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 oxLDL induces endothelial cell proliferation via Rho/ROCK/Akt/p27kip1 signaling: opposite effects of oxLDL and cholesterol loading

2017 ◽  
Vol 313 (3) ◽  
pp. C340-C351 ◽  
Author(s):  
Chongxu Zhang ◽  
Crystal Adamos ◽  
Myung-Jin Oh ◽  
Jugajyoti Baruah ◽  
Manuela A. A. Ayee ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kinase Inhibitor ◽  
Oxidized Ldl ◽  
Endothelial Cell Proliferation ◽  
Dependent Manner ◽  
Akt Inhibitor ◽  
Aortic Endothelial Cells ◽  
Akt Phosphorylation ◽  
Downstream Target ◽  
Underlying Mechanisms

Oxidized modifications of LDL (oxLDL) play a key role in the development of endothelial dysfunction and atherosclerosis. However, the underlying mechanisms of oxLDL-mediated cellular behavior are not completely understood. Here, we compared the effects of two major types of oxLDL, copper-oxidized LDL (Cu2+-oxLDL) and lipoxygenase-oxidized LDL (LPO-oxLDL), on proliferation of human aortic endothelial cells (HAECs). Cu2+-oxLDL enhanced HAECs’ proliferation in a dose- and degree of oxidation-dependent manner. Similarly, LPO-oxLDL also enhanced HAEC proliferation. Mechanistically, both Cu2+-oxLDL and LPO-oxLDL enhance HAEC proliferation via activation of Rho, Akt phosphorylation, and a decrease in the expression of cyclin-dependent kinase inhibitor 1B (p27kip1). Both Cu2+-oxLDL or LPO-oxLDL significantly increased Akt phosphorylation, whereas an Akt inhibitor, MK2206, blocked oxLDL-induced increase in HAEC proliferation. Blocking Rho with C3 or its downstream target ROCK with Y27632 significantly inhibited oxLDL-induced Akt phosphorylation and proliferation mediated by both Cu2+- and LPO-oxLDL. Activation of RhoA was blocked by Rho-GDI-1, which also abrogated oxLDL-induced Akt phosphorylation and HAEC proliferation. In contrast, blocking Rac1 in these cells had no effect on oxLDL-induced Akt phosphorylation or cell proliferation. Moreover, oxLDL-induced Rho/Akt signaling downregulated cell cycle inhibitor p27kip1. Preloading these cells with cholesterol, however, prevented oxLDL-induced Akt phosphorylation and HAEC proliferation. These findings provide a new understanding of the effects of oxLDL on endothelial proliferation, which is essential for developing new treatments against neovascularization and progression of atherosclerosis.

Mechanisms of NOS2 regulation by Rho GTPase signaling in airway epithelial cells

2002 ◽  
Vol 283 (3) ◽  
pp. L604-L611 ◽  
Author(s):  
Nathan C. Kraynack ◽  
Deborah A. Corey ◽  
Heather L. Elmer ◽  
Thomas J. Kelley
Keyword(s):  
Promoter Activity ◽  
Rho Gtpase ◽  
Alveolar Epithelial Cell ◽  
Airway Epithelial Cells ◽  
Epithelial Cell Line ◽  
Airway Epithelial ◽  
Protein Levels ◽  
Human Alveolar Epithelial Cell ◽  
Coa Reductase ◽  
Nos2 Expression

The aberrant dysregulation of the inducible form of nitric oxide synthase (NOS2) is thought to play a role in many inflammatory disorders including cystic fibrosis (CF). The complex regulation of NOS2 expression is the subject of intense investigation, and one intriguing regulatory pathway known to influence NOS2 expression is the Rho GTPase cascade. We examined NOS2 regulation in response to inflammatory cytokines in a human alveolar epithelial cell line treated with inhibitors of different upstream and downstream components of the Rho GTPase pathway to better define potential signaling mechanisms. Statin-mediated 3-hydroxy-3-methylglutaryl-CoA reductase inhibition increased cytokine-dependent activation of the NOS2 promoter, reversible by the addition of geranylgeranyl pyrphosphate. However, inhibition of Rho-associated kinase (ROCK) with Y-27632 resulted in a decrease in NOS2 promoter activity, yet an increase in NOS2 mRNA and protein levels. Our results suggest that prenylation events influence NOS2 promoter activity independently of the Rho GTPase pathway and that Rho GTPase signaling mediated through ROCK suppresses NOS2 production downstream of promoter function at the message and protein level.

RSV infection of human airway epithelial cells causes production of the beta-chemokine RANTES

1997 ◽  
Vol 272 (3) ◽  
pp. L512-L520 ◽  
Author(s):  
S. Becker ◽  
W. Reed ◽  
F. W. Henderson ◽  
T. L. Noah
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cell Cultures ◽  
Airway Epithelial Cells ◽  
Epithelial Cell Line ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Epithelial Cell Cultures ◽  
Rsv Infection ◽  
Syncytial Virus

Infection of airway epithelial cells with respiratory syncytial virus (RSV) results in the production of a restricted number of cytokines, which may modulate the inflammatory response to infection. To get a better understanding of epithelial cell-mediated inflammatory processes in RSV disease, the aim of the present study was to identify the production of mononuclear cell/eosinophil/mast cell inflammatory chemokines [monocyte chemotactic protein (MCP)-1, MCP-3, macrophage inflammatory protein-1beta, and RANTES] during productive RSV infection in airway epithelial cells. Normal human primary bronchial epithelial cell cultures, nasal epithelial cell explants, and the BEAS-2B airway epithelial cell line were inoculated with RSV, and chemokine induction was assessed during the phase of logarithmic increase in infectious virus production. Only RANTES was found to increase in epithelial cell cultures in an infection-dependent manner. Furthermore, RANTES was released only by RSV-producing cells. To determine whether RANTES was induced by RSV infection in vivo, RANTES was measured in nasal lavage fluids (NLF) from children with RSV-positive and RSV-negative upper respiratory infection and children when they were well. RANTES was increased significantly during RSV infection (128 +/- 38 pg/ml NFL) compared with non-RSV infection (42 +/- 12 pg/ml NFL) and with asymptomatic baseline (13 +/- 4 ng/ml NFL) in the same children. Because RANTES is an effective eosinophil and memory T cell chemoattractant and activator and because eosinophil-dominated inflammation is a hallmark of asthmatic airways, RANTES may play a role in the pathogenesis of RSV-induced exacerbations of airway reactivity and wheezing.

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.

scholarly journals Thrombin Induces NF-κB Activation and IL-8/CXCL8 Expression in Lung Epithelial Cells by a Rac1-dependent PI3K/Akt Pathway

2011 ◽  
Vol 286 (12) ◽  
pp. 10483-10494 ◽  
Author(s):  
Chien-Huang Lin ◽  
Hui-Wen Cheng ◽  
Hon-Ping Ma ◽  
Chih-Hsiung Wu ◽  
Chuang-Ye Hong ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Human Lung ◽  
Luciferase Activity ◽  
Lung Epithelial Cells ◽  
Akt Pathway ◽  
Dependent Manner ◽  
Akt Inhibitor ◽  
Iκb Kinase ◽  
Lung Epithelial ◽  
Human Lung Epithelial Cells

We previously showed that thrombin induces interleukin (IL)-8/CXCL8 expression via the protein kinase C (PKC)α/c-Src-dependent IκB kinase α/β (IKKα/β)/NF-κB signaling pathway in human lung epithelial cells. In this study, we further investigated the roles of Rac1, phosphoinositide 3-kinase (PI3K), and Akt in thrombin-induced NF-κB activation and IL-8/CXCL8 expression. Thrombin-induced IL-8/CXCL8 release and IL-8/CXCL8-luciferase activity were attenuated by a PI3K inhibitor (LY294002), an Akt inhibitor (1-l-6-hydroxymethyl-chiro-inositol-2-((R)-2-O-methyl-3-O-octadecylcarbonate)), and the dominant negative mutants of Rac1 (RacN17) and Akt (AktDN). Treatment of cells with thrombin caused activation of Rac and Akt. The thrombin-induced increase in Akt activation was inhibited by RacN17 and LY294002. Stimulation of cells with thrombin resulted in increases in IKKα/β activation and κB-luciferase activity; these effects were inhibited by RacN17, LY294002, an Akt inhibitor, and AktDN. Treatment of cells with thrombin induced Gβγ, p85α, and Rac1 complex formation in a time-dependent manner. These results imply that thrombin activates the Rac1/PI3K/Akt pathway through formation of the Gβγ, Rac1, and p85α complex to induce IKKα/β activation, NF-κB transactivation, and IL-8/CXCL8 expression in human lung epithelial cells.

scholarly journals Inactivation of the Akt/FOXM1 Signaling Pathway by Panobinostat Suppresses the Proliferation and Metastasis of Gastric Cancer Cells

2021 ◽  
Vol 22 (11) ◽  
pp. 5955
Author(s):  
Na-Ri Lee ◽  
Da-Yeah Kim ◽  
Hua Jin ◽  
Ruoyu Meng ◽  
Ok Hee Chae ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Animal Experiments ◽  
Hdac Inhibitors ◽  
Dependent Manner ◽  
Akt Inhibitor ◽  
M Cell ◽  
Gastric Cancer Cells ◽  
Protein Levels

Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Histone deacetylase (HDAC) inhibitors are a new class of cytostatic agents available for the treatment of various cancers and diseases. Although numerous clinical and pre-clinical trials on the anticancer effects of panobinostat have been conducted, only a few reports have investigated its efficacy in gastric cancer. The present study aimed to investigate the effects of panobinostat in gastric cancer cells. Panobinostat significantly inhibited the cell viability and proliferation of the gastric cancer cell lines SNU484 and SNU638 in a dose-dependent manner; it reduced the colony-forming ability of these cells. Moreover, it induced apoptosis as indicated by increased protein levels of cleaved poly ADP-ribose polymerase and cleaved caspase-3. Panobinostat induced the G2/M cell cycle arrest in SNU484 and SNU638 cells and subsequently decreased the G2/M phase regulatory-associated protein expression of p-Wee1, Myt1, and Cdc2. Furthermore, panobinostat significantly inhibited the metastasis of SNU484 and SNU638 cells by regulating the expression of MMP-9 and E-cadherin. Further, it decreased the protein levels of p-Akt and forkhead box protein M1 (FOXM1). These effects were reversed by the Akt agonist SC79 and were accelerated by the Akt inhibitor LY2940002. Moreover, tumor growth in xenograft animal experiments was suppressed by panobinostat. These results indicated that panobinostat inhibits the proliferation, metastasis, and cell cycle progression of gastric cancer cells by promoting apoptosis and inactivating Akt/FOXM1 signaling. Cumulatively, our present study suggests that panobinostat is a potential drug for the treatment of gastric cancer.

scholarly journals Ginsenoside Rg2 Attenuates Doxorubicin-induced Cardiomyocyte Apoptosis via PI3K/Akt Pathway

2021 ◽  
Author(s):  
Boyong Qiu ◽  
Meijiao Mao ◽  
Shuai Zhang ◽  
Bing Deng ◽  
Lin Shen ◽  
...  
Keyword(s):  
Cardiomyocyte Apoptosis ◽  
Cell Counting ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Akt Pathway ◽  
Dependent Manner ◽  
P53 Expression ◽  
Akt Phosphorylation ◽  
Underlying Mechanisms ◽  
Dose Dependent ◽  
Important Drug

Abstract Doxorubicin (DOX) is an important drug for cancer therapy; however, its use is limited by its cardiotoxicity. Ginsenoside Rg2 is extracted from Panax ginseng, which is believed to have cardioprotective properties. However, to date, there have been no reports on whether ginsenoside Rg2 could protect cardiomyocytes against DOX. In this study, we investigated the action and underlying mechanisms of ginsenoside Rg2 upon DOX treatment. This study aimed to explore the cardioprotective effects of ginsenoside Rg2 against DOX treatment. Cell Counting kit-8 was used to determine cell viability and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining was used to detect apoptotic cells. Western blotting was used to investigate the relevant pathways. LY294002 (LY294), a PI3K inhibitor, was used in this study. We found that ginsenoside Rg2 significantly (P < 0.01) neutralized cardiomyocyte apoptosis induced by DOX in a dose-dependent manner, which was blocked by LY294. Moreover, ginsenoside Rg2 upregulated Akt phosphorylation through the PI3K/Akt pathway and inhibited p53 expression. Taken together, Ginsenoside Rg2 attenuates DOX-induced cardiomyocyte apoptosis via the PI3K/Akt pathway.

scholarly journals Oxyresveratrol Inhibits TNF-α-Stimulated Cell Proliferation in Human Immortalized Keratinocytes (HaCaT) by Suppressing AKT Activation

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 63
Author(s):  
Nitwara Wikan ◽  
Phateep Hankittichai ◽  
Phatarawat Thaklaewphan ◽  
Saranyapin Potikanond ◽  
Wutigri Nimlamool
Keyword(s):  
Akt Pathway ◽  
Functional Assay ◽  
Dependent Manner ◽  
Induce Cell Cycle Arrest ◽  
Ki 67 ◽  
Akt Phosphorylation ◽  
Akt Activation ◽  
Cycle Arrest ◽  
Tnf Α ◽  
Psoriasis Therapy

Psoriasis is a complex inflammatory disease characterized by hyperproliferative keratinocyte caused by active PI3K/AKT signaling. TNF-α concentrated in the psoriatic lesions stimulates AKT activation. We previously discovered that oxyresveratrol inhibited inflammation via suppressing AKT phosphorylation, therefore oxyresveratrol may possess a conserved property to block AKT activation and proliferation in keratinocyte in response to TNF-α. Our current study proved that oxyresveratrol exhibited potent anti-proliferative effects against TNF-α. These effects are explained by the findings that oxyresveratrol could potentially inhibit TNF-α-stimulated AKT and GSK3-β activation in a dose-dependent manner, and its inhibitory pattern was comparable to that of a specific PI3K inhibitor. Results from immunofluorescence supported that oxyresveratrol effectively inhibited AKT and GSK3-β activation in individual cells upon TNF-α stimulation. Furthermore, functional assay confirmed that oxyresveratrol repressed the expansion of the HaCaT colony over 3 days, and this was caused by the ability of oxyresveratrol to induce cell cycle arrest at S and G2/M phases and the reduction in the expression of a proliferative marker (Ki-67) and a survival marker (MCL-1). Given the importance of TNF-α and the PI3K/AKT pathway in the psoriatic phenotype, we anticipate that oxyresveratrol, which targets the TNF-α-stimulated PI3K/AKT pathway, would represent a promising psoriasis therapy in the near future.

scholarly journals Akt Phosphorylation Influences Persistent Chlamydial Infection and Chlamydia-Induced Golgi Fragmentation Without Involving Rab14

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaobao Huang ◽  
Jinfeng Tan ◽  
Xiaohong Chen ◽  
Mingna Liu ◽  
Huiling Zhu ◽  
...  
Keyword(s):  
Persistent Infection ◽  
Chlamydial Infection ◽  
Akt Pathway ◽  
Rrna Gene ◽  
Obligate Intracellular Bacterium ◽  
Akt Inhibitor ◽  
Limited Effect ◽  
Akt Phosphorylation ◽  
Obligate Intracellular ◽  
Golgi Fragmentation

Chlamydia trachomatis is an obligate intracellular bacterium that causes multiple diseases involving the eyes, gastrointestinal tract, and genitourinary system. Previous studies have identified that in acute chlamydial infection, C. trachomatis requires Akt pathway phosphorylation and Rab14-positive vesicles to transmit essential lipids from the Golgi apparatus in survival and replication. However, the roles that Akt phosphorylation and Rab14 play in persistent chlamydial infection remain unclear. Here, we discovered that the level of Akt phosphorylation was lower in persistent chlamydial infection, and positively correlated with the effect of activating the development of Chlamydia but did not change the infectivity and 16s rRNA gene expression. Rab14 was found to exert a limited effect on persistent infection. Akt phosphorylation might regulate Chlamydia development and Chlamydia-induced Golgi fragmentation in persistent infection without involving Rab14. Our results provide a new insight regarding the potential of synergistic repressive effects of an Akt inhibitor with antibiotics in the treatment of persistent chlamydial infection induced by penicillin.

Abstract 305: Carvacrol Attenuates Diabetic Cardiomyopathy by Enhancing PI3K/AKT Pathway in STZ-induced Type 1 Diabetic C57BL/6J Mice

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Ning Hou ◽  
Yunpei Mai ◽  
Wenliang Chen ◽  
Faqian Li ◽  
Jiandong Luo
Keyword(s):  
Western Blotting ◽  
Diabetic Cardiomyopathy ◽  
Plasma Concentrations ◽  
Akt Pathway ◽  
Dependent Manner ◽  
Diabetic Mice ◽  
Diabetes Group ◽  
Protein Levels ◽  
Group I

Background: Carvacrol (CAR), a monoterpenic phenol that occurs in many essential oils of the family Labiatae including Origanum , Satureja , Thymbra , Thymus , and Corydothymus species, possess a wide variety of pharmacological properties including antioxidant and anti-inflammatory potential. This present study was designed to investigate the cardiac protective effect of CAR on diabetic cardiomyopathy in STZ-induced type 1 diabetic mice and explore its potential molecular mechanism. Methods: Type 1 diabetes was induced by the intraperitoneal injection of streptozocin (STZ) to male mice at dose of 45 mg/kg body weight (BW). The diabetic animals were divided into three groups containing eight in each: Group I diabetes, Group II and II injected with CAR at 10 and 20 mg/kg BW respectively once daily for 6 weeks. Age matched male C57 mice were used as normal controls. The plasma concentrations of glucose, total cholesterol (TC) and triglycerides (TG) levels were enzymatically determined using commercial kits. The cardiac function was measured by echocardiography. Protein levels of p-PDK1/t-PDK1, p-AKT/t-AKT, p-GSKα/β/t-GSKα/β were detected by Western blotting. Results: STZ-induced C57BL/6J diabetic mice showed an elevation in serum glucose, TG and TC level. Compared to diabetic mice, administration of CAR resulted in significant decrease ( P <0.05) in plasma glucose level in a dose dependent manner, but did not attenuate elevation in TG and TC levels. The abnormal diastolic function in type 1 diabetic mice was significantly reversed by CAR administration. Furthermore, western blotting showed that the expression of p-PDK1, p-AKT and p-GSKα/β were lower in diabetic hearts than C57 hearts while total PDK1, AKT and GSK α/β protein levels were no difference among groups. CAR administration attenuated these decreases in protein phosphorylation. These findings indicate that the impaired PI3K/AKT pathway induced by STZ in diabetic heart can be restored by CAR. Conclusion: Carvacrol has antidiabetic property and can be potentially used to prevent hyperglycemia and diabetic cardiomyopathy.

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