M2-like macrophages in the fibrotic liver protect mice against lethal insults through conferring apoptosis resistance to hepatocytes.

Acute injury in the setting of liver fibrosis is an interesting and still unsettled issue. Most recently, several prominent studies have indicated the favourable effects of liver fibrosis against acute insults. Nevertheless, the underlying mechanisms governing this hepatoprotection remain obscure. In the present study, we hypothesized that macrophages and their M1/M2 activation critically involve in the hepatoprotection conferred by liver fibrosis. Our findings demonstrated that liver fibrosis manifested a beneficial role for host survival and apoptosis resistance. Hepatoprotection in the fibrotic liver was tightly related to innate immune tolerance. Macrophages undertook crucial but divergent roles in homeostasis and fibrosis: depleting macrophages in control mice protected from acute insult; conversely, depleting macrophages in fibrotic liver weakened the hepatoprotection and gave rise to exacerbated liver injury upon insult. The contradictory effects of macrophages can be ascribed, to a great extent, to the heterogeneity in macrophage activation. Macrophages in fibrotic mice exhibited M2-preponderant activation, which was not the case in acutely injured liver. Adoptive transfer of M2-like macrophages conferred control mice conspicuous protection against insult. In vitro, M2-polarized macrophages protected hepatocytes against apoptosis. Together, M2-like macrophages in fibrotic liver exert the protective effects against lethal insults through conferring apoptosis resistance to hepatocytes

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Multiple effects of silymarin on the hepatitis C virus lifecycle

Silymarin, an extract from milk thistle (Silybum marianum), and its purified flavonolignans have been recently shown to inhibit hepatitis C virus (HCV) infection, both in vitro and in vivo. In the current study, we further characterized silymarin's antiviral actions. Silymarin had antiviral effects against hepatitis C virus cell culture (HCVcc) infection that included inhibition of virus entry, RNA and protein expression, and infectious virus production. Silymarin did not block HCVcc binding to cells but inhibited the entry of several viral pseudoparticles (pp), and fusion of HCVpp with liposomes. Silymarin but not silibinin inhibited genotype 2a NS5B RNA-dependent RNA polymerase (RdRp) activity at concentrations 5 to 10 times higher than required for anti-HCVcc effects. Furthermore, silymarin had inefficient activity on the genotype 1b BK and four 1b RDRPs derived from HCV-infected patients. Moreover, silymarin did not inhibit HCV replication in five independent genotype 1a, 1b, and 2a replicon cell lines that did not produce infectious virus. Silymarin inhibited microsomal triglyceride transfer protein activity, apolipoprotein B secretion, and infectious virion production into culture supernatants. Silymarin also blocked cell-to-cell spread of virus. CONCLUSION: Although inhibition of in vitro NS5B polymerase activity is demonstrable, the mechanisms of silymarin's antiviral action appear to include blocking of virus entry and transmission, possibly by targeting the host cell

Hepatoprotective effect of hydromethanolic leaf extract of Musanga cecropioides (Urticaceae) on carbon tetrachloride-induced liver injury and oxidative stress

Objective: Natural antioxidant products are gaining popularity as treatments for various pathological liver injuries. Musanga cecropioides (Urticaceae) leaf extract is used in ethnomedicine for the management of jaundice and other hepatic ailments in Ibibio, Nigeria. This study evaluated the hepatoprotective and antioxidant effects of M. cecropioides hydromethanolic leaf (MCHL) extract against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Methods: Liver damage was induced by administering CCl4 dissolved in liquid paraffin (2 mL/kg bw 1:1 intraperitoneally) after pretreatment with MCHL extract for 7 days. Thereafter, acute hepatotoxicity was evaluated in 36 Wistar rats divided into six groups (A–F) of six animals each. Group A served as the negative control; B received CCl4 1 mL/kg only; C–E received 70.7, 141.4, and 282.8 mg/kg MCHL extract, respectively; and F received silymarin 100 mg/kg daily for 7 days by oral gavage. After 48 h, the rats were sacrificed, and samples obtained from them were assayed for histological and biochemical biomarkers of hepatotoxicity. Result: The MCHL extracts significantly (p < 0.001–0.05) reduced the increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), conjugated bilirubin (CBIL), and total bilirubin (TBIL) levels induced by CCl4 intoxication. There was no significant alteration in haematological indices or weight following administration of the MCHL extracts. Histopathological examinations revealed mitotic bodies in the 141.4 mg/kg MCHL extract-treated rats, an indication of tissue repair processes. Conclusion: The MCHL extract has a dose-specific hepatoprotective effect; hence, the utilisation of this extract for the management of hepatitis requires caution

A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice

Acetaminophen (APAP) overdoses are of major clinical concern. Growing evidence underlines a pathogenic contribution of sterile postinjury inflammation in APAP‐induced acute liver injury (APAP‐ALI) and justifies development of anti‐inflammatory therapies with therapeutic efficacy beyond the therapeutic window of the only current treatment option, N‐acetylcysteine (NAC). The inflammatory mediator, high mobility group box 1 (HMGB1), is a key regulator of a range of liver injury conditions and is elevated in clinical and preclinical APAP‐ALI. The anti‐HMGB1 antibody (m2G7) is therapeutically beneficial in multiple inflammatory conditions, and anti‐HMGB1 polyclonal antibody treatment improves survival in a model of APAP‐ALI. Herein, we developed and investigated the therapeutic efficacy of a partly humanized anti‐HMGB1 monoclonal antibody (mAb; h2G7) and identified its mechanism of action in preclinical APAP‐ALI. The mouse anti‐HMGB1 mAb (m2G7) was partly humanized (h2G7) by merging variable domains of m2G7 with human antibody‐Fc backbones. Effector function‐deficient variants of h2G7 were assessed in comparison with h2G7 in vitro and in preclinical APAP‐ALI. h2G7 retained identical antigen specificity and comparable affinity as m2G7. 2G7 treatments significantly attenuated APAP‐induced serum elevations of alanine aminotransferase and microRNA‐122 and completely abrogated markers of APAP‐induced inflammation (tumor necrosis factor, monocyte chemoattractant protein 1, and chemokine [C‐X‐C motif] ligand 1) with prolonged therapeutic efficacy as compared to NAC. Removal of complement and/or Fc receptor binding did not affect h2G7 efficacy. Conclusion: This is the first report describing the generation of a partly humanized HMGB1‐neutralizing antibody with validated therapeutic efficacy and with a prolonged therapeutic window, as compared to NAC, in APAP‐ALI. The therapeutic effect was mediated by HMGB1 neutralization and attenuation of postinjury inflammation. These results represent important progress toward clinical implementation of HMGB1‐specific therapy as a means to treat APAP‐ALI and other inflammatory conditions. (Hepatology 2016;64:1699‐1710)

Silybum marianum: Beyond Hepatoprotection.

Silybum marianum is a medicinal plant that has long been used as hepatoprotective remedy. It has been used for the treatment of numerous liver disorders characterized by functional impairment or degenerative necrosis. Its hepatoprotective activity is unique and acts in different ways, including antioxidant and anti-inflammatory activities, cell permeability regulator and membrane stabilizer, stimulation of liver regeneration and inhibition of deposition in collagen fibers, which may lead to cirrhosis. Most of documented data with Silybum marianum are about liver disorders; however, recently several beneficial properties on a wide variety of other disorders such as renal protection, hypolipidemic and anti-atherosclerosis activities, cardiovascular protection, prevention of insulin resistance, especially in cirrhotic patients, cancer, and Alzheimer prevention. It is also used as a food remedy. This review article aims to present different aspects of Silybum marianum, especially the data in recently published articles about its effects on different diseases, apart from presenting the aspects of its hepatoprotection

The effect of silymarin on liver injury induced by Thioacetamide in rats

Introduction: In this study the protective effects of Silymarin was investigated against thioacetamide (TAA) induced hepatotoxicity in rat. Methods: In an experimental study 24 male Wistar rats were designated in four equal groups as follows: Control group, the group treated with thioacetamide (TAA), Silymarin (400 mg/kg for 3 weeks) + TAA (400 mg/kg), TAA (400 mg/kg) + Silymarin (400 mg/kg for 3 weeks). The levels of serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) lactate dehydrogenase (LDH) and total bilirubin were measured to assess the hepatotoxicity and hepatoprotection. Results: TAA significantly increased AST, ALT, ALP, LDH and bilirubin. Treatment by Silymarin caused a significant reduction in serum levels of AST, ALT, ALP, LDH and bilirubin contents. Conclusion: The results indicate a protective effect for Silymarin against thioacetamide induced hepatotoxicity which might be due to its ability to block the bioactivity of thioacetamide.</p

Involvement of CYP450 system in hepatoprotective activity of Malaysian Agricultural Research and Development Institute (MARDI)-produced virgin coconut oils.

The present study aims to determine the role of cytochrome P450 (CYP450) enzyme system in hepatoprotective activity of virgin coconut oils produced by Malaysian Agricultural Research and Development Institute (MARDI). Paracetamol (PCM)-induced hepatotoxic rat was used as a model. Liver injury induced by 3 g/kg PCM increased the liver weight and liver enzymes (e.g. alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphate (ALP)) and decreased cell viability indicating liver damage. Histological observation also confirms liver damage indicated by the presence of inflammations and necrosis. Pre-treatment with VCOA or VCOB reversed the significantly (P < 0.05) reversed PCM toxic effect. Groups pre-treated withvirgin coconut oil (VCOs) followed by inhibitor or inducer of CYP450 demonstrated significant (P < 0.0.5) increase in liver weight, liver enzymes levels and decrease in cell viability, which are, however, significantly (P < 0.05) less remarkable as compared to group treated with PCM alone. In conclusion, VCO possessed hepatoprotective effect, which is believed to be mediated via a non-CYP450 system and might be associated partly with the antioxidant potential of the oil. Further studies are warranted to determine the actual mechanisms of hepatoprotection involved