Kehuang capsule inhibits MAPK and AKT signaling pathways to mitigate CCl4-induced acute liver injury

Q2 Medicine Liver Research Pub Date : 2024-12-01 DOI:10.1016/j.livres.2024.11.006

Qinyu Ni , Jiacheng Lin , Weifan Huang , Liu Yang , Ran Li , Tianzhi Tu , Guangfu He , Yueqiu Gao , Xuehua Sun , Xiaoni Kong , Xiaojun Zhu

{"title":"Kehuang capsule inhibits MAPK and AKT signaling pathways to mitigate CCl4-induced acute liver injury","authors":"Qinyu Ni , Jiacheng Lin , Weifan Huang , Liu Yang , Ran Li , Tianzhi Tu , Guangfu He , Yueqiu Gao , Xuehua Sun , Xiaoni Kong , Xiaojun Zhu","doi":"10.1016/j.livres.2024.11.006","DOIUrl":null,"url":null,"abstract":"<div><h3>Background and aims</h3><div>Kehuang (KH) capsule is an herbal medical product approved for the treatment of liver diseases, including liver injury, in China. However, the mechanism is still unclear. This study aimed to elucidate the protective effects of KH capsule against carbon tetrachloride (CCl<sub>4</sub>)-induced acute liver injury (ALI) in a murine model.</div></div><div><h3>Methods</h3><div>Mice were randomly divided into control, model (CCl<sub>4</sub>), CCl<sub>4</sub>+KH_Low and CCl<sub>4</sub>+KH_High group. Liver enzyme levels and histological changes were assessed to evaluate liver injury. Oxidative stress markers and inflammatory cell infiltration in liver tissues were measured. Additionally, network pharmacology was employed to explore the potential mechanisms of KH capsule.</div></div><div><h3>Results</h3><div>KH capsule significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, as well as the necrotic area in liver tissue. KH capsule also decreased the infiltration of macrophages and neutrophils, thereby inhibiting the expression of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). Furthermore, KH capsule decreased liver malondialdehyde (MDA) levels and increased superoxide dismutase (SOD) activity. The number of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)-positive cells in liver tissue was also reduced. The expression of nuclear factor erythroid 2 related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins was significantly elevated, while the protein expression of cytochrome P450 2E1 (CYP2E1) was significantly reduced. Mass spectrometry identified genistein, galangin, wogonin, skullcapflavone II, and hispidulin as potential active ingredients of KH capsule. Network pharmacology analysis revealed enrichment in the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling pathways. Western blot analysis confirmed that KH capsule suppressed AKT, extracellular signal-regulated kinase (ERK), and p38 signaling.</div></div><div><h3>Conclusions</h3><div>These findings suggest that KH capsule could exert protective effects against CCl<sub>4</sub>-induced ALI, with the inhibition of MAPK and PI3K-AKT signaling pathways playing a crucial role in its mechanism of action.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"8 4","pages":"Pages 269-281"},"PeriodicalIF":0.0000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Liver Research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2542568424000679","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Medicine","Score":null,"Total":0}

引用次数: 0

Abstract

Background and aims

Kehuang (KH) capsule is an herbal medical product approved for the treatment of liver diseases, including liver injury, in China. However, the mechanism is still unclear. This study aimed to elucidate the protective effects of KH capsule against carbon tetrachloride (CCl₄)-induced acute liver injury (ALI) in a murine model.

Methods

Mice were randomly divided into control, model (CCl₄), CCl₄+KH_Low and CCl₄+KH_High group. Liver enzyme levels and histological changes were assessed to evaluate liver injury. Oxidative stress markers and inflammatory cell infiltration in liver tissues were measured. Additionally, network pharmacology was employed to explore the potential mechanisms of KH capsule.

Results

KH capsule significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, as well as the necrotic area in liver tissue. KH capsule also decreased the infiltration of macrophages and neutrophils, thereby inhibiting the expression of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). Furthermore, KH capsule decreased liver malondialdehyde (MDA) levels and increased superoxide dismutase (SOD) activity. The number of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)-positive cells in liver tissue was also reduced. The expression of nuclear factor erythroid 2 related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins was significantly elevated, while the protein expression of cytochrome P450 2E1 (CYP2E1) was significantly reduced. Mass spectrometry identified genistein, galangin, wogonin, skullcapflavone II, and hispidulin as potential active ingredients of KH capsule. Network pharmacology analysis revealed enrichment in the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling pathways. Western blot analysis confirmed that KH capsule suppressed AKT, extracellular signal-regulated kinase (ERK), and p38 signaling.

Conclusions

These findings suggest that KH capsule could exert protective effects against CCl₄-induced ALI, with the inhibition of MAPK and PI3K-AKT signaling pathways playing a crucial role in its mechanism of action.

查看原文