The Integrated Analysis of Transcriptomics and Metabolomics Unveils the Therapeutical Effect of Asiatic Acid on Alcoholic Hepatitis in Rats

The present study was to investigate the therapeutical effects and mechanisms of Asiatic acid from Potentilla Chinensis against alcoholic hepatitis. Rats were intragastrically fed with alcohol for 12 weeks to induce alcoholic hepatitis and then treated with various drugs for further 12 weeks. The results showed that Asiatic acid significantly alleviated liver injury caused by alcohol in rats, as evidenced by the improved histological changes and the lower levels of AST, ALT, and TBIL. Besides, Asiatic acid significantly enhanced the activity of ADH and ALDH, promoting alcohol metabolism. Asiatic acid suppressed CYP2E1 activity and NADP+/NADPH ratio, resulting in low ROS production. Further study revealed that Asiatic acid markedly reduced hepatocyte apoptosis by regulating the expression levels of the caspase and Bcl-2 families. Moreover, Asiatic acid could regulate the Keap1/Nrf2 and NF-κB signaling pathway, attenuating oxidative stress and inflammation as a result. Interestingly, the comprehensive analysis of transcriptomics and metabolomics indicated that Asiatic acid regulated the gene expression of Gpat4 and thereby affected the biosynthesis of the metabolites (1-acyl-Sn-glycerol-3-phosphocholine, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine), regulating the glycerophospholipid metabolism pathway and ultimately ameliorating hepatocyte damage. In conclusion, this study demonstrates that Asiatic acid can ameliorate alcoholic hepatitis by modulating the NF-κB and Keap1/Nrf2 signaling pathways and the glycerophospholipid metabolism pathway, which may be developed as a potential medicine for the treatment of alcoholic hepatitis.

Sex Metabolic Differences and Effects on Blood Coagulation Among Rats Exposed to Sodium Dehydroacetate

Sodium dehydroacetate (Na-DHA), a fungicide used in food, feed, cosmetics, and medicine, has been found to cause coagulation aberration accompanied by the inhibition of vitamin K epoxide reductase (VKOR) in the liver in rats. VKOR complex 1 (VKORC1) and VKORC1 like-1 (VKORC1L1) are two homologous VKOR proteins. Little information is available on the effect of Na-DHA on VKORC1L1 in the liver or VKORC1/VKORC1L1 in extrahepatic tissue and sex differences in Na-DHA metabolism. In the present study, after administration of 200 mg/kg Na-DHA by gavage, significant inhibition of VKORC1 or VKORC1L1 expression in tissues, as well as prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), were observed. The PT/APTT in the Na-DHA-exposed males were 1.27- to 1.48-fold/1.17- to 1.37-fold, while the corresponding values in the Na-DHA-exposed females were 1.36- to 2.02-fold/1.20- to 1.70-fold. Serum or tissue Na-DHA concentrations were significantly higher in females than in males. The pharmacokinetic parameters (t1/2, Cmax, AUC0∼24 h, and MRT0∼24 h) of Na-DHA in female rats were significantly higher than those in male rats. Furthermore, cytochrome P450 (CYP) activity was investigated using the cocktail probe method. The results revealed that Na-DHA exhibited an inductive effect on CYP1A2, 2D1/2, and 3A1/2 activities by changing the main pharmacokinetic parameters of probe drugs in male rats. However, no significant change in CYP2E1 activity was found. There were sex differences in the metabolism and coagulation in rats exposed to Na-DHA. The lower metabolism and higher blood Na-DHA concentration in females may be the reasons for higher coagulation sensitivity in female rats.

Protective effects of Erythronium japonicum and Corylopsis coreana Uyeki extracts against 1,3-dichloro-2-propanol-induced hepatotoxicity in rats

Erythronium japonicum (E. japonicum) and Corylopsis coreana Uyeki (C. coreana Uyeki, Korean winter hazel) have been shown to significantly decrease 1,3-dichloro-2-propanol (1,3-DCP)-induced generation of reactive oxygen species and CYP2E1 activity in HuH7, human hepatocytes. In this study, we expanded upon the previous study and investigated the effects of E. japonicum and C. coreana Uyeki extracts on 1,3-DCP-induced liver damage in rats. The pre-treatment of rats with these extracts alleviated a decrease in body weight and reduced 1,3-DCP-induced increase in catalytic activities of hepatic enzymes, such as aspartate aminotransferase and alanine aminotransferase, in the serum. Moreover, treatment with the extracts restored the 1,3-DCP-induced decreases in anti-oxidant enzyme activities, such as the activities of superoxide dismutase and catalase, in the rat liver. Histopathological studies also strongly supported the results of enzyme activities. These results suggest a possibility that the extracts of E. japonicum and C. coreana Uyeki can be a remedy for alleviating 1,3-DCP-induced liver damage in animals.

Protective Effects of Erythronium Japonicum and Corylopsis Coreana Uyeki Extracts Against 1,3-dichloro-2-propanol-induced Hepatotoxicity in Rats

Erythronium japonicum (E. japonicum) and Corylopsis coreana Uyeki (C. coreana Uyeki, Korean winter hazel) have been shown to significantly decrease 1,3-dichloro-2-propanol (1,3-DCP)-induced generation of reactive oxygen species and CYP2E1 activity in HuH7, human hepatocytes. In this study, we expanded upon the previous study and investigated the effects of E. japonicum and C. coreana Uyeki extracts on 1,3-DCP-induced liver damage in rats. The pre-treatment of rats with these extracts alleviated a decrease in body weight and reduced 1,3-DCP-induced increase in catalytic activities of hepatic enzymes, such as aspartate aminotransferase and alanine aminotransferase, in the serum. Moreover, treatment with the extracts restored the 1,3-DCP-induced decreases in anti-oxidant enzyme activities, such as the activities of superoxide dismutase and catalase, in the rat liver. Histopathological studies also strongly supported the results of enzyme activities.

Enhancement of Liver Toxicity on Diabetes Mellitus by a Universal Chemical Pollutant (Acrylonitrile) in Rats

The present study was designed to investigate potential liver damage due to acrylonitrile in Streptozotocin induced diabetes in rats. Twenty-four rats were divided into 4 treatment groups. Nondiabetic control rat receiving distilled water, non-diabetic rat receiving acrylonitrile aqueous solution (10 mg/kg/day), diabetic control rat receiving distilled water and diabetic rat receiving acrylonitrile aqueous solution. All groups received the treatment for 4 weeks. The animals were assessed for hepatoxicity markers in serum, oxidative stress markers, CYP2E1 activity and cyanide formation in tissues. Acrylonitrile significantly elevated serum aminotransferase, alanine aminotransferase, total bilirubin levels, triglycerides and total cholesterol in diabetic groups as compared to normal control group. Antioxidant markers like glutathione showed significant decline while a significant increase in malondialdehyde, superoxide dismutase and catalase in diabetic rats treated with acrylonitrile. CYP2E1 activity was observed in acrylonitrile – exposed nondiabetic and diabetic groups as compared to control. Cyanide formation was raised in both the nondiabetic and diabetic groups as compared to control group. Acrylonitriles can produce acute hepatic injury, induction of diabetes mellitus type II, and accomplish the CYP2E1 enzyme which sequentially leads to generation of oxidative stress and its metabolic product–cyanide that may potentiate the oxidative stress posing more deleterious effect.

Comparing the protective effects of three sulfur compounds against acrylonitrile-induced acute toxicity in CYP2E1-induced rats

Cytochrome P450 2E1 (CYP2E1) can be induced by diabetes mellitus, nonalcoholic liver disease, and obesity. This study assessed the protective effects of three sulfur compounds, namely phenethyl isothiocyanate (PEITC), dimethyl trisulfide (DMTS), and sodium thiosulfate (STS), on acrylonitrile (ACN)-induced acute toxicity in rats enriched with CYP2E1. PEITC and DMTS were administered intragastrically (i.g.), whereas STS was injected intraperitoneally (i.p.) at an identical dose of 0.5 mmol/kg for 3 days in acetone-pretreated rats before ACN (90 mg/kg) injection (i.p.). Acetone-treated rats that expressed high levels of CYP2E1 were more susceptible to ACN-induced acute toxicity. The sulfur compounds reduced the rate of convulsions and loss of the righting reflex in acute ACN-exposed CYP2E1-induced rats; PEITC and DMTS also increased the survival rates. PEITC inhibited hepatic CYP2E1 activity and protected hepatic and cerebral cytochrome c oxidase (CcOx) activities in acute ACN-exposed CYP2E1-enriched rats; DMTS protected hepatic CcOx activity. DMTS attenuated ACN-induced oxidative injury by reducing malondialdehyde (MDA) levels and increasing glutathione content in the brain. STS only reduced cerebral MDA levels, whereas PEITC did not exhibit any antioxidant effects. Collectively, PEITC provided superior protective effects against ACN-induced acute toxicity in rats with increased CYP2E1 activity, followed by DMTS; STS provided limited effects. PEITC and DMTS might be considered as promising chemopreventive agents against ACN-induced acute toxicity in vulnerable subpopulations with increased CYP2E1 activity.