naphthoquinones and Chemical-and-Drug-Induced-Liver-Injury

Acetaminophen (APAP) overdose causes acute liver injury and leads to fatal liver damage. However, the therapies are quite limited. Shikonin is a natural product with antioxidant and anti-inflammatory activities. In the present study, the hepatoprotective effects and the underlying mechanisms of shikonin in APAP-induced hepatotoxicity in vivo and in vitro were investigated. APAP-induced acute liver injury and shikonin pretreatment models were established in vivo and in vitro, as evidenced by serum hepatic enzymes, histological changes, oxidative stress indicators and proinflammatory cytokines. The results revealed that shikonin pretreatment prevented the elevation of serum alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels and markedly reduced APAP-induced histological alterations in liver tissues. Additionally, shikonin restored superoxide dismutase (SOD) expression and glutathione (GSH) content in line with the blockade of oxidative stress. The changes in gene expression involved in oxidative stress including methionine sulfoxide reductase (such as MsrA and MsrB1), heme oxygenase-1 (HO-1), SOD2 and cytochrome P450 2E1 (CYP2E1), were markedly reversed after shikonin therapy. Furthermore, shikonin markedly attenuated the APAP-induced production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) and suppressed the expression of genes related to inflammation. In AML-12 cells, shikonin pretreatment decreased APAP-induced cytotoxicity as measured by CCK-8 assay and LDH release. The changes in gene expression involved in oxidative stress and the inflammatory response were consistent with those in mouse livers. This study indicated that shikonin attenuated APAP-induced acute liver injury via inhibiting oxidative stress and inflammatory responses in vivo and in vitro. These findings offer new insights into the potential therapy for APAP hepatotoxicity.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Inflammation; Male; Mice; Mice, Inbred BALB C; Naphthoquinones; Oxidative Stress

Myeloid-derived suppressor cells (MDSCs) contribute to immune activity suppression and promote the tumor progression. Elimination of MDSCs is a promising cancer therapeutic strategy, and some chemotherapeutic agents have been reported to hamper tumor progression by suppressing MDSCs. Juglone has been showed to exert a direct cytotoxic effect on tumor cells. However, the effect of juglone on MDSCs and anti-tumor immune statue has remained unexplored. In our study, we observed that juglone suppressed tumor growth and metastasis markedly, and the tumor growth suppression in immunocompetent mice was more drastic than that in immunodeficient mice. Juglone reduced the accumulation of MDSCs and increased IFN-γ production by CD8

Topics: Animals; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Chemical and Drug Induced Liver Injury; Fluorouracil; Interferon-gamma; Interleukin-1beta; Liver; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Myeloid-Derived Suppressor Cells; Naphthoquinones; Neoplasms

The Drug-induced liver injury is one of the common unfavourable impacts, which seriously affects any drug therapy. This study documented the hepatoprotective efficacy of lawsone, the major bioactive naphthoquinone present in Lawsonia inermis L. (Lythraceae) using in vitro and in vivo models. Lawsone was isolated from the leaves of L. inermis and its structure was confirmed using spectroscopic data. In-vitro antioxidant effect of lawsone was evaluated using ABTS assay. Hepatoprotective effect of lawsone was determined with RIF-INH treated HepG2 cells and Wistar rats. Administration of RIF-INH reduced the viability of the HepG2 cells and the treatment with lawsone significantly restored the viability of the cells even at lower concentration (7.5 μM). The other parameters such as the leakage of transaminases and MDA levels were also significantly reduced by the treatment with lawsone. Oral administration of lawsone to the animals did not show any toxicity up to 2 g/kg b.w. concentration. Treatment with lawsone to the RIF-INH administered animals significantly lowered the serum transaminases levels. The ratio of albumin to globulin was improved and the level of bilirubin was lowered. This study indicated the hepatoprotective effect of lawsone; detailed investigations will give deeper understanding of the application of lawsone for hepatoprotection.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bilirubin; Cell Survival; Chemical and Drug Induced Liver Injury; Hep G2 Cells; Humans; Isoniazid; L-Lactate Dehydrogenase; Liver; Male; Naphthoquinones; Protective Agents; Rats, Wistar; Rifampin; Serum Albumin; Serum Globulins

Acetaminophen (APAP) overdose-induced acute liver damage is mostly due to overwhelmingly increased oxidative stress. Nuclear factor-erythroid 2-related factor2 (Nrf2) plays an important role in alleviating APAP hepatic toxicity. Shikonin (SHK) enhances Nrf2 in multiple lines of normal cells. Nevertheless, whether SHK protects against APAP-induced liver toxicity remains undefined. This study found SHK defended APAP-induced liver toxicity, as well as reversed the levels of serum alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, and reactive oxygen species (ROS), while it enhanced the liver glutathione (GSH) level in APAP-treated mice. SHK rescued the cell viability and GSH depletion, but neutralized oxidative stress in APAP-treated human normal liver L-02 cells. Mechanically, SHK increased Nrf2 expression in the exposure of APAP at the protein level but not at the mRNA level. Inhibition of Nrf2 blocked the SHK effect in APAP-treated hepatocytes. Furthermore, SHK improved Nrf2 stability through stimulating PI3K/Akt pathway, thus inhibiting GSK-3β. In vivo studies confirmed the close correlation of liver protection of SHK against APAP and Akt/GSK-3β/Nrf2 pathway. In conclusion, this study reveals that SHK prevents APAP hepatotoxicity by upregulation of Nrf2 via PI3K/Akt/GSK-3β pathway. Therefore, SHK may be a promising candidate against APAP-induced liver injury.

Topics: Acetaminophen; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Biopsy; Cell Line; Chemical and Drug Induced Liver Injury; Gene Expression; Glycogen Synthase Kinase 3 beta; Hepatocytes; Male; Mice; Naphthoquinones; NF-E2-Related Factor 2; Oxidative Stress; Phosphorylation; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction

Shikonin possesses anti-inflammatory effects. However, its function in concanavalin A-induced acute liver injury remains uncertain. The aim of the present study was to investigate the functions of shikonin and its mechanism of protection on ConA-induced acute liver injury.. Balb/C mice were exposed to ConA (20 mg/kg) via tail vein injection to establish acute liver injury; shikonin (7.5 mg/kg and 12.5 mg/kg) was intraperitoneally administered 2 h before the ConA injection. The serum liver enzyme levels and the inflammatory cytokine levels were determined at 3, 6, and 24 h after ConA injection.. After the injection of ConA, inflammatory cytokines IL-1β, TNF-α, and IFN-γ were significantly increased. Shikonin significantly ameliorated liver injury and histopathological changes and suppressed the release of inflammatory cytokines. The expressions of Bcl-2 and Bax were markedly affected by shikonin pretreatment. LC3, Beclin-1, and p-JNK expression levels were decreased in the shikonin-pretreated groups compared with the ConA-treated groups. Shikonin attenuated ConA-induced liver injury by reducing apoptosis and autophagy through the inhibition of the JNK pathway.. Our results indicated that shikonin pretreatment attenuates ConA-induced acute liver injury by inhibiting apoptosis and autophagy through the suppression of the JNK pathway.

Topics: Animals; Blotting, Western; Chemical and Drug Induced Liver Injury; Concanavalin A; Immunohistochemistry; Interferon-gamma; Interleukin-1beta; Liver; Male; MAP Kinase Signaling System; Mice, Inbred BALB C; Naphthoquinones; Random Allocation; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha

Plumbagin is a quinonoid constituent extracted from Plumbago genus, and it exhibits diverse pharmacological effects. This study thoroughly investigated the effects of plumbagin on thioacetamide-induced acute and chronic liver injury. Results shown that plumbagin increased survival rate, reduced liver congestion and inflammation, and decreased macrophages and neutrophils in the fulminant hepatic failure model, and remarkably diminished liver fibrosis and inflammation in the chronic liver injury model. Furthermore, plumbagin significantly suppress the HSCs/myofibroblasts activation by reduced expression of markers α-SMA and COL-1/3, and reduced macrophage in liver. In the in vitro study, plumbagin induced apoptosis and suppressed the proliferation of LX-2 cells (human HSCs). Plumbagin treatment increased AMPK phosphorylation and attenuated NF-κB, STAT3, and Akt/mTOR signals in LX-2 cells, while SMAD2 phosphorylation was not changed. Noticeably, plumbagin promoted AMPK binding to p300 which is a cofactor of SMAD complex, this may further competitively decreases the p300/SMAD complex initiated transcription of COL-1/3 and α-SMA. Additionally, plumbagin hampered inflammation related NF-κB signal in RAW 264.7 cells. In conclusion, these findings indicate that plumbagin may be a powerful drug candidate to protect the liver from acute and chronic damage by inhibiting inflammation and collagen production.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Apoptosis; Chemical and Drug Induced Liver Injury; Collagen Type I; Collagen Type III; Cytoprotection; Female; Hepatic Stellate Cells; Humans; Liver; Liver Cirrhosis, Experimental; Liver Failure, Acute; Liver Regeneration; Mice; Mice, Inbred ICR; Myofibroblasts; Naphthoquinones; NF-kappa B; p300-CBP Transcription Factors; Phosphorylation; Proto-Oncogene Proteins c-akt; RAW 264.7 Cells; Signal Transduction; STAT3 Transcription Factor; Thioacetamide; TOR Serine-Threonine Kinases

Quinone toxicity is induced by two principal mechanisms: arylation/alkylation and a redox cycle. We have previously shown that increases in intracellular levels of superoxide anion and cell death induced by 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), a redox cycling quinone, are enhanced by pretreatment of rat primary hepatocytes with cytochrome P450 inhibitors. This indicates a novel interaction of quinones with cytochrome P450, and is thus worthy of further investigation using an in vivo model. The aim of this study was to examine the effects of cytochrome P450 inhibitors on DMNQ-induced hepatotoxicity in rats. When DMNQ was administered intraperitoneally, the activities of serum alanine aminotransferase and aspartate aminotransferase were found to increase in a dose-dependent manner, indicating that hepatotoxicity was induced by treatment with DMNQ. Pretreatment with the cytochrome P450 inhibitors SKF-525A (SKF), cimetidine and ketoconazole potentiated the DMNQ-induced hepatotoxicity. The blood concentration of DMNQ was not affected by administration of SKF. Pretreatment with the antioxidant α-tocopherol almost completely attenuated the hepatotoxicity induced by DMNQ and by the combination of DMNQ with SKF. Levels of reduced glutathione in the liver were decreased and levels of oxidized glutathione were increased by treatment with DMNQ. These effects were potentiated by pretreatment with SKF. DMNQ-induced lipid peroxidation in the liver was also enhanced by pretreatment with SKF. Taken together, these results indicate that DMNQ-induced hepatotoxicity is augmented by inhibition of cytochrome P450 and that this augmentation is due to the enhancement of oxidative stress.

Topics: alpha-Tocopherol; Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Cimetidine; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Glutathione; Ketoconazole; Lipid Peroxidation; Liver; Male; Naphthoquinones; Oxidation-Reduction; Oxidative Stress; Proadifen; Rats; Rats, Wistar; Substrate Cycling

This paper describes the antileishmanial properties of LQB-118, a new compound designed by molecular hybridization, orally active in Leishmania amazonensis-infected BALB/c mice.. In vitro antileishmanial activity was determined in L. amazonensis-infected macrophages. For in vivo studies, LQB-118 was administered intralesionally (15 μg/kg/day, five times a week), intraperitoneally (4.5 mg/kg/day, five times a week) or orally (4.5 mg/kg/day, five times a week) to L. amazonensis-infected BALB/c mice throughout experiments lasting 85 or 105 days. At the end of the experiments, serum levels of alanine aminotransferase, aspartate aminotransferase and creatinine were measured as toxicological parameters.. LQB-118 was active against intracellular amastigotes of L. amazonensis [50% inhibitory concentration (IC(50)) 1.4 μM] and significantly less so against macrophages (IC(50) 18.5 μM). LQB-118 administered intralesionally, intraperitoneally or orally was found to control both lesion and parasite growth in L. amazonensis-infected BALB/c mice, without altering serological markers of toxicity.. These results demonstrate that the molecular hybridization of a naphthoquinone core to pterocarpan yielded a novel antileishmanial compound that was locally and orally active in an experimental cutaneous leishmaniasis model.

Topics: Administration, Oral; Administration, Topical; Alanine Transaminase; Animals; Antiprotozoal Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Creatinine; Disease Models, Animal; Inhibitory Concentration 50; Leishmania mexicana; Leishmaniasis, Cutaneous; Liver; Mice; Mice, Inbred BALB C; Naphthoquinones; Pterocarpans; Rodent Diseases; Serum; Treatment Outcome

The cytoprotective effect of green tea extract and its phenolic compounds against 1,4-naphthoquinone-induced hepatotoxicity was evaluated in primary cultured rat hepatocytes. After exposure to 1,4-naphthoquinone, lactate dehydrogenase (LDH) leakage and cell viability were both improved by the presence of the tea extract and tea polyphenols. This cytoprotective effect was related to the structure of tea polyphenols, the galloyl group of (-)-epigallocatechin-3-gallate and (-)-epicatechin-3-gallate being particularly effective. The production of liquid peroxidation by 1,4-naphthoquinone was not inhibited by the tea extract nor by tea polyphenol addition. After 2 h of incubation, the protein thiol concentration was reduced by 1,4-naphthoquinone, but this reduction was prevented by the tea extract and tea polyphenols. The reduction in protein thiol content of the cells closely paralleled the LDH leakage and loss of cell viability. These results suggest that the mechanism of protection by tea polyphenols against 1,4-naphthoquinone-induced toxicity to rat hepatocytes was due to the maintenance of protein thiol levels.

Topics: Animals; Cells, Cultured; Chemical and Drug Induced Liver Injury; Drug Interactions; Liver; Liver Diseases; Male; Naphthoquinones; Phenols; Plant Extracts; Polymers; Rats; Rats, Sprague-Dawley; Sulfhydryl Compounds; Tea

Luteoskyrin is a hepatotoxic and hepatocarcinogenic bisdihydroanthraquinone produced by Penicillium islandicum Sopp. By observing the EPR spectra of DMPO-spin adducts and luteoskyrin semiquinone radical, we investigated in vitro whether luteoskyrin is reduced to its semiquinone radical leading to the generation of active oxygen species in redox systems catalyzed by NADPH-dependent cytochrome reductases of the liver. We found (1) the formation of luteoskyrin semiquinone radical in the NADPH-cytochrome P-450 reductase system under anaerobic conditions, (2) the generation of O2- in the systems composed of luteoskyrin, NAD(P)H, and either rat liver microsomal NADPH-cytochrome P-450 reductases or submitochondrial particles and (3) dicoumarol showed no effect on the O2- generation in the case of submitochondrial particles. From these results we proposed that luteoskyrin liver injuries are induced by the active oxygen species generated in the process of autoxidation of luteoskyrin semiquinone radical which is produced in the one-electron redox systems catalyzed by the liver NAD(P)H-dependent cytochrome reductases.

Topics: Animals; Carcinogenicity Tests; Chemical and Drug Induced Liver Injury; Electron Spin Resonance Spectroscopy; Free Radicals; Liver; Liver Neoplasms; Mycotoxins; NADH, NADPH Oxidoreductases; Naphthoquinones; Oxidation-Reduction; Penicillium; Rats; Rats, Sprague-Dawley; Superoxides

Topics: Alanine Transaminase; Animals; Chemical and Drug Induced Liver Injury; Cobalt; Dibenzylchlorethamine; Drug Synergism; Female; Liver; Male; Mice; Naphthoquinones; Piperonyl Butoxide; Proadifen; Time Factors

Topics: Aflatoxins; Animal Feed; Animals; Cattle; Chemical and Drug Induced Liver Injury; Chickens; Food Contamination; Humans; Liver Diseases; Male; Mycotoxins; Naphthoquinones; Ochratoxins; Patulin; Rats; Sterigmatocystin; Swine

Topics: Animals; Chemical and Drug Induced Liver Injury; Liver; Male; Mice; Naphthoquinones; Penicillium; Triglycerides

Topics: Animals; Biotransformation; Chemical and Drug Induced Liver Injury; Diet; Kidney; Liver; Male; Mice; Mycotoxins; Naphthoquinones; Penicillium; Pigments, Biological

Topics: Age Factors; Animals; Anthraquinones; Cell Nucleus; Chemical and Drug Induced Liver Injury; Female; Kinetics; Liver; Male; Mice; Mice, Inbred Strains; Microsomes, Liver; Mitochondria, Liver; Naphthoquinones; Penicillium; Proteins; Sex Factors; Subcellular Fractions; Time Factors; Tritium

Topics: Animals; Body Weight; Carcinogens; Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury; Chlorine; Diet; Dose-Response Relationship, Drug; Female; Lethal Dose 50; Liver; Liver Cirrhosis; Liver Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred Strains; Mycotoxins; Naphthoquinones; Necrosis; Oryza; Penicillium; Peptides, Cyclic; Sex Factors