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Total C-21 Steroidal Glycosides From Baishouwu Ameliorate Hepatic and Renal Fibrosis by Regulating IL-1β/MyD88 Inflammation Signaling

ABSTRACT: Fibrosis is a worldwide public health problem, which typically results from chronic diseases and often leads to organ malfunction. Chronic inflammation has been suggested to be the major trigger for fibrogenesis, yet mechanisms by which inflammatory signals drive fibrogenesis have not been fully elucidated. Total C-21 steroidal glycosides (TCSG) from Baishouwu are the main active components of the root of Cynanchum auriculatum Royle ex Wight, which exert hepatoprotective and anti-inflammation properties. In this study, we established a mouse model with the coexistence of hepatic and renal fibrosis and aimed to investigate the effects of TCSG from Baishouwu on fibrosis and explored the potential mechanisms. The results of biochemical and pathological examinations showed that TCSG from Baishouwu improved liver and kidney function and alleviated hepatic and renal fibrosis by reducing collagen and extracellular matrix deposition in bile duct ligation and unilateral ureteral occlusion (BDL&UUO) mice. According to network pharmacology analysis, the mechanisms underlying the effects of TCSG from Baishouwu on hepatic and renal fibrosis were associated with inflammatory response pathways, including “Signaling by interleukins”, “MAP kinase activation”, “MyD88 cascade initiated on plasma membrane”, and “Interleukin-1 family signaling”. Regression analysis and western blot results revealed that IL-1β/MyD88 inflammation signaling played an essential role in the anti-fibrotic effects of TCSG from Baishouwu. Further data displayed that TCSG from Baishouwu affected inflammatory response and extracellular matrix deposition via suppressing the activation of p38 MAPK/JNK and NF-κB p65 signaling cascades both in the liver and kidney of BDL&UUO mice. Thus, our findings suggest TCSG from Baishouwu as a natural regimen against hepatic and renal fibrosis and provide direct evidence that IL-1β/MyD88 signaling crucially contributes to hepatic and renal fibrosis and modulates liver-kidney crosstalk by maintaining tight control over inflammatory responses.

SUBMITTER: Qin T

PROVIDER: S-EPMC8576092 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Oxidative stress plays an important role in the pathology of liver disorders. Total C?21 steroidal glycosides (TCSGs), isolated from the root tuber of Cynanchum auriculatum Royle ex Wight, have been reported to exert numerous effects, including liver protective and antioxidant effects. In order to investigate the potential mechanisms underlying the protective effects of TCSGs on liver function, the present study used the human normal liver cell line, L02, to evaluate the effects of TCSGs on hydrogen peroxide (H2O2)?induced oxidative injury and inflammatory responses. The L02 cells were pretreated with various concentrations of TCSGs, followed by exposure to 1.5 mM H2O2. Cell viability was determined by a 3?(4,5?dimethylthiazol?2?yl)?2,5?diphenyltetrazolium bromide (MTT) assay. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and nitric oxide (NO) were measured using colorimetric assays. The activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH?Px) and the production of malondialdehyde (MDA) were also determined. Intracellular reactive oxygen species (ROS) levels were detected using a fluorescent probe. H2O2?induced oxidative toxicity was attenuated following treatment with TCSGs, as indicated by the increase in cell viability, the decreased levels of ALT, AST, LDH, NO, MDA and ROS, and the increased activities of SOD, CAT and GSH?Px. To further explore the possible mechanisms of action of TCSGs, the nuclear factor erythroid 2?related factor 2 (Nrf2) and nuclear factor??B (NF)??B pathways were examined. The results revealed that treatment with TCSGs markedly induced Nrf2 nuclear translocation and upregulated the expression of heme oxygenase?1 (HO?1) in the L02 cells damaged by H2O2. In addition, pretreatment with TCSGs inhibited the NF??B signaling pathway by blocking the degradation of the inhibitor of nuclear factor ?B? (I?B?), thereby reducing the expression and nuclear translocation of NF??B, as well as reducing the expression of tumor necrosis factor?? (TNF??), interleukin-6 (IL?6), inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX?2). On the whole, the findings of this study demonstrate that TCSGs can protect L02 cells against H2O2?induced oxidative toxicity and inflammatory injury by increasing the expression of Nrf2 and HO?1, mediated by the NF??B signaling pathway.

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Total C-21 Steroidal Glycosides From Baishouwu Ameliorate Hepatic and Renal Fibrosis by Regulating IL-1β/MyD88 Inflammation Signaling

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