VX-765 inhibits pyroptosis and reduces inflammation to prevent acute liver failure by upregulating PPARα expression

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=> "Xin" "apellidos" => "Zhao" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0003" ] ] ] 4 => array:3 [ "nombre" => "Yanjun" "apellidos" => "Qin" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0004" ] ] ] 5 => array:3 [ "nombre" => "Chunhuan" "apellidos" => "Zhang" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "aff0005" ] ] ] 6 => array:3 [ "nombre" => "Hongzhu" "apellidos" => "Yin" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] ] ] 7 => array:4 [ "nombre" => "Caiyan" "apellidos" => "Zhao" "email" => array:1 [ 0 => "zhaocy_2005@163.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0001" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, China" "etiqueta" => "a" "identificador" => "aff0001" ] 1 => array:3 [ "entidad" => "Department of Immunology, Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Hebei Medical University, Shijiazhuang, China" "etiqueta" => "b" "identificador" => "aff0002" ] 2 => array:3 [ "entidad" => "Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China" "etiqueta" => "c" "identificador" => "aff0003" ] 3 => array:3 [ "entidad" => "Department of Emergency, The Third Hospital of Hebei Medical University, Shijiazhuang, China" "etiqueta" => "d" "identificador" => "aff0004" ] 4 => array:3 [ "entidad" => "Department of Scientific Research, The Third Hospital of Hebei Medical University, Shijiazhuang, China" "etiqueta" => "e" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0001" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2547 "Ancho" => 3500 "Tamanyo" => 664810 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0001" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Proinflammatory cytokines and pyroptosis-related protein had higher expression levels as ALF progressed. (A) The gross morphology and HE staining of livers in each group. (B-C) Serum transaminase levels in each group (n=8). (D-F) Gene expressions of IL-1β, IL-18 and caspase-1 were detected by qRT-PCR in each group (n=8). (G) Related proteins were detected by western blotting in the four groups of mice. Representative western blots of two samples from each group were displayed." ] ] ] "textoCompleto" => "1IntroductionAcute liver failure (ALF) is a clinical syndrome characterized by serious inflammatory-mediated hepatocellular injury with high mortality. Liver inflammation heavily affects ALF pathogenesis, and no effective treatment is available except for liver transplantation [<a class="elsevierStyleCrossRef" href="#bib0001">1</a>,<a class="elsevierStyleCrossRef" href="#bib0002">2</a>]. Studies have shown that systemic inflammatory responses are of vital importance in the outcome of ALF. Hepatocyte death in ALF is a result of the activation of systemic inflammatory responses generated by uncontrolled immune-mediated liver injury [<a class="elsevierStyleCrossRef" href="#bib0003">3</a>,<a class="elsevierStyleCrossRef" href="#bib0004">4</a>]. Although great progress has been made in ALF etiology and pathogenesis for the past few years, ALF is a serious and complex liver disease, and the immunological mechanism of organ damage is not fully understood.VX-765 is a selective caspase-1 inhibitor that was shown to attenuate pyroptosis in a large number of studies <a class="elsevierStyleCrossRefs" href="#bib0005">[5–7]</a>. The types of cell death from a molecular perspective include apoptosis, ferroptosis, pyroptosis, etc. As a new mode of cell death, pyroptosis is a kind of programmed lytic cell death closely related to inflammatory responses. During this process, caspase-1 is activated with the release of large amounts of proinflammatory cytokines such as IL-1β and IL-18 [<a class="elsevierStyleCrossRef" href="#bib0008">8</a>,<a class="elsevierStyleCrossRef" href="#bib0009">9</a>]. VX-765 can reduce inflammatory responses in vivo and in vitro, and a number of experiments have suggested that the NF-κB signaling pathway is closely related to this process [<a class="elsevierStyleCrossRef" href="#bib0010">10</a>,<a class="elsevierStyleCrossRef" href="#bib0011">11</a>]. Reportedly, VX-765 can prevent a variety of systemic diseases, such as traumatic brain injury, intestinal ischemia‒reperfusion injury and spinal cord injury. However, the role and pathological mechanism of VX-765 in the context of ALF are not clear.PPARα, which is a nuclear transcription factor, has been confirmed to be involved in apoptosis, lipid metabolism and inflammatory responses <a class="elsevierStyleCrossRefs" href="#bib0012">[12–15]</a>. Numerous studies have shown that PPARα has strong anti-inflammatory effects <a class="elsevierStyleCrossRefs" href="#bib0016">[16–19]</a>. Our earlier studies revealed that PPARα could protect against ALF <a class="elsevierStyleCrossRef" href="#bib0020">[20]</a>. Thus, we hypothesize that the expression levels of proinflammatory cytokines and pyroptosis-related proteins are increased with the progression of ALF and that inhibiting pyroptosis with VX-765 can upregulate PPARα expression, relieve inflammatory responses and protect against ALF.2Materials and Methods2.1Experimental miceWild-type C57BL/6 mice (male, 8-10 weeks) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China) and fed without specific pathogens in the animal facilities of Hebei Medical University. The ALF mouse model was induced by intraperitoneal injection of D-GalN (700 mg/kg; Sigma, St. Louis, MO, USA) and LPS (10 μg/kg; Sigma, St. Louis, MO, USA) or with normal saline in the control group. VX-765 (100 mg/kg; MCE, New Jersey, USA), which can inhibit the expression and activity of caspase-1, was intraperitoneally injected 2 hours prior to D-GalN/LPS treatment in ALF mice. VX-765 was dissolved in dimethyl sulfoxide (DMSO), and 1% DMSO equal to the treatment volume was injected into the control group. PPARα was suppressed by injecting PPARα siRNA (50 μM/kg, RIBOBIO, GUANGZHOU, China) through the tail vein 24 hours before D-GalN/LPS treatment, and the sequence was 5′-CTACAGAGACATGTACTGA-3′. All operations were performed with reference to the manufacturer's manuals. Six hours after D-GalN/LPS injection, the mice were euthanized, and serum samples and liver tissues were obtained for later analysis.2.2Cell culture and treatmentHuman LO2 cells, which were a gift from the Hebei Medical University of China, were cultured in 1640 medium containing penicillin/streptomycin (1%) and fetal bovine serum (10%) in an incubator filled with 5% CO2 at 37°C. LO2 cells were exposed to LPS (20 ng/ml; Sigma) for 6 hours to induce inflammation. VX-765 (50 μM; MCE), which was dissolved in dimethyl sulfoxide (DMSO), was administered 2 hours before LPS. In the same way, 0.1% DMSO equivalent to the volume of the VX-765 treatment group was given to LO2 cells in the control group. PPARα inhibition was achieved by applying PPARα siRNA (50 nM, RIBOBIO, GUANGZHOU, China) 24 hours before LPS, and the sequence was 5′- GGAGCATTGAACATCGAAT-3′.2.3Human specimensIn this study, liver samples in the ALF group were obtained from 10 liver transplantation patients. Chronic hepatitis B (CHB) samples were collected from 10 subjects who underwent liver puncture biopsy. Liver samples in the normal control group were obtained from 10 subjects who underwent hepatectomy during liver transplantation. A summary of the clinical characteristics of the subjects is presented in <a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>.<elsevierMultimedia ident="tbl0001"></elsevierMultimedia>2.4Biochemical measurement and histologyA multiparameter analyzer (LABOSPECT 008 AS, HITACHI, Japan) was used to examine the serum biochemical markers ALT and AST in liver injury according to the automatic program. The liver tissue was fixed in neutral formaldehyde solution at a concentration of 10%, embedded in paraffin and cut into 5 μm slices. After being dewaxed in xylene, the tissue was rehydrated with ethanol and stained with HE. Light microscopy was used to observe pathological characteristics of the liver.2.5Quantitative RT‒PCRTRIzol reagent was used to extract total RNA from hepatic tissue samples. According to the directions, RNA was reverse transcribed into cDNA with the PrimeScriptTM RT Reagent Kit (Takara, Tokyo, Japan). Quantitative RT‒PCR was performed using a SYBR Green RT‒PCR kit (Takara, Tokyo, Japan). The relative expression levels of the target genes were normalized to the level of β-actin, which was the reference gene. ΔΔCt was obtained as follows: ΔCttreated-ΔCtcontrol, and 2−ΔΔCt was used to represent the relative mRNA expression of target genes. The sequences of primers are presented in <a class="elsevierStyleCrossRef" href="#tbl0002">Table 2</a> and <a class="elsevierStyleCrossRef" href="#tbl0003">Table 3</a>.<elsevierMultimedia ident="tbl0002"></elsevierMultimedia><elsevierMultimedia ident="tbl0003"></elsevierMultimedia>2.6Western blotting analysesProteins were extracted from hepatic tissue samples with radioimmunoprecipitation assay (RIPA) buffer containing protease and phosphatase inhibitors. The proteins were subjected to polyacrylamide gel electrophoresis and then transferred to polyvinylidine fluoride (PVDF) membranes (Millipore, Bedford, MA, USA). After being reacted with the primary antibody (1:200-2000) at 4°C overnight, the membranes were washed three times using Tris-buffered saline with Tween-20 (TBST) and then incubated with the indicated secondary antibody (1:4000) at room temperature for 2 hours. Protein bands were detected using enhanced chemiluminescence (ECL) reagents and measured with a Synoptics Syngene bioimaging system. Antibodies against PPARα, IL-1β, IL-18, β-actin (Abcam, Cambridge, MA, USA), NF-κB and caspase-1 (Novus Biologicals, CO, USA) were used.2.7Immunohistochemical stainingThe liver tissue slices were subjected to repair antigen with high pressure cooking in citrate buffer for 15 minutes. Endogenous peroxidase activity was blocked with 3% H2O2, and 15 minutes later, the slices were incubated overnight at 4°C with primary antibodies (Abcam, Cambridge, MA, USA; Novus Biologicals, CO, USA; 1:100-200 dilution). The slices were washed three times with phosphate-buffered saline (PBS) and then incubated with the proper secondary antibody (ZSGB-BIO, Beijing, China) at 37°C for 30 minutes. Furthermore, the slices were washed three times with PBS, visualized with a 3,3’-diaminobenzidine (DAB) Detection Kit and counterstained with hematoxylin. Brown‒yellow staining represented a positive signal.2.8Statistical analysisVariables were initially verified by normal distribution. All statistical results are presented as the mean±S.E.M. Comparisons of two groups were carried out with unpaired Student's t test, while comparisons of more than two groups were performed using one-way ANOVA with Tukey´s multiple comparison posttest. P<0.05 (two-tailed) was considered to indicate a significant difference.2.9Ethical statementWritten informed consent was obtained from all individuals or their families included in the study, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the Institutional Medical Ethics Committee of the Third Affiliated Hospital, Hebei Medical University (W2021-087-1).All animal experiments complied with the ARRIVE guidelines and were carried out in accordance with the U.K. Animals (Scientific Procedures) Act, 1986 and associated guidelines.3Results3.1Proinflammatory cytokines and pyroptosis-associated protein expression increased with the gradual progression of ALFAccording to the time of euthanasia after D-GalN/LPS administration, we first divided the experimental mice into four groups: the normal control group and the ALF groups at 2 hours, 4 hours and 6 hours. D-GalN/LPS was injected intraperitoneally to induce ALF, and the same amount of normal saline was injected into the normal control group. Significant liver damage occurred 4 to 6 hours later, as determined by HE staining (<a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>A). Moreover, the elevated serum transaminase levels (ALT, AST) suggested similar results (<a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>B and <a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>C). The qRT-PCR (<a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>D to <a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>F) and western blotting results (<a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>G) demonstrated that with the progression of ALF, the expression of proinflammatory cytokines, such as IL-1β and IL-18, and the pyroptosis-associated protein caspase-1 was increased significantly.<elsevierMultimedia ident="fig0001"></elsevierMultimedia>3.2VX-765 improved the survival rate of ALF mice, relieved liver pathological damage, and reduced inflammatory responses, thereby protecting against ALF in vivoWe then investigated the role of VX-765, a known pyroptosis inhibitor, in ALF. Intraperitoneal injection of VX-765 2 hours before D-GalN/LPS administration significantly reduced the mortality rate of the mice compared with the ALF group (<a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>A). Six hours after D-GalN/LPS injection, the mice were euthanized. Our results showed that VX-765 not only improved liver gross morphology and histopathological injury but also reduced serum enzyme levels (ALT, AST), proving that VX-765 could prevent ALF (<a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>B to <a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>D). Previous studies have shown that VX-765 can alleviate inflammatory responses by reducing the activity of the NF-κB pathway in other systemic diseases. We evaluated the effect of VX-765 on NF-κB in ALF. As shown in <a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>E to <a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>I, IL-1β, IL-18, and NF-κB mRNA and protein levels were significantly decreased, confirming the anti-inflammatory effect. Our previous study confirmed the role of PPARα in regulating inflammatory responses in ALF. Therefore, we examined the mRNA and protein levels of PPARα to determine whether it was a necessary mediator by which VX-765 could reduce inflammation. We observed that the gene and protein expression levels of PPARα were significantly upregulated compared with those in the D-GalN/LPS group (<a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>H and <a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>I).<elsevierMultimedia ident="fig0002"></elsevierMultimedia>3.3Inhibition of PPARα attenuated the protective effect of VX-765 against ALFNext, we further revealed the protective mechanism by which VX-765 prevents ALF. PPARα protected against ALF in our previous study. By applying PPARα siRNA in the VX-765+D-GalN/LPS-treated group, PPARα inhibition was achieved. As shown in <a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>A, the expression level of PPARα was significantly reduced after PPARα siRNA was administered, as shown by the qRT‒PCR and western blotting results. The protective effect of VX-765 on the liver was significantly reduced, and there was a decrease in the survival rate (<a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>B), deterioration of overall liver morphology and pathological features (<a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>C), increased serum enzyme levels of ALT and AST (<a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>D and <a class="elsevierStyleCrossRef" href="#fig0003">3</a>E), and increased IL-1β, IL-18 and NF-κB expression (<a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>F to <a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>H). These results suggested that in the presence of PPARα siRNA, the protective effect of VX-765 against ALF was reduced. Therefore, it could be concluded that VX-765 reduced inflammation by upregulating the expression level of PPARα, thereby protecting against acute liver failure.<elsevierMultimedia ident="fig0003"></elsevierMultimedia>3.4VX-765 inhibited inflammatory responses by upregulating PPARα expression in vitroWe know that VX-765 suppresses inflammatory responses by upregulating PPARα expression in vivo. To further confirm our findings in vivo, we studied the effects of VX-765 on the inflammatory responses and cellular mechanism. LO2 cells were treated with VX-765 (10, 25 and 50 μM) for 2 hours and then with LPS for 6 hours. With increasing VX-765 concentrations, IL-1β, IL-18 and NF-κB expression levels decreased, while PPARα expression rose gradually in a dose-dependent manner (<a class="elsevierStyleCrossRef" href="#fig0004">Fig. 4</a>A to <a class="elsevierStyleCrossRef" href="#fig0004">Fig. 4</a>E). To further confirm the cellular mechanism, we examined whether VX-765 reduced inflammatory responses by upregulating PPARα in vitro. As shown in <a class="elsevierStyleCrossRef" href="#fig0004">Fig. 4</a>F to <a class="elsevierStyleCrossRef" href="#fig0004">Fig. 4</a>H, when PPARα expression was inhibited by siRNA, the anti-inflammatory effect of VX-765 on LPS-stimulated LO2 cells was significantly reduced.<elsevierMultimedia ident="fig0004"></elsevierMultimedia>3.5Proinflammatory cytokines and pyroptosis-related protein expression was increased, while PPARα expression was decreased in ALF patientsWe then confirmed whether inflammation, pyroptosis, and PPARα were related to the progression of ALF in patients. The expression levels of IL-1β, IL-18, the pyroptosis-associated protein caspase-1 and PPARα in 10 ALF patients infected with HBV, 10 CHB patients and 10 healthy controls were determined. As shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 5</a>A to <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 5</a>D, the mRNA levels of IL-1β, IL-18 and caspase-1 were significantly increased, while PPARα expression decreased with the progression of ALF according to the qRT‒PCR results. Furthermore, western blot and immunohistochemical experiments verified these results in liver tissues (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 5</a>E to <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 5</a>F). Our experiments showed that proinflammatory cytokines and pyroptosis-related protein expression was increased, while PPARα expression was downregulated with the progression of ALF in clinical patients.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>4DiscussionAs a newly developed pyroptosis inhibitor, VX-765 is an oral medicine in development that is designed to inhibit the activation and expression of caspase-1 <a class="elsevierStyleCrossRefs" href="#bib0021">[21–24]</a>. Previous studies have revealed that VX-765 can reduce the expression level and activity of caspase-1 in the heart, prevent myocardial infarction, downregulate the levels of inflammatory cytokines in patients with diabetic nephropathy and attenuate the functional outcomes of mice with traumatic brain injury <a class="elsevierStyleCrossRefs" href="#bib0025">[25–28]</a>. However, the effect and mechanism of VX-765 on ALF remain unclear. The main novel finding of this study is that VX-765 upregulates PPARα expression to reduce inflammatory responses, thereby protecting against acute liver failure.A large number of studies have previously been carried out on the pathophysiology of ALF; however, the mechanism by which organ damage occurs has not been fully revealed. ALF remains a rare but deadly disease if poorly treated [<a class="elsevierStyleCrossRef" href="#bib0029">29</a>,<a class="elsevierStyleCrossRef" href="#bib0030">30</a>]. We need to spare no effort in improving liver support in clinical practice, which may give ALF patients the time necessary for spontaneous recovery or until liver transplantation is available. Exploring new effective treatments for ALF patients is of vital importance, and more studies are needed for this patient population <a class="elsevierStyleCrossRef" href="#bib0031">[31]</a>. Understanding disease progression and multiple organ failure development is necessary for further improvements in survival.ALF features a sudden loss of liver function due to overwhelming hepatocyte death and liver inflammation [<a class="elsevierStyleCrossRef" href="#bib0032">32</a>,<a class="elsevierStyleCrossRef" href="#bib0033">33</a>]. Liver inflammation plays a substantial role in ALF pathogenesis [<a class="elsevierStyleCrossRef" href="#bib0034">34</a>,<a class="elsevierStyleCrossRef" href="#bib0035">35</a>]. The mouse model of peritoneal injection of D-GalN plus LPS is a widely used animal model to study ALF. It is an ideal animal model that has good repeatability, and liver injury is akin to clinical ALF, while extrahepatic toxicity is not obvious <a class="elsevierStyleCrossRefs" href="#bib0036">[36–38]</a>. Therefore, in this study, we used D-GalN/LPS-treated mouse models to further examine the pathogenesis of ALF.As a new mode of programmed cell death, pyroptosis is closely related to inflammatory reactions. During this process, caspase-1 is activated, and large amounts of proinflammatory cytokines such as IL-1β and IL-18 are released [<a class="elsevierStyleCrossRef" href="#bib0039">39</a>,<a class="elsevierStyleCrossRef" href="#bib0040">40</a>]. Previous experiments have shown that inflammatory responses can be reduced by inhibiting pyroptosis, and the NF-κB signaling pathway is closely associated with this process [<a class="elsevierStyleCrossRef" href="#bib0041">41</a>,<a class="elsevierStyleCrossRef" href="#bib0042">42</a>]. In our experiments, proinflammatory factors and pyroptosis-related protein expression increased with the progression of ALF, and for the first time, we revealed that inhibiting pyroptosis with VX-765 significantly relieved liver damage and protected against ALF. To explore the underlying protective mechanism of VX-765 in ALF, we examined the effect of VX-765 on inflammation and found that VX-765 could inhibit inflammation and regulate the activity of NF-κB in vitro and in vivo.PPARα, which is a nuclear transcription factor, is widely involved in inflammatory responses, apoptosis and lipid metabolism <a class="elsevierStyleCrossRefs" href="#bib0043">[43–45]</a>. Our earlier studies showed that PPARα could protect against acute liver failure, and numerous experiments have demonstrated that PPARα acts as a mediator in a variety of diseases <a class="elsevierStyleCrossRefs" href="#bib0046">[46–48]</a>. Furthermore, we hypothesize that PPARα may regulate VX-765-mediated inhibition of inflammation during ALF progression.In the present study, we examined PPARα and inflammatory cytokine expression levels in D-GalN/LPS-treated mice, in LPS-stimulated LO2 cells and in clinical ALF patients. We found that VX-765 could upregulate PPARα expression in vivo and in vitro. Moreover, PPARα expression gradually increased while inflammatory cytokine expression decreased with increasing concentrations of VX-765 in a dose-dependent manner. Furthermore, inflammation was aggravated when PPARα siRNA was used to inhibit PPARα expression, which was accompanied by the exacerbation of liver injuries. These results suggested that the protective effect of VX-765 against ALF was attenuated when PPARα siRNA was applied, which meant that VX-765 could reduce inflammatory responses by upregulating PPARα expression to protect against acute liver failure.5ConclusionsThis study deepened our understanding of the ALF mechanism and provided a fresh perspective on the significance of VX-765 in reducing liver inflammatory responses and protecting against ALF by upregulating PPARα expression. Therefore, VX-765 could improve the outcome of ALF, and oral administration might become a clinical treatment strategy for ALF patients [<a class="elsevierStyleCrossRef" href="#bib0022">22</a>,<a class="elsevierStyleCrossRef" href="#bib0023">23</a>].FundingThis work was supported by Hebei Medical Science Research Project Plan (20221153).Authors' contributionsMingjing Jiao and Caiyan Zhao devised the experiments. Mingjing Jiao and Jiachao Wang conducted the experiments and drafted the manuscript. Hongzhu Yin was in charge of the pathological observation. Xin Zhao and Wenpeng Liu collected the samples. Yanjun Qin and Chunhuan Zhang performed statistical analysis. The final submitted manuscript has been read and approved by all authors." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1892372" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abss0001" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abss0002" "titulo" => "Materials and Methods" ] 2 => array:2 [ "identificador" => "abss0003" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abss0004" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1637484" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xpalclavsec1637483" "titulo" => "Abbreviations" ] 3 => array:2 [ "identificador" => "sec0001" "titulo" => "Introduction" ] 4 => array:3 [ "identificador" => "sec0002" "titulo" => "Materials and Methods" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0003" "titulo" => "Experimental mice" ] 1 => array:2 [ "identificador" => "sec0004" "titulo" => "Cell culture and treatment" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Human specimens" ] 3 => array:2 [ "identificador" => "sec0006" "titulo" => "Biochemical measurement and histology" ] 4 => array:2 [ "identificador" => "sec0007" "titulo" => "Quantitative RT‒PCR" ] 5 => array:2 [ "identificador" => "sec0008" "titulo" => "Western blotting analyses" ] 6 => array:2 [ "identificador" => "sec0009" "titulo" => "Immunohistochemical staining" ] 7 => array:2 [ "identificador" => "sec0010" "titulo" => "Statistical analysis" ] 8 => array:2 [ "identificador" => "sec0011" "titulo" => "Ethical statement" ] ] ] 5 => array:3 [ "identificador" => "sec0012" "titulo" => "Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0013" "titulo" => "Proinflammatory cytokines and pyroptosis-associated protein expression increased with the gradual progression of ALF" ] 1 => array:2 [ "identificador" => "sec0014" "titulo" => "VX-765 improved the survival rate of ALF mice, relieved liver pathological damage, and reduced inflammatory responses, thereby protecting against ALF in vivo" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Inhibition of PPARα attenuated the protective effect of VX-765 against ALF" ] 3 => array:2 [ "identificador" => "sec0016" "titulo" => "VX-765 inhibited inflammatory responses by upregulating PPARα expression in vitro" ] 4 => array:2 [ "identificador" => "sec0017" "titulo" => "Proinflammatory cytokines and pyroptosis-related protein expression was increased, while PPARα expression was decreased in ALF patients" ] ] ] 6 => array:2 [ "identificador" => "sec0018" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0019" "titulo" => "Conclusions" ] 8 => array:2 [ "identificador" => "sec0020" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0021" "titulo" => "Authors' contributions" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-12-27" "fechaAceptado" => "2023-02-23" "PalabrasClave" => array:1 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1637484" "palabras" => array:5 [ 0 => "VX-765" 1 => "NF-κB" 2 => "Acute liver failure" 3 => "Pyroptosis" 4 => "Peroxisome proliferator-activated receptor α" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec1637483" "palabras" => array:22 [ 0 => "ALF" 1 => "ALT" 2 => "AST" 3 => "CHB" 4 => "DAB" 5 => "D-GalN" 6 => "DMSO" 7 => "ECL" 8 => "HBV" 9 => "HE" 10 => "IL-18" 11 => "IL-1β" 12 => "LPS" 13 => "NF-κB" 14 => "PBS" 15 => "PPARα" 16 => "PTA" 17 => "PVDF" 18 => "qRT-PCR" 19 => "RIPA" 20 => "TBIL" 21 => "TBST" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and ObjectivesAs a fatal clinical syndrome, acute liver failure (ALF) is characterized by overwhelming liver inflammation and hepatic cell death. Finding new therapeutic methods has been a challenge in ALF research. VX-765 is a known pyroptosis inhibitor and has been reported to prevent damage in a variety of diseases by reducing inflammation. However, the role of VX-765 in ALF is still unclear. Materials and MethodsALF model mice were treated with D-galactosamine (D-GalN) and lipopolysaccharide (LPS). LO2 cells were stimulated with LPS. Thirty subjects were enrolled in clinical experiments. The levels of inflammatory cytokines, pyroptosis-associated proteins and peroxisome proliferator-activated receptor α (PPARα) were detected using quantitative reverse transcription-polymerase chain reaction (qRT‒PCR), western blotting and immunohistochemistry. An automatic biochemical analyzer was used to determine the serum aminotransferase enzyme levels. Hematoxylin and eosin (HE) staining was used to observe the pathological features of the liver. ResultsWith the progression of ALF, the expression levels of interleukin (IL) -1β, IL-18, caspase-1, and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were increased. VX-765 could reduce the mortality rate of ALF mice, relieve liver pathological damage, and reduce inflammatory responses to protect against ALF. Further experiments showed that VX-765 could protect against ALF through PPARα, and this protective effect against ALF was reduced in the context of PPARα inhibition. ConclusionsAs ALF progresses, inflammatory responses and pyroptosis deteriorate gradually. VX-765 can inhibit pyroptosis and reduce inflammatory responses to protect against ALF by upregulating PPARα expression, thus providing a possible therapeutic strategy for ALF." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abss0001" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abss0002" "titulo" => "Materials and Methods" ] 2 => array:2 [ "identificador" => "abss0003" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abss0004" "titulo" => "Conclusions" ] ] ] ] "multimedia" => array:8 [ 0 => array:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2547 "Ancho" => 3500 "Tamanyo" => 664810 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0001" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Proinflammatory cytokines and pyroptosis-related protein had higher expression levels as ALF progressed. (A) The gross morphology and HE staining of livers in each group. (B-C) Serum transaminase levels in each group (n=8). (D-F) Gene expressions of IL-1β, IL-18 and caspase-1 were detected by qRT-PCR in each group (n=8). (G) Related proteins were detected by western blotting in the four groups of mice. Representative western blots of two samples from each group were displayed." ] ] 1 => array:8 [ "identificador" => "fig0002" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2523 "Ancho" => 3500 "Tamanyo" => 649329 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0002" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "VX-765 protected against ALF in vivo. (A) The survival rate of mice treated with D-GalN/LPS and VX-765+D-GalN/LPS was analyzed (n=10). (B) The gross morphology and HE staining of livers in each group. (C-D) Serum transaminase levels in the three groups (n=8). (E-H) Gene expressions of IL-1β, IL-18, NF-κB and PPARα were detected by qRT-PCR (n=8). (I) The associated protein expressions were analyzed by western blotting. Representative western blots of two samples from each group were displayed." ] ] 2 => array:8 [ "identificador" => "fig0003" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 3031 "Ancho" => 3500 "Tamanyo" => 841451 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0003" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Inhibition of PPARα attenuated the protective effect of VX-765 against ALF. (A) The gene and protein expression levels of PPARα from the VX-765+Control siRNA+D-GalN/LPS-treated mice and the VX-765+PPARα siRNA+D-GalN/LPS-treated mice were measured by qRT-PCR and western blotting respectively (n=8). (B) The survival rate of mice was analyzed (n=10). (C) The gross morphology and HE staining of livers from the D-GalN/LPS group, VX-765+D-GalN/LPS group, VX-765+Control siRNA+ D-GalN/LPS group and VX-765+PPARα siRNA+D-GalN/LPS group. (D-E) Serum transaminase levels from normal control and the above four groups (n=8). (F-H) Gene expressions of IL-1β, IL-18 and NF-κB were detected by qRT-PCR from each group (n=8)." ] ] 3 => array:8 [ "identificador" => "fig0004" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 3146 "Ancho" => 3500 "Tamanyo" => 653287 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0004" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "VX-765 inhibited inflammatory responses by upregulating PPARα expression in vitro. (A-D) After being treated with VX-765 at concentrations of 10μM, 25μM and 50μM respectively for 2 hours, LO2 cells were then treated with LPS for 6 hours with the concentration at 20 ng/ml. The gene expressions of IL-1β, IL-18, NF-κB and PPARα were detected by qRT-PCR at different concentrations of VX-765. (E) Protein expressions of IL-1β, IL-18, NF-κB and PPARα were analyzed by western blotting for groups with different concentrations of VX-765. (F-H) Gene expressions of IL-1β, IL-18 and NF-κB were detected by qRT-PCR for the normal control, LPS, VX-765+LPS, VX-765+Control siRNA+LPS and VX-765+PPARα siRNA+LPS groups respectively." ] ] 4 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 3280 "Ancho" => 3500 "Tamanyo" => 843361 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0005" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "The related gene and protein expression levels in individuals with ALF. (A-E) The expression levels of IL-1β, IL-18, caspase-1 and PPARα were analyzed by qRT-PCR (n=10) and western blotting methods for the three groups. Representative western blots of two samples from each group were displayed. (F) Staining of IL-1β, IL-18, caspase-1 and PPARα in the three groups by immunohistochemistry." ] ] 5 => array:8 [ "identificador" => "tbl0001" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0006" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBIL, total bilirubin; PTA, prothrombin time activity; ALB, albumin." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0001"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0002"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">healthy controls (n=10) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0003"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">CHB patients (n=10) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0004"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">ALF patients (n=10) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0005"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">P-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0006"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Male/Female \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0007"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">7/3 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0008"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">8/2 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0009"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">6/4 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0010"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.647 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0011"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Age (years) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">35.2±6.14 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0013"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">38±5.68 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0014"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">39.1±3.28 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0015"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.241 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0016"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">ALT (U/L) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0017"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">21.5±4.74 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0018"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">104.9±11.65 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0019"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">389.3±214.00 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0020"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0021"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">AST (U/L) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0022"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">27.1±5.9 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0023"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">102±9.49 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0024"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">676.5±399.32 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0025"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0026"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">TBIL (μmol/L) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0027"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">8.84±1.76 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0028"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">25.88±4.71 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0029"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">376.1±109.66 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0030"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0031"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">PTA (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0032"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">96.45±1.87 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0033"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">82.26±4.89 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0034"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">29.18±7.3 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0035"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0036"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">ALB (g/L) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0037"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">47.9±4.84 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0038"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">34.8±3.31 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0039"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">26.02±2.31 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0040"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3163391.png" ] ] ] ] "descripcion" => array:1 [ "en" => "The clinical characteristics of the subjects enrolled in this study" ] ] 6 => array:8 [ "identificador" => "tbl0002" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0007" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0041"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Target gene \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0042"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Forward primers \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0043"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Reverse primers \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0044"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">IL-1β \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0045"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-TTGACGGACCCCAAAAGAT-3′ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0046"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-GATGATCTGAGTGTGAGGGTCTG-3′ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0047"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">IL-18 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0048"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-ACCAGTAGAAGACAATTGCATCAACT-3′ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0049"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-CCAGGTTTTCATCATCTTCAGCTA-3′ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0050"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">NF-κB \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0051"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-AGCTGTGATG AGCAATAGCC-3′ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0052"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-TCATCTTCTC CAGCCTTCTC-3′ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0053"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Caspase-1 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0054"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-AATGAAGTTGCTGCTGGAGG-3′ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0055"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-CATTAGAGTATGTGGTCCCAC-3′ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0056"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">PPARα \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0057"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-GAAGCAGATGACCTGGAAAGT-3′ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0058"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-AGCCTGGACAGCTCCCTAA-3′ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0059"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">β-actin \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0060"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-GCAGATGTGGATCAGCAAGC-3′ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0061"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-GTCAAAGAAAGGGTGTAAAACG-3′ \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3163392.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Primers for mouse genes" ] ] 7 => array:8 [ "identificador" => "tbl0003" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0008" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0062"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Target gene \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0063"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Forward primers \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0064"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Reverse primers \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0065"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">IL-1β \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0066"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-AGCCAGGACAGTCAGCTCTC-3′ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0067"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-AGAGGCCTGGCTCAACAA-3′ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0068"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">IL-18 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0069"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-TTGCTGAGCCCTTTGCTC-3′ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0070"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-GCTTTAGCAGCCAGAGTTGG-3′ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0071"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">NF-κB \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0072"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-AACAGAGAGGATTTCGTTTCCG-3′ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0073"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-TTTGACCTGAGGGTAAGACTTCT-3′ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0074"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Caspase-1 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0075"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-TTTCCGCAAGGTTCGATTTTCA-3′ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0076"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-GGCATCTGCGCTCTACCATC-3′ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0077"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">PPARα \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0078"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-CCGCAATGGACCATGTAAC-3′ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0079"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-CAGCTCTAGCATGGCCTTTT-3′ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0080"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">β-actin \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0081"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′-GATCGCTTCCTCTCGCAACAAACTA-3′ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0082"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5′- ACTGTAGAGATAATGCACCCCGGAC-3′ \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3163393.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Primers for human genes" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "cebibsec1" "bibliografiaReferencia" => array:48 [ 0 => array:3 [ "identificador" => "bib0001" "etiqueta" => "[1]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dynamics of systemic inflammation as a function of developmental stage in pediatric acute liver failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Y Vodovotz" 1 => "D Barclay" 2 => "J Yin" 3 => "RH Squires" 4 => "R. Zamora" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fimmu.2020.610861" "Revista" => array:3 [ "tituloSerie" => "Front Immunol" "fecha" => "2020" "volumen" => "11" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0002" "etiqueta" => "[2]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute liver failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "RQ Gill" 1 => "RK. Sterling" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/00004836-200109000-00005" "Revista" => array:6 [ "tituloSerie" => "J Clin Gastroenterol" "fecha" => "2001" "volumen" => "33" "paginaInicial" => "191" "paginaFinal" => "198" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11500606" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0003" "etiqueta" => "[3]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathophysiology of acute liver failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "V Dong" 1 => "R Nanchal" 2 => "CJ. Karvellas" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ncp.10459" "Revista" => array:6 [ "tituloSerie" => "Nutr Clin Pract" "fecha" => "2020" "volumen" => "35" "paginaInicial" => "24" "paginaFinal" => "29" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31840297" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0004" "etiqueta" => "[4]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Current concepts in acute liver failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M Rovegno" 1 => "M Vera" 2 => "A Ruiz" 3 => "C. 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Mingjing Jiaoa, Jiachao Wangb, Wenpeng Liuc, Xin Zhaoc, Yanjun Qind, Chunhuan Zhange, Hongzhu Yina, Caiyan Zhaoa,

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zhaocy_2005@163.com

Corresponding author.

a Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, China

b Department of Immunology, Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Hebei Medical University, Shijiazhuang, China

c Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China

d Department of Emergency, The Third Hospital of Hebei Medical University, Shijiazhuang, China

e Department of Scientific Research, The Third Hospital of Hebei Medical University, Shijiazhuang, China

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          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">Proinflammatory cytokines and pyroptosis-related protein had higher expression levels as ALF progressed&#46; &#40;A&#41; The gross morphology and HE staining of livers in each group&#46; &#40;B-C&#41; Serum transaminase levels in each group &#40;n&#61;8&#41;&#46; &#40;D-F&#41; Gene expressions of IL-1&#946;&#44; IL-18 and caspase-1 were detected by qRT-PCR in each group &#40;n&#61;8&#41;&#46; &#40;G&#41; Related proteins were detected by western blotting in the four groups of mice&#46; Representative western blots of two samples from each group were displayed&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="cesectitle0008">Introduction</span><p id="para0005" class="elsevierStylePara elsevierViewall">Acute liver failure &#40;ALF&#41; is a clinical syndrome characterized by serious inflammatory-mediated hepatocellular injury with high mortality&#46; Liver inflammation heavily affects ALF pathogenesis&#44; and no effective treatment is available except for liver transplantation &#91;<a class="elsevierStyleCrossRef" href="#bib0001">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0002">2</a>&#93;&#46; Studies have shown that systemic inflammatory responses are of vital importance in the outcome of ALF&#46; Hepatocyte death in ALF is a result of the activation of systemic inflammatory responses generated by uncontrolled immune-mediated liver injury &#91;<a class="elsevierStyleCrossRef" href="#bib0003">3</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0004">4</a>&#93;&#46; Although great progress has been made in ALF etiology and pathogenesis for the past few years&#44; ALF is a serious and complex liver disease&#44; and the immunological mechanism of organ damage is not fully understood&#46;</p><p id="para0006" class="elsevierStylePara elsevierViewall">VX-765 is a selective caspase-1 inhibitor that was shown to attenuate pyroptosis in a large number of studies <a class="elsevierStyleCrossRefs" href="#bib0005">&#91;5&#8211;7&#93;</a>&#46; The types of cell death from a molecular perspective include apoptosis&#44; ferroptosis&#44; pyroptosis&#44; etc&#46; As a new mode of cell death&#44; pyroptosis is a kind of programmed lytic cell death closely related to inflammatory responses&#46; During this process&#44; caspase-1 is activated with the release of large amounts of proinflammatory cytokines such as IL-1&#946; and IL-18 &#91;<a class="elsevierStyleCrossRef" href="#bib0008">8</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0009">9</a>&#93;&#46; VX-765 can reduce inflammatory responses <span class="elsevierStyleItalic">in vivo</span> and <span class="elsevierStyleItalic">in vitro</span>&#44; and a number of experiments have suggested that the NF-&#954;B signaling pathway is closely related to this process &#91;<a class="elsevierStyleCrossRef" href="#bib0010">10</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0011">11</a>&#93;&#46; Reportedly&#44; VX-765 can prevent a variety of systemic diseases&#44; such as traumatic brain injury&#44; intestinal ischemia&#8210;reperfusion injury and spinal cord injury&#46; However&#44; the role and pathological mechanism of VX-765 in the context of ALF are not clear&#46;</p><p id="para0007" class="elsevierStylePara elsevierViewall">PPAR&#945;&#44; which is a nuclear transcription factor&#44; has been confirmed to be involved in apoptosis&#44; lipid metabolism and inflammatory responses <a class="elsevierStyleCrossRefs" href="#bib0012">&#91;12&#8211;15&#93;</a>&#46; Numerous studies have shown that PPAR&#945; has strong anti-inflammatory effects <a class="elsevierStyleCrossRefs" href="#bib0016">&#91;16&#8211;19&#93;</a>&#46; Our earlier studies revealed that PPAR&#945; could protect against ALF <a class="elsevierStyleCrossRef" href="#bib0020">&#91;20&#93;</a>&#46; Thus&#44; we hypothesize that the expression levels of proinflammatory cytokines and pyroptosis-related proteins are increased with the progression of ALF and that inhibiting pyroptosis with VX-765 can upregulate PPAR&#945; expression&#44; relieve inflammatory responses and protect against ALF&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="cesectitle0009">Materials and Methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;1</span><span class="elsevierStyleSectionTitle" id="cesectitle0010">Experimental mice</span><p id="para0008" class="elsevierStylePara elsevierViewall">Wild-type C57BL&#47;6 mice &#40;male&#44; 8-10 weeks&#41; were purchased from Beijing Vital River Laboratory Animal Technology Co&#46;&#44; Ltd&#46; &#40;Beijing&#44; China&#41; and fed without specific pathogens in the animal facilities of Hebei Medical University&#46; The ALF mouse model was induced by intraperitoneal injection of D-GalN &#40;700 mg&#47;kg&#59; Sigma&#44; St&#46; Louis&#44; MO&#44; USA&#41; and LPS &#40;10 &#956;g&#47;kg&#59; Sigma&#44; St&#46; Louis&#44; MO&#44; USA&#41; or with normal saline in the control group&#46; VX-765 &#40;100 mg&#47;kg&#59; MCE&#44; New Jersey&#44; USA&#41;&#44; which can inhibit the expression and activity of caspase-1&#44; was intraperitoneally injected 2 hours prior to D-GalN&#47;LPS treatment in ALF mice&#46; VX-765 was dissolved in dimethyl sulfoxide &#40;DMSO&#41;&#44; and 1&#37; DMSO equal to the treatment volume was injected into the control group&#46; PPAR&#945; was suppressed by injecting PPAR&#945; siRNA &#40;50 &#956;M&#47;kg&#44; RIBOBIO&#44; GUANGZHOU&#44; China&#41; through the tail vein 24 hours before D-GalN&#47;LPS treatment&#44; and the sequence was 5&#8242;-CTACAGAGACATGTACTGA-3&#8242;&#46; All operations were performed with reference to the manufacturer&#39;s manuals&#46; Six hours after D-GalN&#47;LPS injection&#44; the mice were euthanized&#44; and serum samples and liver tissues were obtained for later analysis&#46;</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;2</span><span class="elsevierStyleSectionTitle" id="cesectitle0011">Cell culture and treatment</span><p id="para0009" class="elsevierStylePara elsevierViewall">Human LO2 cells&#44; which were a gift from the Hebei Medical University of China&#44; were cultured in 1640 medium containing penicillin&#47;streptomycin &#40;1&#37;&#41; and fetal bovine serum &#40;10&#37;&#41; in an incubator filled with 5&#37; CO<span class="elsevierStyleInf">2</span> at 37&#176;C&#46; LO2 cells were exposed to LPS &#40;20 ng&#47;ml&#59; Sigma&#41; for 6 hours to induce inflammation&#46; VX-765 &#40;50 &#956;M&#59; MCE&#41;&#44; which was dissolved in dimethyl sulfoxide &#40;DMSO&#41;&#44; was administered 2 hours before LPS&#46; In the same way&#44; 0&#46;1&#37; DMSO equivalent to the volume of the VX-765 treatment group was given to LO2 cells in the control group&#46; PPAR&#945; inhibition was achieved by applying PPAR&#945; siRNA &#40;50 nM&#44; RIBOBIO&#44; GUANGZHOU&#44; China&#41; 24 hours before LPS&#44; and the sequence was 5&#8242;- GGAGCATTGAACATCGAAT-3&#8242;&#46;</p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;3</span><span class="elsevierStyleSectionTitle" id="cesectitle0012">Human specimens</span><p id="para0010" class="elsevierStylePara elsevierViewall">In this study&#44; liver samples in the ALF group were obtained from 10 liver transplantation patients&#46; Chronic hepatitis B &#40;CHB&#41; samples were collected from 10 subjects who underwent liver puncture biopsy&#46; Liver samples in the normal control group were obtained from 10 subjects who underwent hepatectomy during liver transplantation&#46; A summary of the clinical characteristics of the subjects is presented in <a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;4</span><span class="elsevierStyleSectionTitle" id="cesectitle0013">Biochemical measurement and histology</span><p id="para0011" class="elsevierStylePara elsevierViewall">A multiparameter analyzer &#40;LABOSPECT 008 AS&#44; HITACHI&#44; Japan&#41; was used to examine the serum biochemical markers ALT and AST in liver injury according to the automatic program&#46; The liver tissue was fixed in neutral formaldehyde solution at a concentration of 10&#37;&#44; embedded in paraffin and cut into 5 &#956;m slices&#46; After being dewaxed in xylene&#44; the tissue was rehydrated with ethanol and stained with HE&#46; Light microscopy was used to observe pathological characteristics of the liver&#46;</p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;5</span><span class="elsevierStyleSectionTitle" id="cesectitle0014">Quantitative RT&#8210;PCR</span><p id="para0012" class="elsevierStylePara elsevierViewall">TRIzol reagent was used to extract total RNA from hepatic tissue samples&#46; According to the directions&#44; RNA was reverse transcribed into cDNA with the PrimeScript<span class="elsevierStyleSup">TM</span> RT Reagent Kit &#40;Takara&#44; Tokyo&#44; Japan&#41;&#46; Quantitative RT&#8210;PCR was performed using a SYBR Green RT&#8210;PCR kit &#40;Takara&#44; Tokyo&#44; Japan&#41;&#46; The relative expression levels of the target genes were normalized to the level of &#946;-actin&#44; which was the reference gene&#46; &#916;&#916;Ct was obtained as follows&#58; &#916;Ct<span class="elsevierStyleInf">treated</span>-&#916;Ct<span class="elsevierStyleInf">control</span>&#44; and 2<span class="elsevierStyleSup">&#8722;&#916;&#916;Ct</span> was used to represent the relative mRNA expression of target genes&#46; The sequences of primers are presented in <a class="elsevierStyleCrossRef" href="#tbl0002">Table 2</a> and <a class="elsevierStyleCrossRef" href="#tbl0003">Table 3</a>&#46;</p><elsevierMultimedia ident="tbl0002"></elsevierMultimedia><elsevierMultimedia ident="tbl0003"></elsevierMultimedia></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;6</span><span class="elsevierStyleSectionTitle" id="cesectitle0015">Western blotting analyses</span><p id="para0013" class="elsevierStylePara elsevierViewall">Proteins were extracted from hepatic tissue samples with radioimmunoprecipitation assay &#40;RIPA&#41; buffer containing protease and phosphatase inhibitors&#46; The proteins were subjected to polyacrylamide gel electrophoresis and then transferred to polyvinylidine fluoride &#40;PVDF&#41; membranes &#40;Millipore&#44; Bedford&#44; MA&#44; USA&#41;&#46; After being reacted with the primary antibody &#40;1&#58;200-2000&#41; at 4&#176;C overnight&#44; the membranes were washed three times using Tris-buffered saline with Tween-20 &#40;TBST&#41; and then incubated with the indicated secondary antibody &#40;1&#58;4000&#41; at room temperature for 2 hours&#46; Protein bands were detected using enhanced chemiluminescence &#40;ECL&#41; reagents and measured with a Synoptics Syngene bioimaging system&#46; Antibodies against PPAR&#945;&#44; IL-1&#946;&#44; IL-18&#44; &#946;-actin &#40;Abcam&#44; Cambridge&#44; MA&#44; USA&#41;&#44; NF-&#954;B and caspase-1 &#40;Novus Biologicals&#44; CO&#44; USA&#41; were used&#46;</p></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;7</span><span class="elsevierStyleSectionTitle" id="cesectitle0016">Immunohistochemical staining</span><p id="para0014" class="elsevierStylePara elsevierViewall">The liver tissue slices were subjected to repair antigen with high pressure cooking in citrate buffer for 15 minutes&#46; Endogenous peroxidase activity was blocked with 3&#37; H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2&#44;</span> and 15 minutes later&#44; the slices were incubated overnight at 4&#176;C with primary antibodies &#40;Abcam&#44; Cambridge&#44; MA&#44; USA&#59; Novus Biologicals&#44; CO&#44; USA&#59; 1&#58;100-200 dilution&#41;&#46; The slices were washed three times with phosphate-buffered saline &#40;PBS&#41; and then incubated with the proper secondary antibody &#40;ZSGB-BIO&#44; Beijing&#44; China&#41; at 37&#176;C for 30 minutes&#46; Furthermore&#44; the slices were washed three times with PBS&#44; visualized with a 3&#44;3&#8217;-diaminobenzidine &#40;DAB&#41; Detection Kit and counterstained with hematoxylin&#46; Brown&#8210;yellow staining represented a positive signal&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;8</span><span class="elsevierStyleSectionTitle" id="cesectitle0017">Statistical analysis</span><p id="para0015" class="elsevierStylePara elsevierViewall">Variables were initially verified by normal distribution&#46; All statistical results are presented as the mean&#177;S&#46;E&#46;M&#46; Comparisons of two groups were carried out with unpaired Student&#39;s t test&#44; while comparisons of more than two groups were performed using one-way ANOVA with Tukey&#180;s multiple comparison posttest&#46; P&#60;0&#46;05 &#40;two-tailed&#41; was considered to indicate a significant difference&#46;</p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;9</span><span class="elsevierStyleSectionTitle" id="cesectitle0018">Ethical statement</span><p id="para0016" class="elsevierStylePara elsevierViewall">Written informed consent was obtained from all individuals or their families included in the study&#44; and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the Institutional Medical Ethics Committee of the Third Affiliated Hospital&#44; Hebei Medical University &#40;W2021-087-1&#41;&#46;</p><p id="para0017" class="elsevierStylePara elsevierViewall">All animal experiments complied with the ARRIVE guidelines and were carried out in accordance with the U&#46;K&#46; Animals &#40;Scientific Procedures&#41; Act&#44; 1986 and associated guidelines&#46;</p></span></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="cesectitle0019">Results</span><span id="sec0013" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;1</span><span class="elsevierStyleSectionTitle" id="cesectitle0020">Proinflammatory cytokines and pyroptosis-associated protein expression increased with the gradual progression of ALF</span><p id="para0018" class="elsevierStylePara elsevierViewall">According to the time of euthanasia after D-GalN&#47;LPS administration&#44; we first divided the experimental mice into four groups&#58; the normal control group and the ALF groups at 2 hours&#44; 4 hours and 6 hours&#46; D-GalN&#47;LPS was injected intraperitoneally to induce ALF&#44; and the same amount of normal saline was injected into the normal control group&#46; Significant liver damage occurred 4 to 6 hours later&#44; as determined by HE staining &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>A&#41;&#46; Moreover&#44; the elevated serum transaminase levels &#40;ALT&#44; AST&#41; suggested similar results &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>B and <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>C&#41;&#46; The qRT-PCR &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>D to <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>F&#41; and western blotting results &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>G&#41; demonstrated that with the progression of ALF&#44; the expression of proinflammatory cytokines&#44; such as IL-1&#946; and IL-18&#44; and the pyroptosis-associated protein caspase-1 was increased significantly&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia></span><span id="sec0014" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;2</span><span class="elsevierStyleSectionTitle" id="cesectitle0021">VX-765 improved the survival rate of ALF mice&#44; relieved liver pathological damage&#44; and reduced inflammatory responses&#44; thereby protecting against ALF in vivo</span><p id="para0019" class="elsevierStylePara elsevierViewall">We then investigated the role of VX-765&#44; a known pyroptosis inhibitor&#44; in ALF&#46; Intraperitoneal injection of VX-765 2 hours before D-GalN&#47;LPS administration significantly reduced the mortality rate of the mice compared with the ALF group &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>A&#41;&#46; Six hours after D-GalN&#47;LPS injection&#44; the mice were euthanized&#46; Our results showed that VX-765 not only improved liver gross morphology and histopathological injury but also reduced serum enzyme levels &#40;ALT&#44; AST&#41;&#44; proving that VX-765 could prevent ALF &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>B to <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>D&#41;&#46; Previous studies have shown that VX-765 can alleviate inflammatory responses by reducing the activity of the NF-&#954;B pathway in other systemic diseases&#46; We evaluated the effect of VX-765 on NF-&#954;B in ALF&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>E to <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>I&#44; IL-1&#946;&#44; IL-18&#44; and NF-&#954;B mRNA and protein levels were significantly decreased&#44; confirming the anti-inflammatory effect&#46; Our previous study confirmed the role of PPAR&#945; in regulating inflammatory responses in ALF&#46; Therefore&#44; we examined the mRNA and protein levels of PPAR&#945; to determine whether it was a necessary mediator by which VX-765 could reduce inflammation&#46; We observed that the gene and protein expression levels of PPAR&#945; were significantly upregulated compared with those in the D-GalN&#47;LPS group &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>H and <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>I&#41;&#46;</p><elsevierMultimedia ident="fig0002"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;3</span><span class="elsevierStyleSectionTitle" id="cesectitle0022">Inhibition of PPAR&#945; attenuated the protective effect of VX-765 against ALF</span><p id="para0020" class="elsevierStylePara elsevierViewall">Next&#44; we further revealed the protective mechanism by which VX-765 prevents ALF&#46; PPAR&#945; protected against ALF in our previous study&#46; By applying PPAR&#945; siRNA in the VX-765&#43;D-GalN&#47;LPS-treated group&#44; PPAR&#945; inhibition was achieved&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>A&#44; the expression level of PPAR&#945; was significantly reduced after PPAR&#945; siRNA was administered&#44; as shown by the qRT&#8210;PCR and western blotting results&#46; The protective effect of VX-765 on the liver was significantly reduced&#44; and there was a decrease in the survival rate &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>B&#41;&#44; deterioration of overall liver morphology and pathological features &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>C&#41;&#44; increased serum enzyme levels of ALT and AST &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>D and <a class="elsevierStyleCrossRef" href="#fig0003">3</a>E&#41;&#44; and increased IL-1&#946;&#44; IL-18 and NF-&#954;B expression &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>F to <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>H&#41;&#46; These results suggested that in the presence of PPAR&#945; siRNA&#44; the protective effect of VX-765 against ALF was reduced&#46; Therefore&#44; it could be concluded that VX-765 reduced inflammation by upregulating the expression level of PPAR&#945;&#44; thereby protecting against acute liver failure&#46;</p><elsevierMultimedia ident="fig0003"></elsevierMultimedia></span><span id="sec0016" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;4</span><span class="elsevierStyleSectionTitle" id="cesectitle0023">VX-765 inhibited inflammatory responses by upregulating PPAR&#945; expression in vitro</span><p id="para0021" class="elsevierStylePara elsevierViewall">We know that VX-765 suppresses inflammatory responses by upregulating PPAR&#945; expression <span class="elsevierStyleItalic">in vivo</span>&#46; To further confirm our findings <span class="elsevierStyleItalic">in vivo</span>&#44; we studied the effects of VX-765 on the inflammatory responses and cellular mechanism&#46; LO2 cells were treated with VX-765 &#40;10&#44; 25 and 50 &#956;M&#41; for 2 hours and then with LPS for 6 hours&#46; With increasing VX-765 concentrations&#44; IL-1&#946;&#44; IL-18 and NF-&#954;B expression levels decreased&#44; while PPAR&#945; expression rose gradually in a dose-dependent manner &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>A to <a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>E&#41;&#46; To further confirm the cellular mechanism&#44; we examined whether VX-765 reduced inflammatory responses by upregulating PPAR&#945; <span class="elsevierStyleItalic">in vitro</span>&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>F to <a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>H&#44; when PPAR&#945; expression was inhibited by siRNA&#44; the anti-inflammatory effect of VX-765 on LPS-stimulated LO2 cells was significantly reduced&#46;</p><elsevierMultimedia ident="fig0004"></elsevierMultimedia></span><span id="sec0017" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;5</span><span class="elsevierStyleSectionTitle" id="cesectitle0024">Proinflammatory cytokines and pyroptosis-related protein expression was increased&#44; while PPAR&#945; expression was decreased in ALF patients</span><p id="para0022" class="elsevierStylePara elsevierViewall">We then confirmed whether inflammation&#44; pyroptosis&#44; and PPAR&#945; were related to the progression of ALF in patients&#46; The expression levels of IL-1&#946;&#44; IL-18&#44; the pyroptosis-associated protein caspase-1 and PPAR&#945; in 10 ALF patients infected with HBV&#44; 10 CHB patients and 10 healthy controls were determined&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>A to <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>D&#44; the mRNA levels of IL-1&#946;&#44; IL-18 and caspase-1 were significantly increased&#44; while PPAR&#945; expression decreased with the progression of ALF according to the qRT&#8210;PCR results&#46; Furthermore&#44; western blot and immunohistochemical experiments verified these results in liver tissues &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>E to <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>F&#41;&#46; Our experiments showed that proinflammatory cytokines and pyroptosis-related protein expression was increased&#44; while PPAR&#945; expression was downregulated with the progression of ALF in clinical patients&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0018" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle" id="cesectitle0025">Discussion</span><p id="para0023" class="elsevierStylePara elsevierViewall">As a newly developed pyroptosis inhibitor&#44; VX-765 is an oral medicine in development that is designed to inhibit the activation and expression of caspase-1 <a class="elsevierStyleCrossRefs" href="#bib0021">&#91;21&#8211;24&#93;</a>&#46; Previous studies have revealed that VX-765 can reduce the expression level and activity of caspase-1 in the heart&#44; prevent myocardial infarction&#44; downregulate the levels of inflammatory cytokines in patients with diabetic nephropathy and attenuate the functional outcomes of mice with traumatic brain injury <a class="elsevierStyleCrossRefs" href="#bib0025">&#91;25&#8211;28&#93;</a>&#46; However&#44; the effect and mechanism of VX-765 on ALF remain unclear&#46; The main novel finding of this study is that VX-765 upregulates PPAR&#945; expression to reduce inflammatory responses&#44; thereby protecting against acute liver failure&#46;</p><p id="para0024" class="elsevierStylePara elsevierViewall">A large number of studies have previously been carried out on the pathophysiology of ALF&#59; however&#44; the mechanism by which organ damage occurs has not been fully revealed&#46; ALF remains a rare but deadly disease if poorly treated &#91;<a class="elsevierStyleCrossRef" href="#bib0029">29</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0030">30</a>&#93;&#46; We need to spare no effort in improving liver support in clinical practice&#44; which may give ALF patients the time necessary for spontaneous recovery or until liver transplantation is available&#46; Exploring new effective treatments for ALF patients is of vital importance&#44; and more studies are needed for this patient population <a class="elsevierStyleCrossRef" href="#bib0031">&#91;31&#93;</a>&#46; Understanding disease progression and multiple organ failure development is necessary for further improvements in survival&#46;</p><p id="para0025" class="elsevierStylePara elsevierViewall">ALF features a sudden loss of liver function due to overwhelming hepatocyte death and liver inflammation &#91;<a class="elsevierStyleCrossRef" href="#bib0032">32</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0033">33</a>&#93;&#46; Liver inflammation plays a substantial role in ALF pathogenesis &#91;<a class="elsevierStyleCrossRef" href="#bib0034">34</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0035">35</a>&#93;&#46; The mouse model of peritoneal injection of D-GalN plus LPS is a widely used animal model to study ALF&#46; It is an ideal animal model that has good repeatability&#44; and liver injury is akin to clinical ALF&#44; while extrahepatic toxicity is not obvious <a class="elsevierStyleCrossRefs" href="#bib0036">&#91;36&#8211;38&#93;</a>&#46; Therefore&#44; in this study&#44; we used D-GalN&#47;LPS-treated mouse models to further examine the pathogenesis of ALF&#46;</p><p id="para0026" class="elsevierStylePara elsevierViewall">As a new mode of programmed cell death&#44; pyroptosis is closely related to inflammatory reactions&#46; During this process&#44; caspase-1 is activated&#44; and large amounts of proinflammatory cytokines such as IL-1&#946; and IL-18 are released &#91;<a class="elsevierStyleCrossRef" href="#bib0039">39</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0040">40</a>&#93;&#46; Previous experiments have shown that inflammatory responses can be reduced by inhibiting pyroptosis&#44; and the NF-&#954;B signaling pathway is closely associated with this process &#91;<a class="elsevierStyleCrossRef" href="#bib0041">41</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0042">42</a>&#93;&#46; In our experiments&#44; proinflammatory factors and pyroptosis-related protein expression increased with the progression of ALF&#44; and for the first time&#44; we revealed that inhibiting pyroptosis with VX-765 significantly relieved liver damage and protected against ALF&#46; To explore the underlying protective mechanism of VX-765 in ALF&#44; we examined the effect of VX-765 on inflammation and found that VX-765 could inhibit inflammation and regulate the activity of NF-&#954;B <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span>&#46;</p><p id="para0027" class="elsevierStylePara elsevierViewall">PPAR&#945;&#44; which is a nuclear transcription factor&#44; is widely involved in inflammatory responses&#44; apoptosis and lipid metabolism <a class="elsevierStyleCrossRefs" href="#bib0043">&#91;43&#8211;45&#93;</a>&#46; Our earlier studies showed that PPAR&#945; could protect against acute liver failure&#44; and numerous experiments have demonstrated that PPAR&#945; acts as a mediator in a variety of diseases <a class="elsevierStyleCrossRefs" href="#bib0046">&#91;46&#8211;48&#93;</a>&#46; Furthermore&#44; we hypothesize that PPAR&#945; may regulate VX-765-mediated inhibition of inflammation during ALF progression&#46;</p><p id="para0028" class="elsevierStylePara elsevierViewall">In the present study&#44; we examined PPAR&#945; and inflammatory cytokine expression levels in D-GalN&#47;LPS-treated mice&#44; in LPS-stimulated LO2 cells and in clinical ALF patients&#46; We found that VX-765 could upregulate PPAR&#945; expression <span class="elsevierStyleItalic">in vivo</span> and <span class="elsevierStyleItalic">in vitro</span>&#46; Moreover&#44; PPAR&#945; expression gradually increased while inflammatory cytokine expression decreased with increasing concentrations of VX-765 in a dose-dependent manner&#46; Furthermore&#44; inflammation was aggravated when PPAR&#945; siRNA was used to inhibit PPAR&#945; expression&#44; which was accompanied by the exacerbation of liver injuries&#46; These results suggested that the protective effect of VX-765 against ALF was attenuated when PPAR&#945; siRNA was applied&#44; which meant that VX-765 could reduce inflammatory responses by upregulating PPAR&#945; expression to protect against acute liver failure&#46;</p></span><span id="sec0019" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">5</span><span class="elsevierStyleSectionTitle" id="cesectitle0026">Conclusions</span><p id="para0029" class="elsevierStylePara elsevierViewall">This study deepened our understanding of the ALF mechanism and provided a fresh perspective on the significance of VX-765 in reducing liver inflammatory responses and protecting against ALF by upregulating PPAR&#945; expression&#46; Therefore&#44; VX-765 could improve the outcome of ALF&#44; and oral administration might become a clinical treatment strategy for ALF patients &#91;<a class="elsevierStyleCrossRef" href="#bib0022">22</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0023">23</a>&#93;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0027">Funding</span><p id="para0030" class="elsevierStylePara elsevierViewall">This work was supported by <span class="elsevierStyleGrantSponsor" id="gs0001">Hebei Medical Science Research Project Plan</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs0001">20221153</span>&#41;&#46;</p></span><span id="sec0021" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0028">Authors&#39; contributions</span><p id="para0031" class="elsevierStylePara elsevierViewall">Mingjing Jiao and Caiyan Zhao devised the experiments&#46; Mingjing Jiao and Jiachao Wang conducted the experiments and drafted the manuscript&#46; Hongzhu Yin was in charge of the pathological observation&#46; Xin Zhao and Wenpeng Liu collected the samples&#46; Yanjun Qin and Chunhuan Zhang performed statistical analysis&#46; The final submitted manuscript has been read and approved by all authors&#46;</p></span></span>"
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              "titulo" => "Introduction and Objectives"
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          "titulo" => "Abbreviations"
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          "titulo" => "Introduction"
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          "titulo" => "Materials and Methods"
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              "titulo" => "Experimental mice"
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              "titulo" => "Cell culture and treatment"
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              "identificador" => "sec0005"
              "titulo" => "Human specimens"
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            3 => array:2 [
              "identificador" => "sec0006"
              "titulo" => "Biochemical measurement and histology"
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            4 => array:2 [
              "identificador" => "sec0007"
              "titulo" => "Quantitative RT&#8210;PCR"
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              "titulo" => "Western blotting analyses"
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              "titulo" => "Immunohistochemical staining"
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          "titulo" => "Results"
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              "titulo" => "Proinflammatory cytokines and pyroptosis-associated protein expression increased with the gradual progression of ALF"
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              "titulo" => "VX-765 improved the survival rate of ALF mice&#44; relieved liver pathological damage&#44; and reduced inflammatory responses&#44; thereby protecting against ALF in vivo"
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            2 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Inhibition of PPAR&#945; attenuated the protective effect of VX-765 against ALF"
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              "titulo" => "VX-765 inhibited inflammatory responses by upregulating PPAR&#945; expression in vitro"
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              "identificador" => "sec0017"
              "titulo" => "Proinflammatory cytokines and pyroptosis-related protein expression was increased&#44; while PPAR&#945; expression was decreased in ALF patients"
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    "fechaRecibido" => "2022-12-27"
    "fechaAceptado" => "2023-02-23"
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          "clase" => "keyword"
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          "palabras" => array:5 [
            0 => "VX-765"
            1 => "NF-&#954;B"
            2 => "Acute liver failure"
            3 => "Pyroptosis"
            4 => "Peroxisome proliferator-activated receptor &#945;"
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        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abbreviations"
          "identificador" => "xpalclavsec1637483"
          "palabras" => array:22 [
            0 => "ALF"
            1 => "ALT"
            2 => "AST"
            3 => "CHB"
            4 => "DAB"
            5 => "D-GalN"
            6 => "DMSO"
            7 => "ECL"
            8 => "HBV"
            9 => "HE"
            10 => "IL-18"
            11 => "IL-1&#946;"
            12 => "LPS"
            13 => "NF-&#954;B"
            14 => "PBS"
            15 => "PPAR&#945;"
            16 => "PTA"
            17 => "PVDF"
            18 => "qRT-PCR"
            19 => "RIPA"
            20 => "TBIL"
            21 => "TBST"
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    "resumen" => array:1 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0002">Introduction and Objectives</span><p id="spara010" class="elsevierStyleSimplePara elsevierViewall">As a fatal clinical syndrome&#44; acute liver failure &#40;ALF&#41; is characterized by overwhelming liver inflammation and hepatic cell death&#46; Finding new therapeutic methods has been a challenge in ALF research&#46; VX-765 is a known pyroptosis inhibitor and has been reported to prevent damage in a variety of diseases by reducing inflammation&#46; However&#44; the role of VX-765 in ALF is still unclear&#46;</p></span> <span id="abss0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Materials and Methods</span><p id="spara011" class="elsevierStyleSimplePara elsevierViewall">ALF model mice were treated with D-galactosamine &#40;D-GalN&#41; and lipopolysaccharide &#40;LPS&#41;&#46; LO2 cells were stimulated with LPS&#46; Thirty subjects were enrolled in clinical experiments&#46; The levels of inflammatory cytokines&#44; pyroptosis-associated proteins and peroxisome proliferator-activated receptor &#945; &#40;PPAR&#945;&#41; were detected using quantitative reverse transcription-polymerase chain reaction &#40;qRT&#8210;PCR&#41;&#44; western blotting and immunohistochemistry&#46; An automatic biochemical analyzer was used to determine the serum aminotransferase enzyme levels&#46; Hematoxylin and eosin &#40;HE&#41; staining was used to observe the pathological features of the liver&#46;</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Results</span><p id="spara012" class="elsevierStyleSimplePara elsevierViewall">With the progression of ALF&#44; the expression levels of interleukin &#40;IL&#41; -1&#946;&#44; IL-18&#44; caspase-1&#44; and serum alanine aminotransferase &#40;ALT&#41; and aspartate aminotransferase &#40;AST&#41; were increased&#46; VX-765 could reduce the mortality rate of ALF mice&#44; relieve liver pathological damage&#44; and reduce inflammatory responses to protect against ALF&#46; Further experiments showed that VX-765 could protect against ALF through PPAR&#945;&#44; and this protective effect against ALF was reduced in the context of PPAR&#945; inhibition&#46;</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Conclusions</span><p id="spara013" class="elsevierStyleSimplePara elsevierViewall">As ALF progresses&#44; inflammatory responses and pyroptosis deteriorate gradually&#46; VX-765 can inhibit pyroptosis and reduce inflammatory responses to protect against ALF by upregulating PPAR&#945; expression&#44; thus providing a possible therapeutic strategy for ALF&#46;</p></span>"
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          "en" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall">Inhibition of PPAR&#945; attenuated the protective effect of VX-765 against ALF&#46; &#40;A&#41; The gene and protein expression levels of PPAR&#945; from the VX-765&#43;Control siRNA&#43;D-GalN&#47;LPS-treated mice and the VX-765&#43;PPAR&#945; siRNA&#43;D-GalN&#47;LPS-treated mice were measured by qRT-PCR and western blotting respectively &#40;n&#61;8&#41;&#46; &#40;B&#41; The survival rate of mice was analyzed &#40;n&#61;10&#41;&#46; &#40;C&#41; The gross morphology and HE staining of livers from the D-GalN&#47;LPS group&#44; VX-765&#43;D-GalN&#47;LPS group&#44; VX-765&#43;Control siRNA&#43; D-GalN&#47;LPS group and VX-765&#43;PPAR&#945; siRNA&#43;D-GalN&#47;LPS group&#46; &#40;D-E&#41; Serum transaminase levels from normal control and the above four groups &#40;n&#61;8&#41;&#46; &#40;F-H&#41; Gene expressions of IL-1&#946;&#44; IL-18 and NF-&#954;B were detected by qRT-PCR from each group &#40;n&#61;8&#41;&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "fig0004"
        "etiqueta" => "Fig&#46; 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 3146
            "Ancho" => 3500
            "Tamanyo" => 653287
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0004"
            "detalle" => "Fig "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall">VX-765 inhibited inflammatory responses by upregulating PPAR&#945; expression <span class="elsevierStyleItalic">in vitro</span>&#46; &#40;A-D&#41; After being treated with VX-765 at concentrations of 10&#956;M&#44; 25&#956;M and 50&#956;M respectively for 2 hours&#44; LO2 cells were then treated with LPS for 6 hours with the concentration at 20 ng&#47;ml&#46; The gene expressions of IL-1&#946;&#44; IL-18&#44; NF-&#954;B and PPAR&#945; were detected by qRT-PCR at different concentrations of VX-765&#46; &#40;E&#41; Protein expressions of IL-1&#946;&#44; IL-18&#44; NF-&#954;B and PPAR&#945; were analyzed by western blotting for groups with different concentrations of VX-765&#46; &#40;F-H&#41; Gene expressions of IL-1&#946;&#44; IL-18 and NF-&#954;B were detected by qRT-PCR for the normal control&#44; LPS&#44; VX-765&#43;LPS&#44; VX-765&#43;Control siRNA&#43;LPS and VX-765&#43;PPAR&#945; siRNA&#43;LPS groups respectively&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 3280
            "Ancho" => 3500
            "Tamanyo" => 843361
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0005"
            "detalle" => "Fig "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara005" class="elsevierStyleSimplePara elsevierViewall">The related gene and protein expression levels in individuals with ALF&#46; &#40;A-E&#41; The expression levels of IL-1&#946;&#44; IL-18&#44; caspase-1 and PPAR&#945; were analyzed by qRT-PCR &#40;n&#61;10&#41; and western blotting methods for the three groups&#46; Representative western blots of two samples from each group were displayed&#46; &#40;F&#41; Staining of IL-1&#946;&#44; IL-18&#44; caspase-1 and PPAR&#945; in the three groups by immunohistochemistry&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0001"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0006"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spara007" class="elsevierStyleSimplePara elsevierViewall">ALT&#44; alanine aminotransferase&#59; AST&#44; aspartate aminotransferase&#59; TBIL&#44; total bilirubin&#59; PTA&#44; prothrombin time activity&#59; ALB&#44; albumin&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0001"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0002"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">healthy controls &#40;n&#61;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0003"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">CHB patients &#40;n&#61;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0004"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">ALF patients &#40;n&#61;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0005"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">P-value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0006"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Male&#47;Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0007"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">7&#47;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0008"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">8&#47;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0009"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">6&#47;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0010"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;647&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0011"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">35&#46;2&#177;6&#46;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0013"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">38&#177;5&#46;68&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0014"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">39&#46;1&#177;3&#46;28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0015"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;241&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0016"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">ALT &#40;U&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0017"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">21&#46;5&#177;4&#46;74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0018"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">104&#46;9&#177;11&#46;65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0019"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">389&#46;3&#177;214&#46;00&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0020"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#60;0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0021"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">AST &#40;U&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0022"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">27&#46;1&#177;5&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0023"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">102&#177;9&#46;49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0024"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">676&#46;5&#177;399&#46;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0025"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#60;0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0026"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">TBIL &#40;&#956;mol&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0027"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">8&#46;84&#177;1&#46;76&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0028"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">25&#46;88&#177;4&#46;71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0029"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">376&#46;1&#177;109&#46;66&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0030"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#60;0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0031"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">PTA &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">96&#46;45&#177;1&#46;87&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0033"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">82&#46;26&#177;4&#46;89&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0034"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">29&#46;18&#177;7&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0035"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#60;0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0036"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">ALB &#40;g&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0037"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">47&#46;9&#177;4&#46;84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0038"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">34&#46;8&#177;3&#46;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0039"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">26&#46;02&#177;2&#46;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0040"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#60;0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3163391.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara006" class="elsevierStyleSimplePara elsevierViewall">The clinical characteristics of the subjects enrolled in this study</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0002"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0007"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0041"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Target gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0042"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Forward primers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0043"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Reverse primers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0044"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">IL-1&#946;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0045"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8242;-TTGACGGACCCCAAAAGAT-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0046"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8242;-GATGATCTGAGTGTGAGGGTCTG-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0047"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">IL-18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0048"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8242;-ACCAGTAGAAGACAATTGCATCAACT-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0049"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8242;-CCAGGTTTTCATCATCTTCAGCTA-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0050"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NF-&#954;B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0051"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8242;-AGCTGTGATG AGCAATAGCC-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0052"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8242;-TCATCTTCTC CAGCCTTCTC-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0053"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Caspase-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0054"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8242;-AATGAAGTTGCTGCTGGAGG-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0055"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8242;-CATTAGAGTATGTGGTCCCAC-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0056"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">PPAR&#945;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0057"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8242;-GAAGCAGATGACCTGGAAAGT-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0058"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8242;-AGCCTGGACAGCTCCCTAA-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0059"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#946;-actin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0060"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8242;-GCAGATGTGGATCAGCAAGC-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0061"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8242;-GTCAAAGAAAGGGTGTAAAACG-3&#8242;&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 16652681
Original language: English

DOI:10.1016/j.aohep.2023.101082

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