scholarly journals Potential signaling pathway and molecular mechanism of CD2AP associated with proteinuria in glomerular disease

2018 ◽  
Vol 1 (2) ◽  
Author(s):  
Hongzhen Zhong ◽  
◽  
Hongyan Li ◽  
Zhiqing Zhong ◽  
Tianbiao Zhou ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Glomerular Disease

Molecular mechanism of TLR4 mediated T cell immune effect in transfusion-induced acute lung injury based on Slit2/Robo4 signaling pathway

2020 ◽  
Vol 13 ◽  
Author(s):  
Kun Xiao ◽  
Fei Zhao ◽  
WenJie Xie ◽  
Jian Ding ◽  
XiaoAn Gong ◽  
...  
Keyword(s):  
T Cell ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Lung Tissue ◽  
Acute Injury ◽  
Tissue Homogenate ◽  
Control Group ◽  
Pathological Features ◽  
Mhc I ◽  
Immune Effect

Objective: To explore and investigate the molecular mechanism of TLR4 mediated T cell immune effect in transfusion-induced acute injury based on SLIT2/ROBO4 signaling pathway. Methods: Sixty C57/BL6 male mice (Wild type, WT) aged 8 to 10 weeks were randomly divided into 5 groups: 1) normal type WT, 2) LPS control group of WT type lipopolysaccharide, 3) WT type TRALI group (LPS + MHC-I mAb), 4) (TLR4 antibody) lipopolysaccharide LPS control group, 5) (TLR4 antibody) TRALI group (LPS + MHC-I mAb). Mice were dosed with LPS (0.1 mg / kg), and MHC-I mAb (2 mg / kg) was injected into the tail vein 24 hours later for modeling. After 2 hours, mice were sacrificed and experimental samples were collected. HE staining was performed to detect pathological features. The myeloperoxidase (MPO) activity and the level of IL-2, IL-6, TNF, IFN-γ, IL-17A as well as IL-10 were measured in the lung tissue homogenate supernatant. Blood, spleen single cell suspension and bronchoalveolar lavage fluid (BALF) were collected to detect the ratio of Treg and Th17 cells by flow cytometry, respectively. RT-PCR and WB indicated the mRNA or protein expression of CDH5 (Cadherin-5), SLIT2 and ROBO4 in mouse lung tissue and pulmonary vascular tissue respectively. Results: TLR4 mAb treatment decreases the pathological features of LPS induced ALI model in vivo. And so does the MPO activity as well as the level of proinflammatory factors in the lung tissue. TLR4 exerts its function through the changes of Treg/Th17 ratio via SLIT2/ROBO4 signaling pathway and downregulating CDH5 and SETSIP in ALI model. Conclusion: TLR4 mediates immune response in LPS induced ALI model through SLIT2/ROBO4 signaling pathway.

scholarly journals Molecular mechanism underlying the hypolipidemic effect of Shanmei Capsule based on network pharmacology and molecular docking

2021 ◽  
Vol 29 ◽  
pp. 239-256
Author(s):  
Qian Wang ◽  
Lijing Du ◽  
Jiana Hong ◽  
Zhenlin Chen ◽  
Huijian Liu ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Kegg Pathway ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Signal Pathways ◽  
Hypolipidemic Effect ◽  
Active Ingredients ◽  
Pathway Enrichment

BACKGROUND: Shanmei Capsule is a famous preparation in China. However, the related mechanism of Shanmei Capsule against hyperlipidemia has yet to be revealed. OBJECTIVE: To elucidate underlying mechanism of Shanmei Capsule against hyperlipidemia through network pharmacology approach and molecular docking. METHODS: Active ingredients, targets of Shanmei Capsule as well as targets for hyperlipidemia were screened based on database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed via Database for Annotation, Visualization, and Integrated Discovery (DAVID) 6.8 database. Ingredient-target-disease-pathway network was visualized utilizing Cytoscape software and molecular docking was performed by Autodock Vina. RESULTS: Seventeen active ingredients in Shanmei Capsule were screened out with a closely connection with 34 hyperlipidemia-related targets. GO analysis revealed 40 biological processes, 5 cellular components and 29 molecular functions. A total of 15 signal pathways were enriched by KEGG pathway enrichment analysis. The docking results indicated that the binding activities of key ingredients for PPAR-α are equivalent to that of the positive drug lifibrate. CONCLUSIONS: The possible molecular mechanism mainly involved PPAR signaling pathway, Bile secretion and TNF signaling pathway via acting on MAPK8, PPARγ, MMP9, PPARα, FABP4 and NOS2 targets.

scholarly journals CircSOD2 induced epigenetic alteration drives hepatocellular carcinoma progression through activating JAK2/STAT3 signaling pathway

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Zhongwei Zhao ◽  
Jingjing Song ◽  
Bufu Tang ◽  
Shiji Fang ◽  
Dengke Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Migration ◽  
Real Time ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Signaling Axis

Abstract Background Emerging evidence suggests that circular RNAs play critical roles in disease development especially in cancers. Previous genome-wide RNA-seq studies found that a circular RNA derived from SOD2 gene was highly upregulated in hepatocellular carcinoma (HCC), however, the role of circSOD2 in HCC remains largely unknown. Methods The expression profiling of circSOD2 and microRNA in HCC patients were assessed by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). SiRNA or CRISPR-CAS9 were used to silence gene expression. The biological function of circSOD2 in HCC was investigated using in vitro and in vivo studies including, trans-well cell migration, cell apoptosis, cell cycle, CCK8, siRNA interference, western blots, and xenograft mouse model. The underlying molecular mechanism was determined by Chromatin Immunoprecipitation quantitative real time PCR (ChIP-qPCR), bioinformatic analysis, biotin-pull down, RNA immunoprecipitation, 5-mc DNA pulldown and luciferase assays. Results In accordance with previous sequencing results, here, we demonstrated that circSOD2 was highly expressed in HCC tumor tissues compared with normal liver tissues. Mechanically, we showed that histone writer EP300 and WDR5 bind to circSOD2 promoter and trigger its promoter H3K27ac and H3K4me3 modification, respectively, which further activates circSOD2 expression. SiRNA mediated circSOD2 suppression impaired liver cancer cell growth, cell migration, prohibited cell cycle progression and in vivo tumor growth. By acting as a sponge, circSOD2 inhibits miR-502-5p expression and rescues miR-502-5p target gene DNMT3a expression. As a DNA methyltransferase, upregulated DNMA3a suppresses SOCS3 expression by increasing SOCS3 promoter DNA methylation. This event further accelerates SOCS3 downstream JAK2/STAT3 signaling pathway activation. In addition, we also found that activated STAT3 regulates circSOD2 expression in a feedback way. Conclusion The novel signaling axis circSOD2/miR-502-5p/DNMT3a/JAK2/STAT3/circSOD2 provides a better understanding of HCC tumorigenesis. The molecular mechanism underlying this signaling axis offers new prevention and treatment of HCC.

scholarly journals Hepatitis B e Antigen Inhibits NF-κB Activity by Interrupting K63-Linked Ubiquitination of NEMO

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Yuan Wang ◽  
Lei Cui ◽  
Guifang Yang ◽  
Jianbo Zhan ◽  
Liang Guo ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Virus Replication ◽  
Innate Immune ◽  
Regulatory Subunit ◽  
Hepatitis B E Antigen ◽  
Iκb Kinase ◽  
B Virus

ABSTRACTViruses have adopted diverse strategies to suppress antiviral responses. Hepatitis B virus (HBV), a virus that is prevalent worldwide, manipulates the host’s innate immune system to evade scavenging. It is reported that the hepatitis B e antigen (HBeAg) can interfere with NF-κB activity, which then leads to high viral loads, while HBV with the G1896A mutation remains infectious without the production of HBeAg but can induce more severe proinflammatory response and liver damage. The aim of current work was to study the molecular mechanism by which HBeAg suppresses interleukin-1β (IL-1β)-stimulated NF-κB activity, which leads to the suppression of the innate immune responses to HBV infection. Our study revealed that HBeAg could interact with NEMO, a regulatory subunit associated with IκB kinase, which regulates the activation of NF-κB. HBeAg suppressed the IL-1β-induced tumor necrosis factor (TNF)-associated factor 6 (TRAF6)-dependent K63-linked ubiquitination of NEMO, thereby downregulating NF-κB activity and promoting virus replication. We further demonstrated the inhibitory effect of HBeAg on the NF-κB signaling pathway using primary human hepatocytes, HBV-infected HepG2-NTCP cells, and clinical liver samples. Our study reveals a molecular mechanism whereby HBeAg suppresses IL-1β-induced NF-κB activation by decreasing the TRAF6-dependent K63-linked ubiquitination of NEMO, which may thereby enhance HBV replication and promote a persistent infection.IMPORTANCEThe role of HBeAg in inflammatory responses during the infection of hepatitis B virus (HBV) is not fully understood, and several previous reports with regard to the NF-κB pathway are controversial. In this study, we showed that HBeAg could suppress both Toll-like receptor 2 (TLR2)- and IL-1β-induced activation of NF-κB in cells and clinical samples, and we further revealed novel molecular mechanisms. We found that HBeAg can associate with NEMO, the regulatory subunit for IκB kinase (IKK) that controls the NF-κB signaling pathway, and thereby inhibits TRAF6-mediated K63-linked ubiquitination of NEMO, resulting in downregulation of NF-κB activity and promotion of virus replication. In contrast, the HBeAg-negative HBV mutant can induce higher levels of NF-κB activity. These results are important for understanding the HBV-induced pathogenesis of chronic hepatitis and indicate that different clinical measures should be considered to treat HBeAg-positive and HBeAg-negative infections. Our findings represent a conceptual advance in HBV-related suppression of NF-κB signaling.

Regulator 1-Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Signaling Pathway in Investigating the Pathological Characteristics and Molecular Mechanism of Liver Cirrhosis Complicated by Acute Kidney Injury

2022 ◽  
Vol 12 (1) ◽  
pp. 112-120
Author(s):  
Jieqi Gong ◽  
Huanhua Lu
Keyword(s):  
Acute Kidney Injury ◽  
Liver Cirrhosis ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Kidney Injury ◽  
Male Rats ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Duct Ligation

The objective of this study was to investigate the molecular mechanism of the histopathological characteristics of liver cirrhosis (LC) complicated with acute kidney injury (AKI) and the signaling pathway of silent information regulator 1 (SIRT1)-peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) during the pathogenesis of LC. 20 healthy male rats with AKI complicated by laparoscopic cholecystectomy were selected and divided randomly into control group (C group), lipopolysaccharide (LPS) group, bile duct ligation (BDL) group, and model group (lipopolysaccharide+BDL) (D group). The indexes of all the rats were determined, including serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), sarcoplasmic enzyme (Scr), and blood urea nitrogen (BUN); the SIRT1 and PGC-1α expressions in renal tissues of rats from each group was detected. Results showed that the AST and ALT levels in BDL group and D group were higher markedly than those before surgery (P < 0.05). The serum levels of Scr and BUN in D group 4 hours after LPS injection increased hugely compared with before injection (P < 0.05). Compared with BDL group, the protein levels of SIRT1 and PGC-1α in renal tissue of group D were decreased sharply (P < 0.05), and the SIRT1 protein expression was positively correlated with PGC-1α (r = 0.836 and P < 0.01). When LC were complicated with AKI, SIRT1 activity was reduced and PGC-1α expression was inhibited. Moreover, SIRT1-PGC-1α signaling pathway played a protective role in pathogenesis of LC complicated with AKI.

scholarly journals Chlorogenic acid protects PC12 cells against corticosterone-induced neurotoxicity related to inhibition of autophagy and apoptosis

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiaowen Shi ◽  
Nian Zhou ◽  
Jieyi Cheng ◽  
Xunlong Shi ◽  
Hai Huang ◽  
...  
Keyword(s):  
Cell Viability ◽  
Chlorogenic Acid ◽  
Signaling Pathway ◽  
Pc12 Cells ◽  
Molecular Mechanism ◽  
Cell Activity ◽  
Neuronal Cell ◽  
Mtor Signaling ◽  
Specific Marker ◽  
Mtor Signaling Pathway

Abstract Background There are evidences that chlorogenic acid (CGA) has antidepressant effects, however the underlying molecular mechanism has not been well understood. The aim of the study was to explore the neuroprotective effect of CGA on corticosterone (CORT)-induced PC 12 cells and its mechanism, especially the autophagy pathway. Methods PC12 cells were incubated with CORT (0, 100, 200, 400 or 800 μM) for 24 h, cell viability was measured by MTT assay. PC12 cells were cultured with 400 μM of CORT in the absence or presence of CGA (25 μg/ml) for 24 h, morphologies and specific marker of autophagosome were observed by transmission electron microscope (TEM) and confocal immunofluorescence microscopy, respectively. In addition, PC12 cells were treated with different doses of CGA (0, 6.25, 12.5, 25 or 50 μg/ml) with or without CORT (400 μM) for 24 h, cell viability and changes in the morphology were observed, and further analysis of apoptotic and autophagic proteins, and expression of AKT/mTOR signaling pathway were carried out by Western blot. Specific inhibitors of autophagy 3-Methyladenine (3-MA) and chloroquine (CQ) were added to the PC12 cells cultures to explore the potential role of autophagy in CORT-induced neuronal cell apoptosis. Results Besides decreasing PC12 cell activity, CORT could also induce autophagy and apoptosis of PC12 cells, while CGA could reverse these effects. In addition, CGA treatment regulated AKT/mTOR signaling pathway in PC12 cells. CGA, similar to 3-MA and QC, significantly inhibited CORT-induced apoptosis in PC12 cells. Conclusions Our results provide a new molecular mechanism for the treatment of CORT-induced neurotoxicity by CGA, and suggest CGA may be a potential substance which is can alleviate depression.

scholarly journals SOCS1, SOCS3, and PIAS1 Promote Myogenic Differentiation by Inhibiting the Leukemia Inhibitory Factor-Induced JAK1/STAT1/STAT3 Pathway

2009 ◽  
Vol 29 (18) ◽  
pp. 5084-5093 ◽  
Author(s):  
Yarui Diao ◽  
Xi Wang ◽  
Zhenguo Wu
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Leukemia Inhibitory Factor ◽  
Myogenic Differentiation ◽  
E3 Ligase ◽  
Inhibitory Factor ◽  
Dual Roles ◽  
Stat3 Pathway ◽  
Myoblast Proliferation ◽  
Sumo E3 Ligase

ABSTRACT We recently showed that a leukemia inhibitory factor (LIF)-engaged signaling pathway consisting of JAK1, STAT1, and STAT3 plays dual roles in myogenic differentiation: while it participates in myoblast proliferation, it also actively represses differentiation. Downregulation of this pathway is required at the onset of differentiation. However, it remained unclear how this is achieved mechanistically. We now show that SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by specifically inhibiting the LIF-induced JAK1/STAT1/STAT3 pathway via distinct targets; whereas SOCS1 and SOCS3 selectively bind and inhibit JAK1 and gp130, respectively, PIAS1 targets mainly the activated STAT1 and prevents its binding to DNA. We further demonstrated that the SUMO E3-ligase activity of PIAS1 is dispensable for its role in myogenic differentiation. Collectively, our current study revealed a molecular mechanism that explains how the LIF-induced JAK1/STAT1/STAT3 pathway is downregulated upon myogenic differentiation.

Arsenic Trioxide-Mediated Growth Inhibition of Myeloma Cells Is Associated with An Extrinsic Signaling Pathway Involved in Caspase 3 and Caspase 8.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4899-4899
Author(s):  
Jumei Shi ◽  
Yi Wu ◽  
Siqing Wang ◽  
Xiuqin Meng ◽  
Rong Wei ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Arsenic Trioxide ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Caspase 3 ◽  
Myeloma Cell ◽  
Caspase 8 ◽  
Myeloma Cells

Abstract Abstract 4899 Arsenic trioxide (ATO) is a well-known inhibitor of cell proliferation in certain forms of malignancy and has been successfully used in the treatment of acute promyelocytic leukemia. Preclinical and clinical studies showed that ATO has anti-myeloma effects both as a single agent and in the combination therapy; however, the underlying molecular mechanism remains elusive. This study was performed to evaluate the molecular mechanism underlying its anti-myeloma activities. Cells from OPM2, U266, RPMI8226 myeloma cell lines and patients diagnosed with myeloma (n=6) were cultured with various concentrations of ATO for 4 days. Cell growth and viability were assayed by trypan blue dye exclusion. Cell cycle and apoptosis were analyzed by flow cytometry using CellQuest software and Vybrant Apoptosis Assay Kit. Alterations of the signaling pathways induced by ATO were tested by real-time PCR and western blot. ATO induced potent inhibition of myeloma cell growth compared with untreated control cells. Further investigation showed that ATO down-regulated c-Myc and phosphorylated (p)-Rb, while it up-regulated p53, p21Clip1, and p27Kip1 proteins, resulting in G2/M cell cycle arrest and cell growth inhibition. ATO treatment increased mRNA levels of interferon regulatory factor-1 (IRF-1) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as well as protein levels of caspase 8 and cleaved caspase 3, indicating involvement of the extrinsic apoptotic pathway. No significant change was detected in the expression levels of Bax, Bcl-xL caspase 9 and Bcl-2, indicating that the intrinsic signaling pathway was not involved. A pan-caspase inhibitor abrogated ATO-induced apoptosis of myeloma cells. Our data suggest that ATO induces apoptosis in MM cells most likely through an extracellular signaling pathway. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document