iridoids and Chemical-and-Drug-Induced-Liver-Injury

Genipin is an aglycone derived from the geniposide, the most abundant iridoid glucoside constituent of Gardenia jasminoides Ellis. For decades, genipin is the focus of studies as a versatile compound in the treatment of various pathogenic conditions. In particularly, Gardenia jasminoides Ellis has long been used in traditional Chinese medicine for the prevention and treatment of liver disease. Mounting experimental data has proved genipin possesses therapeutic potential for cholestatic, septic, ischemia/reperfusion-triggered acute liver injury, fulminant hepatitis and NAFLD. This critical review is a reflection on the valuable lessons from decades of research regarding pharmacological activities of genipin. Of note, genipin represents choleretic effect by potentiating bilirubin disposal and enhancement of genes in charge of the efflux of a number of organic anions. The anti-inflammatory capability of genipin is mediated by suppression of the production and function of pro-inflammatory cytokines and inflammasome. Moreover, genipin modulates various transcription factor and signal transduction pathway. Genipin appears to trigger the upregulation of several key genes encoding antioxidant and xenobiotic-metabolizing enzymes. Furthermore, the medicinal impact of genipin extends to modulation of regulated cell death, including autophagic cell death, apoptosis, necroptosis and pyroptosis, and modulation of quality of cellular organelle. Another crucial effect of genipin appears to be linked to dual role in targeting uncoupling protein 2 (UCP2). As a typical UCP2-inhibiting compound, genipin could inhibit AMP-activated protein kinase or NF-κB in circumstance. On the contrary, reactive oxygen species production and cellular lipid deposits mediated by genipin through the upregulation of UCP2 is observed in liver steatosis, suggesting the precise role of genipin is disease-specific. Collectively, we comprehensively summarize the mechanisms and pathways associated with the hepatoprotective activity of genipin and discuss potential toxic impact. Notably, our focus is the direct medicinal effect of genipin itself, whereas its utility as a crosslinking agent in tissue engineering is out of scope for the current review. Further studies are therefore required to disentangle these complicated pharmacological properties to confer this natural agent a far greater potency.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cell Death; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Humans; Iridoids; Liver; Massive Hepatic Necrosis; Mitochondria, Liver; Non-alcoholic Fatty Liver Disease; Uncoupling Protein 2

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Cholestasis; Glutathione; Iridoids; Liver; Mice

Gardeniae Fructus (Zhizi in Chinese, ZZ in brief), a commonly used herbal medicine, has aroused wide concern for hepatotoxicity, but the mechanism remains to be investigated. This study was aimed at investigating the mechanism of ZZ-induced liver injury in vivo and in vitro based on metabolomics and evaluating the hepatotoxicity prediction ability of the in vitro model. SD rats were administered with extracted ZZ and HepG2 cells were treated with genipin, the major hepatotoxic metabolite of ZZ. Liver, plasma, intracellular and extracellular samples were obtained for metabolomics analysis. As a result, ZZ caused plasma biochemical and liver histopathological alterations in rats, and induced purine and amino acid metabolism disorder in the liver and pyrimidine, primary bile acids, amino acid metabolism and pantothenate and CoA biosynthesis disorder in the plasma. Pyrimidine, purine, amino acid metabolism and pantothenate and CoA biosynthesis were also found to be disturbed in the genipin-treated HepG2 cells, which exhibited similarity with the result in vivo. This study comprehensively illustrates the underlying mechanism involved in ZZ-related hepatotoxicity from the aspect of metabolome, and provides evidence that identifying hepatotoxicity can be achieved in cells, representing a non-animal alternative for systemic toxicology.

Topics: Animals; Cell Survival; Chemical and Drug Induced Liver Injury; Fruit; Gardenia; Hep G2 Cells; Humans; Iridoids; Plant Extracts; Rats; Rats, Sprague-Dawley

Alcoholic steatosis is one of the most prevalent forms of liver disease, and appropriate insight and application of anti-steatosis drugs must be considered. Geniposide, the major active constituent of the

Topics: Animals; Chemical and Drug Induced Liver Injury; Drug Overdose; Fatty Liver, Alcoholic; Fruit; Gardenia; Iridoids; Male; Phytotherapy; PPAR alpha; Proteome; Proteomics; Rats, Sprague-Dawley; Transcription Factors

The aim of this paper was to screen out relevant genes of geniposide-induced hepatotoxicity based on genomics,in order to provide a scientific basis for the non-clinical evaluation of drugs containing Gardeniae Fructus and geniposide. Fifty-five SD rats were randomly divided into normal control group,24 h group and 72 h group. The changes of appearance,behavior and weight of rats were observed after administration by gavage for 3 days. The activities of ALT and AST were detected. Molecular mechanism of geniposideinduced hepatotoxicity was investigated by Affymetrix miRNA 4. 0 and Affymetrix Rat Gene 2. 0 to examine the gene expression levels in Sprague-Dawley rat livers at 24 h and 72 h after administration of overdose-geniposide( 300 mg·kg-1 daily),and then verified by Realtime quantitative PCR. Compared with the normal control group,the activities of ALT and AST were markedly increased. In addition,experimental results indicated that 324 genes were differentially expressed,among which 259 were up-regulated and 65 down-regulated.Nine candidate genes were verified by qRT-PCR,including Bcl2,Il1 b,Tpm3,MMP2,Col1α1,Ifit1,Aldob,Nr0 b2,Cyp2 c23. And Bcl2,Col1α1,Aldob,Nr0 b2 and Cyp2 c23 were found to be correlated with geniposide-induced hepatotoxicity. This study provides an important clue for mechanism of geniposide-induced hepatotoxicity.

Topics: Animals; Biomarkers; Chemical and Drug Induced Liver Injury; Genomics; Iridoids; Liver; Rats; Rats, Sprague-Dawley

Genipin, as the most effective ingredient of various traditional medications, encompasses antioxidative, anti-inflammatory, and antibacterial capacities. More recently, it is suggested that genipin protects against septic liver damage by restoring autophagy. The purpose of the current study was to explore the protective effect of genipin against carbon tetrachloride- (CCl

Topics: Animals; Autophagy; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Inflammation; Iridoids; Liver; Male; Medicine, Traditional; Mice; Rubiaceae

Topics: Animals; Biomarkers; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Computational Biology; Disease Models, Animal; Drugs, Chinese Herbal; Iridoids; Liver; Metabolic Networks and Pathways; Metabolome; Metabolomics; Rats; Reproducibility of Results; Tandem Mass Spectrometry; Tissue Distribution

Geniposide is a natural hepatotoxic iridoid glycoside. Its hydrolysate of intestinal microbiota, genipin, is thought to be responsible for the hepatotoxicity. However, the underlying mechanism that genipin contributes to the hepatotoxicity of geniposide is not well understood. In this study, we found that genipin spontaneously converted into a reactive dialdehyde intermediate and covalently bond to the primary amine group of free amino acids in both of the phosphate buffers and geniposide-treated rats. Furthermore, genipin dialdehyde can form the covalent linkage to the primary amino group (ε) of lysine side chains of the hepatic proteins in geniposide-treated rats. Pretreatment with β-glucosidase or antibiotics significantly modulated the genipin dialdehyde formation and protein modification, revealing the essential role of microbial glycosidases. The levels of protein adduct were that mapped onto the hepatotoxicity of geniposide. In summary, this study demonstrates that the intestinal microbiota mediated covalent modification of the hepatic protein by genipin dialdehyde may play a crucial role in the liver injury of geniposide. The study is also helpful for understanding the contribution of intestinal microbiota to the metabolic activation of xenobiotics.

Topics: Aldehydes; Amino Acids; Animals; Anti-Bacterial Agents; beta-Glucosidase; Bile; Chemical and Drug Induced Liver Injury; Gastrointestinal Microbiome; Glutathione; Glycoside Hydrolases; Iridoids; Liver; Lysine; Male; Rats; Rats, Sprague-Dawley

Acetaminophen (APAP) is a widely used over-the-counter drug for antipyretic and analgesic, but an overdose will induce acute liver injury. APAP hepatotoxicity has been the most common cause of acute liver failure in western countries with high morbidity and mortality. Geniposide (GP), an iridoid glycoside extracted from the fruit of Gardenia jasminoides, has been reported to exert a profound anti-inflammatory activity on acute and chronic diseases. However, it is never demonstrated whether GP can protect hepatocytes from APAP hepatotoxicity. In this study, we investigated the protective effect and underlying mechanism of GP against AILI. The results showed that GP pretreatment reduced the levels of ALT and AST in a dose-dependent manner and alleviated hepatocyte necrosis and apoptosis in mice exposed at APAP. Moreover, it suppressed the expression of CYP 2E1 and attenuated the exhaustion of GSH and accumulation of MDA in the liver. Furthermore, GP remarkably inhibited inflammatory cells infiltration and mitigated the release of IL-1β and TNF-α, and inhibited Toll-like receptor 4 (TLR4) expression and nuclear factor kappa (NF-κB) activation. These data suggested that GP could effectively protect hepatocytes from APAP hepatotoxicity through the down-regulation of CYP 2E1 expression and the inhibition of TLR4/NF-κB signaling pathway.

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2E1; Down-Regulation; Glutathione; Hepatocytes; Interleukin-1beta; Iridoids; Liver; Macrophages; Male; Malondialdehyde; Mice, Inbred C57BL; Neutrophils; NF-kappa B; Protective Agents; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Hepatotoxicity induced by cyclophosphamide (Cyclo) is a major concern in clinical practice. This study was designed to investigate the possible cytoprotective effect of natural antioxidants as oleuropein and quercetin against Cyclo induced hepatotoxicity via the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Male Wistar rats were randomly divided into six groups and treated for 10 days as follow: Group I (Normal control) received saline, group II (Oleu control): received orally oleuropein 30 mg/kg/day, group III (Quer control): administered orally quercetin 50 mg/kg/day, group IV (Cyclo): received saline and injected with single intraperitoneal (i.p) dose of Cyclo 200 mg/kg at day 5, group V (Oleu ttt): treated with oleuropein plus Cyclo i.p. injection at day 5, and group VI (Quer ttt): treated with quercetin plus Cyclo i.p. injection at day 5. Injection of Cyclo showed marked increase in serum transaminases and alkaline phosphatase, hepatic malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-⍺) levels along with significant reduction in hepatic reduced glutathione (GSH), superoxide dismutase (SOD), and catalase levels in addition to downregulation of hepatic Nrf2 and HO-1 expressions and reduction in hepatic nuclear Nrf2 binding activity when compared with normal group. Histopathological examination of Cyclo treated rats revealed hepatic damage. Both oleuropein and quercetin exhibited an improvement in the biochemical and histopathological findings. In conclusion, the natural antioxidants oleuropein and quercetin counteract the Cyclo induced hepatotoxicity through activation of Nrf2/HO-1 signaling pathway with subsequent suppression of oxidative stress and inflammation.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Biological Products; Chemical and Drug Induced Liver Injury; Cyclophosphamide; Disease Models, Animal; Heme Oxygenase-1; Humans; Iridoid Glucosides; Iridoids; Liver; Male; NF-E2-Related Factor 2; Oxidative Stress; Quercetin; Rats; Rats, Wistar; Signal Transduction

Acute liver failure (ALF) is a life-threatening syndrome resulting from massive inflammation and hepatocyte death. Necroptosis, a programmed cell death controlled by receptor-interacting protein kinase (RIP) 1 and RIP3, has been shown to play an important role in regulating inflammation via crosstalk between other intracellular signaling. The inflammasome is a major intracellular multiprotein that induces inflammatory responses by mediating immune cell infiltration, thus potentiating injury. Genipin, a major active compound of the gardenia fruit, exhibits anti-inflammatory, antioxidant, and anti-apoptotic properties. This study investigated the hepatoprotective mechanisms of genipin on d-galactosamine (GalN) and lipopolysaccharide (LPS)-induced ALF, particularly focusing on interaction between necroptosis and inflammasome. Mice were given an intraperitoneal injection of genipin (25, 50, and 100mg/kg) or necrostatin-1 (Nec-1, a necroptosis inhibitor; 1.8mg/kg) 1h prior to GalN (800mg/kg)/LPS (40μg/kg) injection and were killed 3h after GalN/LPS injection. Genipin improved the survival rate and attenuated increases in serum aminotransferase activities and inflammatory cytokines after GalN/LPS injection. Genipin reduced GalN/LPS-induced increases in RIP3, phosphorylated RIP1 and RIP3 protein expression, and RIP1/RIP3 necrosome complex, similar to the effects of Nec-1. GalN/LPS significantly increased serum levels of high-mobility group box 1 and interleukin (IL)-33, which were attenuated by genipin and Nec-1. Moreover, similar to Nec-1, genipin attenuated GalN/LPS-induced increases in the protein expression levels of NLRP3, ASC, and caspase-1, inflammasome components, and levels of liver and serum IL-1β. Taken together, our findings suggest that genipin ameliorates GalN/LPS-induced hepatocellular damage by suppressing necroptosis-mediated inflammasome signaling.

Topics: Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Galactosamine; Inflammasomes; Iridoids; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Necrosis; NLR Family, Pyrin Domain-Containing 3 Protein; Receptors, Pattern Recognition; Signal Transduction

Fructus Gardenia (FG), containing the major active constituent Geniposide, is widely used in China for medicinal purposes. Currently, clinical reports of FG toxicity have not been published, however, animal studies have shown FG or Geniposide can cause hepatotoxicity in rats. We investigated Geniposide-induced hepatic injury in male Sprague-Dawley rats after 3-day intragastric administration of 100 mg/kg or 300 mg/kg Geniposide. Changes in hepatic histomorphology, serum liver enzyme, serum and hepatic bile acid profiles, and hepatic bile acid synthesis and transportation gene expression were measured. The 300 mg/kg Geniposide caused liver injury evidenced by pathological changes and increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and γ-glutamytransferase (γ-GT). While liver, but not sera, total bile acids (TBAs) were increased 75% by this dose, dominated by increases in taurine-conjugated bile acids (t-CBAs). The 300 mg/kg Geniposide also down-regulated expression of Farnesoid X receptor (FXR), small heterodimer partner (SHP) and bile salt export pump (BSEP). In conclusion, 300 mg/kg Geniposide can induce liver injury with associated changes in bile acid regulating genes, leading to an accumulation of taurine conjugates in the rat liver. Taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA) as well as tauro-α-muricholic acid (T-α-MCA) are potential markers for Geniposide-induced hepatic damage.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; ATP Binding Cassette Transporter, Subfamily B, Member 11; Bile Acids and Salts; Biomarkers; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Early Diagnosis; gamma-Glutamyltransferase; Gene Expression Regulation; Iridoids; Male; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear

Tripterygium glycosides (TG) are commonly used for basic medicine in curing rheumatoid arthritis but with a high incidence of liver injury. Geniposide (GP) has broad and diverse bioactivities, but until now it is still unknown whether GP can protect against TG-induced liver injury. This study, for the first time, observed the possible protection of GP against TG-induced liver injury in mice and its mechanisms underlying. Oral administration of TG (270 mg/kg) induced significant elevation in the levels of serum alanine / aspartate transaminase (ALT/AST), hepatic malondialdehyde (MDA) and pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) (all P < 0.01). On the other hand, remarkably decreased biomarkers, including hepatic glutathione (GSH) level, activities of glutathione transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT), and anti-inflammatory cytokine interleukin (IL)-10, were observed following TG exposure (all P < 0.01). Nevertheless, all of these phenotypes were evidently reversed by pre-administration of GP for 7 continuous days. Further analysis showed that the mRNA expression of hepatic growth factor-beta1 (TGF-β1), one of tissue repair and regeneration cytokines, was enhanced by GP. Taken together, the current research suggests that GP protects against TG-induced liver injury in mice probably involved during attenuating oxidative stress and inflammation, and promoting tissue repair and regeneration.

Topics: Administration, Oral; Alanine Transaminase; Animals; Anti-Inflammatory Agents; Antirheumatic Agents; Chemical and Drug Induced Liver Injury; Gene Expression; Glutathione; Glycosides; Iridoids; Liver; Liver Regeneration; Male; Mice, Inbred Strains; Oxidative Stress; Phytotherapy; RNA, Messenger; Transforming Growth Factor beta1; Tripterygium; Tumor Necrosis Factor-alpha

Alcohol-induced liver injury (ALD) shows obvious metabolic disorders, categorized by a wide range of metabolite abnormalities. High-throughput metabolomics technology appears to be an appropriate solution. In this study, a urine metabolic profile was assessed using a UPLC-Q-TOF/HDMS (liquid chromatography coupled to high resolution mass spectrometry) approach to investigate the underlying molecular mechanisms of ALD and the therapeutic effect of geniposide. The endogenous low-molecular-weight metabolites in the mouse model of ALD were observed and 48 specific biomarkers were identified. Geniposide was found to have a regulatory effect on 32 of them. Furthermore, targeted analysis of biomarkers showed clear separation between the model and geniposide treatment group. Fifteen biomarkers with high contribution to group differentiation were screened out. Also, a comprehensive analysis of a significant disturbance of multiple metabolic pathways indicated that geniposide could modify abnormal metabolism due to ethanol exposure, during which disorders relating to amino acid metabolism and the oxidative stress state could be alleviated. At the same time, accessory examinations, including plasma biochemical indicators and liver tissue pathological analysis, showed similar results. It was suggested that geniposide was effective as a hepatoprotective agent against ethanol-induced liver damage by re-balancing a wide range of metabolic disorders.

Topics: Animals; Biomarkers; Biopsy; Chemical and Drug Induced Liver Injury; Chromatography, Liquid; Cluster Analysis; Disease Models, Animal; Ethanol; Immunohistochemistry; Iridoids; Male; Mass Spectrometry; Metabolic Networks and Pathways; Metabolome; Metabolomics; Mice; Phenotype

Geniposide (GP), an iridoid glucoside extracted from Gardenia jasminoides Ellis fruits, has been used as a herbal medicine to treat liver and gall bladder disorders for many years. However the mechanism of anti-inflammatory is largely unknown. In this study, GP significantly attenuated inflammation in acute liver injury (ALI) mice model and in lipopolysaccharide (LPS)-induced THP-1 cells. It was demonstrated that GP obviously decreased the expression of Methyl-CpG binding protein 2 (MeCP2) in vivo and in vitro. Knockdown of MeCP2 with siRNA suppressed the expressions of IL-6 and TNF-α, while over-expression of MeCP2 had a proinflammatory effect on the expression of IL-6 and TNF-α in LPS-induced THP-1 cells. Mechanistically, it was indicated that GP had anti-inflammatory effects at least in part, through suppressing MeCP2. Interestingly, GP could attenuate expressions of Sonic hedgehog (Shh) and GLIS family zinc finger 1 (GLIS1) but increase Ptched1 (PTCH1) expression. Similar findings were also demonstrated at the protein level by siRNA MeCP2. Furthermore, over-expression of MeCP2 obviously increased Shh and GLIS1 expressions but reduced PTCH1 expression. Taken together, GP may serve as an effective modulator of MeCP2-hedgehog pathway (Hh)-axis during the pathogenesis of inflammation. Our findings shed light on the potential therapeutic feature of GP in recovering inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbon Tetrachloride Poisoning; Cell Line; Chemical and Drug Induced Liver Injury; Gene Expression; Gene Knockdown Techniques; Hedgehog Proteins; Inflammation; Interleukin-6; Iridoids; Liver; Methyl-CpG-Binding Protein 2; Mice; Mice, Inbred C57BL; RNA, Small Interfering; Tumor Necrosis Factor-alpha

Total iridoids and xanthones (TIXS) were extracted from Swertia mussotii Franch, one of the most important eight Tibetan medicines in China, which was recorded in the book of Jingzhu Bencao and used for clinical treatment of cholestatic hepatitis for many years. Our aim was to study the hepatoprotective effect and chemical constituents of the TIXS.. Crude extracts were prepared using 90% ethanol, and individual fractions were collected following HPD-300 macroporous resin column chromatography. HPLC/MS was applied to qualitatively and quantitatively analyze the TIXS. Then, the alpha-naphthylisot hiocyanate-induced liver damage model was used to assess the hepatoprotective effect of the TIXS.. A total of 12 compounds were identified by the fingerprint chromatography of the TIXS, and swertiamarin and swertianolin were shown to be its two main components. Oral administration of the TIXS at a dose of 35, 70 or 140 mg kg(-1), swertiamarin at a dose of 20 mg kg(-1) or swertianolin at a dose of 20 mg kg(-1), for 7 days in mice significantly reduced the alpha-naphthylisot hiocyanate-induced levels of alanine aminotransferase, aspartate aminotransferase and the total and direct bilirubins, and increased the bile flow (P<0.01).. These findings suggest that the TIXS exhibits significant hepatoprotective effect in the liver damage model induced by alpha-naphthylisot hiocyanate. Its active constituents include swertiamarin and swertianolin.

Topics: 1-Naphthylisothiocyanate; Animals; Bile; Chemical and Drug Induced Liver Injury; Iridoids; Liver; Phytotherapy; Protective Agents; Rats, Wistar; Swertia; Xanthones

The objective of this work was to investigate the effects of the methanol extracts of Gentiana cruciata L. aerial parts (GCA) and roots (GCR) against carbon tetrachloride-induced liver injury in rats. Pretreatment with GCA and GCR, containing sweroside, swertiamarin and gentiopicrin in high concentrations, dose-dependently and significantly decreased the levels of serum transaminases, alkaline phosphatase and total bilirubin, whereas an increase in the level of total protein was found compared with the CCl4-treated group. Moreover, oral administration of extracts significantly enhanced antioxidant enzyme activities (superoxide dismutase and catalase), increased the content of glutathione and decreased the content of TBARS. Microscopic evaluations of the liver revealed CCl4-induced lesions and related toxic manifestations that were minimal in the liver of rats pretreated with extracts at the dose of 400 mg per kg b.w. The results suggest that the use of G. cruciata extracts has a merit as a potent candidate in protecting the liver against chemical induced toxicity.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antioxidants; Aspartate Aminotransferases; Bilirubin; Biomarkers; Carbon Tetrachloride; Catalase; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Gentiana; Glutathione; Iridoid Glucosides; Iridoids; Liver; Male; Oxidative Stress; Plant Extracts; Plant Roots; Pyrones; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Evaluating the safety of traditional medicinal herbs and their major active constituents is critical for their widespread usage. Geniposide, a major active constituent with a defined structure from the traditional medicinal herb Gardenia jasminoides ELLIS fruit, exhibits remarkable anti-inflammatory, antiapoptotic, and antifibrotic properties and has been used in a variety of medical fields, mainly for the treatment of liver diseases. However, geniposide-induced hepatotoxicity and methods for the early detection of hepatotoxicity have yet to be reported. In this study, geniposide-induced hepatotoxicity was investigated. In addition, candidate biomarkers for the earlier detection of geniposide-induced hepatotoxicity were identified using a label-free quantitative proteomics approach on a geniposide overdose-induced liver injury in a rat model. Using an accurate intensity-based, absolute quantification (iBAQ)-based, one-step discovery and verification approach, a candidate biomarker panel was easily obtained from individual samples in response to different conditions. To determine the biomarkers' early detection abilities, five candidate biomarkers were selected and tested using enzyme-linked immunosorbent assays (ELISAs). Two biomarkers, glycine N-methyltransferase (GNMT) and glycogen phosphorylase (PYGL), were found to indicate hepatic injuries significantly earlier than the current gold standard liver biomarker. This study provides a first insight into geniposide-induced hepatotoxicity in a rat model and describes a method for the earlier detection of this hepatotoxicity, facilitating the efficient monitoring of drug-induced hepatotoxicity.

Topics: Animals; Biomarkers; Chemical and Drug Induced Liver Injury; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Glycine N-Methyltransferase; Glycogen Phosphorylase; Iridoids; Liver; Male; Proteome; Proteomics; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity

Olives and olive products, an inevitable part of the Mediterranean diet, possess various beneficial effects, such as a decreased risk of cardiovascular disease and cancer. Oleuropein is a non-toxic secoiridoid found in the leaves and fruits of olive (Olea europaea L.). In this study, we have investigated the hepatoprotective activity of oleuropein in carbon tetrachloride (CCl(4))-induced liver injury in male BALB/cN mice. Oleuropein in doses of 100 and 200mg/kg was administered intraperitoneally (ip) once daily for 3 consecutive days, prior to CCl(4) administration (the preventive treatment), or once daily for 2 consecutive days 6h after CCl(4) intoxication (the curative treatment). CCl(4) intoxication resulted in a massive hepatic necrosis and increased plasma transaminases. Liver injury was associated with oxidative/nitrosative stress evidenced by increased nitrotyrosine formation as well as a significant decrease in superoxide dismutase activity and glutathione levels. CCl(4) administration triggered inflammatory response in mice livers by inducing expression of nuclear factor-kappaB, which coincided with the induction of tumor necrosis factor-alpha, cyclooxygenase-2 and inducible nitric oxide synthase. In both treatment protocols, oleuropein significantly attenuated oxidative/nitrosative stress and inflammatory response and improved histological and plasma markers of liver damage. Additionally, in the curative regimen, oleuropein prevented tumor necrosis factor-beta1-mediated activation of hepatic stellate cells, as well as the activation of caspase-3. The hepatoprotective activity of oleuropein was, at least in part, achieved through the NF-E2-related factor 2-mediated induction of heme oxygenase-1. The present study demonstrates antioxidant, anti-inflammatory, antiapoptotic, and antifibrotic activity of oleuropein, with more pronounced therapeutic than prophylactic effects.

Topics: Animals; Antioxidants; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Glutathione; Heme Oxygenase-1; Iridoid Glucosides; Iridoids; Male; Mice; Mice, Inbred BALB C; Oleaceae; Oxidative Stress; Pyrans; Superoxide Dismutase

6,7-Dimethylesculetin (D), geniposide (G) and rhein (R) are the three major active ingredients of Yin-Chen-Hao-Tang (YCHT), a famous Chinese herbal formula, which has been shown to be clinically effective for treating hepatic injury (HI) syndrome. The present study was conducted to investigate the therapeutic and synergistic effects of COC (combination of D, G and R) on HI rats by combining pharmacokinetic with biochemical analysis strategy. Plasma was analyzed by using reversed-phase high performance liquid chromatography (RP-HPLC). Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) models were built to evaluate the therapeutic and synergistic effects of COC at the biochemical level. Here, we report that the COC combination could increase the plasma level, slow elimination rate, exert a more robust therapeutic effect than any one or two of the three individual compounds by hitting multiple targets in a rat model of HI. Overall, this beneficially accounts for the popular view that traditional Chinese medicine (TCM) formula usually takes multi-component to exert their therapeutic effects. We suggest that dissecting the mode of action of clinically effective formula to be capable of producing a sufficient effect at low doses.

Topics: Animals; Anthraquinones; Artemisia; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Drug Combinations; Drug Synergism; Drugs, Chinese Herbal; Gardenia; Iridoids; Least-Squares Analysis; Magnoliopsida; Male; Phytotherapy; Principal Component Analysis; Rats; Rats, Wistar; Rheum; Umbelliferones

The traditional Japanese (kampo) medicine inchinkoto (ICKT) is used in Eastern Asia as a choleretic and hepatoprotective agent. Previously, we reported that ICKT ameliorates murine concanavalin A (con A)-induced hepatitis via suppression of interferon (IFN)-gamma and interleukin (IL)-12 production. In the present study, we investigated the active ingredients of ICKT.. ICKT and extracts of its component herbs were fractionated, and their effects on liver injury and cytokine production in vivo (biochemical markers of liver injury and cytokine levels in serum) and in vitro (cytokine and nitrite production in the cultures of splenocytes and peritoneal macrophages).. Decoctions of component herbs, Artemisiae Capillari Spica (Artemisia capillaris Thunberg: 'Inchinko' in Japanese), Gardeniae Fructus (Gardenia jasminoides Ellis: 'Sanshishi') and Rhei Rhizoma (Rheum palmatum Linné: 'Daio') were administered orally. Inchinko and Sanshishi decreased serum transaminases and IFN-gamma concentrations. Examination of fractions of component herbs suggested that capillarisin, a component of Inchinko, has potent hepatoprotective activity in vivo. In in vitro studies, capillarisin and genipin, an intestinal metabolite of geniposide that is contained in Sanshishi, were examined. IFN-gamma production was significantly suppressed by capillarisin and genipin in con A-stimulated splenocyte culture. Genipin also suppressed IL-1beta, IL-6, and IL-12p70 synthesis. Capillarisin and genipin decreased nitrite release from IFN-gamma-stimulated macrophages.. These results suggested that both Inchinko and Sanshishi may contribute to the protective effects of ICKT against con A hepatitis. Capillarisin was found to be potently hepatoprotective, and genipin may also contribute, especially via modulation of cytokine production.

Topics: Animals; Artemisia; Chemical and Drug Induced Liver Injury; Chromones; Concanavalin A; Cytokines; Disease Models, Animal; Gardenia; Hepatitis; Interferon-gamma; Iridoid Glycosides; Iridoids; Liver; Macrophages; Magnoliopsida; Male; Medicine, Kampo; Mice; Mice, Inbred BALB C; Nitrites; Phytotherapy; Plant Extracts; Rheum; Transaminases

To investigate the hepatoprotective effect of Zhi-Zi-Da-Huang decoction (ZZDHD) and its two fractions (one is extracted with diethyl ether as a solvent from the water extract and is called ZD-DE for short, the other is the remained aqueous fraction after extracted with diethyl ether and is abbreviated as ZD-AQ) against acute alcohol-induced liver injury in rats.. Animals were administered orally with alcohol 6g/kg at 2h after the doses of ZZDHD and two fractions everyday for eight consecutive days except rats in normal group. The protective effect was evaluated by biochemical parameters including aspartate transaminase (AST), alanine transferase (ALT), reduced glutathione (GSH), malondialdehyde (MDA) and superoxide dismutase (SOD). The biochemical observations were supplemented by histopathological examination. HPLC-UV was used for phytochemical analysis of the ZZDHD and its two fractions.. The high dose of ZZDHD exhibited a significant protective effect by reversing the biochemical parameters and histopathological changes. ZD-DE and ZD-AQ demonstrated different protective action in biochemical examination. Partly assayed indexes were ameliorated after administrated the media dose of ZZDHD. HPLC analysis indicated that ZZDHD contained flavonoids, anthraquinones and iridoids, which might be the active chemicals.. This study demonstrated the hepatoprotective activity of ZZDHD thus scientifically supported the usage of this formula.

Topics: Alanine Transaminase; Alcohols; Animals; Anthraquinones; Antioxidants; Aspartate Aminotransferases; Body Weight; Chemical and Drug Induced Liver Injury; Flavonoids; Glutathione; Iridoids; Liver; Magnoliopsida; Male; Malondialdehyde; Plant Extracts; Protective Agents; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

(1) Insomnia should be treated first with non drug measures; this has traditionally involved the use of herbal remedies. (2) About 20 plants are approved in France in the production of medications 'traditionally used' for minor sleep disturbances. Virtually nothing is known of their efficacy or potential dangers. (3) Most of these plants are suspected of toxicity and should therefore be avoided, especially in view of their unproven efficacy. (4) Littleleaf linden, vervain, melissa and orange flower have no demonstrated efficacy but are safe and can therefore be used. Similarly, there are no scientific grounds for rejecting preparations based on hawthorn or passiflora. (5) Available data suggest that valerian extracts have a modest impact on subjective sleep quality; they are nevertheless more effective than a placebo. Valerian products that do not contain valepotriates have no apparent adverse effects. It is best to avoid high-titre alcoholic extracts and powdered valerian root, and to select aqueous extracts and low-titre hydro-alcoholic preparations.

Topics: Anemone; Ballota; Benzodiazepines; Beverages; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Crataegus; Herbal Medicine; Humans; Humulus; Iridoids; Melissa; Passiflora; Phytotherapy; Plant Preparations; Sleep Initiation and Maintenance Disorders; Tilia; Valerian; Verbena

We investigated the effect of tetrahydroswertianolin (THS), a hepatoprotective agent from Swertia japonica, on tumor necrosis factor-alpha (TNF-alpha)-dependent hepatic apoptosis induced by D-galactosamine (D-GalN) (700 mg/kg, i.p.) and lipopolysaccharide (LPS) (10 microg/kg, i.p.) in mice. Apoptotic symptoms were observed at the initial stage of liver damage. By 5 hr after intoxication, hepatic DNA fragmentation had risen to 2123%, with the value in untreated mice set at 100%, without a significant elevation of serum alanine transaminase (ALT) activity. There was a parallel increase in hepatocytes undergoing chromatin condensation and apoptotic body formation. By 8 hr after intoxication, serum ALT activity had risen to 3707 U/L. Pretreatment with THS (50 mg/kg, p.o.) at 18 and 2 hr before intoxication significantly reduced DNA fragmentation to 821% of that in untreated mice and prevented the emergence of chromatin condensation and apoptotic body formation. A significant and dose-dependent reduction in serum ALT activity at 8 hr also was observed with THS pretreatment. These effects of THS were different from those observed from pretreatment with glycyrrhizin (GCR), which is a clinically used hepatoprotective agent with membrane-stabilizing activity. GCR pretreatment (100 mg/kg, p.o.) did not inhibit hepatic DNA fragmentation (1588% of untreated mice), although this compound significantly protected against serum ALT elevation (1463 U/L). These data suggest that an inhibitory effect on the progression of hepatic apoptosis prior to liver injury may be involved in the hepatoprotective mechanisms of THS, whereas it appears that GCR affects the processes after apoptosis. In a separate experiment, we found that the concentration of serum TNF-alpha rose to 2016 pg/mL at 1 hr after intoxication of mice with D-GalN and LPS, but this increase was suppressed by THS pretreatment (10, 50, or 200 mg/kg, p.o.) to 716, 454, or 406 pg/mL, respectively. Further study with a reverse transcriptase-polymerase chain reaction method showed that THS blocked TNF-alpha production at the transcriptional level. Because TNF-alpha is a critical mediator to elicit apoptosis in this model, the property of suppressing TNF-alpha production may be of prime importance for THS inhibition of hepatic apoptosis.

Topics: Analysis of Variance; Animals; Apoptosis; Chemical and Drug Induced Liver Injury; DNA Fragmentation; Enzyme-Linked Immunosorbent Assay; Galactosamine; Glucosides; Iridoid Glucosides; Iridoids; Lipopolysaccharides; Liver Diseases; Male; Mice; Protective Agents; Tumor Necrosis Factor-alpha

The iridoid glycosides including aucubin (AU), catalpol (CA), swertimarin (SW), and gardenoside (GA) are frequently found as natural constituents of many traditional oriental medicinal plants including Chinese herbs. Among these iridoid glycosides, AU was systematically studied for its potent liver-protective activities using experimental systems of hepatic damage. AU showed high liver-protective activity against carbon tetrachloride-induced hepatic damage in mice. Also AU showed significant protective activity against alpha-amanitin-induced hepatic damage in mice, and it prevented a depression of liver RNA biosynthesis caused by alpha-amanitin administration. Potent antidotal effects on mushroom poisoning in beagle dogs ingested with aqueous extract of Amanita virosa was observed; beagle dogs completely survived, even when AU administration was withheld for half an hour after mushroom poisoning. In addition, AU was found to suppress hepatitis B viral DNA replication in vitro. Conversion of AU to its aglycone form appeared to be a prerequisite step for an exhibition of such antiviral activity.

Topics: Amanita; Animals; Antiviral Agents; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Dogs; Drugs, Chinese Herbal; Female; Glucosides; Hepatitis B virus; Iridoid Glucosides; Iridoids; Liver; Mice; Microbial Sensitivity Tests; Mushroom Poisoning

The n-BuOH extract of Swertia japonica showed a significant hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. The activity-guided fractionation led to the isolation of a new tetrahydroxanthone derivative, tetrahydroswertianolin (1), as well as two known iridoids, gentiopicroside (2) and sweroside (3). Their structures were elucidated by spectroscopic methods and chemical reactions. Of the three compounds, 2 and 3 possessed mild hepatoprotective activity at a dose range of 25-50 mg/kg, whereas, 1 exhibited potent activity in a dose-dependent manner. The hepatoprotective effect of tetrahydroswertianolin (1) was stronger than that of glycyrrhizin which was used as a positive control.

Topics: Animals; Chemical and Drug Induced Liver Injury; Galactosamine; Glucosides; Iridoid Glucosides; Iridoids; Lipopolysaccharides; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred Strains; Plant Extracts; Plants, Medicinal; Spectrometry, Mass, Fast Atom Bombardment; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet

An iridoid glucoside, aucubin was isolated from Aucuba japonica leaves and its protective activities against CCl4-induced hepatotoxicity were evaluated by measuring the duration of hypnosis induced by hexobarbital after CCl4 challenge (0.2 ml/kg/day, po) and the levels of serum glutamic-oxalacetic (GOT) and serum glutamic-pyruvic transaminase (GPT). The duration of hypnosis for the saline control group, the CCl4 alone treated group and the aucubin plus CCl4 treated group was 24.8 +/- 8.5, 60.5 +/- 9.5 and 28.0 +/- 3.2 min, respectively. Treatment of mice with aucubin also effectively protected against CCl4-induced increased serum GOT and GPT activities. It was found that aucubin inhibited hepatic RNA and protein syntheses in vivo. Such inhibitory effects of aucubin might be responsible for protective activities against CCl4-induced liver damage.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Glucosides; Glycosides; Hexobarbital; Iridoid Glucosides; Iridoids; Liver; Mice; Protein Biosynthesis; RNA