Silymarin protects the liver from α-naphthylisothiocyanate-induced cholestasis by modulating the expression of genes involved in bile acid homeostasis

Sohail, Imran; Malkani, Naila; Tahir, Nimra; Khalil, Ateeb; Attar, Rükset; Mumtaz, Sidra

doi:10.14715/cmb/2022.68.7.34

Cited by 7 publications

(4 citation statements)

References 27 publications

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“…Cirrhosis is the 11th most common cause of death, accounting for 3.5% of all deaths worldwide [19]. Stage transition from compensated to the decompensated stage is a critical factor affecting mortality in cirrhotic patients.…”

Section: Discussionmentioning

confidence: 99%

Serum metabolomic profiling of patients with liver cirrhosis at different stages

XiaoJuan Li,

Xinxin Xu,

Yu Li

et al. 2024

Cell Mol Biol (Noisy-le-grand)

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An accurate and non-invasive diagnosis of the clinical stage is critical for effectively managing liver cirrhosis. This study aimed to identify serum metabolite biomarkers and clinical features that may reliably predict highrisk cirrhosis. This cross-sectional study recruited 94 cirrhotic patients (70 for identification cohort, 24 for validation cohort) from Minhang Hospital Affiliated with Fudan University between 2018 and 2021, who were analyzed by targeted quantitative metabolomics technique. Baseline clinical characteristics were collected, and different stage cirrhosis classification was performed according to the presence or absence of decompensated events. Potential metabolite biomarkers were screened, and a model for predicting the decompensation stage was created. Finally, the incidence of decompensated outcomes was analyzed. A total of 560 metabolites were detected in the identification cohort. Indole-3-propionic acid (IPA) was the most significantly decreased metabolic biomarker in the decompensated group (P<0.01, |log2FC| >2), having the strongest correlation with hyaluronic acid (r=-0.50, P<0.01). It also performed well for differentiating decompensated cirrhosis with an area under the curve (AUC) of 0.79(0.75 at internal validation). Another diagnostic model consisting of indole-3-propionic acid, hemoglobin, and albumin showed better predictive performance with an AUC of 0.97 (0.91 at internal validation). Also, 31 (44.29%) patients developed decompensated events at a median followup of 22.76±15.24 months. The cumulative incidence of decompensated events based on IPA subgroups (IPA <39.67ng/ml and ≥39.67ng/ml) showed a significant difference (P<0.01). "Indole-3-propionic acid" and a diagnostic model of hemoglobin and albumin can non-invasively identify cirrhotic populations at risk for decompensation, aiding in future management of liver cirrhosis.

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Section: Discussionmentioning

confidence: 99%

Serum metabolomic profiling of patients with liver cirrhosis at different stages

XiaoJuan Li,

Xinxin Xu,

Yu Li

et al. 2024

Cell Mol Biol (Noisy-le-grand)

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“…Thus, there could be a substantial portion of patients with cholestasis of various etiologies. Although there is limited evidence available on the positive effect of silymarin on drug-induced cholestasis in mouse models ( 12 ), the authors were not able to assess the efficacy of silymarin in the case of cholestasis caused by extrahepatic factors e.g., bile duct obstruction.…”

Section: Discussionmentioning

confidence: 99%

Optimal dose of silymarin for the management of drug‑induced liver injury in oncology

Kohutek

Bystrický

2023

Mol Clin Oncol

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Systemic oncological treatment may cause drug-induced liver injury (DILI). Therefore, there is a pressing need for an active drug able to accelerate liver regeneration. Silymarin mitigates oxidative stress, and inhibits pro-inflammatory and pro-apoptotic cytokines and the fibrotic transformation of liver tissue. Currently, there are a lack of data regarding the optimal dosage of silymarin and its efficacy. Thus, the present retrospective study aimed to determine the optimal dose of silymarin for use in oncological DILI treatment. For this purpose, 180 patients with solid malignancies treated with systemic oncological therapy and silymarin between January, 2015 and November, 2021 were enrolled in the study. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (Bil) levels, as well as the dose of silymarin were assessed at the initiation of silymarin treatment, after 3-6 weeks and after 6-12 weeks. Pearson's correlation analysis was performed to evaluate the correlation between the initial dose of silymarin (IDoS), and the ALT, AST and Bil levels. The effects of four independent variables, namely IDoS, the initial dose reduction of systemic treatment, the systemic treatment dose reduction at first assessment (DR1M) and the elevation of the silymarin dose at first control on the ALT, AST and Bil levels were evaluated using regression analysis. The median IDoS was 450 mg. A decrease in or the stabilization of the ALT, AST and Bil levels after 6-12 weeks were observed in 68.63, 65.85 and 53.25% of patients, respectively. There was a weak correlation between IDoS and the decrease in ALT and AST levels after 6-12 weeks (correlation coefficient, R=0.361 and 0.277 respectively, P<0.001). No significant correlation between the IDoS and a decrease in Bil levels was observed. DR1M was a negative predictor for a decrease in Bil levels in patients with liver tumors. On the whole, the present study demonstrates that silymarin appears to be efficient in alleviating DILI at a dose of 300-450 mg. A further increase in the dose of silymarin may not lead to an adequate increase in its efficacy.

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“…UDCA is a steroid bile acid widely utilized for treating various cholestatic liver diseases. 24) Simultaneously, there are literature reports that UDCA may alleviate bile acids induced cytotoxicity by activating FXR receptors, 25,26) which is similar to the mechanism of action of YZH. Furthermore, we verified the active ingredients of YZH and explained the pharmacological mechanisms of GPA, BA and CHA on preventing CsA-induced cholestasis.…”

Section: Introductionmentioning

confidence: 88%

Effects of Yinzhihuang on Alleviating Cyclosporine A-Induced Cholestatic Liver Injury via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Vitro and in Vivo

Qin,

Tan,

Han

et al. 2023

Biological & Pharmaceutical Bulletin

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Yinzhihuang (YZH), a traditional Chinese medicine prescription, was widely used to treat cholestasis. Cholestatic liver injury limited the use of the immunosuppressive drug cyclosporine A (CsA) in preventing organ rejection after solid organ transplantation. Clinical evidences suggested that YZH could enhance bile acids and bilirubin clearance, providing a potential therapeutic strategy against CsA-induced cholestasis. Nevertheless, it remains unclear whether YZH can effectively alleviate CsA-induced cholestatic liver injury, as well as the molecular mechanisms responsible for its hepatoprotective effects. The purpose of the present study was to investigate the hepatoprotective effects of YZH on CsA-induced cholestatic liver injury and explore its molecular mechanisms in vivo and vitro. The results demonstrated that YZH significantly improved the CsA-induced cholestatic liver injury and reduced the level of liver function markers in serum of Sprague-Dawley (SD) rats. Targeted protein and gene analysis indicated that YZH increased bile acids and bilirubin efflux into bile through the regulation of multidrug resistance-associated protein 2 (Mrp2), bile salt export pump (Bsep), sodium taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide 2 (Oatp2) transport systems, as well as upstream nuclear receptors farnesoid X receptor (Fxr). Moreover, YZH modulated enzymes involved in bile acids synthesis and bilirubin metabolism including Cyp family 7 subfamily A member 1 (Cyp7a1) and uridine 5'-diphosphate (UDP) glucuronosyltransferase family 1 member A1 (Ugt1a1). Furthermore, the active components geniposidic acid, baicalin and chlorogenic acid exerted regulated metabolic enzymes and transporters in LO2 cells. In conclusion, YZH may prevent CsAinduced cholestasis by regulating the transport systems, metabolic enzymes, and upstream nuclear receptors Fxr to restore bile acid and bilirubin homeostasis. These findings highlight the potential of YZH as a therapeutic intervention for CsA-induced cholestasis and open avenues for further research into its clinical applications.

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Silymarin protects the liver from α-naphthylisothiocyanate-induced cholestasis by modulating the expression of genes involved in bile acid homeostasis

Cited by 7 publications

References 27 publications

Serum metabolomic profiling of patients with liver cirrhosis at different stages

Serum metabolomic profiling of patients with liver cirrhosis at different stages

Optimal dose of silymarin for the management of drug‑induced liver injury in oncology

Effects of Yinzhihuang on Alleviating Cyclosporine A-Induced Cholestatic Liver Injury <i>via</i> Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes <i>in Vitro</i> and <i>in Vivo</i>

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