Gynostemma pentaphyllum is a herbaceous vine of Cucurbitaceae family, and its principal pharmacological components, gypenosides (GPs), have been proved to be effective in various liver diseases. However, the mechanisms of GPs on liver injury are still to be studied for further. This investigation utilized the CCl₄-induced liver injury rat model (LI) to comprehensively explore the mechanism of action of GPs in the treatment of chemical liver injury by comparing the metabolomic changes in four groups rats. In this study, the therapeutic efficacy of GPs in a liver injury rat model induced by weekly gavage of CCl₄ was evaluated by inflammatory factors, oxidative damage indexes, and histopathological sections. Then, GC-MS technology was used to identify the metabolic profile of GPs in treating liver injury. Finally, the content variation of metabolites (BAs and SCFAs) was measured to elucidate the mechanism of GPs in the treatment of CCl₄-induced liver injury. After 8 weeks of administration, GPs effectively reduced the degree of LI and appeared a substantial tendency of reversing in the levels of MDA, GSH, CYP7E1, CYP7A1 and CYP27A1. Untargeted metabolomics suggested that GPs may play a role in BAs and SCFAs metabolism. Targeted metabolomics and ELISA confirmed the key role of GPs in increasing SCFAs levels and regulating BAs metabolism. Overall, this study indicated that GPs can alleviate CCl₄-induced liver injury. And GPs may exert beneficial effects on LI by affecting their metabolites (SCFAs and BAs).

2024-12-01·Cellular and Molecular Life Sciences

S100A8/A9-activated IFNγ+ NK cells trigger β-cell necroptosis in hepatitis B virus-associated liver cirrhosis

Article

作者: Li, Lanjuan ; Li, Xuehui ; Cai, Rui ; Diao, Hongyan ; Wu, Zhongwen ; Ru, MingHui ; Hong, Liang ; Meng, Yuting ; Wang, Baohua

BACKGROUND AND AIMSHepatitis B virus (HBV)-associated liver cirrhosis (LC), a common condition with high incidence and mortality rates, is often associated with diabetes mellitus (DM). However, the molecular mechanisms underlying impaired glucose regulation during HBV-associated LC remain unclear.METHODSData from 63 patients with LC and 62 patients with LC-associated DM were analysed. Co-culture of NK cells and islet β cell lines were used to study the glucose regulation mechanism. A mouse model of LC was used to verify the effect of S100A8/A9 on the glucose regulation.RESULTSHigher levels of interferon (IFN)-γ derived from natural killer (NK) cells and lower levels of insulin emerged in the peripheral blood of patients with both LC and DM compared with those from patients with LC only. IFN-γ derived from NK cells facilitated β cell necroptosis and impaired insulin production. Furthermore, S100A8/A9 elevation in patients with both LC and DM was found to upregulate IFN-γ production in NK cells. Consistently, in the mouse model for LC, mice treated with carbon tetrachloride (CCL₄) and S100A8/A9 exhibited increased blood glucose, impaired insulin production, increased IFN-γ, and increased β cells necroptosis compared with those treated with CCL₄. Mechanistically, S100A8/A9 activated the p38 MAPK pathway to increase IFN-γ production in NK cells. These effects were diminished after blocking RAGE.CONCLUSIONTogether, the data indicate that IFN-γ produced by NK cells induces β cell necroptosis via the S100A8/A9-RAGE-p38 MAPK axis in patients with LC and DM. Reduced levels of S100A8/A9, NK cells, and IFN-γ could be valuable for the treatment of LC with DM. Accumulation of S100A8/A9 in patients with LC may indicate the emergence of DM.

2024-12-01·Toxicology Reports

Peripheral serum iTRAQ-based proteomic characteristics of carbon tetrachloride-induced acute liver injury in Macaca fascicularis

Article

作者: Wei, Li ; Shuangxing, Li ; Li, Sun ; Dongmei, Chen ; Xingchao, Geng ; Yufa, Miao

Carbon tetrachloride (CCl₄) is a potent chemical compound that can induce liver cells necrosis. The purpose of this study was to evaluate the hepatic toxicity of CCl₄ exposure in Macaca fascicularis to explore the liver toxicity mechanism using a proteomic approach. One animal (no.F6) was intoxicated by oral gavage with 15 % CCl₄ solution (10 mL/kg, dissolved in edible peanut oil), and was sacrificed at 48 h after CCl₄ administration. Another blank control animal (no.F4) was sacrificed at the same time. The liver cells of the blank control animal showed normal hepatocyte morphology. However, the hepatocytes at 48 h time point after CCl₄ administration showed necrosis and vacuolation histopathologically. The animal No.F7∼F12 and no.M7∼M12 were administrated by gavage with 15 % CCl₄ solution (10 mL/kg, dissolved in edible peanut oil). Blood samples were collected before gavage administration, and served as the 0 h blank control samples. Then, blood samples were collected at 2 h, 48 h, 72 h and 168 h after CCl₄ exposure, and served as the test samples. Routine biochemistry and immunical parameters were performed using biochemistry analyzer for all serum. Then the serum from male and female animals at 0 h, 2 h, 48 h, and 72 h was mixed, respectively. The peripheral serum proteins at 0 h, 2 h, 48 h, and 72 h were extracted, then the proteins were enzymatically hydrolyzed and the peptides were isotopic labeled by isobaric tags for relative and absolute quantification (iTRAQ). Finally, the UniProt Protein Sequence Library of Macaca fascicularis was queried to identify and compare the differential proteins between different time points. The results showed that, as traditional biomarkers of liver injury, alanine aminotransferases (ALT) and aspartate aminotransferases (AST) showed a typical time-effect curve. Compared with 0 h, there were totally 55, 323, and 158 differential proteins (P value <0.05, Ratio fold >1.5, FDR<0.05) at 2 h, 48 h and 72 h, respectively. GO enrichment analysis of differentially expressed proteins only at 48 h involved 3 cellular components (P adjust value <0.05), and differential proteins at other time points had no significant enrichment. Furthermore, KEGG enrichment analysis showed that the toxicity effect of CCl₄ at different time points after administration was mediated through 22 pathways such as biosynthesis of antibiotics, carbon metabolism, biosynthesis of amino acids, peroxisome, cysteine and methionine metabolism, arginine biosynthesis, and complement and coagulation cascades (P adjust value <0.05). Among them, the counts of signaling pathway involved biosynthesis of antibiotics, carbon metabolism and biosynthesis of amino acids were more than 10 and the three pathways may play a greater role in toxicity progress after administration of CCl₄. PPI network analysis showed that there were 3, 52, and 13 nodes in the interaction of differential proteins at 2 h, 48 h, and 72 h, respectively. In conclusion, many differential proteins in peripheral blood were detected after CCl₄ administration, and the GO and KEGG enrichment analysis showed the toxicological mechanisms of CCl₄-induced liver injury and potential protection reaction mechanism for CCl₄ detoxication may be related with multi biological processes, signaling pathway and targets.

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2024-09-25

·Business Wire

New Study Demonstrates Power of Depixus’ Scalable Single Molecule Interactomics Platform to Accelerate RNA-Targeted Drug Development

PARIS--( BUSINESS WIRE )--A new research study published in Nature Communications highlights how Depixus’ scalable single molecule technology can provide detailed mechanistic insights into RNA-ligand binding, supporting the development of novel therapeutics. Based on magnetic force spectroscopy (MFS), Depixus’ large scale interactomics platform is the first analytical technology capable of exploring dynamic biomolecular interactions both in real time and from thousands of individual molecules in parallel. The study was led by Dr. John “Jay” Schneekloth, Jr. a leading expert in RNA-targeted drug discovery at the National Cancer Institute, part of the US National Institutes of Health. Depixus’ scalable MFS platform was used to probe the interactions between the Bacillus subtilis (Bsu) PreQ 1 bacterial riboswitch and either its natural ligand (PreQ 1 ) or a synthetic small molecule known as Compound 4. Riboswitches are structured sequences of RNA commonly found in the 5′ untranslated regions of bacterial mRNAs that help to control metabolic pathways. Ligands such as metabolites bind to the riboswitch, inducing a conformational change in the secondary structure and altering gene expression. This makes them an attractive group of novel antibacterial drug targets. In a key part of the study, Depixus’ MFS platform was used to precisely measure the effects of either PreQ 1 or Compound 4 binding on immobilized target riboswitch RNA aptamers. The results showed both ligands stabilized the RNA structure, and the effect of compound concentration was measured. Importantly, analysis of MFS data streams coming from individual interactions revealed that the two ligands had very distinct modes of action - a distinction that would have been missed using other analytical techniques that only generate surrogate or bulk, averaged measurements. Jimmy Ouellet, Chief Scientist at Depixus, said “This study highlights how our ability to carry out independent analysis of individual biomolecular interactions enables us to visualize RNA-ligand interactions in real time, gathering valuable insights into distinct mechanisms of action. With our large-scale MFS platform we now have a technology that can see biology as it really happens, exploring the mechanistic impact of compounds on their targets at the level of individual molecules, generating detailed information about binding kinetics and more.” Depixus’ unique platform delivers valuable data about a wide range of individual dynamic molecular interactions - including between RNA, DNA, proteins and small molecules - decoding disease mechanisms and unlocking faster routes to more effective therapies. Find out more at depixus.com Reference: Parmar S, et al. Nat Commun. (2024) 15:8173.

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