scholarly journals SIRT1 Regulates the Inflammatory Response of Vascular Adventitial Fibroblasts through Autophagy and Related Signaling Pathway

2017 ◽  
Vol 41 (2) ◽  
pp. 569-582 ◽  
Author(s):  
Wei-Rong Wang ◽  
Ting-Ting Li ◽  
Ting Jing ◽  
Yan-Xiang Li ◽  
Xiao-Feng Yang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
Degradation Pathway ◽  
Sirtuin 1 ◽  
Akt Inhibitor ◽  
Cellular Survival ◽  
Akt Phosphorylation ◽  
Transmission Electron ◽  
Tnf Α ◽  
Adventitial Fibroblasts

Background/Aims: Autophagy is a lysosomal degradation pathway that is essential for cellular survival, differentiation, and homeostasis. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase, plays a pivotal role in modulation of autophagy. Recent studies found that autophagy was involved in the regulation of inflammatory response. In this study, we aimed to determine the effect of SIRT1 on autophagy and inflammation, and whether autophagy can regulate the inflammatory response in vascular adventitial fibroblasts (VAFs). Methods: Cell autophagy was evaluated by fluorescence microscope and transmission electron microscopy. The expression of protein and mRNA were determined by Western blot analysis and real time-PCR. The production of cytokine was detected by ELISA. Results: TNF-α induced autophagy and increased SIRT1 expression in VAFs. SIRT1 activator resveratrol enhanced TNF-α-induced VAF autophagy. In contrast, SIRT1 knockdown attenuated VAF autophagy. Both the Akt inhibitor MK2206 and mTOR inhibitor rapamycin further increased TNF-α-induced VAF autophagy. Furthermore, SIRT1 knockdown increased Akt phosphorylation and inhibited the autophagy in VAFs. However, MK2206 attenuated the effect of SIRT1 knockdown on VAF autophagy. In addition, ingenuity pathway analysis showed that there is a relationship between cell autophagy and inflammation. We found that SIRT1 knockdown increased the expression of NLRP3 and interleukin (IL)-6 and promoted the production of IL-1β in VAFs. Further study showed that autophagy activation decreased the expression of NLRP3 and IL-6 and inhibited the production of IL-1β, whereas autophagy inhibition increased the inflammatory response of VAFs. More importantly, our study showed that autophagy was involved in the degradation of NLRP3 through the autophagy-lysosome pathway. Conclusion: SIRT1 not only regulates VAF autophagy through the Akt/mTOR signaling pathway but also suppresses the inflammatory response of VAFs through autophagy.

Hydroxytyrosol regulates the autophagy of vascular adventitial fibroblasts through the SIRT1-mediated signaling pathway

2018 ◽  
Vol 96 (1) ◽  
pp. 88-96 ◽  
Author(s):  
Weirong Wang ◽  
Ting Jing ◽  
Xiaofeng Yang ◽  
Yanhao He ◽  
Bo Wang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
Docking Studies ◽  
Sirtuin 1 ◽  
Autophagic Flux ◽  
Tnf Α ◽  
Adventitial Fibroblasts ◽  
Factor Α ◽  
Necrosis Factor ◽  
Inflammatory Effect

Hydroxytyrosol (HT), a phenolic compound in olive oil, exerts an anti-inflammatory effect in cardiovascular diseases. Recent studies found that autophagy was a therapeutic target of diseases. However, the effect of HT on autophagy in vascular adventitial fibroblasts (VAFs) remains unknown. Thus, in this study, we aimed to determine the effect of HT on cell autophagy and related signaling pathway and whether HT regulates the inflammatory response through autophagy in VAFs. Our results showed that HT promoted cell autophagy by increasing the conversion of LC3 and Beclin1 expression and the autophagic flux in VAFs stimulated with tumor necrosis factor-α (TNF-α). HT also upregulated the expression of the deacetylase sirtuin 1 (SIRT1) protein and mRNA compared with the TNF-α group. The molecular docking studies showed the good compatibility between HT and SIRT1, indicating that HT might act through SIRT1. Further study found that HT regulated autophagy through SIRT1-mediated Akt/mTOR suppression in VAFs. In addition, HT inhibited TNF-α-induced inflammatory response in VAFs through SIRT1. Furthermore, the study showed that HT inhibited the inflammatory response of VAFs through autophagy. These findings indicate that HT regulates the autophagy of VAFs through SIRT1-mediated Akt/mTOR suppression and then inhibits the inflammatory response of VAFs.

scholarly journals Cichoric Acid Ameliorates Monosodium Urate-Induced Inflammatory Response by Reducing NLRP3 Inflammasome Activation via Inhibition of NF-kB Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Qi Wang ◽  
Bingfeng Lin ◽  
Zhifeng Li ◽  
Jie Su ◽  
Yulin Feng
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Gouty Arthritis ◽  
Inflammasome Activation ◽  
Cichoric Acid ◽  
Monosodium Urate ◽  
Protein Levels ◽  
Nlrp3 Inflammasome Activation ◽  
Tnf Α

Gouty arthritis is characterized by the deposition of monosodium urate (MSU) within synovial joints and tissues due to increased urate concentrations. Here, we elucidated the role of the natural compound cichoric acid (CA) on the MSU crystal-stimulated inflammatory response. The THP-1-derived macrophages (THP-Ms) were pretreated with CA and then stimulated with MSU suspensions. The protein levels of p65 and IκBα, the activation of the NF-κB signaling pathway by measuring the expression of its downstream inflammatory cytokines, and the activity of NLRP3 inflammasome were measured by western blotting and ELISA. CA treatment markedly inhibited the degradation of IκBα and the activation of NF-κB signaling pathway and reduced the levels of its downstream inflammatory genes such as IL-1β, TNF-α, COX-2, and PGE2 in the MSU-stimulated THP-M cells. Therefore, we infer that CA effectively alleviated MSU-induced inflammation by suppressing the degradation of IκBα, thereby reducing the activation of the NF-κB signaling pathway and the NLRP3 inflammasome. These results suggest that CA could be a novel therapeutic strategy in averting acute episodes of gout.

Rice protein hydrolysates (RPHs) inhibit the LPS-stimulated inflammatory response and phagocytosis in RAW264.7 macrophages by regulating the NF-κB signaling pathway

RSC Advances ◽  
2016 ◽  
Vol 6 (75) ◽  
pp. 71295-71304 ◽  
Author(s):  
Li Wen ◽  
Yuehua Chen ◽  
Li Zhang ◽  
Huixin Yu ◽  
Zhou Xu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Protein Hydrolysates ◽  
Rice Protein ◽  
Phagocytic Ability ◽  
Raw264.7 Macrophages ◽  
Tnf Α

Different RPH components inhibit LPS-induced NO and TNF-α production. RPHs-C-7-3 inhibits the expression of pro-inflammatory expression. RPHs-C-7-3 suppresses the LPS-stimulated phagocytic ability. RPHs-C-7-3 regulates the nuclear translocation of p65.

scholarly journals Long noncoding RNA MALAT1 contributes to inflammatory response of microglia following spinal cord injury via the modulation of a miR-199b/IKKβ/NF-κB signaling pathway

2018 ◽  
Vol 315 (1) ◽  
pp. C52-C61 ◽  
Author(s):  
Heng-Jun Zhou ◽  
Li-Qing Wang ◽  
Duan-Bu Wang ◽  
Jian-Bo Yu ◽  
Yu Zhu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Signaling Pathway ◽  
Proinflammatory Cytokines ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Tnf Α ◽  
Cord Injury

Long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was widely recognized to be implicated in human cancer, vascular diseases, and neurological disorders. This study was to explore the role and underlying mechanism of MALAT1 in acute spinal cord injury (ASCI). ASCI models in adult rats were established and demonstrated by a numerical decrease in BBB scores. Expression profile of MALAT1 and miR-199b following ASCI in rats and in vitro was determined using quantitative real-time PCR. RNA pull-down assays combined with RIP assays were performed to explore the interaction between MALAT1 and miR-199b. In the present study, MALAT1 expression was significantly increased (2.4-fold that of control) in the spinal cord of the rat contusion epicenter accompanied by activation of IKKβ/NF-κB signaling pathway and an increase in the level of proinflammatory cytokines TNF-α and IL-1β. Upon treatment with LPS, MALAT1 expression dramatically increased in the microglia in vitro, but knockdown of MALAT1 attenuated LPS-induced activation of MGs and TNF-α and IL-1β production. Next, we confirmed that LPS-induced MALAT1 activated IKKβ/NF-κB signaling pathway and promoted the production of proinflammatory cytokines TNF-α and IL-1β through downregulating miR-199b. More importantly, MALAT1 knockdown gradually improved the hindlimb locomotor activity of ASCI rats as well as inhibited TNF-α, IL-1β levels, and Iba-1 protein, the marker of activated microglia in injured spinal cords. Our study demonstrated that MALAT1 was dysregulated in ASCI rats and in LPS-activated MGs, and MALAT1 knockdown was expected to attenuate ASCI through repressing inflammatory response of MGs.

scholarly journals Anti-Inflammatory Effects of Neochlorogenic Acid Extract from Mulberry Leaf (Morus alba L.) Against LPS-Stimulated Inflammatory Response through Mediating the AMPK/Nrf2 Signaling Pathway in A549 Cells

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1385 ◽  
Author(s):  
Xiao-han Gao ◽  
Sun-dong Zhang ◽  
Li-tao Wang ◽  
Liang Yu ◽  
Xue-lian Zhao ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
A549 Cells ◽  
Morus Alba ◽  
Mulberry Leaf ◽  
Tnf Α ◽  
Nrf2 Signaling Pathway ◽  
Acute Pneumonia ◽  
Neochlorogenic Acid ◽  
Anti Inflammatory

Neochlorogenic acid (nCGA) is a phenolic compound isolated from mulberry leaf (Morus alba L.), which possesses multiple pharmacological activities containing antioxidant and anti-inflammatory effects. However, the role of nCGA in the treatment of acute pneumonia and the underlying molecular mechanism are still unclear. Hence, the aim of study is to investigate the anti-inflammatory properties of nCGA on LPS-stimulated inflammation in A549 cells. In the present study, results reported that nCGA without cytotoxicity significantly reduced the production of TNF-α, IL-6, and NO, and further suppressed the proteins of iNOS, COX2, TNF-α, IL-6 expression. Furthermore, nCGA also inhibited NF-κB activation and blocked MAPKs signaling pathway phosphorylation. In addition, we found nCGA significantly increased the expression of HO-1 via activating the AMPK/Nrf2 signaling pathway to attenuate the inflammatory response, whereas this protective effect of nCGA was reversed by pre-treatment with compound C (C.C, an AMPK inhibitor). Therefore, all these results indicated that nCGA might act as a natural anti-inflammatory agent for the treatment of acute pneumonia.

scholarly journals Neuroglobin Regulates Wnt/β-Catenin and NFκB Signaling Pathway through Dvl1

2018 ◽  
Vol 19 (7) ◽  
pp. 2133 ◽  
Author(s):  
Yu Xun ◽  
Zhen Li ◽  
Yingxin Tang ◽  
Manjun Yang ◽  
Shengwen Long ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ectopic Expression ◽  
Degradation Pathway ◽  
Diphenyltetrazolium Bromide ◽  
Tnf Α ◽  
Screening Study ◽  
Mtt Assays ◽  
Two Hybrid ◽  
Hybrid Screening

Neuroglobin is an endogenous neuroprotective protein, but the underlying neuroprotective mechanisms remain to be elucidated. Our previous yeast two-hybrid screening study identified that Dishevelled-1, a key hub protein of Wnt/β-Catenin signaling, is an interaction partner of Neuroglobin. In this study, we further examined the role of Neuroglobin in regulating Dishevelled-1 and the downstream Wnt/β-Catenin and NFκB signaling pathway. We found that Neuroglobin directly interacts with Dishevelled-1 by co-immunoprecipitation, and the two proteins are co-localized in both cytoplasma and nucleus of SK-N-SH cells. Moreover, the ectopic expression of Neuroglobin promotes the degradation of exogenous and endogenous Dishevelled-1 through the proteasomal degradation pathway. Furthermore, our results showed that Neuroglobin significantly inhibits the luciferase activity of Topflash reporter and the expression of β-Catenin mediated by Dishevelled-1 in SK-N-SH cells. In addition, we also documented that Neuroglobin enhances TNF-α-induced NFκB activation via down-regulating Dishevelled-1. Finally, 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assays showed that Neuroglobin is an important neuroprotectant that protects SK-N-SH cells from TNF-α-induced decrease in cell viability. Taken together, these findings demonstrated that Neuroglobin functions as an important modulator of the Wnt/β-Catenin and NFκB signaling pathway through regulating Dishevelled-1.

SIRT6 inhibits TNF-α-induced inflammation of vascular adventitial fibroblasts through ROS and Akt signaling pathway

2017 ◽  
Vol 357 (1) ◽  
pp. 88-97 ◽  
Author(s):  
Yanhao He ◽  
Yunfang Xiao ◽  
Xiaofeng Yang ◽  
Yanxiang Li ◽  
Bo Wang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Tnf Α ◽  
Adventitial Fibroblasts

Activation of cAMP-guanine exchange factor confers PKA-independent protection from hepatocyte apoptosis

2004 ◽  
Vol 287 (2) ◽  
pp. G334-G343 ◽  
Author(s):  
Kimberly A. Cullen ◽  
John McCool ◽  
M. Sawkat Anwer ◽  
Cynthia R. L. Webster
Keyword(s):  
Bile Acid ◽  
Protective Effect ◽  
Signaling Pathway ◽  
Fas Ligand ◽  
Kinase Inhibitor ◽  
Pi3 Kinase ◽  
Akt Phosphorylation ◽  
Tnf Α ◽  
Induced Apoptosis

cAMP has previously been shown to promote cell survival in a variety of cell types, but the downstream signaling pathway(s) of this antiapoptotic effect is unclear. Thus the role of cAMP signaling through PKA and cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs) in cAMP's antiapoptotic action was investigated in the present study. cAMP's protective effect against bile acid-, Fas ligand-, and TNF-α-induced apoptosis in rat hepatocytes was largely unaffected by the selective PKA inhibitor, Rp-8-(4-chlorophenylthio)-cAMP (Rp-cAMP). In contrast, a novel cAMP analog, 8-(4-chlorophenylthio)-2′- O-methyl (CPT-2-Me)-cAMP, which activated cAMP-GEFs in hepatocytes without activating PKA, protected hepatocytes against apoptosis induced by bile acids, Fas ligand, and TNF-α. The role of cAMP-GEF and PKA on activation of Akt, a kinase implicated in cAMP survival signaling, was investigated. Inhibition of PKA with RP-cAMP had no effect on cAMP-mediated Akt phosphorylation, whereas CPT-2-Me-cAMP, which did not activate PKA, induced phosphatidylinositol 3-kinase (PI3-kinase)-dependent activation of Akt. Pretreatment of hepatocytes with the PI3-kinase inhibitor, Ly-294002, prevented CPT-2-Me-cAMP's protective effect against bile acid and Fas ligand, but not TNF-α-mediated apoptosis. Glucagon, CPT-cAMP, and CPT-2-Me-cAMP all activated Rap 1, a downstream effector of cAMP-GEF. These results suggest that a PKA-independent cAMP/cAMP-GEF/Rap pathway exists in hepatocytes and that activation of cAMP-GEFs promotes Akt phosphorylation and hepatocyte survival. Thus a cAMP/cAMP-GEF/Rap/PI3-kinase/Akt signaling pathway may confer protection against bile acid- and Fas-induced apoptosis in hepatocytes.

scholarly journals Suppression of Sirtuin-1 Increases IL-6 Expression by Activation of the Akt Pathway During Allergic Asthma

2017 ◽  
Vol 43 (5) ◽  
pp. 1950-1960 ◽  
Author(s):  
Lingling Tang ◽  
Qingge Chen ◽  
Ziyu Meng ◽  
Li Sun ◽  
Linyun Zhu ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Sirtuin 1 ◽  
Akt Pathway ◽  
Epithelial Cell Line ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Mice Model ◽  
Akt Inhibitor ◽  
Akt Phosphorylation ◽  
Protein Levels

Background/Aims: A growing number of studies have demonstrated that the activity and expression level of sirtuin-1 (SIRT1) are decreased in asthma patients; however, the mechanisms underlying decreased SIRT1 expression and function are still not completely understood. Interleukin (IL)-6 plays important roles in inflammation during allergic asthma. In this study, we examined whether loss of SIRT1 activity regulated the expression of IL-6 and further verified the underlying mechanisms. Methods: The human airway epithelial cell line 16HBE was used to test the effects of the SIRT1 inhibitor (salermide) on expression of IL-6. IL-6 mRNA and protein expression were assessed with real-time polymerase chain reaction (PCR), immunochemistry, and ELISA. OVA-challenged mice were used as an asthma model to investigate the effect of SIRT1 activation on IL-6 and relative Akt phosphorylation level. Results: We found that inhibition of SIRT1 increased IL-6 mRNA and protein levels in a time-dependent manner, which was accompanied by increased Akt pathway activation in 16HBE cells. Furthermore activation of Akt showed upregulated expression of the IL-6 protein whereas Akt inhibitor, LY294002 or Akt siRNA significantly inhibited SIRT1-regulated IL-6 expression. Conversely, activation of SIRT1 inhibited Akt activation and IL-6 expression in an asthmatic mice model and 16HBE cells. Conclusion: Our results indicate the potential role of SIRT1 in regulating inflammation by modulation of IL-6 expression in an Akt-dependent manner during allergic asthma.

scholarly journals SIRT1 inhibits rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and inflammatory response via suppressing NF-κB pathway

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Guoqing Li ◽  
Zhongbing Xia ◽  
Ying Liu ◽  
Fanru Meng ◽  
Xia Wu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Sirtuin 1 ◽  
Migration And Invasion ◽  
Synovial Hyperplasia ◽  
Sirt1 Expression ◽  
Tnf Α ◽  
Synovial Tissues ◽  
Inflammatory Phenotypes

Rheumatoid arthritis (RA) is an autoimmune disease of the joints characterized by synovial hyperplasia and chronic inflammation. Fibroblast-like synoviocytes (FLS) play a central role in RA initiation, progression, and perpetuation. Prior studies showed that sirtuin 1 (SIRT1), a deacetylase participating in a broad range of transcriptional and metabolic regulations, may impact cell proliferation and inflammatory responses. However, the role of SIRT1 in RA–FLS was unclear. Here, we explored the effects of SIRT1 on the aggressiveness and inflammatory responses of cultured RA-FLS. SIRT1 expression was significantly lower in synovial tissues and FLS from RA patients than from healthy controls. Overexpression of SIRT1 significantly inhibited RA-FLS proliferation, migration, and invasion. SIRT1 overexpression also significantly increased RA-FLS apoptosis and caspase-3 and -8 activity. Focusing on inflammatory phenotypes, we found SIRT1 significantly reduced RA-FLS secretion of TNF-α, IL-6, IL-8, and IL-1β. Mechanistic studies further revealed SIRT1 suppressed NF-κB pathway by reducing p65 protein expression, phosphorylation, and acetylation in RA-FLS. Our results suggest SIRT1 is a key regulator in RA pathogenesis by suppressing aggressive phenotypes and inflammatory response of FLS. Enhancing SIRT1 expression or function in FLS could be therapeutic beneficial for RA by inhibiting synovial hyperplasia and inflammation.

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