MFG-E8 Knockout Aggravated Nonalcoholic Steatohepatitis by Promoting the Activation of TLR4/NF-κB Signaling in Mice

Hu, Jun; Du, Hui; Yuan, Yinglin; Guo, Peipei; Yang, Jing; Yin, Xinru; Liu, Jin; Wu, Shengwang; Wan, Jingyuan; Gong, Xia

doi:10.1155/2022/5791915

Cited by 7 publications

(5 citation statements)

References 50 publications

(52 reference statements)

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“…Liver injury may retain the active surface of HSCs and accelerate the migration of inflammatory cells to the injured liver, secreting a significant number of inflammatory mediators such as TNF- α , IL-6, and IL-1 β to enhance the development of liver fibrosis [ 10 – 12 , 40 , 41 ]. TAK-242 was also observed to reduce the incidence of liver inflammation and fibrosis in Hu et al's research [ 42 ]. Similarly, the current research found that TAK-242 lowered the levels of inflammatory factors IL-1 β , IL-6, and TNF- α in the liver.…”

Section: Discussionmentioning

confidence: 99%

TAK-242 Ameliorates Hepatic Fibrosis by Regulating the Liver-Gut Axis

Liu

Chen

et al. 2022

BioMed Research International

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Objective. The aims of this study were to investigate the impact of TAK-242 on the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear transcription factor-κB (NF-κB) signal transduction pathway in rats with hepatic fibrosis (HF) using the liver gut axis and to investigate the molecular mechanism of its intervention on HF. Methods. SPF grade SD male rats were randomly allocated to the control, model, and TAK-242 groups. For 8 weeks, the model and TAK-242 groups received 3 mL·kg-1 (the initial dose 5 mL·kg-1) intraperitoneal injections of 40% CCL4 olive oil solution. TAK-242 (5 mg·kg-1) was administered once a day for 5 days after modeling. The pathological alterations of liver and small intestine tissues in each group were observed using H&E and Masson staining. ELISA was used to measure serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (DBIL), total bilirubin (TBIL), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). RT-qPCR was utilized to identify the mRNA expression level of IL-1β, IL-6, TNF-α, TLR4, MyD88, and NF-κB in rat liver and small intestine tissues. The protein level of IL-1β, IL-6, TNF-α, TLR4, MyD88, and NF-κB protein in rat liver and small intestine tissues was determined utilizing Western blot and IHC. Results. TAK-242 significantly reduced AST, ALT, TBIL, and DBIL expression in HF rats’ serum ( P < 0.01 ) and alleviated liver tissue injury. Hematoxylin-eosin (H&E) and Masson staining revealed inflammatory cell infiltration and fibrous proliferation in the liver and small intestine tissue in the model group and partial cell swelling in the TAK-242 group, which indicated a considerable improvement compared to the model group. RT-qPCR, Western blot, and IHC data indicated that TAK-242 reduced the IL-1β, IL-6, TNF-α, TLR4, MyD88, and NF-κB expression in the liver and small intestine tissues of HF rats. Conclusion. TAK-242 might downregulate the TLR4/MyD88/NF-κB signal pathway through the liver-gut axis, suppress the inflammatory response, and eventually alleviate HF in rats.

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Section: Discussionmentioning

confidence: 99%

TAK-242 Ameliorates Hepatic Fibrosis by Regulating the Liver-Gut Axis

Liu

Chen

et al. 2022

BioMed Research International

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“…further found that it plays a vital role in the process of non-alcoholic steatohepatitis (NASH). When MFG-E8 is knocked down, liver steatosis and lipid accumulation are aggravated, and fibrosis is promoted, confirming that this is related to the activation of the TLR4/NF-κB signalling pathway after the knockdown of MFG-E8 [ 35 ]. Sodium-glucose cotransporter 2 (SGLT2) inhibitors can improve hepatic steatosis and fibrosis in patients with chronic liver disease.…”

Section: Liver Microenvironment and Liver Fibrosismentioning

confidence: 91%

The role of hepatic microenvironment in hepatic fibrosis development

et al. 2022

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Aim Fibrosis is a common pathological feature of most types of chronic liver injuries. There is no specific treatment for liver fibrosis at present. The liver microenvironment, which fosters the survival and activity of liver cells, plays an important role in maintaining the normal structure and physiological function of the liver. The aim of this review is to deeply understand the role of the liver microenvironment in the dynamic and complicated development of liver fibrosis. Methods After searching in Elsevier ScienceDirect, PubMed and Web of Science databases using ‘liver fibrosis’ and ‘microenvironment’ as keywords, studies related to microenvironment in liver fibrosis was compiled and examined. Results The homeostasis of the liver microenvironment is disrupted during the development of liver fibrosis, affecting liver cell function, causing various types of cell reactions, and changing the cell-cell and cell-matrix interactions, eventually affecting fibrosis formation. Conclusion Liver microenvironment may be important for identifying potential therapeutic targets, and restoring microenvironment homeostasis may be an important strategy for promoting the reversal of liver fibrosis. KEY MESSAGES The homeostasis of the liver microenvironment is disrupted in liver fibrosis; A pro-fibrotic microenvironment is formed during the development of liver fibrosis; Restoring microenvironment homeostasis may be an important strategy for promoting the reversal of liver fibrosis.

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“…Joints from mice were fixed in 4% PFA for 14 h and decalcified in 14% EDTA for 3 d. Furthermore, the cartilage from human was also fixed in 4% PFA for 16 h and decalcified in 14% EDTA for 5 d. Afterward, the joints and cartilage were preserved in an optimum cutting temperature (OCT) compound, cut to a thickness of 10μm, and subjected to immunofluorescence using antibodies recognizing Toll-like receptor 7 (Boster, China, 1:100).The immunofluorescence protocol can be found in our previously published article. 26 …”

Section: Methodsmentioning

confidence: 99%

“…The process of mRNA and cDNA was conducted following the previously described method. 26 Primers of interest genes were designed using NCBI Primer-Blast software. Primer sequences in Supplementary Table S2 .…”

Section: Methodsmentioning

confidence: 99%

Identification and Analysis of Neutrophil Extracellular Trap-Related Genes in Osteoarthritis by Bioinformatics and Experimental Verification

Luan,

Yang,

Kuang

et al. 2023

JIR

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Background Osteoarthritis (OA) is a common joint disease with long-term pain and dysfunction that negatively affects the quality of life of patients. Neutrophil extracellular traps (NETs), consisting of DNA, proteins and cytoplasm, are released by neutrophils and play an important role in a variety of diseases. However, the relationship between OA and NETs is unclear. Methods In our study, we used bioinformatics to explore the relationship between OA and NETs and the potential biological markers. GSE55235, GSE55457, GSE117999 and GSE98918 were downloaded from the Gene Expression Omnibus (GEO) database for subsequent analysis.After differential analysis of OA expression matrices, intersection with NET-related genes (NRGs) was taken to identify Differentially expressed NRGs (DE-NRGs) in OA processes. Evaluation of immune cell infiltration by ssGSEA and CIBERSORT algorithm. The GSVA method was used to analyze the activity changes of Neutrophils pathway, Neutrophil degranulation and Neutrophil granule constituents pathway. Results Based on RandomForest (RF), Least Absolute Shrinkage and Selection Operator (LASSO), and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) learning algorithms, five core genes (CRISPLD2, IL1B, SLC25A37, MMP9, and TLR7) were identified to construct an OA-related nomogram model for predicting OA progression. ROC curve results for these genes validated the nomogram’s reliability. Correlation analysis, functional enrichment, and drug predictions were performed for the core genes. TLR7 emerged as a key focus due to its high importance ranking in RF and SVM-RFE analyses. Gene Set Enrichment Analysis (GSEA) revealed a strong association between TLR7 and the Neutrophil extracellular trap pathway. Expression of core genes was demonstrated in mice OA models and human OA samples. TLR7 expression in ATDC5 cell line was significantly higher than control after TNFα induction, along with increased IL6 and MMP13. Conclusion TLR7 may be related to NETs and affects OA.

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MFG-E8 Knockout Aggravated Nonalcoholic Steatohepatitis by Promoting the Activation of TLR4/NF-κB Signaling in Mice

Cited by 7 publications

References 50 publications

TAK-242 Ameliorates Hepatic Fibrosis by Regulating the Liver-Gut Axis

TAK-242 Ameliorates Hepatic Fibrosis by Regulating the Liver-Gut Axis

The role of hepatic microenvironment in hepatic fibrosis development

Identification and Analysis of Neutrophil Extracellular Trap-Related Genes in Osteoarthritis by Bioinformatics and Experimental Verification

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