejero-Barrera" ] 2 => array:2 [ "nombre" => "Soraya" "apellidos" => "Salas-Silva" ] 3 => array:2 [ "nombre" => "Arturo" "apellidos" => "Simoni-Nieves" ] 4 => array:2 [ "nombre" => "Alejandro" "apellidos" => "Escobedo-Calvario" ] 5 => array:2 [ "nombre" => "Luis E." "apellidos" => "Gomez-Quiroz" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268120300661?idApp=UINPBA00004N" "url" => "/16652681/0000001900000005/v5_202012011817/S1665268120300661/v5_202012011817/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Curcumin downregulates Smad pathways and reduces hepatic stellate cells activation in experimental fibrosis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "497" "paginaFinal" => "506" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Erika Hernández-Aquino, Marco A. Quezada-Ramírez, Angélica Silva-Olivares, Erika Ramos-Tovar, Rosa E. Flores-Beltrán, José Segovia, Mineko Shibayama, Pablo Muriel" "autores" => array:8 [ 0 => array:3 [ "nombre" => "Erika" "apellidos" => "Hernández-Aquino" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Marco A." "apellidos" => "Quezada-Ramírez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Angélica" "apellidos" => "Silva-Olivares" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Erika" "apellidos" => "Ramos-Tovar" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 4 => array:3 [ "nombre" => "Rosa E." "apellidos" => "Flores-Beltrán" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "José" "apellidos" => "Segovia" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 6 => array:3 [ "nombre" => "Mineko" "apellidos" => "Shibayama" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 7 => array:4 [ "nombre" => "Pablo" "apellidos" => "Muriel" "email" => array:1 [ 0 => "pmuriel@cinvestav.mx" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional, Mexico City, Mexico" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Physiology, Biophysics and Neurosciences, Cinvestav-IPN, Mexico City, Mexico" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Mexico City, Mexico" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "School of Higher Education in Medicine-IPN, Mexico City, Mexico" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 1 "multimedia" => array:5 [ "identificador" => "fig0035" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 886 "Ancho" => 2213 "Tamanyo" => 76926 ] ] ] ] "textoCompleto" => "1IntroductionDespite the progress in the study and management of liver diseases, millions of people worldwide still suffer from chronic hepatic illness. The incidence and prevalence of fibrosis, conducing to cirrhosis, is important to understanding the burden of hepatic disease [<a class="elsevierStyleCrossRef" href="#bib0005">1</a>]. However, no effective antifibrotic therapy has been approved to date. Activated hepatic stellate cells (HSCs) are the major drivers of liver fibrogenesis, producing exacerbated amounts of extracellular matrix (ECM) proteins. Therefore, pharmacological treatment to decrease activated HSCs may constitute an effective antifibrotic therapy [<a class="elsevierStyleCrossRef" href="#bib0010">2</a>,<a class="elsevierStyleCrossRef" href="#bib0015">3</a>].Transforming growth factor-β (TGF-β) is widely recognized for its profibrogenic effects, inducing several profibrogenic factors, and most importantly inducing HSC activation. Several studies have reported that TGF-β mediates its effects through Smad3 phosphorylation in its MH2 domain (carboxyl-terminal); however, in recent years, it has been reported that Smad3 actively participates in the profibrogenic process independent of its activation via TGF-β [<a class="elsevierStyleCrossRef" href="#bib0020">4</a>]. The MAPK family can phosphorylate Smad3 in its linker domain, resulting in the induction of PAI-1 expression, which is involved in HSC proliferation and migration processes, favoring fibrosis [<a class="elsevierStyleCrossRef" href="#bib0025">5</a>,<a class="elsevierStyleCrossRef" href="#bib0030">6</a>].Curcumin, a polyphenol found in the root of the Curcuma longa plant, has been widely reported to be a hepatoprotective plant in various liver diseases [<a class="elsevierStyleCrossRefs" href="#bib0035">7–10</a>]. However, the mechanism of action of curcumin in reducing fibrosis has not been completely elucidated. Furthermore, the effect of curcumin in the noncanonical Smad profibrotic pathway has not been investigated. Consequently, the objective of this study was to investigate whether curcumin could reduce hepatic fibrosis in a carbon tetrachloride (CCl4)-induced model of cirrhosis and if so, to determine the canonical/noncanonical Smad3 pathways, and/or HSCs activation/deactivation pathways that may be involved in this protective effect.2Materials and methods2.1Animal treatmentMale Wistar rats (initially weighing 100–120 g.) were provided by the Laboratory Animals Production and Experimentation Unit (UPEAL). Rats were maintained on a standard diet of Rat Chow® with free access to drinking water under controlled conditions. After the acclimation period (1 week), the rats (n = 32) were administered the following treatments: The control group (n = 8) was given 0.3% carboxymethylcellulose at a dose of 1 mL daily through an intragastric tube. The CCl4 group (n = 8) was administered 400 mg CCl4/kg body weight i.p. three times per week, dissolved in mineral oil for 12 weeks. The CCl4 + curcumin group (n = 8) was administered CCl4, as in the CCl4 group for 12 weeks, plus 100 mg of curcumin/kg twice a day at the beginning of the week 9 of CCl4 treatment for 4 weeks, by gavage. The curcumin only group (n = 8) was administered 100 mg of curcumin/kg twice a day for 4 weeks by gavage. The curcumin dose in this study has been previously evaluated and used with successful results [<a class="elsevierStyleCrossRef" href="#bib0045">9</a>,<a class="elsevierStyleCrossRef" href="#bib0050">10</a>]. Rats were euthanized under ketamine (100 mg/kg) and xylazine (8 mg/kg body weight) anesthesia. All rats were sacrificed following 12 weeks of the experiment. Blood was collected by cardiac puncture and centrifuged at 1300 rpm for 15 min; serum obtained was used for biochemical determinations. The liver was quickly removed, sectioned, and appropriately stored before each analysis was conducted. The rest of the liver was stored at −72 °C.All animal care and experimental procedures complied with the Institution’s guidelines, as well as the Mexican official regulation (NOM- 062-ZOO-1999). This research protocol (protocol number 207−16) was approved by the institutional animal care and use committee from CINVESTAV-IPN.2.2Biochemical analysesLiver damage was assessed by measuring the activities of alanine aminotransferase (ALT) [<a class="elsevierStyleCrossRef" href="#bib0055">11</a>], alkaline phosphatase (AP) [<a class="elsevierStyleCrossRef" href="#bib0060">12</a>], and γ-glutamyl transpeptidase (γ-GTP) [<a class="elsevierStyleCrossRef" href="#bib0065">13</a>] in serum samples of blood that were centrifuged at 1300 rpm for 15 min. Protein concentration was determined via the Bradford method using bovine serum albumin as a standard [<a class="elsevierStyleCrossRef" href="#bib0070">14</a>]. The content of reduced glutathione (GSH) in the liver was evaluated in fresh tissue samples [<a class="elsevierStyleCrossRef" href="#bib0075">15</a>]. Small pieces of liver were separated for glycogen determination using anthrone reagent [<a class="elsevierStyleCrossRef" href="#bib0080">16</a>]. Collagen concentrations were determined by measuring the hydroxyproline content in the liver samples as described previously [<a class="elsevierStyleCrossRef" href="#bib0085">17</a>].2.3Hematoxylin, eosin, Masson’s trichrome stains, and immunohistochemistryLiver samples were fixed with 10% formaldehyde (in 1X PBS) for 24 h, then, hematoxylin and eosin (H & E) and Masson’s trichrome stains were performed; next, samples were mounted with Permount polymer. Sections were prepared for immunohistochemistry (IHC) as described previously [<a class="elsevierStyleCrossRef" href="#bib0090">18</a>]. The antibodies used for IHC are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. All stained slides were visualized using a light microscope (80i, Eclipse; Nikon, Tokyo, Japan).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>2.4ZymographyProteolytic activity was assayed with gelatin-substrate acrylamide gels as described previously [<a class="elsevierStyleCrossRef" href="#bib0095">19</a>]. Gels were digitized and then analyzed densitometrically with an image analysis software (ImageJ, 1.46 r, NIH, Bethesda, Maryland, USA).2.5Western blot assaysProtein analysis by western blot was performed as previously described [<a class="elsevierStyleCrossRef" href="#bib0100">20</a>]. Antibodies used for western blot are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Protein concentration was measured using the bicinchoninic acid method [<a class="elsevierStyleCrossRef" href="#bib0105">21</a>]. The images were digitized, and the intensity of each band was quantiﬁed using densitometric scanning with ImageJ software (NIH) [<a class="elsevierStyleCrossRef" href="#bib0110">22</a>].2.6RNA extraction, RT-PCR, and qRT-PCRTissue RNA was extracted and assayed as previously described [<a class="elsevierStyleCrossRef" href="#bib0090">18</a>,<a class="elsevierStyleCrossRef" href="#bib0100">20</a>] and β-Actin was used as the housekeeping gene to normalize mRNA levels. Gels were digitized. qRT-PCR was performed using 0.5 μL of cDNA added to 4.5 μL of master mix (Kapa SYBR Fast Universal qPCR Kit REF KK4601, Merck Mexico). Reaction conditions recommended by the manufacturer were followed. qRT-PCR was performed in an Eco thermocycler (Illumina). The relative mRNA levels of α-SMA (Forward 5′-GAATGAACGCTTCCGCTGCC-3′/Reverse 5′-TCCTGTCAGCAATGCCTGGG-3ʹ) and Smad3 (Forward 5′-TGATCCCTCCAATTCAGAGC-3′/Reverse 5′-AAAGACCTCCCCTCCAATGT-3′) were calculated by the comparative threshold cycle (Ct) method using β-actin (Forward 5ʹ TGGCACCACACCTTCTACA-3ʹ/Reverse 5ʹ-TCACGCACGATTTCCC-3ʹ) as an internal control for normalization. The fold change in the expression of each target gene was calculated by the 2−ΔΔCt method [<a class="elsevierStyleCrossRef" href="#bib0115">23</a>].2.7Transmission electron microscopyRepresentative liver tissues were processed for transmission electron microscopy (TEM) as previously described [<a class="elsevierStyleCrossRef" href="#bib0120">24</a>].2.8Statistical analysisResults are expressed as mean values ± SE. Comparisons were carried out via one-way variance analysis followed by Tukey’s test, utilizing the Graph Pad Prism software, version 6.01 (GraphPad Software Inc., San Diego, CA, USA). Differences were considered statistically significant when P was <0.05. The group sizes referred to independent values.3Results3.1Curcumin attenuated macroscopic, microscopic, and ultrastructural alterations produced by CCl4The control rat liver had an intense brown color, smooth, and soft surface (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A). Treatment with CCl4 produced liver macronodular fibrosis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B) and curcumin attenuated the macroscopic effects produced by CCl4 administration (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C). Hepatic tissue from CCl4-treated rats (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>F) showed a distortion of the parenchyma, bile duct proliferation, and steatosis but curcumin decreased these alterations. Large areas of normal hepatocytes were found, but some hepatocytes maintained discrete deposits of hemosiderin and nuclear atypia (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>G). <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>J shows a cirrhotic liver section stained with Masson’s trichrome, where large amounts of collagen can be observed forming regeneration nodules. In the CCl4 + curcumin group, normal areas were observed, as well as a considerable decrease in collagen fibers (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>K). The control group showed a normal liver ultrastructure by TEM images, where several mitochondria and typical nuclei can be observed, and the liver appeared healthy (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>M). On the other hand, cirrhotic livers showed abundant lipid droplets and disorganized mitochondria with loss of cristae and internal structure as well as large areas of collagen deposition (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>N). Importantly, hepatic parenchyma from animals intoxicated with CCl4 plus curcumin (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>O) had fewer collagen fibers, and alterations were attenuated. Curcumin-only-treated rats showed no alterations when compared to the control group.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>3.2Curcumin attenuated oxidative stress, serum markers of liver damage, and glycogen depletion in rats treated with CCl4After CCl4 intoxication, ALT, FA, and γ-GTP serum activities were significantly elevated; curcumin treatment partial or completely ameliorated these alterations (<a class="elsevierStyleCrossRef" href="#fig0010">Figs. 2</a>A-C). GSH and glycogen contents were elevated during liver cirrhosis, and curcumin restored these parameters (<a class="elsevierStyleCrossRef" href="#fig0010">Figs. 2</a>D and E). Healthy rats treated with curcumin did not exhibit any modified parameters.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>3.3Administration of curcumin reversed inflammation in cirrhotic ratsTreatment with CCl4 for 12 weeks increased immunoreactivity to NF-κB (p65) and IL-1β in hepatic tissue; interestingly, intense positivity colocalized with collagen fibers accumulation (arrows) (<a class="elsevierStyleCrossRef" href="#fig0015">Figs. 3</a>B and G). In the group treated with CCl4 and curcumin, immunoreactivity to NF-κB (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>C) and IL-1β (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>H) decreased significantly. The percentage of immunoreactivity to NF-κB and IL-1β is shown in <a class="elsevierStyleCrossRef" href="#fig0015">Figs. 3</a>E and J, respectively. Besides, protein levels of NF-κB, IL-1β, and IL-10 increased significantly by CCl4 intoxication compared to the control group, and curcumin administration restored basal levels of NF-κB, IL-1β, and IL-10 (<a class="elsevierStyleCrossRef" href="#fig0015">Figs. 3</a>K-M). Rats treated with only curcumin showed no changes in cytokines levels.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>3.4Effect of curcumin on extracellular matrix remodeling in rats treated with CCl4Collagen, quantitatively assessed as the hepatic hydroxyproline content, significantly increased in the CCl4 group when compared to the control group; notably, after curcumin administration for 4 weeks, collagen values decreased significantly (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>A). Protein levels of CTGF, MMP-13, and activity of MMP-2 and MMP-9 were elevated compared to the control group, and curcumin administration restored these factors to normal levels (<a class="elsevierStyleCrossRef" href="#fig0020">Figs. 4</a>B-E). Treatment of healthy rats with curcumin did not modify proteins or activities.<elsevierMultimedia ident="fig0020"></elsevierMultimedia>3.5Effect of curcumin on HSC transdifferentiationHepatic parenchyma from CCl4-damaged rats exhibited large areas of positive reaction to TGF-β and α-SMA and this reaction colocalized with fibrotic zones, rich in collagen and HSCs (arrows) (<a class="elsevierStyleCrossRef" href="#fig0025">Figs. 5</a>B and G), and curcumin decreased TGF-β and α-SMA positivity (<a class="elsevierStyleCrossRef" href="#fig0025">Figs. 5</a>C and H); the percentages of immunoreactivity to TGF-β and α-SMA are shown in <a class="elsevierStyleCrossRef" href="#fig0025">Figs. 5</a>E and J, respectively. Western blotting results showed that TGF-β and α-SMA protein levels in the livers of CCl4-treated rats were significantly elevated compared to those in the control group and that curcumin significantly reversed this alteration (<a class="elsevierStyleCrossRef" href="#fig0025">Figs. 5</a>K and L). At the mRNA level, hepatotoxicity significantly increased α-Sma levels and curcumin reversed this increase (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>M). Rats treated with CCl4 showed decreased levels of Smad7, and curcumin administration significantly attenuated this effect (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>N). Curcumin administered to healthy rats did not modify the studied parameters.<elsevierMultimedia ident="fig0025"></elsevierMultimedia>3.6Administration of curcumin inhibits the JNK-Smad3 pathway<a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a> shows that CCl4 increased the pJNK/JNK ratio (A), and levels of pSmad3L (B), Smad3 (C) proteins, and Smad3 mRNA (D). Curcumin significantly reversed these effects. Curcumin administered to healthy rats did not modify the studied parameters.<elsevierMultimedia ident="fig0030"></elsevierMultimedia>4DiscussionThis study provides evidence that curcumin administration attenuates CCl4-induced liver cirrhosis. Our results suggest that an antifibrotic action of curcumin may be associated with its ability to deactivate and/or eliminate transdifferentiated HSCs, the most active producers of fibrotic tissue in the liver parenchyma. Curcumin downregulated the TGF-β signaling pathway, the main HSCs transdifferentiation inductor, as well as the JNK-Smad3 pathway, involved in the proliferation and migration of HSCs. Moreover, curcumin restored Smad7 levels, an important antifibrotic protein. This polyphenol helped to attenuate the proinflammatory cytokine cascade by blocking the NF-κB factor.4.1Curcumin downregulates the profibrogenic JNK-Smad3 pathwayPreviously, it has been reported that curcumin reduces acute and chronic liver damage [<a class="elsevierStyleCrossRefs" href="#bib0035">7–10</a>]. In the present study, it was observed, for the first time, that curcumin re-established normal JNK and Smad3, mRNA, and protein levels that were upregulated by CCl4-induced chronic liver damage, thereby leading to downregulation of the JNK-Smad3 pathway; as a result, profibrogenic and mitogenic pSmad3L [<a class="elsevierStyleCrossRef" href="#bib0025">5</a>,<a class="elsevierStyleCrossRef" href="#bib0030">6</a>] was decreased and progression of fibrosis was attenuated. It seems that more Smad protein is synthesized in the CCl4 group (please note that Smad3 mRNA was increased) and more Smad3 is phosphorylated. Our results suggest that phosphorylation is increased too because pJNK was upregulated in the CCl4 group. In summary, the present results suggest that CCl4 increased the synthesis and phosphorylation of Smad3, and curcumin attenuated both effects.4.2Curcumin alleviates fibrosis by increasing the antifibrotic Smad7 proteinCurcumin re-established normal Smad7 levels, which is a negative regulator of the liver fibrogenic process. Smad7 intracellularly binds to TβRI, preventing Smad3 phosphorylation and Smads3-Smad4 heterocomplex formation, thus blocking the profibrogenic activity in the canonical TGF-β pathway. Additionally, in the nucleus, Smad7 binds to DNA and impedes binding of the Smad3-Smad4 heterocomplex to DNA [<a class="elsevierStyleCrossRefs" href="#bib0125">25–28</a>].During chronic liver damage, Smad7 levels remain low, leading to an uncontrolled fibrotic response; low levels of Smad7 in activated HSCs may exacerbate TGF-β profibrogenic effects during the progression of liver fibrosis [<a class="elsevierStyleCrossRef" href="#bib0145">29</a>,<a class="elsevierStyleCrossRef" href="#bib0150">30</a>]. Therefore, the upregulation of Smad7 by curcumin seems to be another antifibrotic mechanism of this molecule by blocking the TGF-β pathway, which may help in triggering the resolution of fibrosis.4.3Curcumin reduces the number of activated HSCIt is worth noting that curcumin treatment resulted in a reduction in the number of activated HSCs. This effect could be mediated by an increase in Smad7 levels and downregulation of TGF-β canonical and non-canonical pathways or other curcumin-independent effects such as deactivation, senescence, or apoptosis of HSCs [<a class="elsevierStyleCrossRefs" href="#bib0155">31–34</a>]. Taken together, the results of the present study and evidence from previous studies, suggest that one of the main antifibrotic mechanisms of curcumin is the decrease in activated profibrogenic HSCs.4.4Curcumin sustains beneficial effects by regulating MMPsMMPs are key regulators of the synthesis and degradation of ECM [<a class="elsevierStyleCrossRef" href="#bib0175">35</a>], which is the main reservoir of signaling molecules by binding growth factors such as CTGF, TGF-β, and PDGF [<a class="elsevierStyleCrossRef" href="#bib0180">36</a>]. MMP13 is responsible for the cleavage of CTGF [<a class="elsevierStyleCrossRef" href="#bib0185">37</a>]. Furthermore, the high proteolytic activities of MMP2 and 9 promote the dissociation of TNF-α and IL-1β from ECM, conducing to an exacerbation of the inflammatory process [<a class="elsevierStyleCrossRef" href="#bib0190">38</a>]. The results of the present study suggest that curcumin may support antifibrotic activity by modulating MMPs, thus regulating the release from the ECM of pro-inflammatory and pro-fibrogenic factors.4.5Curcumin attenuates the proinflammatory NF-κB pathwayIt has been reported that NF-κB inhibition promotes apoptosis of HSCs, preventing liver fibrosis consequently [<a class="elsevierStyleCrossRef" href="#bib0195">39</a>,<a class="elsevierStyleCrossRef" href="#bib0200">40</a>]. Curcumin reduces NF-κB mRNA, as well as Toll-like receptor 2, Toll-like receptor 4, and MyD88 adapter in activated HSCs, leading to their apoptosis [<a class="elsevierStyleCrossRefs" href="#bib0205">41–43</a>]. Therefore, it is likely that NF-κB inhibition by curcumin may explain, in part, its antifibrotic actions by both blocking inflammation and inducing HSC apoptosis.5ConclusionIt can be concluded that curcumin attenuated CCl4-induced cirrhosis by downregulating canonical and non-canonical Smad pathways, restoring Smad 7 levels, blocking NF-κB proinflammatory cytokine production, and decreasing the number of activated HSCs in the hepatic parenchyma. These results may be of clinical importance in the treatment of cirrhotic patients; however, more basic and controlled prospective studies in humans are required before suggesting curcumin as a safe anti-cirrhotic remedy.Limitations and perspectivesActivated HSCs are the main responsible for fibrogenesis. Therefore, it is generally recognized that the most suitable approach to induce remission of liver fibrosis consists of “eliminating” activated HSCs. Herein, we found that curcumin reduced activated HSCs. However, the mechanism remains to be dilucidated. The possible mechanisms include apoptosis, necrosis, and senescence of these cells. The deactivation of profibrogenic HSCs to a quiescent state seems to be a suitable approach. Therefore, research on the molecular pathways leading to the “elimination” of activated HSCs will provide specific targets to produce regression of the fibrotic state. Moreover, the specific molecular targets of curcumin (or any putative antifibrotic drug) on activated HSCs must be investigated to illuminate the antifibrotic pathways involved and to improve therapy.FundingThis work was supported by the National Council of Science and Technology (Conacyt) of Mexico, No. 253037 to Muriel P., No. 237523 to Shibayama M., and No. 239516 to Segovia J.; fellowship No. 358378 to Hernández-Aquino E. from Conacyt.Conflict of interestThe authors have no conflict of interest to report." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1424241" "titulo" => "Graphical abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:3 [ "identificador" => "xres1424240" "titulo" => "Abstract" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0010" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abst0015" "titulo" => "Materials and Methods" ] 2 => array:2 [ "identificador" => "abst0020" "titulo" => "Results and Conclusions" ] ] ] 2 => array:2 [ "identificador" => "xpalclavsec1301800" "titulo" => "Keywords" ] 3 => array:2 [ "identificador" => "xpalclavsec1301799" "titulo" => "Abbreviations" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Animal treatment" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Biochemical analyses" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Hematoxylin, eosin, Masson’s trichrome stains, and immunohistochemistry" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Zymography" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Western blot assays" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "RNA extraction, RT-PCR, and qRT-PCR" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Transmission electron microscopy" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0055" "titulo" => "Results" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Curcumin attenuated macroscopic, microscopic, and ultrastructural alterations produced by CCl" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Curcumin attenuated oxidative stress, serum markers of liver damage, and glycogen depletion in rats treated with CCl" ] 2 => array:2 [ "identificador" => "sec0070" "titulo" => "Administration of curcumin reversed inflammation in cirrhotic rats" ] 3 => array:2 [ "identificador" => "sec0075" "titulo" => "Effect of curcumin on extracellular matrix remodeling in rats treated with CCl" ] 4 => array:2 [ "identificador" => "sec0080" "titulo" => "Effect of curcumin on HSC transdifferentiation" ] 5 => array:2 [ "identificador" => "sec0085" "titulo" => "Administration of curcumin inhibits the JNK-Smad3 pathway" ] ] ] 7 => array:3 [ "identificador" => "sec0090" "titulo" => "Discussion" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0095" "titulo" => "Curcumin downregulates the profibrogenic JNK-Smad3 pathway" ] 1 => array:2 [ "identificador" => "sec0100" "titulo" => "Curcumin alleviates fibrosis by increasing the antifibrotic Smad7 protein" ] 2 => array:2 [ "identificador" => "sec0105" "titulo" => "Curcumin reduces the number of activated HSC" ] 3 => array:2 [ "identificador" => "sec0110" "titulo" => "Curcumin sustains beneficial effects by regulating MMPs" ] 4 => array:2 [ "identificador" => "sec0115" "titulo" => "Curcumin attenuates the proinflammatory NF-κB pathway" ] ] ] 8 => array:2 [ "identificador" => "sec0120" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0125" "titulo" => "Limitations and perspectives" ] 10 => array:2 [ "identificador" => "sec0130" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0135" "titulo" => "Conflict of interest" ] 12 => array:2 [ "identificador" => "xack497215" "titulo" => "Acknowledgments" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-03-02" "fechaAceptado" => "2020-05-28" "PalabrasClave" => array:1 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1301800" "palabras" => array:6 [ 0 => "Fibrosis" 1 => "Smad" 2 => "Curcumin" 3 => "CCl4" 4 => "TGF-β" 5 => "HSC." ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec1301799" "palabras" => array:18 [ 0 => "CCl4" 1 => "TGF-β" 2 => "CTGF" 3 => "α-SMA" 4 => "IL" 5 => "HSCs" 6 => "ECM" 7 => "ROS" 8 => "ALT" 9 => "AP" 10 => "γ-GTP" 11 => "GSH" 12 => "Col-I" 13 => "MMP" 14 => "JNK" 15 => "PAI-1" 16 => "TEM" 17 => "CUR" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and ObjectivesCurcumin, a polyphenol, is a natural compound that has been widely studied as a hepatoprotector; however, only a few studies have examined its ability to reduce fibrosis in previously established cirrhosis. The objective of this study was to investigate whether curcumin could reduce carbon tetrachloride (CCl4)-induced fibrosis and if so, to determine the action mechanisms involved in the reduction process. Materials and MethodsCCl4 was administered to male Wistar rats (400 mg/kg, three times a week, i. p.) for 12 weeks; curcumin (100 mg/kg body weight twice per day, p. o.) was administered from week 9–12 of CCl4 treatment. Biochemical markers of hepatic injury and oxidative stress were evaluated. Hematoxylin and eosin, Masson’s trichrome stains, transmission electron microscopy; immunohistochemistry, and zymography assays were carried out. Moreover, Smad3 and α-SMA mRNA and protein levels were studied. Western blotting by TGF-β, CTGF, Col-I, MMP-13, NF-κB, IL-1, IL-10, Smad7, pSmad3, and pJNK proteins was developed. Results and ConclusionsCurcumin reduced liver damage, oxidative stress, fibrosis, and restored normal activity of MMP-9 and MMP-2. Besides, curcumin restored NF-κB, IL-1, IL-10, TGF-β, CTGF, Col-I, MMP-13, and Smad7 protein levels. On the other hand, curcumin decreased JNK and Smad3 phosphorylation. Furthermore, curcumin treatment decreased α-SMA and Smad3 protein and mRNA levels. Curcumin normalized GSH, and NF-κB, JNK-Smad3, and TGF-β-Smad3 pathways, leading to a decrement in activated hepatic stellate cells, thereby producing its antifibrotic effects." "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0010" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abst0015" "titulo" => "Materials and Methods" ] 2 => array:2 [ "identificador" => "abst0020" "titulo" => "Results and Conclusions" ] ] ] ] "multimedia" => array:8 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2405 "Ancho" => 3417 "Tamanyo" => 1573065 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Macroscopic, microscopic, and ultrastructural effects of curcumin in rats treated with CCl4. Macroscopic appearance (A-D) and representative liver sections stained using H&E (E-H), Masson's trichrome (I-L), and transmission electron microscopy (TEM) (M-P) of livers of the control rats, rats treated with CCl4 for 12 weeks (CCl4), rats treated with CCl4 + curcumin (CUR) (CCl4 + CUR) and rats treated with CUR alone. n: nucleus; m: mitochondria; ld: lipid droplets; cf: collagen fibers." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1886 "Ancho" => 3083 "Tamanyo" => 224385 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Curcumin attenuated serum indicators of hepatic injury restored oxidative stress markers, and glycogen content in rats treated with CCl4. Activities of alkaline phosphatase (AP) (A), γ-glutamyl transpeptidase (γ-GTP) (B), and alanine aminotransferase (ALT) (C), liver reduced glutathione (GSH) (D) and glycogen levels (E) were determined in control rats, rats treated with CCl4 for 12 weeks (CCl4), rats treated with CCl4 + curcumin (CUR) (CCl4+ CUR), and rats treated with CUR alone. Each bar represents the average value of eight rats (n = 8) ± standard error. a means P < 0.05 with respect to the control group and b means P < 0.05 with respect to the CCl4 group." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 3958 "Ancho" => 3333 "Tamanyo" => 1508654 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Administration of curcumin attenuated inflammatory environment in rats with experimental cirrhosis. Representative NF-κB (AD), and IL-1β (FI) immunohistochemistry. The percentage of immunoreactivity to NF-κB (E), and IL-1β (J). Representative NF-κB (p65) (K), IL-1β (L), and IL-10 (M) western blot (WB) of the control rats livers, rats treated with CCl4, rats treated with CCl4 + curcumin (CUR), and rats treated with CUR alone. Immunohistochemistry positivity is indicated by arrows; results are expressed as % of the area with immunoreactivity. Each bar represents the average value of three rats (n = 3) (each rat with three fields averaged) ± standard error. In WB, densitometric analyses were performed using β-actin as internal control. Each bar represents the average value of four rats (n = 4) ± standard error. a means P < 0.05 with respect to the control group and b means P < 0.05 with respect to the CCl4 group." ] ] 3 => array:8 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 2485 "Ancho" => 3417 "Tamanyo" => 404599 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Curcumin reduced collagen accumulation and extracellular matrix remodeling proteins in cirrhotic rats with experimental liver cirrhosis. Total collagen levels (A), representative western blot (WB) of CTGF (B), and MMP-13 (C) as well as representative MMP-2 (D) and MMP-9 (E) zymography (F) of livers derived from control rats, rats treated with CCl4 for 12 weeks (CCl4), rats treated with CCl4+ curcumin (CUR) (CCl4+ CUR), and rats treated with CUR alone. In the total collagen graph, each bar represents the average value of eight rats (n = 8) ± standard error. In WB, densitometric analyses were performed using β-actin as the internal control and each bar represents the average value of four rats (n = 4) ± standard error. In the zymography assay, densitometric analyses were performed and each bar represents the average value of three rats (n = 3) ± standard error. a means P < 0.05 with respect to the control group and b means P < 0.05 with respect to the CCl4 group." ] ] 4 => array:8 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 4006 "Ancho" => 3417 "Tamanyo" => 1694427 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Effect of curcumin on hepatic stellate cells transdifferentiation and TGF-β pathway. Representative TGF-β (AD), and α-SMA (FI) immunohistochemistry. The percentage of immunoreactivity to TGF-β (E), and α-SMA (J). Representative western blot (WB) of TGF-β (K) and α-SMA (L). Representative α-SMA qRT-PCR graph and RT-PCR gel (M), and representative Smad7 WB (N) of control rats, rats treated with CCl4, rats treated with CCl4 + curcumin (CUR), and rats treated with CUR alone. Immunohistochemistry positivity is indicated by arrows; results are expressed as % of the area with immunoreactivity. Each bar represents the average value of three rats (n = 3) (each rat with three fields averaged) ± standard error. In WB, densitometric analyses were performed using β-actin as internal control. Each bar represents the average value of four rats (n = 4) ± standard error. In qRT-PCR, β-actin was used as a reference gene to normalize α-SMA mRNA levels. The relative change of expression was calculated using the 2ΔΔCt method. Each bar represents the average value of three rats (n = 3) ± standard error. a means P < 0.05 with respect to the control group and b means P < 0.05 with respect to the CCl4 group." ] ] 5 => array:8 [ "identificador" => "fig0030" "etiqueta" => "Fig. 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 2868 "Ancho" => 2667 "Tamanyo" => 376826 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0030" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Administration of curcumin inhibits the JNK-Smad3 pathway. Representative western blot (WB) of pJNK (A), pSmad3L (B), and Smad3 (C), as well as Smad3 qRT-PCR graph and RT-PCR gel (D) of control rats, rats treated with CCl4 for 12 weeks (CCl4), rats treated with CCl4 + curcumin (CCl4 + CUR), and rats treated with CUR alone. In WB, densitometric analyses were performed using JNK or β-actin as internal controls. Each bar represents the average value of four rats (n = 4) ± standard error. In qRT-PCR β-actin was used as a reference gene to normalize Smad3 mRNA levels. The relative change of expression was calculated using the 2−ΔΔCt method. Each bar represents the average value of three rats (n = 3) ± standard error. a means P < 0.05 with respect to the control group and b means P < 0.05 with respect to the CCl4 group." ] ] 6 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0035" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Protein \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Company \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Origin \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Catalog number \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">WB dilution \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IHQ dilution \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGF-β \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Millipore \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CA, USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">05−1423 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:25 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">α-SMA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sigma-Aldrich \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Missouri, USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A5691 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:25 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CTGF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Santa Cruz Biotechnology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CA, USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SC-365,970 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">______ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">COL-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sigma-Aldrich \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Missouri, USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C2456 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">______ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMP-13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Millipore \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MA, USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAB13426 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">______ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NF-κB (P65) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Millipore \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MA, USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAB3026 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:50 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-1β \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Millipore \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cambridge, UK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AB1832P \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:25 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Thermo Fisher Scientific \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CA, USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ARC9102 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">______ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smad3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abcam \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MA, USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ab65847 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">______ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psmad3L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abcam \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cambridge, UK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ab63403 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:250 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">______ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smad7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abcam \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cambridge, UK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ab90086 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">______ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JNK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cell Signaling Technology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MA, USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9252 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">______ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">pJNK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abcam \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cambridge, UK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ab131499 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">______ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">β-actin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Thermo Fisher Scientific \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CA, USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AM4302 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1:500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">______ \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2442735.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Antibodies used in Western blot and immunohistochemistry techniques." ] ] 7 => array:5 [ "identificador" => "fig0035" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 886 "Ancho" => 2213 "Tamanyo" => 76926 ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:43 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "[1]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The liver: general aspects and epidemiology" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P. Muriel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/B978-0-12-804274-8.00001-1" "LibroEditado" => array:5 [ "editores" => "P.Muriel" "titulo" => "Liver pathophysiology: therapies and antioxidants." "paginaInicial" => "3" "paginaFinal" => "22" "serieFecha" => "2017" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "[2]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fighting liver fibrosis to reduce mortality associated with chronic liver diseases: the importance of new molecular targets and biomarkers" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P. Muriel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ebiom.2019.01.009" "Revista" => array:6 [ "tituloSerie" => "EBioMedicine" "fecha" => "2019" "volumen" => "40" "paginaInicial" => "35" "paginaFinal" => "36" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30745133" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "[3]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "T. Kisseleva" 1 => "D.A. Brenner" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1440-1746.2006.04658.x" "Revista" => array:5 [ "tituloSerie" => "J Gastroenterol Hepatol" "fecha" => "2007" "volumen" => "1" "paginaInicial" => "S73" "paginaFinal" => "8" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "[4]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "TGF-β signalling and liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "I. Fabregat" 1 => "J. Moreno-Càceres" 2 => "A. Sánchez" 3 => "S. Dooley" 4 => "B. Dewidar" 5 => "G. Giannelli" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/febs.13665" "Revista" => array:6 [ "tituloSerie" => "FEBS J" "fecha" => "2016" "volumen" => "283" "paginaInicial" => "2219" "paginaFinal" => "2232" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26807763" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "[5]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Reversible human TGF-β signal shifting between tumor suppression and fibro-carcinogenesis: implications of Smad Phospho-Isoforms for hepatic epithelial-mesenchymal transitions" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "K. Yoshida" 1 => "M. Murata" 2 => "T. Yamaguchi" 3 => "K. Matsuzaki" 4 => "K. Okazaki" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3390/jcm5010007" "Revista" => array:4 [ "tituloSerie" => "J Clin Med" "fecha" => "2016" "volumen" => "5" "paginaInicial" => "7" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "[6]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Differential regulation of TGF-β/Smad signaling in hepatic stellate cells between acute and chronic liver injuries" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K. Yoshida" 1 => "K. Matsuzaki" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fphys.2012.00053" "Revista" => array:5 [ "tituloSerie" => "Front Physiol" "fecha" => "2012" "volumen" => "3" "paginaInicial" => "53" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22457652" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "[7]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatoprotective properties of curcumin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "K. Reyes-Gordillo" 1 => "R. Shah" 2 => "M.R. Lakshman" 3 => "R.E. Flores-Beltrán" 4 => "P. Muriel" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:5 [ "editores" => "P.Muriel" "titulo" => "Liver pathophysiology: therapies and antioxidants" "paginaInicial" => "583" "paginaFinal" => "604" "serieFecha" => "2017" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "[8]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cellular and molecular mechanisms of curcumin in prevention and treatment of disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S.S. Patel" 1 => "A. Acharya" 2 => "R.S. Ray" 3 => "R. Agrawal" 4 => "R. Raghuwanshi" 5 => "P. Jain" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/10408398.2018.1552244" "Revista" => array:5 [ "tituloSerie" => "Crit Rev Food Sci Nutr" "fecha" => "2019" "volumen" => "11" "paginaInicial" => "1" "paginaFinal" => "53" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "[9]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Curcumin protects against acute liver damage in the rat by inhibiting NF-kappaB, proinflammatory cytokines production and oxidative stress" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "K. Reyes-Gordillo" 1 => "J. Segovia" 2 => "M. Shibayama" 3 => "P. Vergara" 4 => "M.G. Moreno" 5 => "P. Muriel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bbagen.2007.02.004" "Revista" => array:6 [ "tituloSerie" => "Biochim Biophys Acta" "fecha" => "2007" "volumen" => "1770" "paginaInicial" => "989" "paginaFinal" => "996" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17383825" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "[10]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Curcumin prevents and reverses cirrhosis induced by bile duct obstruction or CCl4 in rats: role of TGF-beta modulation and oxidative stress" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Reyes-Gordillo" 1 => "J. Segovia" 2 => "M. Shibayama" 3 => "V. Tsutsumi" 4 => "P. Vergara" 5 => "M.G. Moreno" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1472-8206.2008.00611.x" "Revista" => array:6 [ "tituloSerie" => "Fundam Clin Pharmacol" "fecha" => "2008" "volumen" => "22" "paginaInicial" => "417" "paginaFinal" => "427" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18705752" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "[11]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "S. Reitman" 1 => "S. Frankel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/ajcp/28.1.56" "Revista" => array:6 [ "tituloSerie" => "Am J Clin Pathol" "fecha" => "1957" "volumen" => "28" "paginaInicial" => "56" "paginaFinal" => "63" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/13458125" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "[12]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Enzymes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "H.U. Bergmeyer" 1 => "M. Grabl" 2 => "H.E. Walter" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:5 [ "editores" => "J.Bergmeyer, M.Grabl" "titulo" => "Methods of enzymatic analysis" "paginaInicial" => "269" "paginaFinal" => "270" "serieFecha" => "1986" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "[13]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Gamma-Glutamyltransferase in kidney brush border membranes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H. Glossmann" 1 => "D.M. Neville" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/0014-5793(72)80075-9" "Revista" => array:6 [ "tituloSerie" => "FEBS Lett" "fecha" => "1972" "volumen" => "19" "paginaInicial" => "340" "paginaFinal" => "344" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11946246" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "[14]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M.M. Bradford" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/0003-2697(76)90527-3" "Revista" => array:6 [ "tituloSerie" => "Anal Biochem" "fecha" => "1976" "volumen" => "72" "paginaInicial" => "248" "paginaFinal" => "254" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/942051" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "[15]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J. Sedlak" 1 => "R.H. Lindsay" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/0003-2697(68)90092-4" "Revista" => array:6 [ "tituloSerie" => "Anal Biochem" "fecha" => "1968" "volumen" => "25" "paginaInicial" => "192" "paginaFinal" => "205" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4973948" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "[16]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The estimation of glycogen with the anthrone reagent" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "S. Seifter" 1 => "S. Dayton" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Biochem" "fecha" => "1950" "volumen" => "25" "paginaInicial" => "191" "paginaFinal" => "200" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15401229" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "[17]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A specific method for the analysis of hydroxyproline in tissues and urine" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "D.J. Prockop" 1 => "S. Udenfriend" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/0003-2697(60)90050-6" "Revista" => array:6 [ "tituloSerie" => "Anal Biochem" "fecha" => "1960" "volumen" => "1" "paginaInicial" => "228" "paginaFinal" => "239" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/13738134" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "[18]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Stevia prevents experimental cirrhosis by reducing hepatic myofibroblasts and modulating molecular profibrotic pathways" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "E. Ramos-Tovar" 1 => "L.D. Buendia-Montaño" 2 => "S. Galindo-Gómez" 3 => "E. Hernández-Aquino" 4 => "V. Tsutsumi" 5 => "P. Muriel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/hepr.13275" "Revista" => array:6 [ "tituloSerie" => "Hepatol Res" "fecha" => "2019" "volumen" => "49" "paginaInicial" => "212" "paginaFinal" => "223" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30338893" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "[19]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nicotinic acid prevents experimental liver fibrosis by attenuating the prooxidant process" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J. Arauz" 1 => "Y. Rivera-Espinoza" 2 => "M. Shibayama" 3 => "L. Favari" 4 => "R.E. Flores-Beltrán" 5 => "P. Muriel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.intimp.2015.05.045" "Revista" => array:6 [ "tituloSerie" => "Int Immunopharmacol" "fecha" => "2015" "volumen" => "28" "paginaInicial" => "244" "paginaFinal" => "251" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26093271" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "[20]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Stevia prevents acute and chronic liver injury induced by carbon tetrachloride by blocking oxidative stress through Nrf2 upregulation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Ramos-Tovar" 1 => "E. Hernández-Aquino" 2 => "S. Casas-Grajales" 3 => "L.D. Buendia-Montaño" 4 => "S. Galindo-Gómez" 5 => "J. Camacho" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1155/2018/3823426" "Revista" => array:3 [ "tituloSerie" => "Oxid Med Cell Longev" "fecha" => "2018" "volumen" => "19" ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "[21]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Measurement of protein using bicinchoninic acid" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.K. Smith" 1 => "R.I. Krohn" 2 => "G.T. Hermanson" 3 => "A.K. Mallia" 4 => "F.H. Gartner" 5 => "M.D. Frovenzano" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/0003-2697(85)90442-7" "Revista" => array:6 [ "tituloSerie" => "Anal Biochem" "fecha" => "1985" "volumen" => "150" "paginaInicial" => "76" "paginaFinal" => "85" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3843705" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "[22]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "NIH image to imageJ: 25 years of image analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "C.A. Schneider" 1 => "W.S. Rasband" 2 => "K.W. Eliceiri" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nmeth.2089" "Revista" => array:6 [ "tituloSerie" => "Nat Methods" "fecha" => "2012" "volumen" => "9" "paginaInicial" => "671" "paginaFinal" => "675" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22930834" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "[23]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K.J. Livak" 1 => "T.D. Schmittgen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1006/meth.2001.1262" "Revista" => array:6 [ "tituloSerie" => "Methods" "fecha" => "2001" "volumen" => "25" "paginaInicial" => "402" "paginaFinal" => "408" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11846609" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "[24]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Naringenin attenuates the progression of liver fibrosis via inactivation of hepatic stellate cells and profibrogenic pathways" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Hernández-Aquino" 1 => "M.A. Quezada-Ramírez" 2 => "A. Silva-Olivares" 3 => "S. Casas-Grajales" 4 => "E. Ramos-Tovar" 5 => "R.E. Flores-Beltrán" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ejphar.2019.172730" "Revista" => array:3 [ "tituloSerie" => "Eur J Pharmacol" "fecha" => "2019" "volumen" => "865" ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "[25]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Curcumin attenuates angiogenesis in liver fibrosis and inhibits angiogenic properties of hepatic stellate cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Zhang" 1 => "Z. Zhang" 2 => "L. Chen" 3 => "D. Kong" 4 => "X. Zhang" 5 => "C. Lu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/jcmm.12286" "Revista" => array:6 [ "tituloSerie" => "J Cell Mol Med" "fecha" => "2014" "volumen" => "18" "paginaInicial" => "1392" "paginaFinal" => "1406" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24779927" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "[26]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulation of TGF-beta signaling by Smad7" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "X. Yan" 1 => "Z. Liu" 2 => "Y. Chen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/abbs/gmp018" "Revista" => array:5 [ "tituloSerie" => "Acta Biochim Biophys Sin (Shanghai)" "fecha" => "2009" "volumen" => "41" "paginaInicial" => "263" "paginaFinal" => "272" ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "[27]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Smad7 antagonizes transforming growth factor signaling in the nucleus by interfering with functional Smad-DNA complex formation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Zhang" 1 => "T. Fei" 2 => "L. Zhang" 3 => "R. Zhang" 4 => "F. Chen" 5 => "Y. Ning" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/MCB.01636-06" "Revista" => array:6 [ "tituloSerie" => "Mol Cell Biol" "fecha" => "2007" "volumen" => "27" "paginaInicial" => "4488" "paginaFinal" => "4499" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17438144" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "[28]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Smad7 protein interacts with receptor-regulated Smads (R-Smads) to inhibit transforming growth factor-β (TGF-β)/Smad signaling" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "X. Yan" 1 => "H. Liao" 2 => "M. Cheng" 3 => "X. Shi" 4 => "X. Lin" 5 => "X.H. Feng" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1074/jbc.m115.694281" "Revista" => array:6 [ "tituloSerie" => "J Biol Chem" "fecha" => "2016" "volumen" => "291" "paginaInicial" => "382" "paginaFinal" => "392" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26555259" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "[29]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Tahashi" 1 => "K. Matsuzaki" 2 => "M. Date" 3 => "K. Yoshida" 4 => "F. Furukawa" 5 => "Y. Sugano" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2002.30083" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2002" "volumen" => "35" "paginaInicial" => "49" "paginaFinal" => "61" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11786959" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "[30]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Dooley" 1 => "J. Hamzavi" 2 => "K. Breitkopf" 3 => "E. Wiercinska" 4 => "H.M. Said" 5 => "J. Lorenzen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0016-5085(03)00666-8" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2003" "volumen" => "125" "paginaInicial" => "178" "paginaFinal" => "191" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12851882" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "[31]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of curcumin on the proliferation and apoptosis of hepatic stellate cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.C. Shu" 1 => "Y.J. He" 2 => "X. Lv" 3 => "J.R. Zhao" 4 => "J.R. Zhao" 5 => "Y. Shen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1590/S0100-879X2009005000041" "Revista" => array:6 [ "tituloSerie" => "Braz J Med Biol Res" "fecha" => "2009" "volumen" => "42" "paginaInicial" => "1173" "paginaFinal" => "1178" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19918672" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "[32]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Curcumin prevents liver fibrosis by inducing apoptosis and suppressing activation of hepatic stellate cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "J.C. Shu" 1 => "Y.J. He" 2 => "X. Lv" 3 => "G.R. Ye" 4 => "L.X. Wang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s11418-009-0347-3" "Revista" => array:6 [ "tituloSerie" => "J Nat Med" "fecha" => "2009" "volumen" => "63" "paginaInicial" => "415" "paginaFinal" => "420" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19554395" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "[33]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Curcumin, the main active constituent of turmeric (Curcuma longa L.), induces apoptosis in hepatic stellate cells by modulating the abundance of apoptosis-related growth factors" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y.J. He" 1 => "K. Kuchta" 2 => "X. Lv" 3 => "Y. Lin" 4 => "G.R. Ye" 5 => "X.Y. Liu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1515/znc-2015-4143" "Revista" => array:5 [ "tituloSerie" => "Z Naturforsch, C, J Biosci" "fecha" => "2015" "volumen" => "70" "paginaInicial" => "281" "paginaFinal" => "285" ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "[34]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic stellate cell interferes with NK cell regulation of fibrogenesis via curcumin induced senescence of hepatic stellate cell" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Jin" 1 => "Y. Jia" 2 => "Z. Yao" 3 => "J. Huang" 4 => "M. Hao" 5 => "S. Yao" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cellsig.2017.02.006" "Revista" => array:6 [ "tituloSerie" => "Cell Signal" "fecha" => "2017" "volumen" => "33" "paginaInicial" => "79" "paginaFinal" => "85" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28188823" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "[35]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Matrix metalloproteinases in liver injury, repair and fibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S. Duarte" 1 => "J. Baber" 2 => "T. Fujii" 3 => "A.J. Coito" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.matbio.2015.01.004" "Revista" => array:6 [ "tituloSerie" => "Matrix Biol" "fecha" => "2015" "volumen" => "44-46" "paginaInicial" => "147" "paginaFinal" => "156" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25599939" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "[36]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Therapeutic pro-fibrogenic signaling pathways in fibroblasts" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "S. Cannito" 1 => "E. Novo" 2 => "M. Parola" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.addr.2017.05.017" "Revista" => array:6 [ "tituloSerie" => "Adv Drug Deliv Rev" "fecha" => "2017" "volumen" => "121" "paginaInicial" => "57" "paginaFinal" => "84" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28578015" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "[37]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "MMP-13 deletion decreases profibrogenic molecules and attenuates N -nitrosodimethylamine-induced liver injury and fibrosis in mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J. George" 1 => "M. Tsutsumi" 2 => "M. Tsuchishima" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/jcmm.13304" "Revista" => array:6 [ "tituloSerie" => "J Cell Mol Med" "fecha" => "2017" "volumen" => "21" "paginaInicial" => "3821" "paginaFinal" => "3835" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28782260" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "[38]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver fibrosis: understanding the dynamics of bidirectional wound repair to inform the design of markers and therapies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.P. Iredale" 1 => "A. Pellicoro" 2 => "J.A. Fallowfield" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000456581" "Revista" => array:6 [ "tituloSerie" => "Dig Dis" "fecha" => "2017" "volumen" => "35" "paginaInicial" => "310" "paginaFinal" => "313" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28467988" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "[39]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nuclear factor kappaB in proliferation, activation and apoptosis in rat hepatic stellate cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A. Lang" 1 => "R. Schoonhoven" 2 => "S. Tuvia" 3 => "D.A. Brenner" 4 => "R.A. Rippe" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0168-8278(00)80159-2" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2000" "volumen" => "33" "paginaInicial" => "49" "paginaFinal" => "58" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10905586" "web" => "Medline" ] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0200" "etiqueta" => "[40]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhibition of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Oakley" 1 => "M. Meso" 2 => "J.P. Iredale" 3 => "K. Green" 4 => "C.J. Marek" 5 => "X. Zhou" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2004.10.003" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2005" "volumen" => "128" "paginaInicial" => "108" "paginaFinal" => "120" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15633128" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0205" "etiqueta" => "[41]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Curcumin promotes apoptosis of activated hepatic stellate cells by inhibiting protein expression of the MyD88 pathway" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y.J. He" 1 => "K. Kuchta" 2 => "Y.M. Deng" 3 => "S. Cameron" 4 => "Y. Lin" 5 => "X.Y. Liu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-0043-113044" "Revista" => array:6 [ "tituloSerie" => "Planta Med" "fecha" => "2017" "volumen" => "83" "paginaInicial" => "1392" "paginaFinal" => "1396" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28628927" "web" => "Medline" ] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0210" "etiqueta" => "[42]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Curcumin induces apoptosis in hepatic stellate cells via inhibition of the MyD88 pathway" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.C. Shu" 1 => "K. Kuchta" 2 => "Y.J. He" 3 => "Y.M. Deng" 4 => "Y. Lin" 5 => "G.R. Ye" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-0035-156591" "Revista" => array:5 [ "tituloSerie" => "Planta Med" "fecha" => "2015" "volumen" => "81" "paginaInicial" => "1392" "paginaFinal" => "1396" ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0215" "etiqueta" => "[43]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Protective effects of curcumin against hepatic fibrosis induced by carbon tetrachloride: modulation of high-mobility group box 1, Toll-like receptor 4 and 2 expression" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "C.T. Tu" 1 => "Q.Y. Yao" 2 => "B.L. Xu" 3 => "J.Y. Wang" 4 => "C.H. Zhou" 5 => "S.C. Zhang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.fct.2012.05.050" "Revista" => array:6 [ "tituloSerie" => "Food Chem Toxicol" "fecha" => "2012" "volumen" => "50" "paginaInicial" => "3343" "paginaFinal" => "3351" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22683883" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack497215" "titulo" => "Acknowledgments" "texto" => "The authors thank Laura D. Buendia-Montaño, Rafael Leyva, Benjamín E. Chavez, and Ricardo Gaxiola for their excellent technical assistance. The authors also acknowledge the Animal Lab Facility, UPEAL-Cinvestav." "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/16652681/0000001900000005/v5_202012011817/S166526812030065X/v5_202012011817/en/main.assets" "Apartado" => array:4 [ "identificador" => "78265" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original Articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/16652681/0000001900000005/v5_202012011817/S166526812030065X/v5_202012011817/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S166526812030065X?idApp=UINPBA00004N"]

Statistics

Original article

Erika Hernández-Aquinoa, Marco A. Quezada-Ramírezb, Angélica Silva-Olivaresc, Erika Ramos-Tovard, Rosa E. Flores-Beltrána, José Segoviab, Mineko Shibayamac, Pablo Muriela,

Corresponding author

pmuriel@cinvestav.mx

Corresponding author.

a Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional, Mexico City, Mexico

b Department of Physiology, Biophysics and Neurosciences, Cinvestav-IPN, Mexico City, Mexico

c Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Mexico City, Mexico

d School of Higher Education in Medicine-IPN, Mexico City, Mexico

Read

2923

Times
was read the article

542

Total PDF

2381

Total HTML

Share statistics

 array:24 [
  "pii" => "S166526812030065X"
  "issn" => "16652681"
  "doi" => "10.1016/j.aohep.2020.05.006"
  "estado" => "S300"
  "fechaPublicacion" => "2020-09-01"
  "aid" => "218"
  "copyright" => "Fundaci&#243;n Cl&#237;nica M&#233;dica Sur&#44; A&#46;C&#46;"
  "copyrightAnyo" => "2020"
  "documento" => "article"
  "crossmark" => 1
  "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
  "subdocumento" => "fla"
  "cita" => "Ann Hepatol. 2020;19:497-506"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:1 [
    "total" => 0
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S1665268120300569"
    "issn" => "16652681"
    "doi" => "10.1016/j.aohep.2020.06.002"
    "estado" => "S300"
    "fechaPublicacion" => "2020-09-01"
    "aid" => "215"
    "copyright" => "Fundaci&#243;n Cl&#237;nica M&#233;dica Sur&#44; A&#46;C&#46;"
    "documento" => "article"
    "crossmark" => 1
    "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
    "subdocumento" => "fla"
    "cita" => "Ann Hepatol. 2020;19:507-15"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
      "titulo" => "Identification of mutations in the S gene of hepatitis B virus in HIV positive Mexican patients with occult hepatitis B virus infection"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "507"
          "paginaFinal" => "515"
        ]
      ]
      "contieneResumen" => array:1 [
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig0005"
          "etiqueta" => "Fig&#46; 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr1.jpeg"
              "Alto" => 4131
              "Ancho" => 2175
              "Tamanyo" => 356162
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Phylogenetic tree constructed by the Maximum Likelihood analysis of the S region of hepatitis B virus &#40;HBV&#41; isolates from 18 patients with occult HBV infection &#40;filled circle&#41; and including 23 GenBank sequences of genotypes A&#8211;H &#40;GenBank accession number and HBV genotype indicated&#44; genotype H unfilled circle&#41;&#46; The bootstrap values are indicated for the major nodes as a percentage of the data obtained from 1000 replicates&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Karina Enriquez-Navarro, Angelica Maldonado-Rodriguez, Othon Rojas-Montes, Rocio Torres-Ibarra, Leticia Bucio-Ortiz, Miguel A&#46; De la Cruz, Jesus Torres-Flores, Beatriz Xoconostle-Cazares, Rosalia Lira"
          "autores" => array:9 [
            0 => array:2 [
              "nombre" => "Karina"
              "apellidos" => "Enriquez-Navarro"
            ]
            1 => array:2 [
              "nombre" => "Angelica"
              "apellidos" => "Maldonado-Rodriguez"
            ]
            2 => array:2 [
              "nombre" => "Othon"
              "apellidos" => "Rojas-Montes"
            ]
            3 => array:2 [
              "nombre" => "Rocio"
              "apellidos" => "Torres-Ibarra"
            ]
            4 => array:2 [
              "nombre" => "Leticia"
              "apellidos" => "Bucio-Ortiz"
            ]
            5 => array:2 [
              "nombre" => "Miguel A&#46;"
              "apellidos" => "De la Cruz"
            ]
            6 => array:2 [
              "nombre" => "Jesus"
              "apellidos" => "Torres-Flores"
            ]
            7 => array:2 [
              "nombre" => "Beatriz"
              "apellidos" => "Xoconostle-Cazares"
            ]
            8 => array:2 [
              "nombre" => "Rosalia"
              "apellidos" => "Lira"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268120300569?idApp=UINPBA00004N"
    "url" => "/16652681/0000001900000005/v5_202012011817/S1665268120300569/v5_202012011817/en/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S1665268120300661"
    "issn" => "16652681"
    "doi" => "10.1016/j.aohep.2020.06.005"
    "estado" => "S300"
    "fechaPublicacion" => "2020-09-01"
    "aid" => "219"
    "copyright" => "Fundaci&#243;n Cl&#237;nica M&#233;dica Sur&#44; A&#46;C&#46;"
    "documento" => "article"
    "crossmark" => 1
    "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
    "subdocumento" => "fla"
    "cita" => "Ann Hepatol. 2020;19:489-96"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
      "titulo" => "Mediterranean-like mix of fatty acids induces cellular protection on lipid-overloaded hepatocytes from western diet fed mice"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "489"
          "paginaFinal" => "496"
        ]
      ]
      "contieneResumen" => array:1 [
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:8 [
          "identificador" => "fig0020"
          "etiqueta" => "Fig&#46; 4"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr4.jpeg"
              "Alto" => 1607
              "Ancho" => 2421
              "Tamanyo" => 146433
            ]
          ]
          "detalles" => array:1 [
            0 => array:3 [
              "identificador" => "at0020"
              "detalle" => "Fig&#46; "
              "rol" => "short"
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Cellular functionality by MTT assay</span>&#46; Control and western cells were treated or not with high mono and polyunsaturated fatty acids &#40;HMPFA&#41; or high saturated fatty acids &#40;HSFA&#41; according <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; for 24&#8239;h&#46; Each bar represents the mean&#8239;&#177;&#8239;SEM in at least four mice&#44; &#42;p&#8239;&#60;&#8239;0&#46;05 vs control cells&#44; &#35; p&#8239;&#60;&#8239;0&#46;05 vs western cells&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Lyssia Castellanos-Tapia, Mar&#237;a Elizabeth Tejero-Barrera, Soraya Salas-Silva, Arturo Simoni-Nieves, Alejandro Escobedo-Calvario, Luis E&#46; Gomez-Quiroz"
          "autores" => array:6 [
            0 => array:2 [
              "nombre" => "Lyssia"
              "apellidos" => "Castellanos-Tapia"
            ]
            1 => array:2 [
              "nombre" => "Mar&#237;a Elizabeth"
              "apellidos" => "Tejero-Barrera"
            ]
            2 => array:2 [
              "nombre" => "Soraya"
              "apellidos" => "Salas-Silva"
            ]
            3 => array:2 [
              "nombre" => "Arturo"
              "apellidos" => "Simoni-Nieves"
            ]
            4 => array:2 [
              "nombre" => "Alejandro"
              "apellidos" => "Escobedo-Calvario"
            ]
            5 => array:2 [
              "nombre" => "Luis E&#46;"
              "apellidos" => "Gomez-Quiroz"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268120300661?idApp=UINPBA00004N"
    "url" => "/16652681/0000001900000005/v5_202012011817/S1665268120300661/v5_202012011817/en/main.assets"
  ]
  "en" => array:19 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
    "titulo" => "Curcumin downregulates Smad pathways and reduces hepatic stellate cells activation in experimental fibrosis"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "497"
        "paginaFinal" => "506"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Erika Hern&#225;ndez-Aquino, Marco A&#46; Quezada-Ram&#237;rez, Ang&#233;lica Silva-Olivares, Erika Ramos-Tovar, Rosa E&#46; Flores-Beltr&#225;n, Jos&#233; Segovia, Mineko Shibayama, Pablo Muriel"
        "autores" => array:8 [
          0 => array:3 [
            "nombre" => "Erika"
            "apellidos" => "Hern&#225;ndez-Aquino"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "Marco A&#46;"
            "apellidos" => "Quezada-Ram&#237;rez"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "Ang&#233;lica"
            "apellidos" => "Silva-Olivares"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
            ]
          ]
          3 => array:3 [
            "nombre" => "Erika"
            "apellidos" => "Ramos-Tovar"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">d</span>"
                "identificador" => "aff0020"
              ]
            ]
          ]
          4 => array:3 [
            "nombre" => "Rosa E&#46;"
            "apellidos" => "Flores-Beltr&#225;n"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
            ]
          ]
          5 => array:3 [
            "nombre" => "Jos&#233;"
            "apellidos" => "Segovia"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
            ]
          ]
          6 => array:3 [
            "nombre" => "Mineko"
            "apellidos" => "Shibayama"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
            ]
          ]
          7 => array:4 [
            "nombre" => "Pablo"
            "apellidos" => "Muriel"
            "email" => array:1 [
              0 => "pmuriel@cinvestav.mx"
            ]
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:4 [
          0 => array:3 [
            "entidad" => "Laboratory of Experimental Hepatology&#44; Department of Pharmacology&#44; Cinvestav-IPN&#44; Av&#46; Instituto Polit&#233;cnico Nacional&#44; Mexico City&#44; Mexico"
            "etiqueta" => "a"
            "identificador" => "aff0005"
          ]
          1 => array:3 [
            "entidad" => "Department of Physiology&#44; Biophysics and Neurosciences&#44; Cinvestav-IPN&#44; Mexico City&#44; Mexico"
            "etiqueta" => "b"
            "identificador" => "aff0010"
          ]
          2 => array:3 [
            "entidad" => "Department of Infectomics and Molecular Pathogenesis&#44; Cinvestav-IPN&#44; Mexico City&#44; Mexico"
            "etiqueta" => "c"
            "identificador" => "aff0015"
          ]
          3 => array:3 [
            "entidad" => "School of Higher Education in Medicine-IPN&#44; Mexico City&#44; Mexico"
            "etiqueta" => "d"
            "identificador" => "aff0020"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 1
      "multimedia" => array:5 [
        "identificador" => "fig0035"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "fx1.jpeg"
            "Alto" => 886
            "Ancho" => 2213
            "Tamanyo" => 76926
          ]
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="sect0040">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Despite the progress in the study and management of liver diseases&#44; millions of people worldwide still suffer from chronic hepatic illness&#46; The incidence and prevalence of fibrosis&#44; conducing to cirrhosis&#44; is important to understanding the burden of hepatic disease &#91;<a class="elsevierStyleCrossRef" href="#bib0005">1</a>&#93;&#46; However&#44; no effective antifibrotic therapy has been approved to date&#46; Activated hepatic stellate cells &#40;HSCs&#41; are the major drivers of liver fibrogenesis&#44; producing exacerbated amounts of extracellular matrix &#40;ECM&#41; proteins&#46; Therefore&#44; pharmacological treatment to decrease activated HSCs may constitute an effective antifibrotic therapy &#91;<a class="elsevierStyleCrossRef" href="#bib0010">2</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0015">3</a>&#93;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Transforming growth factor-&#946; &#40;TGF-&#946;&#41; is widely recognized for its profibrogenic effects&#44; inducing several profibrogenic factors&#44; and most importantly inducing HSC activation&#46; Several studies have reported that TGF-&#946; mediates its effects through Smad3 phosphorylation in its MH2 domain &#40;carboxyl-terminal&#41;&#59; however&#44; in recent years&#44; it has been reported that Smad3 actively participates in the profibrogenic process independent of its activation via TGF-&#946; &#91;<a class="elsevierStyleCrossRef" href="#bib0020">4</a>&#93;&#46; The MAPK family can phosphorylate Smad3 in its linker domain&#44; resulting in the induction of PAI-1 expression&#44; which is involved in HSC proliferation and migration processes&#44; favoring fibrosis &#91;<a class="elsevierStyleCrossRef" href="#bib0025">5</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0030">6</a>&#93;&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Curcumin&#44; a polyphenol found in the root of the <span class="elsevierStyleItalic">Curcuma longa</span> plant&#44; has been widely reported to be a hepatoprotective plant in various liver diseases &#91;<a class="elsevierStyleCrossRefs" href="#bib0035">7&#8211;10</a>&#93;&#46; However&#44; the mechanism of action of curcumin in reducing fibrosis has not been completely elucidated&#46; Furthermore&#44; the effect of curcumin in the noncanonical Smad profibrotic pathway has not been investigated&#46; Consequently&#44; the objective of this study was to investigate whether curcumin could reduce hepatic fibrosis in a carbon tetrachloride &#40;CCl<span class="elsevierStyleInf">4</span>&#41;-induced model of cirrhosis and if so&#44; to determine the canonical&#47;noncanonical Smad3 pathways&#44; and&#47;or HSCs activation&#47;deactivation pathways that may be involved in this protective effect&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="sect0045">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0050">Animal treatment</span><p id="par0020" class="elsevierStylePara elsevierViewall">Male Wistar rats &#40;initially weighing 100&#8211;120&#8239;g&#46;&#41; were provided by the Laboratory Animals Production and Experimentation Unit &#40;UPEAL&#41;&#46; Rats were maintained on a standard diet of Rat Chow&#174; with free access to drinking water under controlled conditions&#46; After the acclimation period &#40;1 week&#41;&#44; the rats &#40;<span class="elsevierStyleItalic">n</span> &#61; 32&#41; were administered the following treatments&#58; The control group &#40;<span class="elsevierStyleItalic">n</span> &#61; 8&#41; was given 0&#46;3&#37; carboxymethylcellulose at a dose of 1&#8239;mL daily through an intragastric tube&#46; The CCl<span class="elsevierStyleInf">4</span> group &#40;<span class="elsevierStyleItalic">n</span> &#61; 8&#41; was administered 400&#8239;mg CCl<span class="elsevierStyleInf">4</span>&#47;kg body weight i&#46;p&#46; three times per week&#44; dissolved in mineral oil for 12 weeks&#46; The CCl<span class="elsevierStyleInf">4</span> &#43; curcumin group &#40;<span class="elsevierStyleItalic">n</span> &#61; 8&#41; was administered CCl<span class="elsevierStyleInf">4</span>&#44; as in the CCl<span class="elsevierStyleInf">4</span> group for 12 weeks&#44; plus 100&#8239;mg of curcumin&#47;kg twice a day at the beginning of the week 9 of CCl<span class="elsevierStyleInf">4</span> treatment for 4 weeks&#44; by gavage&#46; The curcumin only group &#40;<span class="elsevierStyleItalic">n</span> &#61; 8&#41; was administered 100&#8239;mg of curcumin&#47;kg twice a day for 4 weeks by gavage&#46; The curcumin dose in this study has been previously evaluated and used with successful results &#91;<a class="elsevierStyleCrossRef" href="#bib0045">9</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0050">10</a>&#93;&#46; Rats were euthanized under ketamine &#40;100&#8239;mg&#47;kg&#41; and xylazine &#40;8&#8239;mg&#47;kg body weight&#41; anesthesia&#46; All rats were sacrificed following 12 weeks of the experiment&#46; Blood was collected by cardiac puncture and centrifuged at 1300&#8239;rpm for 15&#8239;min&#59; serum obtained was used for biochemical determinations&#46; The liver was quickly removed&#44; sectioned&#44; and appropriately stored before each analysis was conducted&#46; The rest of the liver was stored at &#8722;72&#8239;&#176;C&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">All animal care and experimental procedures complied with the Institution&#8217;s guidelines&#44; as well as the Mexican official regulation &#40;NOM- 062-ZOO-1999&#41;&#46; This research protocol &#40;protocol number 207&#8722;16&#41; was approved by the institutional animal care and use committee from CINVESTAV-IPN&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0055">Biochemical analyses</span><p id="par0030" class="elsevierStylePara elsevierViewall">Liver damage was assessed by measuring the activities of alanine aminotransferase &#40;ALT&#41; &#91;<a class="elsevierStyleCrossRef" href="#bib0055">11</a>&#93;&#44; alkaline phosphatase &#40;AP&#41; &#91;<a class="elsevierStyleCrossRef" href="#bib0060">12</a>&#93;&#44; and &#947;-glutamyl transpeptidase &#40;&#947;-GTP&#41; &#91;<a class="elsevierStyleCrossRef" href="#bib0065">13</a>&#93; in serum samples of blood that were centrifuged at 1300&#8239;rpm for 15&#8239;min&#46; Protein concentration was determined via the Bradford method using bovine serum albumin as a standard &#91;<a class="elsevierStyleCrossRef" href="#bib0070">14</a>&#93;&#46; The content of reduced glutathione &#40;GSH&#41; in the liver was evaluated in fresh tissue samples &#91;<a class="elsevierStyleCrossRef" href="#bib0075">15</a>&#93;&#46; Small pieces of liver were separated for glycogen determination using anthrone reagent &#91;<a class="elsevierStyleCrossRef" href="#bib0080">16</a>&#93;&#46; Collagen concentrations were determined by measuring the hydroxyproline content in the liver samples as described previously &#91;<a class="elsevierStyleCrossRef" href="#bib0085">17</a>&#93;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0060">Hematoxylin&#44; eosin&#44; Masson&#8217;s trichrome stains&#44; and immunohistochemistry</span><p id="par0035" class="elsevierStylePara elsevierViewall">Liver samples were fixed with 10&#37; formaldehyde &#40;in 1X PBS&#41; for 24&#8239;h&#44; then&#44; hematoxylin and eosin &#40;H &#38; E&#41; and Masson&#8217;s trichrome stains were performed&#59; next&#44; samples were mounted with Permount polymer&#46; Sections were prepared for immunohistochemistry &#40;IHC&#41; as described previously &#91;<a class="elsevierStyleCrossRef" href="#bib0090">18</a>&#93;&#46; The antibodies used for IHC are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; All stained slides were visualized using a light microscope &#40;80i&#44; Eclipse&#59; Nikon&#44; Tokyo&#44; Japan&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0065">Zymography</span><p id="par0040" class="elsevierStylePara elsevierViewall">Proteolytic activity was assayed with gelatin-substrate acrylamide gels as described previously &#91;<a class="elsevierStyleCrossRef" href="#bib0095">19</a>&#93;&#46; Gels were digitized and then analyzed densitometrically with an image analysis software &#40;ImageJ&#44; 1&#46;46&#8239;r&#44; NIH&#44; Bethesda&#44; Maryland&#44; USA&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;5</span><span class="elsevierStyleSectionTitle" id="sect0070">Western blot assays</span><p id="par0045" class="elsevierStylePara elsevierViewall">Protein analysis by western blot was performed as previously described &#91;<a class="elsevierStyleCrossRef" href="#bib0100">20</a>&#93;&#46; Antibodies used for western blot are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Protein concentration was measured using the bicinchoninic acid method &#91;<a class="elsevierStyleCrossRef" href="#bib0105">21</a>&#93;&#46; The images were digitized&#44; and the intensity of each band was quanti&#64257;ed using densitometric scanning with ImageJ software &#40;NIH&#41; &#91;<a class="elsevierStyleCrossRef" href="#bib0110">22</a>&#93;&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;6</span><span class="elsevierStyleSectionTitle" id="sect0075">RNA extraction&#44; RT-PCR&#44; and qRT-PCR</span><p id="par0050" class="elsevierStylePara elsevierViewall">Tissue RNA was extracted and assayed as previously described &#91;<a class="elsevierStyleCrossRef" href="#bib0090">18</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0100">20</a>&#93; and <span class="elsevierStyleItalic">&#946;-Actin</span> was used as the housekeeping gene to normalize mRNA levels&#46; Gels were digitized&#46; qRT-PCR was performed using 0&#46;5&#8239;&#956;L of cDNA added to 4&#46;5&#8239;&#956;L of master mix &#40;Kapa SYBR Fast Universal qPCR Kit REF KK4601&#44; Merck Mexico&#41;&#46; Reaction conditions recommended by the manufacturer were followed&#46; qRT-PCR was performed in an Eco thermocycler &#40;Illumina&#41;&#46; The relative mRNA levels of &#945;-<span class="elsevierStyleItalic">SMA</span> &#40;Forward 5&#8242;-GAATGAACGCTTCCGCTGCC-3&#8242;&#47;Reverse 5&#8242;-TCCTGTCAGCAATGCCTGGG-3&#697;&#41; and Smad3 &#40;Forward 5&#8242;-TGATCCCTCCAATTCAGAGC-3&#8242;&#47;Reverse 5&#8242;-AAAGACCTCCCCTCCAATGT-3&#8242;&#41; were calculated by the comparative threshold cycle &#40;Ct&#41; method using <span class="elsevierStyleItalic">&#946;-actin</span> &#40;Forward 5&#697; TGGCACCACACCTTCTACA-3&#697;&#47;Reverse 5&#697;-TCACGCACGATTTCCC-3&#697;&#41; as an internal control for normalization&#46; The fold change in the expression of each target gene was calculated by the 2<span class="elsevierStyleSup">&#8722;&#916;&#916;Ct</span> method &#91;<a class="elsevierStyleCrossRef" href="#bib0115">23</a>&#93;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;7</span><span class="elsevierStyleSectionTitle" id="sect0080">Transmission electron microscopy</span><p id="par0055" class="elsevierStylePara elsevierViewall">Representative liver tissues were processed for transmission electron microscopy &#40;TEM&#41; as previously described &#91;<a class="elsevierStyleCrossRef" href="#bib0120">24</a>&#93;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;8</span><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">Results are expressed as mean values&#8239;&#177;&#8239;SE&#46; Comparisons were carried out via one-way variance analysis followed by Tukey&#8217;s test&#44; utilizing the Graph Pad Prism software&#44; version 6&#46;01 &#40;GraphPad Software Inc&#46;&#44; San Diego&#44; CA&#44; USA&#41;&#46; Differences were considered statistically significant when P was &#60;0&#46;05&#46; The group sizes referred to independent values&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0095">Curcumin attenuated macroscopic&#44; microscopic&#44; and ultrastructural alterations produced by CCl<span class="elsevierStyleInf">4</span></span><p id="par0065" class="elsevierStylePara elsevierViewall">The control rat liver had an intense brown color&#44; smooth&#44; and soft surface &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46; Treatment with CCl<span class="elsevierStyleInf">4</span> produced liver macronodular fibrosis &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41; and curcumin attenuated the macroscopic effects produced by CCl<span class="elsevierStyleInf">4</span> administration &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C&#41;&#46; Hepatic tissue from CCl<span class="elsevierStyleInf">4</span>-treated rats &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>F&#41; showed a distortion of the parenchyma&#44; bile duct proliferation&#44; and steatosis but curcumin decreased these alterations&#46; Large areas of normal hepatocytes were found&#44; but some hepatocytes maintained discrete deposits of hemosiderin and nuclear atypia &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>G&#41;&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>J shows a cirrhotic liver section stained with Masson&#8217;s trichrome&#44; where large amounts of collagen can be observed forming regeneration nodules&#46; In the CCl<span class="elsevierStyleInf">4</span> &#43; curcumin group&#44; normal areas were observed&#44; as well as a considerable decrease in collagen fibers &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>K&#41;&#46; The control group showed a normal liver ultrastructure by TEM images&#44; where several mitochondria and typical nuclei can be observed&#44; and the liver appeared healthy &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>M&#41;&#46; On the other hand&#44; cirrhotic livers showed abundant lipid droplets and disorganized mitochondria with loss of cristae and internal structure as well as large areas of collagen deposition &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>N&#41;&#46; Importantly&#44; hepatic parenchyma from animals intoxicated with CCl<span class="elsevierStyleInf">4</span> plus curcumin &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>O&#41; had fewer collagen fibers&#44; and alterations were attenuated&#46; Curcumin-only-treated rats showed no alterations when compared to the control group&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0100">Curcumin attenuated oxidative stress&#44; serum markers of liver damage&#44; and glycogen depletion in rats treated with CCl<span class="elsevierStyleInf">4</span></span><p id="par0070" class="elsevierStylePara elsevierViewall">After CCl<span class="elsevierStyleInf">4</span> intoxication&#44; ALT&#44; FA&#44; and &#947;-GTP serum activities were significantly elevated&#59; curcumin treatment partial or completely ameliorated these alterations &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figs&#46; 2</a>A-C&#41;&#46; GSH and glycogen contents were elevated during liver cirrhosis&#44; and curcumin restored these parameters &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figs&#46; 2</a>D and E&#41;&#46; Healthy rats treated with curcumin did not exhibit any modified parameters&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0105">Administration of curcumin reversed inflammation in cirrhotic rats</span><p id="par0075" class="elsevierStylePara elsevierViewall">Treatment with CCl<span class="elsevierStyleInf">4</span> for 12 weeks increased immunoreactivity to NF-&#954;B &#40;p65&#41; and IL-1&#946; in hepatic tissue&#59; interestingly&#44; intense positivity colocalized with collagen fibers accumulation &#40;arrows&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figs&#46; 3</a>B and G&#41;&#46; In the group treated with CCl<span class="elsevierStyleInf">4</span> and curcumin&#44; immunoreactivity to NF-&#954;B &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>C&#41; and IL-1&#946; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>H&#41; decreased significantly&#46; The percentage of immunoreactivity to NF-&#954;B and IL-1&#946; is shown in <a class="elsevierStyleCrossRef" href="#fig0015">Figs&#46; 3</a>E and J&#44; respectively&#46; Besides&#44; protein levels of NF-&#954;B&#44; IL-1&#946;&#44; and IL-10 increased significantly by CCl<span class="elsevierStyleInf">4</span> intoxication compared to the control group&#44; and curcumin administration restored basal levels of NF-&#954;B&#44; IL-1&#946;&#44; and IL-10 &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figs&#46; 3</a>K-M&#41;&#46; Rats treated with only curcumin showed no changes in cytokines levels&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0110">Effect of curcumin on extracellular matrix remodeling in rats treated with CCl<span class="elsevierStyleInf">4</span></span><p id="par0080" class="elsevierStylePara elsevierViewall">Collagen&#44; quantitatively assessed as the hepatic hydroxyproline content&#44; significantly increased in the CCl<span class="elsevierStyleInf">4</span> group when compared to the control group&#59; notably&#44; after curcumin administration for 4 weeks&#44; collagen values decreased significantly &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A&#41;&#46; Protein levels of CTGF&#44; MMP-13&#44; and activity of MMP-2 and MMP-9 were elevated compared to the control group&#44; and curcumin administration restored these factors to normal levels &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Figs&#46; 4</a>B-E&#41;&#46; Treatment of healthy rats with curcumin did not modify proteins or activities&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;5</span><span class="elsevierStyleSectionTitle" id="sect0115">Effect of curcumin on HSC transdifferentiation</span><p id="par0085" class="elsevierStylePara elsevierViewall">Hepatic parenchyma from CCl<span class="elsevierStyleInf">4</span>-damaged rats exhibited large areas of positive reaction to TGF-&#946; and &#945;-SMA and this reaction colocalized with fibrotic zones&#44; rich in collagen and HSCs &#40;arrows&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Figs&#46; 5</a>B and G&#41;&#44; and curcumin decreased TGF-&#946; and &#945;-SMA positivity &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Figs&#46; 5</a>C and H&#41;&#59; the percentages of immunoreactivity to TGF-&#946; and &#945;-SMA are shown in <a class="elsevierStyleCrossRef" href="#fig0025">Figs&#46; 5</a>E and J&#44; respectively&#46; Western blotting results showed that TGF-&#946; and &#945;-SMA protein levels in the livers of CCl<span class="elsevierStyleInf">4</span>-treated rats were significantly elevated compared to those in the control group and that curcumin significantly reversed this alteration &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Figs&#46; 5</a>K and L&#41;&#46; At the mRNA level&#44; hepatotoxicity significantly increased <span class="elsevierStyleItalic">&#945;-Sma</span> levels and curcumin reversed this increase &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>M&#41;&#46; Rats treated with CCl<span class="elsevierStyleInf">4</span> showed decreased levels of Smad7&#44; and curcumin administration significantly attenuated this effect &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>N&#41;&#46; Curcumin administered to healthy rats did not modify the studied parameters&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;6</span><span class="elsevierStyleSectionTitle" id="sect0120">Administration of curcumin inhibits the JNK-Smad3 pathway</span><p id="par0090" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a> shows that CCl<span class="elsevierStyleInf">4</span> increased the pJNK&#47;JNK ratio &#40;A&#41;&#44; and levels of pSmad3L &#40;B&#41;&#44; Smad3 &#40;C&#41; proteins&#44; and Smad3 mRNA &#40;D&#41;&#46; Curcumin significantly reversed these effects&#46; Curcumin administered to healthy rats did not modify the studied parameters&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle" id="sect0125">Discussion</span><p id="par0095" class="elsevierStylePara elsevierViewall">This study provides evidence that curcumin administration attenuates CCl<span class="elsevierStyleInf">4</span>-induced liver cirrhosis&#46; Our results suggest that an antifibrotic action of curcumin may be associated with its ability to deactivate and&#47;or eliminate transdifferentiated HSCs&#44; the most active producers of fibrotic tissue in the liver parenchyma&#46; Curcumin downregulated the TGF-&#946; signaling pathway&#44; the main HSCs transdifferentiation inductor&#44; as well as the JNK-Smad3 pathway&#44; involved in the proliferation and migration of HSCs&#46; Moreover&#44; curcumin restored Smad7 levels&#44; an important antifibrotic protein&#46; This polyphenol helped to attenuate the proinflammatory cytokine cascade by blocking the NF-&#954;B factor&#46;</p><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0130">Curcumin downregulates the profibrogenic JNK-Smad3 pathway</span><p id="par0100" class="elsevierStylePara elsevierViewall">Previously&#44; it has been reported that curcumin reduces acute and chronic liver damage &#91;<a class="elsevierStyleCrossRefs" href="#bib0035">7&#8211;10</a>&#93;&#46; In the present study&#44; it was observed&#44; for the first time&#44; that curcumin re-established normal JNK and Smad3&#44; mRNA&#44; and protein levels that were upregulated by CCl<span class="elsevierStyleInf">4</span>-induced chronic liver damage&#44; thereby leading to downregulation of the JNK-Smad3 pathway&#59; as a result&#44; profibrogenic and mitogenic pSmad3L &#91;<a class="elsevierStyleCrossRef" href="#bib0025">5</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0030">6</a>&#93; was decreased and progression of fibrosis was attenuated&#46; It seems that more Smad protein is synthesized in the CCl<span class="elsevierStyleInf">4</span> group &#40;please note that Smad3 mRNA was increased&#41; and more Smad3 is phosphorylated&#46; Our results suggest that phosphorylation is increased too because pJNK was upregulated in the CCl<span class="elsevierStyleInf">4</span> group&#46; In summary&#44; the present results suggest that CCl<span class="elsevierStyleInf">4</span> increased the synthesis and phosphorylation of Smad3&#44; and curcumin attenuated both effects&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0135">Curcumin alleviates fibrosis by increasing the antifibrotic Smad7 protein</span><p id="par0105" class="elsevierStylePara elsevierViewall">Curcumin re-established normal Smad7 levels&#44; which is a negative regulator of the liver fibrogenic process&#46; Smad7 intracellularly binds to T&#946;RI&#44; preventing Smad3 phosphorylation and Smads3-Smad4 heterocomplex formation&#44; thus blocking the profibrogenic activity in the canonical TGF-&#946; pathway&#46; Additionally&#44; in the nucleus&#44; Smad7 binds to DNA and impedes binding of the Smad3-Smad4 heterocomplex to DNA &#91;<a class="elsevierStyleCrossRefs" href="#bib0125">25&#8211;28</a>&#93;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">During chronic liver damage&#44; Smad7 levels remain low&#44; leading to an uncontrolled fibrotic response&#59; low levels of Smad7 in activated HSCs may exacerbate TGF-&#946; profibrogenic effects during the progression of liver fibrosis &#91;<a class="elsevierStyleCrossRef" href="#bib0145">29</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0150">30</a>&#93;&#46; Therefore&#44; the upregulation of Smad7 by curcumin seems to be another antifibrotic mechanism of this molecule by blocking the TGF-&#946; pathway&#44; which may help in triggering the resolution of fibrosis&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0140">Curcumin reduces the number of activated HSC</span><p id="par0115" class="elsevierStylePara elsevierViewall">It is worth noting that curcumin treatment resulted in a reduction in the number of activated HSCs&#46; This effect could be mediated by an increase in Smad7 levels and downregulation of TGF-&#946; canonical and non-canonical pathways or other curcumin-independent effects such as deactivation&#44; senescence&#44; or apoptosis of HSCs &#91;<a class="elsevierStyleCrossRefs" href="#bib0155">31&#8211;34</a>&#93;&#46; Taken together&#44; the results of the present study and evidence from previous studies&#44; suggest that one of the main antifibrotic mechanisms of curcumin is the decrease in activated profibrogenic HSCs&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0145">Curcumin sustains beneficial effects by regulating MMPs</span><p id="par0120" class="elsevierStylePara elsevierViewall">MMPs are key regulators of the synthesis and degradation of ECM &#91;<a class="elsevierStyleCrossRef" href="#bib0175">35</a>&#93;&#44; which is the main reservoir of signaling molecules by binding growth factors such as CTGF&#44; TGF-&#946;&#44; and PDGF &#91;<a class="elsevierStyleCrossRef" href="#bib0180">36</a>&#93;&#46; MMP13 is responsible for the cleavage of CTGF &#91;<a class="elsevierStyleCrossRef" href="#bib0185">37</a>&#93;&#46; Furthermore&#44; the high proteolytic activities of MMP2 and 9 promote the dissociation of TNF-&#945; and IL-1&#946; from ECM&#44; conducing to an exacerbation of the inflammatory process &#91;<a class="elsevierStyleCrossRef" href="#bib0190">38</a>&#93;&#46; The results of the present study suggest that curcumin may support antifibrotic activity by modulating MMPs&#44; thus regulating the release from the ECM of pro-inflammatory and pro-fibrogenic factors&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4&#46;5</span><span class="elsevierStyleSectionTitle" id="sect0150">Curcumin attenuates the proinflammatory NF-&#954;B pathway</span><p id="par0125" class="elsevierStylePara elsevierViewall">It has been reported that NF-&#954;B inhibition promotes apoptosis of HSCs&#44; preventing liver fibrosis consequently &#91;<a class="elsevierStyleCrossRef" href="#bib0195">39</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0200">40</a>&#93;&#46; Curcumin reduces NF-&#954;B mRNA&#44; as well as Toll-like receptor 2&#44; Toll-like receptor 4&#44; and MyD88 adapter in activated HSCs&#44; leading to their apoptosis &#91;<a class="elsevierStyleCrossRefs" href="#bib0205">41&#8211;43</a>&#93;&#46; Therefore&#44; it is likely that NF-&#954;B inhibition by curcumin may explain&#44; in part&#44; its antifibrotic actions by both blocking inflammation and inducing HSC apoptosis&#46;</p></span></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">5</span><span class="elsevierStyleSectionTitle" id="sect0155">Conclusion</span><p id="par0130" class="elsevierStylePara elsevierViewall">It can be concluded that curcumin attenuated CCl<span class="elsevierStyleInf">4</span>-induced cirrhosis by downregulating canonical and non-canonical Smad pathways&#44; restoring Smad 7 levels&#44; blocking NF-&#954;B proinflammatory cytokine production&#44; and decreasing the number of activated HSCs in the hepatic parenchyma&#46; These results may be of clinical importance in the treatment of cirrhotic patients&#59; however&#44; more basic and controlled prospective studies in humans are required before suggesting curcumin as a safe anti-cirrhotic remedy&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Limitations and perspectives</span><p id="par0135" class="elsevierStylePara elsevierViewall">Activated HSCs are the main responsible for fibrogenesis&#46; Therefore&#44; it is generally recognized that the most suitable approach to induce remission of liver fibrosis consists of &#8220;eliminating&#8221; activated HSCs&#46; Herein&#44; we found that curcumin reduced activated HSCs&#46; However&#44; the mechanism remains to be dilucidated&#46; The possible mechanisms include apoptosis&#44; necrosis&#44; and senescence of these cells&#46; The deactivation of profibrogenic HSCs to a quiescent state seems to be a suitable approach&#46; Therefore&#44; research on the molecular pathways leading to the &#8220;elimination&#8221; of activated HSCs will provide specific targets to produce regression of the fibrotic state&#46; Moreover&#44; the specific molecular targets of curcumin &#40;or any putative antifibrotic drug&#41; on activated HSCs must be investigated to illuminate the antifibrotic pathways involved and to improve therapy&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Funding</span><p id="par0140" class="elsevierStylePara elsevierViewall">This work was supported by the <span class="elsevierStyleGrantSponsor" id="gs0005">National Council of Science and Technology</span> &#40;Conacyt&#41; of Mexico&#44; No&#46; <span class="elsevierStyleGrantNumber" refid="gs0005">253037</span> to Muriel P&#46;&#44; No&#46; <span class="elsevierStyleGrantNumber" refid="gs0005">237523</span> to Shibayama M&#46;&#44; and No&#46; <span class="elsevierStyleGrantNumber" refid="gs0005">239516</span> to Segovia J&#46;&#59; fellowship No&#46; <span class="elsevierStyleGrantNumber" refid="gs0005">358378</span> to Hern&#225;ndez-Aquino E&#46; from Conacyt&#46;</p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conflict of interest</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to report&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:14 [
        0 => array:3 [
          "identificador" => "xres1424241"
          "titulo" => "Graphical abstract"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0005"
            ]
          ]
        ]
        1 => array:3 [
          "identificador" => "xres1424240"
          "titulo" => "Abstract"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "abst0010"
              "titulo" => "Introduction and Objectives"
            ]
            1 => array:2 [
              "identificador" => "abst0015"
              "titulo" => "Materials and Methods"
            ]
            2 => array:2 [
              "identificador" => "abst0020"
              "titulo" => "Results and Conclusions"
            ]
          ]
        ]
        2 => array:2 [
          "identificador" => "xpalclavsec1301800"
          "titulo" => "Keywords"
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec1301799"
          "titulo" => "Abbreviations"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Materials and methods"
          "secciones" => array:8 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Animal treatment"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Biochemical analyses"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Hematoxylin&#44; eosin&#44; Masson&#8217;s trichrome stains&#44; and immunohistochemistry"
            ]
            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Zymography"
            ]
            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Western blot assays"
            ]
            5 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "RNA extraction&#44; RT-PCR&#44; and qRT-PCR"
            ]
            6 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Transmission electron microscopy"
            ]
            7 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Statistical analysis"
            ]
          ]
        ]
        6 => array:3 [
          "identificador" => "sec0055"
          "titulo" => "Results"
          "secciones" => array:6 [
            0 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Curcumin attenuated macroscopic&#44; microscopic&#44; and ultrastructural alterations produced by CCl"
            ]
            1 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Curcumin attenuated oxidative stress&#44; serum markers of liver damage&#44; and glycogen depletion in rats treated with CCl"
            ]
            2 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Administration of curcumin reversed inflammation in cirrhotic rats"
            ]
            3 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Effect of curcumin on extracellular matrix remodeling in rats treated with CCl"
            ]
            4 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Effect of curcumin on HSC transdifferentiation"
            ]
            5 => array:2 [
              "identificador" => "sec0085"
              "titulo" => "Administration of curcumin inhibits the JNK-Smad3 pathway"
            ]
          ]
        ]
        7 => array:3 [
          "identificador" => "sec0090"
          "titulo" => "Discussion"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0095"
              "titulo" => "Curcumin downregulates the profibrogenic JNK-Smad3 pathway"
            ]
            1 => array:2 [
              "identificador" => "sec0100"
              "titulo" => "Curcumin alleviates fibrosis by increasing the antifibrotic Smad7 protein"
            ]
            2 => array:2 [
              "identificador" => "sec0105"
              "titulo" => "Curcumin reduces the number of activated HSC"
            ]
            3 => array:2 [
              "identificador" => "sec0110"
              "titulo" => "Curcumin sustains beneficial effects by regulating MMPs"
            ]
            4 => array:2 [
              "identificador" => "sec0115"
              "titulo" => "Curcumin attenuates the proinflammatory NF-&#954;B pathway"
            ]
          ]
        ]
        8 => array:2 [
          "identificador" => "sec0120"
          "titulo" => "Conclusion"
        ]
        9 => array:2 [
          "identificador" => "sec0125"
          "titulo" => "Limitations and perspectives"
        ]
        10 => array:2 [
          "identificador" => "sec0130"
          "titulo" => "Funding"
        ]
        11 => array:2 [
          "identificador" => "sec0135"
          "titulo" => "Conflict of interest"
        ]
        12 => array:2 [
          "identificador" => "xack497215"
          "titulo" => "Acknowledgments"
        ]
        13 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2020-03-02"
    "fechaAceptado" => "2020-05-28"
    "PalabrasClave" => array:1 [
      "en" => array:2 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1301800"
          "palabras" => array:6 [
            0 => "Fibrosis"
            1 => "Smad"
            2 => "Curcumin"
            3 => "CCl<span class="elsevierStyleInf">4</span>"
            4 => "TGF-&#946;"
            5 => "HSC&#46;"
          ]
        ]
        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abbreviations"
          "identificador" => "xpalclavsec1301799"
          "palabras" => array:18 [
            0 => "CCl<span class="elsevierStyleInf">4</span>"
            1 => "TGF-&#946;"
            2 => "CTGF"
            3 => "&#945;-SMA"
            4 => "IL"
            5 => "HSCs"
            6 => "ECM"
            7 => "ROS"
            8 => "ALT"
            9 => "AP"
            10 => "&#947;-GTP"
            11 => "GSH"
            12 => "Col-I"
            13 => "MMP"
            14 => "JNK"
            15 => "PAI-1"
            16 => "TEM"
            17 => "CUR"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction and Objectives</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Curcumin&#44; a polyphenol&#44; is a natural compound that has been widely studied as a hepatoprotector&#59; however&#44; only a few studies have examined its ability to reduce fibrosis in previously established cirrhosis&#46; The objective of this study was to investigate whether curcumin could reduce carbon tetrachloride &#40;CCl<span class="elsevierStyleInf">4</span>&#41;-induced fibrosis and if so&#44; to determine the action mechanisms involved in the reduction process&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Materials and Methods</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">CCl<span class="elsevierStyleInf">4</span> was administered to male Wistar rats &#40;400&#8239;mg&#47;kg&#44; three times a week&#44; i&#46; p&#46;&#41; for 12 weeks&#59; curcumin &#40;100&#8239;mg&#47;kg body weight twice per day&#44; p&#46; o&#46;&#41; was administered from week 9&#8211;12 of CCl<span class="elsevierStyleInf">4</span> treatment&#46; Biochemical markers of hepatic injury and oxidative stress were evaluated&#46; Hematoxylin and eosin&#44; Masson&#8217;s trichrome stains&#44; transmission electron microscopy&#59; immunohistochemistry&#44; and zymography assays were carried out&#46; Moreover&#44; Smad3 and &#945;-SMA mRNA and protein levels were studied&#46; Western blotting by TGF-&#946;&#44; CTGF&#44; Col-I&#44; MMP-13&#44; NF-&#954;B&#44; IL-1&#44; IL-10&#44; Smad7&#44; pSmad3&#44; and pJNK proteins was developed&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results and Conclusions</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Curcumin reduced liver damage&#44; oxidative stress&#44; fibrosis&#44; and restored normal activity of MMP-9 and MMP-2&#46; Besides&#44; curcumin restored NF-&#954;B&#44; IL-1&#44; IL-10&#44; TGF-&#946;&#44; CTGF&#44; Col-I&#44; MMP-13&#44; and Smad7 protein levels&#46; On the other hand&#44; curcumin decreased JNK and Smad3 phosphorylation&#46; Furthermore&#44; curcumin treatment decreased &#945;-SMA and Smad3 protein and mRNA levels&#46; Curcumin normalized GSH&#44; and NF-&#954;B&#44; JNK-Smad3&#44; and TGF-&#946;-Smad3 pathways&#44; leading to a decrement in activated hepatic stellate cells&#44; thereby producing its antifibrotic effects&#46;</p></span>"
        "secciones" => array:3 [
          0 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Introduction and Objectives"
          ]
          1 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Materials and Methods"
          ]
          2 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Results and Conclusions"
          ]
        ]
      ]
    ]
    "multimedia" => array:8 [
      0 => array:8 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 2405
            "Ancho" => 3417
            "Tamanyo" => 1573065
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0005"
            "detalle" => "Fig&#46; "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Macroscopic&#44; microscopic&#44; and ultrastructural effects of curcumin in rats treated with CCl<span class="elsevierStyleInf">4</span></span>&#46; Macroscopic appearance &#40;A-D&#41; and representative liver sections stained using H&#38;E &#40;E-H&#41;&#44; Masson&#39;s trichrome &#40;I-L&#41;&#44; and transmission electron microscopy &#40;TEM&#41; &#40;M-P&#41; of livers of the control rats&#44; rats treated with CCl<span class="elsevierStyleInf">4</span> for 12 weeks &#40;CCl<span class="elsevierStyleInf">4</span>&#41;&#44; rats treated with CCl<span class="elsevierStyleInf">4</span> &#43; curcumin &#40;CUR&#41; &#40;CCl<span class="elsevierStyleInf">4</span> &#43; CUR&#41; and rats treated with CUR alone&#46; n&#58; nucleus&#59; m&#58; mitochondria&#59; ld&#58; lipid droplets&#59; cf&#58; collagen fibers&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1886
            "Ancho" => 3083
            "Tamanyo" => 224385
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0010"
            "detalle" => "Fig&#46; "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Curcumin attenuated serum indicators of hepatic injury restored oxidative stress markers&#44; and glycogen content in rats treated with CCl<span class="elsevierStyleInf">4</span>&#46;</span> Activities of alkaline phosphatase &#40;AP&#41; <span class="elsevierStyleBold">&#40;A&#41;</span>&#44; &#947;-glutamyl transpeptidase &#40;&#947;-GTP&#41; <span class="elsevierStyleBold">&#40;B&#41;</span>&#44; and alanine aminotransferase &#40;ALT&#41; <span class="elsevierStyleBold">&#40;C&#41;</span>&#44; liver reduced glutathione &#40;GSH&#41; <span class="elsevierStyleBold">&#40;D&#41;</span> and glycogen levels <span class="elsevierStyleBold">&#40;E&#41;</span> were determined in control rats&#44; rats treated with CCl<span class="elsevierStyleInf">4</span> for 12 weeks &#40;CCl<span class="elsevierStyleInf">4</span>&#41;&#44; rats treated with CCl<span class="elsevierStyleInf">4</span> &#43; curcumin &#40;CUR&#41; &#40;CCl<span class="elsevierStyleInf">4</span>&#43; CUR&#41;&#44; and rats treated with CUR alone&#46; Each bar represents the average value of eight rats &#40;n&#8239;&#61;&#8239;8&#41; &#177; standard error&#46; <span class="elsevierStyleBold">a</span> means P&#8239;&#60;&#8239;0&#46;05 with respect to the control group and <span class="elsevierStyleBold">b</span> means P&#8239;&#60;&#8239;0&#46;05 with respect to the CCl<span class="elsevierStyleInf">4</span> group&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 3958
            "Ancho" => 3333
            "Tamanyo" => 1508654
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0015"
            "detalle" => "Fig&#46; "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Administration of curcumin attenuated inflammatory environment in rats with experimental cirrhosis&#46;</span> Representative NF-&#954;B &#40;A<span class="elsevierStyleGlyphsbnd"></span>D&#41;&#44; and IL-1&#946; &#40;F<span class="elsevierStyleGlyphsbnd"></span>I&#41; immunohistochemistry&#46; The percentage of immunoreactivity to NF-&#954;B <span class="elsevierStyleBold">&#40;E&#41;</span>&#44; and IL-1&#946; <span class="elsevierStyleBold">&#40;J&#41;</span>&#46; Representative NF-&#954;B &#40;p65&#41; <span class="elsevierStyleBold">&#40;K&#41;</span>&#44; IL-1&#946; <span class="elsevierStyleBold">&#40;L&#41;</span>&#44; and IL-10 <span class="elsevierStyleBold">&#40;M&#41;</span> western blot &#40;WB&#41; of the control rats livers&#44; rats treated with CCl<span class="elsevierStyleInf">4</span>&#44; rats treated with CCl<span class="elsevierStyleInf">4</span> &#43; curcumin &#40;CUR&#41;&#44; and rats treated with CUR alone&#46; Immunohistochemistry positivity is indicated by arrows&#59; results are expressed as &#37; of the area with immunoreactivity&#46; Each bar represents the average value of three rats &#40;n&#8239;&#61;&#8239;3&#41; &#40;each rat with three fields averaged&#41; &#177; standard error&#46; In WB&#44; densitometric analyses were performed using &#946;-actin as internal control&#46; Each bar represents the average value of four rats &#40;n&#8239;&#61;&#8239;4&#41; &#177; standard error&#46; <span class="elsevierStyleBold">a</span> means P&#8239;&#60;&#8239;0&#46;05 with respect to the control group and <span class="elsevierStyleBold">b</span> means P&#8239;&#60;&#8239;0&#46;05 with respect to the CCl<span class="elsevierStyleInf">4</span> group&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "fig0020"
        "etiqueta" => "Fig&#46; 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 2485
            "Ancho" => 3417
            "Tamanyo" => 404599
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0020"
            "detalle" => "Fig&#46; "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Curcumin reduced collagen accumulation and extracellular matrix remodeling proteins in cirrhotic rats with experimental liver cirrhosis&#46;</span> Total collagen levels <span class="elsevierStyleBold">&#40;A&#41;</span>&#44; representative western blot &#40;WB&#41; of CTGF <span class="elsevierStyleBold">&#40;B&#41;</span>&#44; and MMP-13 <span class="elsevierStyleBold">&#40;C&#41;</span> as well as representative MMP-2 <span class="elsevierStyleBold">&#40;D&#41;</span> and MMP-9 <span class="elsevierStyleBold">&#40;E&#41;</span> zymography &#40;<span class="elsevierStyleBold">F</span>&#41; of livers derived from control rats&#44; rats treated with CCl<span class="elsevierStyleInf">4</span> for 12 weeks &#40;CCl<span class="elsevierStyleInf">4</span>&#41;&#44; rats treated with CCl<span class="elsevierStyleInf">4</span>&#43; curcumin &#40;CUR&#41; &#40;CCl<span class="elsevierStyleInf">4</span>&#43; CUR&#41;&#44; and rats treated with CUR alone&#46; In the total collagen graph&#44; each bar represents the average value of eight rats &#40;n&#8239;&#61;&#8239;8&#41; &#177; standard error&#46; In WB&#44; densitometric analyses were performed using &#946;-actin as the internal control and each bar represents the average value of four rats &#40;n&#8239;&#61;&#8239;4&#41; &#177; standard error&#46; In the zymography assay&#44; densitometric analyses were performed and each bar represents the average value of three rats &#40;n&#8239;&#61;&#8239;3&#41; &#177; standard error&#46; <span class="elsevierStyleBold">a</span> means P&#8239;&#60;&#8239;0&#46;05 with respect to the control group and <span class="elsevierStyleBold">b</span> means P&#8239;&#60;&#8239;0&#46;05 with respect to the CCl<span class="elsevierStyleInf">4</span> group&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "fig0025"
        "etiqueta" => "Fig&#46; 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 4006
            "Ancho" => 3417
            "Tamanyo" => 1694427
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0025"
            "detalle" => "Fig&#46; "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Effect of curcumin on hepatic stellate cells transdifferentiation and TGF-&#946; pathway&#46;</span> Representative TGF-&#946; &#40;A<span class="elsevierStyleGlyphsbnd"></span>D&#41;&#44; and &#945;-SMA &#40;F<span class="elsevierStyleGlyphsbnd"></span>I&#41; immunohistochemistry&#46; The percentage of immunoreactivity to TGF-&#946; <span class="elsevierStyleBold">&#40;E&#41;</span>&#44; and &#945;-SMA <span class="elsevierStyleBold">&#40;J&#41;</span>&#46; Representative western blot &#40;WB&#41; of TGF-&#946; <span class="elsevierStyleBold">&#40;K&#41;</span> and &#945;-SMA <span class="elsevierStyleBold">&#40;L&#41;</span>&#46; Representative <span class="elsevierStyleItalic">&#945;-SMA</span> qRT-PCR graph and RT-PCR gel <span class="elsevierStyleBold">&#40;M&#41;</span>&#44; and representative Smad7 WB <span class="elsevierStyleBold">&#40;N&#41;</span> of control rats&#44; rats treated with CCl<span class="elsevierStyleInf">4</span>&#44; rats treated with CCl<span class="elsevierStyleInf">4</span> &#43; curcumin &#40;CUR&#41;&#44; and rats treated with CUR alone&#46; Immunohistochemistry positivity is indicated by arrows&#59; results are expressed as &#37; of the area with immunoreactivity&#46; Each bar represents the average value of three rats &#40;n&#8239;&#61;&#8239;3&#41; &#40;each rat with three fields averaged&#41; &#177; standard error&#46; In WB&#44; densitometric analyses were performed using &#946;-actin as internal control&#46; Each bar represents the average value of four rats &#40;n&#8239;&#61;&#8239;4&#41; &#177; standard error&#46; In qRT-PCR&#44; <span class="elsevierStyleItalic">&#946;-actin</span> was used as a reference gene to normalize <span class="elsevierStyleItalic">&#945;-SMA</span> mRNA levels&#46; The relative change of expression was calculated using the 2<span class="elsevierStyleSup">&#916;&#916;Ct</span> method&#46; Each bar represents the average value of three rats &#40;n&#8239;&#61;&#8239;3&#41; &#177; standard error&#46; <span class="elsevierStyleBold">a</span> means P&#8239;&#60;&#8239;0&#46;05 with respect to the control group and <span class="elsevierStyleBold">b</span> means P&#8239;&#60;&#8239;0&#46;05 with respect to the CCl<span class="elsevierStyleInf">4</span> group&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "fig0030"
        "etiqueta" => "Fig&#46; 6"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr6.jpeg"
            "Alto" => 2868
            "Ancho" => 2667
            "Tamanyo" => 376826
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0030"
            "detalle" => "Fig&#46; "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Administration of curcumin inhibits the JNK-Smad3 pathway&#46;</span> Representative western blot &#40;WB&#41; of pJNK <span class="elsevierStyleBold">&#40;A&#41;</span>&#44; pSmad3L <span class="elsevierStyleBold">&#40;B&#41;</span>&#44; and Smad3 <span class="elsevierStyleBold">&#40;C&#41;</span>&#44; as well as <span class="elsevierStyleItalic">Smad3</span> qRT-PCR graph and RT-PCR gel <span class="elsevierStyleBold">&#40;D&#41;</span> of control rats&#44; rats treated with CCl<span class="elsevierStyleInf">4</span> for 12 weeks &#40;CCl<span class="elsevierStyleInf">4</span>&#41;&#44; rats treated with CCl<span class="elsevierStyleInf">4</span> &#43; curcumin &#40;CCl<span class="elsevierStyleInf">4</span> &#43; CUR&#41;&#44; and rats treated with CUR alone&#46; In WB&#44; densitometric analyses were performed using JNK or &#946;-actin as internal controls&#46; Each bar represents the average value of four rats &#40;n&#8239;&#61;&#8239;4&#41; &#177; standard error&#46; In qRT-PCR <span class="elsevierStyleItalic">&#946;-actin</span> was used as a reference gene to normalize <span class="elsevierStyleItalic">Smad3</span> mRNA levels&#46; The relative change of expression was calculated using the 2<span class="elsevierStyleSup">&#8722;&#916;&#916;Ct</span> method&#46; Each bar represents the average value of three rats &#40;n&#8239;&#61;&#8239;3&#41; &#177; standard error&#46; <span class="elsevierStyleBold">a</span> means P&#8239;&#60;&#8239;0&#46;05 with respect to the control group and <span class="elsevierStyleBold">b</span> means P&#8239;&#60;&#8239;0&#46;05 with respect to the CCl<span class="elsevierStyleInf">4</span> group&#46;</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0035"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Company&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Origin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Catalog number&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">WB dilution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IHQ dilution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGF-&#946;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Millipore&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CA&#44; USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">05&#8722;1423&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#945;-SMA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sigma-Aldrich&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Missouri&#44; USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A5691&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CTGF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Santa Cruz Biotechnology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CA&#44; USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SC-365&#44;970&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#95;&#95;&#95;&#95;&#95;&#95;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">COL-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sigma-Aldrich&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Missouri&#44; USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">C2456&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#95;&#95;&#95;&#95;&#95;&#95;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MMP-13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Millipore&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MA&#44; USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MAB13426&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#95;&#95;&#95;&#95;&#95;&#95;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NF-&#954;B &#40;P65&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Millipore&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MA&#44; USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MAB3026&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-1&#946;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Millipore&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cambridge&#44; UK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AB1832P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Thermo Fisher Scientific&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CA&#44; USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ARC9102&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#95;&#95;&#95;&#95;&#95;&#95;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Smad3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abcam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MA&#44; USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ab65847&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#95;&#95;&#95;&#95;&#95;&#95;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Psmad3L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abcam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cambridge&#44; UK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ab63403&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;250&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#95;&#95;&#95;&#95;&#95;&#95;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Smad7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abcam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cambridge&#44; UK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ab90086&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#95;&#95;&#95;&#95;&#95;&#95;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JNK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cell Signaling Technology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MA&#44; USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9252&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#95;&#95;&#95;&#95;&#95;&#95;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">pJNK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abcam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cambridge&#44; UK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ab131499&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#95;&#95;&#95;&#95;&#95;&#95;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#946;-actin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Thermo Fisher Scientific&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CA&#44; USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AM4302&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#58;500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#95;&#95;&#95;&#95;&#95;&#95;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2442735.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Antibodies used in Western blot and immunohistochemistry techniques&#46;</p>"
        ]
      ]
      7 => array:5 [
        "identificador" => "fig0035"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "fx1.jpeg"
            "Alto" => 886
            "Ancho" => 2213
            "Tamanyo" => 76926
          ]
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:43 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "&#91;1&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The liver&#58; general aspects and epidemiology"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "P&#46; Muriel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/B978-0-12-804274-8.00001-1"
                      "LibroEditado" => array:5 [
                        "editores" => "P&#46;Muriel"
                        "titulo" => "Liver pathophysiology&#58; therapies and antioxidants&#46;"
                        "paginaInicial" => "3"
                        "paginaFinal" => "22"
                        "serieFecha" => "2017"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "&#91;2&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fighting liver fibrosis to reduce mortality associated with chronic liver diseases&#58; the importance of new molecular targets and biomarkers"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "P&#46; Muriel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ebiom.2019.01.009"
                      "Revista" => array:6 [
                        "tituloSerie" => "EBioMedicine"
                        "fecha" => "2019"
                        "volumen" => "40"
                        "paginaInicial" => "35"
                        "paginaFinal" => "36"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30745133"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "&#91;3&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "T&#46; Kisseleva"
                            1 => "D&#46;A&#46; Brenner"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1440-1746.2006.04658.x"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Gastroenterol Hepatol"
                        "fecha" => "2007"
                        "volumen" => "1"
                        "paginaInicial" => "S73"
                        "paginaFinal" => "8"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "&#91;4&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "TGF-&#946; signalling and liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "I&#46; Fabregat"
                            1 => "J&#46; Moreno-C&#224;ceres"
                            2 => "A&#46; S&#225;nchez"
                            3 => "S&#46; Dooley"
                            4 => "B&#46; Dewidar"
                            5 => "G&#46; Giannelli"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/febs.13665"
                      "Revista" => array:6 [
                        "tituloSerie" => "FEBS J"
                        "fecha" => "2016"
                        "volumen" => "283"
                        "paginaInicial" => "2219"
                        "paginaFinal" => "2232"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26807763"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "&#91;5&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Reversible human TGF-&#946; signal shifting between tumor suppression and fibro-carcinogenesis&#58; implications of Smad Phospho-Isoforms for hepatic epithelial-mesenchymal transitions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "K&#46; Yoshida"
                            1 => "M&#46; Murata"
                            2 => "T&#46; Yamaguchi"
                            3 => "K&#46; Matsuzaki"
                            4 => "K&#46; Okazaki"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/jcm5010007"
                      "Revista" => array:4 [
                        "tituloSerie" => "J Clin Med"
                        "fecha" => "2016"
                        "volumen" => "5"
                        "paginaInicial" => "7"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "&#91;6&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Differential regulation of TGF-&#946;&#47;Smad signaling in hepatic stellate cells between acute and chronic liver injuries"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "K&#46; Yoshida"
                            1 => "K&#46; Matsuzaki"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fphys.2012.00053"
                      "Revista" => array:5 [
                        "tituloSerie" => "Front Physiol"
                        "fecha" => "2012"
                        "volumen" => "3"
                        "paginaInicial" => "53"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22457652"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "&#91;7&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatoprotective properties of curcumin"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "K&#46; Reyes-Gordillo"
                            1 => "R&#46; Shah"
                            2 => "M&#46;R&#46; Lakshman"
                            3 => "R&#46;E&#46; Flores-Beltr&#225;n"
                            4 => "P&#46; Muriel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:5 [
                        "editores" => "P&#46;Muriel"
                        "titulo" => "Liver pathophysiology&#58; therapies and antioxidants"
                        "paginaInicial" => "583"
                        "paginaFinal" => "604"
                        "serieFecha" => "2017"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "&#91;8&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cellular and molecular mechanisms of curcumin in prevention and treatment of disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46;S&#46; Patel"
                            1 => "A&#46; Acharya"
                            2 => "R&#46;S&#46; Ray"
                            3 => "R&#46; Agrawal"
                            4 => "R&#46; Raghuwanshi"
                            5 => "P&#46; Jain"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/10408398.2018.1552244"
                      "Revista" => array:5 [
                        "tituloSerie" => "Crit Rev Food Sci Nutr"
                        "fecha" => "2019"
                        "volumen" => "11"
                        "paginaInicial" => "1"
                        "paginaFinal" => "53"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "&#91;9&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Curcumin protects against acute liver damage in the rat by inhibiting NF-kappaB&#44; proinflammatory cytokines production and oxidative stress"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "K&#46; Reyes-Gordillo"
                            1 => "J&#46; Segovia"
                            2 => "M&#46; Shibayama"
                            3 => "P&#46; Vergara"
                            4 => "M&#46;G&#46; Moreno"
                            5 => "P&#46; Muriel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bbagen.2007.02.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Biochim Biophys Acta"
                        "fecha" => "2007"
                        "volumen" => "1770"
                        "paginaInicial" => "989"
                        "paginaFinal" => "996"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17383825"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "&#91;10&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Curcumin prevents and reverses cirrhosis induced by bile duct obstruction or CCl4 in rats&#58; role of TGF-beta modulation and oxidative stress"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46; Reyes-Gordillo"
                            1 => "J&#46; Segovia"
                            2 => "M&#46; Shibayama"
                            3 => "V&#46; Tsutsumi"
                            4 => "P&#46; Vergara"
                            5 => "M&#46;G&#46; Moreno"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1472-8206.2008.00611.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Fundam Clin Pharmacol"
                        "fecha" => "2008"
                        "volumen" => "22"
                        "paginaInicial" => "417"
                        "paginaFinal" => "427"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18705752"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "&#91;11&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46; Reitman"
                            1 => "S&#46; Frankel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/ajcp/28.1.56"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Clin Pathol"
                        "fecha" => "1957"
                        "volumen" => "28"
                        "paginaInicial" => "56"
                        "paginaFinal" => "63"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/13458125"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "&#91;12&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Enzymes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46;U&#46; Bergmeyer"
                            1 => "M&#46; Grabl"
                            2 => "H&#46;E&#46; Walter"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:5 [
                        "editores" => "J&#46;Bergmeyer, M&#46;Grabl"
                        "titulo" => "Methods of enzymatic analysis"
                        "paginaInicial" => "269"
                        "paginaFinal" => "270"
                        "serieFecha" => "1986"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "&#91;13&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Gamma-Glutamyltransferase in kidney brush border membranes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "H&#46; Glossmann"
                            1 => "D&#46;M&#46; Neville"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/0014-5793(72)80075-9"
                      "Revista" => array:6 [
                        "tituloSerie" => "FEBS Lett"
                        "fecha" => "1972"
                        "volumen" => "19"
                        "paginaInicial" => "340"
                        "paginaFinal" => "344"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11946246"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "&#91;14&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "M&#46;M&#46; Bradford"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/0003-2697(76)90527-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "Anal Biochem"
                        "fecha" => "1976"
                        "volumen" => "72"
                        "paginaInicial" => "248"
                        "paginaFinal" => "254"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/942051"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0075"
              "etiqueta" => "&#91;15&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Estimation of total&#44; protein-bound&#44; and nonprotein sulfhydryl groups in tissue with Ellman&#8217;s reagent"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46; Sedlak"
                            1 => "R&#46;H&#46; Lindsay"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/0003-2697(68)90092-4"
                      "Revista" => array:6 [
                        "tituloSerie" => "Anal Biochem"
                        "fecha" => "1968"
                        "volumen" => "25"
                        "paginaInicial" => "192"
                        "paginaFinal" => "205"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4973948"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0080"
              "etiqueta" => "&#91;16&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The estimation of glycogen with the anthrone reagent"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46; Seifter"
                            1 => "S&#46; Dayton"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Biochem"
                        "fecha" => "1950"
                        "volumen" => "25"
                        "paginaInicial" => "191"
                        "paginaFinal" => "200"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15401229"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0085"
              "etiqueta" => "&#91;17&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A specific method for the analysis of hydroxyproline in tissues and urine"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "D&#46;J&#46; Prockop"
                            1 => "S&#46; Udenfriend"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/0003-2697(60)90050-6"
                      "Revista" => array:6 [
                        "tituloSerie" => "Anal Biochem"
                        "fecha" => "1960"
                        "volumen" => "1"
                        "paginaInicial" => "228"
                        "paginaFinal" => "239"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/13738134"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0090"
              "etiqueta" => "&#91;18&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Stevia prevents experimental cirrhosis by reducing hepatic myofibroblasts and modulating molecular profibrotic pathways"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "E&#46; Ramos-Tovar"
                            1 => "L&#46;D&#46; Buendia-Monta&#241;o"
                            2 => "S&#46; Galindo-G&#243;mez"
                            3 => "E&#46; Hern&#225;ndez-Aquino"
                            4 => "V&#46; Tsutsumi"
                            5 => "P&#46; Muriel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/hepr.13275"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatol Res"
                        "fecha" => "2019"
                        "volumen" => "49"
                        "paginaInicial" => "212"
                        "paginaFinal" => "223"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30338893"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "&#91;19&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nicotinic acid prevents experimental liver fibrosis by attenuating the prooxidant process"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "J&#46; Arauz"
                            1 => "Y&#46; Rivera-Espinoza"
                            2 => "M&#46; Shibayama"
                            3 => "L&#46; Favari"
                            4 => "R&#46;E&#46; Flores-Beltr&#225;n"
                            5 => "P&#46; Muriel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.intimp.2015.05.045"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int Immunopharmacol"
                        "fecha" => "2015"
                        "volumen" => "28"
                        "paginaInicial" => "244"
                        "paginaFinal" => "251"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26093271"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "&#91;20&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Stevia prevents acute and chronic liver injury induced by carbon tetrachloride by blocking oxidative stress through Nrf2 upregulation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Ramos-Tovar"
                            1 => "E&#46; Hern&#225;ndez-Aquino"
                            2 => "S&#46; Casas-Grajales"
                            3 => "L&#46;D&#46; Buendia-Monta&#241;o"
                            4 => "S&#46; Galindo-G&#243;mez"
                            5 => "J&#46; Camacho"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1155/2018/3823426"
                      "Revista" => array:3 [
                        "tituloSerie" => "Oxid Med Cell Longev"
                        "fecha" => "2018"
                        "volumen" => "19"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "&#91;21&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Measurement of protein using bicinchoninic acid"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46;K&#46; Smith"
                            1 => "R&#46;I&#46; Krohn"
                            2 => "G&#46;T&#46; Hermanson"
                            3 => "A&#46;K&#46; Mallia"
                            4 => "F&#46;H&#46; Gartner"
                            5 => "M&#46;D&#46; Frovenzano"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/0003-2697(85)90442-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Anal Biochem"
                        "fecha" => "1985"
                        "volumen" => "150"
                        "paginaInicial" => "76"
                        "paginaFinal" => "85"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3843705"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "&#91;22&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "NIH image to imageJ&#58; 25 years of image analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "C&#46;A&#46; Schneider"
                            1 => "W&#46;S&#46; Rasband"
                            2 => "K&#46;W&#46; Eliceiri"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nmeth.2089"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Methods"
                        "fecha" => "2012"
                        "volumen" => "9"
                        "paginaInicial" => "671"
                        "paginaFinal" => "675"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22930834"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "&#91;23&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Analysis of relative gene expression data using real-time quantitative PCR and the 2&#40;-Delta Delta C&#40;T&#41;&#41; Method"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "K&#46;J&#46; Livak"
                            1 => "T&#46;D&#46; Schmittgen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1006/meth.2001.1262"
                      "Revista" => array:6 [
                        "tituloSerie" => "Methods"
                        "fecha" => "2001"
                        "volumen" => "25"
                        "paginaInicial" => "402"
                        "paginaFinal" => "408"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11846609"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "&#91;24&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Naringenin attenuates the progression of liver fibrosis via inactivation of hepatic stellate cells and profibrogenic pathways"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Hern&#225;ndez-Aquino"
                            1 => "M&#46;A&#46; Quezada-Ram&#237;rez"
                            2 => "A&#46; Silva-Olivares"
                            3 => "S&#46; Casas-Grajales"
                            4 => "E&#46; Ramos-Tovar"
                            5 => "R&#46;E&#46; Flores-Beltr&#225;n"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ejphar.2019.172730"
                      "Revista" => array:3 [
                        "tituloSerie" => "Eur J Pharmacol"
                        "fecha" => "2019"
                        "volumen" => "865"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "&#91;25&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Curcumin attenuates angiogenesis in liver fibrosis and inhibits angiogenic properties of hepatic stellate cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; Zhang"
                            1 => "Z&#46; Zhang"
                            2 => "L&#46; Chen"
                            3 => "D&#46; Kong"
                            4 => "X&#46; Zhang"
                            5 => "C&#46; Lu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/jcmm.12286"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Cell Mol Med"
                        "fecha" => "2014"
                        "volumen" => "18"
                        "paginaInicial" => "1392"
                        "paginaFinal" => "1406"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24779927"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "&#91;26&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Regulation of TGF-beta signaling by Smad7"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "X&#46; Yan"
                            1 => "Z&#46; Liu"
                            2 => "Y&#46; Chen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/abbs/gmp018"
                      "Revista" => array:5 [
                        "tituloSerie" => "Acta Biochim Biophys Sin &#40;Shanghai&#41;"
                        "fecha" => "2009"
                        "volumen" => "41"
                        "paginaInicial" => "263"
                        "paginaFinal" => "272"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "&#91;27&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Smad7 antagonizes transforming growth factor signaling in the nucleus by interfering with functional Smad-DNA complex formation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Zhang"
                            1 => "T&#46; Fei"
                            2 => "L&#46; Zhang"
                            3 => "R&#46; Zhang"
                            4 => "F&#46; Chen"
                            5 => "Y&#46; Ning"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/MCB.01636-06"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mol Cell Biol"
                        "fecha" => "2007"
                        "volumen" => "27"
                        "paginaInicial" => "4488"
                        "paginaFinal" => "4499"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17438144"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "&#91;28&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Smad7 protein interacts with receptor-regulated Smads &#40;R-Smads&#41; to inhibit transforming growth factor-&#946; &#40;TGF-&#946;&#41;&#47;Smad signaling"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "X&#46; Yan"
                            1 => "H&#46; Liao"
                            2 => "M&#46; Cheng"
                            3 => "X&#46; Shi"
                            4 => "X&#46; Lin"
                            5 => "X&#46;H&#46; Feng"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1074/jbc.m115.694281"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Biol Chem"
                        "fecha" => "2016"
                        "volumen" => "291"
                        "paginaInicial" => "382"
                        "paginaFinal" => "392"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26555259"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "&#91;29&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46; Tahashi"
                            1 => "K&#46; Matsuzaki"
                            2 => "M&#46; Date"
                            3 => "K&#46; Yoshida"
                            4 => "F&#46; Furukawa"
                            5 => "Y&#46; Sugano"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2002.30083"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2002"
                        "volumen" => "35"
                        "paginaInicial" => "49"
                        "paginaFinal" => "61"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11786959"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "&#91;30&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Dooley"
                            1 => "J&#46; Hamzavi"
                            2 => "K&#46; Breitkopf"
                            3 => "E&#46; Wiercinska"
                            4 => "H&#46;M&#46; Said"
                            5 => "J&#46; Lorenzen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0016-5085(03)00666-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "2003"
                        "volumen" => "125"
                        "paginaInicial" => "178"
                        "paginaFinal" => "191"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12851882"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "&#91;31&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of curcumin on the proliferation and apoptosis of hepatic stellate cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;C&#46; Shu"
                            1 => "Y&#46;J&#46; He"
                            2 => "X&#46; Lv"
                            3 => "J&#46;R&#46; Zhao"
                            4 => "J&#46;R&#46; Zhao"
                            5 => "Y&#46; Shen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1590/S0100-879X2009005000041"
                      "Revista" => array:6 [
                        "tituloSerie" => "Braz J Med Biol Res"
                        "fecha" => "2009"
                        "volumen" => "42"
                        "paginaInicial" => "1173"
                        "paginaFinal" => "1178"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19918672"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "&#91;32&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Curcumin prevents liver fibrosis by inducing apoptosis and suppressing activation of hepatic stellate cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "J&#46;C&#46; Shu"
                            1 => "Y&#46;J&#46; He"
                            2 => "X&#46; Lv"
                            3 => "G&#46;R&#46; Ye"
                            4 => "L&#46;X&#46; Wang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s11418-009-0347-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Nat Med"
                        "fecha" => "2009"
                        "volumen" => "63"
                        "paginaInicial" => "415"
                        "paginaFinal" => "420"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19554395"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "&#91;33&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Curcumin&#44; the main active constituent of turmeric &#40;Curcuma longa L&#46;&#41;&#44; induces apoptosis in hepatic stellate cells by modulating the abundance of apoptosis-related growth factors"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46;J&#46; He"
                            1 => "K&#46; Kuchta"
                            2 => "X&#46; Lv"
                            3 => "Y&#46; Lin"
                            4 => "G&#46;R&#46; Ye"
                            5 => "X&#46;Y&#46; Liu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1515/znc-2015-4143"
                      "Revista" => array:5 [
                        "tituloSerie" => "Z Naturforsch&#44; C&#44; J Biosci"
                        "fecha" => "2015"
                        "volumen" => "70"
                        "paginaInicial" => "281"
                        "paginaFinal" => "285"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "&#91;34&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatic stellate cell interferes with NK cell regulation of fibrogenesis via curcumin induced senescence of hepatic stellate cell"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Jin"
                            1 => "Y&#46; Jia"
                            2 => "Z&#46; Yao"
                            3 => "J&#46; Huang"
                            4 => "M&#46; Hao"
                            5 => "S&#46; Yao"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.cellsig.2017.02.006"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell Signal"
                        "fecha" => "2017"
                        "volumen" => "33"
                        "paginaInicial" => "79"
                        "paginaFinal" => "85"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28188823"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "&#91;35&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Matrix metalloproteinases in liver injury&#44; repair and fibrosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "S&#46; Duarte"
                            1 => "J&#46; Baber"
                            2 => "T&#46; Fujii"
                            3 => "A&#46;J&#46; Coito"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.matbio.2015.01.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Matrix Biol"
                        "fecha" => "2015"
                        "volumen" => "44-46"
                        "paginaInicial" => "147"
                        "paginaFinal" => "156"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25599939"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "&#91;36&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Therapeutic pro-fibrogenic signaling pathways in fibroblasts"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "S&#46; Cannito"
                            1 => "E&#46; Novo"
                            2 => "M&#46; Parola"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.addr.2017.05.017"
                      "Revista" => array:6 [
                        "tituloSerie" => "Adv Drug Deliv Rev"
                        "fecha" => "2017"
                        "volumen" => "121"
                        "paginaInicial" => "57"
                        "paginaFinal" => "84"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28578015"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "&#91;37&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MMP-13 deletion decreases profibrogenic molecules and attenuates N -nitrosodimethylamine-induced liver injury and fibrosis in mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46; George"
                            1 => "M&#46; Tsutsumi"
                            2 => "M&#46; Tsuchishima"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/jcmm.13304"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Cell Mol Med"
                        "fecha" => "2017"
                        "volumen" => "21"
                        "paginaInicial" => "3821"
                        "paginaFinal" => "3835"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28782260"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "&#91;38&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver fibrosis&#58; understanding the dynamics of bidirectional wound repair to inform the design of markers and therapies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46;P&#46; Iredale"
                            1 => "A&#46; Pellicoro"
                            2 => "J&#46;A&#46; Fallowfield"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000456581"
                      "Revista" => array:6 [
                        "tituloSerie" => "Dig Dis"
                        "fecha" => "2017"
                        "volumen" => "35"
                        "paginaInicial" => "310"
                        "paginaFinal" => "313"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28467988"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "&#91;39&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nuclear factor kappaB in proliferation&#44; activation and apoptosis in rat hepatic stellate cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "A&#46; Lang"
                            1 => "R&#46; Schoonhoven"
                            2 => "S&#46; Tuvia"
                            3 => "D&#46;A&#46; Brenner"
                            4 => "R&#46;A&#46; Rippe"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0168-8278(00)80159-2"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2000"
                        "volumen" => "33"
                        "paginaInicial" => "49"
                        "paginaFinal" => "58"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10905586"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "&#91;40&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inhibition of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; Oakley"
                            1 => "M&#46; Meso"
                            2 => "J&#46;P&#46; Iredale"
                            3 => "K&#46; Green"
                            4 => "C&#46;J&#46; Marek"
                            5 => "X&#46; Zhou"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.gastro.2004.10.003"
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "2005"
                        "volumen" => "128"
                        "paginaInicial" => "108"
                        "paginaFinal" => "120"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15633128"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "&#91;41&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Curcumin promotes apoptosis of activated hepatic stellate cells by inhibiting protein expression of the MyD88 pathway"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46;J&#46; He"
                            1 => "K&#46; Kuchta"
                            2 => "Y&#46;M&#46; Deng"
                            3 => "S&#46; Cameron"
                            4 => "Y&#46; Lin"
                            5 => "X&#46;Y&#46; Liu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1055/s-0043-113044"
                      "Revista" => array:6 [
                        "tituloSerie" => "Planta Med"
                        "fecha" => "2017"
                        "volumen" => "83"
                        "paginaInicial" => "1392"
                        "paginaFinal" => "1396"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28628927"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "&#91;42&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Curcumin induces apoptosis in hepatic stellate cells via inhibition of the MyD88 pathway"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;C&#46; Shu"
                            1 => "K&#46; Kuchta"
                            2 => "Y&#46;J&#46; He"
                            3 => "Y&#46;M&#46; Deng"
                            4 => "Y&#46; Lin"
                            5 => "G&#46;R&#46; Ye"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1055/s-0035-156591"
                      "Revista" => array:5 [
                        "tituloSerie" => "Planta Med"
                        "fecha" => "2015"
                        "volumen" => "81"
                        "paginaInicial" => "1392"
                        "paginaFinal" => "1396"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "&#91;43&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Protective effects of curcumin against hepatic fibrosis induced by carbon tetrachloride&#58; modulation of high-mobility group box 1&#44; Toll-like receptor 4 and 2 expression"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "C&#46;T&#46; Tu"
                            1 => "Q&#46;Y&#46; Yao"
                            2 => "B&#46;L&#46; Xu"
                            3 => "J&#46;Y&#46; Wang"
                            4 => "C&#46;H&#46; Zhou"
                            5 => "S&#46;C&#46; Zhang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.fct.2012.05.050"
                      "Revista" => array:6 [
                        "tituloSerie" => "Food Chem Toxicol"
                        "fecha" => "2012"
                        "volumen" => "50"
                        "paginaInicial" => "3343"
                        "paginaFinal" => "3351"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22683883"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
    "agradecimientos" => array:1 [
      0 => array:4 [
        "identificador" => "xack497215"
        "titulo" => "Acknowledgments"
        "texto" => "<p id="par0150" class="elsevierStylePara elsevierViewall">The authors thank Laura D&#46; Buendia-Monta&#241;o&#44; Rafael Leyva&#44; Benjam&#237;n E&#46; Chavez&#44; and Ricardo Gaxiola for their excellent technical assistance&#46; The authors also acknowledge the Animal Lab Facility&#44; UPEAL-Cinvestav&#46;</p>"
        "vista" => "all"
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/16652681/0000001900000005/v5_202012011817/S166526812030065X/v5_202012011817/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "78265"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Original Articles"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/16652681/0000001900000005/v5_202012011817/S166526812030065X/v5_202012011817/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S166526812030065X?idApp=UINPBA00004N"
]

Article information

ISSN: 16652681
Original language: English

DOI:10.1016/j.aohep.2020.05.006

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 October	22	3	25
2024 September	35	3	38
2024 August	36	12	48
2024 July	37	3	40
2024 June	60	6	66
2024 May	49	2	51
2024 April	33	7	40
2024 March	71	7	78
2024 February	52	11	63
2024 January	56	3	59
2023 December	54	4	58
2023 November	64	5	69
2023 October	68	6	74
2023 September	58	10	68
2023 August	58	11	69
2023 July	45	3	48
2023 June	50	2	52
2023 May	100	8	108
2023 April	82	3	85
2023 March	62	3	65
2023 February	67	11	78
2023 January	59	8	67
2022 December	42	7	49
2022 November	40	8	48
2022 October	38	15	53
2022 September	48	11	59
2022 August	26	21	47
2022 July	35	5	40
2022 June	29	8	37
2022 May	29	14	43
2022 April	36	6	42
2022 March	72	13	85
2022 February	57	11	68
2022 January	46	15	61
2021 December	22	16	38
2021 November	30	14	44
2021 October	51	21	72
2021 September	42	12	54
2021 August	54	9	63
2021 July	31	12	43
2021 June	17	16	33
2021 May	24	12	36
2021 April	80	36	116
2021 March	28	17	45
2021 February	50	20	70
2021 January	35	7	42
2020 December	21	21	42
2020 November	29	10	39
2020 October	38	11	49
2020 September	102	30	132
2020 August	7	8	15
2020 July	4	5	9

Show all

Indexed in:

Follow us:

Statistics

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter