transforming-growth-factor-beta and Chemical-and-Drug-Induced-Liver-Injury--Chronic

Leflunomide-induced liver injury has been an important problem since its approval. Although, severe cases of leflunomide-induced liver injury leading to hospitalization are rare, the risk is higher with concurrent liver disease or use of other hepatotoxic drugs. The current study was conducted to investigate the potential protective effects of carvedilol and crocin alone and in combination against leflunomide-induced hepatic injury and to clarify the possible mechanism(s) through which carvedilol and crocin may elicit their effects. Fifty male albino mice were allocated into five groups: normal control group, leflunomide group, carvedilol group, crocin group, and combination group. These groups were given vehicle, leflunomide, leflunomide plus carvedilol, leflunomide plus crocin, and leflunomide plus combination of carvedilol and crocin, respectively. The study was conducted for 8 weeks, and different parameters were assessed. The results demonstrated that leflunomide significantly increased the serum levels of AST, ALT, ALP, hepatic MDA, nitrite, mTOR gene, PI3K gene, TGF-β, and the pathological changes alongside with the significant decrease of serum albumin, total protein, hepatic catalase, and GSH. While the coadministration of carvedilol, crocin and their combination with leflunomide significantly decreased the serum levels of AST, ALT, ALP, hepatic MDA, mTOR gene, PI3K gene, TGF-β, and the pathological changes alongside with the significant elevation of serum albumin, total protein, hepatic catalase, and GSH. This study is suggesting several solutions for Leflunomide-induced hepatotoxicity demonstrated by the protective effect of the antihypertensive drug carvedilol, the natural product crocin, and their combination which was demonstrated to be superior to each drug alone.

Topics: Animals; Carvedilol; Catalase; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Leflunomide; Liver; Male; Mice; Oxidative Stress; Phosphatidylinositol 3-Kinases; Serum Albumin; TOR Serine-Threonine Kinases; Transforming Growth Factor beta

Bovine pancreatic trypsin inhibitor (BPTI) has been reported to relieve liver ischemia-reperfusion-induced injury in rats.. This study was designed to determine whether the recombinant BPTI (rBPTI) can prevent the chronic liver injury induced by CCl4 in rats.. Fifty male Wistar rats were divided into five groups. Rats were treated with 40% CCl4 at a dose of 2 ml/kg body weight twice a week subcutaneously for 12 weeks. In the 8th week, they were administered intraperitoneally with rBPTI (80 MU/kg), BPTI (80 MU/kg) or hepatocyte growth-promoting factor (pHGF; 100 mg/kg) daily for the next 4 weeks.. rBPTI significantly prevented the disruption of liver function of alanine aminotransferase (ALT; 172.7 ± 18.16 versus 141.2 ± 15.28, p=0.003), aspartate aminotransferase (AST; 225.10 ± 36.54 versus 170.06 ± 27.14, p=0.007) and hydroxyproline (Hyp; 1.14 ± 0.27 versus 0.62 ± 0.17, p=0.001). rBPTI significantly decreased the level of thiobarbituric acid reactive substances (TBARS; 1.15 ± 0.16 versus 0.87 ± 0.15, p=0.003) and increased the activities of superoxide dismutase (SOD; 6.07 ± 0.95 versus 7.75 ± 1.12, p=0.007). rBPTI reduced the production of cytokines of IL-1β and TGF-β. The hepatocyte necrosis, fibrosis, fatty degeneration and inflammatory cell infiltration were ameliorated by rBPTI administration.. This study demonstrated that rBPTI exerted a hepatoprotective effect on chronic liver fibrosis induced by CCl4, which suggests that rBPTI may have the potential application for chronic liver injury induced by drugs metabolism and toxic substances.

Topics: Alanine Transaminase; Animals; Aprotinin; Aspartate Aminotransferases; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury, Chronic; Cytoprotection; Disease Models, Animal; Fatty Liver; Hydroxyproline; Inflammation Mediators; Interleukin-1beta; Liver; Liver Cirrhosis, Experimental; Male; Necrosis; Protective Agents; Rats; Rats, Wistar; Recombinant Proteins; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Transforming Growth Factor beta

Allopurinol is an inhibitor of xanthine oxidase. The aim of this work was to evaluate the efficacy of allopurinol to reverse the experimental cirrhosis induced by CCl4. Rats received CCl4 for 8 weeks, and immediately after allopurinol was administered for 4 weeks more. Allopurinol reversed all markers of liver damage and oxidative stress to normal values, restoring the metabolic capacity of the liver. Chronic injury by CCl4 induced significant overexpression of profibrogenic cytokine TGF-β, while allopurinol decreased this production and consequently decreased the collagen content. Moreover, allopurinol is capable of partially inhibiting NF-κB. These findings suggest that allopurinol is capable of reversing the cirrhosis induced by CCl4, modulating oxidative stress, TGF-β expression and NF-κB nuclear translocation.

Topics: Allopurinol; Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury, Chronic; Collagen; Glutathione; Glutathione Disulfide; Glycogen; Lipid Peroxidation; Liver; Male; NF-kappa B; Oxidative Stress; Rats; Rats, Wistar; Transforming Growth Factor beta; Xanthine Oxidase