SRT1720 Alleviates ANIT-Induced Cholestasis in a Mouse Model

Yu, Luting; Liu, Xiaoxin; Yuan, Zihang; Li, Xiaojiaoyang; Yang, Hang; Yuan, Ziqiao; Sun, Lixin; Zhang, Luyong; Jiang, Zhengzhou

doi:10.3389/fphar.2017.00256

Cited by 40 publications

(23 citation statements)

References 46 publications

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“…2E). Celastrol, a pentacyclic triterpene found in the roots of the Tripterygium Wilfordi (thunder god vine), was able to increase Sirt1 mRNA levels (25). In agreement with a previous study, Sirt1 mRNA levels and SIRT1 protein levels were significantly induced and Ac-p53 levels were significantly decreased by 0.1 and 1.0 M celastrol in primary mouse hepatocytes (Fig.…”

Section: Molecular and Cellular Proteomics 183 523supporting

confidence: 91%

Celastrol Protects From Cholestatic Liver Injury Through Modulation of SIRT1-FXR Signaling

Zhao

Liu

Cheng

et al. 2019

Molecular & Cellular Proteomics

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The present study used metabolomics, transcriptomics, protein analysis by immunoblots, chemical inhibition and gene knockout mice to determine the effects of celastrol on cholestasis and its mechanisms. Samples from patients were used to validate our findings, and the data supported the conclusions that celastrol protected against cholestatic liver injury through modulation of the SIRT1 and FXR. Graphical Abstract Highlights• 1. Celastrol alleviated cholestatic liver injury.• 2. Celastrol inhibited the decrease of SIRT1 induced by deoxycholic acid.• 3. SIRT1-FXR signaling pathway mediated the effect of celastrol.Celastrol, derived from the roots of the Tripterygium Wilfordi, shows a striking effect on obesity. In the present study, the role of celastrol in cholestasis was investigated using metabolomics and transcriptomics. Celastrol treatment significantly alleviated cholestatic liver injury in mice induced by ␣-naphthyl isothiocyanate (ANIT) and thioacetamide (TAA). Celastrol was found to activate sirtuin 1 (SIRT1), increase farnesoid X receptor (FXR) signaling and inhibit nuclear factor-kappa B and P53 signaling. The protective role of celastrol in cholestatic liver injury was diminished in mice on co-administration of SIRT1 inhibitors. Further, the effects of celastrol on cholestatic liver injury were dramatically decreased in Fxr-null mice, suggesting that the SIRT1-FXR signaling pathway mediates the protective effects of celastrol. These observations demonstrated a novel role for celastrol in protecting against cholestatic liver injury through modulation of the SIRT1 and FXR.

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Section: Molecular and Cellular Proteomics 183 523supporting

confidence: 91%

Celastrol Protects From Cholestatic Liver Injury Through Modulation of SIRT1-FXR Signaling

Zhao

Liu

Cheng

et al. 2019

Molecular & Cellular Proteomics

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“…The release of reactive oxygen and nitrogen species and the associated nitro-oxidative stress play a key role in the pathogenesis of different types of liver injury including cholestatic damage [5,23]. In the current study, elevations of lipid peroxidation and reduced antioxidant statuses were observed among the hepatic tissues of LCA-treated animals.…”

Section: Discussionmentioning

confidence: 68%

“…Nrf2 can regulate the expression and activation of variety of enzymes that counteract oxidative stress and promote cell survival [30,31]. In addition, studies have shown that the activation of Nrf2 can safeguard against cholestasis caused by bile duct ligation and alphanaphthyl isocyanate models via the induction of many anti-oxidative genes [5,32,33]. The induction of HO-1 can confer hepatoprotection in various models of hepatic injuries [34,35].…”

Section: Discussionmentioning

confidence: 99%

“…Stress conditions activate Nrf2 release and its translocation into the nucleus where it induces the expression of antioxidant cytoprotective genes such as superoxide dismutase (SOD), the glutamate-cysteine ligase modifier (GCLm), the catalytic (GCLc) subunit, NAD(P)H: quinone oxidoreductase (Nqo1), and heme oxygenase-1 (HO-1) [6]. Previous studies have shown that the activation of Nrf2 signaling along with its target genes provide protection against cholestatic liver injury induced by either bile duct ligation or the administration of alpha-naphthyl isothiocyanate [4][5]7].…”

Section: Introductionmentioning

confidence: 99%

“…Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a transcription factor that plays an important role in the amelioration of various inflammatory diseases, including cholestatic hepatic injury [4][5]. Under normal conditions, Nrf2 exists as heterodimers with the cytosolic repressor Keap1.…”

Section: Introductionmentioning

confidence: 99%

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Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

El‐Agamy

Almaramhy

Ahmed

et al. 2018

Cell Physiol Biochem

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Background/Aims: Phosphodiesterase-5 inhibitors have beneficial effects in multiple liver diseases possibly through the reduction of oxidative stress and inflammatory response. However, these effects have not yet been examined in cholestatic liver dysfunction. Hence, this study aimed to explore the ability of vardenafil, a known phosphodiesterase-5 inhibitor, to repress lithocholic acid (LCA)-induced cholestatic liver injury and investigate the possible molecular pathways. Methods: Male Swiss albino mice were treated with LCA (0.125 mg/g) twice daily for 7 days to induce cholestatic liver damage. Vardenafil was administered 3 days before and throughout the administration of LCA. Serum markers of hepatotoxicity and hepatic nitro-oxidative stress along with antioxidant parameters were measured, and the histopathology of liver tissues was assessed. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes was examined using PCR. The activation of nuclear factor kappa-B (NF-κB) and the levels of inflammatory cytokines were determined. NLRP3 inflammasome and its components were studied by PCR and western blot. Results: LCA induced marked cholestatic liver damage as demonstrated by increased serum transaminases, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), bilirubin, and bile acids. Examination of liver specimens confirmed the biochemical results. Nitro-oxidative stress parameters were significantly elevated along with reduced antioxidant capacity in hepatic tissue following LCA administration. LCA suppressed Nrf2 and its target genes and decreased the mRNA expression and binding capacity of Nrf2 as well as the mRNA expression of GCLm, GCLc, Nqo1, and HO-1. Additionally, LCA enhanced the activation of NF-κB, which was accompanied by elevations of inflammatory cytokines. Importantly, LCA induced the activation of NLRP3 inflammasome. LCA increased the expression of NLRP3, ASC, caspase-1, and IL-1β genes and proteins in hepatic tissue. The activities of IL-1β and caspase-1 were increased in the LCA group. Interestingly, vardenafil ameliorated LCA-induced hepatic injury and alleviated all biochemical, histopathological, and inflammatory parameters. Conclusions: These data elucidated the effects of Nrf2 inhibition and NLRP3 inflammasome activation in LCA-induced liver injury. The hepatoprotective activity of vardenafil in LCA-induced cholestatic damage may result from the drug’s ability to activate Nrf2 signaling and prevent the activation of NLRP3, which could suppress the inflammatory responses in hepatic tissue. Thus, vardenafil can be considered a novel anti-inflammatory remedy for cholestatic liver damage.

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Probiotic Lactobacillus rhamnosus GG Prevents Liver Fibrosis Through Inhibiting Hepatic Bile Acid Synthesis and Enhancing Bile Acid Excretion in Mice

et al. 2020

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Background and Aims Cholestatic liver disease is characterized by gut dysbiosis and excessive toxic hepatic bile acids (BAs). Modification of gut microbiota and repression of BA synthesis are potential strategies for the treatment of cholestatic liver disease. The purpose of this study was to examine the effects and to understand the mechanisms of the probiotic Lactobacillus rhamnosus GG (LGG) on hepatic BA synthesis, liver injury, and fibrosis in bile duct ligation (BDL) and multidrug resistance protein 2 knockout (Mdr2−/−) mice. Approach and Results Global and intestine‐specific farnesoid X receptor (FXR) inhibitors were used to dissect the role of FXR. LGG treatment significantly attenuated liver inflammation, injury, and fibrosis with a significant reduction of hepatic BAs in BDL mice. Hepatic concentration of taurine‐β‐muricholic acid (T‐βMCA), an FXR antagonist, was markedly increased in BDL mice and reduced in LGG‐treated mice, while chenodeoxycholic acid, an FXR agonist, was decreased in BDL mice and normalized in LGG‐treated mice. LGG treatment significantly increased the expression of serum and ileum fibroblast growth factor 15 (FGF‐15) and subsequently reduced hepatic cholesterol 7α‐hydroxylase and BA synthesis in BDL and Mdr2−/− mice. At the molecular level, these changes were reversed by global and intestine‐specific FXR inhibitors in BDL mice. In addition, LGG treatment altered gut microbiota, which was associated with increased BA deconjugation and increased fecal and urine BA excretion in both BDL and Mdr2−/− mice. In vitro studies showed that LGG suppressed the inhibitory effect of T‐βMCA on FXR and FGF‐19 expression in Caco‐2 cells. Conclusion LGG supplementation decreases hepatic BA by increasing intestinal FXR–FGF‐15 signaling pathway–mediated suppression of BA de novo synthesis and enhances BA excretion, which prevents excessive BA‐induced liver injury and fibrosis in mice.

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SRT1720 Alleviates ANIT-Induced Cholestasis in a Mouse Model

Cited by 40 publications

References 46 publications

Celastrol Protects From Cholestatic Liver Injury Through Modulation of SIRT1-FXR Signaling

Celastrol Protects From Cholestatic Liver Injury Through Modulation of SIRT1-FXR Signaling

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

Probiotic Lactobacillus rhamnosus GG Prevents Liver Fibrosis Through Inhibiting Hepatic Bile Acid Synthesis and Enhancing Bile Acid Excretion in Mice

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