iridoids and Cholestasis

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

Swertiamarin (SW), which belongs to iridoid glycosides, is one of the main components of Swertia plants in Gentianaceae family, including Swertia pseudochinensis H. Hara and Swertia mileensis T. N. Ho et W. L. Shi. There are mainly used in traditional Chinese medicine for the treatment of hepatic and biliary disease such as jaundice.. This experiment aimed to explore the protective mechanism of SW on cholestasis induced by alpha-naphthylisothiocyanate in rats.. Healthy rats were randomly divided into the control, model (ANIT, 50 mg/kg), ursodeoxycholic acid (UDCA, 80 mg/kg), and low-dose (SW, 80 mg/kg), medium-dose (SW, 100 mg/kg), and high-dose (SW, 150 mg/kg) groups. The hepatic protective effect of SW was preliminarily evaluated by measurement of serum biochemical indicators and liver morphological evaluation. Moreover, metabolomics and proteomics analysis were used to explore the protective mechanism of SW on cholestasis. The expression of related proteins was determined by Western blot and polymerase chain reaction, and the important proteins were verified by cell experiments in vitro.. SW (100 mg/kg) can reduce the serum levels of the model group. The hepatocyte of the medium-dose treatment group was arranged neatly without evident inflammation. SW can partially reverse the changes in cholestasis metabolites, such as taurocholic acid, SM (d18:1/16:0), all-trans-retinoic acid and other products of rats. The main metabolic pathways affected were primary bile acid synthesis, glycerophospholipid metabolism, sphingolipid metabolism and retinol metabolism. SW medium-dose treatment group showed effective reversal of 25 related proteins and it can remarkably reduce the contents of NTCP and CYP27A1 in rat liver and increase the protein expressions of CYP7A1, CYP8B1, bile salt export pump, multidrug resistance-associated protein and FXR.. SW can alleviate ANIT-induced cholestasis, which by activating the farnesoid X receptor and bile acid excretion pathway.

Topics: 1-Naphthylisothiocyanate; Animals; Bile Acids and Salts; Cholestasis; Iridoid Glucosides; Iridoid Glycosides; Iridoids; Liver; Pyrones; Rats; Swertia

Geniposide (GE) is one of the major iridoid glycosides isolated from the fruit of Gardenia jasminoides Ellis that has been used to treat hepatic disorders including cholestasis. However, the underlying mechanisms for GE ameliorating the reduction in bile acids accumulation by α-naphthylisothiocyanate (ANIT) remain unclear.. The purpose of this study is to characterize the efficacy of GE in regulation of bile acids uptake, synthesis, metabolism, and transport in ANIT-induced rats.. Sprague-Dawley rats were orally administrated with vehicle, GE (25, 50, and 100mg/kg), and ursodeoxycholic acid (UDCA) (60mg/kg) once daily for seven days. On the fifth day, a single dose of ANIT (75mg/kg) was administrated via oral gavage. Blood biochemical determination, bile flow rate and liver histopathology were measured to evaluate the protective effect of GE. The mRNA expressions and protein levels of transporters and enzymes involved in bile acids homeostasis were determined by quantitative real-time polymerase chain reaction (PCR) and western blot to study the underlying mechanism of GE against ANIT-induced rats.. GE (25, 50, and 100mg/kg, po) dose-dependently prevented ANIT-induced changes in serum markers for liver injury. GE treatment reduced basolateral bile acids uptake via repression of OATP2 (P<0.05). Bile acids biosynthesis was decreased through down-regulation of CYP7A1, CYP8B1, and CYP27A1 (P<0.05). GE significantly increased canalicular bile acids secretion via BSEP (P<0.05), subsequently stimulating bile flow during cholestasis. GE also markedly enhanced mRNA level of basolateral transporter OSTβ (P<0.01). Bile acids transported to the plasma were cleared into the urine, resulting in down-regulation of plasma bile acids. However, GE did not alter the mRNA levels of CYP3A2, UGT1A1 and SULT2A1. Furthermore, the gene and protein expression analysis demonstrated activation of FXR, PXR, and SHP after GE administration.. GE attenuates ANIT-induced hepatotoxicity and cholestasis in rats, due to regulation enzymes and transporters responsible for bile acids homeostasis.

Topics: 1-Naphthylisothiocyanate; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cholestasis; Cytochrome P-450 Enzyme System; Down-Regulation; Glucuronosyltransferase; Homeostasis; Iridoids; Liver; Organic Anion Transporters; Pregnane X Receptor; Protective Agents; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Sulfotransferases

Chinese herbal medicinal formulation Yinzhihuang injection is widely used in clinic for jaundice and chronic liver diseases in eastern Asian countries. However, the pharmacologically active components and the underlying mechanism are unclear. In this study, 30 male ICR mice were randomly assigned into 6 groups： normal control, model control, chlorogenic acid group, geniposide group, baicalin group and wogonoside group. The liver function, liver pathological changes and bile acid metabolism-related gene expression in mice were assayed. The serum levels of ALT, AST, ALP, TBA in chlorogenic acid group (15.89±2.53), (18.32±2.56), (26.38±9.87) U•L⁻¹, (40.63±7.67) μmol•L⁻¹, respectively and geniposide group (20.54±2.36), (24.28±5.19), (35.09±5.03) U•L⁻¹, (42.86±7.11) μmol•L⁻¹, respectively were lower than those in the model control group (59.52±10.94), (128.37±17.97),(169.52±9.62) U•L⁻¹, (132.50±33.00) μmol•L⁻¹, respectively. Hematoxylin-eosin staining showed necrosis, infiltration of inflammation cell in chlorogenic acid group and geniposide group were milder than those in the model control group. Q-PCR analysis revealed the expression of bile acid metabolism-related genes was normalized after treatment with chlorogenic acid or geniposide. Chlorogenic acid and geniposide improved the liver injury and cholestasis effectively, and reversed the mRNA expression of bile acid metabolism-related genes induced by ANIT. So, chlorogenic acid and geniposide were protective for cholestasis, suggesting their pharmacodynamic effect in Yinzhihuang injection.

Topics: Alanine Transaminase; Animals; Chlorogenic Acid; Cholestasis; Cholesterol 7-alpha-Hydroxylase; Cytochrome P450 Family 8; Drugs, Chinese Herbal; Flavonoids; Humans; Iridoids; Liver; Male; Mice; Mice, Inbred ICR

Herb pair serves as the basic building block of a traditional Chinese medicine (TCM) formula. The rhubarb-gardenia herb pair (RGHP), composed of rhubarb and gardenia, has meaningful clinical effects to cure cholestasis diseases. This study was designed to confirm the expected synergistic effects of RGHP at pharmacodynamic and pharmacokinetic levels.. Thirty male Sprague-Dawley rats were divided into control, model and drug-treated groups. After intragastrically administrated with α-naphthylisothiocyanate (ANIT) to induce cholestasis, rats were treated with rhubarb, gardenia or RGHP. For pharmacodynamic study, biochemical and histopathological tests were performed to assess the hepatoprotective effects. While for pharmacokinetic study, a LC-MS method was developed for determination of five main chemical markers, namely genipin, rhein, aloe emodin, emodin and chrysophanol in rat plasma.. The biochemical and histopathological tests suggested that RGHP exerted enhanced hepatoprotective effects against the ANIT-induced cholestasis compared with single herbs. The pharmacokinetic study indicated RGHP could significantly elevate systemic exposure level and prolong retention time of five markers in comparison with rhubarb or gardenia alone.. The present study demonstrated the synergistic effects of RGHP in ANIT-induced cholestatic rats at pharmacodynamic and pharmacokinetic levels, and has significant enlightenments for the rational use of the related TCM formulas containing RGHP.

Topics: 1-Naphthylisothiocyanate; Alanine Transaminase; Alkaline Phosphatase; Animals; Anthraquinones; Aspartate Aminotransferases; Bilirubin; Cholestasis; Drug Synergism; Emodin; Fruit; Gardenia; Iridoids; Liver; Male; Plant Extracts; Protective Agents; Rats, Sprague-Dawley; Rheum; Rhizome