Dataset Information

Jieduan-Niwan Formula Reduces Liver Apoptosis in a Rat Model of Acute-on-Chronic Liver Failure by Regulating the E2F1-Mediated Intrinsic Apoptosis Pathway.

ABSTRACT: Acute-on-chronic liver failure (ACLF) is a serious and complicated disease that threatens human health because its pathogenesis is unclear, and the outcome of the current therapies has been less than satisfactory. A national famous doctor of traditional Chinese medicine, Qian Ying, created the Jieduan-Niwan Formula (JDNW), based on his long-term clinical experience. However, despite the good clinical outcome, the biological mechanism by which it works is unknown. In the current study, we established an ACLF rat model by administering human serum albumin (HSA) combined with D-galactosamine (D-GalN) and lipopolysaccharide (LPS) to explore the potential mechanism of JDNW in treating ACLF. The rats were treated with JDNW by administration of the model substances and sacrificed after 4, 8, and 12?h. Then we divided the rats into normal group, model at 4?h, model at 8?h, model at 12?h, JDNW at 4?h, JDNW at 8?h, and JDNW at 12?h. Biochemical and histopathological examinations were performed to compare the rats in different groups. Compared with the ACLF model group, expression levels of alanine transaminase, aspartate aminotransferase, total bilirubin, and TNF-? and IL-6 proteins were reduced in the JDNW group at the corresponding time points, the survival rates of rats were increased, and the pathological condition of the liver was improved. In addition, JDNW treatment improved the ultrastructure of hepatocytes and mitochondria and decreased the hepatocyte apoptosis index. E2F1, P53, P73, Apaf-1, p14ARF, caspase-3, caspase-6, and caspase-7 levels in the JDNW group were distinctly lower than those in the untreated rats. Moreover, Bcl-2 and Mcl-1 levels increased. Thus, JDNW decreases ACLF-induced mortality in rats by modulating the E2F1-mediated intrinsic apoptotic pathway.

SUBMITTER: Yang W

PROVIDER: S-EPMC6885299 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Jieduan-Niwan Formula Reduces Liver Apoptosis in a Rat Model of Acute-on-Chronic Liver Failure by Regulating the E2F1-Mediated Intrinsic Apoptosis Pathway.

Yang Wenlong W Hao Yulin Y Hou Weixin W Fang Xian X Fang Peng P Jiang Tianyuan T Ma Chongyang C Zhang Qiuyun Q

Evidence-based complementary and alternative medicine : eCAM 20191111

Acute-on-chronic liver failure (ACLF) is a serious and complicated disease that threatens human health because its pathogenesis is unclear, and the outcome of the current therapies has been less than satisfactory. A national famous doctor of traditional Chinese medicine, Qian Ying, created the Jieduan-Niwan Formula (JDNW), based on his long-term clinical experience. However, despite the good clinical outcome, the biological mechanism by which it works is unknown. In the current study, we establi ...[more]

PMID: 31827563

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Project description:BackgroundAcute-on-chronic liver failure (ACLF) is a clinical syndrome with acute jaundice and coagulation dysfunction caused by various inducements on the basis of chronic liver disease. Western medical treatment is limited. Previous studies have confirmed that Jieduan-Niwan Formula (JDNW Formula), an empirical prescription for the treatment of ACLF, can inhibit inflammation and resist hepatocyte apoptosis. However, potential targets and mechanisms still need to be explored.MethodsIn this study, network pharmacological analysis was performed to investigate the key components and potential mechanisms of JDNW Formula treating ACLF. Firstly, we predicted the potential active ingredients of JDNW Formula and the corresponding potential targets through TCMSP, BATMAN-TCM platform, and literature supplement. Then, the ACLF targets database was built using OMIM, DisGeNET, and GeneCard database. Based on the matching targets between JDNW Formula and ACLF, the PPI network was constructed for MCODE analysis and common targets were enriched by Metascape. Furthermore, the ACLF rat model was used to verify the potential mechanism of JDNW Formula in treating ACLF.Results132 potential bioactive components of JDNW Formula and 168 common targets were obtained in this study. The enrichment analysis shows that the AMPK signaling pathway was associated with the treating effects of JDNW Formula. Quercetin was hypothesized to be the key bioactive ingredient in JDNW Formula and has a good binding affinity to AMPK based on molecular docking verification. JDNW Formula and quercetin were verified to treat ACLF by regulating the AMPK/PGC-1α signaling pathway as a prediction.ConclusionThe study predicted potential mechanisms of JDNW Formula in the treatment of ACLF, involving downregulation of inflammatory factor expression, antioxidant stress, and inhibition of hepatocyte apoptosis. JDNW Formula may improve mitochondrial quality in ACLF via the AMPK signaling pathway, which serves as a guide for further study.

Project description:The Qingchangligan formula (QCLGF) is a traditional Chinese medicine that has significant clinical potential for patients with acute liver failure (ALF). However, the experimental evidence of the effect of QCLGF on ALF and the associated mechanisms remain elusive. We aimed to evaluate the function of QCLGF in ALF and the underlying mechanism. ALF was induced in rats by intraperitoneal injection of D-GalN (1100 mg/kg). The Qingchangligan formula was administered to the rats (6.725 g/kg · d) for 5 days, and the model group and the control group were given the same amount of physiological saline. Then 16S rRNA gene sequencing, high performance gas chromatography-mass spectrometry (GC-MS), and RNA-seq analysis were performed on the samples. The levels of ALT and AST in the ALF rats were abnormal (5322.08 ± 566.27 U/L and 7655.95 ± 1238.08 U/L, respectively) compared with the normal control (98.98 ± 6.90 U/L and 99.63 ± 10.94 U/L, respectively). The levels of ALT and AST in the QCLGF rats (2997.67 ± 469.24 U/L and 4158.40 ± 596.07 U/L, respectively) were closer the normal control group. Liver HE staining showed that the degree of liver damage in the QCLGF rats was lighter than that in the ALF rats. The overall structure of the gut microbiota after ALF was significantly altered, including Proteobacteria, Blautia, Romboutsia, Parabacteroides, UCG-008, Parasutterella, Ruminococcus, norank_f:Lachnospiraceae, the Eubacterium_xylanophilum_group, Oscillibacter, and Eisenbergiella. QCLGF balanced the structure and abundance of intestinal flora. The levels of D(+)galactose, isopropyl beta-D-1-thiogalactopyranoside and D-mannitol were lighter in the plasma of the ALF rats than in the normal control rats, but there were significantly elevated levels of those metabolites in the QCLGF rats. The gene expression changed significantly in the ALF rats. QCLGF regulated the expression of THBS1 and the KEGG pathways of carbohydrate metabolism, lipid metabolism, signal transduction, the immune system, and infectious disease: bacterial. QCLGF may alleviating intestinal flora disorder, regulating galactose metabolism and downregulating the expression of THBS1 to alleviate D-GalN induced acute liver failure.

Project description:BackgroundDeposition and accumulation of silver nanoparticles (Ag-nps) in the liver have been shown to induce hepatotoxicity in animal studies. The hepatotoxicity may include oxidative stress, abnormalities in energy metabolism, and cell death. Studies have indicated that autophagy is an intracellular event involving balance of energy, nutrients, and turnover of subcellular organelles. The present study was undertaken to test the hypothesis that autophagy plays a role in mediating hepatotoxicity in animal after exposure to Ag-nps. Focus was placed on interrelationship between energy metabolism, autophagy, apoptosis and hepatic dysfunction.MethodsSprague Dawley rats were intraperitoneally injected with Ag-nps (10-30 nm in diameter) at concentration of 500 mg kg(-1). All animals were sacrificed on days 1, 4, 7, 10 and 30 after exposure and blood and liver tissues were collected for further studies.ResultsUptake of Ag-nps was quite prompt and not proportional to the blood Ag concentration. Declination of ATP (-64% in days 1) and autophagy (determined by LC3-II protein expression and morphological evaluation) increased and peaked on the first day. The ATP content remained at low level even though the autophagy has been activated. Apoptosis (based on caspase-3 protein expression and TUNEL-positive cells staining) began to rise sigmoidally at days 1 and 4, reached a peak level at day 7, and remained at the same levels during days 7-30 post exposure. Meanwhile, autophagy exhibited a gradual decrease from days 1-10 and the decrease at day 30 was statistically significant as compared to day 0 (sham group). Inflammatory reaction (histopathological evaluation) was found at day 10 and preceded to an advanced degree at day 30 when liver function was impaired.ConclusionsThese results indicate that following Ag-nps administration, autophagy was induced; however, failure to preserve autophagy compounded with energy reduction led to apoptosis and the eventual impairment of liver function. The study provides an in-vivo evidence of hepatotoxicity by continuous exposure of Ag-nps in rats.

Project description:BackgroundThe gut microbiome affects the occurrence and development of NAFLD, but its mechanism has not yet been fully elucidated. Chinese medicine is a new treatment strategy to improve NAFLD by regulating the gut microbiome. Tianhuang formula (TH) has been proved to have a lipid-lowering effect in which constituents of ginsenoside Rb1, ginsenoside Rg1, ginsenoside Rb, ginsenoside Re, and ginsenoside R1 from Panax notoginseng and berberine, palmatine, and coptisine from Coptis chinensis have low drug permeability, which results in poor intestinal absorption into the human body, and are thus able to come into contact with the gut microflora for a longer time. Therefore, it might be able to influence the gut microbial ecosystem, but it still needs to be investigated.MethodThe characteristics of the gut microbiome were represented by 16S rRNA sequencing, and the metabolites in intestinal contents and liver were discovered by non-targeted metabolomics. Correlation analysis and fermentation experiments revealed the relationship between the gut microbiome and metabolites. Blood biochemical indicators, liver function indicators, and oxidation-related indicators were assayed. H&E staining and Oil Red O staining were used to analyze the characteristics of hepatic steatosis. RT-qPCR and western blotting were used to detect the expression of genes and proteins in liver tissues, and fecal microbial transplantation (FMT) was performed to verify the role of the gut microbiome.ResultsGut microbiome especially Lactobacillus reduced, metabolites such as 5-Methoxyindoleacetate (5-MIAA) significantly reduced in the liver and intestinal contents, the level of hepatic GSH and SOD reduced, MDA increased, and the protein expression of Nrf2 also reduced in NAFLD mice induced by high-fat diet (HFD). The normal diet mice transplanted with NAFLD mice feces showed oxidative liver injury, indicating that the NAFLD was closely related to the gut microbiome. TH and TH-treated mice feces both can reshape the gut microbiome, increase the abundance of Lactobacillus and the content of 5-MIAA in intestinal contents and liver, and improve oxidative liver injury. This indicated that the effect of TH improving NAFLD was related to the gut microbiome, especially Lactobacillus. 5-MIAA, produced by Lactobacillus, was proved with fermentation experiments in vitro. Further experiments proved that 5-MIAA activated the Nrf2 pathway to improve oxidative stress in NAFLD mice induced by HFD. TH reshaped the gut microbiome, increased the abundance of Lactobacillus and its metabolite 5-MIAA to alleviate oxidative stress, and improved NAFLD.ConclusionThe study has demonstrated a mechanism by which the gut microbiome modulated oxidative stress in NAFLD mice induced by HFD. The traditional Chinese medicine TH improved NAFLD by regulating the gut microbiome, and its mechanism was related to the "Lactobacillus-5-MIAA-Nrf2" pathway. It provided a promising way for the intervention of NAFLD.

Dataset Information

Jieduan-Niwan Formula Reduces Liver Apoptosis in a Rat Model of Acute-on-Chronic Liver Failure by Regulating the E2F1-Mediated Intrinsic Apoptosis Pathway.

Publications

Jieduan-Niwan Formula Reduces Liver Apoptosis in a Rat Model of Acute-on-Chronic Liver Failure by Regulating the E2F1-Mediated Intrinsic Apoptosis Pathway.

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