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Zhao YY, Xie L, Wang RY, Yan Y, Liu LL. Treponema pallidum Protein TpF1 Inhibits Migration by Impairing Actin Polymerization via Toll-Like Receptor 4/PI3K/AKT in Microglia. ACS Infect Dis 2025; 11:1104-1113. [PMID: 40272988 DOI: 10.1021/acsinfecdis.4c00868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2025]
Abstract
Treponema pallidum induces a host immune response during central nervous system (CNS) invasion, prompting microglia to migrate to the site of injury, where they release effector molecules or phagocytose pathogens. However, the role of impaired microglial migration in the pathogenesis of T. pallidum infection remains poorly understood. In this study, we sought to explore the molecular mechanisms by which the T. pallidum protein TpF1 inhibits microglial migration. Microglial HMC3 cells were used to assess the effects of TpF1 on cellular migration and its impact on actin polymerization. Our findings demonstrate that TpF1 significantly reduces microglial migration in both horizontal and vertical directions. This effect correlates with a marked decrease in the filamentous actin (F-actin)/globular actin (G-actin) ratio, as confirmed by immunofluorescence analysis, which revealed a considerable reduction in F-actin levels. Moreover, TpF1 was found to suppress the expression of Toll-like receptor 4 (TLR4), phosphorylated PI3K (P-PI3K)/PI3K, phosphorylated AKT (P-AKT)/AKT, and Rac1. Inhibition of the TLR4/PI3K/AKT signaling pathway further impaired actin polymerization and migration. Collectively, our study identifies a novel mechanism by which TpF1 disrupts microglial migration via the TLR4/PI3K/AKT pathway, providing valuable insights into immune evasion strategies during T. pallidum-induced CNS infection.
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Affiliation(s)
- Yuan-Yi Zhao
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
| | - Lin Xie
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
| | - Ruo-Ying Wang
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
| | - Ya Yan
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
| | - Li-Li Liu
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen 361004, China
- Xiamen Clinical Laboratory Quality Control Center, Xiamen 361004, Fujian, China
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2
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Gong SQ, Liu H, Wu JL, Xu JX. Effects of daphnetin on the mechanism of epithelial-mesenchymal transition induced by HMGB1 in human lung adenocarcinoma cells (A549 cell line). Biotechnol Genet Eng Rev 2024; 40:1489-1510. [PMID: 36994673 DOI: 10.1080/02648725.2023.2194092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 03/19/2023] [Indexed: 03/31/2023]
Abstract
As a cancer with the highest incidence in recent years, lung cancer is mainly composed of three diseases: non-small cell lung cancer, small cell lung cancer and neuroendocrine tumor. The morbidity and mortality of this malignant tumor are the highest in both male and female populations worldwide. In my country, lung cancer has become the most common cancer disease and the leading cause of cancer death, so it is extremely important to find lung cancer therapeutic targets. Based on previous studies, we speculated that the TLR4-Myd88-NFκB pathway may be involved in hmgb1-induced EMT in A549 cells, and daphnetin may also inhibit hmgb1-induced EMT through the TLR4-Myd88-NFκB pathway in A549 cells, but related studies have not linked it to hmgb1-induced EMT. Therefore, the innovation of this study is to test these two conjectures and analyze how daphnetin affects the epithelial-mesenchymal transition (EMT) mechanism induced by HMGB1 in human lung adenocarcinoma cells (A549 cell line), aiming at lung adenocarcinoma cells, foundation for clinical treatment. The proliferation rate and the migrating cell number presented an obvious decrease in the HMGB1+TLR4-shRNA group and the HMGB1+daphnetin group relative to the HMGB1 group (P < 0.0001). The intracellular expression of TLR4, Myd88, NFκB, vimentin and snail1 proteins were significantly decreased (P < 0.001), while that of E-cadherin presented a remarkable increase (P < 0.001) in the HMGB1+TLR4-shRNA and HMGB1+daphnetin group compared with the HMGB1 group. TLR4-MyD88-NFκB pathway is associated with HMGB1-induced EMT in A549 cells. Daphnetin had an inhibitory effect on HMGB1-induced EMT via the TLR4-Myd88-NF-κB pathway in A549 cells.
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Affiliation(s)
- Shu-Qi Gong
- Nanchang University, Nan Chang city, China
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Nanchang University, Nan Chang city, China
| | - Hua Liu
- Nanchang University, Nan Chang city, China
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Nanchang University, Nan Chang city, China
| | - Jin-Lan Wu
- Nanchang University, Nan Chang city, China
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Nanchang University, Nan Chang city, China
| | - Jiang-Xia Xu
- Nanchang University, Nan Chang city, China
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Nanchang University, Nan Chang city, China
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3
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Qi B, Zheng Y, Gao W, Qi Z, Gong Y, Liu Y, Wang Y, Cheng X, Ning M, Lang Y, Feng J, Li T. Alpha-lipoic acid impedes myocardial ischemia-reperfusion injury, myocardial apoptosis, and oxidative stress by regulating HMGB1 expression. Eur J Pharmacol 2022; 933:175295. [PMID: 36152839 DOI: 10.1016/j.ejphar.2022.175295] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/16/2022] [Accepted: 09/16/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND Inflammation, oxidative stress, and apoptosis contribute to myocardial ischemia/reperfusion injury (I/RI). Alpha-lipoic acid (ALA) plays a critical role in I/RI by impeding apoptosis and inflammation. Here, we aimed to explore the underlying mechanisms of ALA after I/RI. METHODS The left anterior descending coronary artery (LAD) was ligated, and H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to establish an I/RI model. Prior to this, H9c2 cells and rats were treated using an appropriate amount of ALA. The cardiac function, inflammatory factors, and myocardial pathology were assessed in vitro. We detected cell viability, apoptosis, and oxidative stress-related factors in vivo. Moreover, proteins of the HMGB1/TLR4/NF-κB signaling pathway were detected both in vivo and in vitro. RESULTS We observed that ALA increased cell viability in vitro and decreased apoptosis in vitro and in vivo. ALA inhibited reactive oxygen species production, decreased malondialdehyde, and increased superoxide dismutase activity to resist oxidative stress in vitro. ALA also reduced the expression of inflammatory cytokines (IL-6, IL-1β, and TNF-α) in vivo. ALA also suppressed the levels of the apoptotic protein, Bax, and increased the expression of the anti-apoptotic protein Bcl-2, in vitro and in vivo. Moreover, we observed that ALA significantly inhibited the cytoplasmic localization of HMGB1, which might attenuate MI/RI or H/R via HMGB1/TLR4/NF-κB pathway. CONCLUSION ALA regulates HMGB1 translocation and attenuates I/R via the HMGB1/TLR4/NF-κB signaling pathway, thus impeding apoptosis, oxidation, and inflammation, and might be a potential target for myocardial ischemia/reperfusion injury.
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Affiliation(s)
- Bingcai Qi
- Department of Heart Center, The Third Central Clinical College of Tianjin Medical University, Tianjin, 300170, China; Department of Heart Center, Tianjin Third Central Hospital, 83 Jintang Road, Hedong District, Tianjin, 300170, China; Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China; Artificial Cell Engineering Technology Research Center, Tianjin, China.
| | - Yue Zheng
- Department of Heart Center, Tianjin Third Central Hospital, 83 Jintang Road, Hedong District, Tianjin, 300170, China; School of Medicine, Nankai University, Tianjin, 300071, China; Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China; Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Wenqing Gao
- Department of Heart Center, Tianjin Third Central Hospital, 83 Jintang Road, Hedong District, Tianjin, 300170, China; Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China; Artificial Cell Engineering Technology Research Center, Tianjin, China.
| | - Zhenchang Qi
- Department of Heart Center, The Third Central Clinical College of Tianjin Medical University, Tianjin, 300170, China; Department of Heart Center, Tianjin Third Central Hospital, 83 Jintang Road, Hedong District, Tianjin, 300170, China; Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China; Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Yijie Gong
- Department of Heart Center, The Third Central Clinical College of Tianjin Medical University, Tianjin, 300170, China; Department of Heart Center, Tianjin Third Central Hospital, 83 Jintang Road, Hedong District, Tianjin, 300170, China; Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China; Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Yanwu Liu
- Department of Heart Center, The Third Central Clinical College of Tianjin Medical University, Tianjin, 300170, China; Department of Heart Center, Tianjin Third Central Hospital, 83 Jintang Road, Hedong District, Tianjin, 300170, China; Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China; Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Yuchao Wang
- Department of Heart Center, Tianjin Third Central Hospital, 83 Jintang Road, Hedong District, Tianjin, 300170, China; School of Medicine, Nankai University, Tianjin, 300071, China; Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China; Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Xian Cheng
- Department of Heart Center, The Third Central Clinical College of Tianjin Medical University, Tianjin, 300170, China; Department of Heart Center, Tianjin Third Central Hospital, 83 Jintang Road, Hedong District, Tianjin, 300170, China; Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China; Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Meng Ning
- Department of Heart Center, Tianjin Third Central Hospital, 83 Jintang Road, Hedong District, Tianjin, 300170, China; Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China; Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Yuheng Lang
- Department of Heart Center, The Third Central Clinical College of Tianjin Medical University, Tianjin, 300170, China; Department of Heart Center, Tianjin Third Central Hospital, 83 Jintang Road, Hedong District, Tianjin, 300170, China; Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China; Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Jianyu Feng
- Department of Heart Center, The Third Central Clinical College of Tianjin Medical University, Tianjin, 300170, China; Department of Heart Center, Tianjin Third Central Hospital, 83 Jintang Road, Hedong District, Tianjin, 300170, China; Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China; Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Tong Li
- Department of Heart Center, The Third Central Clinical College of Tianjin Medical University, Tianjin, 300170, China; Department of Heart Center, Tianjin Third Central Hospital, 83 Jintang Road, Hedong District, Tianjin, 300170, China; School of Medicine, Nankai University, Tianjin, 300071, China; Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China; Artificial Cell Engineering Technology Research Center, Tianjin, China.
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VCP interaction with HMGB1 promotes hepatocellular carcinoma progression by activating the PI3K/AKT/mTOR pathway. J Transl Med 2022; 20:212. [PMID: 35562734 PMCID: PMC9102726 DOI: 10.1186/s12967-022-03416-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 04/27/2022] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common pathological type of liver cancer. Valosin-containing protein (VCP) is a member of the AAA-ATPase family associated with multiple molecular functions and involved in tumor metastasis and prognosis. However, the role of VCP in HCC progression is still unclear. METHODS We examined the expression of VCP in HCC using the RNA sequencing and microarray data from public databases and measured it in clinical samples and cell lines by western blot, and immunohistochemistry (IHC). We also evaluated the correlation between VCP and clinical features. The VCP-interacting proteins were identified by co-immunoprecipitation combined with mass spectrometry (CoIP/MS). The underlying molecular mechanisms were investigated using in vitro and in vivo models of HCC. RESULTS We found that VCP expression is significantly increased in tumor tissues and is associated with advanced TNM stages and poorer prognosis in HCC patients. In vitro analyses revealed that VCP overexpression promoted HCC cell proliferation, migration, and invasion via PI3K/AKT/mTOR pathway activation. Conversely, VCP knockdown resulted in the reverse phenotypes. In vivo studies indicated that up-regulated VCP expression accelerated tumor growth in a subcutaneous HCC model. The D1 domain of VCP and A box of HMGB1 were identified as the critical regions for their interaction, and D1 area was required for the tumor-promoting effects induced by VCP expression. VCP enhanced the protein stability of HMGB1 by decreasing its degradation via ubiquitin-proteasome process. Inhibition of HMGB1 markedly attenuated VCP-mediated HCC progression and downstream activation of PI3K/AKT/mTOR signals. CONCLUSION Collectively, these findings demonstrate that VCP is a potential prognostic biomarker in HCC and exhibits oncogenic roles via PI3K/AKT/mTOR pathway activation. HMGB1 played an essential role in VCP-mediated HCC progression, indicating that VCP and HMGB1 are potential therapeutic targets in human HCC.
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Li Q, Xu M, Li Z, Li T, Wang Y, Chen Q, Wang Y, Feng J, Yin X, Lu C. Maslinic Acid Attenuates Ischemia/Reperfusion Injury-Induced Myocardial Inflammation and Apoptosis by Regulating HMGB1-TLR4 Axis. Front Cardiovasc Med 2021; 8:768947. [PMID: 34859077 PMCID: PMC8631436 DOI: 10.3389/fcvm.2021.768947] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 10/07/2021] [Indexed: 12/15/2022] Open
Abstract
Aims: The inflammatory response and apoptosis are the major pathological features of myocardial ischemia/reperfusion injury (MI/RI). Maslinic acid (MA), a natural pentacyclic triterpene with various bioactivities, plays critical roles in the multiple cellular biological processes, but its protective effects on the pathophysiological processes of MI/RI have not been extensively investigated. Our study aimed to determine whether MA treatment alleviate ischemia/reperfusion (I/R)-induced myocardial inflammation and apoptosis both in vitro and in vivo, and further reveal the underlying mechanisms. Methods and results: An MI/RI rat model was successfully established by ligating the left anterior descending coronary artery and H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to mimic I/R injury. In addition, prior to H/R stimulation or myocardial I/R operation, the H9c2 cells or rats were treated with varying concentrations of MA or vehicle for 24 h and two consecutive days, respectively. In this study, our results showed that MA could obviously increase the cell viability and decrease the cardiac enzymes release after H/R in vitro. MA could significantly improve the H/R-induced cardiomyocyte injury and I/R-induced myocardial injury in a dose-dependent manner. Moreover, MA suppressed the expression of inflammatory cytokines (tumor necrosis factor alpha [TNF-α, interleukin-1β [IL-1β and interleukin-6 [IL-6]) and the expressions of apoptosis-related proteins (cleaved caspase-3 and Bax) as well as increased the levels of anti-apoptotic protein Bcl-2 expression both in vitro and in vivo. Mechanistically, MA significantly inhibited nuclear translocation of nuclear factor-κB (NF-κB) p65 after H/R via regulating high mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4) axis. Conclusion: Taken together, MA treatment may alleviate MI/RI by suppressing both the inflammation and apoptosis in a dose-dependent manner, and the cardioprotective effect of MA may be partly attributable to the inactivation of HMGB1/TLR4/NF-κB pathway, which offers a new therapeutic strategy for MI/RI.
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Affiliation(s)
- Qi Li
- School of Medicine, Nankai University, Tianjin, China.,Department of Cardiology, Tianjin First Center Hospital, Tianjin, China
| | - Mengping Xu
- Department of Cardiology, Tianjin First Center Hospital, Tianjin, China
| | - Zhuqing Li
- School of Medicine, Nankai University, Tianjin, China.,Department of Cardiology, Tianjin First Center Hospital, Tianjin, China
| | - Tingting Li
- Department of Cardiology, Tianjin First Center Hospital, Tianjin, China.,Department of Cardiology, The First Center Clinic College of Tianjin Medical University, Tianjin, China
| | - Yilin Wang
- Department of Cardiology, Tianjin First Center Hospital, Tianjin, China.,Department of Cardiology, The First Center Clinic College of Tianjin Medical University, Tianjin, China
| | - Qiao Chen
- Department of Cardiology, Tianjin First Center Hospital, Tianjin, China.,Department of Cardiology, The First Center Clinic College of Tianjin Medical University, Tianjin, China
| | - Yanxin Wang
- Department of Cardiology, Tianjin First Center Hospital, Tianjin, China.,Department of Cardiology, The First Center Clinic College of Tianjin Medical University, Tianjin, China
| | - Jiaxin Feng
- Department of Cardiology, Tianjin First Center Hospital, Tianjin, China.,Department of Cardiology, The First Center Clinic College of Tianjin Medical University, Tianjin, China
| | - Xuemei Yin
- Department of Cardiology, Tianjin First Center Hospital, Tianjin, China.,Department of Cardiology, The First Center Clinic College of Tianjin Medical University, Tianjin, China
| | - Chengzhi Lu
- School of Medicine, Nankai University, Tianjin, China.,Department of Cardiology, Tianjin First Center Hospital, Tianjin, China
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Ghanbari M, Momen Maragheh S, Aghazadeh A, Mehrjuyan SR, Hussen BM, Abdoli Shadbad M, Dastmalchi N, Safaralizadeh R. Interleukin-1 in obesity-related low-grade inflammation: From molecular mechanisms to therapeutic strategies. Int Immunopharmacol 2021; 96:107765. [PMID: 34015596 DOI: 10.1016/j.intimp.2021.107765] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/27/2021] [Accepted: 05/04/2021] [Indexed: 12/13/2022]
Abstract
Since adipose tissue (AT) can upregulate pro-inflammatory interleukins (ILs) via storing extra lipids in obesity, obesity is considered the leading cause of chronic low-grade inflammation. These ILs can pave the way for the infiltration of immune cells into the AT, ultimately resulting in low-grade inflammation and dysregulation of adipocytes. IL-1, which is divided into two subclasses, i.e., IL-1α and IL-1β, is a critical pro-inflammatory factor. In obesity, IL-1α and IL-1β can promote insulin resistance via impairing the function of adipocytes and promoting inflammation. The current study aims to review the detailed molecular mechanisms and the roles of IL-1α and IL-1β and their antagonist, interleukin-1 receptor antagonist(IL-1Ra), in developing obesity-related inflammatory complications, i.e., type II diabetes (T2D), non-alcoholic steatohepatitis (NASH), atherosclerosis, and cognitive disorders. Besides, the current study discusses the recent advances in natural drugs, synthetic agents, and gene therapy approaches to treat obesity-related inflammatory complications via suppressing IL-1.
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Affiliation(s)
- Mohammad Ghanbari
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | - Aida Aghazadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | | | - Mahdi Abdoli Shadbad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narges Dastmalchi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Reza Safaralizadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
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Ren S, Pan L, Yang L, Niu Z, Wang L, Feng H, Yuan M. miR-29a-3p transferred by mesenchymal stem cells-derived extracellular vesicles protects against myocardial injury after severe acute pancreatitis. Life Sci 2021; 272:119189. [PMID: 33571516 DOI: 10.1016/j.lfs.2021.119189] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 01/28/2021] [Accepted: 02/06/2021] [Indexed: 02/05/2023]
Abstract
AIMS Acute pancreatitis (AP) is an inflammatory disease of the pancreas that may affect local tissues or remote organ systems, while severe acute pancreatitis (SAP) is a life-threatening disorder associated with multiple organ failure. In this investigation, we set about to determine whether microRNA-29a-3p (miR-29a-3p) carried by mesenchymal stem cell (MSCs)-derived extracellular vesicles (EVs) affects the myocardial injury during SAP. MAIN METHODS EVs were isolated from MSCs of rat bone marrow by differential centrifugation. An SAP rat model was developed and treated with MSCs-EVs and/or alteration of miR-29a-3p and HMGB1 expression, followed by assessment of the rats' cardiac function and inflammation. Next, cardiomyocytes H9C2 were co-cultured with MSC-EVs and internalization of EVs was evaluated, followed by evaluation of whether EVs could transmit miR-29a-3p cargos into H9C2 cells and affect their biological functions. KEY FINDINGS EVs derived from MSCs were observed to protect against SAP-induced myocardial injury. In SAP-induced rats, miR-29a-3p was under-expressed in myocardial tissues. In addition, we also confirmed that miR-29a-3p could be transferred into the H9C2 cardiomyocytes by MSC-derived EVs, which downregulated the expression of inflammatory markers and improve cardiac function to attenuate myocardial injury. Furthermore, miR-29a-3p inhibited the expression of HMGB1 to downregulate TLR4 expression and further inactivate the Akt signaling pathway. SIGNIFICANCE These findings support the cardioprotective action of miR-29a-3p transmitted by MSCs-derived EVs in SAP-induced myocardial injury via downregulation of the HMGB1/TLR4/Akt axis, highlighting a promising target for the EV-based therapy for SAP.
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Affiliation(s)
- Song Ren
- Department of Geriatric Digestive Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China
| | - Longfei Pan
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China.
| | - Linqing Yang
- Department of Nursing, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China
| | - Zequn Niu
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China
| | - Liming Wang
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China
| | - Hui Feng
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China
| | - Miao Yuan
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China
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Yoon JH, Lee N, Youn K, Jo MR, Kim HR, Lee DS, Ho CT, Jun M. Dieckol Ameliorates Aβ Production via PI3K/Akt/GSK-3β Regulated APP Processing in SweAPP N2a Cell. Mar Drugs 2021; 19:md19030152. [PMID: 33804171 PMCID: PMC8001366 DOI: 10.3390/md19030152] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/06/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023] Open
Abstract
The proteolytic processing of amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase releases amyloid-β peptide (Aβ), which deposits in amyloid plaques and contributes to the initial causative events of Alzheimer’s disease (AD). In the present study, the regulatory mechanism of APP processing of three phlorotannins was elucidated in Swedish mutant APP overexpressed N2a (SweAPP N2a) cells. Among the tested compounds, dieckol exhibited the highest inhibitory effect on both intra- and extracellular Aβ accumulation. In addition, dieckol regulated the APP processing enzymes, such as α-secretase (ADAM10), β-secretase, and γ-secretase, presenilin-1 (PS1), and their proteolytic products, sAPPα and sAPPβ, implying that the compound acts on both the amyloidogenic and non-amyloidogenic pathways. In addition, dieckol increased the phosphorylation of protein kinase B (Akt) at Ser473 and GSK-3β at Ser9, suggesting dieckol induced the activation of Akt, which phosphorylated GSK-3β. The specific phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 triggered GSK-3β activation and Aβ expression. In addition, co-treatment with LY294002 noticeably blocked the effect of dieckol on Aβ production, demonstrating that dieckol promoted the PI3K/Akt signaling pathway, which in turn inactivated GSK-3β, resulting in the reduction in Aβ levels.
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Affiliation(s)
- Jeong-Hyun Yoon
- Department of Health Sciences, The graduate School of Dong-A University, Busan 49315, Korea; (J.-H.Y.); (N.L.)
| | - Nayoung Lee
- Department of Health Sciences, The graduate School of Dong-A University, Busan 49315, Korea; (J.-H.Y.); (N.L.)
| | - Kumju Youn
- Department of Food Science and Nutrition, Dong-A University, Busan 49315, Korea;
| | - Mi Ra Jo
- Division of Food Safety and Processing Research, National Institute of Fisheries Science, Busan 46083, Korea;
| | - Hyeung-Rak Kim
- Department of Food Science and Nutrition, Pukyong National University, Busan 48513, Korea;
| | - Dong-Seok Lee
- School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea;
| | - Chi-Tang Ho
- Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA;
| | - Mira Jun
- Department of Health Sciences, The graduate School of Dong-A University, Busan 49315, Korea; (J.-H.Y.); (N.L.)
- Department of Food Science and Nutrition, Dong-A University, Busan 49315, Korea;
- Correspondence: ; Tel.: +82-51-200-7323
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Tan Y, Sun D, Chen J, Li R, Wang S. Ginsenoside Rb3 alleviates smoke-induced lung injury via the H19/miR-29b-3p/HGMB1/TLR4 signalling pathway. J Cell Mol Med 2021; 25:2725-2729. [PMID: 33523607 PMCID: PMC7933968 DOI: 10.1111/jcmm.15844] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 07/27/2020] [Accepted: 08/19/2020] [Indexed: 12/18/2022] Open
Abstract
The over-activation of inflammation is involved in the pathogenesis of smoke-induced lung injury (SILI), while Rb3 treatment may alleviate smoke-induced lung injury by down-regulating the expression of H19, a regulator of miR-29b expression. Moreover, HMGB1 is an important mediator of inflammation. Therefore, in this study, we set up an animal model of SILI and treated it with Rb3 to study the effect of Rb3 on the treatment of SILI and the involvement of H19/miR-29b/HMGB1/TLR4 signalling. SILI mice treated with Rb3 before H&E staining and TUNEL assay were conducted to observe the pathological damages and status of apoptosis in each group. Real-time PCR, Western blot, computational analysis and luciferase assays were utilized to establish the signalling pathway involved in the pathogenesis of SILI and the action of Rb3 treatment. Rb3 treatment alleviated pathological changes in the lungs while decreasing the levels of W/D ratio and cell apoptotic index. H19 was validated to sponge miR-29b-3p, while HMGB1 mRNA was validated to be a target gene of miR-29b-3. As a result, a signalling pathway of H19/miR-29b-3p/HMGB1 was established. Cell viability was evidently reduced after 72 hours of treatment with CSE, but the treatment of Rb3 elevated the expression of H19 and HMBG1 in the presence of CSE. Also, CSE-induced inhibition of miR-29b-3p expression was restored by Rb3. The findings of this study collectively demonstrated that Rb3 exhibited its therapeutic effect during the treatment of SILI via modulating the H19/miR-29b-3p/HMBG1 signalling pathway.
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Affiliation(s)
- Yan Tan
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, China
| | - Danxiong Sun
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, China
| | - Juan Chen
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, China
| | - Rufang Li
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, China
| | - Shenglan Wang
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, China
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10
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Zhang Y, Li M, Zhang Q, Wang Z, Li X, Bao J, Zhang H. Arthpyrone L, a New Pyridone Alkaloid from a Deep-Sea Arthrinium sp., Inhibits Proliferation of MG63 Osteosarcoma Cells by Inducing G0/G1 Arrest and Apoptosis. Chem Biodivers 2021; 18:e2000639. [PMID: 33427403 DOI: 10.1002/cbdv.202000639] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 01/11/2021] [Indexed: 01/20/2023]
Abstract
Fractionation of the ethanol extract of a marine fungus, Arthrinium sp., afforded a new pyridone alkaloid (arthpyrone L (1)), the structure with absolute configuration of which was established by comprehensive spectroscopic analyses. In vitro cell viability assays revealed that compound 1 showed antiproliferative effects toward human A549 (lung), MG63, U2OS (bone), MCF-7 and MDA-MB-231 (breast) cancer cells. MG63 cell lines were chosen for further biological evaluations and presented apoptosis and cell cycle arrest (G0/G1 phase) upon treatment of 1. Subsequent mechanism studies demonstrated that the growth inhibition of 1 against MG63 cells was via activation of caspase-modulated apoptotic pathway and inhibition of PI3K/Akt pathway.
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Affiliation(s)
- Yuying Zhang
- School of Biological Science and Technology, University of Jinan, Jinan, 250022, P. R. China
| | - Mengru Li
- School of Biological Science and Technology, University of Jinan, Jinan, 250022, P. R. China
| | - Qianqian Zhang
- School of Biological Science and Technology, University of Jinan, Jinan, 250022, P. R. China
| | - Zhaoyang Wang
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, P. R. China
| | - Xiuxiu Li
- School of Biological Science and Technology, University of Jinan, Jinan, 250022, P. R. China
| | - Jie Bao
- School of Biological Science and Technology, University of Jinan, Jinan, 250022, P. R. China
| | - Hua Zhang
- School of Biological Science and Technology, University of Jinan, Jinan, 250022, P. R. China
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11
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Liu J, Li M, Kong L, Cao M, Zhang M, Wang Y, Song C, Fang X, Chen H, Zhang C. CircARID1A regulates mouse skeletal muscle regeneration by functioning as a sponge of miR-6368. FASEB J 2021; 35:e21324. [PMID: 33421208 DOI: 10.1096/fj.202001992r] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/30/2020] [Accepted: 12/14/2020] [Indexed: 12/21/2022]
Abstract
The noncoding RNAs play important role in growth and development of mammalian skeletal muscle. Recent work has shown that circRNAs are abundant in skeletal muscle tissue, with significant changes in their expression patterns during muscle development and aging. We identified a novel circRNA called circARID1A that is highly expressed in mice skeletal muscle compare to its linear transcript. Experiments shown that circARID1A significantly inhibited the process of C2C12 cell proliferation and promoted its differentiation. Interactions between circRNA and miRNA were screened by miRNA gene chip sequencing. The results indicated that circARID1A can sponge miR-6368, which was further verified by miRNA sensor and other experiments. Besides, miR-6368 is a commonly expressed miRNA that regulates the expression of several target genes including Tlr4. A mouse model of skeletal muscle injury was successfully established to explore the role of circARID1A in skeletal muscle development and regeneration in vivo. Moreover, we found the overexpression of circARID1A significantly promoted the regeneration of skeletal muscle. The results of our study suggest that circARID1A may regulate skeletal muscle cell development and regeneration by sponging miR-6368.
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Affiliation(s)
- Jia Liu
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou, China
| | - MengLu Li
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou, China
| | - LingHao Kong
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou, China
| | - MengWen Cao
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou, China
| | - MoLan Zhang
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou, China
| | - YanHong Wang
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou, China
| | - ChengChuang Song
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou, China
| | - XingTang Fang
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou, China
| | - Hong Chen
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou, China
| | - ChunLei Zhang
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou, China
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12
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Haque N, Fareez IM, Fong LF, Mandal C, Kasim NHA, Kacharaju KR, Soesilawati P. Role of the CXCR4-SDF1-HMGB1 pathway in the directional migration of cells and regeneration of affected organs. World J Stem Cells 2020. [DOI: 10.4252/wjsc.v12.i9.0000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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13
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Haque N, Fareez IM, Fong LF, Mandal C, Abu Kasim NH, Kacharaju KR, Soesilawati P. Role of the CXCR4-SDF1-HMGB1 pathway in the directional migration of cells and regeneration of affected organs. World J Stem Cells 2020; 12:938-951. [PMID: 33033556 PMCID: PMC7524697 DOI: 10.4252/wjsc.v12.i9.938] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 06/18/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
In recent years, several studies have reported positive outcomes of cell-based therapies despite insufficient engraftment of transplanted cells. These findings have created a huge interest in the regenerative potential of paracrine factors released from transplanted stem or progenitor cells. Interestingly, this notion has also led scientists to question the role of proteins in the secretome produced by cells, tissues or organisms under certain conditions or at a particular time of regenerative therapy. Further studies have revealed that the secretomes derived from different cell types contain paracrine factors that could help to prevent apoptosis and induce proliferation of cells residing within the tissues of affected organs. This could also facilitate the migration of immune, progenitor and stem cells within the body to the site of inflammation. Of these different paracrine factors present within the secretome, researchers have given proper consideration to stromal cell-derived factor-1 (SDF1) that plays a vital role in tissue-specific migration of the cells needed for regeneration. Recently researchers recognized that SDF1 could facilitate site-specific migration of cells by regulating SDF1-CXCR4 and/or HMGB1-SDF1-CXCR4 pathways which is vital for tissue regeneration. Hence in this study, we have attempted to describe the role of different types of cells within the body in facilitating regeneration while emphasizing the HMGB1-SDF1-CXCR4 pathway that orchestrates the migration of cells to the site where regeneration is needed.
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Affiliation(s)
- Nazmul Haque
- Department of Oral Biology and Biomedical Sciences, Faculty of Dentistry, MAHSA University, Selangor 42610, Malaysia
| | - Ismail M Fareez
- Department of Oral Biology and Biomedical Sciences, Faculty of Dentistry, MAHSA University, Selangor 42610, Malaysia
| | - Liew Fong Fong
- Department of Oral Biology and Biomedical Sciences, Faculty of Dentistry, MAHSA University, Selangor 42610, Malaysia
| | - Chanchal Mandal
- Biotechnology and Genetic Engineering Discipline, Life Science, Khulna University, Khulna 9208, Bangladesh
| | - Noor Hayaty Abu Kasim
- Faculty of Dentistry, University Kebangsaan Malaysia, Kuala Lumpur 50300, Malaysia
- Faculty of Dental Medicine, Universitas Airlangga, Surabaya 411007, Indonesia
| | - Kranthi Raja Kacharaju
- Department of Conservative Dentistry, Faculty of Dentistry MAHSA University, Selangor 42610, Malaysia
| | - Pratiwi Soesilawati
- Department of Oral Biology, Faculty of Dental Medicine, Universitas Airlangga, Surabaya 60115, Indonesia
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14
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Qaradakhi T, Gadanec LK, McSweeney KR, Abraham JR, Apostolopoulos V, Zulli A. The Anti-Inflammatory Effect of Taurine on Cardiovascular Disease. Nutrients 2020; 12:E2847. [PMID: 32957558 PMCID: PMC7551180 DOI: 10.3390/nu12092847] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/02/2020] [Accepted: 09/12/2020] [Indexed: 12/12/2022] Open
Abstract
Taurine is a non-protein amino acid that is expressed in the majority of animal tissues. With its unique sulfonic acid makeup, taurine influences cellular functions, including osmoregulation, antioxidation, ion movement modulation, and conjugation of bile acids. Taurine exerts anti-inflammatory effects that improve diabetes and has shown benefits to the cardiovascular system, possibly by inhibition of the renin angiotensin system. The beneficial effects of taurine are reviewed.
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Affiliation(s)
- Tawar Qaradakhi
- Institute for Health and Sport, Victoria University, Melbourne, VIC 8001, Australia; (L.K.G.); (K.R.M.); (J.R.A.); (V.A.); (A.Z.)
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15
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Zhu XS, Zhou HY, Yang F, Zhang HS, Ma KZ. miR-381-3p inhibits high glucose-induced vascular smooth muscle cell proliferation and migration by targeting HMGB1. J Gene Med 2020; 23:e3274. [PMID: 32902022 DOI: 10.1002/jgm.3274] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 09/02/2020] [Accepted: 09/02/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Hyperglycemia increases the risk of many cardiovascular diseases (CVD), and the dysregulation of proliferation and migration in vascular smooth muscle cells (VSMCs) also participates in the pathogenesis of CVD. miR-381-3p is known to suppress the proliferation and migration of multiple human cell types. Nevertheless, the function of miR-381-3p in VSMCs remains largely indistinct. METHODS A quantitative real-time polymerase chain reaction (qRT-PCR) was employed to investigate miR-381-3p expression in high-glucose-induced VSMCs. Inflammatory cytokines tumor necrosis factor-α, interleukin-1β and interleukin-6, as well as oxidative stress markers SOD and MDA, were determined by an enzyme-linked immunosorbent assay. Reactive oxygen species generation was examined using a 2,7'-dichlorofluorescein kit. The proliferation, migration and apoptosis of VSMCs were monitored by 3-(4,5-dimethylthiazl2-yl)-2,5-diphenyltetazolium bromide (MTT), transwell and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays. The TargetScan database (http://www.targetscan.org) was employed to seek the potential target gene of miR-381-3p. Interaction between miR-381-3p and HMGB1 was determined by a qRT-PCR, western blotting and a luciferase reporter assay. RESULTS miR-381-3p expression was significantly reduced in a VSMCs dysfunction model induced by high-glucose in a dose- and time-dependent manner. Transfection of miR-381-3p mimics suppressed the inflammation, oxidative stress, proliferation and migration of VSMCs, whereas apoptosis of VSMCs was promoted, and the transfection of miR-381-3p inhibitors had the opposite effect. Mechanistically, HMGB1, an important factor in inflammation response, was confirmed as a target gene of miR-381-3p. CONCLUSIONS miR-381-3p targets HMGB1 to suppress the inflammation, oxidative stress, proliferation and migration of high-glucose-induced VSMCs by targeting HMGB1.
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Affiliation(s)
- Xiao-Shan Zhu
- Department of Cardiology, Xiangyang Central Hospital, Affliated Hospital of Hubei College of Arts and Science, Xiangyang City, Hubei Province, 441021, China
| | - Han-Yun Zhou
- Department of Cardiology, Xiangyang Central Hospital, Affliated Hospital of Hubei College of Arts and Science, Xiangyang City, Hubei Province, 441021, China
| | - Feng Yang
- Department of Cardiology, Xiangyang Central Hospital, Affliated Hospital of Hubei College of Arts and Science, Xiangyang City, Hubei Province, 441021, China
| | - Hong-Shen Zhang
- Department of Cardiology, Xiangyang Central Hospital, Affliated Hospital of Hubei College of Arts and Science, Xiangyang City, Hubei Province, 441021, China
| | - Ke-Zhong Ma
- Department of Cardiology, Xiangyang Central Hospital, Affliated Hospital of Hubei College of Arts and Science, Xiangyang City, Hubei Province, 441021, China
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16
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Ding P, Ding Y, Tian Y, Lei X. Circular RNA circ_0010283 regulates the viability and migration of oxidized low‑density lipoprotein‑induced vascular smooth muscle cells via an miR‑370‑3p/HMGB1 axis in atherosclerosis. Int J Mol Med 2020; 46:1399-1408. [PMID: 32945389 PMCID: PMC7447304 DOI: 10.3892/ijmm.2020.4703] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 07/06/2020] [Indexed: 12/15/2022] Open
Abstract
Atherosclerosis is a disease during which the inside of an artery narrows due to the accumulation of plaque, and vascular smooth muscle cells (VSMCs) are involved in the progression of atherosclerosis. Circular RNAs (circRNAs) have been reported to be involved in the progression of atherosclerosis. However, the role of circ_0010283 in atherosclerosis progression remains unclear. The present study aimed to investigate the functions and the mechanism of circ_0010283 in oxidized low-density lipoprotein (ox-LDL)-induced VSMCs and to identify new potential biomarkers for the treatment of atherosclerosis. Cell viability and migration were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assays. The relationship between microRNA (miR)-370-3p and circ_0010283 or high mobility group box 1 (HMGB1) was predicated by online software and confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay. The results of the present study demonstrated that the expression levels of circ_0010283 and HMGB1 were significantly upregulated in ox-LDL-induced VSMCs compared with those in VSMCs without ox-LDL induction, whereas the expression of miR-370-3p was downregulated. Knockdown of circ_0010283 suppressed VSMC viability and migration, as well as the expression of viability-associated proteins cyclin D1 and proliferating cell nuclear antigen, and migration-associated proteins matrix metalloproteinase 2 (MMP2) and MMP9 in ox-LDL-induced VSMCs compared with untreated VSMCs. In addition, miR-370-3p was demonstrated to be a target of circ_0010283 and to target HMGB1; thus, circ_0010283 regulated HMGB1 expression via miR-370-3p. Further experiments indicated that inhibition of miR-370-3p reversed the circ_0010283 silencing-mediated inhibitory effects on VMSC viability and migration. Additionally, the miR-370-3p-mediated suppressive effects on cell viability and migration were rescued by overexpression of HMGB1. In conclusion, circ_0010283 mediated cell viability and migration via a miR-370-3p/HMGB1 axis in ox-LDL-induced VSMCs.
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Affiliation(s)
- Peng Ding
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, Shanxi 710000, P.R. China
| | - Yi Ding
- Department of Nephrology and Endocrinology, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, Shanxi 710000, P.R. China
| | - Ye Tian
- Department of Neurology, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, Shanxi 710000, P.R. China
| | - Xiaochun Lei
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, Shanxi 710000, P.R. China
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17
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Liu M, Huang X, Tian Y, Yan X, Wang F, Chen J, Zhang Q, Zhang Q, Yuan X. Phosphorylated GSK‑3β protects stress‑induced apoptosis of myoblasts via the PI3K/Akt signaling pathway. Mol Med Rep 2020; 22:317-327. [PMID: 32377749 PMCID: PMC7248528 DOI: 10.3892/mmr.2020.11105] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 02/17/2020] [Indexed: 01/02/2023] Open
Abstract
Facial jaw muscle is involved in the occurrence, development, treatment and maintenance of maxillofacial deformities. The structure and function of this tissue can be altered by changes in external stimuli, and orthodontists can regulate its reconstruction using orthopedic forces. The PI3K/Akt signaling pathway is most well‑known for its biological functions in cell proliferation, survival and apoptosis. In the present study, the effects of the PI3K/Akt signaling pathway in cyclic stretch‑induced myoblast apoptosis were investigated. For this purpose, L6 rat myoblasts were cultured under mechanical stimulation and treated with the PI3K kinase inhibitor, LY294002, to elucidate the role of the PI3K/Akt signaling pathway. Cells were stained with Hoechst 33258 to visualize morphological changes and apoptosis of myoblasts, and western blotting was performed to detect expression of Akt, phosphorylated (p)‑Akt (Ser473), glycogen synthase kinase 3β (GSK‑3β) and p‑GSK‑3β (Ser9). After addition of PI3K inhibitor, the expression of total Akt and GSK‑3β did not significantly differ among groups; however, the levels of p‑Akt and p‑GSK‑3β were lower in inhibitor‑treated groups than in those treated with loading stress alone. In addition, the rate of apoptosis in myoblasts subjected to cyclic stretch increased in a time‑dependent manner, peaking at 24 h. Collectively, it was also demonstrated that the PI3K/Akt/GSK‑3β pathway plays an important role in stretch‑induced myoblast apoptosis.
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Affiliation(s)
- Meixi Liu
- Department of Orthodontics II, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
- School of Stomatology of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Xia Huang
- Department of Nursing and Hospital Infection Management, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Yihong Tian
- Department of Orthodontics II, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
- School of Stomatology of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Xiao Yan
- Department of Orthodontics II, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Fang Wang
- Department of Orthodontics, Xiaoshan Branch of Hangzhou Stomatology Hospital, Hangzhou, Zhejiang 310000, P.R. China
| | - Junbo Chen
- School of Stomatology of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Qi Zhang
- School of Stomatology of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Qiang Zhang
- Department of Orthodontics II, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Xiao Yuan
- Department of Orthodontics II, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
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18
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Zhai R, Blondonnet R, Ebrahimi E, Belville C, Audard J, Gross C, Choltus H, Henrioux F, Constantin JM, Pereira B, Blanchon L, Sapin V, Jabaudon M. The receptor for advanced glycation end-products enhances lung epithelial wound repair: An in vitro study. Exp Cell Res 2020; 391:112030. [PMID: 32330509 DOI: 10.1016/j.yexcr.2020.112030] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/17/2020] [Accepted: 04/19/2020] [Indexed: 12/22/2022]
Abstract
Re-epithelialization of the alveolar surface is a key process of lung alveolar epithelial barrier repair after acute lung injury. The receptor for advanced glycation end-products (RAGE) pathway plays key roles in lung homeostasis, and its involvement in wound repair has been already reported in human bronchial epithelial cells. However, its effects on lung alveolar epithelial repair after injury remain unknown. We investigated whether RAGE stimulation with its ligands high-mobility group box 1 protein (HMGB1) or advanced glycation end-products (AGEs), alone or associated with RAGE inhibition using RAGE antagonist peptide, affects in vitro wound healing in human alveolar epithelial A549 cells. We further asked whether these effects could be associated with changes in cell proliferation and migration. We found that treatment of A549 cells with HMGB1 or AGEs promotes RAGE-dependent wound healing after a scratch assay. In addition, both RAGE ligands increased cell proliferation in a RAGE-dependent manner. Treatment with HMGB1 increased migration of alveolar epithelial cells at 12 h, independently of RAGE, whereas AGEs stimulated migration as measured 48 h after injury in a RAGE-dependent manner. Taken together, these results suggest that RAGE pathway is involved in lung alveolar epithelial wound repair, possibly through enhanced cell migration and proliferation.
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Affiliation(s)
- Ruoyang Zhai
- Université Clermont Auvergne, CNRS, INSERM, GReD, Clermont-Ferrand, France
| | - Raiko Blondonnet
- Université Clermont Auvergne, CNRS, INSERM, GReD, Clermont-Ferrand, France; Department of Perioperative Medicine, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Ebrahim Ebrahimi
- Université Clermont Auvergne, CNRS, INSERM, GReD, Clermont-Ferrand, France; Department of Perioperative Medicine, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Corinne Belville
- Université Clermont Auvergne, CNRS, INSERM, GReD, Clermont-Ferrand, France
| | - Jules Audard
- Université Clermont Auvergne, CNRS, INSERM, GReD, Clermont-Ferrand, France; Department of Perioperative Medicine, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Christelle Gross
- Université Clermont Auvergne, CNRS, INSERM, GReD, Clermont-Ferrand, France
| | - Helena Choltus
- Université Clermont Auvergne, CNRS, INSERM, GReD, Clermont-Ferrand, France
| | - Fanny Henrioux
- Université Clermont Auvergne, CNRS, INSERM, GReD, Clermont-Ferrand, France
| | - Jean-Michel Constantin
- Sorbonne University, GRC 29, AP-HP, DMU DREAM, Department of Anesthesiology and Critical Care, Pitié-Salpêtrière Hospital, Paris, France
| | - Bruno Pereira
- Biostatistics Unit, Department of Clinical Research and Innovation (DRCI), CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Loic Blanchon
- Université Clermont Auvergne, CNRS, INSERM, GReD, Clermont-Ferrand, France
| | - Vincent Sapin
- Université Clermont Auvergne, CNRS, INSERM, GReD, Clermont-Ferrand, France; Department of Medical Biochemistry and Molecular Genetics, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Matthieu Jabaudon
- Université Clermont Auvergne, CNRS, INSERM, GReD, Clermont-Ferrand, France; Department of Perioperative Medicine, CHU Clermont-Ferrand, Clermont-Ferrand, France; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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19
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HOTTIP knockdown inhibits cell proliferation and migration via regulating miR-490-3p/HMGB1 axis and PI3K-AKT signaling pathway in ox-LDL-induced VSMCs. Life Sci 2020; 248:117445. [PMID: 32081664 DOI: 10.1016/j.lfs.2020.117445] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 02/13/2020] [Accepted: 02/17/2020] [Indexed: 12/31/2022]
Abstract
AIMS Atherosclerosis (AS) is a common cardiovascular disease with complicated pathogenesis. Long non-coding RNAs (lncRNAs) have been reported to be associated with AS progression. We aimed to explore the role and underlying mechanism of HOXA transcript at the distal tip (HOTTIP) in AS. MATERIALS AND METHODS Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression of HOTTIP, miR-490-3p and high mobility group B 1 (HMGB1) in AS patients' sera and oxidized low-density lipoprotein (ox-LDL) induced human aortic vascular smooth muscle cells (HA-VSMCs). Cell Counting Kit-8 (CCK-8) assay and transwell assay were conducted to evaluate the proliferation and migration of HA-VSMCs, respectively. Western blot assay was carried out to determine the levels of proliferating cell nuclear antigen (PCNA), matrix metalloprotein 2 (MMP2), MMP9 and HMGB1. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted to verify the targeting association between HOTTIP and miR-490-3p, as well as miR-490-3p and HMGB1. KEY FINDINGS HOTTIP and HMGB1 were upregulated and miR-490-3p was downregulated in the sera of AS patients and ox-LDL-stimulated HA-VSMCs. HOTTIP knockdown suppressed ox-LDL induced proliferation and migration in HA-VSMCs. MiR-490-3p was identified as a target of HOTTIP and HOTTIP overexpression abolished the inhibition on cell proliferation and migration mediated by miR-490-3p in ox-LDL-induced HA-VSMCs. Moreover, miR-490-3p inhibition promoted cell proliferation and migration by directly targeting HMGB1 in ox-LDL-induced HA-VSMCs. Besides, HOTTIP knockdown repressed the activation of PI3K-AKT signaling pathway. SIGNIFICANCE HOTTIP knockdown suppressed cell proliferation and migration by regulating miR-490-3p/HMGB1 axis and PI3K-AKT pathway in ox-LDL-induced HA-VSMCs.
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Xu Q, Liang Y, Liu X, Zhang C, Liu X, Li H, Liang J, Yang G, Ge Z. miR‑132 inhibits high glucose‑induced vascular smooth muscle cell proliferation and migration by targeting E2F5. Mol Med Rep 2019; 20:2012-2020. [PMID: 31257477 DOI: 10.3892/mmr.2019.10380] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 03/18/2019] [Indexed: 11/06/2022] Open
Abstract
The dysregulated behavior of vascular smooth muscle cells (VSMCs) serves an important role in the pathogenesis of cardiovascular diseases in diabetes. The present study aimed to investigate the effects of microRNA (miR)‑132 on the proliferation and migration of VSMCs under high glucose conditions to mimic diabetes. We observed that the expression of miR‑132 was significantly decreased and that of E2F transcription factor 5 (E2F5) was upregulated in high glucose (HG)‑treated VSMCs or those obtained from diabetic rats. A dual luciferase reporter gene assay revealed that miR‑132 could specifically bind to the 3'‑untranslated region of E2F5 and significantly suppress the luciferase activity. The proliferation and migration of diabetic rat or HG‑treated VSMCs were increased compared with non‑diabetic rat VSMCs and those under normal glucose conditions. Upregulation of miR‑132 significantly inhibited the proliferation and migration of diabetic rat VSMCs; similar effects were observed following E2F5 downregulation. The inhibitory effects of miR‑132 on the proliferation and migration of HG‑treated VSMCs could be reversed by E2F5 overexpression. In conclusion, miR‑132 was proposed to inhibit the proliferation and migration of diabetic rat or high‑glucose‑treated VSMCs by targeting E2F5. The findings of the present study suggested that increasing the expression of miR‑132 may serve as a novel therapeutic approach to inhibit the progression of cardiovascular disease in diabetes.
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Affiliation(s)
- Qun Xu
- Department of Geriatric Cardiology, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Ying Liang
- Department of Geriatric Cardiology, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Xiangjuan Liu
- Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Chunmei Zhang
- Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xiaoqian Liu
- Department of Geriatric Cardiology, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Hong Li
- Department of Geriatric Cardiology, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Jiangjiu Liang
- Department of Geriatric Cardiology, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Guang Yang
- Department of Geriatric Cardiology, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Zhiming Ge
- Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
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da Silva Oliveira VR, Santos-Eichler RA, Dale CS. Photobiomodulation increases cell viability via AKT activation in an in vitro model of diabetes induced by glucose neurotoxicity. Lasers Med Sci 2019; 35:149-156. [DOI: 10.1007/s10103-019-02808-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 05/14/2019] [Indexed: 01/22/2023]
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Li FJ, Zhang CL, Luo XJ, Peng J, Yang TL. Involvement of the MiR-181b-5p/HMGB1 Pathway in Ang II-induced Phenotypic Transformation of Smooth Muscle Cells in Hypertension. Aging Dis 2019; 10:231-248. [PMID: 31011475 PMCID: PMC6457049 DOI: 10.14336/ad.2018.0510] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 05/10/2018] [Indexed: 12/16/2022] Open
Abstract
Phenotypic transformation of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling in hypertension. High mobility group box-1 (HMGB1) has been reported to be involved in several pathogenic processes including VSMC proliferation and migration. The present study was designed to determine the role of HMGB1 in VSMC phenotypic transformation in hypertension. First, we demonstrated that HMGB1 was elevated in a model of Ang II-induced VSMC phenotypic transformation, which showed down-regulation of contractile proteins and up-regulation of synthetic proteins. Knockdown of HMGB1 and losartan could block the phenotypic transformation. Next, we identified three potential miRNAs for upstream regulation of HMGB1 by bioinformatic analysis; only miR-181b-5p was significantly down-regulated in Ang II-treated cells. Co-treating the cells with miR-181b-5p mimics suppressed HMGB1 expression as well as the phenotypic transformation, migration, and proliferation. Furthermore, the luciferase reporter gene assay confirmed the direct interaction between miR-181b-5p and HMGB1. Finally, to extend these cell-based studies to clinical patients, we demonstrated that plasma miR-181b-5p levels were decreased, while Ang II and HMGB1 levels, as well as the intima-media thickness (IMT) were increased in hypertensive patients; these effects were reversed following the administration of angiotensin receptor blockers. Based on these observations, we conclude that the down-regulation of miR-181b-5p leads to the elevation of HMGB1 levels in hypertensive patients, which accounts, at least partially, for VSMCs phenotypic transformation and vascular remodeling. Our findings also highlight that the plasma levels of miR-181b-5p and HMGB1 may serve as novel biomarkers for vascular remodeling in the hypertensive patients.
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Affiliation(s)
- Feng-Juan Li
- 1Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Cheng-Long Zhang
- 1Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xiu-Ju Luo
- 2Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha410013, China
| | - Jun Peng
- 3Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.,4Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Tian-Lun Yang
- 1Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
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23
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Liu Y, Fan D. Ginsenoside Rg5 induces apoptosis and autophagy via the inhibition of the PI3K/Akt pathway against breast cancer in a mouse model. Food Funct 2019; 9:5513-5527. [PMID: 30207362 DOI: 10.1039/c8fo01122b] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Breast cancer is the most frequently diagnosed cancer and has become the main cause of cancer-related death among women worldwide. Traditional chemotherapy for breast cancer has serious side effects for patients, such as the first-line drug docetaxel. Ginsenoside Rg5, a rare ginsenoside and the main ingredient extracted from fine black ginseng, has been proved to have anti-breast cancer efficacy in vitro. Here, the in vivo anti-breast cancer efficacy, side effects and potential molecular mechanisms of Rg5 were investigated on a BALB/c nude mouse model of human breast cancer. The tumor growth inhibition rate of high dose Rg5 (20 mg kg-1) was 71.4 ± 9.4%, similar to that of the positive control docetaxel (72.0 ± 9.1%). Compared to docetaxel, Rg5 showed fewer side effects in the treatment of breast cancer. Treatment with Rg5 induced apoptosis and autophagy in breast cancer tissues. Rg5 was proved to induce caspase-dependent apoptosis via the activation of the extrinsic death receptor and intrinsic mitochondrial signaling pathways. The autophagy induction was related to the formation of an autophagosome and accumulation of LC3BII, P62 and critical Atg proteins. Further studies showed that Rg5 in a dose-dependent manner induced apoptosis and autophagy through the inhibition of the PI3K/Akt signaling pathway as indicated by the reduced phosphorylation level of PI3K and Akt. Taken together, Rg5 could be a novel and promising clinical antitumor drug targeting breast cancer.
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Affiliation(s)
- Yannan Liu
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi'an, Shaanxi 710069, China.
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Liu Y, Chen Y, Tan L, Zhao H, Xiao N. Linc00299/miR-490-3p/AURKA axis regulates cell growth and migration in atherosclerosis. Heart Vessels 2019; 34:1370-1380. [PMID: 30734057 DOI: 10.1007/s00380-019-01356-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 02/01/2019] [Indexed: 12/16/2022]
Abstract
Long non-coding RNA (lncRNA) plays a crucial role in regulating various cellular processes in atherosclerosis. The present study identified the regulation of Linc00299, via miR-490-3p targeting Aurora kinase A (AURKA), on migration and proliferation of endothelial cells and vascular smooth muscle cells (VSMCs) during atherosclerosis. The expression of RNAs was assessed by real-time PCR. The proliferation, apoptosis and migration were detected using MTT assay, Annexin V/PI staining and Transwell system, respectively. Bindings of Linc00299/miR-490-3p and subsequent miR-490-3p/AURKA were verified by luciferase and biotin pull-down assays. The protein expression of AURKA was detected by Western blotting. Expressions of Linc00299 and miR-490-3p were upregulated and downregulated in atherosclerosis patients, respectively. Both Linc00299 knockdown and miR-490-3p overexpression suppressed cell proliferation, increased apoptosis and inhibited migration of VSMCs and HUVECs. Linc00299 directly bound to miR-490-3p which targeted AURKA. The regulation of Linc00299 on expression of AURKA and proliferation and migration of VSMCs were dependent on miR-490-3p. Atherosclerosis-increased Linc00299 acts as a sponge of miR-490-3p to upregulate AURKA, and as a result increases proliferation and migration in VSMCs and HUVECs. Our study reveals an important effect of Linc00299/miR-490-3p/AURKA axis on regulating cell proliferation and migration in atherosclerosis.
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Affiliation(s)
- Yong Liu
- Affiliated Hospital of Hebei University, No 212 Yuhua East Road, Baoding, 071000, Hebei, China
| | - Yaqing Chen
- Affiliated Hospital of Hebei University, No 212 Yuhua East Road, Baoding, 071000, Hebei, China
| | - Lili Tan
- Affiliated Hospital of Hebei University, No 212 Yuhua East Road, Baoding, 071000, Hebei, China
| | - Hongmei Zhao
- Affiliated Hospital of Hebei University, No 212 Yuhua East Road, Baoding, 071000, Hebei, China
| | - Nuan Xiao
- Affiliated Hospital of Hebei University, No 212 Yuhua East Road, Baoding, 071000, Hebei, China.
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Dai M, Xiao R, Cai L, Ge T, Zhu L, Hu Q. HMGB1 is mechanistically essential in the development of experimental pulmonary hypertension. Am J Physiol Cell Physiol 2018; 316:C175-C185. [PMID: 30517029 DOI: 10.1152/ajpcell.00148.2018] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pulmonary hypertension (PH) is a mortal disease featuring pulmonary vascular constriction and remodeling, right heart failure, and eventual death. Several reports showed that high-mobility group box 1 (HMGB1) appears to be critical for the development of PH; the underlying mechanism, however, has not been revealed. Experiments in the present study demonstrated that HMGB1 levels were elevated in the lung tissue and blood plasma of rats after chronic hypoxia exposure and monocrotaline treatment. HMGB1 was originally located within the nucleus and translocated to the cytoplasm of pulmonary artery smooth muscle cells (PASMCs) upon hypoxia exposure, a process that appeared to be mediated by endogenous H2O2. Exposure to HMGB1 mobilized calcium signaling in PASMCs, a response that was attenuated by extracellular Ca2+ removal, Toll-like receptor 4 (TLR4) inhibition by TAK-242, or transient receptor potential channel (TRPC) suppression with 2-aminoethoxydiphenyl borate (2-APB) and SKF-96365. The sustained phosphorylation of the Akt pathway modulated HMGB1-induced migration of PASMCs. The blockage of HMGB1 with glycyrrhizin or anti-HMGB1 neutralizing antibody attenuated lung inflammation and PH establishment in rats after hypoxia exposure and monocrotaline treatment. The above findings reveal the mechanistic importance of HMGB1 in PH through TLR4- and TRPC-associated Ca2+ influx and Akt phosphorylation-driven PASMC migration.
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Affiliation(s)
- Mao Dai
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Pulmonary Diseases of Ministry of Health, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Rui Xiao
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Pulmonary Diseases of Ministry of Health, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Luyao Cai
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Pulmonary Diseases of Ministry of Health, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Tong Ge
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Pulmonary Diseases of Ministry of Health, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Liping Zhu
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Pulmonary Diseases of Ministry of Health, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Qinghua Hu
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Pulmonary Diseases of Ministry of Health, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
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Zhou BH, Tan PP, Jia LS, Zhao WP, Wang JC, Wang HW. PI3K/AKT signaling pathway involvement in fluoride-induced apoptosis in C2C12 cells. CHEMOSPHERE 2018; 199:297-302. [PMID: 29448197 DOI: 10.1016/j.chemosphere.2018.02.057] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 02/06/2018] [Accepted: 02/08/2018] [Indexed: 06/08/2023]
Abstract
To investigate the mechanisms of fluoride-induced apoptosis, a fluoride-induced C2C12 skeletal muscle cell (C2C12 cell) model was established in this study, and the viability of the C2C12 cells was measured using an MTT assay. Cell morphological changes were observed via haematoxylin and eosin staining and transmission electron microscopy. Apoptosis was monitored through Hoechst staining. The mRNA and protein expression of PI3K, PDK1, AKT1, BAD, Bcl-2, Bax and caspase-9 were detected through real-time PCR and western blotting, respectively. The results showed that the survival rates of C2C12 cells decreased gradually with an increasing fluoride doses. The C2C12 cell structure was seriously damaged by fluoride, presenting with pyknosis, mitochondrial ridge disruption and swollen endoplasmic reticulum. Furthermore, the expression of mRNA in PI3K, BAD, Bcl-2, Bax and caspase-9 were significantly increased in the fluoride group (P < 0.01), while the expression of PDK1 was markedly decreased (P < 0.01). The expression of protein in BAD, Bcl-2 and Bax were significantly increased in the fluoride group (P < 0.01), while the expression of PDK1 and P-AKT1 was markedly decreased (P < 0.01). In conclusion, fluoride-induced apoptosis in C2C12 cells is related to the PI3K/AKT signaling pathway.
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Affiliation(s)
- Bian-Hua Zhou
- Henan Provincial Open Laboratory of Key Disciplines, Environment and Animal Products Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, Henan, 471000, PR China.
| | - Pan-Pan Tan
- Henan Provincial Open Laboratory of Key Disciplines, Environment and Animal Products Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, Henan, 471000, PR China
| | - Liu-Shu Jia
- Henan Provincial Open Laboratory of Key Disciplines, Environment and Animal Products Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, Henan, 471000, PR China
| | - Wen-Peng Zhao
- Henan Provincial Open Laboratory of Key Disciplines, Environment and Animal Products Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, Henan, 471000, PR China
| | - Ji-Cang Wang
- Henan Provincial Open Laboratory of Key Disciplines, Environment and Animal Products Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, Henan, 471000, PR China
| | - Hong-Wei Wang
- Henan Provincial Open Laboratory of Key Disciplines, Environment and Animal Products Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, Henan, 471000, PR China.
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Xie X, Zhu T, Chen L, Ding S, Chu H, Wang J, Yao H, Chao J. MCPIP1-induced autophagy mediates ischemia/reperfusion injury in endothelial cells via HMGB1 and CaSR. Sci Rep 2018; 8:1735. [PMID: 29379093 PMCID: PMC5788920 DOI: 10.1038/s41598-018-20195-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 01/16/2018] [Indexed: 11/25/2022] Open
Abstract
Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) plays a important role in ischemia/reperfusion (I/R) injury. Autophagy is involved in activating endothelial cells in response to I/R. However, researchers have not clearly determined whether MCPIP1 mediates I/R injury in endothelial cells via autophagy, and its downstream mechanism remains unclear. Western blotting analyses and immunocytochemistry were applied to detect protein levels were detected in HUVECs. An in vitro scratch assay was used to detect cell migration. Cells were transfected with siRNAs to knockdown MCPIP1 and high mobility group box 1 (HMGB1) expression. The pharmacological activator of autophagy rapamycin and the specific calcium-sensing receptor (CaSR) inhibitor NPS-2143 were used to confirm the roles of autophagy and CaSR in I/R injury. I/R induced HMGB1 and CaSR expression, which subsequently upreguated the migration and apoptosis of HUVECs and coincided with the increase of autophagy. HMGB1 was involved in cell migration, whereas CaSR specifically participated in I/R-induced HUVEC apoptosis. Based on these findings, I/R-induced MCPIP1 expression regulates the migration and apoptosis of HUVECs via HMGB1 and CaSR, respectively, suggesting a new therapeutic targetof I/R injury.
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Affiliation(s)
- Xiaolong Xie
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China
| | - Tiebing Zhu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China. .,Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu, 210009, China.
| | - Lulu Chen
- Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu, 210009, China
| | - Shuang Ding
- Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu, 210009, China
| | - Han Chu
- Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu, 210009, China
| | - Jing Wang
- Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu, 210009, China
| | - Honghong Yao
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China.,Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing, Jiangsu, 210096, China
| | - Jie Chao
- Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu, 210009, China. .,Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing, Jiangsu, 210096, China. .,Department of Respiration, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China.
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Cheng Y, Xiong J, Chen Q, Xia J, Zhang Y, Yang X, Tao K, Zhang S, He S. Hypoxia/reoxygenation-induced HMGB1 translocation and release promotes islet proinflammatory cytokine production and early islet graft failure through TLRs signaling. Biochim Biophys Acta Mol Basis Dis 2016; 1863:354-364. [PMID: 27838489 DOI: 10.1016/j.bbadis.2016.11.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 10/20/2016] [Accepted: 11/08/2016] [Indexed: 02/05/2023]
Abstract
High-mobility group box 1 (HMGB1) translocation and release, which is involved in several tissue types of ischemia-reperfusion injuries, activate innate immunity by inducing proinflammatory cytokine production through its interaction with toll-like receptors (TLRs). Our objective was to determine the role of HMGB1 and the degree of activation of TLR-related signal transduction pathways in hypoxia/reoxygenation (H/R)-induced proinflammatory cytokine production and intra-islet graft inflammation. After islets are exposed to hypoxia-reoxygenation for 24h, TLR2/4 expression and TLR-mediated signaling was up-regulated in islets, and HMGB1 was translocated from the nucleus to the cytoplasm and released to the extracellular space. With H/R exposure, proinflammatory cytokine production (IL-1β and TNF-α) and islet injury were significantly increased, and these effects depend on TLR2/4 signaling pathways. Exogenous HMGB1 also induces islet inflammation and increases the phosphorylation of STAT3, p38 and IκBα in wild-type islets. TLR2 deficiency in TLR2-KO islets resulted in the inhibition of IL-1β production and STAT3/p38 phosphorylation after HMGB1 exposure. TLR4 deficiency in TLR4-KO islets resulted in the inhibition of TNF-α production and IκBα phosphorylation after HMGB1 exposure. Pre-incubation of the STAT3, p38, or NF-κB inhibitors significantly inhibited HMGB1-induced IL-1β or TNF-α production in islets, but the effect of HMGB1 or H/R-induced islet injury was not counteracted by a separate treatment of the STAT3 inhibitor, p38 inhibitor, or NF-κB inhibitors. HMGB1 inhibition by ethyl pyruvate or blockade by neutralizing antibodies significantly decreased the phosphorylation of STAT3, p38 and IκBα, the production of IL-1β and TNF-α, and the islet injury in wild-type islets after exposure to H/R and significantly improved early islet graft failure. Thus, our results suggest that HMGB1 released from H/R induced islets works in an autocrine manner to up-regulate STAT or p38 and augment IL-1β production via TLR2, and up-regulate NF-κB and augment TNF-α production via TLR4 in intra-islet, which are associated with H/R-induced islet injury and early graft failure.
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Affiliation(s)
- Yao Cheng
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China; Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Junjie Xiong
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, P.R. China
| | - Quan Chen
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jie Xia
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yi Zhang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, P.R. China
| | - Xiaoyan Yang
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Kun Tao
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Shuang Zhang
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Sirong He
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China.
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Cheng Y, Wang D, Wang B, Li H, Xiong J, Xu S, Chen Q, Tao K, Yang X, Zhu Y, He S. HMGB1 translocation and release mediate cigarette smoke-induced pulmonary inflammation in mice through a TLR4/MyD88-dependent signaling pathway. Mol Biol Cell 2016; 28:201-209. [PMID: 27807045 PMCID: PMC5221624 DOI: 10.1091/mbc.e16-02-0126] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 10/20/2016] [Accepted: 10/26/2016] [Indexed: 02/05/2023] Open
Abstract
Cigarette smoke (CS) increases up-regulation of TLR4-mediated signaling and induces TLR4-dependent inflammation in lungs. CS exposure–induced HMGB1 translocation and release of HMGB1 controls CS-induced inflammatory response. MGB1 induces TLR4-mediated proinflammatory cytokine production and activates NF-κB and JNK/p38 pathways. We performed studies to determine the role of high-mobility group box 1 (HMGB1) in cigarette smoke (CS)–induced pulmonary inflammation. After mice were exposed to five cigarettes four times a day for 3 d, toll-like receptor 4 (TLR4) expression and TLR4-mediated signaling were significantly up-regulated, and HMGB1 had translocated from the nucleus to the cytoplasm in lung epithelial cells and then been released into the extracellular lung space. On CS exposure, inflammatory cell recruitment and proinflammatory cytokine production were significantly increased in lung tissue and bronchoalveolar lavage, and these effects depended on the TLR4 signaling pathway. HMGB1 inhibition decreased the CS-induced inflammatory response, whereas treatment with exogenous HMGB1 aggravated the damage and increased the phosphorylation of JNK, p38, and IκBα in the lungs of wild-type mice but not in TLR4-knockout mice. Blockade of TLR4 action or TLR4 knockout significantly inhibited HMGB1-induced proinflammatory cytokine production in mouse tracheal epithelial (MTE) cells and lung tissues. In addition, a MyD88 deficiency inhibited JNK, p38, and IκBα phosphorylation, and this effect was associated with the suppressed production of TNF-α and IL-1β in MTE cells and lung tissues in response to CS stimulation. Thus HMGB1 activates the NF-κB and JNK/p38 pathways through TLR4/MyD88-dependent signaling and induces an inflammatory response in lungs exposed to CS.
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Affiliation(s)
- Yao Cheng
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chong-qing 400016, China.,Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chong-qing 400016, China
| | - Dan Wang
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chong-qing 400016, China.,Department of Respiration Medicine, Sichuan University, Chengdu, Sichuan 610041, China
| | - Bin Wang
- Institute of Life Science, Chongqing Medical University, Chong-qing 400016, China
| | - Huanan Li
- College of Biomedical Engineering, Chongqing Medical University, Chong-qing 400016, China
| | - Junjie Xiong
- Department of General Surgery, Sichuan University, Chengdu, Sichuan 610041, China
| | - Shuyun Xu
- Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Quan Chen
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chong-qing 400016, China
| | - Kun Tao
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chong-qing 400016, China
| | - Xiaoyan Yang
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chong-qing 400016, China
| | - Yu Zhu
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chong-qing 400016, China
| | - Sirong He
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chong-qing 400016, China
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Zhang W, Zhang M, Wang Z, Cheng Y, Liu H, Zhou Z, Han B, Chen B, Yao H, Chao J. Neogambogic acid prevents silica-induced fibrosis via inhibition of high-mobility group box 1 and MCP-1-induced protein 1. Toxicol Appl Pharmacol 2016; 309:129-40. [PMID: 27616297 DOI: 10.1016/j.taap.2016.09.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 08/13/2016] [Accepted: 09/06/2016] [Indexed: 12/26/2022]
Abstract
BACKGROUND Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO2); early stages are characterized by alveolar inflammation, and later stages are characterized by progressive lung fibrosis. Mounting evidence indicates that high-mobility group box 1 (HMGB1) is involved in pulmonary fibrosis. Whether neogambogic acid (NGA) inhibits macrophage and fibroblast activation induced by SiO2 by targeting HMGB1 remains unclear. METHODS AND RESULTS Experiments using cultured mouse macrophages (RAW264.7 cells) demonstrated that SiO2 treatment induces the expression of HMGB1 in a time- and dose-dependent manner via mitogen-activated protein kinases (MAPKs) and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway; in turn, this expression causes macrophage apoptosis and fibroblast activation. Pretreating macrophages with NGA inhibited the HMGB1 expression induced by SiO2 and attenuated both macrophage apoptosis and fibroblast activation. Moreover, NGA directly inhibited MCP-1-induced protein 1 (MCPIP1) expression, as well as markers of fibroblast activation and migration induced by SiO2. Furthermore, the effects of NGA on macrophages and fibroblasts were confirmed in vivo by exposing mice to SiO2. CONCLUSION NGA can prevent SiO2-induced macrophage activation and apoptosis via HMGB1 inhibition and SiO2-induced fibrosis via the MCPIP1 pathway. Targeting HMGB1 and MCPIP1 with NGA could provide insights into the potential development of a therapeutic approach for alleviating the inflammation and fibrosis induced by SiO2.
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Affiliation(s)
- Wei Zhang
- Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China; Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China; Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China; Department of Respiration, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Mei Zhang
- Department of Respiration, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
| | - Zhongjiang Wang
- Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Yusi Cheng
- Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Haijun Liu
- Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Zewei Zhou
- Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China; Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Bing Han
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Baoan Chen
- Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Honghong Yao
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China; Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China.
| | - Jie Chao
- Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China; Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China; Department of Respiration, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
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Lee GL, Wu JY, Tsai CS, Lin CY, Tsai YT, Lin CS, Wang YF, Yet SF, Hsu YJ, Kuo CC. TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function. Int J Mol Sci 2016; 17:ijms17091394. [PMID: 27563891 PMCID: PMC5037674 DOI: 10.3390/ijms17091394] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 08/11/2016] [Accepted: 08/17/2016] [Indexed: 11/29/2022] Open
Abstract
Migration of vascular smooth muscle cells (VSMCs) into the intima is considered to be a vital event in the pathophysiology of atherosclerosis. Despite substantial evidence supporting the pathogenic role of Toll-like receptor 4 (TLR4) in the progression of atherogenesis, its function in the regulation of VSMC migration remains unclear. The goal of the present study was to elucidate the mechanism by which TLR4 regulates VSMC migration. Inhibitor experiments revealed that TLR4-induced IL-6 secretion and VSMC migration were mediated via the concerted actions of MyD88 and TRIF on the activation of p38 MAPK and ERK1/2 signaling. Neutralizing anti-IL-6 antibodies abrogated TLR4-driven VSMC migration and F-actin polymerization. Blockade of p38 MAPK or ERK1/2 signaling cascade inhibited TLR4 agonist-mediated activation of cAMP response element binding protein (CREB). Moreover, siRNA-mediated suppression of CREB production repressed TLR4-induced IL-6 production and VSMC migration. Rac-1 inhibitor suppressed TLR4-driven VSMC migration but not IL-6 production. Importantly, the serum level of IL-6 and TLR4 endogenous ligand HMGB1 was significantly higher in patients with coronary artery diseases (CAD) than in healthy subjects. Serum HMGB1 level was positively correlated with serum IL-6 level in CAD patients. The expression of both HMGB1 and IL-6 was clearly detected in the atherosclerotic tissue of the CAD patients. Additionally, there was a positive association between p-CREB and HMGB1 in mouse atherosclerotic tissue. Based on our findings, we concluded that, upon ligand binding, TLR4 activates p38 MAPK and ERK1/2 signaling through MyD88 and TRIF in VSMCs. These signaling pathways subsequently coordinate an additive augmentation of CREB-driven IL-6 production, which in turn triggers Rac-1-mediated actin cytoskeleton to promote VSMC migration.
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Affiliation(s)
- Guan-Lin Lee
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan.
- Graduate Institutes of Life Sciences, National Defense Medical Center, Neihu, Taipei 11490, Taiwan.
| | - Jing-Yiing Wu
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan.
| | - Chien-Sung Tsai
- Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Neihu, Taipei 11490, Taiwan.
| | - Chih-Yuan Lin
- Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Neihu, Taipei 11490, Taiwan.
| | - Yi-Ting Tsai
- Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Neihu, Taipei 11490, Taiwan.
| | - Chin-Sheng Lin
- Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Neihu, Taipei 11490, Taiwan.
| | - Yi-Fu Wang
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan.
- Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan.
| | - Shaw-Fang Yet
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan.
| | - Yu-Juei Hsu
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Neihu, Taipei 11490, Taiwan.
- Department of Biochemistry, National Defense Medical Center, Neihu, Taipei 11490, Taiwan.
| | - Cheng-Chin Kuo
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan.
- Graduate Institutes of Life Sciences, National Defense Medical Center, Neihu, Taipei 11490, Taiwan.
- Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan.
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan.
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Yang J, Chen L, Ding J, Fan Z, Li S, Wu H, Zhang J, Yang C, Wang H, Zeng P, Yang J. MicroRNA-24 inhibits high glucose-induced vascular smooth muscle cell proliferation and migration by targeting HMGB1. Gene 2016; 586:268-273. [PMID: 27085480 DOI: 10.1016/j.gene.2016.04.027] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Revised: 04/05/2016] [Accepted: 04/07/2016] [Indexed: 12/21/2022]
Abstract
Dysfunction of vascular smooth muscle cells (VSMCs) performs a key role in the pathogenesis of diabetic vascular disease. Recent studies have reported that microRNA-24 (miR-24) may be implicated in diabetes and atherosclerotic vascular diseases. This study was designed to explore the role of miR-24 on VSMC proliferation and migration under high glucose conditions mimicking diabetes, and reveal the underlying mechanism. VSMCs were isolated from rat thoracic aortas, treated with normal glucose (NG, 5.5mM) or high glucose (HG, 30mM) during an incubation period. Cell viability, proliferation and migration were detected by trypan blue staining, BrdU incorporation assay and transwell chamber assay. Gene and protein expression were analyzed by qRT-PCR and Western blot respectively. We also used electrophoretic mobility shift assay (EMSA) to detect nuclear factor kappaB (NF-κB) DNA binding. TNF-α and IL-6 levels were determined by enzyme-linked immunosorbent assay. The results showed that adenovirus-mediated miR-24 overexpression significantly inhibited HG-stimulated VSMC proliferation and migration. Meanwhile, high mobility group box-1 (HMGB1) as a target of miR-24, was also markedly suppressed after miR-24 transfection. Additionally, NF-κB nuclear translocation and DNA binding, TNF-α and IL-6 production were all decreased associated with the down-regulation of HMGB1. The above data indicated that miR-24 is a crucial regulator of high glucose-induced proliferation and migration in VSMCs, and suggests that elevation of miR-24 in vascular system may be a novel therapeutic strategy to prevent the development of diabetic atherosclerosis.
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MESH Headings
- Animals
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Cell Survival
- Cells, Cultured
- Glucose/pharmacology
- HMGB1 Protein/metabolism
- Interleukin-6/biosynthesis
- Male
- MicroRNAs/metabolism
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/physiology
- NF-kappa B/metabolism
- Rats, Sprague-Dawley
- Tumor Necrosis Factor-alpha/biosynthesis
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Affiliation(s)
- Jian Yang
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Lihua Chen
- Department of Optometry and Ophthalmology, Yichang Central People's Hospital, Yichang 443000, Hubei Province, China
| | - Jiawang Ding
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Zhixing Fan
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Song Li
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Hui Wu
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Jing Zhang
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Chaojun Yang
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Huibo Wang
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Ping Zeng
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Jun Yang
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, Hubei Province, China.
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Ding JW, Zheng XX, Zhou T, Tong XH, Luo CY, Wang XA. HMGB1Modulates the Treg/Th17 Ratio in Atherosclerotic Patients. J Atheroscler Thromb 2016; 23:737-45. [PMID: 26830200 PMCID: PMC7399277 DOI: 10.5551/jat.31088] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 11/16/2015] [Indexed: 01/14/2023] Open
Abstract
AIM Atherosclerosis (AS) characterized as a chronic inflammatory disease. Multiple immune cells and inflammatory cytokines, such as high mobility group protein (HMGB1), regulatory T (Treg) cells, T helper (Th17) cells, and inflammation-related cytokines, play a key role in its pathophysiology. A large number of studies report that HMGB1 and Th17 cells may promote atherosclerosis progression, whereas Treg cells may play a protective role in atherosclerosis; thus, alterations in the Treg/Th17 ratio may exist in atherosclerosis diseases. Up till now, the relationships between HMGB1 levels and the Treg/Th17 ratio remain incompletely understood. The major purpose of this study was to investigate the relationship between HMGB1 levels and the Treg/Th17 ratio in patients with coronary artery atherosclerotic plaques. METHODS We enrolled patients with coronary atherosclerosis and normal coronary artery as the research subjects. Flow cytometry was used to analyze the Treg cells, the Th17 cells frequency, and the Treg/Th17 ratio. Otherwise, real-time polymerase chain reaction was used for assays the mRNA expressions of HMGB1, retinoic acid-related orphan nuclear receptor C (RORC), and forkhead-winged helix transcription factor (Foxp3). Moreover, enzyme-linked immunosorbent assays were used to detect the level of protein and cytokines, such as HMGB1, IL-10, TGF-β1, IL-17A, and IL-23. RESULTS Using flow cytometry, we observed a significantly increased of Th17 cell frequency, whereas Treg cell frequency significantly decreased in atherosclerotic patients. Consistently, the levels of RORC mRNA were significantly increased in coronary atherosclerosis (AS) group compared to normal coronary artery (NCA) group (P＜0.01). In contrast, the expression of Foxp3 mRNA was markedly lower in the AS group than in the NCA group (P＜0.01). Furthermore, we observed the serum concentrations of HMGB1, IL-17A, and IL-23 were significantly higher in the AS group than in the NCA group (P＜0.01, respectively), whereas the concentrations of serum IL-10 and TGF-β1 were significantly lower in the AS group than in the NCA group (P＜0.01, respectively). In addition, we also found that HMGB1 levels showed negative correlation with the Treg/Th17 ratio in the two groups (r=－0.6984, P＜0.01). CONCLUSIONS The data in our study indicated that HMGB1 may promote atherosclerosis progression via modulating the imbalance in the Treg/Th17 ratio.
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Affiliation(s)
- Jia-wang Ding
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Hubei Province, China
- Institute of Cardiovascular Diseases, China Three Gorges University, Hubei Province, China
| | - Xia-xia Zheng
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Hubei Province, China
- Institute of Cardiovascular Diseases, China Three Gorges University, Hubei Province, China
| | - Tian Zhou
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Hubei Province, China
- Institute of Cardiovascular Diseases, China Three Gorges University, Hubei Province, China
| | - Xiao-hong Tong
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Hubei Province, China
- Institute of Cardiovascular Diseases, China Three Gorges University, Hubei Province, China
| | - Cai-yun Luo
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Hubei Province, China
- Institute of Cardiovascular Diseases, China Three Gorges University, Hubei Province, China
| | - Xin-an Wang
- Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Hubei Province, China
- Institute of Cardiovascular Diseases, China Three Gorges University, Hubei Province, China
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Fan Z, Yang J, Yang J, Yang C, Guo X. HMGB1: A promising therapeutic approach for atherosclerosis. Int J Cardiol 2016; 202:507-508. [PMID: 26440462 DOI: 10.1016/j.ijcard.2015.09.101] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 09/24/2015] [Indexed: 11/10/2022]
Affiliation(s)
- Zhixing Fan
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Jian Yang
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, Hubei Province, China.
| | - Jun Yang
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Chaojun Yang
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Xin Guo
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, Hubei Province, China
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Adams Waldorf KM, Singh N, Mohan AR, Young RC, Ngo L, Das A, Tsai J, Bansal A, Paolella L, Herbert BR, Sooranna SR, Gough GM, Astley C, Vogel K, Baldessari AE, Bammler TK, MacDonald J, Gravett MG, Rajagopal L, Johnson MR. Uterine overdistention induces preterm labor mediated by inflammation: observations in pregnant women and nonhuman primates. Am J Obstet Gynecol 2015; 213:830.e1-830.e19. [PMID: 26284599 DOI: 10.1016/j.ajog.2015.08.028] [Citation(s) in RCA: 106] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 07/13/2015] [Accepted: 08/10/2015] [Indexed: 11/29/2022]
Abstract
OBJECTIVE Uterine overdistention is thought to induce preterm labor in women with twin and multiple pregnancies, but the pathophysiology remains unclear. We investigated for the first time the pathogenesis of preterm birth associated with rapid uterine distention in a pregnant nonhuman primate model. STUDY DESIGN A nonhuman primate model of uterine overdistention was created using preterm chronically catheterized pregnant pigtail macaques (Macaca nemestrina) by inflation of intraamniotic balloons (N = 6), which were compared to saline controls (N = 5). Cesarean delivery was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex (Austin, TX), and enzyme-linked immunosorbent assay were used to measure messenger RNA (mRNA) and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human (amniocytes, amnion, myometrium) tissues. Statistical analysis employed analysis of covariance and Wilcoxon rank sum. Biomechanical forces were calculated using the law of Laplace. RESULTS Preterm labor occurred in 3 of 6 animals after balloon inflation and correlated with greater balloon volume and uterine wall stress. Significant elevations of inflammatory cytokines and prostaglandins occurred following uterine overdistention in an "inflammatory pulse" that correlated with preterm labor (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-6, IL-8, CCL2, prostaglandin E2, prostaglandin F2α, all P < .05). A similar inflammatory response was observed in amniocytes in vitro following mechanical stretch (IL1β, IL6, and IL8 mRNA multiple time points, P < .05), in amnion of women with polyhydramnios (IL6 and TNF mRNA, P < .05) and in amnion (TNF-α) and myometrium of women with twins in early labor (IL6, IL8, CCL2, all P < .05). Genes differentially expressed in the nonhuman primate after balloon inflation and in women with polyhydramnios and twins are involved in tissue remodeling and muscle growth. CONCLUSION Uterine overdistention by inflation of an intraamniotic balloon is associated with an inflammatory pulse that precedes and correlates with preterm labor. Our results indicate that inflammation is an early event after a mechanical stress on the uterus and leads to preterm labor when the stress is sufficiently great. Further, we find evidence of uterine tissue remodeling and muscle growth as a common, perhaps compensatory, response to uterine distension.
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Affiliation(s)
| | - Natasha Singh
- Department of Obstetrics and Gynecology, Chelsea and Westminster Hospital, Imperial College London, London, United Kingdom
| | - Aarthi R Mohan
- Department of Cancer and Surgery, Imperial College London, London, United Kingdom
| | - Roger C Young
- Department of Obstetrics and Gynecology, University of Tennessee Health Science Center, Memphis, TN
| | - Lisa Ngo
- Department of Pediatric Infectious Diseases and Microbiology, Seattle Children's Research Institute, Seattle, WA
| | - Ananya Das
- Department of Cancer and Surgery, Imperial College London, London, United Kingdom
| | - Jesse Tsai
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA
| | - Aasthaa Bansal
- Pharmaceutical Outcomes Research and Policy Program, University of Washington, Seattle, WA
| | - Louis Paolella
- School of Medicine, University of Washington, Seattle, WA
| | - Bronwen R Herbert
- Department of Cancer and Surgery, Imperial College London, London, United Kingdom
| | - Suren R Sooranna
- Department of Cancer and Surgery, Imperial College London, London, United Kingdom
| | - G Michael Gough
- Washington National Primate Research Center, University of Washington, Seattle, WA
| | - Cliff Astley
- Washington National Primate Research Center, University of Washington, Seattle, WA
| | - Keith Vogel
- Washington National Primate Research Center, University of Washington, Seattle, WA
| | - Audrey E Baldessari
- Washington National Primate Research Center, University of Washington, Seattle, WA
| | - Theodor K Bammler
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA
| | - James MacDonald
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA
| | - Michael G Gravett
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA; Global Alliance to Prevent Prematurity and Stillbirth, Seattle Children's Research Institute, Seattle, WA
| | - Lakshmi Rajagopal
- Department of Pediatrics and Global Health, University of Washington, Seattle, WA; Department of Pediatric Infectious Diseases and Microbiology, Seattle Children's Research Institute, Seattle, WA
| | - Mark R Johnson
- Department of Obstetrics and Gynecology, Imperial College London, London, United Kingdom
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Modulation of Human Macrophage Responses to Mycobacterium tuberculosis by Silver Nanoparticles of Different Size and Surface Modification. PLoS One 2015; 10:e0143077. [PMID: 26580078 PMCID: PMC4651328 DOI: 10.1371/journal.pone.0143077] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 10/31/2015] [Indexed: 11/19/2022] Open
Abstract
Exposure to silver nanoparticles (AgNP) used in consumer products carries potential health risks including increased susceptibility to infectious pathogens. Systematic assessments of antimicrobial macrophage immune responses in the context of AgNP exposure are important because uptake of AgNP by macrophages may lead to alterations of innate immune cell functions. In this study we examined the effects of exposure to AgNP with different particle sizes (20 and 110 nm diameters) and surface chemistry (citrate or polyvinlypyrrolidone capping) on cellular toxicity and innate immune responses against Mycobacterium tuberculosis (M.tb) by human monocyte-derived macrophages (MDM). Exposures of MDM to AgNP significantly reduced cellular viability, increased IL8 and decreased IL10 mRNA expression. Exposure of M.tb-infected MDM to AgNP suppressed M.tb-induced expression of IL1B, IL10, and TNFA mRNA. Furthermore, M.tb-induced IL-1β, a cytokine critical for host resistance to M.tb, was inhibited by AgNP but not by carbon black particles indicating that the observed immunosuppressive effects of AgNP are particle specific. Suppressive effects of AgNP on the M.tb-induced host immune responses were in part due to AgNP-mediated interferences with the TLR signaling pathways that culminate in the activation of the transcription factor NF-κB. AgNP exposure suppressed M.tb-induced expression of a subset of NF-κB mediated genes (CSF2, CSF3, IFNG, IL1A, IL1B, IL6, IL10, TNFA, NFKB1A). In addition, AgNP exposure increased the expression of HSPA1A mRNA and the corresponding stress-induced Hsp72 protein. Up-regulation of Hsp72 by AgNP can suppress M.tb-induced NF-κB activation and host immune responses. The observed ability of AgNP to modulate infectious pathogen-induced immune responses has important public health implications.
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Good DW, George T, Watts BA. High-mobility group box 1 inhibits HCO(3)(-) absorption in medullary thick ascending limb through a basolateral receptor for advanced glycation end products pathway. Am J Physiol Renal Physiol 2015; 309:F720-30. [PMID: 26180239 DOI: 10.1152/ajprenal.00227.2015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 07/07/2015] [Indexed: 12/31/2022] Open
Abstract
High-mobility group box 1 (HMGB1) is a damage-associated molecule implicated in mediating kidney dysfunction in sepsis and sterile inflammatory disorders. HMGB1 is a nuclear protein released extracellularly in response to infection or injury, where it interacts with Toll-like receptor 4 (TLR4) and other receptors to mediate inflammation. Previously, we demonstrated that LPS inhibits HCO(3)(-) absorption in the medullary thick ascending limb (MTAL) through a basolateral TLR4-ERK pathway (Watts BA III, George T, Sherwood ER, Good DW. Am J Physiol Cell Physiol 301: C1296-C1306, 2011). Here, we examined whether HMGB1 could inhibit HCO(3)(-) absorption through the same pathway. Adding HMGB1 to the bath decreased HCO(3)(-) absorption by 24% in isolated, perfused rat and mouse MTALs. In contrast to LPS, inhibition by HMGB1 was preserved in MTALs from TLR4(-/-) mice and was unaffected by ERK inhibitors. Inhibition by HMGB1 was eliminated by the receptor for advanced glycation end products (RAGE) antagonist FPS-ZM1 and by neutralizing anti-RAGE antibody. Confocal immunofluorescence showed expression of RAGE in the basolateral membrane domain. Inhibition of HCO(3)(-) absorption by HMGB1 through RAGE was additive to inhibition by LPS through TLR4 and to inhibition by Gram-positive bacterial molecules through TLR2. Bath amiloride, which selectively prevents inhibition of MTAL HCO(3)(-) absorption mediated through Na⁺/H⁺ exchanger 1 (NHE1), eliminated inhibition by HMGB1. We conclude that HMGB1 inhibits MTAL HCO(3)(-) absorption through a RAGE-dependent pathway distinct from TLR4-mediated inhibition by LPS. These studies provide new evidence that HMGB1-RAGE signaling acts directly to impair the transport function of renal tubules. They reveal a novel paradigm for sepsis-induced renal tubule dysfunction, whereby exogenous pathogen-associated molecules and endogenous damage-associated molecules act directly and independently to inhibit MTAL HCO(3)(-) absorption through different receptor signaling pathways.
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Affiliation(s)
- David W Good
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas; and Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas
| | - Thampi George
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas; and
| | - Bruns A Watts
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas; and
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Vuohelainen V, Hämäläinen M, Paavonen T, Karlsson S, Moilanen E, Mennander A. Inhibition of monoamine oxidase A increases recovery after experimental cardiac arrest. Interact Cardiovasc Thorac Surg 2015; 21:441-9. [PMID: 26116370 DOI: 10.1093/icvts/ivv175] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 05/27/2015] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Perioperative myocardial infarction (MI) with ischaemia-reperfusion injury (IRI) is a devastating entity occurring in 1-2% of patients after cardiac surgery. The molecular pathway leading to myocardial cellular destruction after MI may include monoamine oxidases. We experimentally investigated whether moclobemide, a monoamine oxidase inhibitor, enhances myocardial recovery after cardiac arrest and MI. METHODS Fifty-six syngeneic Fischer rats underwent heterotopic cardiac transplantation to induce reversible IRI after cardiac arrest. Twenty-eight rats also underwent permanent ligation of the left anterior descending coronary artery to induce MI after cardiac arrest. Twenty-eight rats with or without MI were treated with subcutaneous moclobemide 10 mg/kg/day. Methods used to study myocardial recovery were microdialysis for intramyocardial metabolism, histology and quantitative reverse-transcription polymerase chain reaction for high-mobility group box-1 (HMGB1), haeme oxygenase-1 (HO-1), interleukin-6, hypoxia-inducible factor 1α and macrophages (CD68). RESULTS Pyruvate increased in MI treated with moclobemide versus IRI with moclobemide (29.19 ± 7.64 vs 13.86 ± 8.49 µM, P = 0.028), reflecting metabolic activity after cardiac arrest and reperfusion. Myocardial inflammation increased in MI compared with IRI after 1 h (0.80 ± 0.56 vs 0, point score units [PSUs], P = 0.003), but decreased after 5 days in MI treated with moclobemide versus MI alone (0.80 ± 0.83 vs 2.00 ± 0.70, PSU, P = 0.033). Expressions of HMGB1, CD68 and HO-1 decreased in MI treated with moclobemide versus MI alone (1.33 ± 0.20 vs 1.75 ± 0.24, fold changes [FCs], P = 0.028; 5.15 ± 1.10 vs 9.59 ± 2.75, FC, P = 0.050; 10.41 ± 4.17 vs 21.28 ± 10.01, FC, P = 0.047), indicating myocardial recovery and increased cellularity of remote intramyocardial arteries. CONCLUSIONS Moclobemide enhances myocardial recovery after cardiac arrest and MI; inhibition of remote myocardial changes may be achieved by targeting treatment against monoamine oxidase.
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Affiliation(s)
- Vilma Vuohelainen
- Heart Hospital, Cardiac Research, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland
| | - Mari Hämäläinen
- The Immunopharmacology Research Group, University of Tampere School of Medicine, Tampere, Finland
| | - Timo Paavonen
- Department of Pathology, Fimlab, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland
| | - Sari Karlsson
- Department of Anesthesiology, Intensive Care Unit, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland
| | - Eeva Moilanen
- The Immunopharmacology Research Group, University of Tampere School of Medicine, Tampere, Finland
| | - Ari Mennander
- Heart Hospital, Cardiac Research, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland
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Zhang W, Lavine KJ, Epelman S, Evans SA, Weinheimer CJ, Barger PM, Mann DL. Necrotic myocardial cells release damage-associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo. J Am Heart Assoc 2015; 4:e001993. [PMID: 26037082 PMCID: PMC4599537 DOI: 10.1161/jaha.115.001993] [Citation(s) in RCA: 133] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Tissue injury triggers inflammatory responses that promote tissue fibrosis; however, the mechanisms that couple tissue injury, inflammation, and fibroblast activation are not known. Given that dying cells release proinflammatory "damage-associated molecular patterns" (DAMPs), we asked whether proteins released by necrotic myocardial cells (NMCs) were sufficient to activate fibroblasts in vitro by examining fibroblast activation after stimulation with proteins released by necrotic myocardial tissue, as well as in vivo by injecting proteins released by necrotic myocardial tissue into the hearts of mice and determining the extent of myocardial inflammation and fibrosis at 72 hours. METHODS AND RESULTS The freeze-thaw technique was used to induce myocardial necrosis in freshly excised mouse hearts. Supernatants from NMCs contained multiple DAMPs, including high mobility group box-1 (HMGB1), galectin-3, S100β, S100A8, S100A9, and interleukin-1α. NMCs provoked a significant increase in fibroblast proliferation, α-smooth muscle actin activation, and collagen 1A1 and 3A1 mRNA expression and significantly increased fibroblast motility in a cell-wounding assay in a Toll-like receptor 4 (TLR4)- and receptor for advanced glycation end products-dependent manner. NMC stimulation resulted in a significant 3- to 4-fold activation of Akt and Erk, whereas pretreatment with Akt (A6730) and Erk (U0126) inhibitors decreased NMC-induced fibroblast proliferation dose-dependently. The effects of NMCs on cell proliferation and collagen gene expression were mimicked by several recombinant DAMPs, including HMGB1 and galectin-3. Moreover, immunodepletion of HMGB1 in NMC supernatants abrogated NMC-induced cell proliferation. Finally, injection of NMC supernatants or recombinant HMGB1 into the heart provoked increased myocardial inflammation and fibrosis in wild-type mice but not in TLR4-deficient mice. CONCLUSIONS These studies constitute the initial demonstration that DAMPs released by NMCs induce fibroblast activation in vitro, as well as myocardial inflammation and fibrosis in vivo, at least in part, through TLR4-dependent signaling.
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Affiliation(s)
- Weili Zhang
- Division of Nephrology, Department of Internal Medicine, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (W.Z.)
| | - Kory J Lavine
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO (K.J.L., S.A.E., C.J.W., P.M.B., D.L.M.)
| | - Slava Epelman
- Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital and University Health Network, University of Toronto, Ontario, Canada (S.E.) Faculty of Medicine, University of Toronto, Ontario, Canada (S.E.)
| | - Sarah A Evans
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO (K.J.L., S.A.E., C.J.W., P.M.B., D.L.M.)
| | - Carla J Weinheimer
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO (K.J.L., S.A.E., C.J.W., P.M.B., D.L.M.)
| | - Philip M Barger
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO (K.J.L., S.A.E., C.J.W., P.M.B., D.L.M.)
| | - Douglas L Mann
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO (K.J.L., S.A.E., C.J.W., P.M.B., D.L.M.)
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Lee CC, Wang CN, Lee YL, Tsai YR, Liu JJ. High mobility group box 1 induced human lung myofibroblasts differentiation and enhanced migration by activation of MMP-9. PLoS One 2015; 10:e0116393. [PMID: 25692286 PMCID: PMC4332862 DOI: 10.1371/journal.pone.0116393] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 12/10/2014] [Indexed: 11/21/2022] Open
Abstract
High mobility group box 1 (HMGB1) is a nuclear protein that involves the binding with DNA and influences chromatin regulation and transcription. HMGB1 is also a cytokine that can activate monocytes and neutrophils involved in inflammation. In this study, we investigated the role of HMGB1 on cellular activation using human fibroblast cell line WI-38. After treatment with 1, 10, and 100 ng/mL of HMGB1 for 24 h, we did not find obviously cytotoxicity and cellular proliferation of WI-38 cells by MTT and BrdU incorporation assay, respectively. However, we found that treatment with 10 and 100 ng/mL of HMGB1 induced the differentiation of lung fibroblasts into myofibroblasts and myofibroblasts showed higher migration ability through activation of matrix metalloproteinase (MMP)-9 activation. To delineate the mechanism underlying HMGB1-induced cellular migration, we examined HMGB1-induced mitogen activated protein kinases (MAPKs), including extracellular signal related kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen activated protein kinase (p38) phosphorylation, as well as nuclear factor (NF)-κB nuclear translocation. Using specific inhibitors and shRNAs of protein kinases, we observed that repression of ERK, JNK, p38, and NF-κB all inhibited HMGB1-induced cellular differentiation, migration and MMP-9 activation in WI-38 cells. In addition, knocking down of RAGE but not TLR2 and TLR4 by shRNAs attenuated HMGB1-induced myofibroblast differentiation and migration. In conclusion, our study demonstrated that HMGB1 induced lung fibroblasts’ differentiation into myofibroblasts and enhanced cell migration through induction of MMP-9 activation and the RAGE-MAPK and NF-κB interaction signaling pathways. Targeting HMGB1 might be a potential therapeutic approach for alleviation of airway remodeling seen in chronic airway inflammatory diseases.
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Affiliation(s)
- Chen-Chen Lee
- Department of Microbiology and Immunology, School of Medicine, China Medical University, Taichung, Taiwan
- Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung, Taiwan
- * E-mail:
| | - Chien-Neng Wang
- Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung, Taiwan
| | - Yueh-Lun Lee
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yi-Ru Tsai
- Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung, Taiwan
| | - Jau-Jin Liu
- Department of Microbiology and Immunology, School of Medicine, China Medical University, Taichung, Taiwan
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Cottone L, Capobianco A, Gualteroni C, Perrotta C, Bianchi ME, Rovere-Querini P, Manfredi AA. 5-Fluorouracil causes leukocytes attraction in the peritoneal cavity by activating autophagy and HMGB1 release in colon carcinoma cells. Int J Cancer 2014; 136:1381-9. [PMID: 25098891 DOI: 10.1002/ijc.29125] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 07/17/2014] [Accepted: 07/22/2014] [Indexed: 12/24/2022]
Abstract
Signals released by leukocytes contribute to tumor growth and influence the efficacy of antineoplastic treatments. The outcome of peritoneal carcinomatosis treatments is unsatisfactory, possibly because chemotherapy activates events that have in the long-term deleterious effects. In this study we offer evidence that 5-fluorouracile (5-FU), besides provoking apoptosis of MC38 colon carcinoma cells, induces a striking attraction of leukocytes both in an orthotopic model of colon carcinomatosis in vivo and in monocyte-migration assays in vitro. Leukocyte attraction depends on the presence of High Mobility Group Box 1 (HMGB1), an endogenous immune adjuvant and chemoattractant released by dying cells. Leukocyte recruitment is prevented in vivo and in vitro using blocking antibodies against HMGB1 and its competitive antagonist BoxA or by interfering with HMGB1 expression. Autophagy is required for leukocyte chemoattraction, since the latter abates upon pharmacological blockade of the autophagic flux while activation of autophagy per se, in the absence of death of colon carcinoma cells, is not sufficient to attract leukocytes. Our results identify autophagy induction and HMGB1 release in colon carcinoma cells as key events responsible for 5-FU elicited leukocyte attraction and define a novel rate-limiting target for combinatorial therapies.
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Affiliation(s)
- Lucia Cottone
- Division of Regenerative Medicine, San Raffaele Scientific Institute, Milano, Italy; School of Medicine, Vita-Salute San Raffaele University, Milano, Italy
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Sadamura-Takenaka Y, Ito T, Noma S, Oyama Y, Yamada S, Kawahara KI, Inoue H, Maruyama I. HMGB1 promotes the development of pulmonary arterial hypertension in rats. PLoS One 2014; 9:e102482. [PMID: 25032709 PMCID: PMC4102514 DOI: 10.1371/journal.pone.0102482] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 06/19/2014] [Indexed: 11/18/2022] Open
Abstract
Rationale Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. However, the molecular and cellular mechanisms driving inflammation have not been fully elucidated. Objectives To elucidate the roles of high mobility group box 1 protein (HMGB1), a ubiquitous DNA-binding protein with extracellular pro-inflammatory activity, in a rat model of PAH. Methods Male Sprague-Dawley rats were administered monocrotaline (MCT). Concentrations of HMGB1 in bronchoalveolar lavage fluid (BALF) and serum, and localization of HMGB1 in the lung were examined over time. The protective effects of anti-HMGB1 neutralizing antibody against MCT-induced PAH were tested. Results HMGB1 levels in BALF were elevated 1 week after MCT injection, and this elevation preceded increases of other pro-inflammatory cytokines, such as TNF-α, and the development of PAH. In contrast, serum HMGB1 levels were elevated 4 weeks after MCT injection, at which time the rats began to die. Immunohistochemical analyses indicated that HMGB1 was translocated to the extranuclear space in periarterial infiltrating cells, alveolar macrophages, and bronchial epithelial cells of MCT-injected rats. Anti-HMGB1 neutralizing antibody protected rats against MCT-induced lung inflammation, thickening of the pulmonary artery wall, and elevation of right ventricular systolic pressure, and significantly improved the survival of the MCT-induced PAH rats. Conclusions Our results identify extracellular HMGB1 as a promoting factor for MCT-induced PAH. The blockade of HMGB1 activity improved survival of MCT-induced PAH rats, and thus might be a promising therapy for the treatment of PAH.
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Affiliation(s)
- Yukari Sadamura-Takenaka
- Department of Pulmonary Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Takashi Ito
- Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Satoshi Noma
- Department of Pulmonary Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Yoko Oyama
- Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | | | - Ko-ichi Kawahara
- Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, Japan
| | - Hiromasa Inoue
- Department of Pulmonary Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Ikuro Maruyama
- Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- * E-mail:
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Oxygen Glucose Deprivation/Reperfusion Astrocytes Promotes Primary Neural Stem/Progenitor Cell Proliferation by Releasing High-Mobility Group Box 1. Neurochem Res 2014; 39:1440-50. [DOI: 10.1007/s11064-014-1333-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 05/06/2014] [Accepted: 05/10/2014] [Indexed: 01/09/2023]
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Rohde D, Schön C, Boerries M, Didrihsone I, Ritterhoff J, Kubatzky KF, Völkers M, Herzog N, Mähler M, Tsoporis JN, Parker TG, Linke B, Giannitsis E, Gao E, Peppel K, Katus HA, Most P. S100A1 is released from ischemic cardiomyocytes and signals myocardial damage via Toll-like receptor 4. EMBO Mol Med 2014; 6:778-94. [PMID: 24833748 PMCID: PMC4203355 DOI: 10.15252/emmm.201303498] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Members of the S100 protein family have been reported to function as endogenous danger signals (alarmins) playing an active role in tissue inflammation and repair when released from necrotic cells. Here, we investigated the role of S100A1, the S100 isoform with highest abundance in cardiomyocytes, when released from damaged cardiomyocytes during myocardial infarction (MI). Patients with acute MI showed significantly increased S100A1 serum levels. Experimental MI in mice induced comparable S100A1 release. S100A1 internalization was observed in cardiac fibroblasts (CFs) adjacent to damaged cardiomyocytes. In vitro analyses revealed exclusive S100A1 endocytosis by CFs, followed by Toll-like receptor 4 (TLR4)-dependent activation of MAP kinases and NF-κB. CFs exposed to S100A1 assumed an immunomodulatory and anti-fibrotic phenotype characterized i.e. by enhanced intercellular adhesion molecule-1 (ICAM1) and decreased collagen levels. In mice, intracardiac S100A1 injection recapitulated these transcriptional changes. Moreover, antibody-mediated neutralization of S100A1 enlarged infarct size and worsened left ventricular functional performance post-MI. Our study demonstrates alarmin properties for S100A1 from necrotic cardiomyocytes. However, the potentially beneficial role of extracellular S100A1 in MI-related inflammation and repair warrants further investigation.
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Affiliation(s)
- David Rohde
- Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany
| | - Christoph Schön
- Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany
| | - Melanie Boerries
- Institute of Molecular Medicine and Cell Research, Freiburg University, Freiburg, Germany German Consortium for Translational Cancer Research (DKTK), Partner site Freiburg German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ieva Didrihsone
- Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany
| | - Julia Ritterhoff
- Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany
| | - Katharina F Kubatzky
- Division for Microbiology and Hygiene, Department of Infectious Diseases, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany
| | - Mirko Völkers
- Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany
| | - Nicole Herzog
- Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany
| | - Mona Mähler
- Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany
| | - James N Tsoporis
- Division of Cardiology, Department of Medicine, Keenan Research Centre Li Ka Shing Knowledge Institute St. Michael's Hospital University of Toronto, Ontario, Canada
| | - Thomas G Parker
- Division of Cardiology, Department of Medicine, Keenan Research Centre Li Ka Shing Knowledge Institute St. Michael's Hospital University of Toronto, Ontario, Canada
| | - Björn Linke
- Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Evangelos Giannitsis
- Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany
| | - Erhe Gao
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Karsten Peppel
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Hugo A Katus
- Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany German Centre for Cardiovascular Research (DZHK), Partner site Heidelberg/Mannheim Heidelberg University Hospital Heidelberg University, Heidelberg, Germany
| | - Patrick Most
- Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA German Centre for Cardiovascular Research (DZHK), Partner site Heidelberg/Mannheim Heidelberg University Hospital Heidelberg University, Heidelberg, Germany
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Owens CD, Gasper WJ, Rahman AS, Conte MS. Vein graft failure. J Vasc Surg 2013; 61:203-16. [PMID: 24095042 DOI: 10.1016/j.jvs.2013.08.019] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Revised: 08/12/2013] [Accepted: 08/14/2013] [Indexed: 02/06/2023]
Abstract
After the creation of an autogenous lower extremity bypass graft, the vein must undergo a series of dynamic structural changes to stabilize the arterial hemodynamic forces. These changes, which are commonly referred to as remodeling, include an inflammatory response, the development of a neointima, matrix turnover, and cellular proliferation and apoptosis. The sum total of these processes results in dramatic alterations in the physical and biomechanical attributes of the arterialized vein. The most clinically obvious and easily measured of these is lumen remodeling of the graft. However, although somewhat less precise, wall thickness, matrix composition, and endothelial changes can be measured in vivo within the healing vein graft. Recent translational work has demonstrated the clinical relevance of remodeling as it relates to vein graft patency and the systemic factors influencing it. By correlating histologic and molecular changes in the vein, insights into potential therapeutic strategies to prevent bypass failure and areas for future investigation are explored.
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Affiliation(s)
- Christopher D Owens
- Division of Vascular and Endovascular Surgery, University of California San Francisco Medical Center, San Francisco, Calif.
| | - Warren J Gasper
- Division of Vascular and Endovascular Surgery, University of California San Francisco Medical Center, San Francisco, Calif
| | - Amreen S Rahman
- Division of Vascular and Endovascular Surgery, University of California San Francisco Medical Center, San Francisco, Calif
| | - Michael S Conte
- Division of Vascular and Endovascular Surgery, University of California San Francisco Medical Center, San Francisco, Calif
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Ding HS, Yang J, Chen P, Yang J, Bo SQ, Ding JW, Yu QQ. The HMGB1-TLR4 axis contributes to myocardial ischemia/reperfusion injury via regulation of cardiomyocyte apoptosis. Gene 2013; 527:389-393. [PMID: 23727604 DOI: 10.1016/j.gene.2013.05.041] [Citation(s) in RCA: 112] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Revised: 04/30/2013] [Accepted: 05/08/2013] [Indexed: 01/12/2023]
Abstract
Toll-like receptor 4 (TLR4) and its ligand high mobility group box 1 (HMGB1), are known for playing central roles in ischemia-reperfusion injury in myocardium. However, the detailed mechanisms of TLR4 and HMGB1 are not fully understood. The aim of this study was to investigate the effects and possible mechanisms of the HMGB1-TLR4 axis and cardiomyocyte apoptosis on myocardial ischemic damage. Artificial oxygen ventilated anesthetized C3H/HeN mice and C3H/HeJ mice were subjected to 30 min of left anterior descending coronary artery occlusion followed by 6h of reperfusion. The myocardial infarct size, HMGB1 levels, apoptosis index, Bax, Bcl-2 and TNF-α mRNA levels were assessed. The results showed that a lowered amount of cardiomyocyte apoptosis and infarct size in the myocardium of TLR4-mutant mice after myocardial I/R and that TLR4 deficiency notably inhibited the expression of HMGB1 and TNF-a, both of which were up-regulated by ischemia/reperfusion. These findings suggest that the HMGB1-TLR4 axis plays a pathogenic role in triggering cardiomyocyte apoptosis during myocardial I/R injury and that the possible mechanism for this process is the result of released cytokines and inflammatory response involved in the HMGB1/TLR4-related pathway.
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Affiliation(s)
- Hua-Sheng Ding
- Institute of Cardiovascular Diseases, China Three Gorges University, 443000 Yichang, Hubei Province, China
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Lee CC, Lai YT, Chang HT, Liao JW, Shyu WC, Li CY, Wang CN. Inhibition of high-mobility group box 1 in lung reduced airway inflammation and remodeling in a mouse model of chronic asthma. Biochem Pharmacol 2013; 86:940-9. [PMID: 23948063 DOI: 10.1016/j.bcp.2013.08.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Revised: 07/19/2013] [Accepted: 08/02/2013] [Indexed: 01/06/2023]
Abstract
The role of high-mobility group box 1 (HMGB1) in chronic allergic asthma is currently unclear. Both airway neutrophilia and eosinophilia and increase in HMGB1 expression in the lungs in our murine model of chronic asthma. Inhibition of HMGB1 expression in lung in ovalbumin (OVA)-immunized mice decreased induced airway inflammation, mucus formation, and collagen deposition in lung tissues. Analysis of the numbers of CD4(+) T helper (Th) cells in the mediastinal lymph nodes and lungs revealed that Th17 showed greater increases than Th2 cells and Th1 cells in OVA-immunized mice; further, the numbers of Th1, Th2, and Th17 cells decreased in anti-HMGB1 antibody (Ab)-treated mice. In OVA-immunized mice, TLR-2 and TLR-4 expression, but not RAGE expression, was activated in the lungs and attenuated after anti-HMGB1 Ab treatment. The results showed that increase in HMGB1 release and expression in the lungs could be an important pathological mechanism underlying chronic allergic asthma and HMGB1 might a potential therapeutic target for chronic allergic asthma.
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Affiliation(s)
- Chen-Chen Lee
- Department of Microbiology and Immunology, School of Medicine, China Medicine University, Taichung, Taiwan; Graduate Institute of Immunology, College of Medicine, China Medicine University, Taichung, Taiwan; Graduate Institute of Basic Medical Science, College of Medicine, China Medicine University, Taichung, Taiwan.
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Cirillo P, Giallauria F, Di Palma V, Maresca F, Ziviello F, Bevilacqua M, Vigorito C, Trimarco B. Cardiovascular disease and high-mobility group box 1--is a new inflammatory killer in town? Angiology 2013; 64:343-355. [PMID: 22942130 DOI: 10.1177/0003319712458032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
High-mobility group box 1 (HMGB-1) is a nuclear protein physiologically involved in the maintaining of DNA structure in the nucleus. When tissue damage occurs, necrotic cells as well as inflammatory cells, once activated, release this protein in circulating blood, where it seems to exert a direct proinflammatory action. Thus, HMGB-1 might be involved in the pathophysiology of several diseases, including cardiovascular disease. However, the experimental evidence has not yet clarified its cardiovascular role which is still debated. Specifically, it is still not completely resolved whether HMGB-1 plays a protective or detrimental role on cardiovascular function. In this review, we consider the role of HMGB-1 in pathological conditions and comment on the role of this protein in the cardiovascular disease.
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Affiliation(s)
- Plinio Cirillo
- Department of Clinical Medicine, Cardiovascular and Immunological Science, University of Naples Federico II, Naples, Italy.
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Yang D, Wei F, Tewary P, Howard OMZ, Oppenheim JJ. Alarmin-induced cell migration. Eur J Immunol 2013; 43:1412-8. [PMID: 23619968 PMCID: PMC6331004 DOI: 10.1002/eji.201243138] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Revised: 03/13/2013] [Accepted: 04/22/2013] [Indexed: 12/30/2022]
Abstract
Alarmins are endogenous, constitutively available, damage-associated molecular patterns that upon release can mobilize and activate various leukocytes for the induction of innate and adaptive immune responses. For our immune system to function appropriately, it relies on navigating various leukocytes to distinct places at the right time. The direction of cell migration is determined by chemotactic factors that include classical chemoattractants, chemokines, certain growth factors, and alarmins. This viewpoint provides an overview of alarmin-induced cell migration. Alarmins are capable of inducing the migration of diverse types of leukocytes and nonleukocytes either directly by triggering specific receptors or indirectly by inducing production of chemokines through the activation of various leukocytes via pattern recognition receptors. The receptors used by alarmins to directly induce cell migration can either be Gαi protein-coupled receptors or receptors such as the receptor for advanced glycation end products; however, the intracellular signaling events responsible for the direct chemotactic activities of alarmins are, to date, only partially elucidated. Given that alarmins act in concert with chemokines to regulate the recruitment and trafficking of leukocytes, these damage-associated molecular patterns are potentially involved in diverse biological processes as discussed in this viewpoint.
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Affiliation(s)
- De Yang
- Basic Research Program, Scientific Application and International Corporation–Frederick, Inc., Frederick, MD, USA
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, National Cancer Institute, Frederick National Laboratories for Cancer Research, Frederick, MD, USA
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Feng Wei
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, National Cancer Institute, Frederick National Laboratories for Cancer Research, Frederick, MD, USA
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Poonam Tewary
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, National Cancer Institute, Frederick National Laboratories for Cancer Research, Frederick, MD, USA
| | - O. M. Zack Howard
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, National Cancer Institute, Frederick National Laboratories for Cancer Research, Frederick, MD, USA
| | - Joost J. Oppenheim
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, National Cancer Institute, Frederick National Laboratories for Cancer Research, Frederick, MD, USA
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Wang FP, Li L, Li J, Wang JY, Wang LY, Jiang W. High mobility group box-1 promotes the proliferation and migration of hepatic stellate cells via TLR4-dependent signal pathways of PI3K/Akt and JNK. PLoS One 2013; 8:e64373. [PMID: 23696886 PMCID: PMC3655989 DOI: 10.1371/journal.pone.0064373] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 04/12/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The migration of hepatic stellate cells (HSCs) is essential to the hepatic fibrotic response, and recently High-mobility group box 1 (HMGB1) has been shown up-regulated during liver fibrosis. Nevertheless, whether HMGB1 can modulate the proliferation and migration of HSCs is poorly understood, as well as the involved intracellular signaling. In this study, we examined the effect of HMGB1 on proliferation, migration, pro-fibrotic function of HSCs and investigated whether toll-like family of receptor 4 (TLR4) dependent signal pathway is involved in the intracellular signaling regulation. METHODOLOGY/PRINCIPAL FINDINGS Modified transwell chamber system to mimic the space of Disse was used to evaluate the migration of human primary HSCs, and the protein expressions of related signal factors were evaluated by western blot. Cell proliferation was analyzed by MTT assay, the pro-fibrotic functions of HSCs by qRT-PCR and ELISA respectively. Recombinant human HMGB1 could significantly promote migration of HSCs under both haptotactic and chemotactic stimulation, especially the latter. Human TLR4 neutralizing antibody could markedly inhibit HMGB1-induced migration of HSCs. HMGB1 could enhance the phosphorylation of JNK and PI3K/Akt, and TLR4 neutralizing antibody inhibited HMGB1-enhanced phosphorylation of JNK and PI3K/Akt and activation of NF-κB. JNK inhibitor (SP600125) and PI3K inhibitor (LY 294002) significantly inhibited HMGB1-induced proliferation and migration of HSCs, and also reduced HMGB1-enhanced related collagen expressions and pro-fibrotic cytokines production. CONCLUSIONS/SIGNIFICANCE HMGB1 could significantly enhance migration of HSCs in vitro, and TLR4-dependent JNK and PI3K/Akt signal pathways are involved in the HMGB1-induced proliferation, migration and pro-fibrotic effects of HSCs, which indicates HMGB1 might be an effective target to treat liver fibrosis.
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Affiliation(s)
- Fu-ping Wang
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lei Li
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing Li
- Department of Gastroenterology, Tongji Hospital, Tongji University, Shanghai, China
| | - Ji-yao Wang
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ling-yan Wang
- Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Jiang
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
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