peoniflorin and Chemical-and-Drug-Induced-Liver-Injury

The risks of Zinc oxide nanoparticles (ZnO NPs) applications in biological medicine, food processing industry, agricultural production and the biotoxicity brought by environmental invasion of ZnO NPs both gradually troubled the public due to the lack of research on detoxification strategies. TFEB-regulated autophagy-pyroptosis pathways were found as the crux of the hepatotoxicity induced by ZnO NPs in our latest study. Here, our study served as a connecting link between preceding toxic target and the following protection mechanism of Paeoniflorin (PF). According to a combined analysis of network pharmacology/molecular docking-intestinal microbiota-metabolomics first developed in our study, PF alleviated the hepatotoxicity of ZnO NPs from multiple aspects. The hepatic inflammatory injury and hepatocyte pyroptosis in mice liver exposed to ZnO NPs was significantly inhibited by PF. And the intestinal microbiota disorder and liver metabolic disturbance were rescued. The targets predicted by bioinformatics and the signal trend in subacute toxicological model exhibited the protectiveness of PF related to the SIRT1-mTOR-TFEB pathway. These evidences clarified multiple protective mechanisms of PF which provided a novel detoxification approach against ZnO NPs, and further provided a strategy for the medicinal value development of PF.

Topics: Animals; Chemical and Drug Induced Liver Injury; Mice; Molecular Docking Simulation; Nanoparticles; Pyroptosis; Zinc Oxide

Acute liver injury (ALI) is a poor prognosis and high mortality complication of sepsis. Paeoniflorin (PF) has remarkable anti-inflammatory effects in different disease models. Here, we explored the protective effect and underlying molecular mechanisms of PF against lipopolysaccharide (LPS)-induced ALI. Sprague-Dawley rats received intraperitoneal (i.p.) injection of PF for 7 days, 1 h after the last administration, and rats were injected i.p. 10 mg/kg LPS. PF improved liver structure and function, reduced hepatic reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) levels, and increased superoxide dismutase (SOD) activity. Western blot analysis suggested that PF significantly inhibited expression of inflammatory cytokines (TNF-α, IL-1β, and IL-18) and inhibited activation of the NLRP3 inflammasome. PF or mitochondrial ROS scavenger (mito-TEMPO) significantly improved liver mitochondrial function by scavenging mitochondrial ROS (mROS), restoring mitochondrial membrane potential loss and increasing level of ATP and enzyme activity of complex I and III. In addition, PF increased expression of sirtuin-1 (SIRT1), forkhead box O1 (FOXO1a) and manganese superoxide dismutase (SOD2), and increased FOXO1a nuclear retention. However, the inhibitor of SIRT1 (EX527) abolished the protective effect of PF. Taken together, PF promotes mROS clearance to inhibit mitochondrial damage and activation of the NLRP3 inflammasome via SIRT1/FOXO1a/SOD2 signaling.

Topics: Animals; Chemical and Drug Induced Liver Injury; Glucosides; Inflammasomes; Inflammation; Lipopolysaccharides; Liver; Monoterpenes; Nerve Tissue Proteins; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Sirtuin 1; Superoxide Dismutase

Drug-induced liver injury (DILI), represented by acetaminophen (APAP), is a common cause of acute liver failure in clinics. Paeoniflorin (PF) has been proven to demonstrate a significant hepatoprotective effect. However, it is still unclear whether it can be a potential agent against hepatotoxicity induced by APAP. This study aimed to explore the preventive and therapeutic effects and mechanisms of PF on APAP-induced liver injury.. Different doses of PF (50, 100, and 200 mg/kg) were given to C57BL/6 male mice for five consecutive days. After 12 h of APAP (250 mg/kg i.p.) treatment, blood and liver tissues were collected and isolated for detection.. The results showed that the therapeutic effects of PF on APAP mice were presented in the downregulation of the content of serum indices and significantly improved hepatic tissue edema and inflammatory infiltration. Meanwhile, PF reduces the level of the mitochondrial metabolic enzyme. Ulteriorly, it was found that PF has a downregulating effect on the apoptotic reaction and could inhibit the protein expression of CYP2E1/JNK signaling, which in turn reduces the damage of APAP.. Our findings showed that PF acted as a protective agent against APAP-induced hepatotoxicity by inhibiting JNK-related signals, suggesting a novel insight into treating APAP-induced liver injury.

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Liver; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Oxidative Stress

Apoptosis induced by the bile acids in the liver is considered to play a pivotal role in the pathogenesis of cholestatic disease. Increasing evidence has demonstrated that Paeoniflorin (PF) exerts therapeutic effect on severe cholestatic liver diseases. However, whether PF could protect against alpha-naphthylisothiocyanate (ANIT)-induced cholestasis by inhibiting apoptosis remains unclear. In this study, we mainly investigated the effect and anti-apoptosis mechanism of PF on cholestasis. Experimental results indicated that PF pretreatment could attenuate liver damage and cholestasis by ANIT in rats, lift the biliary excretion in addition to decrease serum indices (ALT, AST, DBIL, TBIL, TBA, ALP and ϒ-GT) and conspicuous neutrophil infiltration and cell apoptosis in liver evidenced by TUNEL staining. Furthermore, the pro-apoptosis genes expression of Bax, Caspase-9 and Caspase-3 increased by ANIT were prominently reduced after PF treatment. The increase of anti-apoptosis gene and main regulator Bcl-2 in mitochondria by ANIT was largely reversed by PF pre-treatment. In summary, our study demonstrated that PF pre-treatment not only significantly attenuated ANIT-induced cholestasis and liver injury, but also largely reduced cell apoptosis in liver, thus may act as a potential therapeutic agent for cholestasis disease.

Topics: 1-Naphthylisothiocyanate; Animals; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers; Chemical and Drug Induced Liver Injury; Cholestasis; Cytokines; Genes, bcl-2; Glucosides; Liver; Mitochondria; Monoterpenes; Neutrophil Infiltration; Rats; Rats, Wistar; Signal Transduction

Cholestasis is a leading cause of hepatic accumulation of bile acids resulting in liver injury, fibrosis, and liver failure. Paeoniflorin displays bright prospects in liver protective effect. However, its molecular mechanism has not been well-explored. This study was designed to assess the effects and possible mechanisms of paeoniflorin against alpha-naphthylisothiocyanate-induced liver injury. Ultraperformance liquid chromatography coupled with quadrupole time-of-flight combined with principle component analysis and partial least squares discriminant analysis were integrated to obtain differentiating metabolites for the pathways and clarify mechanisms of disease. The results indicated that paeoniflorin could remarkably downregulate serum biochemical indexes and alleviate the histological damage of liver tissue. Different expression of 14 metabolites demonstrated that paeoniflorin mainly regulated the dysfunctions of glycerophospholipid metabolism and primary bile acid biosynthesis. Moreover, several pathways such as arginine and proline metabolism, ether lipid metabolism, and arachidonic acid metabolism were also related to the efficacy. In conclusion, paeoniflorin has indicated favorable pharmacological effect on serum biochemical indexes and pathological observation on cholestatic model. And metabolomics is a promising approach to unraveling hepatoprotective effects by partially regulating the perturbed pathways, which provide insights into mechanisms of cholestasis.

Topics: 1-Naphthylisothiocyanate; Animals; Chemical and Drug Induced Liver Injury; Cholestasis; Drugs, Chinese Herbal; Glucosides; Male; Metabolome; Monoterpenes; Rats; Rats, Sprague-Dawley

It is well established that macrophage infiltration is involved in concanavalin A (conA)-induced liver injury. However, the role of macrophages in conA-induced renal injury remains unknown. The aims of this study were to investigate macrophage infiltration in conA-induced renal injury and determine whether paeoniflorin (PF) could inhibit macrophage infiltration into the kidney.. BALB/C mice were pre-treated with or without PF 2 h (h) before conA injection. At 8 h after con A injection, all the mice were sacrificed; The liver and kidney histology were studied. The renal CD68 expression was detected by immunohistochemical and real-time PCR analysis. The level of expression of C-X-C chemokine receptor type 3 (CXCR3) was analyzed by western blot, immunohistochemical and real-time PCR. The pathophysiological involvement of CXCR3 in macrophage infiltration were investigated using dual-colour immunofluorescence microscopy.. PF administration significantly reduced the elevated serum levels of alanine transaminase (ALT), blood urea nitrogen (BUN), creatinine (Cr) and the severity of liver and renal damage compared with that in the conA-vehicle group. PF administration inhibited the increase in renal IL1β mRNA expression and concentration. Furthermore, immunohistochemical analysis showed that macrophages secreted CXCR3 in the kidneys of the conA-vehicle mice. Immunofluorescence microscopy demonstrated CXCR3 bound tightly to C-X-C motif ligand 11 (CXCL11) in the kidneys of the conA-vehicle mice and showed that PF treatment could suppress CXCR3/CXCL11 over-activation.. Macrophage infiltration was a notable pathological change in the kidneys of conA-treated mice. PF administration attenuated conA-induced renal damage, at least in part, by inhibiting the over-activated CXCR3/CXCL11 signal axis.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Chemical and Drug Induced Liver Injury; Chemokine CXCL11; Concanavalin A; Disease Models, Animal; Female; Glucosides; Immunohistochemistry; Kidney; Macrophages; Mice; Mice, Inbred BALB C; Microscopy, Fluorescence; Monoterpenes; Real-Time Polymerase Chain Reaction; Receptors, CXCR3

Macrophages in other organs (e.g. kidneys, lungs, and spleen, et. al) have rarely been reported in the development of liver fibrosis. Therefore, it is important to investigate macrophage activation in the main organs in liver fibrosis. We investigated the potential antifibrogenic effects of paeoniflorin (PF) in a dimethylnitrosamine (DMN)-induced rat model with special focus on inhibiting macrophage activation in the main organs.. Rat hepatic fibrosis was induced by treatment with DMN three times weekly over a 4-week period. DMN rats were treated with water, PF, or gadolinium chloride (GdCl3) from the beginning of the 3rd week. The expression of CD68, marker of macrophage, was investigated using immunohistochemical, real-time PCR, and western blot analysis.. Hepatic hydroxyproline content markedly decreased and histopathology improved in the DMN-PF rats. Expression of desmin and collagen 1 decreased notably in DMN-PF liver. CD68 expression in the liver, spleen and kidney increased markedly after 2 weeks but decreased in DMN-water rats. PF and GdCl3 decreased CD68 expression in the liver and spleen and there was no effect on kidney. CD68 expression in the lung increased gradually during the course of DMN-induced liver fibrosis, and PF inhibited CD68 expression in the lung significantly while GdCl3 increased CD68 markedly. Expression of tumor necrosis factor (TNF-α) was decreased significantly by GdCl3 in the liver, as revealed by real-time PCR analysis. However, GdCl3 could not decrease TNF-α level in the serum by enzyme linked immunosorbent assay (ELISA).. Macrophage activation was disrupted in the liver, spleen, lung and kidney during development of DMN-induced liver fibrosis. PF administration attenuated DMN-induced liver fibrosis at least in part by regulating macrophage disruption in the main organs.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Benzoates; Bridged-Ring Compounds; Chemical and Drug Induced Liver Injury; Collagen Type I; Desmin; Dimethylnitrosamine; Disease Models, Animal; Glucosides; Hydroxyproline; Kidney; Liver; Liver Cirrhosis; Lung; Macrophages; Male; Monoterpenes; Paeonia; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Spleen; Tumor Necrosis Factor-alpha