Salvianolic acid B blocks hepatic stellate cell activation via FGF19/FGFR4 signaling

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"documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2021;20C:" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Accuracy of non-invasive methods/models for predicting esophageal varices in patients with compensated advanced chronic liver disease secondary to nonalcoholic fatty liver disease" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2624 "Ancho" => 2917 "Tamanyo" => 305282 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Flowchart of the studied patients. NAFLD, nonalcoholic fatty liver disease; EGD, esophagogastroduodenoscopy." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Humberto O. Galizzi, Claudia A. Couto, Daniela O.L. Taranto, Samuel I.O. Araújo, Eduardo G. Vilela" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Humberto O." "apellidos" => "Galizzi" ] 1 => array:2 [ "nombre" => "Claudia A." "apellidos" => "Couto" ] 2 => array:2 [ "nombre" => "Daniela O.L." "apellidos" => "Taranto" ] 3 => array:2 [ "nombre" => "Samuel I.O." "apellidos" => "Araújo" ] 4 => array:2 [ "nombre" => "Eduardo G." "apellidos" => "Vilela" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268120300764?idApp=UINPBA00004N" "url" => "/16652681/000000200000000C/v2_202101071056/S1665268120300764/v2_202101071056/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1665268120301472" "issn" => "16652681" "doi" => "10.1016/j.aohep.2020.07.010" "estado" => "S300" "fechaPublicacion" => "2021-01-01" "aid" => "242" "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. 2021;20C:" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Carcinoembryonic antigen, α-fetoprotein, and Ki67 as biomarkers and prognostic factors in intrahepatic cholangiocarcinoma: A retrospective cohort study" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 3621 "Ancho" => 3008 "Tamanyo" => 448344 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Kaplan–Meier plots of overall survival (OS) contrasting positive versus negative expression of AFP, CEA, CD10, CD34, and Ki67. (A) Association between OS and AFP expression. Patients with high AFP expression had significantly shorter OS (P = 0.002). (B) Association between OS and CEA expression. Patients with high CEA expression had significantly shorter OS (P < 0.0001). (C) Association between OS and CD10 expression, showing no statistically significant difference. (D) Association between OS and CD34 expression, showing no statistically significant difference. (E) Association between OS and Ki67 expression. Patients with high Ki67 expression had significantly shorter OS (P < 0.0001)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Zeyuan Qiang, Wenhua Zhang, Shuai Jin, Kunfu Dai, Yuting He, Lianyuan Tao, Haibo Yu" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Zeyuan" "apellidos" => "Qiang" ] 1 => array:2 [ "nombre" => "Wenhua" "apellidos" => "Zhang" ] 2 => array:2 [ "nombre" => "Shuai" "apellidos" => "Jin" ] 3 => array:2 [ "nombre" => "Kunfu" "apellidos" => "Dai" ] 4 => array:2 [ "nombre" => "Yuting" "apellidos" => "He" ] 5 => array:2 [ "nombre" => "Lianyuan" "apellidos" => "Tao" ] 6 => array:2 [ "nombre" => "Haibo" "apellidos" => "Yu" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268120301472?idApp=UINPBA00004N" "url" => "/16652681/000000200000000C/v2_202101071056/S1665268120301472/v2_202101071056/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Salvianolic acid B blocks hepatic stellate cell activation via FGF19/FGFR4 signaling" "tieneTextoCompleto" => true "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Shuxia Tian, Min Chen, Bing Wang, Yonglong Han, Haonan Shang, Junming Chen" "autores" => array:6 [ 0 => array:3 [ "nombre" => "Shuxia" "apellidos" => "Tian" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "1" "identificador" => "fn0005" ] ] ] 1 => array:3 [ "nombre" => "Min" "apellidos" => "Chen" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "1" "identificador" => "fn0005" ] ] ] 2 => array:3 [ "nombre" => "Bing" "apellidos" => "Wang" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Yonglong" "apellidos" => "Han" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "Haonan" "apellidos" => "Shang" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 5 => array:4 [ "nombre" => "Junming" "apellidos" => "Chen" "email" => array:1 [ 0 => "gzrktyx@163.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, China" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Shanghai Jiaotong University Affiliated Sixth People's Hospital, China" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author:" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2142 "Ancho" => 2933 "Tamanyo" => 307890 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Effects of several natural products on fibroblast growth factor (FGF) 19 secretion by LX-2 cells. LX-2 cells were treated with different concentrations of (A) tanshione IIA, (B) salvianolic acid B, (C) baicalin, (D) puerarin, and (E) saikosaponin D as indicated. Culture media were collected after 24 h, and FGF19 level was measured by enzyme-linked immunosorbent assay. Values represent mean ± standard deviation (n = 5). **P <  0.01, ***P <  0.001." ] ] ] "textoCompleto" => "1IntroductionLiver fibrosis is characterized by excessive accumulation of extracellular matrix (ECM) in the liver in response to injuries. Many factors including chronic viral infection, alcohol abuse, and nonalcoholic steatohepatitis (NASH) may cause liver fibrosis. Activated hepatic stellate cells (HSCs) are considered the main source of ECM in fibrotic liver [<a class="elsevierStyleCrossRef" href="#bib0005">1</a>,<a class="elsevierStyleCrossRef" href="#bib0010">2</a>]. Currently, there are very limited options for the treatment of liver fibrosis. Therefore, exploring the mechanisms underlying HSC activation and identifying novel drugs that can prevent HSC activation are important for improving therapeutic efficiency among patients with chronic liver diseases.The fibroblast growth factor (FGF) family is a large family of proteins that play crucial roles in development and metabolism. Among 22 known FGFs, the FGF19 subfamily members, including FGF19, FGF21, and FGF23, lack a heparin-binding domain; therefore, they cannot bind to heparin sulfate, which allows them to easily enter circulation as endocrine hormones [<a class="elsevierStyleCrossRef" href="#bib0015">3</a>]. FGF19 (FGF15 in mouse) is mainly produced in the intestine in response to bile acid (BA). The activation of farnesoid X receptor (FXR) by liver-derived BA strongly induces the secretion of FGF19, which subsequently travels back to the liver through the portal vein and binds to the FGF receptor 4 (FGFR4)/β-Klotho complex on hepatocytes to reduce BA synthesis [<a class="elsevierStyleCrossRef" href="#bib0020">4</a>]. The key enzymes required for BA synthesis such as Cyp7a1 and Cyp8b1 are the downstream targets of FGF19 in the liver [<a class="elsevierStyleCrossRef" href="#bib0020">4</a>,<a class="elsevierStyleCrossRef" href="#bib0025">5</a>].Some recent studies showed that serum FGF19 level was correlated with liver damage and cholestasis [<a class="elsevierStyleCrossRefs" href="#bib0030">6–8</a>]. Moreover, patients with decreased FGF19 level showed more severe hepatic inflammation and fibrosis [<a class="elsevierStyleCrossRef" href="#bib0045">9</a>], whereas a negative correlation was found between serum FGF19 level and fibrosis in patients with alcoholic hepatitis [<a class="elsevierStyleCrossRef" href="#bib0050">10</a>]. The beneficial effect of FGF19 in liver fibrosis was further confirmed by several reports by examining direct FGF19 treatment in liver fibrosis animal models [<a class="elsevierStyleCrossRefs" href="#bib0055">11–14</a>]. Importantly, FGF19 analog treatment significantly improved liver fibrosis in patients with NASH and primary sclerosing cholangitis during phase II clinical trials [<a class="elsevierStyleCrossRef" href="#bib0075">15</a>,<a class="elsevierStyleCrossRef" href="#bib0080">16</a>]. However, whether FGF19 can be directly produced by HSCs in an autocrine manner and whether drugs that regulate its secretion can be used to treat liver fibrosis remain unknown.The dried root of Salvia miltiorrhiza Bunge (Lamiaceae) has been used to treat various diseases in China for many years as a very commonly used traditional Chinese medicine (TCM) [<a class="elsevierStyleCrossRef" href="#bib0085">17</a>]. S. miltiorrhiza has shown prominent antifibrotic effects in liver fibrosis models [<a class="elsevierStyleCrossRefs" href="#bib0090">18–20</a>]. Several bioactive chemical components such as salvianolic acid B and tanshinone IIA have been isolated from S. miltiorrhiza. Several previous studies explored the antifibrotic potential of these S. miltiorrhiza derived bioactive chemical components including salvianolic acid B. Smad2/3, NF-κB and Angiotensin II signaling has been proposed to be the targets of these compounds [<a class="elsevierStyleCrossRefs" href="#bib0105">21–24</a>]. However, the antifibrotic effects of these compounds have not been fully elucidated. In this study, we tested the antifibrotic effects of bioactive compounds derived from S. miltiorrhiza in human HSC cell lines and examined the potential role of FGF19 in the beneficial effects of these compounds.2Materials and methods2.1Cell culture and treatmentLX-2 cells were obtained from the cell bank of the Chinese Academy of Science (Shanghai, China) and were cultured in RPMI 1640 medium (Hyclone, Logan, UT, USA) supplemented with 10% fetal bovine serum (Invitrogen, Carlsbad, CA, USA) and 1% penicillin–streptomycin solution (Solarbio, Beijing, China). The cells were cultured in a humidified incubator with 5% CO2 at 37 °C. The cells were treated with 100 ng/mL lipopolysaccharide (LPS, from Sigma, St. Louis, MO, USA, Cat. No: L2880), salvianolic acid B, tanshinone IIA, baicalin, puerarin, and saikosaponin (Aladdin, Shanghai, China) at different concentrations for the indicated times shown in figures. The same volume of DMSO was used as the vehicle control.2.2Cell proliferation assayLX-2 cells (1 × 104 cells/well) were seeded into 96-well plates and treated with salvianolic acid B, tanshinone IIA, baicalin, puerarin, and saikosaponin at 37 °C for 72 h. Cell proliferation was determined using the Cell Counting Kit-8 assay according to the manufacturer’s instructions (SAB, Nanjing, China). Optical density value was measured at a wavelength of 450 nm.2.3RNA isolation and quantitative reverse transcription polymerase chain reaction (RT-qPCR)Total RNA from LX-2 cells was extracted using the TRIzol reagent (Thermo Fisher Scientific, Waltham, MA, USA). Total RNA was reverse transcribed into cDNA, using the RevertAid First Strand cDNA Synthesis Kit (Thermo Fisher Scientific). The SYBRGreen quantitative polymerase chain reaction (qPCR) master mix (Thermo Fisher Scientific) was used to quantify cDNA on the ABI 7300 real-time PCR system (Applied Biosystem, Foster City, CA) in a 20-µl PCR reaction. qPCR was performed using the following settings: predenaturation at 95 °C for 10 s, denaturation at 95 °C for 10 s, and 40 elongation cycles at 60 °C for 30 s. The expression level of the housekeeping gene glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used to normalize results. The 2−ΔΔCt method was performed to calculate relative expression levels. The PCR primer sequences used are listed below:FGFR4Primer F 5′-CCCTCGAATAGGCACAGTTAC-3′Primer R 5′-GCCTCCAATGCGGTTCTC-3′Transforming growth factor-β (TGF-β)Primer F 5′-CGTGGAGGGGAAATTGAGG-3′Primer R 5′-GCCATGAGAAGCAGGAAAGG-3′α-Smooth muscle actin (α-SMA)Primer F 5′-GACGAAGCACAGAGCAAAAG-3′Primer R 5′-ACAGCACCGCCTGGATAG-3′Collagen1a1 (COL1A1)Primer F 5′-GAGGCATGTCTGGTTCGG-3′Primer R 5′-TGGTAGGTGATGTTCTGGGAG-3′GAPDHPrimer F 5′-AATCCCATCACCATCTTC-3′Primer R 5′-AGGCTGTTGTCATACTTC-3′2.4Hydroxyproline content measurementHydroxyproline content was measured using a hydroxyproline assay kit (Jiancheng, Nanjing, China) according to the manufacturer’s instructions.2.5Enzyme-linked immunosorbent assay (ELISA)FGF19 level in culture medium was measured using a human FGF19 ELISA kit (Abcam, Cambridge, MA, USA) according to the manufacturer’s instructions.2.6Western blottingCells were lysed with RIPA buffer (Beyotime, Shanghai, China) on ice for 30 min. Protein level was measured using a BCA protein assay kit (Bio-Rad Laboratories, Hercules, CA, USA). A total of 20 µg protein was applied to each lane and separated using 10 % sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Then, the separated proteins were transferred to polyvinylidene difluoride membranes. The membranes were blocked with 5% milk at room temperature for 1 h. The membranes were incubated with primary antibodies diluted in 5% milk at 4 °C overnight. The primary antibodies used in this study included the following: α-SMA (Cell Signaling Technology, Danvers, MA, USA), COL1A1 (Cell Signaling Technology), TGF-β (Abcam), FGFR4 (Abcam), FGF19 (Abcam), and GAPDH (Proteintech, Rosemont, IL USA). The membranes were incubated with horseradish peroxidase-conjugated secondary antibodies (Beyotime) at room temperature for 1 h. Enhanced chemiluminescence chromogenic substrate (Thermo Fisher Scientific) was used to visualize protein bands.2.7RNA interferenceCells were transfected with 50 nM small interfering RNA (siRNA) targeting FGFR4 (siFGFR4) or negative control siRNA (siNC) using the Lipofectamine 2000 reagent (Invitrogen) according to the manufacturer’s instructions. The siRNA sequences are listed below:siFGFR4-1: 5′-GCAGAAUCUCACCUUGAUUUU-3′siFGFR4-2: 5′-CCAGGUAUACGGACAUCAUUU-3′siFGFR4-3: 5′-GCGUCCACCACAUUGACUAUU-3′siNC: 5′-CAGUACUUUUGUGUAGUACAA-3′2.8Plasmid constructionTo overexpress FGFR4, the full-length Homo sapiens FGFR4 coding sequence (CDS) was synthesized by GENEWIZ according to the guidelines of the National Center for Biotechnology Information database (NM_002011.5). FGFR4 CDS was cloned into the pcDNA3.1 vector (Addgene). LX-2 cells were transfected with the construct using the Lipofectamine 2000 reagent (Invitrogen) according to the manufacturer’s instructions.2.9ImmunofluorescenceLX-2 cells cultured on the coverslips were fixed with 1% paraformaldehyde solution containing 0.05% of Triton X-100 for 5 min at room temperature. Fixed cells were stained with phalloidin-TRITC solution at 100 μg/mL for 2 h at room temperature. Nuclei were stained with 4′,6-Diamidino-2-phenylindole dihydrochloride (DAPI, Beyotime Biotech.). The images were obtained using a BX51 OLYMPUS microscope.2.10Statistical analysisData are presented as mean ± standard deviation. Statistical analyses were performed using Graphpad Prism (San Diego, CA) for all experiments. Data from multiple groups were compared with one-way ANOVA. Differences between two groups were analyzed using Student’s t-test. P-value of <0.05 was considered to indicate a statistically significant difference.3Results3.1Salvianolic acid B promotes FGF19 secretion by LX-2 cellsWe first tested whether HSCs can secrete FGF19 using the human HSC cell line LX-2. Cells were cultured for 24 h, and approximately 170 µM FGF19 was detected in the culture medium (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A), which indicated that HSCs can secrete FGF19 in an autocrine manner. LX-2 cells were treated with two bioactive compounds derived from S. miltiorrhiza, salvianolic acid B and tanshinone IIA. Both compounds increased FGF19 secretion in a dose-dependent manner (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A and B). In contrast, several other antifibrotic natural products isolated from other TCM such as baicalin [<a class="elsevierStyleCrossRef" href="#bib0125">25</a>], puerarin [<a class="elsevierStyleCrossRef" href="#bib0130">26</a>], and saikosaponin D [<a class="elsevierStyleCrossRef" href="#bib0135">27</a>] had no effects on FGF19 secretion by LX-2 cells (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C–E). Interestingly, salvianolic acid B showed more potent effects on FGF19 secretion by LX-2 cells than the other tested compounds. Therefore, salvianolic acid B was selected for the following experiments. To evaluated the potential cytotoxicity effects of salvianolic acid B on LX-2 cells, we checked cell viability by using MTT assay. As shown in Fig. S1A, 1.0–5.0 µM did not show any cytotoxicity effects. In addition, LX-2 cells showed normal morphology with 1.0–5.0 µM salvianolic acid B treatment (Fig. S1B).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>3.2Salvianolic acid B inhibits LPS-induced activation and LX-2 cell proliferationWe evaluated the effects of salvianolic acid B on LPS-induced HSC proliferation and activation. As shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A, LX-2 proliferation significantly increased in the presence of LPS and the cotreatment with LPS and salvianolic acid B significantly blocked LPS-induced proliferation of LX-2 cells in a dose-dependent manner. LPS also considerably increased the hydroxyproline content of LX-2 cells, a marker of HSC activation. Treatment with salvianolic acid B substantially reduced LPS-induced increase in hydroxyproline content in a dose-dependent manner (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B). Consistently, other markers for HSC activation, such as α-SMA and COL1A1 were reduced in both mRNA and protein levels with salvianolic acid B treatment (<a class="elsevierStyleCrossRef" href="#fig0010">Fig.2</a>C-D). Previous study indicated that most of the actin F filaments were depolymerized in quiescent LX-2 cells while in activated LX2 cells, actin F filaments were fully polymerized [<a class="elsevierStyleCrossRef" href="#bib0140">28</a>]. So, we checked actin F filaments by immunofluorescence. As shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>E, LPS significantly increased polymerization of actin F filaments in LX-2 cells, while much less polymerization of actin F filaments were observed in the presence of salvianolic acid B. These data confirmed that salvianolic acid B can effectively block the activation and proliferation of LX-2 cells.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>3.3Salvianolic acid B restored LPS-induced decrease in FGF19 and FGFR4 expression levelsAs shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A, LX-2 cells can secrete FGF19; therefore, we explored whether LPS-induced HSC activation would affect FGF19 secretion. As shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A and B, LPS treatment considerably reduced both FGF19 mRNA and protein levels. Moreover, the mRNA and protein levels of FGFR4, the FGF19 receptor, decreased in the presence of LPS. These data suggested that FGF19/FGFR4 signaling was greatly impaired during LX-2 activation. When treated with different doses of salvianolic acid B, LPS-induced decrease in mRNA and protein levels of both FGF19 and FGFR4 were partially or almost fully restored (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A and B).<elsevierMultimedia ident="fig0015"></elsevierMultimedia>3.4Antifibrotic effects of salvianolic acid B depend on FGF19/FGFR4 signalingTo determine whether the antifibrotic effects of salvianolic acid B were mediated by regulating FGF19/FGFR4 signaling, we used siRNA to knock down FGFR4 expression in LX-2 cells. In addition, FGF4R was overexpressed through the transfection of the pcDNA-FGF4R plasmid. Both FGFR4 knockdown and overexpression were verified by examining its mRNA and protein levels in LX-2 cells (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>A and B). We tested the impact of FGFR4 knockdown on LPS-induced cell proliferation. As expected, salvianolic acid B inhibited LPS-induced LX-2 cell proliferation; however, this inhibitory effect was abolished by FGFR4 siRNA treatment (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>A). Moreover, FGFR4 overexpression considerably blocked LPS-induced cell proliferation (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>A). Similar to the cell proliferation data, FGFR4 siRNA treatment abolished the inhibitory effects of salvianolic acid B on HSC activation, as assessed by measuring hydroxyproline level as well as mRNA and protein levels of several HSC activation markers such as TGF-β, α-SMA, and COL1A1 (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>B–D). In contrast, FGFR4 overexpression substantially blocked LPS-induced HSC activation (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>B–D). These data strongly supported the critical role of FGF19/FGFR4 signaling in LPS-induced HSC proliferation and activation. We also demonstrated that the antifibrotic effects of salvianolic acid B are mediated by the regulation of FGF19/FGFR4 signaling.<elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia>4DiscussionIn this study, we found that FGF19 could be produced by HSCs and that FGFR4 was expressed in HSCs. LPS treatment impaired FGF19/FGFR4 signaling by downregulating both FGF19 and FGFR4 expressions. Salvianolic acid B, a bioactive compound isolated from the TCM S. miltiorrhiza, showed a strong ability to enhance FGF19 secretion and to restore FGF19/FGFR4 expression impaired by LPS treatment. Finally, we confirmed that the antifibrotic effects of salvianolic acid B were mediated by restoring FGF19/FGFR4 signaling during LPS-induced HSC proliferation and activation.As a unique “hormone-like” FGF, FGF19 has been reported to exert strong regulatory activity during energy metabolism and BA homeostasis [<a class="elsevierStyleCrossRef" href="#bib0145">29</a>]. Enterocytes of the terminal ileum are considered a major source of FGF19 [<a class="elsevierStyleCrossRef" href="#bib0150">30</a>]. In response to BA, the nuclear receptor FXR is activated and translocated to the FXR-responsive element in the intron area of FGF19 to initiate FGF19 transcription [<a class="elsevierStyleCrossRef" href="#bib0155">31</a>]. Some other mechanisms are also involved in the regulation of FGF19 expression including sterol regulatory element-binding protein 2, vitamin D receptor, and retinoid X receptor [<a class="elsevierStyleCrossRef" href="#bib0160">32</a>,<a class="elsevierStyleCrossRef" href="#bib0165">33</a>]. We found that FGF19 can also be secreted by HSCs (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A–E). Interestingly, LPS treatment significantly blocked FGF19 secretion by HSCs (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A–B). A previous report showed that LPS might reduce FXR expression [<a class="elsevierStyleCrossRef" href="#bib0170">34</a>], which could explain why LPS treatment was associated with decreased FGF19 secretion.FGF19 binds to the FGFR4/β-Klotho complex, with its major target being the liver [<a class="elsevierStyleCrossRef" href="#bib0175">35</a>]. A recent report suggested that HSCs were also targeted by FGF19 [<a class="elsevierStyleCrossRef" href="#bib0070">14</a>]. Our study confirmed that FGFR4 is expressed on HSCs (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A and B). We also showed that enhanced FGF19/FGFR4 signaling, mediated by FGFR4 overexpression, blocked HSC proliferation and activation (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>A–D). These data not only support the antifibrotic role of FGF19/FGFR4 signaling proposed in previous reports [<a class="elsevierStyleCrossRef" href="#bib0060">12</a>,<a class="elsevierStyleCrossRef" href="#bib0065">13</a>,<a class="elsevierStyleCrossRef" href="#bib0080">16</a>] but also provide evidence for the direct role of FGF19 in HSC proliferation and activation, which may prevent the development of liver fibrosis.TCM drugs have been used to treat liver fibrosis for many years, and the efficacy of several TCM drugs has been tested for the treatment of chronic liver diseases associated with fibrosis or cirrhosis [<a class="elsevierStyleCrossRef" href="#bib0180">36</a>]. Many TCM drugs for fibrotic liver disease contain S. miltiorrhiza as a major ingredient [<a class="elsevierStyleCrossRef" href="#bib0180">36</a>]. The antifibrotic effects of S. miltiorrhiza have been well-documented in several mouse and rat liver fibrosis models induced by different factors including chemicals, parasites, and iron overload [<a class="elsevierStyleCrossRefs" href="#bib0090">18–20</a>,<a class="elsevierStyleCrossRefs" href="#bib0185">37–41</a>]. Several mechanisms have been proposed to explain the antifibrotic effects of S. miltiorrhiza and its extracts. Treatment with S. miltiorrhiza possibly decreases the production of TGF-β, a potent activator of HSCs [<a class="elsevierStyleCrossRef" href="#bib0100">20</a>,<a class="elsevierStyleCrossRef" href="#bib0200">40</a>]. S. miltiorrhiza can also alleviate oxidative stress in liver fibrosis models [<a class="elsevierStyleCrossRef" href="#bib0195">39</a>]. Some other studies have attributed the beneficial effects of S. miltiorrhiza against liver fibrosis to the regulation of autophagy and nature killer cells [<a class="elsevierStyleCrossRef" href="#bib0095">19</a>,<a class="elsevierStyleCrossRef" href="#bib0205">41</a>]. Here, we identified a novel mechanism that can explain the antifibrotic effects of S. miltiorrhiza. Both salvianolic acid B and tanshinone IIA, two of the most important bioactive compounds derived from S. miltiorrhiza, showed strong activity in promoting FGF19 secretion (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A and B). We further tested the effects of salvianolic acid B, which showed a better ability to promote FGF19 secretion than tanshinone IIA, using an LPS-induced HSC proliferation and activation model. Our result confirmed that the antifibrotic effects were mediated by FGF19/FGFR4 signaling using FGFR4 siRNA (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>A–D).Chronic inflammation in the liver was considered as a major driving force for liver fibrosis. Many inflammatory cells, including Kupffer cells, neutrophils and T cells as wells as cytokines derived from these cells, such as TGF-β, IL-1 and TNF-α were critical in supporting HSC activation and ECM production [<a class="elsevierStyleCrossRef" href="#bib0210">42</a>]. Interestingly, salvianolic acid B showed prominent anti-inflammatory effects in several LPS induced inflammatory organ damage models [<a class="elsevierStyleCrossRefs" href="#bib0215">43–45</a>]. Although whether the anti-inflammatory effects of salvianolic acid B contribute to the regulation of FGF19/FGFR4 signaling in HSCs in vivo is not clear, the inhibition of inflammation will be helpful to prevent fibrogenesis and improve the resolution of liver fibrosis in chronic liver diseases.5ConclusionSalvianolic acid B could promote FGF19 secretion by the HSC cell line LX-2. The increased FGF19 expression and activation of FGF19/FGFR4 signaling were necessary for salvianolic acid B-mediated decrease in LPS-induced LX-2 cell proliferation and activation. Our study detailed a potential mechanism for the antifibrotic effects of S. miltiorrhiza.AbbreviationsECMextracellular matrixNASHnonalcoholic steatohepatitisHSCshepatic stellate cellsFGFFibroblast growth factorsBAbile acidFXRfarnesoid X receptorPSCprimary sclerosing cholangitisTCMTraditional Chinese MedicineLPSlipopolysaccharideCCK-8Cell Counting Kit-8RT-qPCRreverse transcription-quantitative polymerase chain reaction.CDScoding sequenceSREBP2sterol regulatory element-binding protein 2VDRvitamin D receptorRXRretinoid X receptorNKnature killerFinancial supportThis study was supported by grants from National Natural Science Foundation of China [81774061], the key subjects construction in the health system of Pudong New Area [PWZxk2017-02], Traditional Chinese Medicine Heritage and Science and Technology Innovation Project of Shanghai [ZYKC2019035] and Special Project of Integrated Traditional Chinese and Western Medicine of Shanghai [ZHYY-ZXYJHZX-201910].Conflict of interestThe authors declare no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1446266" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1319400" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:10 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Cell culture and treatment" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Cell proliferation assay" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "RNA isolation and quantitative reverse transcription polymerase chain reaction (RT-qPCR)" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Hydroxyproline content measurement" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Enzyme-linked immunosorbent assay (ELISA)" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Western blotting" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "RNA interference" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Plasmid construction" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Immunofluorescence" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Statistical analysis" ] ] ] 4 => array:3 [ "identificador" => "sec0065" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Salvianolic acid B promotes FGF19 secretion by LX-2 cells" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Salvianolic acid B inhibits LPS-induced activation and LX-2 cell proliferation" ] 2 => array:2 [ "identificador" => "sec0080" "titulo" => "Salvianolic acid B restored LPS-induced decrease in FGF19 and FGFR4 expression levels" ] 3 => array:2 [ "identificador" => "sec0085" "titulo" => "Antifibrotic effects of salvianolic acid B depend on FGF19/FGFR4 signaling" ] ] ] 5 => array:2 [ "identificador" => "sec0090" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0095" "titulo" => "Conclusion" ] 7 => array:2 [ "identificador" => "sec0100" "titulo" => "Financial support" ] 8 => array:2 [ "identificador" => "sec0105" "titulo" => "Conflict of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-04-07" "fechaAceptado" => "2020-07-27" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1319400" "palabras" => array:4 [ 0 => "Salvianolic acid B" 1 => "Lipopolysaccharide" 2 => "Fibroblast growth 19" 3 => "Hepatic stellate cell" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and objectivesThe activation of hepatic stellate cells (HSCs) is the main cause of liver fibrosis. The beneficial effects of fibroblast growth factor (FGF) 19 on liver fibrosis were recently reported. The S. miltiorrhiza as well as S. miltiorrhiza derived bioactive chemical components has shown prominent antifibrotic effects in liver fibrosis but the mechanism is still not fully understood. We aimed to investigate the bioactive compounds derived from S. miltiorrhiza which exerts antifibrotic effects in HSCs via regulating FGF19. Materials and methodsFGF19 level in culture media was determined by enzyme-linked immunosorbent assay. Cell proliferation was measured by Cell Counting Kit-8 assay. Further, mRNA and protein expressions were assessed by quantitative polymerase chain reaction and western blotting, respectively. Knocking down of FGF receptor 4 (FGFR4) by transfection with siRNA was used to confirm the role of FGF19/FGFR4 signaling. ResultsUsing the human HSC cell line LX-2, we screened several natural products and found that bioactive compounds isolated from Salvia miltiorrhiza, particularly salvianolic acid B, strongly upregulated FGF19 secretion by LX-2 cells. We further showed that salvianolic acid B inhibited lipopolysaccharide (LPS)-induced HSC proliferation and activation. LPS treatment may also reduce the mRNA and protein levels of FGF19 and its receptor FGFR4. Salvianolic acid B treatment restored the impaired expressions of FGF19 and FGFR4. Finally, FGFR4 knockdown abolished the antifibrotic effects of salvianolic acid B in the LPS-induced HSC activation model. ConclusionsSalvianolic acid B prevented LPS-induced HSC proliferation and activation by enhancing antifibrotic FGF19/FGFR4 signaling." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] ] "NotaPie" => array:1 [ 0 => array:3 [ "etiqueta" => "1" "nota" => "Contributed equally." "identificador" => "fn0005" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "The following is Supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0115" ] ] ] ] "multimedia" => array:6 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2142 "Ancho" => 2933 "Tamanyo" => 307890 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Effects of several natural products on fibroblast growth factor (FGF) 19 secretion by LX-2 cells. LX-2 cells were treated with different concentrations of (A) tanshione IIA, (B) salvianolic acid B, (C) baicalin, (D) puerarin, and (E) saikosaponin D as indicated. Culture media were collected after 24 h, and FGF19 level was measured by enzyme-linked immunosorbent assay. Values represent mean ± standard deviation (n = 5). **P <  0.01, ***P <  0.001." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3751 "Ancho" => 3175 "Tamanyo" => 937038 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Salvianolic acid B inhibits LPS-induced activation and proliferation of LX-2 cells. LX-2 cells were treated with different concentrations of salvianolic acid B, as indicated, with or without 100 ng/mL LPS. (A) OD450 values were measured 0, 24, 48, and 72 h after treatment using Cell Counting Kit-8 reagents. (B) Hydroxyproline level was measured using a hydroxyproline assay kit. mRNA (C) and protein (D) levels of α-SMA and COL1A1. (E) F-actin immunofluorescent staining. Values represent mean ± standard deviation (n = 5). *P <  0.05, **P <  0.01, ***P <  0.001." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 911 "Ancho" => 2508 "Tamanyo" => 169820 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Salvianolic acid B restores LPS induced FGF19 and FGFR4 downregulation. LX-2 cells were treated with different concentrations of salvianolic acid B, as indicated, with or without 100 ng/mL LPS. (A) Fibroblast growth factor (FGF19) and FGF receptor 4 (FGFR4) mRNA levels were measured by quantitative reverse transcription polymerase chain reaction. (B) FGF19, FGFR4, and glyceraldehyde 3-phosphate dehydrogenase protein levels were measured by western blotting. Values represent mean ± standard deviation (n = 5). *P < 0.05, **P < 0.01, ***P < 0.001." ] ] 3 => array:8 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1032 "Ancho" => 2175 "Tamanyo" => 140550 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Validation of fibroblast growth factor FGF receptor 4 (FGFR4) knockdown and overexpression. LX-2 cells were transfected with FGFR4 siRNA (siFGFR4-1, 2, and 3), negative control siRNA (siNC), empty vector (Vector), and FGFR4 overexpression vector (oeFGFR4). After 48 h, (A) mRNA and (B) protein levels of FGFR4 were measured by quantitative reverse transcription polymerase chain reaction and western blotting, respectively. Values represent mean ± standard deviation (n = 5). **P <  0.01 vs siNC group, ##P <  0.01 vs Vector 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" => 2922 "Ancho" => 3175 "Tamanyo" => 558458 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Fibroblast growth factor (FGF19)/FGF receptor 4 (FGFR4) signaling is required for the antifibrotic effects of salvianolic acid B. LX-2 cells were transfected with FGFR4 small interfering RNA (siRNA) (siFGFR4-1, 2, and 3), negative control siRNA (siNC), empty vector (Vector), and FGFR4 overexpression vector (oeFGFR4). The cells were treated with or without LPS and salvianolic acid B. (A) OD450 values were measured 0, 24, 48, and 72 h after treatment with Cell Counting Kit-8 reagents. (B) Hydroxyproline level was measured using a hydroxyproline assay kit. (C) FGFR4, FGF receptor 4 (TGF-β), α-smooth muscle actin (α-SMA), and Collagen1a1 (COL1A1) mRNA levels were measured by quantitative reverse transcription polymerase chain reaction. (D) FGFR4, TGF-β, α-SMA, COL1A1, and GAPDH protein levels were measured by western blotting. Values represent mean ± standard deviation (n = 5). *P <  0.05, **P <  0.01, ***P <  0.001." ] ] 5 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.docx" "ficheroTamanyo" => 1233141 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:45 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "[1]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver fibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R. Bataller" 1 => "D.A. Brenner" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI24282" "Revista" => array:7 [ "tituloSerie" => "J Clin Invest" "fecha" => "2005" "volumen" => "115" "paginaInicial" => "209" "paginaFinal" => "218" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15690074" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0167814019329998" "estado" => "S300" "issn" => "01678140" ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "[2]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathogenesis of liver fibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "V. Hernandez-Gea" 1 => "S.L. Friedman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1146/annurev-pathol-011110-130246" "Revista" => array:7 [ "tituloSerie" => "Annu Rev Pathol" "fecha" => "2011" "volumen" => "6" "paginaInicial" => "425" "paginaFinal" => "456" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21073339" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0167814019331184" "estado" => "S300" "issn" => "01678140" ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "[3]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "FGF19 subfamily members: FGF19 and FGF21" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "K. Dolegowska" 1 => "M. Marchelek-Mysliwiec" 2 => "M. Nowosiad-Magda" 3 => "M. Slawinski" 4 => "B. Dolegowska" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s13105-019-00675-7" "Revista" => array:6 [ "tituloSerie" => "J Physiol Biochem" "fecha" => "2019" "volumen" => "75" "paginaInicial" => "229" "paginaFinal" => "240" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30927227" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "[4]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "K.H. Song" 1 => "T. Li" 2 => "E. Owsley" 3 => "S. Strom" 4 => "J.Y. Chiang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.22627" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2009" "volumen" => "49" "paginaInicial" => "297" "paginaFinal" => "305" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19085950" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "[5]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "B. Kong" 1 => "L. Wang" 2 => "J.Y. Chiang" 3 => "Y. Zhang" 4 => "C.D. Klaassen" 5 => "G.L. Guo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.25740" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2012" "volumen" => "56" "paginaInicial" => "1034" "paginaFinal" => "1043" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22467244" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "[6]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association between serum atypical fibroblast growth factors 21 and 19 and pediatric nonalcoholic fatty liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Alisi" 1 => "S. Ceccarelli" 2 => "N. Panera" 3 => "F. Prono" 4 => "S. Petrini" 5 => "C. De Stefanis" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pone.0084567" "Revista" => array:5 [ "tituloSerie" => "PLoS One" "fecha" => "2013" "volumen" => "8" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24386394" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0167814019301501" "estado" => "S300" "issn" => "01678140" ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "[7]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Expression of hepatic Fibroblast Growth Factor 19 is enhanced in Primary Biliary Cirrhosis and correlates with severity of the disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Wunsch" 1 => "M. Milkiewicz" 2 => "U. Wasik" 3 => "J. Trottier" 4 => "A. Kempinska-Podhorodecka" 5 => "E. Elias" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/srep13462" "Revista" => array:6 [ "tituloSerie" => "Sci Rep" "fecha" => "2015" "volumen" => "5" "paginaInicial" => "13462" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26293907" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S1470204514712070" "estado" => "S300" "issn" => "14702045" ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "[8]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Circulating FGF19 closely correlates with bile acid synthesis and cholestasis in patients with primary biliary cirrhosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Z. Li" 1 => "B. Lin" 2 => "G. Lin" 3 => "Y. Wu" 4 => "Y. Jie" 5 => "X. Li" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pone.0189910" "Revista" => array:4 [ "tituloSerie" => "PLoS One" "fecha" => "2017" "volumen" => "12" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29287100" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "[9]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Loss of ileum decreases serum fibroblast growth factor 19 in relation to liver inflammation and fibrosis in pediatric onset intestinal failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A. Mutanen" 1 => "J. Lohi" 2 => "P. Heikkila" 3 => "H. Jalanko" 4 => "M.P. Pakarinen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2015.01.004" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2015" "volumen" => "62" "paginaInicial" => "1391" "paginaFinal" => "1397" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25595885" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "[10]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Brandl" 1 => "P. Hartmann" 2 => "L.J. Jih" 3 => "D.P. Pizzo" 4 => "J. Argemi" 5 => "M. Ventura-Cots" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2018.03.031" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2018" "volumen" => "69" "paginaInicial" => "396" "paginaFinal" => "405" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29654817" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "[11]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M. Zhou" 1 => "R.M. Learned" 2 => "S.J. Rossi" 3 => "A.M. DePaoli" 4 => "H. Tian" 5 => "L. Ling" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.28257" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2016" "volumen" => "63" "paginaInicial" => "914" "paginaFinal" => "929" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26418580" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "[12]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M. Zhou" 1 => "R.M. Learned" 2 => "S.J. Rossi" 3 => "A.M. DePaoli" 4 => "H. Tian" 5 => "L. Ling" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep4.1108" "Revista" => array:6 [ "tituloSerie" => "Hepatol Commun" "fecha" => "2017" "volumen" => "1" "paginaInicial" => "1024" "paginaFinal" => "1042" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29404440" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "[13]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Suppression of hepatic bile acid synthesis by a non-tumorigenic FGF19 analogue protects mice from fibrosis and hepatocarcinogenesis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.M. Gadaleta" 1 => "N. Scialpi" 2 => "C. Peres" 3 => "M. Cariello" 4 => "B. Ko" 5 => "J. Luo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41598-018-35496-z" "Revista" => array:6 [ "tituloSerie" => "Sci Rep" "fecha" => "2018" "volumen" => "8" "paginaInicial" => "17210" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30464200" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S016781401933021X" "estado" => "S300" "issn" => "01678140" ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "[14]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Direct and indirect effects of fibroblast growth factor (FGF) 15 and FGF19 on liver fibrosis development" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.D. Schumacher" 1 => "B. Kong" 2 => "J. Wu" 3 => "D. Rizzolo" 4 => "L.E. Armstrong" 5 => "M.D. Chow" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.510240222" "Revista" => array:3 [ "tituloSerie" => "Hepatology" "fecha" => "2019" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8690415" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "[15]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.A. Harrison" 1 => "M.E. Rinella" 2 => "M.F. Abdelmalek" 3 => "J.F. Trotter" 4 => "A.H. Paredes" 5 => "H.L. Arnold" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(18)30474-4" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2018" "volumen" => "391" "paginaInicial" => "1174" "paginaFinal" => "1185" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29519502" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "[16]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G.M. Hirschfield" 1 => "O. Chazouilleres" 2 => "J.P. Drenth" 3 => "D. Thorburn" 4 => "S.A. Harrison" 5 => "C.S. Landis" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2018.10.035" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2019" "volumen" => "70" "paginaInicial" => "483" "paginaFinal" => "493" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30414864" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "[17]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Salvia miltiorrhiza: a potential red light to the development of cardiovascular diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Wang" 1 => "R. Ma" 2 => "C. Liu" 3 => "H. Liu" 4 => "R. Zhu" 5 => "S. Guo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2174/1381612822666161010105242" "Revista" => array:6 [ "tituloSerie" => "Curr Pharm Des" "fecha" => "2017" "volumen" => "23" "paginaInicial" => "1077" "paginaFinal" => "1097" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27748194" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "[18]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anti-fibrotic effect of PF2401-SF, a standardized fraction of Salvia miltiorrhiza, in thioacetamide-induced experimental rats liver fibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.R. Parajuli" 1 => "Y.Z. Zhao" 2 => "H. Jin" 3 => "J.H. Chi" 4 => "S.Y. Li" 5 => "Y.C. Kim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s12272-014-0425-2" "Revista" => array:6 [ "tituloSerie" => "Arch Pharm Res" "fecha" => "2015" "volumen" => "38" "paginaInicial" => "549" "paginaFinal" => "555" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25005065" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "[19]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Salvia miltiorrhiza ameliorates liver fibrosis by activating hepatic natural killer cells in vivo and in vitro" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Y. Peng" 1 => "T. Yang" 2 => "K. Huang" 3 => "L. Shen" 4 => "Y. Tao" 5 => "C. Liu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fphar.2018.00762" "Revista" => array:5 [ "tituloSerie" => "Front Pharmacol" "fecha" => "2018" "volumen" => "9" "paginaInicial" => "762" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30061833" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "[20]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Salvia miltiorrhiza reduces experimentally-induced hepatic fibrosis in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S. Wasser" 1 => "J.M. Ho" 2 => "H.K. Ang" 3 => "C.E. Tan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0168-8278(98)80257-2" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "1998" "volumen" => "29" "paginaInicial" => "760" "paginaFinal" => "771" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9833914" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "[21]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Salvianolic acid B exerts anti-liver fibrosis effects via inhibition of MAPK-mediated phospho-Smad2/3at linker regions in vivo and in vitro" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Wu" 1 => "W. Chen" 2 => "H. Ding" 3 => "D. Li" 4 => "G. Wen" 5 => "C. Zhang" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Life Sci" "fecha" => "2019" "volumen" => "239" ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "[22]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Salvianolic acid B inhibits activation of human primary hepatic stellate cells through downregulation of the myocyte enhancer factor 2 signaling pathway" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "W. Zhang" 1 => "J. Ping" 2 => "Y. Zhou" 3 => "G. Chen" 4 => "L. Xu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fphar.2019.00322" "Revista" => array:5 [ "tituloSerie" => "Front Pharmacol" "fecha" => "2019" "volumen" => "10" "paginaInicial" => "322" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31031620" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "[23]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Salvianolic acid B attenuates rat hepatic fibrosis via downregulating angiotensin II signaling" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Li" 1 => "L. Wang" 2 => "X. Yan" 3 => "Q. Wang" 4 => "Y. Tao" 5 => "J. Li" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1155/2012/293650" "Revista" => array:5 [ "tituloSerie" => "Evid Based Complement Alternat Med" "fecha" => "2012" "volumen" => "2012" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23320026" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0167814019301501" "estado" => "S300" "issn" => "01678140" ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "[24]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhibitory effects of salvianolic acid B on CCl(4)-induced hepatic fibrosis through regulating NF-kappaB/IkappaBalpha signaling" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "R. Wang" 1 => "X.Y. Yu" 2 => "Z.Y. Guo" 3 => "Y.J. Wang" 4 => "Y. Wu" 5 => "Y.F. Yuan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jep.2012.09.048" "Revista" => array:6 [ "tituloSerie" => "J Ethnopharmacol" "fecha" => "2012" "volumen" => "144" "paginaInicial" => "592" "paginaFinal" => "598" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23041223" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "[25]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Baicalin inhibits PDGF-BB-induced hepatic stellate cell proliferation, apoptosis, invasion, migration and activation via the miR-3595/ACSL4 axis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "X. Wu" 1 => "F. Zhi" 2 => "W. Lun" 3 => "Q. Deng" 4 => "W. Zhang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3892/ijmm.2018.3427" "Revista" => array:6 [ "tituloSerie" => "Int J Mol Med" "fecha" => "2018" "volumen" => "41" "paginaInicial" => "1992" "paginaFinal" => "2002" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29393361" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "[26]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Puerarin protects against CCl4-induced liver fibrosis in mice: possible role of PARP-1 inhibition" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Wang" 1 => "X.L. Shi" 2 => "M. Feng" 3 => "X. Wang" 4 => "Z.H. Zhang" 5 => "X. Zhao" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.intimp.2016.06.008" "Revista" => array:6 [ "tituloSerie" => "Int Immunopharmacol" "fecha" => "2016" "volumen" => "38" "paginaInicial" => "238" "paginaFinal" => "245" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27318789" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "[27]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Saikosaponin-d attenuates the development of liver fibrosis by preventing hepatocyte injury" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Fan" 1 => "X. Li" 2 => "P. Li" 3 => "N. Li" 4 => "T. Wang" 5 => "H. Shen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1139/O07-010" "Revista" => array:7 [ "tituloSerie" => "Biochem Cell Biol" "fecha" => "2007" "volumen" => "85" "paginaInicial" => "189" "paginaFinal" => "195" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17534399" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0167814019331184" "estado" => "S300" "issn" => "01678140" ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "[28]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cellular and molecular effects of Baccharis dracunculifolia D.C. and Plectranthus barbatus Andrews medicinal plant extracts on retinoid metabolism in the human hepatic stellate cell LX-2" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "C.M. da Silva" 1 => "F.H. Caetano" 2 => "F.D.C. Pereira" 3 => "M.A.M. Morales" 4 => "K.K. Sakane" 5 => "K.C.M. Moraes" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s12906-019-2591-8" "Revista" => array:5 [ "tituloSerie" => "BMC Complement Altern Med" "fecha" => "2019" "volumen" => "19" "paginaInicial" => "222" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31438947" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "[29]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "C. Degirolamo" 1 => "C. Sabba" 2 => "A. Moschetta" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrd.2015.9" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Drug Discov" "fecha" => "2016" "volumen" => "15" "paginaInicial" => "51" "paginaFinal" => "69" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26567701" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "[30]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. Inagaki" 1 => "M. Choi" 2 => "A. Moschetta" 3 => "L. Peng" 4 => "C.L. Cummins" 5 => "J.G. McDonald" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cmet.2005.09.001" "Revista" => array:7 [ "tituloSerie" => "Cell Metab" "fecha" => "2005" "volumen" => "2" "paginaInicial" => "217" "paginaFinal" => "225" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16213224" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0923753419375209" "estado" => "S300" "issn" => "09237534" ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "[31]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.A. Holt" 1 => "G. Luo" 2 => "A.N. Billin" 3 => "J. Bisi" 4 => "Y.Y. McNeill" 5 => "K.F. Kozarsky" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1101/gad.1083503" "Revista" => array:6 [ "tituloSerie" => "Genes Dev" "fecha" => "2003" "volumen" => "17" "paginaInicial" => "1581" "paginaFinal" => "1591" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12815072" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "[32]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "SREBP-2 negatively regulates FXR-dependent transcription of FGF19 in human intestinal cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. Miyata" 1 => "T. Hata" 2 => "Y. Yamazoe" 3 => "K. Yoshinari" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bbrc.2013.11.126" "Revista" => array:7 [ "tituloSerie" => "Biochem Biophys Res Commun" "fecha" => "2014" "volumen" => "443" "paginaInicial" => "477" "paginaFinal" => "482" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24321096" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0302283817304943" "estado" => "S300" "issn" => "03022838" ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "[33]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulation of bile acid synthesis by fat-soluble vitamins A and D" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "D.R. Schmidt" 1 => "S.R. Holmstrom" 2 => "K. Fon Tacer" 3 => "A.L. Bookout" 4 => "S.A. Kliewer" 5 => "D.J. 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Schuppan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2014.03.009" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2014" "volumen" => "61" "paginaInicial" => "166" "paginaFinal" => "168" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24780816" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "[37]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anti-fibrotic effects of a hot-water extract from Salvia miltiorrhiza roots on liver fibrosis induced by biliary obstruction in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J.X. Nan" 1 => "E.J. Park" 2 => "H.C. Kang" 3 => "P.H. Park" 4 => "J.Y. Kim" 5 => "D.H. Sohn" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1211/0022357011775406" "Revista" => array:6 [ "tituloSerie" => "J Pharm Pharmacol" "fecha" => "2001" "volumen" => "53" "paginaInicial" => "197" "paginaFinal" => "204" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11273016" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "[38]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multitargeted inhibition of hepatic fibrosis in chronic iron-overloaded mice by Salvia miltiorrhiza" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Zhang" 1 => "Y. Zhang" 2 => "Y. Xie" 3 => "Y. Gao" 4 => "J. Ma" 5 => "J. Yuan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jep.2013.05.028" "Revista" => array:6 [ "tituloSerie" => "J Ethnopharmacol" "fecha" => "2013" "volumen" => "148" "paginaInicial" => "671" "paginaFinal" => "681" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23707206" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "[39]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term administration of Salvia miltiorrhiza ameliorates carbon tetrachloride-induced hepatic fibrosis in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "T.Y. Lee" 1 => "G.J. Wang" 2 => "J.H. Chiu" 3 => "H.C. Lin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1211/0022357022098" "Revista" => array:6 [ "tituloSerie" => "J Pharm Pharmacol" "fecha" => "2003" "volumen" => "55" "paginaInicial" => "1561" "paginaFinal" => "1568" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14713368" "web" => "Medline" ] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0200" "etiqueta" => "[40]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Standardized Salvia miltiorrhiza extract suppresses hepatic stellate cell activation and attenuates steatohepatitis induced by a methionine-choline deficient diet in mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "H.S. Lee" 1 => "W.C. Son" 2 => "J.E. Ryu" 3 => "B.A. Koo" 4 => "Y.S. Kim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3390/molecules19068189" "Revista" => array:6 [ "tituloSerie" => "Molecules" "fecha" => "2014" "volumen" => "19" "paginaInicial" => "8189" "paginaFinal" => "8211" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24941342" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0205" "etiqueta" => "[41]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The anti-hepatic fibrosis effects of dihydrotanshinone I are mediated by disrupting the yes-associated protein and transcriptional enhancer factor D2 complex and stimulating autophagy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Ge" 1 => "H. Liu" 2 => "Y. Zhang" 3 => "N. Li" 4 => "S. Zhao" 5 => "W. Zhao" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/bph.13766" "Revista" => array:6 [ "tituloSerie" => "Br J Pharmacol" "fecha" => "2017" "volumen" => "174" "paginaInicial" => "1147" "paginaFinal" => "1160" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28257144" "web" => "Medline" ] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0210" "etiqueta" => "[42]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver inflammation and fibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Y. Koyama" 1 => "D.A. Brenner" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI88881" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "2017" "volumen" => "127" "paginaInicial" => "55" "paginaFinal" => "64" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28045404" "web" => "Medline" ] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0215" "etiqueta" => "[43]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Salvianolic acid B inhibits the TLR4-NFkappaB-TNFalpha pathway and attenuates neonatal rat cardiomyocyte injury induced by lipopolysaccharide" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "J. Wang" 1 => "Y. Zhang" 2 => "L.L. Guo" 3 => "G.J. Wu" 4 => "R.H. Liu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s11655-011-0877-x" "Revista" => array:6 [ "tituloSerie" => "Chin J Integr Med" "fecha" => "2011" "volumen" => "17" "paginaInicial" => "775" "paginaFinal" => "779" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22101700" "web" => "Medline" ] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0220" "etiqueta" => "[44]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Salvianolic acid B attenuates lipopolysaccharide-induced acute lung injury in rats through inhibition of apoptosis, oxidative stress and inflammation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "D.H. Zhao" 1 => "Y.J. Wu" 2 => "S.T. Liu" 3 => "R.Y. Liu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3892/etm.2017.4534" "Revista" => array:6 [ "tituloSerie" => "Exp Ther Med" "fecha" => "2017" "volumen" => "14" "paginaInicial" => "759" "paginaFinal" => "764" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28672996" "web" => "Medline" ] ] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0225" "etiqueta" => "[45]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Salvianolic acid B suppresses inflammatory mediator levels by downregulating NF-kappaB in a rat model of rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Z.B. Xia" 1 => "Y.J. Yuan" 2 => "Q.H. Zhang" 3 => "H. Li" 4 => "J.L. Dai" 5 => "J.K. Min" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.12659/msm.907084" "Revista" => array:6 [ "tituloSerie" => "Med Sci Monit" "fecha" => "2018" "volumen" => "24" "paginaInicial" => "2524" "paginaFinal" => "2532" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29691361" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/16652681/000000200000000C/v2_202101071056/S1665268120301745/v2_202101071056/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/16652681/000000200000000C/v2_202101071056/S1665268120301745/v2_202101071056/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268120301745?idApp=UINPBA00004N"]

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Shuxia Tiana,1, Min Chena,1, Bing Wangb, Yonglong Hanb, Haonan Shangb, Junming Chena,b,

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gzrktyx@163.com

Corresponding author:

a Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, China

b Shanghai Jiaotong University Affiliated Sixth People's Hospital, China

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    "titulo" => "Salvianolic acid B blocks hepatic stellate cell activation via FGF19&#47;FGFR4 signaling"
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        "autoresLista" => "Shuxia Tian, Min Chen, Bing Wang, Yonglong Han, Haonan Shang, Junming Chen"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Effects of several natural products on fibroblast growth factor &#40;FGF&#41; 19 secretion by LX-2 cells&#46; LX-2 cells were treated with different concentrations of &#40;A&#41; tanshione IIA&#44; &#40;B&#41; salvianolic acid B&#44; &#40;C&#41; baicalin&#44; &#40;D&#41; puerarin&#44; and &#40;E&#41; saikosaponin D as indicated&#46; Culture media were collected after 24&#8239;h&#44; and FGF19 level was measured by enzyme-linked immunosorbent assay&#46; Values represent mean&#8239;&#177;&#8239;standard deviation &#40;n&#8239;&#61;&#8239;5&#41;&#46; &#42;&#42;<span class="elsevierStyleItalic">P</span>&#8239;&#60;&#8239; 0&#46;01&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">P</span>&#8239;&#60;&#8239; 0&#46;001&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Liver fibrosis is characterized by excessive accumulation of extracellular matrix &#40;ECM&#41; in the liver in response to injuries&#46; Many factors including chronic viral infection&#44; alcohol abuse&#44; and nonalcoholic steatohepatitis &#40;NASH&#41; may cause liver fibrosis&#46; Activated hepatic stellate cells &#40;HSCs&#41; are considered the main source of ECM in fibrotic liver &#91;<a class="elsevierStyleCrossRef" href="#bib0005">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0010">2</a>&#93;&#46; Currently&#44; there are very limited options for the treatment of liver fibrosis&#46; Therefore&#44; exploring the mechanisms underlying HSC activation and identifying novel drugs that can prevent HSC activation are important for improving therapeutic efficiency among patients with chronic liver diseases&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The fibroblast growth factor &#40;FGF&#41; family is a large family of proteins that play crucial roles in development and metabolism&#46; Among 22 known FGFs&#44; the FGF19 subfamily members&#44; including FGF19&#44; FGF21&#44; and FGF23&#44; lack a heparin-binding domain&#59; therefore&#44; they cannot bind to heparin sulfate&#44; which allows them to easily enter circulation as endocrine hormones &#91;<a class="elsevierStyleCrossRef" href="#bib0015">3</a>&#93;&#46; FGF19 &#40;FGF15 in mouse&#41; is mainly produced in the intestine in response to bile acid &#40;BA&#41;&#46; The activation of farnesoid X receptor &#40;FXR&#41; by liver-derived BA strongly induces the secretion of FGF19&#44; which subsequently travels back to the liver through the portal vein and binds to the FGF receptor 4 &#40;FGFR4&#41;&#47;&#946;-Klotho complex on hepatocytes to reduce BA synthesis &#91;<a class="elsevierStyleCrossRef" href="#bib0020">4</a>&#93;&#46; The key enzymes required for BA synthesis such as Cyp7a1 and Cyp8b1 are the downstream targets of FGF19 in the liver &#91;<a class="elsevierStyleCrossRef" href="#bib0020">4</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0025">5</a>&#93;&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Some recent studies showed that serum FGF19 level was correlated with liver damage and cholestasis &#91;<a class="elsevierStyleCrossRefs" href="#bib0030">6&#8211;8</a>&#93;&#46; Moreover&#44; patients with decreased FGF19 level showed more severe hepatic inflammation and fibrosis &#91;<a class="elsevierStyleCrossRef" href="#bib0045">9</a>&#93;&#44; whereas a negative correlation was found between serum FGF19 level and fibrosis in patients with alcoholic hepatitis &#91;<a class="elsevierStyleCrossRef" href="#bib0050">10</a>&#93;&#46; The beneficial effect of FGF19 in liver fibrosis was further confirmed by several reports by examining direct FGF19 treatment in liver fibrosis animal models &#91;<a class="elsevierStyleCrossRefs" href="#bib0055">11&#8211;14</a>&#93;&#46; Importantly&#44; FGF19 analog treatment significantly improved liver fibrosis in patients with NASH and primary sclerosing cholangitis during phase II clinical trials &#91;<a class="elsevierStyleCrossRef" href="#bib0075">15</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0080">16</a>&#93;&#46; However&#44; whether FGF19 can be directly produced by HSCs in an autocrine manner and whether drugs that regulate its secretion can be used to treat liver fibrosis remain unknown&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The dried root of <span class="elsevierStyleItalic">Salvia miltiorrhiza</span> Bunge &#40;Lamiaceae&#41; has been used to treat various diseases in China for many years as a very commonly used traditional Chinese medicine &#40;TCM&#41; &#91;<a class="elsevierStyleCrossRef" href="#bib0085">17</a>&#93;&#46; <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">miltiorrhiza</span> has shown prominent antifibrotic effects in liver fibrosis models &#91;<a class="elsevierStyleCrossRefs" href="#bib0090">18&#8211;20</a>&#93;&#46; Several bioactive chemical components such as salvianolic acid B and tanshinone IIA have been isolated from <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">miltiorrhiza</span>&#46; Several previous studies explored the antifibrotic potential of these <span class="elsevierStyleItalic">S&#46; miltiorrhiza</span> derived bioactive chemical components including salvianolic acid B&#46; Smad2&#47;3&#44; NF-&#954;B and Angiotensin II signaling has been proposed to be the targets of these compounds &#91;<a class="elsevierStyleCrossRefs" href="#bib0105">21&#8211;24</a>&#93;&#46; However&#44; the antifibrotic effects of these compounds have not been fully elucidated&#46; In this study&#44; we tested the antifibrotic effects of bioactive compounds derived from <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">miltiorrhiza</span> in human HSC cell lines and examined the potential role of FGF19 in the beneficial effects of these compounds&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="sect0040">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0045">Cell culture and treatment</span><p id="par0025" class="elsevierStylePara elsevierViewall">LX-2 cells were obtained from the cell bank of the Chinese Academy of Science &#40;Shanghai&#44; China&#41; and were cultured in RPMI 1640 medium &#40;Hyclone&#44; Logan&#44; UT&#44; USA&#41; supplemented with 10&#37; fetal bovine serum &#40;Invitrogen&#44; Carlsbad&#44; CA&#44; USA&#41; and 1&#37; penicillin&#8211;streptomycin solution &#40;Solarbio&#44; Beijing&#44; China&#41;&#46; The cells were cultured in a humidified incubator with 5&#37; CO<span class="elsevierStyleInf">2</span> at 37&#8239;&#176;C&#46; The cells were treated with 100&#8239;ng&#47;mL lipopolysaccharide &#40;LPS&#44; from Sigma&#44; St&#46; Louis&#44; MO&#44; USA&#44; Cat&#46; No&#58; L2880&#41;&#44; salvianolic acid B&#44; tanshinone IIA&#44; baicalin&#44; puerarin&#44; and saikosaponin &#40;Aladdin&#44; Shanghai&#44; China&#41; at different concentrations for the indicated times shown in figures&#46; The same volume of DMSO was used as the vehicle control&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0050">Cell proliferation assay</span><p id="par0030" class="elsevierStylePara elsevierViewall">LX-2 cells &#40;1&#8239;&#215;&#8239;10<span class="elsevierStyleSup">4</span> cells&#47;well&#41; were seeded into 96-well plates and treated with salvianolic acid B&#44; tanshinone IIA&#44; baicalin&#44; puerarin&#44; and saikosaponin at 37&#8239;&#176;C for 72&#8239;h&#46; Cell proliferation was determined using the Cell Counting Kit-8 assay according to the manufacturer&#8217;s instructions &#40;SAB&#44; Nanjing&#44; China&#41;&#46; Optical density value was measured at a wavelength of 450&#8239;nm&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0055">RNA isolation and quantitative reverse transcription polymerase chain reaction &#40;RT-qPCR&#41;</span><p id="par0035" class="elsevierStylePara elsevierViewall">Total RNA from LX-2 cells was extracted using the TRIzol reagent &#40;Thermo Fisher Scientific&#44; Waltham&#44; MA&#44; USA&#41;&#46; Total RNA was reverse transcribed into cDNA&#44; using the RevertAid First Strand cDNA Synthesis Kit &#40;Thermo Fisher Scientific&#41;&#46; The SYBRGreen quantitative polymerase chain reaction &#40;qPCR&#41; master mix &#40;Thermo Fisher Scientific&#41; was used to quantify cDNA on the ABI 7300 real-time PCR system &#40;Applied Biosystem&#44; Foster City&#44; CA&#41; in a 20-&#181;l PCR reaction&#46; qPCR was performed using the following settings&#58; predenaturation at 95&#8239;&#176;C for 10&#8239;s&#44; denaturation at 95&#8239;&#176;C for 10&#8239;s&#44; and 40 elongation cycles at 60&#8239;&#176;C for 30&#8239;s&#46; The expression level of the housekeeping gene glyceraldehyde 3-phosphate dehydrogenase &#40;GAPDH&#41; was used to normalize results&#46; The 2<span class="elsevierStyleSup">&#8722;&#916;&#916;Ct</span> method was performed to calculate relative expression levels&#46; The PCR primer sequences used are listed below&#58;</p><p id="par0040" class="elsevierStylePara elsevierViewall">FGFR4</p><p id="par0045" class="elsevierStylePara elsevierViewall">Primer F 5&#8242;-CCCTCGAATAGGCACAGTTAC-3&#8242;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Primer R 5&#8242;-GCCTCCAATGCGGTTCTC-3&#8242;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Transforming growth factor-&#946; &#40;TGF-&#946;&#41;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Primer F 5&#8242;-CGTGGAGGGGAAATTGAGG-3&#8242;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Primer R 5&#8242;-GCCATGAGAAGCAGGAAAGG-3&#8242;</p><p id="par0070" class="elsevierStylePara elsevierViewall">&#945;-Smooth muscle actin &#40;&#945;-SMA&#41;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Primer F 5&#8242;-GACGAAGCACAGAGCAAAAG-3&#8242;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Primer R 5&#8242;-ACAGCACCGCCTGGATAG-3&#8242;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Collagen1a1 &#40;COL1A1&#41;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Primer F 5&#8242;-GAGGCATGTCTGGTTCGG-3&#8242;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Primer R 5&#8242;-TGGTAGGTGATGTTCTGGGAG-3&#8242;</p><p id="par0100" class="elsevierStylePara elsevierViewall">GAPDH</p><p id="par0105" class="elsevierStylePara elsevierViewall">Primer F 5&#8242;-AATCCCATCACCATCTTC-3&#8242;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Primer R 5&#8242;-AGGCTGTTGTCATACTTC-3&#8242;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0060">Hydroxyproline content measurement</span><p id="par0115" class="elsevierStylePara elsevierViewall">Hydroxyproline content was measured using a hydroxyproline assay kit &#40;Jiancheng&#44; Nanjing&#44; China&#41; according to the manufacturer&#8217;s instructions&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;5</span><span class="elsevierStyleSectionTitle" id="sect0065">Enzyme-linked immunosorbent assay &#40;ELISA&#41;</span><p id="par0120" class="elsevierStylePara elsevierViewall">FGF19 level in culture medium was measured using a human FGF19 ELISA kit &#40;Abcam&#44; Cambridge&#44; MA&#44; USA&#41; according to the manufacturer&#8217;s instructions&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;6</span><span class="elsevierStyleSectionTitle" id="sect0070">Western blotting</span><p id="par0125" class="elsevierStylePara elsevierViewall">Cells were lysed with RIPA buffer &#40;Beyotime&#44; Shanghai&#44; China&#41; on ice for 30&#8239;min&#46; Protein level was measured using a BCA protein assay kit &#40;Bio-Rad Laboratories&#44; Hercules&#44; CA&#44; USA&#41;&#46; A total of 20&#8239;&#181;g protein was applied to each lane and separated using 10 &#37; sodium dodecyl sulfate-polyacrylamide gel electrophoresis&#46; Then&#44; the separated proteins were transferred to polyvinylidene difluoride membranes&#46; The membranes were blocked with 5&#37; milk at room temperature for 1&#8239;h&#46; The membranes were incubated with primary antibodies diluted in 5&#37; milk at 4&#8239;&#176;C overnight&#46; The primary antibodies used in this study included the following&#58; &#945;-SMA &#40;Cell Signaling Technology&#44; Danvers&#44; MA&#44; USA&#41;&#44; COL1A1 &#40;Cell Signaling Technology&#41;&#44; TGF-&#946; &#40;Abcam&#41;&#44; FGFR4 &#40;Abcam&#41;&#44; FGF19 &#40;Abcam&#41;&#44; and GAPDH &#40;Proteintech&#44; Rosemont&#44; IL USA&#41;&#46; The membranes were incubated with horseradish peroxidase-conjugated secondary antibodies &#40;Beyotime&#41; at room temperature for 1&#8239;h&#46; Enhanced chemiluminescence chromogenic substrate &#40;Thermo Fisher Scientific&#41; was used to visualize protein bands&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;7</span><span class="elsevierStyleSectionTitle" id="sect0075">RNA interference</span><p id="par0130" class="elsevierStylePara elsevierViewall">Cells were transfected with 50&#8239;nM small interfering RNA &#40;siRNA&#41; targeting FGFR4 &#40;siFGFR4&#41; or negative control siRNA &#40;siNC&#41; using the Lipofectamine 2000 reagent &#40;Invitrogen&#41; according to the manufacturer&#8217;s instructions&#46; The siRNA sequences are listed below&#58;</p><p id="par0135" class="elsevierStylePara elsevierViewall">siFGFR4-1&#58; 5&#8242;-GCAGAAUCUCACCUUGAUUUU-3&#8242;</p><p id="par0140" class="elsevierStylePara elsevierViewall">siFGFR4-2&#58; 5&#8242;-CCAGGUAUACGGACAUCAUUU-3&#8242;</p><p id="par0145" class="elsevierStylePara elsevierViewall">siFGFR4-3&#58; 5&#8242;-GCGUCCACCACAUUGACUAUU-3&#8242;</p><p id="par0150" class="elsevierStylePara elsevierViewall">siNC&#58; 5&#8242;-CAGUACUUUUGUGUAGUACAA-3&#8242;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;8</span><span class="elsevierStyleSectionTitle" id="sect0080">Plasmid construction</span><p id="par0155" class="elsevierStylePara elsevierViewall">To overexpress FGFR4&#44; the full-length <span class="elsevierStyleItalic">Homo sapiens</span> FGFR4 coding sequence &#40;CDS&#41; was synthesized by GENEWIZ according to the guidelines of the National Center for Biotechnology Information database &#40;NM&#95;002011&#46;5&#41;&#46; FGFR4 CDS was cloned into the pcDNA3&#46;1 vector &#40;Addgene&#41;&#46; LX-2 cells were transfected with the construct using the Lipofectamine 2000 reagent &#40;Invitrogen&#41; according to the manufacturer&#8217;s instructions&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;9</span><span class="elsevierStyleSectionTitle" id="sect0085">Immunofluorescence</span><p id="par0160" class="elsevierStylePara elsevierViewall">LX-2 cells cultured on the coverslips were fixed with 1&#37; paraformaldehyde solution containing 0&#46;05&#37; of Triton X-100 for 5&#8239;min at room temperature&#46; Fixed cells were stained with phalloidin-TRITC solution at 100&#8239;&#956;g&#47;mL for 2&#8239;h at room temperature&#46; Nuclei were stained with 4&#8242;&#44;6-Diamidino-2-phenylindole dihydrochloride &#40;DAPI&#44; Beyotime Biotech&#46;&#41;&#46; The images were obtained using a BX51 OLYMPUS microscope&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;10</span><span class="elsevierStyleSectionTitle" id="sect0090">Statistical analysis</span><p id="par0165" class="elsevierStylePara elsevierViewall">Data are presented as mean&#8239;&#177;&#8239;standard deviation&#46; Statistical analyses were performed using Graphpad Prism &#40;San Diego&#44; CA&#41; for all experiments&#46; Data from multiple groups were compared with one-way ANOVA&#46; Differences between two groups were analyzed using Student&#8217;s <span class="elsevierStyleItalic">t</span>-test&#46; <span class="elsevierStyleItalic">P</span>-value of &#60;0&#46;05 was considered to indicate a statistically significant difference&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0100">Salvianolic acid B promotes FGF19 secretion by LX-2 cells</span><p id="par0170" class="elsevierStylePara elsevierViewall">We first tested whether HSCs can secrete FGF19 using the human HSC cell line LX-2&#46; Cells were cultured for 24&#8239;h&#44; and approximately 170 &#181;M FGF19 was detected in the culture medium &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#44; which indicated that HSCs can secrete FGF19 in an autocrine manner&#46; LX-2 cells were treated with two bioactive compounds derived from <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">miltiorrhiza</span>&#44; salvianolic acid B and tanshinone IIA&#46; Both compounds increased FGF19 secretion in a dose-dependent manner &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A and B&#41;&#46; In contrast&#44; several other antifibrotic natural products isolated from other TCM such as baicalin &#91;<a class="elsevierStyleCrossRef" href="#bib0125">25</a>&#93;&#44; puerarin &#91;<a class="elsevierStyleCrossRef" href="#bib0130">26</a>&#93;&#44; and saikosaponin D &#91;<a class="elsevierStyleCrossRef" href="#bib0135">27</a>&#93; had no effects on FGF19 secretion by LX-2 cells &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C&#8211;E&#41;&#46; Interestingly&#44; salvianolic acid B showed more potent effects on FGF19 secretion by LX-2 cells than the other tested compounds&#46; Therefore&#44; salvianolic acid B was selected for the following experiments&#46; To evaluated the potential cytotoxicity effects of salvianolic acid B on LX-2 cells&#44; we checked cell viability by using MTT assay&#46; As shown in Fig&#46; S1A&#44; 1&#46;0&#8211;5&#46;0&#8239;&#181;M did not show any cytotoxicity effects&#46; In addition&#44; LX-2 cells showed normal morphology with 1&#46;0&#8211;5&#46;0&#8239;&#181;M salvianolic acid B treatment &#40;Fig&#46; S1B&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0105">Salvianolic acid B inhibits LPS-induced activation and LX-2 cell proliferation</span><p id="par0175" class="elsevierStylePara elsevierViewall">We evaluated the effects of salvianolic acid B on LPS-induced HSC proliferation and activation&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#44; LX-2 proliferation significantly increased in the presence of LPS and the cotreatment with LPS and salvianolic acid B significantly blocked LPS-induced proliferation of LX-2 cells in a dose-dependent manner&#46; LPS also considerably increased the hydroxyproline content of LX-2 cells&#44; a marker of HSC activation&#46; Treatment with salvianolic acid B substantially reduced LPS-induced increase in hydroxyproline content in a dose-dependent manner &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#46; Consistently&#44; other markers for HSC activation&#44; such as &#945;-SMA and COL1A1 were reduced in both mRNA and protein levels with salvianolic acid B treatment &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46;2</a>C-D&#41;&#46; Previous study indicated that most of the actin F filaments were depolymerized in quiescent LX-2 cells while in activated LX2 cells&#44; actin F filaments were fully polymerized &#91;<a class="elsevierStyleCrossRef" href="#bib0140">28</a>&#93;&#46; So&#44; we checked actin F filaments by immunofluorescence&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>E&#44; LPS significantly increased polymerization of actin F filaments in LX-2 cells&#44; while much less polymerization of actin F filaments were observed in the presence of salvianolic acid B&#46; These data confirmed that salvianolic acid B can effectively block the activation and proliferation of LX-2 cells&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0110">Salvianolic acid B restored LPS-induced decrease in FGF19 and FGFR4 expression levels</span><p id="par0180" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#44; LX-2 cells can secrete FGF19&#59; therefore&#44; we explored whether LPS-induced HSC activation would affect FGF19 secretion&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A and B&#44; LPS treatment considerably reduced both FGF19 mRNA and protein levels&#46; Moreover&#44; the mRNA and protein levels of FGFR4&#44; the FGF19 receptor&#44; decreased in the presence of LPS&#46; These data suggested that FGF19&#47;FGFR4 signaling was greatly impaired during LX-2 activation&#46; When treated with different doses of salvianolic acid B&#44; LPS-induced decrease in mRNA and protein levels of both FGF19 and FGFR4 were partially or almost fully restored &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A and B&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0115">Antifibrotic effects of salvianolic acid B depend on FGF19&#47;FGFR4 signaling</span><p id="par0185" class="elsevierStylePara elsevierViewall">To determine whether the antifibrotic effects of salvianolic acid B were mediated by regulating FGF19&#47;FGFR4 signaling&#44; we used siRNA to knock down FGFR4 expression in LX-2 cells&#46; In addition&#44; FGF4R was overexpressed through the transfection of the pcDNA-FGF4R plasmid&#46; Both FGFR4 knockdown and overexpression were verified by examining its mRNA and protein levels in LX-2 cells &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A and B&#41;&#46; We tested the impact of FGFR4 knockdown on LPS-induced cell proliferation&#46; As expected&#44; salvianolic acid B inhibited LPS-induced LX-2 cell proliferation&#59; however&#44; this inhibitory effect was abolished by FGFR4 siRNA treatment &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>A&#41;&#46; Moreover&#44; FGFR4 overexpression considerably blocked LPS-induced cell proliferation &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>A&#41;&#46; Similar to the cell proliferation data&#44; FGFR4 siRNA treatment abolished the inhibitory effects of salvianolic acid B on HSC activation&#44; as assessed by measuring hydroxyproline level as well as mRNA and protein levels of several HSC activation markers such as TGF-&#946;&#44; &#945;-SMA&#44; and COL1A1 &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>B&#8211;D&#41;&#46; In contrast&#44; FGFR4 overexpression substantially blocked LPS-induced HSC activation &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>B&#8211;D&#41;&#46; These data strongly supported the critical role of FGF19&#47;FGFR4 signaling in LPS-induced HSC proliferation and activation&#46; We also demonstrated that the antifibrotic effects of salvianolic acid B are mediated by the regulation of FGF19&#47;FGFR4 signaling&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle" id="sect0120">Discussion</span><p id="par0190" class="elsevierStylePara elsevierViewall">In this study&#44; we found that FGF19 could be produced by HSCs and that FGFR4 was expressed in HSCs&#46; LPS treatment impaired FGF19&#47;FGFR4 signaling by downregulating both FGF19 and FGFR4 expressions&#46; Salvianolic acid B&#44; a bioactive compound isolated from the TCM <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">miltiorrhiza</span>&#44; showed a strong ability to enhance FGF19 secretion and to restore FGF19&#47;FGFR4 expression impaired by LPS treatment&#46; Finally&#44; we confirmed that the antifibrotic effects of salvianolic acid B were mediated by restoring FGF19&#47;FGFR4 signaling during LPS-induced HSC proliferation and activation&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">As a unique &#8220;hormone-like&#8221; FGF&#44; FGF19 has been reported to exert strong regulatory activity during energy metabolism and BA homeostasis &#91;<a class="elsevierStyleCrossRef" href="#bib0145">29</a>&#93;&#46; Enterocytes of the terminal ileum are considered a major source of FGF19 &#91;<a class="elsevierStyleCrossRef" href="#bib0150">30</a>&#93;&#46; In response to BA&#44; the nuclear receptor FXR is activated and translocated to the FXR-responsive element in the intron area of <span class="elsevierStyleItalic">FGF19</span> to initiate FGF19 transcription &#91;<a class="elsevierStyleCrossRef" href="#bib0155">31</a>&#93;&#46; Some other mechanisms are also involved in the regulation of FGF19 expression including sterol regulatory element-binding protein 2&#44; vitamin D receptor&#44; and retinoid X receptor &#91;<a class="elsevierStyleCrossRef" href="#bib0160">32</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0165">33</a>&#93;&#46; We found that FGF19 can also be secreted by HSCs &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#8211;E&#41;&#46; Interestingly&#44; LPS treatment significantly blocked FGF19 secretion by HSCs &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A&#8211;B&#41;&#46; A previous report showed that LPS might reduce FXR expression &#91;<a class="elsevierStyleCrossRef" href="#bib0170">34</a>&#93;&#44; which could explain why LPS treatment was associated with decreased FGF19 secretion&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">FGF19 binds to the FGFR4&#47;&#946;-Klotho complex&#44; with its major target being the liver &#91;<a class="elsevierStyleCrossRef" href="#bib0175">35</a>&#93;&#46; A recent report suggested that HSCs were also targeted by FGF19 &#91;<a class="elsevierStyleCrossRef" href="#bib0070">14</a>&#93;&#46; Our study confirmed that FGFR4 is expressed on HSCs &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A and B&#41;&#46; We also showed that enhanced FGF19&#47;FGFR4 signaling&#44; mediated by FGFR4 overexpression&#44; blocked HSC proliferation and activation &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A&#8211;D&#41;&#46; These data not only support the antifibrotic role of FGF19&#47;FGFR4 signaling proposed in previous reports &#91;<a class="elsevierStyleCrossRef" href="#bib0060">12</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0065">13</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0080">16</a>&#93; but also provide evidence for the direct role of FGF19 in HSC proliferation and activation&#44; which may prevent the development of liver fibrosis&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">TCM drugs have been used to treat liver fibrosis for many years&#44; and the efficacy of several TCM drugs has been tested for the treatment of chronic liver diseases associated with fibrosis or cirrhosis &#91;<a class="elsevierStyleCrossRef" href="#bib0180">36</a>&#93;&#46; Many TCM drugs for fibrotic liver disease contain <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">miltiorrhiza</span> as a major ingredient &#91;<a class="elsevierStyleCrossRef" href="#bib0180">36</a>&#93;&#46; The antifibrotic effects of <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">miltiorrhiza</span> have been well-documented in several mouse and rat liver fibrosis models induced by different factors including chemicals&#44; parasites&#44; and iron overload &#91;<a class="elsevierStyleCrossRefs" href="#bib0090">18&#8211;20</a>&#44;<a class="elsevierStyleCrossRefs" href="#bib0185">37&#8211;41</a>&#93;&#46; Several mechanisms have been proposed to explain the antifibrotic effects of <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">miltiorrhiza</span> and its extracts&#46; Treatment with <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">miltiorrhiza</span> possibly decreases the production of TGF-&#946;&#44; a potent activator of HSCs &#91;<a class="elsevierStyleCrossRef" href="#bib0100">20</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0200">40</a>&#93;&#46; <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">miltiorrhiza</span> can also alleviate oxidative stress in liver fibrosis models &#91;<a class="elsevierStyleCrossRef" href="#bib0195">39</a>&#93;&#46; Some other studies have attributed the beneficial effects of <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">miltiorrhiza</span> against liver fibrosis to the regulation of autophagy and nature killer cells &#91;<a class="elsevierStyleCrossRef" href="#bib0095">19</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0205">41</a>&#93;&#46; Here&#44; we identified a novel mechanism that can explain the antifibrotic effects of <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">miltiorrhiza</span>&#46; Both salvianolic acid B and tanshinone IIA&#44; two of the most important bioactive compounds derived from <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">miltiorrhiza</span>&#44; showed strong activity in promoting FGF19 secretion &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A and B&#41;&#46; We further tested the effects of salvianolic acid B&#44; which showed a better ability to promote FGF19 secretion than tanshinone IIA&#44; using an LPS-induced HSC proliferation and activation model&#46; Our result confirmed that the antifibrotic effects were mediated by FGF19&#47;FGFR4 signaling using FGFR4 siRNA &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A&#8211;D&#41;&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Chronic inflammation in the liver was considered as a major driving force for liver fibrosis&#46; Many inflammatory cells&#44; including Kupffer cells&#44; neutrophils and T cells as wells as cytokines derived from these cells&#44; such as TGF-&#946;&#44; IL-1 and TNF-&#945; were critical in supporting HSC activation and ECM production &#91;<a class="elsevierStyleCrossRef" href="#bib0210">42</a>&#93;&#46; Interestingly&#44; salvianolic acid B showed prominent anti-inflammatory effects in several LPS induced inflammatory organ damage models &#91;<a class="elsevierStyleCrossRefs" href="#bib0215">43&#8211;45</a>&#93;&#46; Although whether the anti-inflammatory effects of salvianolic acid B contribute to the regulation of FGF19&#47;FGFR4 signaling in HSCs <span class="elsevierStyleItalic">in vivo</span> is not clear&#44; the inhibition of inflammation will be helpful to prevent fibrogenesis and improve the resolution of liver fibrosis in chronic liver diseases&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">5</span><span class="elsevierStyleSectionTitle" id="sect0125">Conclusion</span><p id="par0215" class="elsevierStylePara elsevierViewall">Salvianolic acid B could promote FGF19 secretion by the HSC cell line LX-2&#46; The increased FGF19 expression and activation of FGF19&#47;FGFR4 signaling were necessary for salvianolic acid B-mediated decrease in LPS-induced LX-2 cell proliferation and activation&#46; Our study detailed a potential mechanism for the antifibrotic effects of <span class="elsevierStyleItalic">S</span>&#46; <span class="elsevierStyleItalic">miltiorrhiza</span>&#46;<span class="elsevierStyleDefList"><span class="elsevierStyleSectionTitle" id="sect0130">Abbreviations</span><span class="elsevierStyleDefTerm">ECM</span><span class="elsevierStyleDefDescription"><p id="par0220" class="elsevierStylePara elsevierViewall">extracellular matrix</p></span><span class="elsevierStyleDefTerm">NASH</span><span class="elsevierStyleDefDescription"><p id="par0225" class="elsevierStylePara elsevierViewall">nonalcoholic steatohepatitis</p></span><span class="elsevierStyleDefTerm">HSCs</span><span class="elsevierStyleDefDescription"><p id="par0230" class="elsevierStylePara elsevierViewall">hepatic stellate cells</p></span><span class="elsevierStyleDefTerm">FGF</span><span class="elsevierStyleDefDescription"><p id="par0235" class="elsevierStylePara elsevierViewall">Fibroblast growth factors</p></span><span class="elsevierStyleDefTerm">BA</span><span class="elsevierStyleDefDescription"><p id="par0240" class="elsevierStylePara elsevierViewall">bile acid</p></span><span class="elsevierStyleDefTerm">FXR</span><span class="elsevierStyleDefDescription"><p id="par0245" class="elsevierStylePara elsevierViewall">farnesoid X receptor</p></span><span class="elsevierStyleDefTerm">PSC</span><span class="elsevierStyleDefDescription"><p id="par0250" class="elsevierStylePara elsevierViewall">primary sclerosing cholangitis</p></span><span class="elsevierStyleDefTerm">TCM</span><span class="elsevierStyleDefDescription"><p id="par0255" class="elsevierStylePara elsevierViewall">Traditional Chinese Medicine</p></span><span class="elsevierStyleDefTerm">LPS</span><span class="elsevierStyleDefDescription"><p id="par0260" class="elsevierStylePara elsevierViewall">lipopolysaccharide</p></span><span class="elsevierStyleDefTerm">CCK-8</span><span class="elsevierStyleDefDescription"><p id="par0265" class="elsevierStylePara elsevierViewall">Cell Counting Kit-8</p></span><span class="elsevierStyleDefTerm">RT-qPCR</span><span class="elsevierStyleDefDescription"><p id="par0270" class="elsevierStylePara elsevierViewall">reverse transcription-quantitative polymerase chain reaction&#46;</p></span><span class="elsevierStyleDefTerm">CDS</span><span class="elsevierStyleDefDescription"><p id="par0275" class="elsevierStylePara elsevierViewall">coding sequence</p></span><span class="elsevierStyleDefTerm">SREBP2</span><span class="elsevierStyleDefDescription"><p id="par0280" class="elsevierStylePara elsevierViewall">sterol regulatory element-binding protein 2</p></span><span class="elsevierStyleDefTerm">VDR</span><span class="elsevierStyleDefDescription"><p id="par0285" class="elsevierStylePara elsevierViewall">vitamin D receptor</p></span><span class="elsevierStyleDefTerm">RXR</span><span class="elsevierStyleDefDescription"><p id="par0290" class="elsevierStylePara elsevierViewall">retinoid X receptor</p></span><span class="elsevierStyleDefTerm">NK</span><span class="elsevierStyleDefDescription"><p id="par0295" class="elsevierStylePara elsevierViewall">nature killer</p></span></span></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Financial support</span><p id="par0300" class="elsevierStylePara elsevierViewall">This study was supported by grants from <span class="elsevierStyleGrantSponsor" id="gs0005">National Natural Science Foundation of China</span> &#91;<span class="elsevierStyleGrantNumber" refid="gs0005">81774061</span>&#93;&#44; the key subjects construction in the health system of <span class="elsevierStyleGrantSponsor" id="gs0010">Pudong New Area</span> &#91;<span class="elsevierStyleGrantNumber" refid="gs0010">PWZxk2017-02</span>&#93;&#44; <span class="elsevierStyleGrantSponsor" id="gs0015">Traditional Chinese Medicine Heritage and Science and Technology</span> Innovation Project of Shanghai &#91;<span class="elsevierStyleGrantNumber" refid="gs0015">ZYKC2019035</span>&#93; and Special Project of Integrated <span class="elsevierStyleGrantSponsor" id="gs0020">Traditional Chinese and Western Medicine of Shanghai</span> &#91;<span class="elsevierStyleGrantNumber" refid="gs0020">ZHYY-ZXYJHZX-201910</span>&#93;&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflict of interest</span><p id="par0305" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Materials and methods"
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              "titulo" => "Cell culture and treatment"
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              "identificador" => "sec0020"
              "titulo" => "Cell proliferation assay"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "RNA isolation and quantitative reverse transcription polymerase chain reaction &#40;RT-qPCR&#41;"
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              "identificador" => "sec0030"
              "titulo" => "Hydroxyproline content measurement"
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              "titulo" => "Enzyme-linked immunosorbent assay &#40;ELISA&#41;"
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              "titulo" => "Western blotting"
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              "titulo" => "RNA interference"
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              "identificador" => "sec0050"
              "titulo" => "Plasmid construction"
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              "titulo" => "Immunofluorescence"
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          "titulo" => "Results"
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              "titulo" => "Salvianolic acid B promotes FGF19 secretion by LX-2 cells"
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              "titulo" => "Salvianolic acid B inhibits LPS-induced activation and LX-2 cell proliferation"
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              "identificador" => "sec0080"
              "titulo" => "Salvianolic acid B restored LPS-induced decrease in FGF19 and FGFR4 expression levels"
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              "titulo" => "Antifibrotic effects of salvianolic acid B depend on FGF19&#47;FGFR4 signaling"
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          "titulo" => "Discussion"
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    "fechaRecibido" => "2020-04-07"
    "fechaAceptado" => "2020-07-27"
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            0 => "Salvianolic acid B"
            1 => "Lipopolysaccharide"
            2 => "Fibroblast growth 19"
            3 => "Hepatic stellate cell"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objectives</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">The activation of hepatic stellate cells &#40;HSCs&#41; is the main cause of liver fibrosis&#46; The beneficial effects of fibroblast growth factor &#40;FGF&#41; 19 on liver fibrosis were recently reported&#46; The <span class="elsevierStyleItalic">S&#46; miltiorrhiza</span> as well as <span class="elsevierStyleItalic">S&#46; miltiorrhiza</span> derived bioactive chemical components has shown prominent antifibrotic effects in liver fibrosis but the mechanism is still not fully understood&#46; We aimed to investigate the bioactive compounds derived from <span class="elsevierStyleItalic">S&#46;</span> miltiorrhiza which exerts antifibrotic effects in HSCs via regulating FGF19&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">FGF19 level in culture media was determined by enzyme-linked immunosorbent assay&#46; Cell proliferation was measured by Cell Counting Kit-8 assay&#46; Further&#44; mRNA and protein expressions were assessed by quantitative polymerase chain reaction and western blotting&#44; respectively&#46; Knocking down of FGF receptor 4 &#40;FGFR4&#41; by transfection with siRNA was used to confirm the role of FGF19&#47;FGFR4 signaling&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Using the human HSC cell line LX-2&#44; we screened several natural products and found that bioactive compounds isolated from <span class="elsevierStyleItalic">Salvia miltiorrhiza</span>&#44; particularly salvianolic acid B&#44; strongly upregulated FGF19 secretion by LX-2 cells&#46; We further showed that salvianolic acid B inhibited lipopolysaccharide &#40;LPS&#41;-induced HSC proliferation and activation&#46; LPS treatment may also reduce the mRNA and protein levels of FGF19 and its receptor FGFR4&#46; Salvianolic acid B treatment restored the impaired expressions of FGF19 and FGFR4&#46; Finally&#44; FGFR4 knockdown abolished the antifibrotic effects of salvianolic acid B in the LPS-induced HSC activation model&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Salvianolic acid B prevented LPS-induced HSC proliferation and activation by enhancing antifibrotic FGF19&#47;FGFR4 signaling&#46;</p></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Effects of several natural products on fibroblast growth factor &#40;FGF&#41; 19 secretion by LX-2 cells&#46; LX-2 cells were treated with different concentrations of &#40;A&#41; tanshione IIA&#44; &#40;B&#41; salvianolic acid B&#44; &#40;C&#41; baicalin&#44; &#40;D&#41; puerarin&#44; and &#40;E&#41; saikosaponin D as indicated&#46; Culture media were collected after 24&#8239;h&#44; and FGF19 level was measured by enzyme-linked immunosorbent assay&#46; Values represent mean&#8239;&#177;&#8239;standard deviation &#40;n&#8239;&#61;&#8239;5&#41;&#46; &#42;&#42;<span class="elsevierStyleItalic">P</span>&#8239;&#60;&#8239; 0&#46;01&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">P</span>&#8239;&#60;&#8239; 0&#46;001&#46;</p>"
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                      "titulo" => "Liver fibrosis"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46; Bataller"
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                      "doi" => "10.1172/JCI24282"
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                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "2005"
                        "volumen" => "115"
                        "paginaInicial" => "209"
                        "paginaFinal" => "218"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15690074"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pathogenesis of liver fibrosis"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "V&#46; Hernandez-Gea"
                            1 => "S&#46;L&#46; Friedman"
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                    0 => array:2 [
                      "doi" => "10.1146/annurev-pathol-011110-130246"
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                        "tituloSerie" => "Annu Rev Pathol"
                        "fecha" => "2011"
                        "volumen" => "6"
                        "paginaInicial" => "425"
                        "paginaFinal" => "456"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21073339"
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                            3 => "M&#46; Slawinski"
                            4 => "B&#46; Dolegowska"
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                      ]
                    ]
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                        "tituloSerie" => "J Physiol Biochem"
                        "fecha" => "2019"
                        "volumen" => "75"
                        "paginaInicial" => "229"
                        "paginaFinal" => "240"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30927227"
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                            4 => "J&#46;Y&#46; Chiang"
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                      "titulo" => "Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
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                            2 => "S&#46;J&#46; Rossi"
                            3 => "A&#46;M&#46; DePaoli"
                            4 => "H&#46; Tian"
                            5 => "L&#46; Ling"
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                    0 => array:2 [
                      "doi" => "10.1002/hep4.1108"
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                        "tituloSerie" => "Hepatol Commun"
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                        "volumen" => "1"
                        "paginaInicial" => "1024"
                        "paginaFinal" => "1042"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29404440"
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                    0 => array:2 [
                      "titulo" => "Suppression of hepatic bile acid synthesis by a non-tumorigenic FGF19 analogue protects mice from fibrosis and hepatocarcinogenesis"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;M&#46; Gadaleta"
                            1 => "N&#46; Scialpi"
                            2 => "C&#46; Peres"
                            3 => "M&#46; Cariello"
                            4 => "B&#46; Ko"
                            5 => "J&#46; Luo"
                          ]
                        ]
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                    0 => array:2 [
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                        "tituloSerie" => "Sci Rep"
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                        "volumen" => "8"
                        "paginaInicial" => "17210"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30464200"
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                          "issn" => "01678140"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Direct and indirect effects of fibroblast growth factor &#40;FGF&#41; 15 and FGF19 on liver fibrosis development"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "B&#46; Kong"
                            2 => "J&#46; Wu"
                            3 => "D&#46; Rizzolo"
                            4 => "L&#46;E&#46; Armstrong"
                            5 => "M&#46;D&#46; Chow"
                          ]
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                    ]
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                    0 => array:2 [
                      "doi" => "10.1002/hep.510240222"
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                        "tituloSerie" => "Hepatology"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8690415"
                            "web" => "Medline"
                          ]
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              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
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                        0 => array:2 [
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                          "autores" => array:6 [
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                            1 => "M&#46;E&#46; Rinella"
                            2 => "M&#46;F&#46; Abdelmalek"
                            3 => "J&#46;F&#46; Trotter"
                            4 => "A&#46;H&#46; Paredes"
                            5 => "H&#46;L&#46; Arnold"
                          ]
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                      ]
                    ]
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                        "paginaInicial" => "1174"
                        "paginaFinal" => "1185"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29519502"
                            "web" => "Medline"
                          ]
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              ]
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                  "contribucion" => array:1 [
                    0 => array:2 [
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                          "autores" => array:6 [
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                            1 => "O&#46; Chazouilleres"
                            2 => "J&#46;P&#46; Drenth"
                            3 => "D&#46; Thorburn"
                            4 => "S&#46;A&#46; Harrison"
                            5 => "C&#46;S&#46; Landis"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2018.10.035"
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                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2019"
                        "volumen" => "70"
                        "paginaInicial" => "483"
                        "paginaFinal" => "493"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30414864"
                            "web" => "Medline"
                          ]
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                      ]
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              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "<span class="elsevierStyleItalic">Salvia miltiorrhiza</span>&#58; a potential red light to the development of cardiovascular diseases"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "R&#46; Ma"
                            2 => "C&#46; Liu"
                            3 => "H&#46; Liu"
                            4 => "R&#46; Zhu"
                            5 => "S&#46; Guo"
                          ]
                        ]
                      ]
                    ]
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                        "tituloSerie" => "Curr Pharm Des"
                        "fecha" => "2017"
                        "volumen" => "23"
                        "paginaInicial" => "1077"
                        "paginaFinal" => "1097"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27748194"
                            "web" => "Medline"
                          ]
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                    0 => array:2 [
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                      "autores" => array:1 [
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                          "etal" => true
                          "autores" => array:6 [
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                            1 => "Y&#46;Z&#46; Zhao"
                            2 => "H&#46; Jin"
                            3 => "J&#46;H&#46; Chi"
                            4 => "S&#46;Y&#46; Li"
                            5 => "Y&#46;C&#46; Kim"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s12272-014-0425-2"
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                        "tituloSerie" => "Arch Pharm Res"
                        "fecha" => "2015"
                        "volumen" => "38"
                        "paginaInicial" => "549"
                        "paginaFinal" => "555"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25005065"
                            "web" => "Medline"
                          ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
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                          "etal" => false
                          "autores" => array:6 [
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                            1 => "T&#46; Yang"
                            2 => "K&#46; Huang"
                            3 => "L&#46; Shen"
                            4 => "Y&#46; Tao"
                            5 => "C&#46; Liu"
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                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Front Pharmacol"
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                        "volumen" => "9"
                        "paginaInicial" => "762"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30061833"
                            "web" => "Medline"
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                          "etal" => false
                          "autores" => array:4 [
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                            2 => "H&#46;K&#46; Ang"
                            3 => "C&#46;E&#46; Tan"
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                        "tituloSerie" => "J Hepatol"
                        "fecha" => "1998"
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                        "paginaInicial" => "760"
                        "paginaFinal" => "771"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9833914"
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                            3 => "D&#46; Li"
                            4 => "G&#46; Wen"
                            5 => "C&#46; Zhang"
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                      ]
                    ]
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                        "tituloSerie" => "Life Sci"
                        "fecha" => "2019"
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              ]
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            21 => array:3 [
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                          "autores" => array:5 [
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                            "web" => "Medline"
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                            4 => "Y&#46; Tao"
                            5 => "J&#46; Li"
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                        "tituloSerie" => "Evid Based Complement Alternat Med"
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                        "volumen" => "2012"
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                        "paginaFinal" => "598"
                        "link" => array:1 [
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                            2 => "W&#46; Lun"
                            3 => "Q&#46; Deng"
                            4 => "W&#46; Zhang"
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                        ]
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                    ]
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                        "tituloSerie" => "Int J Mol Med"
                        "fecha" => "2018"
                        "volumen" => "41"
                        "paginaInicial" => "1992"
                        "paginaFinal" => "2002"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29393361"
                            "web" => "Medline"
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                0 => array:2 [
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                    0 => array:2 [
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                          "etal" => true
                          "autores" => array:6 [
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                            1 => "X&#46;L&#46; Shi"
                            2 => "M&#46; Feng"
                            3 => "X&#46; Wang"
                            4 => "Z&#46;H&#46; Zhang"
                            5 => "X&#46; Zhao"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Int Immunopharmacol"
                        "fecha" => "2016"
                        "volumen" => "38"
                        "paginaInicial" => "238"
                        "paginaFinal" => "245"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27318789"
                            "web" => "Medline"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Saikosaponin-d attenuates the development of liver fibrosis by preventing hepatocyte injury"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "X&#46; Li"
                            2 => "P&#46; Li"
                            3 => "N&#46; Li"
                            4 => "T&#46; Wang"
                            5 => "H&#46; Shen"
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                        ]
                      ]
                    ]
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                        "paginaInicial" => "189"
                        "paginaFinal" => "195"
                        "link" => array:1 [
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                            3 => "M&#46;A&#46;M&#46; Morales"
                            4 => "K&#46;K&#46; Sakane"
                            5 => "K&#46;C&#46;M&#46; Moraes"
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                        ]
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                    ]
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                  "host" => array:1 [
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                      "doi" => "10.1186/s12906-019-2591-8"
                      "Revista" => array:5 [
                        "tituloSerie" => "BMC Complement Altern Med"
                        "fecha" => "2019"
                        "volumen" => "19"
                        "paginaInicial" => "222"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31438947"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
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                ]
              ]
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            28 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "&#91;29&#93;"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Therapeutic potential of the endocrine fibroblast growth factors FGF19&#44; FGF21 and FGF23"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "C&#46; Degirolamo"
                            1 => "C&#46; Sabba"
                            2 => "A&#46; Moschetta"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nrd.2015.9"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Drug Discov"
                        "fecha" => "2016"
                        "volumen" => "15"
                        "paginaInicial" => "51"
                        "paginaFinal" => "69"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26567701"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            29 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "&#91;30&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Inagaki"
                            1 => "M&#46; Choi"
                            2 => "A&#46; Moschetta"
                            3 => "L&#46; Peng"
                            4 => "C&#46;L&#46; Cummins"
                            5 => "J&#46;G&#46; McDonald"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.cmet.2005.09.001"
                      "Revista" => array:7 [
                        "tituloSerie" => "Cell Metab"
                        "fecha" => "2005"
                        "volumen" => "2"
                        "paginaInicial" => "217"
                        "paginaFinal" => "225"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16213224"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0923753419375209"
                          "estado" => "S300"
                          "issn" => "09237534"
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                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "&#91;31&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;A&#46; Holt"
                            1 => "G&#46; Luo"
                            2 => "A&#46;N&#46; Billin"
                            3 => "J&#46; Bisi"
                            4 => "Y&#46;Y&#46; McNeill"
                            5 => "K&#46;F&#46; Kozarsky"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1101/gad.1083503"
                      "Revista" => array:6 [
                        "tituloSerie" => "Genes Dev"
                        "fecha" => "2003"
                        "volumen" => "17"
                        "paginaInicial" => "1581"
                        "paginaFinal" => "1591"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12815072"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "&#91;32&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "SREBP-2 negatively regulates FXR-dependent transcription of FGF19 in human intestinal cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46; Miyata"
                            1 => "T&#46; Hata"
                            2 => "Y&#46; Yamazoe"
                            3 => "K&#46; Yoshinari"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bbrc.2013.11.126"
                      "Revista" => array:7 [
                        "tituloSerie" => "Biochem Biophys Res Commun"
                        "fecha" => "2014"
                        "volumen" => "443"
                        "paginaInicial" => "477"
                        "paginaFinal" => "482"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24321096"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0302283817304943"
                          "estado" => "S300"
                          "issn" => "03022838"
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                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "&#91;33&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Regulation of bile acid synthesis by fat-soluble vitamins A and D"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "D&#46;R&#46; Schmidt"
                            1 => "S&#46;R&#46; Holmstrom"
                            2 => "K&#46; Fon Tacer"
                            3 => "A&#46;L&#46; Bookout"
                            4 => "S&#46;A&#46; Kliewer"
                            5 => "D&#46;J&#46; Mangelsdorf"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1074/jbc.M110.116004"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Biol Chem"
                        "fecha" => "2010"
                        "volumen" => "285"
                        "paginaInicial" => "14486"
                        "paginaFinal" => "14494"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20233723"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            33 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "&#91;34&#93;"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Farnesoid X receptor agonist GW4064 ameliorates lipopolysaccharide-induced ileocolitis through TLR4&#47;MyD88 pathway related mitochondrial dysfunction in mice"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46;M&#46; Liu"
                            1 => "J&#46;F&#46; Liao"
                            2 => "T&#46;Y&#46; Lee"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bbrc.2017.06.129"
                      "Revista" => array:6 [
                        "tituloSerie" => "Biochem Biophys Res Commun"
                        "fecha" => "2017"
                        "volumen" => "490"
                        "paginaInicial" => "841"
                        "paginaFinal" => "848"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28647362"
                            "web" => "Medline"
                          ]
                        ]
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                    ]
                  ]
                ]
              ]
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            34 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "&#91;35&#93;"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver-specific activities of FGF19 require Klotho beta"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "B&#46;C&#46; Lin"
                            1 => "M&#46; Wang"
                            2 => "C&#46; Blackmore"
                            3 => "L&#46;R&#46; Desnoyers"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1074/jbc.M704244200"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Biol Chem"
                        "fecha" => "2007"
                        "volumen" => "282"
                        "paginaInicial" => "27277"
                        "paginaFinal" => "27284"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17627937"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            35 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "&#91;36&#93;"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Traditional Chinese Medicine &#40;TCM&#41; for fibrotic liver disease&#58; hope and hype"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "L&#46; Zhang"
                            1 => "D&#46; Schuppan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2014.03.009"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2014"
                        "volumen" => "61"
                        "paginaInicial" => "166"
                        "paginaFinal" => "168"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24780816"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
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                ]
              ]
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              "identificador" => "bib0185"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anti-fibrotic effects of a hot-water extract from <span class="elsevierStyleItalic">Salvia miltiorrhiza</span> roots on liver fibrosis induced by biliary obstruction in rats"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "J&#46;X&#46; Nan"
                            1 => "E&#46;J&#46; Park"
                            2 => "H&#46;C&#46; Kang"
                            3 => "P&#46;H&#46; Park"
                            4 => "J&#46;Y&#46; Kim"
                            5 => "D&#46;H&#46; Sohn"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1211/0022357011775406"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pharm Pharmacol"
                        "fecha" => "2001"
                        "volumen" => "53"
                        "paginaInicial" => "197"
                        "paginaFinal" => "204"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11273016"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            37 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "&#91;38&#93;"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multitargeted inhibition of hepatic fibrosis in chronic iron-overloaded mice by <span class="elsevierStyleItalic">Salvia miltiorrhiza</span>"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "Y&#46; Zhang"
                            2 => "Y&#46; Xie"
                            3 => "Y&#46; Gao"
                            4 => "J&#46; Ma"
                            5 => "J&#46; Yuan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jep.2013.05.028"
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                        "tituloSerie" => "J Ethnopharmacol"
                        "fecha" => "2013"
                        "volumen" => "148"
                        "paginaInicial" => "671"
                        "paginaFinal" => "681"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23707206"
                            "web" => "Medline"
                          ]
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                      ]
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                ]
              ]
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            38 => array:3 [
              "identificador" => "bib0195"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Long-term administration of <span class="elsevierStyleItalic">Salvia miltiorrhiza</span> ameliorates carbon tetrachloride-induced hepatic fibrosis in rats"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
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                            1 => "G&#46;J&#46; Wang"
                            2 => "J&#46;H&#46; Chiu"
                            3 => "H&#46;C&#46; Lin"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1211/0022357022098"
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                        "tituloSerie" => "J Pharm Pharmacol"
                        "fecha" => "2003"
                        "volumen" => "55"
                        "paginaInicial" => "1561"
                        "paginaFinal" => "1568"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14713368"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0200"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Standardized <span class="elsevierStyleItalic">Salvia miltiorrhiza</span> extract suppresses hepatic stellate cell activation and attenuates steatohepatitis induced by a methionine-choline deficient diet in mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "H&#46;S&#46; Lee"
                            1 => "W&#46;C&#46; Son"
                            2 => "J&#46;E&#46; Ryu"
                            3 => "B&#46;A&#46; Koo"
                            4 => "Y&#46;S&#46; Kim"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/molecules19068189"
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                        "tituloSerie" => "Molecules"
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                        "volumen" => "19"
                        "paginaInicial" => "8189"
                        "paginaFinal" => "8211"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24941342"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0205"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The anti-hepatic fibrosis effects of dihydrotanshinone I are mediated by disrupting the yes-associated protein and transcriptional enhancer factor D2 complex and stimulating autophagy"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "H&#46; Liu"
                            2 => "Y&#46; Zhang"
                            3 => "N&#46; Li"
                            4 => "S&#46; Zhao"
                            5 => "W&#46; Zhao"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/bph.13766"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Pharmacol"
                        "fecha" => "2017"
                        "volumen" => "174"
                        "paginaInicial" => "1147"
                        "paginaFinal" => "1160"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28257144"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            41 => array:3 [
              "identificador" => "bib0210"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver inflammation and fibrosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Y&#46; Koyama"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI88881"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "2017"
                        "volumen" => "127"
                        "paginaInicial" => "55"
                        "paginaFinal" => "64"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28045404"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            42 => array:3 [
              "identificador" => "bib0215"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Salvianolic acid B inhibits the TLR4-NFkappaB-TNFalpha pathway and attenuates neonatal rat cardiomyocyte injury induced by lipopolysaccharide"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
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                            1 => "Y&#46; Zhang"
                            2 => "L&#46;L&#46; Guo"
                            3 => "G&#46;J&#46; Wu"
                            4 => "R&#46;H&#46; Liu"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s11655-011-0877-x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Chin J Integr Med"
                        "fecha" => "2011"
                        "volumen" => "17"
                        "paginaInicial" => "775"
                        "paginaFinal" => "779"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22101700"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
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                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib0220"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Salvianolic acid B attenuates lipopolysaccharide-induced acute lung injury in rats through inhibition of apoptosis&#44; oxidative stress and inflammation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
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                            1 => "Y&#46;J&#46; Wu"
                            2 => "S&#46;T&#46; Liu"
                            3 => "R&#46;Y&#46; Liu"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3892/etm.2017.4534"
                      "Revista" => array:6 [
                        "tituloSerie" => "Exp Ther Med"
                        "fecha" => "2017"
                        "volumen" => "14"
                        "paginaInicial" => "759"
                        "paginaFinal" => "764"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28672996"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "&#91;45&#93;"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Salvianolic acid B suppresses inflammatory mediator levels by downregulating NF-kappaB in a rat model of rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Z&#46;B&#46; Xia"
                            1 => "Y&#46;J&#46; Yuan"
                            2 => "Q&#46;H&#46; Zhang"
                            3 => "H&#46; Li"
                            4 => "J&#46;L&#46; Dai"
                            5 => "J&#46;K&#46; Min"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.12659/msm.907084"
                      "Revista" => array:6 [
                        "tituloSerie" => "Med Sci Monit"
                        "fecha" => "2018"
                        "volumen" => "24"
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Article information

ISSN: 16652681
Original language: English

DOI:10.1016/j.aohep.2020.07.013

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	7	1	8
2024 October	50	6	56
2024 September	50	8	58
2024 August	35	8	43
2024 July	36	7	43
2024 June	43	4	47
2024 May	47	5	52
2024 April	52	11	63
2024 March	43	7	50
2024 February	49	7	56
2024 January	33	5	38
2023 December	79	7	86
2023 November	50	7	57
2023 October	68	16	84
2023 September	30	6	36
2023 August	35	9	44
2023 July	52	5	57
2023 June	43	1	44
2023 May	80	18	98
2023 April	51	1	52
2023 March	33	6	39
2023 February	38	2	40
2023 January	38	7	45
2022 December	46	10	56
2022 November	66	17	83
2022 October	43	11	54
2022 September	50	10	60
2022 August	27	13	40
2022 July	27	14	41
2022 June	17	11	28
2022 May	29	13	42
2022 April	38	10	48
2022 March	39	8	47
2022 February	29	6	35
2022 January	46	6	52
2021 December	29	17	46
2021 November	21	5	26
2021 October	18	15	33
2021 September	18	12	30
2021 August	10	3	13
2021 July	10	8	18
2021 June	20	8	28
2021 May	33	6	39
2021 April	84	16	100
2021 March	21	8	29
2021 February	16	9	25
2021 January	12	3	15
2020 December	6	9	15
2020 November	5	3	8
2020 October	0	2	2

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