astaxanthine and Chemical-and-Drug-Induced-Liver-Injury

Topics: Acetaminophen; Acetylcysteine; Autophagy; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Ferroptosis; Heme Oxygenase-1; Hereditary Sensory and Motor Neuropathy; Humans; Liver; NF-E2-Related Factor 2; Oxidative Stress; Silicon Dioxide; Xanthophylls

The aim of this study is to probe a new function of astaxanthin (AST) from Haematococcus pluvialis on chemotherapeutic drug induced liver injury in mice. Doxorubicin-induced liver injury was treated with different doses of AST, and the body weight, food intake, urinalysis, liver function, and oxidative stress indexes were examined. The hepatocyte apoptosis level, pathological sections of liver tissue and the expression of antioxidant related genes were also determined. This study found that DOX could induce serious liver injury through cytotoxicity. AST treatment could decrease the level of liver function indexes (ALT, GOT, ALP and TBil), reduce the concentration of MDA and ROS, and increase the activities of SOD, CAT and GPX in the liver. AST could also repair the damaged hepatocyte in mice with liver injury and reduce the degree of the cellular apoptosis. In addition, AST could interfere with the expression of some related genes in the Keap1/Nrf2 signaling pathway by downregulating the expression of Keap1 and activating the transcription factor Nrf2 via enhancing the level of ERK, which upregulates downstream peroxiredoxins. The present research found and illustrated a new food function of AST, indicating that AST could be used in the therapy of chemotherapy induced side effects.

Topics: Animals; Antineoplastic Agents; Apoptosis; Chemical and Drug Induced Liver Injury; Chlorophyta; Disease Models, Animal; Dose-Response Relationship, Drug; Doxorubicin; Hepatocytes; Kelch-Like ECH-Associated Protein 1; Liver Cirrhosis; Male; Mice; Mice, Inbred ICR; NF-E2-Related Factor 2; Protective Agents; Xanthophylls

Topics: Acute Disease; Animals; Antioxidants; Capsaicin; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Liposomes; Male; Rats; Rats, Wistar; Xanthophylls

Astaxanthin (AXT) is classified as a xanthophyll carotenoid compound which have broader functions including potent antioxidant, anti-inflammatory and neuroprotective properties. Considerable researches have demonstrated that AXT shows preventive and therapeutic properties against for Diabetes, Osteoarthritis and Rheumatoid Arthritis. However, the protective effect of AXT on liver disease has not yet been reported. In this study, we investigated effects of AXT on ethanol-induced liver injury in chronic plus binge alcohol feeding model. The hepatic steatosis and inflammation induced by ethanol administration were alleviated by AXT. Serum levels of aspartate transaminase and alanine transaminase were decreased in the livers of AXT administrated group. The ethanol-induced expression of cytochrome P450 2E1 (CYP2E1), pro-inflammatory proteins, cytokines, chemokines and reactive oxygen species (ROS) levels were also reduced in the livers of AXT administrated group. Moreover, ethanol-induced infiltration of neutrophils was decreased in the livers of AXT administrated group. Docking model and pull-down assay showed that AXT directly binds to the DNA binding site of STAT3. Moreover, AXT decreased STAT3 phosphorylation in the liver of AXT administration group. Therefore, these results suggest that AXT could prevent ethanol-induced hepatic injury via inhibition of oxidant and inflammatory responses via blocking of STAT3 activity.

Topics: Animals; Antioxidants; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cytokines; Disease Models, Animal; Ethanol; Inflammation; Liver; Male; Mice; Oxidative Stress; Phosphorylation; Reactive Oxygen Species; Signal Transduction; STAT3 Transcription Factor; Xanthophylls

Acetaminophen (APAP) is a conventional drug widely used in the clinic because of its antipyretic-analgesic effects. However, accidental or intentional APAP overdoses induce liver injury and even acute liver failure (ALF). Astaxanthin (ASX) is the strongest antioxidant in nature that shows preventive and therapeutic properties, such as ocular protection, anti-tumor, anti-diabetes, anti-inflammatory, and immunomodulatory effects. The aim of present study was to determine whether ASX pretreatment provides protection against APAP-induced liver failure.. Male C57BL/6 mice were randomly divided into 7 groups, including control, oil, ASX (30mg/kg or 60mg/kg), APAP and APAP+ASX (30mg/kg or 60mg/kg) groups. Saline, olive oil and ASX were administered for 14days. The APAP and APAP+ASX groups were given a peritoneal injection of 700mg/kg or 300mg/kg APAP to determine the 5-day survival rate and for further observation, respectively. Blood and liver samples were collected to detect alanine transaminase (ALT), aspartate transaminase (AST), inflammation, oxidative stress and antioxidant systems, and to observe histopathologic changes and key proteins in the mitogen-activated protein kinase (MAPK) family.. ASX pretreatment before APAP increased the 5-day survival rate in a dose-dependent manner and reduced the ALT, AST, hepatic necrosis, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), oxidative stress and pro-inflammatory factors. ASX protected against APAP toxicity by inhibiting the depletion of glutathione (GSH) and superoxide dismutase (SOD). Administration of ASX did not change the expression of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and P38. However, phosphorylation of JNK, ERK and P38 was reduced, consistent with the level of tumor necrosis factor alpha (TNF-α) and TNF receptor-associated factor 2 (TRAF2).. ASX provided protection for the liver against APAP hepatotoxicity by alleviating hepatocyte necrosis, blocking ROS generation, inhibiting oxidative stress, and reducing apoptosis by inhibiting the TNF-α-mediated JNK signal pathway and by phosphorylation of ERK and P38, which made sense in preventing and treating liver damage.

Topics: Acetaminophen; Alanine Transaminase; Animals; Antioxidants; Apoptosis; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Glutathione; JNK Mitogen-Activated Protein Kinases; Lipid Peroxidation; Liver; Male; Mice; Mice, Inbred C57BL; Signal Transduction; TNF Receptor-Associated Factor 2; Tumor Necrosis Factor-alpha; Xanthophylls

Lipopolysaccharide (LPS)-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST), a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an effective alternative use for the improvement of bioavailability of the hydrophobic compound. We hypothesized that AST encapsulated within liposomes (LA) apparently shows improved stability and transportability compared to that of free AST. To investigate whether LA administration can efficiently prevent the LPS-induced acute hepatotoxicity, male Sprague-Dawley rats (n = six per group) were orally administered liposome-encapsulated AST at 2, 5 or 10 mg/kg-day (LA-2, LA-5, and LA-10) for seven days and then were LPS-challenged (i.p., 5 mg/kg). The LA-10 administered group, but not the other groups, exhibited a significant amelioration of serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), blood urea nitrogen (BUN), creatinine (CRE), hepatic malondialdehyde (MDA) and glutathione peroxidase (GSH-Px), IL-6, and hepatic nuclear NF-κB and inducible nitric oxide synthase (iNOS), suggesting that LA at a 10 mg/kg-day dosage renders hepatoprotective effects. Moreover, the protective effects were even superior to that of positive control N-acetylcysteine (NAC, 200 mg/kg-day). Histopathologically, NAC, free AST, LA-2 and LA-5 partially, but LA-10 completely, alleviated the acute inflammatory status. These results indicate that hydrophobic AST after being properly encapsulated by liposomes improves bioavailability and can also function as potential drug delivery system in treating hepatotoxicity.

Topics: Animals; Antioxidants; Body Weight; Chemical and Drug Induced Liver Injury; Fibrinolytic Agents; Glutathione; Interleukin-6; Lipopolysaccharides; Liposomes; Male; Malondialdehyde; Nanocapsules; NF-kappa B; Nitric Oxide Synthase Type II; Organ Size; Oxidative Stress; Protective Agents; Rats; Rats, Sprague-Dawley; Xanthophylls

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) represents a potential health risk and hepatotoxicity. Astaxanthin (ASTA) exhibits antioxidant properties and can influence hepatotoxicity. Therefore, the present study was carried out for using ASTA against hepatotoxicity induced by TCDD in the liver of rats. Animals were treated intraperitoneally daily with TCDD (8 µg/kg body weight (b.w.)), ASTA (12.5 mg/kg b.w. and 25 mg/kg b.w.) and TCDD plus ASTA (12.5 and 25 mg/kg b.w.) for 21 days. TCDD significantly decreased the activities of antioxidant enzymes and resulted in serious pathological findings. Moreover, the rate of micronucleus (MN) in hepatocytes increased after treating with TCDD. The activities of enzymes, frequencies of MNs and liver histology in lower dosage group of ASTA remained unchanged compared with the control group. In rats treated with ASTA, at higher dosage alone, the MNs remained unchanged and the activities of antioxidant enzymes significantly increased. The presence of ASTA (except for lower dose) with TCDD alleviated its pathological effects in hepatic tissue. ASTA also prevented the suppression of antioxidant enzymes in the livers of animals exposed to TCDD and displayed a strong protective effect against MNs. Thus, the present findings might provide new insight into the development of therapeutic and preventive approaches of TCDD toxicity.

Topics: Analysis of Variance; Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Histocytochemistry; Liver; Male; Micronucleus Tests; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley; Xanthophylls

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automate

Topics: Animals; Chemical and Drug Induced Liver Injury; Cluster Analysis; Databases, Factual; Humans; MEDLINE; Mice; Models, Chemical; Molecular Conformation; Quantitative Structure-Activity Relationship

Astaxanthin is one of many carotenoids present in marine animals, vegetables and fruits. Since carotenoids are known to have antioxidant properties, we tested to determine if astaxanthin could have protective effects in the CCl4-treated rat liver by activating the antioxidant system. Astaxanthin blocked the increase of glutamate-oxalacetate transaminase (GOT) and glutamate-pyruvate transaminase (GTP) activity and thiobarbituric acid reactive substances (TBARS) in response to carbon tetrachloride (CCl4), while causing an increase in glutathione (GSH) levels and superoxide dismutase (SOD) activities in the CCl4-treated rat liver. These results suggest that astaxanthin protects liver damage induced by CCl4 by inhibiting lipid peroxidation and stimulating the cellular antioxidant system.

Topics: Adjuvants, Immunologic; Animals; beta Carotene; Body Weight; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Glutathione Reductase; Lipid Peroxidation; Liver; Male; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Xanthophylls