scholarly journals Gene Profiling of Toll-like Receptor Signaling Pathways in Neutrophils of Patients With Acute-on-chronic Liver Failure

2021 ◽  
Author(s):  
Yi Zhang ◽  
Wei Wu ◽  
Yijie Wang ◽  
Lingjia Tong ◽  
Meng Hong ◽  
...  
Keyword(s):  
Liver Failure ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Tissue Injury ◽  
Fold Change ◽  
Chronic Liver ◽  
Chronic Liver Failure ◽  
Tlr Signaling ◽  
Compensated Cirrhosis ◽  
Tlr Signaling Pathway

Abstract Objectives: Toll-like receptors (TLRs) of neutrophils play a crucial role in detecting pathogens and organ/tissue injury in acute-on-chronic liver failure (ACLF). However, little is known about the exact mechanisms and the potential signaling pathways. The aim of this study was to investigate alterations of TLR signaling pathways in neutrophils of ACLF patients.Methods: Twenty-seven patients with compensated cirrhosis (n=9), de-compensated cirrhosis (n=9) and ACLF (n=9) were enrolled in the study. Neutrophils were isolated, and alterations in TLR signaling pathways were evaluated using an RT² Profiler™ PCR Array. The fold change for each gene (2(-∆∆CT)) was compared among the groups. Genes with a fold change ratio of ≥2 or ≤0.5 along with a p value of < 0.05 were considered to be differentially expressed.Results: A total of 17 genes were up-regulated in neutrophils from patients with compensated cirrhosis, which were mainly distributed in adaptors, TLR-interacting proteins and downstream pathways. Six genes were detected in patients with de-compensated cirrhosis. A trend of down-regulation of genes in the TLR signaling pathway was observed in neutrophils of patients with cirrhosis and ACLF. TLR3, IFNG, IL1B, TBK1, CCL2 and LTA were downregulated in neutrophils. Moreover, CD14 and IL10 were up regulated in neutrophils of ACLF patients.Conclusions: TLR signaling pathway genes were differentially regulated in neutrophils between cirrhosis and ACLF. In ACLF patients, there was defective expression of TLR3 and IFN, along with enhanced CD14 and IL10 expression, characterized by transcriptional alterations of neutrophils.

scholarly journals Gene profiling of Toll-like receptor signalling pathways in neutrophils of patients with acute-on-chronic liver failure

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yi Zhang ◽  
Wei Wu ◽  
Yijie Wang ◽  
Lingjia Tong ◽  
Meng Hong ◽  
...  
Keyword(s):  
Liver Failure ◽  
Tissue Injury ◽  
Fold Change ◽  
Chronic Liver ◽  
Signalling Pathway ◽  
Decompensated Cirrhosis ◽  
Signalling Pathways ◽  
Chronic Liver Failure ◽  
Compensated Cirrhosis ◽  
Tlr Signalling

Abstract Objectives Toll-like receptors (TLRs) on neutrophils play a crucial role in detecting pathogens and organ/tissue injury in acute-on-chronic liver failure (ACLF). However, little is known about the exact mechanisms and potential signalling pathways. The aim of this study was to investigate alterations in TLR signalling pathways in neutrophils of ACLF patients. Methods Twenty-seven patients with compensated cirrhosis (n = 9), decompensated cirrhosis (n = 9) and ACLF (n = 9) were enrolled in the study. Neutrophils were isolated, and alterations in TLR signalling pathways were evaluated using an RT2 Profiler™ PCR Array. The fold change for each gene (2(−∆∆CT)) was compared among the groups. Genes with a fold change ratio of ≥ 2 or ≤ 0.5 along with a p value of < 0.05 were considered to be differentially expressed. Results A total of 17 genes were upregulated in neutrophils from patients with compensated cirrhosis and were mainly distributed in adaptors, TLR-interacting proteins and downstream pathways. Six genes were detected in patients with decompensated cirrhosis. A trend of downregulation of genes in the TLR signalling pathway was observed in neutrophils of patients with cirrhosis and ACLF. TLR3, IFNG, IL1B, TBK1, CCL2 and LTA were downregulated in neutrophils. Moreover, CD14 and IL10 were upregulated in neutrophils of ACLF patients. Conclusions TLR signalling pathway genes were differentially regulated in neutrophils between cirrhosis and ACLF. In ACLF patients, defective expression of TLR3 and IFN, along with enhanced CD14 and IL10 expression, was characterized by transcriptional alterations of neutrophils.

scholarly journals Protective Effects of Taraxacum officinale L. (Dandelion) Root Extract in Experimental Acute on Chronic Liver Failure

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 504
Author(s):  
Iulia Olimpia Pfingstgraf ◽  
Marian Taulescu ◽  
Raluca Maria Pop ◽  
Remus Orăsan ◽  
Laurian Vlase ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Failure ◽  
Tissue Injury ◽  
Taraxacum Officinale ◽  
Chronic Liver ◽  
Root Extract ◽  
Protective Effects ◽  
Stress Tests ◽  
Chronic Liver Failure

Background: Taraxacum officinale (TO) or dandelion has been frequently used to prevent or treat different liver diseases because of its rich composition in phytochemicals with demonstrated effect against hepatic injuries. This study aimed to investigate the possible preventing effect of ethanolic TO root extract (TOERE) on a rat experimental acute on chronic liver failure (ACLF) model. Methods: Chronic liver failure (CLF) was induced by human serum albumin, and ACLF was induced in CLF by D-galactosamine and lipopolysaccharide (D-Gal-LPS). Five groups (n = 5) of male Wistar rats (200–250 g) were used: ACLF, ACLF-silymarin (200 mg/kg b.w./day), three ACLF-TO administered in three doses (200 mg, 100 mg, 50 mg/kg b.w./day). Results: The in vivo results showed that treatment with TOERE administered in three chosen doses before ACLF induction reduced serum liver injury markers (AST, ALT, ALP, GGT, total bilirubin), renal tests (creatinine, urea), and oxidative stress tests (TOS, OSI, MDA, NO, 3NT). Histopathologically, TOERE diminished the level of liver tissue injury and 3NT immunoexpression. Conclusions: This paper indicated oxidative stress reduction as possible mechanisms for the hepatoprotective effect of TOERE in ACLF and provided evidence for the preventive treatment.

scholarly journals Hepatoprotective Effect of Yiqijianpi Formula (YQJPF) on Liver Failure Through Modulation of Hypoxic and Apoptosis Pathways

2020 ◽  
Author(s):  
Li Tang ◽  
Feixia Wang ◽  
Lingyan Xiao ◽  
Min Shen ◽  
Siwei Xia ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Failure ◽  
Signaling Pathways ◽  
Tunel Assay ◽  
Chronic Liver ◽  
Active Components ◽  
Chronic Liver Failure ◽  
Apoptosis Pathway ◽  
L02 Cells

Abstract BackgroundAcute-on-chronic liver failure (ACLF) is a severe complication of cirrhosis, which seriously endanger human life and health. Yiqijianpi decoction (YQJPF) is a Traditional Chinese Medicine (TCM) formula that has been widely used in the treatment of liver failure with significant effect. The purpose of this study was to investigate the active components and mechanism to ameliorate acute on chronic liver failure(ACLF).MethodsLPS combined with D-Gal was used to establish the rat model of ACLF, pathological examination was detected by H&E staining, liver function test was assayed by ELISA. LPS was used to induce hepatocytes injury in vitro. Cell proliferation assay, TUNEL assay were used in human hepatic L02 cells. The active components and putative targets of YQJPF were predicted by network pharmacology approach and GEO analysis. Functional and pathway enrichment analysis were presented by using String, Cytoscape and Metascape. Further, experimental validation was done to verify the effect of YQJPF on PI3K/AKT-HIF-1ɑ and apoptosis-related signaling pathways by using Immunohistochemistry and Western blotting.ResultsAfter being treated with YQJPF, the rat liver injury and fibrosis were alleviated, and Cell Counting Kit-8 assay, TUNEL assay indicated YQJPF also inhibited the apoptosis in hepatic L02 cells. Through network pharmacologic analysis, 135 active components in YQJPF decoction, 573 known therapeutic targets and 2940 liver failure-related human genes were identified. 163 gene symbols maybe the key for liver failure treatment by YQJPF decoction. VEGF-A was hub gene in PPI network. The KEGG pathway and GO enrichment analyses indicated that the PI3K/AKT, HIF-1 signaling pathways were the prominently enriched signaling pathways. In vivo, YQJPF upregulated the expression of PI3K/AKT-HIF1-ɑ and VEGF-A. Moreover apoptosis pathway were verified by up-regulating Bcl2 expression and down-regulating Bax expression in vivo and in vitro.ConclusionYQJPF is beneficial for alleviating liver failure, may regulate hypoxic liver injury through PI3K/AKT-HIF1α dependent apoptosis pathway.

scholarly journals Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation

Gut ◽  
2020 ◽  
pp. gutjnl-2019-320170 ◽  
Author(s):  
Sofia Monteiro ◽  
Josephine Grandt ◽  
Frank Erhard Uschner ◽  
Nina Kimer ◽  
Jan Lysgård Madsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Failure ◽  
Chronic Liver ◽  
Inflammasome Activation ◽  
Chronic Liver Failure ◽  
Experimental Cirrhosis ◽  
Detection Rates ◽  
Compensated Cirrhosis ◽  
Duct Ligation ◽  
European Foundation

ObjectiveSystemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACLF development in compensated and recompensated patients.Design249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACLF development. Two external cohorts (n=327) (recompensation, AD and ACLF) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1β (caspase-1-dependent), were measured. In rats, bile duct ligation-induced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1β levels and upstream/downstream gene expression were measured.ResultsPatients developing ACLF showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACLF development than compensated patients. Baseline CLIF-C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACLF development in compensated and CLIF-C AD and IL-1β in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1β levels with higher hepatic gene expression. Higher IL-1β detection rates in recompensated patients developing ACLF and higher IL-1α and IL-1β detection rates in patients with ACLF were confirmed in the two external cohorts.ConclusionPrevious AD is an important risk factor for fatal ACLF development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACLF development and IL-1α in compensated cirrhosis and IL-1β in recompensated cirrhosis.

scholarly journals Network Pharmacology Approach to Explore the Potential Mechanisms of Jieduan-Niwan Formula Treating Acute-on-Chronic Liver Failure

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Jiajun Liang ◽  
Mengli Wu ◽  
Chen Bai ◽  
Chongyang Ma ◽  
Peng Fang ◽  
...  
Keyword(s):  
Liver Failure ◽  
Signaling Pathway ◽  
Enrichment Analysis ◽  
Clinical Syndrome ◽  
Chronic Liver ◽  
Network Pharmacology ◽  
Inflammatory Factor ◽  
Hepatocyte Apoptosis ◽  
Chronic Liver Failure ◽  
Ampk Signaling

Background. Acute-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. Methods. In 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. Results. 132 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. Conclusion. The 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.

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