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Hung Vu M, Shiwakoti S, Ko JY, Bang G, Lee E, Kim E, Park SH, Park EH, Woo Kim C, Young Kim J, Sim HH, Chang K, Kim MS, Oak MH. Niclosamide attenuates calcification in human heart valvular interstitial cells through inhibition of the AMPK/mTOR signaling pathway. Biochem Pharmacol 2024; 230:116614. [PMID: 39515588 DOI: 10.1016/j.bcp.2024.116614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 10/01/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Calcific aortic valve disease (CAVD) is a considerable health burden with a lack of effective therapeutic options. There is an urgent need to develop interventions that inhibit the osteogenic transformation of valvular interstitial cells (VICs) and delay the calcification process. Niclosamide, an FDA-approved anti-helminthic drug, has emerged as a promising candidate that demonstrates a negative regulatory effect on porcine VICs calcification. However, its molecular mechanism in human VICs (hVICs) remains to be investigated. In this study, high-resolution mass spectrometry-based proteomics and phosphoproteomics were employed, and 8373 proteins and 3697 phosphosites were identified in hVICs treated with a pro-calcifying medium and niclosamide. The quantitative proteomic and phosphoproteomic analysis resulted in the identification of calcification markers and osteogenesis-associated proteins. Bioinformatic analysis of the protein-protein interaction network and affected kinase prediction revealed that the AMPK/mTOR/p70S6K signaling cascade was altered upon calcific induction and niclosamide treatment. Further validation indicated that niclosamide inhibited the calcification of hVICs by targeting the mammalian target of the rapamycin (mTOR) signaling pathway. This study provides the first evidence that niclosamide could prevent osteoblastic differentiation in hVICs partially through the inhibition of the AMPK/mTOR/p70S6k signaling pathway, thereby mitigating hVICs calcification. These findings present a foundation for potential therapeutic strategies to impede the progression of CAVD and provide valuable insights into the pharmacological effects of niclosamide on human VICs.
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Affiliation(s)
- Minh Hung Vu
- Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea
| | - Saugat Shiwakoti
- College of Pharmacy, Mokpo National University, 1666 Yeongsan-Ro, Cheonggye-Myeon, Muan-Gun, Jeonnam 58554, Republic of Korea
| | - Ju-Young Ko
- College of Pharmacy, Mokpo National University, 1666 Yeongsan-Ro, Cheonggye-Myeon, Muan-Gun, Jeonnam 58554, Republic of Korea
| | - Geul Bang
- Digital Omics Research Center, Korea Basic Science Institute, Ochang, 28119, Republic of Korea
| | - Eunmi Lee
- Cardiovascular Research Institute for Intractable Disease, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Eunmin Kim
- Cardiovascular Research Institute for Intractable Disease, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Sin-Hee Park
- Cardiovascular Research Institute for Intractable Disease, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Eun-Hye Park
- Cardiovascular Research Institute for Intractable Disease, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Chan Woo Kim
- Cardiovascular Research Institute for Intractable Disease, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jin Young Kim
- Digital Omics Research Center, Korea Basic Science Institute, Ochang, 28119, Republic of Korea; Critical Diseases Diagnostics Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Hwan-Hee Sim
- College of Pharmacy, Mokpo National University, 1666 Yeongsan-Ro, Cheonggye-Myeon, Muan-Gun, Jeonnam 58554, Republic of Korea
| | - Kiyuk Chang
- Cardiovascular Research Institute for Intractable Disease, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Division of Cardiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Min-Sik Kim
- Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea.
| | - Min-Ho Oak
- College of Pharmacy, Mokpo National University, 1666 Yeongsan-Ro, Cheonggye-Myeon, Muan-Gun, Jeonnam 58554, Republic of Korea.
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Yu X, Pu H, Voss M. Overview of anti-inflammatory diets and their promising effects on non-communicable diseases. Br J Nutr 2024; 132:898-918. [PMID: 39411832 PMCID: PMC11576095 DOI: 10.1017/s0007114524001405] [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: 02/14/2024] [Revised: 06/26/2024] [Accepted: 08/03/2024] [Indexed: 11/20/2024]
Abstract
An anti-inflammatory diet is characterised by incorporating foods with potential anti-inflammatory properties, including fruits, vegetables, whole grains, nuts, legumes, spices, herbs and plant-based protein. Concurrently, pro-inflammatory red and processed meat, refined carbohydrates and saturated fats are limited. This article explores the effects of an anti-inflammatory diet on non-communicable diseases (NCD), concentrating on the underlying mechanisms that connect systemic chronic inflammation, dietary choices and disease outcomes. Chronic inflammation is a pivotal contributor to the initiation and progression of NCD. This review provides an overview of the intricate pathways through which chronic inflammation influences the pathogenesis of conditions including obesity, type II diabetes mellitus, CVD, autoinflammatory diseases, cancer and cognitive disorders. Through a comprehensive synthesis of existing research, we aim to identify some bioactive compounds present in foods deemed anti-inflammatory, explore their capacity to modulate inflammatory pathways and, consequently, to prevent or manage NCD. The findings demonstrated herein contribute to an understanding of the interplay between nutrition, inflammation and chronic diseases, paving a way for future dietary recommendations and research regarding preventive or therapeutic strategies.
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Affiliation(s)
- Xiaoping Yu
- School of Medicine and Nursing, Chengdu University, Chengdu610106, People’s Republic of China
| | - Haomou Pu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu611137, People’s Republic of China
| | - Margaret Voss
- Department of Nutrition and Food Studies, Falk College, Syracuse University, Syracuse, NY13244, USA
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Stanciu SM, Jinga M, Miricescu D, Stefani C, Nica RI, Stanescu-Spinu II, Vacaroiu IA, Greabu M, Nica S. mTOR Dysregulation, Insulin Resistance, and Hypertension. Biomedicines 2024; 12:1802. [PMID: 39200267 PMCID: PMC11351979 DOI: 10.3390/biomedicines12081802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 08/04/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Worldwide, diabetes mellitus (DM) and cardiovascular diseases (CVDs) represent serious health problems associated with unhealthy diet and sedentarism. Metabolic syndrome (MetS) is characterized by obesity, dyslipidemia, hyperglycemia, insulin resistance (IR) and hypertension. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase with key roles in glucose and lipid metabolism, cell growth, survival and proliferation. mTOR hyperactivation disturbs glucose metabolism, leading to hyperglycemia and further to IR, with a higher incidence in the Western population. Metformin is one of the most used hypoglycemic drugs, with anti-inflammatory, antioxidant and antitumoral properties, having also the capacity to inhibit mTOR. mTOR inhibitors such as rapamycin and its analogs everolimus and temsirolimus block mTOR activity, decrease the levels of glucose and triglycerides, and reduce body weight. The link between mTOR dysregulation, IR, hypertension and mTOR inhibitors has not been fully described. Therefore, the main aim of this narrative review is to present the mechanism by which nutrients, proinflammatory cytokines, increased salt intake and renin-angiotensin-aldosterone system (RAAS) dysregulation induce mTOR overactivation, associated further with IR and hypertension development, and also mTOR inhibitors with higher potential to block the activity of this protein kinase.
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Affiliation(s)
- Silviu Marcel Stanciu
- Department of Internal Medicine and Gastroenterology, Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital, “Dr. Carol Davila”, 010825 Bucharest, Romania; (S.M.S.); (M.J.)
| | - Mariana Jinga
- Department of Internal Medicine and Gastroenterology, Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital, “Dr. Carol Davila”, 010825 Bucharest, Romania; (S.M.S.); (M.J.)
| | - Daniela Miricescu
- Discipline of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania;
| | - Constantin Stefani
- Department of Family Medicine and Clinical Base, Central Military Emergency University Hospital, “Dr. Carol Davila”, 010825 Bucharest, Romania;
| | - Remus Iulian Nica
- Surgery Department, Central Military Emergency University Hospital, “Dr. Carol Davila”, 010825 Bucharest, Romania;
- Discipline of General Surgery, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanotari Blvd, 054474 Bucharest, Romania
| | - Iulia-Ioana Stanescu-Spinu
- Discipline of Physiology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
| | - Ileana Adela Vacaroiu
- Department of Nephrology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Maria Greabu
- Discipline of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania;
| | - Silvia Nica
- Emergency Discipline, University Hospital of Bucharest, 050098 Bucharest, Romania;
- Department of Emergency and First Aid, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
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Tarantino G, Citro V. What are the common downstream molecular events between alcoholic and nonalcoholic fatty liver? Lipids Health Dis 2024; 23:41. [PMID: 38331795 PMCID: PMC10851522 DOI: 10.1186/s12944-024-02031-1] [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: 11/05/2023] [Accepted: 01/25/2024] [Indexed: 02/10/2024] Open
Abstract
Liver fat storage, also called hepatic steatosis, is increasingly common and represents a very frequent diagnosis in the medical field. Excess fat is not without consequences. In fact, hepatic steatosis contributes to the progression toward liver fibrosis. There are two main types of fatty liver disease, alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD). Although AFLD and NAFLD are similar in their initial morphological features, both conditions involve the same evolutive forms. Moreover, there are various common mechanisms underlying both diseases, including alcoholic liver disease and NAFLD, which are commonalities. In this Review, the authors explore similar downstream signaling events involved in the onset and progression of the two entities but not completely different entities, predominantly focusing on the gut microbiome. Downstream molecular events, such as the roles of sirtuins, cytokeratins, adipokines and others, should be considered. Finally, to complete the feature, some new tendencies in the therapeutic approach are presented.
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Affiliation(s)
| | - Vincenzo Citro
- Department of General Medicine, Umberto I Hospital, Nocera Inferiore, SA, 84014, Italy
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Duan W, Shi R, Yang F, Zhou Z, Wang L, Huang Z, Zang S. FSTL3 partially mediates the association of increased nonalcoholic fatty liver disease fibrosis risk with acute myocardial infarction in patients with type 2 diabetes mellitus. Cardiovasc Diabetol 2023; 22:297. [PMID: 37904173 PMCID: PMC10617048 DOI: 10.1186/s12933-023-02024-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 10/11/2023] [Indexed: 11/01/2023] Open
Abstract
BACKGROUND The study aimed to investigate an association of increased liver fibrosis with acute myocardial infarction (AMI), and to investigate the mediating effect of serum follistatin-like protein 3 (FSTL3) on the association in patients with type 2 diabetes mellitus (T2DM). METHOD A total of 1424 participants were included in this study, and were firstly divided into two groups: 429 T2DM patients and 995 T2DM patients with NAFLD to assess the association of NAFLD and AMI. Then 995 T2DM co-existent NAFLD patients were categorized by NAFLD fibrosis risk to explore the association between NAFLD fibrosis risk and AMI. Immunohistochemistry staining and semi-quantitative analysis of liver FSTL3 were performed in 60 patients with NAFLD. There were 323 individuals (191 without AMI and 132 with AMI) in T2DM co-existent NAFLD patients who had serum samples, and serum FSTL3 was tested and mediation effect of FSTL3 in association of NAFLD fibrosis and AMI was performed. RESULTS First, increased NAFLD fibrosis risk was an independent risk factor for AMI in patients with T2DM and co-existent NAFLD. In addition, analysis of Gene Expression Omnibus (GEO) database and immunohistochemical staining confirmed the increased expression of FSTL3 in the liver of NAFLD patients with fibrosis. Serum FSTL3 significantly increased in patients with high NAFLD fibrosis risk and AMI, and closely associated with NAFLD fibrosis and AMI severity in T2DM patients with co-existent NAFLD. Most importantly, analysis of the level of mediation revealed that increased serum FSTL3 partially mediated the association of increased NAFLD fibrosis risk with AMI in T2DM patients with co-existent NAFLD. CONCLUSIONS NAFLD fibrosis was closely associated with AMI in T2DM patients. FSTL3 expression was enriched in the liver of NAFLD patients with significant and advanced fibrosis, and serum FSTL3 partially mediated the association of increased liver fibrosis risk with AMI in T2DM patients.
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Affiliation(s)
- Wenfei Duan
- Department of Endocrinology, The Fifth People's Hospital of Shanghai, Fudan University, 801 Heqing Road, Minhang District, Shanghai, 200240, China
| | - Ruixiao Shi
- Department of Traditional Chinese Medicine, Maqiao Community Health Service Center, Minhang District, Shanghai, 20111, China
- Center of Community-Based Health Research, Fudan University, Shanghai, China
| | - Fang Yang
- Department of Genetics and Developmental Science, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Zhoujunhao Zhou
- Department of Endocrinology, The Fifth People's Hospital of Shanghai, Fudan University, 801 Heqing Road, Minhang District, Shanghai, 200240, China
| | - Lihong Wang
- Department of Endocrinology, The Fifth People's Hospital of Shanghai, Fudan University, 801 Heqing Road, Minhang District, Shanghai, 200240, China
| | - Zhe Huang
- Department of Genetics and Developmental Science, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
| | - Shufei Zang
- Department of Endocrinology, The Fifth People's Hospital of Shanghai, Fudan University, 801 Heqing Road, Minhang District, Shanghai, 200240, China.
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Ren Y, Zhang H. Emerging role of exosomes in vascular diseases. Front Cardiovasc Med 2023; 10:1090909. [PMID: 36937921 PMCID: PMC10017462 DOI: 10.3389/fcvm.2023.1090909] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 01/11/2023] [Indexed: 03/06/2023] Open
Abstract
Exosomes are biological small spherical lipid bilayer vesicles secreted by most cells in the body. Their contents include nucleic acids, proteins, and lipids. Exosomes can transfer material molecules between cells and consequently have a variety of biological functions, participating in disease development while exhibiting potential value as biomarkers and therapeutics. Growing evidence suggests that exosomes are vital mediators of vascular remodeling. Endothelial cells (ECs), vascular smooth muscle cells (VSMCs), inflammatory cells, and adventitial fibroblasts (AFs) can communicate through exosomes; such communication is associated with inflammatory responses, cell migration and proliferation, and cell metabolism, leading to changes in vascular function and structure. Essential hypertension (EH), atherosclerosis (AS), and pulmonary arterial hypertension (PAH) are the most common vascular diseases and are associated with significant vascular remodeling. This paper reviews the latest research progress on the involvement of exosomes in vascular remodeling through intercellular information exchange and provides new ideas for understanding related diseases.
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Affiliation(s)
- Yi Ren
- Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Graduate School, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Honggang Zhang
- Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Cheng G, Huang X, You P, Feng P, Jia S, Zhang J, You H, Chang F. TIPE2 protects cardiomyocytes from ischemia‑reperfusion‑induced apoptosis by decreasing cell autophagy via the mTORC1 signaling pathway. Exp Ther Med 2022; 24:613. [PMID: 36160908 PMCID: PMC9490124 DOI: 10.3892/etm.2022.11550] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 12/20/2019] [Indexed: 11/18/2022] Open
Abstract
In cardiac ischemia-reperfusion (I/R), autophagy of hyperactivated cardiomyocytes degrades normal proteins and organelles, destroys cells and causes irreversible cell death. The present study aimed to determine the molecular mechanism through which TNF-α-induced protein 8-like protein 2 (TIPE2) regulates cardiomyocyte apoptosis via autophagy in I/R. The results revealed that the number of apoptotic cells and the protein expression levels of TIPE2 in the heart tissue of I/R model mice were significantly increased. In vitro, the overexpression of TIPE2 decreased oxygen glucose deprivation (OGD)-induced autophagy, apoptosis and activation of the mTOR complex 1 (mTORC1) signaling pathway in H9c2 cells. Treatment with the mTORC1 inhibitor not only inhibited the TIPE2-activated mTORC1 signaling pathway, but also increased OGD-induced autophagy and apoptosis of H9c2 cells. In conclusion, the results of the present study revealed that TIPE2 may protect cardiomyocytes from I/R-induced apoptosis by decreasing cell autophagy via the mTORC1 signaling pathway.
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Affiliation(s)
- Gong Cheng
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710068, P.R. China
| | - Xiaoyan Huang
- Department of Central Laboratory, Shaanxi Provincial People's Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710068, P.R. China
| | - Penghua You
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710068, P.R. China
| | - Panpan Feng
- Department of General Medicine, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710021, P.R. China
| | - Shuo Jia
- Department of Emergency, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, P.R. China
| | - Ji Zhang
- Department of Emergency, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, P.R. China
| | - Hongjun You
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710068, P.R. China
| | - Fengjun Chang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710068, P.R. China
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Marceau F, Petitclerc E. C5a receptor antagonism coming of age for vascular pathology. Int Immunopharmacol 2022; 110:109042. [PMID: 35843145 DOI: 10.1016/j.intimp.2022.109042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/06/2022] [Accepted: 07/07/2022] [Indexed: 11/05/2022]
Abstract
The Food and Drug Administration recently approved the new drug avacopan for a relatively rare disease, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. Avacopan is an antagonist of receptor-1 for anaphylatoxin C5a (C5aR1) that is the first one to meet all expectations of an orally bioavailable drug. Pharmacological effects of C5a on vascular tissue are reviewed; they are essentially indirect, via resident or infiltrating leukocytes, and largely mediated by vasoconstrictor prostanoids that are potentially thrombogenic. The in vivo acute neutropenic effect of C5a and various responses of isolated neutrophils to the peptide have been exploited in the preclinical development of avacopan, but not the prominent hemodynamic responses. Possible clinical risks and extension of therapeutic C5aR1 blockade are discussed. Therapeutic intervention on the blood-derived peptide C5a and on its G protein coupled receptor for specific forms of vascular injury contrasts with other current research approaches in vascular pathology, such as investigating the roles of cytokines and intracellular signaling.
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Affiliation(s)
- François Marceau
- Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Québec-Université Laval, Québec, QC G1V 4G2, Canada.
| | - Eric Petitclerc
- Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Québec-Université Laval, Québec, QC G1V 4G2, Canada
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Shen H, Pei H, Zhai L, Guan Q, Wang G. Salvianolic acid C improves cerebral ischemia reperfusion injury through suppressing microglial cell M1 polarization and promoting cerebral angiogenesis. Int Immunopharmacol 2022; 110:109021. [PMID: 35810493 DOI: 10.1016/j.intimp.2022.109021] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/25/2022] [Accepted: 06/30/2022] [Indexed: 11/18/2022]
Abstract
This study aimed to investigate the mechanism of salvianolic acid C (SAC), the active ingredient in Salvia miltiorrhiza, in improving cerebral ischemia injury. The mouse microglial cells BV2 and mouse endothelial cells bEnd.3 were used as the objects of study. LPS/IFN-γ was applied to simulate the BV2 polarization, and bEnd.3 cells were treated under hypoxic condition. The BV2 cell polarization level was measured through flow cytometry (FCM), the TLR4 and MyD88 expression levels were detected by fluorescence staining, whereas the expression of inflammatory factors TNF-α, IL-6 and IL-1β was analyzed through ELISA. Tubule formation assay was also conducted to observe the tubule formation ability of bEnd.3 cells in vitro, and the level of VEGFR2 was detected by fluorescence staining. Cells were treated with the PKM2 inhibitor IN3, aiming to observe the influence of SAC on glycolysis of BV2 cells. In addition, the mouse model of cerebral ischemia was constructed through the middle cerebral artery occlusion (MCAO) method, and the pathological changes in brain tissues were detected after SAC intervention. Meanwhile, the levels of IBA-1, CD31 and ZO-1 were determined through histochemical staining. Nissl staining to detect nerve cell damage. In BV2 cell experiment, SAC suppressed the M1 polarization of BV2 cells, reduced the inflammatory factor levels, and inhibited the activation of TLR4 signal through suppressing glycolysis. When PKM2 was suppressed, the effects of SAC were antagonized. In the bEnd.3 model, SAC promoted tubule formation in bEnd.3 cells under hypoxic condition, and increased the expression of VEGFR2 and Notch1. In the mouse model, SAC improved the neurological function in MCAO mice, and inhibited the activation of microglial cells and the expression of inflammatory factors. At the same time, SAC up-regulated the expression of ZO-1 and CD31, and maintained the blood-brain barrier (BBB) function. As a major component of Salvia miltiorrhiza, SAC can suppress microglial cell polarization and promote tubule formation in endothelial cells to exert the neurological repair function in cerebral ischemia. SAC is a multi-functional neuroprotective small molecule.
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Affiliation(s)
- Heping Shen
- Department of Neurology, The Second Affiliated Hospital of Jiaxing University, China
| | - Hongyan Pei
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Liping Zhai
- Department of Neurology, The Second Affiliated Hospital of Jiaxing University, China
| | - Qiaobing Guan
- Department of Neurology, The Second Affiliated Hospital of Jiaxing University, China.
| | - Genghuan Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Jiaxing University, China.
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Fan ZY, Chen YP, Chen L, Zhang XQ, Chen LL, Lu B, Wang Y, Xu W, Xu WH, Zhang JP. The matrine derivate MASM inhibits astrocyte reactivity and alleviates experimental autoimmune encephalomyelitis in mice. Int Immunopharmacol 2022; 108:108771. [PMID: 35461109 DOI: 10.1016/j.intimp.2022.108771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 03/28/2022] [Accepted: 04/10/2022] [Indexed: 11/30/2022]
Abstract
Astrocytes (AST) play an important role in the pathogenesis of neurological disorders, and their activation is involved in the progression of multiple sclerosis (MS). (6aS, 10S, 11aR, 11bR, 11cS)-10-methylaminododecahydro-3a, 7a-diaza-benzo (de) anthracene-8-thione (MASM), a novel derivative of matrine, exhibits vast pharmacological activities, such as anti-tumor, anti-fibrosis and immune regulation. In this study, we demonstrate that MASM is a promising agent for the treatment of experimental autoimmune encephalomyelitis (EAE). MASM not only inhibited inflammatory responses in LPS-stimulated astrocytes, but also suppressed the formation of reactive A1 astrocyte and maintained astrocytic functions, including the ability to promote synapse formation and phagocytose synapses and myelin debris. Importantly, MASM could significantly alleviate the development of EAE, with significant inhibition of inflammation, demyelination, axon loss and the body weight loss. Meanwhile, MASM also inhibited the activation of astrocytes and improved the function of BBB in vivo. These findings provide novel insights into the protective effect of MASM on EAE, which may be a promising drug candidate for treatment of EAE.
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Affiliation(s)
- Zhi-Yun Fan
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, PR China
| | - Ya-Ping Chen
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, PR China
| | - Li Chen
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, PR China
| | - Xiao-Qin Zhang
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, PR China
| | - Lin-Lin Chen
- College of Pharmacy, Second Military Medical University, Shanghai 200433, PR China
| | - Bin Lu
- College of Pharmacy, Second Military Medical University, Shanghai 200433, PR China
| | - Yan Wang
- College of Pharmacy, Second Military Medical University, Shanghai 200433, PR China
| | - Wei Xu
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, PR China
| | - Wei-Heng Xu
- College of Pharmacy, Second Military Medical University, Shanghai 200433, PR China.
| | - Jun-Ping Zhang
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, PR China; College of Pharmacy, Second Military Medical University, Shanghai 200433, PR China.
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11
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Astragaloside IV ameliorates peripheral immunosuppression induced by cerebral ischemia through inhibiting HPA axis. Int Immunopharmacol 2022; 105:108569. [DOI: 10.1016/j.intimp.2022.108569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/12/2022] [Accepted: 01/20/2022] [Indexed: 11/23/2022]
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12
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Zhao N, Li Y, Wang C, Xue Y, Peng L, Wang T, Zhao Y, Xu G, Yu S. DJ-1 activates the Atg5-Atg12-Atg16L1 complex via Sirt1 to influence microglial polarization and alleviate cerebral ischemia/reperfusion-induced inflammatory injury. Neurochem Int 2022; 157:105341. [PMID: 35429577 DOI: 10.1016/j.neuint.2022.105341] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 03/29/2022] [Accepted: 04/05/2022] [Indexed: 12/22/2022]
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Huang L, Su W, Wu Z, Zheng L, Lv C. Glucosamine suppresses oxidative stress and induces protective autophagy in osteoblasts by blocking the ROS/Akt/mTOR signaling pathway. Cell Biol Int 2022; 46:829-839. [PMID: 35191133 DOI: 10.1002/cbin.11783] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/24/2021] [Accepted: 01/25/2022] [Indexed: 11/06/2022]
Abstract
Oxidative stress are the crucial pathogenic factors in osteoporosis. Cell autophagy, a major form of self-digestion, plays critical functions in different forms of stress by devouring harmful cytosolic proteins or organelles for the renewal of organelles and to maintain cellular homeostasis. Glucosamine (GlcN) has been widely utilized in treatments for patients with osteoarthritis-related joint pain. It has potential antioxidant effects and its pharmacological effect in osteoblasts remain unclear. The present study aimed to investigate whether autophagy participates the protective effects of GlcN in osteoblasts under oxidative stress and the possible mechanism. First of all, MC3T3-E1 cells were treated with hydrogen peroxide (H2O2) to induce oxidative stress, as assessed by viability assays, apoptosis, the intracellular ROS production. GlcN was capable of inducing autophagy and protected osteoblasts from those cytotoxic effects. Moreover, it significantly attenuated H2O2-induced oxidative stress as measured by malondialdehyde (MDA), glutathione (GSH), nitrite and superoxide dismutase (SOD) level. Importantly, the autophagy level increased in osteoblasts treated with GlcN as represented by an increased in both Beclin1 expression and the LC3 II/I ratio. Immunofluorescence analysis of autophagosomes also confirmed the above results. In addition, GlcN decreased the mammalian target of rapamycin (mTOR) and protein kinase B (Akt). However, the Akt activator (SC79) suppressed the autophagy level induced by GlcN in osteoblasts. Consequently, the antioxidant effects of GlcN were mediated, at least in part, by enhancing autophagy through the Akt/mTOR pathway. These results suggested that GlcN might be a promising candidate for osteoporosis treatment. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Lintuo Huang
- Department of Orthopedics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Wei Su
- Department of Orthopedics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Ziqian Wu
- Department of Neurology Rehabilitation, Wenzhou Chinese Medicine Hospital, Wenzhou, 325000, China
| | - Lidan Zheng
- Department of Orthopedics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Chen Lv
- Department of Orthopedics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
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Cao M, Luo H, Li D, Wang S, Xuan L, Sun L. Research advances on circulating Long noncoding RNAs as biomarkers of cardiovascular diseases. Int J Cardiol 2022; 353:109-117. [PMID: 35143876 DOI: 10.1016/j.ijcard.2022.01.070] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/26/2022] [Accepted: 01/31/2022] [Indexed: 12/12/2022]
Abstract
Cardiovascular diseases (CVD) such as myocardial ischemia, myocardial infarction, heart failure, atherosclerosis, hypertension, arrhythmia, and their complications diseases are associated with increased morbidity and mortality, it is necessary to develop new diagnostic markers for CVD. LncRNAs have become a new class of biomarkers in CVD with good development prospects. Numerous studies have confirmed lncRNAs feasibility as diagnostic, prognostic and predictive tools for different types of CVD. In this review, we summarized the available knowledge regarding the clinical application value and pathophysiological mechanism of circulating lncRNA as potential biomarkers of cardiovascular disease. We reviewed the scope of application and changes of circulating lncRNAs such as ZFAS1, CDR1AS, CHAST, UCA1, HOTAIR, MIAT, NEAT1, LIPCAR, H19, NRF, NRON, MHRT, PVT1, Heat2, CASC7, GAS5, MALAT1, APPAT, HIF1A-AS1, KCNQ1OT1, NEXN in different kinds of CVD and discussed their clinical application potential as biomarker, which can help us better understand the mechanism of CVD.
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Affiliation(s)
- Mingyi Cao
- Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, China
| | - Huishan Luo
- Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, China
| | - Danning Li
- Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, China
| | - Shengjie Wang
- Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, China
| | - Lina Xuan
- Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, China
| | - Lihua Sun
- Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, China.
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15
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Welles JE, Lacko H, Kawasawa YI, Dennis MD, Jefferson LS, Kimball SR. An integrative approach to assessing effects of a short-term Western diet on gene expression in rat liver. Front Endocrinol (Lausanne) 2022; 13:1032293. [PMID: 36387860 PMCID: PMC9643360 DOI: 10.3389/fendo.2022.1032293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/12/2022] [Indexed: 12/05/2022] Open
Abstract
Consumption of a diet rich in saturated fatty acids and carbohydrates contributes to the accumulation of fat in the liver and development of non-alcoholic steatohepatitis (NASH). Herein we investigated the hypothesis that short-term consumption of a high fat/sucrose Western diet (WD) alters the genomic and translatomic profile of the liver in association with changes in signaling through the protein kinase mTORC1, and that such alterations contribute to development of NAFLD. The results identify a plethora of mRNAs that exhibit altered expression and/or translation in the liver of rats consuming a WD compared to a CD. In particular, consumption of a WD altered the abundance and ribosome association of mRNAs involved in lipid and fatty acid metabolism, as well as those involved in glucose metabolism and insulin signaling. Hepatic mTORC1 signaling was enhanced when rats were fasted overnight and then refed in the morning; however, this effect was blunted in rats fed a WD as compared to a CD. Despite similar plasma insulin concentrations, fatty acid content was elevated in the liver of rats fed a WD as compared to a CD. We found that feeding had a significant positive effect on ribosome occupancy of 49 mRNAs associated with hepatic steatosis (e.g., LIPE, LPL), but this effect was blunted in the liver of rats fed a WD. In many cases, changes in ribosome association were independent of alterations in mRNA abundance, suggesting a critical role for diet-induced changes in mRNA translation in the expression of proteins encoded by those mRNAs. Overall, the findings demonstrate that short-term consumption of a WD impacts hepatic gene expression by altering the abundance of many mRNAs, but also causes wide-spread variation in mRNA translation that potentially contribute to development of hepatic steatosis.
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Affiliation(s)
- Jaclyn E. Welles
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, United States
| | - Holly Lacko
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, United States
| | - Yuka Imamura Kawasawa
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA, United States
| | - Michael D. Dennis
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, United States
| | - Leonard S. Jefferson
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, United States
| | - Scot R. Kimball
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, United States
- *Correspondence: Scot R. Kimball,
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Yang W, Su G, Liu Y. Silencing p62 reduces ox-LDL-induced M1 polarization and inflammation in macrophages by inhibiting mTOR/NF-κB signaling pathways. EUR J INFLAMM 2022. [DOI: 10.1177/1721727x221110348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Macrophages can change their phenotypes according to the changes in the microenvironment, and thus have various functions, that is, macrophages polarization. Macrophage phenotype is associated with the progression of atherosclerotic plaques. Studies have shown a large accumulation of p62 protein in atherosclerotic plaques. Whether the accumulation of p62 protein affects the level of macrophage polarization and inflammation and its mechanism is not clear. The p62 levels of macrophages treated with ox-LDL were detected by western blotting and qRT-PCR. Several polarizing markers and cytokines associated with atherosclerosis were detected by western blotting, ELISA, qRT-PCR, and flow cytometry to assess macrophage phenotype. The effect of p62 on the treatment of macrophage polarization by ox-LDL was studied by silencing p62 by gene silencing technique. The activity of mTOR and NF-κB signaling pathways was evaluated by detecting p-mTOR and intranuclear p65 levels in western blotting to explore the mechanism of p62. Rapamycin inhibited mTOR to demonstrate its role in activating the NF-κB signaling pathway and in ox-LDL therapy of p62 induced M1 polarization in macrophages. ox-LDL induced a significant increase in p62 and an increase in M1 markers and inflammatory cytokines. After p62 silencing, M1 markers and inflammatory cytokines decreased significantly, while M2 markers and anti-inflammatory cytokines increased significantly. Silencing p62 inhibited p-mTOR and p65 nuclear translocation. Rapamycin inhibited ox-LDL-induced p65 nuclear translocation and M1 markers, and increased M2 markers. p62 protein accumulation in ox-LDL treatment macrophages induces M1 polarization and inflammatory cytokines through the mTOR/NF-κB pathway.
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Affiliation(s)
- Wei Yang
- Department of Laboratory Diagnostics, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
- Department of Laboratory Diagnosis, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Guangming Su
- Department of Laboratory Diagnostics, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Yanhong Liu
- Department of Laboratory Diagnosis, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Tong J, Cong L, Jia Y, He BL, Guo Y, He J, Li D, Zou B, Li J. Follistatin Alleviates Hepatic Steatosis in NAFLD via the mTOR Dependent Pathway. Diabetes Metab Syndr Obes 2022; 15:3285-3301. [PMID: 36325432 PMCID: PMC9621035 DOI: 10.2147/dmso.s380053] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 10/07/2022] [Indexed: 11/13/2022] Open
Abstract
PURPOSE In this study, we aimed to investigate the effect of follistatin (FST) on hepatic steatosis in NAFLD and the underlying mechanism, which has rarely been reported before. METHODS Liver samples from NAFLD patients and normal liver samples (from liver donors) were collected to investigate hepatic FST expression in humans. Additionally, human liver cells (LO2) were treated with free fatty acid (FFA) to induce lipid accumulation. Furthermore, lentivirus with FST overexpression or knockdown vectors were used to generate stable cell lines, which were subsequently treated with FFA or FFA and rapamycin. In the animal experiments, male C57BL/6J mice were fed with a high-fat diet (HFD) to induce NAFLD, after which the adeno-associated virus (AAV) gene vectors for FST overexpression were administered. In both cell culture and mice, we evaluated morphological changes and the protein expression of sterol regulatory element-binding protein1 (SREBP1), acetyl-CoA carboxylase1 (ACC1), carbohydrate-responsive element-binding protein (ChREBP), fatty acid synthase (FASN), and Akt/mTOR signaling. The body weight and serum parameters of the mice were also measured. RESULTS Hepatic FST expression level was higher in NAFLD patients compared to normal samples. In LO2 cells, FST overexpression alleviated lipid accumulation and lipogenesis, whereas FST knockdown aggravated hepatic steatosis. FST could regulate Akt/mTOR signaling, and the mTOR inhibitor rapamycin abolished the effect of FST knockdown on hepatic de novo lipogenesis (DNL). Furthermore, FST expression was increased in HFD mice compared to the corresponding controls. FST overexpression in mice reduced body weight gain, hyperlipidemia, hepatic DNL, and suppressed Akt/mTOR signaling. CONCLUSION Hepatic FST expression increases in NAFLD and plays a protective role in hepatic steatosis. FST overexpression gene therapy alleviates hepatic steatosis via the mTOR pathway.Therefore, gene therapy for FST is a promising treatment in NAFLD.
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Affiliation(s)
- Junlu Tong
- Department of Endocrinology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China
- Department of Central Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China
| | - Li Cong
- Department of Endocrinology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China
| | - Yingbin Jia
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China
| | - Bai-Liang He
- Guangdong Provincial Key Laboratory of Biomedical Imaging, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China
| | - Yifan Guo
- Department of Endocrinology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China
| | - Jianzhong He
- Department of Pathology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China
| | - Decheng Li
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China
| | - Baojia Zou
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China
| | - Jian Li
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China
- Correspondence: Jian Li; Baojia Zou, Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China, Tel +86-756-252-8781, Email ;
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18
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Yuxiong Y, Xujin X, Yi T, Ya C, Yujuan L, Shanshan H, Huiwen W. Brain-specific TRAF7 deletion ameliorates traumatic brain injury by suppressing MEKK3-regulated glial inflammation and neuronal death. Int Immunopharmacol 2021; 103:108219. [PMID: 34953447 DOI: 10.1016/j.intimp.2021.108219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 09/26/2021] [Accepted: 09/30/2021] [Indexed: 11/05/2022]
Abstract
Neuronal death and neuroinflammation play critical roles in regulating the progression of traumatic brain injury (TBI). However, associated pathogenesis has not been fully understood. Tumor necrosis factor receptor-associated factor 7 (TRAF7), as the unique noncanonical member of the TRAF family, mediates various essential biological processes. Nevertheless, the effects of TRAF7 on TBI are still unclear. In this study, we showed that TRAF7 expression was markedly up-regulated in cortex and hippocampus of mice after TBI. Brain-specific TRAF7 deletion markedly ameliorated neuronal death in cortical and hippocampal samples of TBI mice, accompanied with cognitive impairments and motor dysfunction. Moreover, the aberrant activation of astrocyte and microglia in cortex and hippocampus of TBI mice was significantly restrained by TRAF7 conditional knockout in brain, as indicated by the increased expression of GFAP and Iba1. In addition, the releases of pro-inflammatory factors caused by TBI were also considerably diminished by brain-specific TRAF7 knockout, which were largely through the blockage of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways. Importantly, mitogen-activated protein kinase kinase kinase 3 (MEKK3) expression levels were greatly enhanced in cortex and hippocampus of mice with TBI, while being dramatically ameliorated by TRAF7 knockout in brain. Mechanistically, we showed that TRAF7 directly interacted with MEKK3. Of note, MEKK3 over-expression almost abrogated the capacity of TRAF7 knockout to mitigate neuronal death and neuroinflammation in the isolated primary cortical neurons and glial cells upon oxygen-glucose-deprivation/reperfusion (OGD/R) stimulation. Collectively, TRAF7 may be an important molecular switch that leads to TBI in a MEKK3-dependent manner, and can be served as a therapeutic target for TBI treatment.
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Affiliation(s)
- Yin Yuxiong
- Department of Anesthesiology, the 940(th) Hospital of Joint Logistics Support Force, Lanzhou, Gansu 730050, China
| | - Xiang Xujin
- Department of Anesthesiology, the 940(th) Hospital of Joint Logistics Support Force, Lanzhou, Gansu 730050, China
| | - Tang Yi
- Department of Anesthesiology, the 940(th) Hospital of Joint Logistics Support Force, Lanzhou, Gansu 730050, China
| | - Chen Ya
- Department of Anesthesiology, the 940(th) Hospital of Joint Logistics Support Force, Lanzhou, Gansu 730050, China
| | - Li Yujuan
- Department of Anesthesiology, the 940(th) Hospital of Joint Logistics Support Force, Lanzhou, Gansu 730050, China
| | - Hu Shanshan
- Department of Anesthesiology, the 940(th) Hospital of Joint Logistics Support Force, Lanzhou, Gansu 730050, China
| | - Wang Huiwen
- Department of Anesthesiology, the 940(th) Hospital of Joint Logistics Support Force, Lanzhou, Gansu 730050, China.
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Exosomal microRNA-98-5p from hypoxic bone marrow mesenchymal stem cells inhibits myocardial ischemia-reperfusion injury by reducing TLR4 and activating the PI3K/Akt signaling pathway. Int Immunopharmacol 2021; 101:107592. [PMID: 34715573 DOI: 10.1016/j.intimp.2021.107592] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 12/16/2022]
Abstract
OBJECTIVE MicroRNAs (miRNAs) are essential biomarkers during development of human diseases. We aimed to explore the role of hypoxia-induced bone marrow mesenchymal stem cells (BMSCs)-derived exosomal miR-98-5p in myocardial ischemia-reperfusion injury (MI/RI). METHODS BMSCs were isolated, cultured, stimulated by hypoxia and transfected with adenovirus expressing miR-98-5p. The exosomes were extracted from BMSCs and named as BMSC-exos. The rat MI/RI models were established by ligation of left anterior descending artery and were respectively injected. Then, hemodynamic indices, myocardial enzymes, oxidative stress factors, inflammatory factors, macrophage infiltration and infarct size in these rats were determined. Expression of miR-98-5p, toll-like receptor 4 (TLR4) and the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling pathway-related proteins was assessed. The target relation between miR-98-5p and TLR4 was confirmed by bioinformatic method and dual luciferase report gene assay. RESULTS MiR-98-5p was downregulated, TLR4 was upregulated and the PI3K/Akt signaling pathway was inactivated in MI/RI rat myocardial tissues. Exosomal miR-98-5p from hypoxic BMSCs promoted cardiac function and suppressed myocardial enzyme levels, oxidative stress, inflammation response, macrophage infiltration and infarct size in I/R myocardial tissues. Moreover, TRL4 was targeted by miR-98-5p and miR-98-5p activated PI3K/Akt signaling pathway. CONCLUSION Hypoxia-induced BMSC-exos elevated miR-98-5p to protect against MI/RI. This study may be helpful for treatment of MI/RI.
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20
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Hou Y, Yang D, Wang X, Wang H, Zhang H, Wang P, Liu Y, Gao X, Yang J, Wu C. Pseudoginsenoside-F11 promotes functional recovery after transient cerebral ischemia by regulating the microglia/macrophage polarization in rats. Int Immunopharmacol 2021; 99:107896. [PMID: 34246061 DOI: 10.1016/j.intimp.2021.107896] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 06/01/2021] [Accepted: 06/13/2021] [Indexed: 02/06/2023]
Abstract
The polarization of microglia/macrophages after cerebral ischemia is critical for post-stroke damage/recovery. Previously, we found that pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, has neuroprotective effects on permanent and transient cerebral ischemia in rats. This study aimed to investigate the effects and potential mechanisms of PF11 on microglia/macrophage polarization following transient cerebral ischemia in rats. In vivo data showed that oral administration of PF11 (12 mg/kg) significantly attenuated cognitive deficits and sensorimotor dysfunction, infarct volume and brain edema in transient middle cerebral artery occlusion (tMCAO)-treated rats, as well as reduced the loss of neurons and the over-activation of microglia in penumbra of ipsilateral striatum and cortex. Notably, the proportion of M2 microglia/macrophages in the total activated microglia/macrophages peaked on day 14 after tMCAO in rats, while PF11 promoted its peak advancing to day 3 post-tMCAO, which allowing the damaged brain to enter the repair period more quickly. Furthermore, PF11 increased the expression of anti-inflammatory markers and decreased the expression of pro-inflammatory markers in ipsilateral striatum and cortex. In addition, in vitro data showed that PF11 inhibited the induction of M1 microglia by oxygen glucose deprivation/re-oxygenation (OGD/R)-induced neurons, and promoted the polarization of microglia to M2 phenotype in a Jumonji domain-containing protein 3 (Jmjd3)-dependent manner. Moreover, PF11 promoted the protection of M2 microglia and attenuated the exacerbation of M1 microglia on OGD/R-induced neuronal damage. Taken together, these results indicate that PF11 protects ischemic neurons by promoting M2 microglia/macrophage polarization in a Jmjd3-dependent manner, ultimately facilitating the functional recovery following transient cerebral ischemia.
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Affiliation(s)
- Ying Hou
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Depeng Yang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Xianshi Wang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Huiyang Wang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Haotian Zhang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Pengwei Wang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Yinglu Liu
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Xiaoyun Gao
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Jingyu Yang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China.
| | - Chunfu Wu
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China.
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Liu W, Ye Q, Xi W, Li Y, Zhou X, Wang Y, Ye Z, Hai K. The ERK/CREB/PTN/syndecan-3 pathway involves in heparin-mediated neuro-protection and neuro-regeneration against cerebral ischemia-reperfusion injury following cardiac arrest. Int Immunopharmacol 2021; 98:107689. [PMID: 34153666 DOI: 10.1016/j.intimp.2021.107689] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 03/23/2021] [Accepted: 04/18/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Heparin, a commonly used anticoagulant, has been found to improve cerebral ischemia-reperfusion injury (CIR-CA) following cardiopulmonary resuscitation (CPR). Here, we aimed to explore the role of pleiotrophin (PTN)/syndecan-3 pathway in heparin therapy for CIR-CA. MATERIALS AND METHODS The CA-CPR model was constructed in Sprague-Dawley (SD) rats, which were treated with low molecular weight heparin, and the neurological changes and brain histopathological changes were evaluated. For in-vitro experiments, the ischemic injury model of primary neurons was established by oxygen and glucose deprivation (OGD), and the neuron regeneration was detected via the Cell counting Kit-8 (CCK8) method, flow cytometry and microscopy. CREB antagonist (KG-501), ERK antagonist (PD98059) and si-PTN were used respectively to inhibit the expression of CREB, ERK and PTN in cells, so as to explore the role of heparin in regulating neuronal regeneration. RESULTS Compared with the sham rats, the neurological deficits and cerebral edema of CA-CPR rats were significantly improved after heparin treatment. Heparin also attenuated OGD-mediated neuronal apoptosis and promoted neurite outgrowth in vitro. Moreover, heparin attenuated CA-CPR-mediated neuronal apoptosis and microglial neuroinflammation. In terms of the mechanism, heparin upregulated the expression of ERK, CREB, NF200, BDNF, NGF, PTN and syndecan-3 in the rat brains. Inhibition of ERK, CREB and interference with PTN expression notably weakened the heparin-mediated neuroprotective effects and restrained the expression of ERK/CREB and PTN/syndecan-3 pathway. CONCLUSION Heparin attenuates the secondary brain injury induced by CA-CPR through regulating the ERK/CREB-mediated PTN/syndecan-3 pathway.
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Affiliation(s)
- Wenxun Liu
- Ningxia Medical University, Yinchuan 750004, Ningxia, China; Department of Anesthesiology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan 750002, Ningxia, China; Ningxia Anesthesia Clinincal Medical Research Center, Yinchuan 750002, Ningxia, China
| | - Qingshan Ye
- Department of Anesthesiology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan 750002, Ningxia, China; Ningxia Anesthesia Clinincal Medical Research Center, Yinchuan 750002, Ningxia, China
| | - Wenhua Xi
- Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Yan Li
- Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Xiaohong Zhou
- Department of Anesthesiology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan 750002, Ningxia, China
| | - Yun Wang
- Department of Anesthesiology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan 750002, Ningxia, China; Ningxia Anesthesia Clinincal Medical Research Center, Yinchuan 750002, Ningxia, China
| | - Zhenhai Ye
- Department of Anesthesiology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan 750002, Ningxia, China
| | - Kerong Hai
- Department of Anesthesiology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan 750002, Ningxia, China; Ningxia Anesthesia Clinincal Medical Research Center, Yinchuan 750002, Ningxia, China.
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22
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HJURP is a prognostic biomarker for clear cell renal cell carcinoma and is linked to immune infiltration. Int Immunopharmacol 2021; 99:107899. [PMID: 34217993 DOI: 10.1016/j.intimp.2021.107899] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 01/11/2023]
Abstract
BACKGROUND Clear cell renal cell carcinoma (ccRCC) is the most prevalent and highly malignant pathological type of kidney cancer. Finding more precise biomarkers is critical for enhancing the prognosis of patients with ccRCC. Multiple studies have suggested that Holliday junction recognition protein (HJURP) promotes tumor progression and predicts poor prognosis in a variety of cancers. However, the role of HJURP in ccRCC remains unclear. METHODS The ccRCC dataset was obtained from The Cancer Genome Atlas (TCGA), and the relationship between HJURP expression and ccRCC clinical features was investigated using R software. The effect of HJURP expression on survival was assessed using survival probabilities and Cox regression. Gene set enrichment analysis (GSEA) was used to identify HJURP-related signaling pathways in ccRCC. Finally, Tumor IMmune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA)were used to analyzethe correlation between HJURP expression and immunocyte infiltrates in ccRCC. RESULTS HJURP expression was upregulated in ccRCC. Increased HJURP expression was associated with poor pathological features and correlated with poor prognosis in patients with ccRCC. Cox regression further found that HJURP expression was a high-risk factor for ccRCC patients. GSEA revealed that HJURP was closely linked to multiple immune-related signaling pathways. In ccRCC, HJURP expression was closely correlated with infiltration of various immune cells and expression of a wide range of immunocyte gene markers. CONCLUSION HJURP is a potential independent prognostic marker in ccRCC that plays an essential role in the tumor microenvironment by regulating immunocyte infiltration.
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Association between tubulointerstitial CD8+T cells and renal prognosis in lupus nephritis. Int Immunopharmacol 2021; 99:107877. [PMID: 34217995 DOI: 10.1016/j.intimp.2021.107877] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/06/2021] [Accepted: 04/13/2021] [Indexed: 11/20/2022]
Abstract
OBJECTIVE Inflammatory cell infiltration is a pathological change commonly seen in renal biopsies from patients with lupus nephritis(LN), but its clinicalcorrelationwith clinical parameters and prognosis is unclear. METHODS Included in this retrospective study were 197 patients with ISN/ RPS Class III-V LN, in whom renal biopsy was performed to analyze the histological pattern. Tubulointerstitial infiltrates were quantitated by standard histochemical staining. Clinical and histologic variables were evaluated using a Cox proportional hazards model. End-stagerenaldisease(ESRD) progression was defined as a two-fold increase in serum creatinine (SCr) after biopsy, GFR decreased over 40%, initiation of dialysis, transplantation, or death. RESULTS Of the 197 patients, 166 patients (84.3%) had proliferative LN. The number of tubulointerstitial infiltrates was the lowest in LN patients with ISN/RPS class V, and the number of CD68+ macrophages was the highest in all ISN/RPS classes of LN. In addition, the number of CD8+T cell infiltrates was positively correlated the SLEDAI sore, SCr level, proteinuria, the ratio of glomerulosclerosis and the degree of tubulointerstitial inflammation, interstitial fibrosis and tubular atrophy, activity and chronicity indices, and negatively correlated with C3 level at presentation. Multivariate survival analysis showed that tubulointerstitial CD8 + T cells > 130/mm2 was associated with ESRD progression (HR 1.007; 95% CI 1.003 to 1.011; p < 0.001). CONCLUSION Tubulointerstitial CD8+T cells correlate with clinicohistologic impairment in LN. Tubulointerstitial CD8+T cells > 130/mm2 is independently associated with an unfavorable long-term kidney outcome.
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Cong L, Xie X, Liu S, Xiang L, Zhang Y, Cao J, Fu X. 7-Difluoromethoxy-5,4'-dimethoxy-genistein attenuates macrophages apoptosis to promote plaque stability via TIPE2/TLR4 axis in high fat diet-fed ApoE -/- mice. Int Immunopharmacol 2021; 96:107477. [PMID: 33813367 DOI: 10.1016/j.intimp.2021.107477] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 01/27/2021] [Accepted: 02/03/2021] [Indexed: 12/17/2022]
Abstract
Promoting plaque stability is of great significance for prevention and treatment of cardiovascular diseases. 7-difluoromethoxy-5,4'-dimethoxygenistein (DFMG) is a novel active compound synthesized using genistein, which exerts anti-atherosclerotic effect. In this study, we evaluated effects of DFMG on plaque stability in ApoE-/- mice fed with high fat diet (HFD), and explored the molecular mechanism by using ApoE-/-TLR4-/- mice and RAW264.7 cells. Here, we found that DFMG significantly reduced plaque areas, macrophages infiltration and apoptosis, and TLR4 expression in HFD-fed ApoE-/- mice. Meanwhile, DFMG increased collagen fibers, smooth muscle cells and TIPE2 expression in plaques and media. Besides, TLR4 knockout promoted the protective effects of DFMG on plaques. In vitro, DFMG decreased lysophosphatidylcholine (LPC)-induced macrophages apoptosis and TLR4, while upregulated TIPE2. Moreover, TIPE2 reduced TLR4, MyD88, p-NF-κB p65Ser276, cleaved Caspase-3 overproduction, and enhanced effects of DFMG on LPC-induced macrophages. Overall, our study demonstrates that DFMG can promote plaque stability by reducing macrophage apoptosis through TIPE2/TLR4 signaling pathway, which suggests DFMG should be used to develop food additives or drugs for preventing atherosclerosis.
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Affiliation(s)
- Li Cong
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Changsha 410013, China; School of Medicine, Hunan Normal University, Changsha 410013, China
| | - Xiaolin Xie
- School of Medicine, Hunan Normal University, Changsha 410013, China
| | - Sujuan Liu
- School of Medicine, Hunan Normal University, Changsha 410013, China
| | - Liping Xiang
- School of Medicine, Hunan Normal University, Changsha 410013, China
| | - Yong Zhang
- School of Medicine, Hunan Normal University, Changsha 410013, China
| | - Jianguo Cao
- School of Medicine, Hunan Normal University, Changsha 410013, China
| | - Xiaohua Fu
- School of Medicine, Hunan Normal University, Changsha 410013, China.
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Wang WY, Xie L, Zou XS, Li N, Yang YG, Wu ZJ, Tian XY, Zhao GY, Chen MH. Inhibition of extracellular signal-regulated kinase/calpain-2 pathway reduces neuroinflammation and necroptosis after cerebral ischemia-reperfusion injury in a rat model of cardiac arrest. Int Immunopharmacol 2021; 93:107377. [PMID: 33517223 DOI: 10.1016/j.intimp.2021.107377] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 01/06/2021] [Accepted: 01/06/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Cerebral ischemia-reperfusion injury (CIRI) is the leading cause of poor neurological prognosis after cardiopulmonary resuscitation (CPR). We previously reported that the extracellular signal-regulated kinase (ERK) activation mediates CIRI. Here, we explored the potential ERK/calpain-2 pathway role in CIRI using a rat model of cardiac arrest (CA). METHODS Adult male Sprague-Dawley rats suffered from CA/CPR-induced CIRI, received saline, DMSO, PD98059 (ERK1/2 inhibitor, 0.3 mg/kg), or MDL28170 (calpain inhibitor, 3.0 mg/kg) after spontaneous circulation recovery. The survival rate and the neurological deficit score (NDS) were utilized to assess the brain function. Hematoxylin stain, Nissl staining, and transmission electron microscopy were used to evaluate the neuron injury. The expression levels of p-ERK, ERK, calpain-2, neuroinflammation-related markers (GFAP, Iba1, IL-1β, TNF-α), and necroptosis proteins (TNFR1, RIPK1, RIPK3, p-MLKL, and MLKL) in the brain tissues were determined by western blotting and immunohistochemistry. Fluorescent multiplex immunohistochemistry was used to analyze the p-ERK, calpain-2, and RIPK3 co-expression in neurons, and RIPK3 expression levels in microglia or astrocytes. RESULTS At 24 h after CA/CPR, the rats in the saline-treated and DMSO groups presented with injury tissue morphology, low NDS, ERK/calpain-2 pathway activation, and inflammatory cytokine and necroptosis protein over-expression in the brain tissue. After PD98059 and MDL28170 treatment, the brain function was improved, while inflammatory response and necroptosis were suppressed by ERK/calpain-2 pathway inhibition. CONCLUSION Inflammation activation and necroptosis involved in CA/CPR-induced CIRI were regulated by the ERK/calpain-2 signaling pathway. Inhibition of that pathway can reduce neuroinflammation and necroptosis after CIRI in the CA model rats.
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Affiliation(s)
- Wen-Yan Wang
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Lu Xie
- Department of Physiology, Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Xin-Sen Zou
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Nuo Li
- Department of Physiology, Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Ye-Gui Yang
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Zhi-Jiang Wu
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Xin-Yue Tian
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Gao-Yang Zhao
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Meng-Hua Chen
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China.
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Dahou S, Smahi MCE, Nouari W, Dahmani Z, Benmansour S, Ysmail-Dahlouk L, Miliani M, Yebdri F, Fakir N, Laoufi MY, Chaib-Draa M, Tourabi A, Aribi M. L-Threoascorbic acid treatment promotes S. aureus-infected primary human endothelial cells survival and function, as well as intracellular bacterial killing, and immunomodulates the release of IL-1β and soluble ICAM-1. Int Immunopharmacol 2021; 95:107476. [PMID: 33676147 DOI: 10.1016/j.intimp.2021.107476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Vitamin C (ascorbic acid, AscH2) has been shown to enhance immunity. Here, we studied its immunomodulatory effect on human endothelial cells (ECs) during S. aureus infection. MATERIALS AND METHODS The ex vivo effects of AscH2 were performed on primary human umbilical vein endothelial cells (HUVECs) infected or not with S. aureus. RESULTS AscH2 treatment induced a marked downregulation of nitric oxide (NO) production and a moderate upregulation of arginase activity in S. aureus-infected HUVECs (respectively, p < 0.05 and p > 0.05). Although the upregulated release levels of soluble intercellular adhesion molecular 1 (sICAM-1/sCD54) and sE-selectin (sCD62E) molecules were not significantly different between treated and untreated S. aureus-infected HUVECs, AscH2 treatment induced reversing effect on sICAM-1 release when comparing to uninfected control HUVECs. Moreover, AscH2 treatment appears to have a significant effect on preventing HUVEC necrosis induced by S. aureus infection (p < 0.05). Furthermore, AscH2 treatment induced a significant upregulation of cell protective redox biomarker in S. aureus-infected, as shown by superoxide dismutase (SOD) activity (p < 0.05), but not by catalase activity (p > 0.05). Additionally, S. aureus infection markedly downregulated total bound calcium ions (bCa2+) levels as compared to control HUVECs, whereas, AscH2 treatment induced a slight upregulation of bCa2+ levels in infected HUVECs as compared to infected and untreated HUVECs (p > 0.05). On the other hand, AscH2 treatment downregulated increased total cellular cholesterol content (tccCHOL) levels in HUVECs induced by S. aureus infection (p < 0.05). In addition, AscH2 treatment markedly reversed S. aureus effect on upregulation of intracellular glucose (iGLU) levels within infected HUVECs (p < 0.05). Moreover, AscH2 treatment significantly downregulated S. aureus growth (p < 0.05), and significantly upregulated bacterial internalization and intracellular killing by HUVECs (p < 0.05), as well as their cell cycle activation (p < 0.01). Finally, AscH2 treatment has a slight effect on the production of interleukin 6 (IL-6), but induced a marked downregulation of that of IL-1β in S. aureus-infected HUVECs (respectively, p > 0.05, and p < 0.05). CONCLUSIONS Our outcomes demonstrated that, during S. aureus infection, AscH2 treatment promotes human ECs survival and function, as well as prevents inflammatory response exacerbation, while inducing bactericidal activity.
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Affiliation(s)
- Sara Dahou
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Mohammed Chems-Eddine Smahi
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria; Neonatal Department of Specialized Maternal and Child Hospital of Tlemcen, 13000, Tlemcen, Algeria
| | - Wafa Nouari
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Zoheir Dahmani
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Souheila Benmansour
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria; Neonatal Department of Specialized Maternal and Child Hospital of Tlemcen, 13000, Tlemcen, Algeria
| | - Lamia Ysmail-Dahlouk
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Maroua Miliani
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Fadela Yebdri
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Nassima Fakir
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Mohammed Yassine Laoufi
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria; Neonatal Department of Specialized Maternal and Child Hospital of Tlemcen, 13000, Tlemcen, Algeria
| | - Mouad Chaib-Draa
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Amina Tourabi
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria
| | - Mourad Aribi
- Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria.
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Nguyen VN, Abagyan R, Tsunoda SM. Mtor inhibitors associated with higher cardiovascular adverse events-A large population database analysis. Clin Transplant 2021; 35:e14228. [PMID: 33476406 DOI: 10.1111/ctr.14228] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/04/2021] [Accepted: 01/12/2021] [Indexed: 12/17/2022]
Abstract
There are limited real-world data available regarding adverse events (AEs) of immunosuppressants. We utilized the FDA Adverse Event Reporting System (FAERS) database from 2004 to 2018 to perform a retrospective database analysis. We analyzed AE reports due to the individual agents tacrolimus, sirolimus, or everolimus and compared reporting odds ratios of the mTOR inhibitors to tacrolimus. The mTOR inhibitors arm had 1282 reports with 4176 AEs, while the tacrolimus arm had a total of 7587 reports with 20 940 individual AEs. mTOR inhibitors had significantly higher incidences of cardiovascular (ROR 1.95, 95% CI 1.70, 2.23), dermatologic (ROR 1.34, 95% CI 1.04, 1.73), endocrine (ROR 1.52, 95% CI 1.26, 1.82), gastrointestinal (ROR 1.15, 95% CI 1.01, 1.30), infectious disease (ROR 1.35, 95% 1.20, 1.52), musculoskeletal (ROR 1.39, 95% CI 1.13, 1.70), pulmonary (ROR 3.46, 95% 2.97, 4.03), renal (ROR 1.27, 95% CI 1.10, 1.46), and vascular AEs (ROR 3.10, 95% CI 2.14, 4.49). Across every organ type, mTOR inhibitors had greater cardiovascular AEs compared to tacrolimus, specifically in arteriosclerosis, heart failure, hypotension, tachycardia, chest pain, edema, and pericardial disorders. mTOR inhibitors may be associated with higher cardiovascular AEs. Further investigation is required to determine the potential mechanism of this effect.
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Affiliation(s)
- Vi N Nguyen
- Department of Pharmacy, University of California San Diego, La Jolla, CA, USA
| | - Ruben Abagyan
- Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA
| | - Shirley M Tsunoda
- Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA
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Qiu X, Liang X, Li H, Sun R. LPS-induced vein endothelial cell injury and acute lung injury have Btk and Orai 1 to regulate SOC-mediated calcium influx. Int Immunopharmacol 2021; 90:107039. [PMID: 33127334 DOI: 10.1016/j.intimp.2020.107039] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 09/06/2020] [Accepted: 09/21/2020] [Indexed: 12/25/2022]
Abstract
Patients with sepsis and sepsis-related complications have a high mortality. Endothelial cell dysfunction plays a central role in sepsis pathophysiological process. In sepsis patients, endothelial cell apoptosis is associated with intracellular calcium overload. Multiple functions in the apoptotic process have been found to be regulated by calcium signaling. Our previous work had proved that LPS-induced cell injury was associated with store-operated calcium (SOC) entry mediated by stromal interaction molecule-1 (STIM 1) in Human umbilical vein endothelial cells (HUVEC), but the underlying molecular mechanism has not been adequately defined. Here we report that the LPS-induced cell injury is related to the calcium overload in HUVEC. SOC entry mediated by calcium release-activated calcium modulator (Orai) 1 and transient receptor potential canonical (TRPC) 1 was associated with LPS-induced calcium overload and cell apoptosis. Bruton's tyrosine kinase (Btk)/Phospholipase C(PLC) γ/inositol 1,4,5-triphosphate receptor (IP3R) played a major role in regulating calcium overload in LPS-induced HUVEC. Knockdown of Btk markedly inhibited the expressions of Orai 1 and its downstream molecule IP3R but not that of TRPC1 in LPS-induced HUVEC. In mice, knockdown of Btk and Orai 1 inhibited LPS-induced calcium overload, pulmonary vascular endothelial cell (VEC) injury and acute lung injury. These findings demonstrated that Btk acts as a regulator of calcium-dependent signaling, especially in the Orai 1-mediated SOC entry of the LPS-induced VEC.
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Affiliation(s)
- Xiaochen Qiu
- Department of General Surgery, the Eighth Medical Center, Chinese PLA (People's Liberation Army) General Hospital, Beijing 100091, China
| | - Xiaobo Liang
- Department of Dermatology, the Eighth Medical Center, Chinese PLA (People's Liberation Army) General Hospital, Beijing 100091, China
| | - Hengyu Li
- Department of Breast and Thyroid Surgery, Changhai Hospital, the Second Military Medical University, Shanghai 200433, China
| | - Rongju Sun
- Department of Emergency, the First Medical Center, Chinese PLA (People's Liberation Army) General Hospital, Beijing 100853, China.
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Chen C, Xu Y. RETRACTED: Long noncoding RNA LINC00671 exacerbates osteoarthritis by promoting ONECUT2-mediated Smurf2 expression and extracellular matrix degradation. Int Immunopharmacol 2021; 90:106846. [PMID: 33168412 DOI: 10.1016/j.intimp.2020.106846] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/20/2020] [Accepted: 07/26/2020] [Indexed: 12/15/2022]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Authors and Editor-in-Chief. The corresponding author contacted the journal and stated: “…we have obtained different results from this paper (onecut2 targeted regulation of Smurf2 / GSK-3 β part), and repeated experiments cannot fully verify this result”. The authors requested retraction of the article. Concern was also raised about the integrity of an image in Figure 1H, which appears to also be found in another publication, as detailed here: https://pubpeer.com/publications/FBECF0BCB952DCC563AA5C4D760B32 and here: https://docs.google.com/spreadsheets/d/1r0MyIYpagBc58BRF9c3luWNlCX8VUvUuPyYYXzxWvgY/edit#gid=262337249. The journal requested the corresponding author comment on these concerns and provide the raw data. The authors were unable to satisfactorily fulfill this request. The Editor-in-Chief assessed the case and decided to retract the article.
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Affiliation(s)
- Chengwei Chen
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, PR China; Department of Orthopaedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, PR China
| | - Yaozeng Xu
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, PR China.
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Li K, Cui M, Zhang K, Wang G, Zhai S. M1 macrophages-derived extracellular vesicles elevate microRNA-185-3p to aggravate the development of atherosclerosis in ApoE -/- mice by inhibiting small mothers against decapentaplegic 7. Int Immunopharmacol 2021; 90:107138. [PMID: 33302032 DOI: 10.1016/j.intimp.2020.107138] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 10/26/2020] [Accepted: 10/26/2020] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Extracellular vesicles (EVs) are vital mediators of transferring microRNAs (miRNAs). We focused on effect of miR-185-3p that mediated by macrophages-derived EVs on atherosclerosis (AS) by targeting small mothers against decapentaplegic 7 (Smad7). METHODS EVs were extracted from M1 macrophages and identified. ApoE-/- mice were treated with EVs, EVs containing miR-185-3p inhibitor or mimic, then the pathological changes of mouse aorta were observed. The levels of blood lipid, cell adhesion molecules, oxidative stress factors, inflammatory factors, and proliferation and apoptosis of vascular endothelial cells were assessed. Expression of miR-185-3p and Smad7 was detected and the targeting relationship between miR-185-3p and Smad7 was validated. RESULTS MiR-185-3p was upregulated while Smad7 was downregulated in atherosclerotic mouse aorta. M1 macrophages-derived EVs elevated miR-185-3p to promote development of AS pathology and levels of blood lipid, endothelial cellular adhesion, oxidative stress factors and inflammatory factors, suppressed cell proliferation and promoted cell apoptosis of vascular endothelial cells in atherosclerotic mice through downregulating Smad7. Smad7 was a target gene of miR-185-3p and miR-185-3p could inhibit expression of Smad7. CONCLUSION M1 macrophages-derived EVs and upregulated miR-185-3p aggravated the development of AS in ApoE-/- mice by negatively regulating Smad7. This research may further the understanding of AS mechanism.
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Affiliation(s)
- Kun Li
- Department of Vascular and Endovascular Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou 450003, China
| | - Mingzhe Cui
- Department of Vascular and Endovascular Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou 450003, China
| | - Kewei Zhang
- Department of Vascular and Endovascular Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou 450003, China
| | - Guoquan Wang
- Department of Vascular and Endovascular Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou 450003, China
| | - Shuiting Zhai
- Department of Vascular and Endovascular Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou 450003, China.
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Integrated bioinformatics analysis identified COL11A1 as an immune infiltrates correlated prognosticator in pancreatic adenocarcinoma. Int Immunopharmacol 2020; 90:106982. [PMID: 33129696 DOI: 10.1016/j.intimp.2020.106982] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 08/21/2020] [Accepted: 09/04/2020] [Indexed: 12/26/2022]
Abstract
Pancreatic adenocarcinoma (PAAD) is the most common pancreatic cancer, with high mortality rate and limited treatment options. Tumor infiltrating cells and genes in microenvironment are emerging as pivotal players in PAAD progression and prognosis. In this study, we obtained genes expression data set GSE119794 of PAAD, which contains data from 10 tumor and 10 normal samples. A total of 262 differentially expressed genes (DEGs), including 169 up-regulated and 93 down-regulated genes, were obtained based on expression fold change and significance. Combining the pathway analysis of DEGs and GSEA analysis of all genes, four KEGG pathways were enriched. The 4 pathways include pancreatic secretion, protein digestion and absorption, fat digestion and absorption, and PPAR signaling pathways. Functional enrichment of Gene Ontology significantly enriched extracellular matrix, an important component in microenvironment. In the Protein-protein interaction (PPI) network, we screened out 3 hub genes of COL11A1, KRT19 and CXCL5 by CytoHubba. At last, the expression level, prognostic significance and correlation with tumor infiltrates were validated in TCGA database, with GEPIA and TIMER. The validation identified Collagen Type XI Alpha 1 Chain (COL11A1), an extracellular matrix structural constituent, as a hazardous prognosticator with significant correlation with macrophage, neutrophil and dendritic cells. In sum, we identified COL11A1 as an immune infiltrates correlated prognosticator in pancreatic adenocarcinoma.
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Zhao H, Wei J, Sun J. Roles of TGF-β signaling pathway in tumor microenvirionment and cancer therapy. Int Immunopharmacol 2020; 89:107101. [PMID: 33099067 DOI: 10.1016/j.intimp.2020.107101] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/10/2020] [Accepted: 10/10/2020] [Indexed: 12/15/2022]
Abstract
Transforming growth factor β (TGF- β) signaling pathway has pleiotropic effects on cell proliferation, differentiation, adhesion, senescence, and apoptosis. TGF-β can be widely produced by various immune or non-immune cells and regulate cell behaviors through autocrine and paracrine. It plays essential roles in biological processes including embryological development, immune response, and tumor progression. Few cell signalings can contribute to so many pleiotropic functions as the TGF- β signaling pathway in mammals. The significant function of TGF-β signaling in tumor progression and evasion leading it to draw great attention in scientific and clinical research. Understanding the mechanism of TGF- β signaling provides us with chances to potentiate the effectiveness and selectivity of this therapeutic method. Herein, we review the molecular and cellular mechanisms of TGF-β signaling in carcinomas and tumor microenvironment. Then, we enumerate main achievements of TGF-β blockades used or being evaluated in cancer therapy, providing us opportunities to improve therapeutical approaches in the tumor which thrive in a TGF-β-rich environment.
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Affiliation(s)
- Haodi Zhao
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 30072, PR China
| | - Jing Wei
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China
| | - Jian Sun
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 30072, PR China; Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China.
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Atractylenolide III alleviates the apoptosis through inhibition of autophagy by the mTOR-dependent pathway in alveolar macrophages of human silicosis. Mol Cell Biochem 2020; 476:809-818. [PMID: 33078341 DOI: 10.1007/s11010-020-03946-w] [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: 06/13/2020] [Accepted: 10/10/2020] [Indexed: 12/16/2022]
Abstract
Silica-induced apoptosis of alveolar macrophages (AMs) is an essential part of silicosis formation. Autophagy tends to present a bidirectional effect on apoptosis. Our previous study found that the blockade of autophagy degradation might aggravate the apoptosis of AMs in human silicosis. We presume that targeting the autophagic pathway is regarded as a promising new strategy for silicosis fibrosis. As a main active component of the Atractylodes rhizome, Atractylenolide III (ATL-III) has been widely applied in clinical anti-inflammation. However, the effect and mechanism of ATL-III on autophagy in AMs of silicosis are unknown. In this study, we found that ATL-III might inhibit autophagy by mTOR-dependent manner, thereby improving the blockage of autophagic degradation in AMs. ATL-III alleviated the apoptosis of AMs in human silicosis. Furthermore, Rapamycin reversed the protective effect of ATL-III in AMs. These results indicate that ATL-III may be a potentially protective ingredient targeting autophagy for workers exposed to silica dust. These findings also suggest that inhibition of autophagy may be an effective way to alleviate the apoptosis of AMs in silicosis.
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Jiang N, Li Z, Li Z, Zhang Y, Yu Z, Wan P, Zhu Y, Li Y, Su W, Zhuo Y. Laquinimod exerts anti-inflammatory and antiapoptotic effects in retinal ischemia/reperfusion injury. Int Immunopharmacol 2020; 88:106989. [PMID: 33182069 DOI: 10.1016/j.intimp.2020.106989] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 08/22/2020] [Accepted: 09/07/2020] [Indexed: 11/15/2022]
Abstract
Retinal ischemia/reperfusion (I/R) occurs in various vision disabled ocular diseases, involved in acute glaucoma, diabetic retinopathy, ischemic optic neuropathy, hypertensive retinopathy and retinal vascular occlusion. Laquinimod (LQ), a new type of immunosuppressant, has been reported to exert anti-inflammatory effects on autoimmune diseases. This research aims to investigate the protective effect of LQ on I/R damage by focusing on inhibiting dysregulated neuroinflammation and neuronal apoptosis. In our study, mice were treated with LQ after high intraocular pressure (IOP)-induced retinal I/R injury. The data showed that LQ significantly attenuated high IOP-induced retinal ganglion cell (RGC) death and inner plexiform layer (IPL) thinning and inhibited microglial activation. The results of qRT-PCR, flow cytometry and Luminex multiplex assays demonstrated the anti-inflammatory action of LQ in BV2 cells stimulated with lipopolysaccharide (LPS). In addition, primary RGC apoptosis induced by oxygen-glucose deprivation/reperfusion (OGD/R) was also directly suppressed by LQ. Importantly, LQ inhibited the expression of cleaved caspase-8 and the downstream NLRP3 inflammasome and IL-1β. In conclusion, our findings offer the first evidence that LQ treatment prevents retinal I/R damage. Furthermore, LQ could directly inhibit RGC apoptosis. Caspase-8 activation and subsequent inflammation can also be suppressed by LQ, which suggests that LQ may act through inhibiting the caspase-8 pathway. This study demonstrates a new mechanism of LQ and provides beneficial preclinical data for the clinical application of LQ.
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Affiliation(s)
- Nan Jiang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Zhidong Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Zuohong Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yingying Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Ziyu Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Peixing Wan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yingting Zhu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yiqing Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Wenru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
| | - Yehong Zhuo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
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Shang X, Li J, Wang H, Li Z, Lin J, Chen D, Wang H. CMTM6 is positively correlated with PD-L1 expression and immune cells infiltration in lung squamous carcinoma. Int Immunopharmacol 2020; 88:106864. [PMID: 32866782 DOI: 10.1016/j.intimp.2020.106864] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 07/13/2020] [Accepted: 07/28/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The aim of this study was to clarify the association between CMTM6 and PD-L1 expression as well as microenvironment in lung squamous carcinoma (LUSC). MATERIAL AND METHODS Using Spearman's correlation and Tumor Immune Estimation Resource (TIMER), we analyzed the relationship between CMTM6 and PD-L1 mRNA in LUSC. Immunohistochemistry (IHC) assay was applied to validate the correlation between CMTM6 and PD-L1 protein level in 80 LUSC samples originated from Shandong Provincial Hospital. Then, using The Cancer Genome Atlas (TCGA) database and fisher test, we analyzed the differential mutation genes in high and low CMTM6 expression group. TISIDB was used to explore the distribution of CMTM6 across immune- and molecular-subtypes. TCGA database and Gene Set variation analysis (GSVA) were used to analyze the relationship between CMTM6 and immune genes, immune related pathways. RESULT Positive correlation between CMTM6 and PD-L1 in mRNA and protein level was found in LUSC patients. More gene mutations were found in CMTM6 high expression group compared with low expression group. Meanwhile, we also found the correlation between CMTM6 expression and molecular subtypes, immune genes, immune related pathways. Furthermore, our result revealed that B cells memory, T cells memory testing, T cells folicular helper, macrophages M0, macrophages M1 and neutrophils varied significantly between patients with CMTM6 high and low expression group. Finally, we found that CMTM6 expression was positively related to CD8 + T cell, macrophage, neutrophil and dendtritic cell (all, P < 0.05) and negatively related to CD4 + T cell (P = 0.018). CONCLUSION CMTM6 is positively associated with PD-L1 expression and correlates with infiltration of immune cells in microenvironment of lung squamous carcinoma.
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Affiliation(s)
- Xiaoling Shang
- Department of Clinical Laboratory, Shandong University, Jinan 250012, China; Department of Clinical Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Jia Li
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine (TCM), Shanghai 200032, China
| | - Hui Wang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Zhenxiang Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Jiamao Lin
- Department of Internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Dawei Chen
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China.
| | - Haiyong Wang
- Department of Internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China.
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Resveratrol protects against apoptosis induced by interleukin-1β in nucleus pulposus cells via activating mTOR/caspase-3 and GSK-3β/caspase-3 pathways. Biosci Rep 2020; 40:225857. [PMID: 32696949 PMCID: PMC7391128 DOI: 10.1042/bsr20202019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/18/2020] [Accepted: 07/21/2020] [Indexed: 02/08/2023] Open
Abstract
Objective: The purpose of the present study was to investigate the specific downstream signaling pathway mediated by PI3K/Akt in resveratrol (RES) anti-apoptosis of nucleus pulposus cells (NPCs). Materials and methods: Human NPCs were cultured and divided into six groups. Interleukin (IL)-1β was used to induce apoptosis and RES to inhibit apoptosis. Fluorescence-activated cell sorting (FACS) analysis was used to test apoptotic incidence of NPCs, cell counting kit-8 (CCK-8) assay was performed to detect cell viability, The expression level of caspase-3 mRNA was detected by RT-qPCR, and protein levels were determined by Western blot. Results: Flow cytometry analysis showed that IL-1β increased the apoptosis rate of NPCs in each group, and RES significantly decreased the apoptosis rate, while rapamycin (RAPA) and SB216763 inhibited the effect of RES and increased the apoptosis rate again. Similarly, CCK-8 showed that IL-1β decreased activity of NPCs in each group, while RES increased cell activity, RAPA and SB216763 inhibited the effect of RES and decreased cell activity. RT-qPCR results showed IL-1β significantly increased the level of caspase-3 expression, but it was significantly decreased by using RES, RAPA and SB216763 respectively attenuated effects of RES. Western blot results showed that activated caspase-3 was inhibited by RES effect, and was up-regulated again after the addition of RAPA and SB216763. In addition, p-mTOR and p-GSK-3β were up-regulated by RES and down-regulated by RAPA and SB216763. Conclusion: RES can inhibit apoptosis induced by IL-1β in human NPCs. PI3K/Akt/mTOR/caspase-3 and PI3K/Akt/GSK-3β/caspase-3 pathways are potential mechanisms underlying this process.
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Identification of the prognostic value of immune gene signature and infiltrating immune cells for esophageal cancer patients. Int Immunopharmacol 2020; 87:106795. [PMID: 32707495 DOI: 10.1016/j.intimp.2020.106795] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/05/2020] [Accepted: 07/06/2020] [Indexed: 01/06/2023]
Abstract
BACKGROUND Esophageal cancer (ESCA) is one of the deadliest solid malignancies with worse survival rate worldwide. Here, we aimed to establish an immune-gene prognostic signature for predicting patients' survival and providing accurate targets for personalized therapy or immunotherapy. METHODS Gene expression profile of patients with ESCA were download from The Cancer Genome Atlas (TCGA) database (dataset 1: n = 159) and immune-related genes from the ImmPORT database. Dataset 1 was subdivided into two groups (dataset 2: n = 80; dataset 3: n = 79). Kaplan-Meier and receiver operating characteristic (ROC) curves were plotted to validate the predictive effect of the prognostic signature on the three datasets. TIMER and CIBERSORT analysis were used to evaluate the correlation between the prognostic signature and infiltrating immune cells. RESULTS We constructed a prognostic signature composed of six immune genes (HSPA6, S100A12, FABP3, DKK1, OSM and NR2F2). Kaplan-Meier curves validated the good predictive ability of the prognostic signature in datasets 1, 2 and 3 (P = 0.0034, P = 0.0081, and P = 0.0363, respectively). The area under the curve (AUC) of the ROC curves validated the predictive accuracy of the immune signature (AUCs = 0.757, 0.800, and 0.701, respectively). We also revealed the good prognostic value of the immune cells, including activated memory CD4 T cells, T follicular helper cells and monocytes. Potential target drugs, including Olopatadine and Amlexanox, were identified for clinical therapies to improve patients' survival outcomes. CONCLUSION Our study indicated that the immune-related prognostic signature could serve as a novel biomarker for predicting patients' prognosis and providing new immunotherapy targets in ESCA.
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Ashrafizadeh M, Farhood B, Eleojo Musa A, Taeb S, Najafi M. Damage-associated molecular patterns in tumor radiotherapy. Int Immunopharmacol 2020; 86:106761. [PMID: 32629409 DOI: 10.1016/j.intimp.2020.106761] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 06/26/2020] [Accepted: 06/27/2020] [Indexed: 02/06/2023]
Abstract
Radiotherapy is one of the most common modalities for the treatment of cancer. One of the most promising effects of radiotherapy is immunologic cell death and the release of danger alarms, which are known as damage-associated molecular patterns (DAMPs). DAMPs are able to trigger cancer cells and other cells within tumor microenvironment (TME), either for suppression or promotion of tumor growth. Heat shock proteins (HSPs) including HSP70 and HSP90, high mobility group box 1 (HMGB1), and adenosine triphosphate (ATP) and its metabolites such as adenosine are the most common danger alarms that are released after radiotherapy-induced immunologic cell death. Some DAMPs including adenosine is able to interact with both cancer cells as well as other cells in TME to promote tumor growth and resistance to radiotherapy. However, others are able to trigger anti-tumor immunity or both tumor suppressive and immunosuppressive mechanisms depending on affected cells. In this review, we explain the mechanisms behind the release of radiation-induced DAMPs, and its consequences on cells within tumor. Targeting of these mechanisms may be in favor of tumor control in combination with radiotherapy and radioimmunotherapy.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Ahmed Eleojo Musa
- Department of Medical Physics, Tehran University of Medical Sciences (International Campus), Tehran, Iran
| | - Shahram Taeb
- Ionizing and Non-Ionizing Radiation Protection Research Center (INIRPRC), Shiraz University of Medical Sciences, Shiraz, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Li F, Guo H, Wang Y, Liu B, Zhou H. Profiles of tumor-infiltrating immune cells and prognostic genes associated with the microenvironment of bladder cancer. Int Immunopharmacol 2020; 85:106641. [PMID: 32470882 DOI: 10.1016/j.intimp.2020.106641] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 05/22/2020] [Accepted: 05/22/2020] [Indexed: 12/14/2022]
Abstract
The immune microenvironment in bladder cancer (BC) and its significance still remain poorly understood. The present work aims to investigate tumor-infiltrating immune cells (TIICs) and prognostic genes associated with the tumor microenvironment (TME) of BC. The immune and stromal scores of BC samples from The Cancer Genome Atlas database were downloaded from the ESTIMATE website. Based on these scores, BC samples were assigned to the high and low score groups and 429 intersecting differentially expressed genes were identified. Functional enrichment analysis further revealed that these genes dramatically participated in the immune-related biological processes and signaling pathways. Two TME-related genes, angiotensin II receptor type 2 (AGTR2) and sclerostin domain containing 1 (SOSTDC1), were identified to establish an immune-related risk model using Cox regression analyses. Intriguingly, patients with high-risk scores had poor outcomes (p < 0.001). The areas under the curve for the risk model in predicting 3- and 5-year survival rates were 0.692 and 0.707, respectively. Kaplan-Meier survival analysis showed that the expression of AGTR2 and SOSTDC1 significantly correlated with the overall survival of BC patients. Additionally, 22 TIICs in the BC microenvironment were analyzed with the CIBERSORT algorithm. This study indicated that the effective components of TME affected the clinical outcomes of BC patients and might provide a basis for the development of new immunotherapies for BC patients.
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Affiliation(s)
- Faping Li
- Department of Urology, the First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Hui Guo
- Department of Urology, the First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Yishu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, Jilin, China
| | - Bin Liu
- Department of Urology, the First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Honglan Zhou
- Department of Urology, the First Hospital of Jilin University, Changchun 130021, Jilin, China.
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PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells. Sci Rep 2019; 9:16787. [PMID: 31728028 PMCID: PMC6856095 DOI: 10.1038/s41598-019-53098-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 10/21/2019] [Indexed: 12/20/2022] Open
Abstract
Endothelial pro-inflammatory activation plays a pivotal role in atherosclerosis, and many pro-inflammatory and atherogenic signals converge upon mechanistic target of rapamycin (mTOR). Inhibitors of mTOR complex 1 (mTORC1) reduced atherosclerosis in preclinical studies, but side effects including insulin resistance and dyslipidemia limit their clinical use in this context. Therefore, we investigated PRAS40, a cell type-specific endogenous modulator of mTORC1, as alternative target. Indeed, we previously found PRAS40 gene therapy to improve metabolic profile; however, its function in endothelial cells and its role in atherosclerosis remain unknown. Here we show that PRAS40 negatively regulates endothelial mTORC1 and pro-inflammatory signaling. Knockdown of PRAS40 in endothelial cells promoted TNFα-induced mTORC1 signaling, proliferation, upregulation of inflammatory markers and monocyte recruitment. In contrast, PRAS40-overexpression blocked mTORC1 and all measures of pro-inflammatory signaling. These effects were mimicked by pharmacological mTORC1-inhibition with torin1. In an in vivo model of atherogenic remodeling, mice with induced endothelium-specific PRAS40 deficiency showed enhanced endothelial pro-inflammatory activation as well as increased neointimal hyperplasia and atherosclerotic lesion formation. These data indicate that PRAS40 suppresses atherosclerosis via inhibition of endothelial mTORC1-mediated pro-inflammatory signaling. In conjunction with its favourable effects on metabolic homeostasis, this renders PRAS40 a potential target for the treatment of atherosclerosis.
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Zhang Y, Yang Y, Li X, Chen D, Tang G, Men T. Thalidomide ameliorate graft chronic rejection in an allogenic kidney transplant model. Int Immunopharmacol 2019; 71:32-39. [PMID: 30877871 DOI: 10.1016/j.intimp.2018.12.035] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 12/13/2018] [Accepted: 12/14/2018] [Indexed: 01/23/2023]
Abstract
Chronic T cell mediated rejection (TCMR), which is characterized by infiltration of the interstitium by T cells and macrophages, still remains a major barrier to the long-term survival of kidney transplantation. Our recent report indicated that thalidomide can attenuate graft arteriosclerosis in an aortic transplant model. In this study, we investigated the effect of thalidomide on chronic TCMR in a rat model of kidney transplantation. Fischer or Lewis kidney allografts were transplanted into Lewis recipient rats. After kidney transplantation, recipient rats were divided into 3 groups: the isograft (Iso) group, allograft (Allo) group, and thalidomide (Tha) group. Rats were sacrificed at 8 weeks after kidney transplantation, and blood and kidney samples were collected. Serum concentrations of creatinine (SCr),interleukin (IL)-2, IL-6, IL-17, and TNF-α in recipients were determined, and flow cytometry was used to detect the percentages of CD4+CD25+, CD4+ Foxp3+and CD4+Th17+ cell subsets in the peripheral blood. Grafts were procured for histopathological examination, and the expressions of α-SMA, transforming growth-β1 (TGF-β1), and VEGF in kidney grafts were investigated using Western blot. Thalidomide treatment significantly ameliorated chronic rejection, reduced renal allograft tissue damage, and decreased serum creatinine levels. Attenuation of chronic TCMR was due to the prohibited production of inflammatory cytokines, altered distribution of the CD4+ CD25+ FoxP3+ regulatory T (Treg) and CD4+ Th17+ cells in the peripheral blood, and decreased expression of TGF-β1, α-SMA, and VEGF in the kidney graft. These results demonstrated that thalidomide could effectively ameliorate chronic TCMR in a rat kidney transplant model.
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Affiliation(s)
- Yan Zhang
- Department of Urology, Qianfoshan Hospital Affiliated to Shandong University, China; Transplantation Center, The First Affiliate Hospital of Wenzhou Medical University, China
| | - Yu Yang
- Department of Urology, Qianfoshan Hospital Affiliated to Shandong University, China; Department of Urology, The First Affiliate Hospital of Wenzhou Medical University, China
| | - Xianduo Li
- Department of Urology, Qianfoshan Hospital Affiliated to Shandong University, China
| | - Dongdong Chen
- Department of Urology, Qianfoshan Hospital Affiliated to Shandong University, China
| | - Guanbao Tang
- Department of Urology, Qianfoshan Hospital Affiliated to Shandong University, China
| | - Tongyi Men
- Department of Urology, Qianfoshan Hospital Affiliated to Shandong University, China.
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Liu Y, Yang F, Zou S, Qu L. Rapamycin: A Bacteria-Derived Immunosuppressant That Has Anti-atherosclerotic Effects and Its Clinical Application. Front Pharmacol 2019; 9:1520. [PMID: 30666207 PMCID: PMC6330346 DOI: 10.3389/fphar.2018.01520] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 12/11/2018] [Indexed: 12/20/2022] Open
Abstract
Atherosclerosis (AS) is the leading cause of stroke and death worldwide. Although many lipid-lowering or antiplatelet medicines have been used to prevent the devastating outcomes caused by AS, the serious side effects of these medicines cannot be ignored. Moreover, these medicines are aimed at preventing end-point events rather than addressing the formation and progression of the lesion. Rapamycin (sirolimus), a fermentation product derived from soil samples, has immunosuppressive and anti-proliferation effects. It is an inhibitor of mammalian targets of rapamycin, thereby stimulating autophagy pathways. Several lines of evidence have demonstrated that rapamycin possess multiple protective effects against AS through various molecular mechanisms. Moreover, it has been used successfully as an anti-proliferation agent to prevent in-stent restenosis or vascular graft stenosis in patients with coronary artery disease. A thorough understanding of the biomedical regulatory mechanism of rapamycin in AS might reveal pathways for retarding AS. This review summarizes the current knowledge of biomedical mechanisms by which rapamycin retards AS through action on various cells (endothelial cells, macrophages, vascular smooth muscle cells, and T-cells) in early and advanced AS and describes clinical and potential clinical applications of the agent.
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Affiliation(s)
- Yandong Liu
- Department of Vascular and Endovascular Surgery, Changzheng Hospital Affiliated to the Second Military Medical University, Shanghai, China
| | - Futang Yang
- Department of Vascular and Endovascular Surgery, Changzheng Hospital Affiliated to the Second Military Medical University, Shanghai, China
| | - Sili Zou
- Department of Vascular and Endovascular Surgery, Changzheng Hospital Affiliated to the Second Military Medical University, Shanghai, China
| | - Lefeng Qu
- Department of Vascular and Endovascular Surgery, Changzheng Hospital Affiliated to the Second Military Medical University, Shanghai, China
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Mladenović B, Mladenović N, Brzački V, Petrović N, Kamenov A, Golubović M, Ničković V, Stojanović NM, Sokolović DT. Exogenous putrescine affects polyamine and arginine metabolism in rat liver following bile ductus ligation. Can J Physiol Pharmacol 2018; 96:1232-1237. [DOI: 10.1139/cjpp-2018-0332] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Rat bile duct ligation (BDL) represents a useful method that mimics obstructive extrahepatic cholestasis, which is known to be a frequent disorder in humans. Polyamines (putrescine, spermidine, and spermine) are one of the key molecules regulating cell proliferation and differentiation. This work aimed to evaluate the potential beneficial properties of putrescine in rat BDL model by studying several biochemical parameters reflecting liver function and polyamine metabolism. Rats that were subjected to BDL were injected with putrescine (150 mg/kg) for 9 days, while in parallel another group with BDL remained untreated. Two control groups were included as well, sham-opened and putrescine-treated group. The following plasma parameters: ALT, AST, γ-GT, ALP, bilirubin, bile acids, as well as liver malondialdehyde and polyamine concentration and the activity of enzymes involved in polyamine metabolism were studied. After BDL, significant alterations in plasma biochemical parameters occurred, where a 9-day putrescine treatment significantly alleviated liver function deterioration. Putrescine also increased liver polyamines’ concentrations and polyamine and diamine oxidase activities in rats submitted to BDL. Our results demonstrated, for the first time, that putrescine plays an important role in preserving liver tissue function in rats with experimentally induced cholestasis.
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Affiliation(s)
- Bojan Mladenović
- Clinic for Gastroenterology, Clinical Center Niš, 18000 Niš, Serbia
- Department of Internal Medicine, Faculty of Medicine, University of Niš, Zorana Ðinđića 81, 18000 Niš, Serbia
| | - Nikola Mladenović
- Institute for Cardiovascular Diseases Sremska Kamenica, Put doktora Goldmana 4, 21208 Sremska Kamenica, Serbia
| | - Vesna Brzački
- Clinic for Gastroenterology, Clinical Center Niš, 18000 Niš, Serbia
- Department of Internal Medicine, Faculty of Medicine, University of Niš, Zorana Ðinđića 81, 18000 Niš, Serbia
| | - Nemanja Petrović
- Institute for Cardiovascular Diseases Sremska Kamenica, Put doktora Goldmana 4, 21208 Sremska Kamenica, Serbia
| | - Aleksandar Kamenov
- Clinic for Cardiovascular and Transplantation Surgery, Clinical Center Niš, 18000 Niš, Serbia
| | - Mladjan Golubović
- Clinic for Anesthesiology and Intensive Therapy, Department for Cardiosurgery, Clinical Center Nis, 18000 Niš, Serbia
| | | | | | - Dušan T. Sokolović
- Department of Biochemistry, Faculty of Medicine, University of Niš, Zorana Ðinđića 81, 18000 Niš, Serbia
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Comparative haemato-immunotoxic impacts of long-term exposure to tartrazine and chlorophyll in rats. Int Immunopharmacol 2018; 63:145-154. [DOI: 10.1016/j.intimp.2018.08.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 07/30/2018] [Accepted: 08/03/2018] [Indexed: 01/25/2023]
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Zhang X, Shao F, Zhu L, Ze Y, Zhu D, Bi Y. Cardiovascular and microvascular outcomes of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized controlled cardiovascular outcome trials with trial sequential analysis. BMC Pharmacol Toxicol 2018; 19:58. [PMID: 30223891 PMCID: PMC6142638 DOI: 10.1186/s40360-018-0246-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Efficacy trials showed that glucagon-like peptide-1 receptor (GLP1R) agonists reduced metabolic risk factors in addition to glucose lowering, but the cardiovascular and microvascular efficacy of this drug class remains to be determined. We aimed to evaluate the overall cardiovascular and microvascular efficacy of GLP1R agonists by performing a meta-analysis with trial sequential analysis. METHODS Randomized controlled, cardiovascular outcomes trials including at least 2000 patient-years' follow-up and 100 composite cardiovascular events were included. Trial sequential analysis (TSA) was performed and the quality of evidence was graded. RESULTS Thirty-three thousand four hundred fifty-seven patients and 4105 cardiovascular events from 4 large trials were included. GLP1R agonists were associated with a statistically significant reduction in risks for all-cause mortality (hazard ratio [HR]: 0.88, 95% CI: 0.81 to 0.95; number needed to treat [NNT]: 286 person-years), cardiovascular mortality (HR: 0.87, 95% CI: 0.79 to 0.96; NNT: 412 person-years), stroke (HR: 0.87, 95% CI: 0.76 to 0.98; NNT: 209 person-years) and the composite adverse cardiovascular outcome (MACE; HR: 0.91, 95% CI: 0.85 to 0.96; NNT: 241 person-years). The magnitude of benefit on MACE was attenuated in patients with a history of congestive heart failure (HR: 0.96, 95% CI: 0.85 to 1.08 with; HR: 0.87, 95% CI: 0.77 to 1.00 without). The risks for hospitalization for heart failure and myocardial infarction were not significantly different. The quality of the evidence was deemed as moderate to high based on GRADE approach. TSA provided firm evidence for a 10% reduction in all-cause mortality, a 15% reduction in MACE, and lack of a 15% reduction in hospitalization for heart failure, but evidence remains inconclusive for cardiovascular mortality and myocardial infarction. GLP1R agonists numerically reduced the rates for nephropathy but the risk for retinopathy was similar. CONCLUSIONS Meta-analysis with trial sequential analysis suggested that GLP1R agonists significantly reduced the risk for all-cause mortality and composite cardiovascular outcomes, but the reduction of cardiovascular mortality remains to be confirmed.
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Affiliation(s)
- Xiaowen Zhang
- Department of Endocrinology, Affiliated Drum Tower Hospital, Nanjing University School of Medicine, 321 Zhongshan Road, Nanjing, Jiangsu Province, 210008 China
| | - Fei Shao
- Department of Endocrinology, Affiliated Drum Tower Hospital, Nanjing University School of Medicine, 321 Zhongshan Road, Nanjing, Jiangsu Province, 210008 China
- Department of Endocrinology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, Jiangsu Province, 210008 China
| | - Lin Zhu
- Department of Endocrinology, Affiliated Drum Tower Hospital, Nanjing University School of Medicine, 321 Zhongshan Road, Nanjing, Jiangsu Province, 210008 China
| | - Yuyang Ze
- Department of Endocrinology, Affiliated Drum Tower Hospital, Nanjing University School of Medicine, 321 Zhongshan Road, Nanjing, Jiangsu Province, 210008 China
| | - Dalong Zhu
- Department of Endocrinology, Affiliated Drum Tower Hospital, Nanjing University School of Medicine, 321 Zhongshan Road, Nanjing, Jiangsu Province, 210008 China
| | - Yan Bi
- Department of Endocrinology, Affiliated Drum Tower Hospital, Nanjing University School of Medicine, 321 Zhongshan Road, Nanjing, Jiangsu Province, 210008 China
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Lv C, Wang L, Zhu X, Lin W, Chen X, Huang Z, Huang L, Yang S. Glucosamine promotes osteoblast proliferation by modulating autophagy via the mammalian target of rapamycin pathway. Biomed Pharmacother 2018; 99:271-277. [PMID: 29334671 DOI: 10.1016/j.biopha.2018.01.066] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 01/10/2018] [Accepted: 01/11/2018] [Indexed: 12/16/2022] Open
Abstract
Glucosamine is effective in the treatment of osteoarthritis; however, its effect on osteoporosis remains unclear. Decreased activity of osteoblasts is the main cause of osteoporosis. Here, we examined the effects of glucosamine on osteoblasts. The potential underlying mechanisms were explored. The results showed that glucosamine had a biphasic effect on the viability of hFOB1.19 osteoblasts. At low concentrations (<0.6 mM), glucosamine induced hFOB1.19 cell proliferation, whereas at high concentrations (>0.8 mM) it induced apoptosis. The autophagy inhibitor 3-methyladenine (3-MA) was used to verify that glucosamine modulated hFOB1.19 cell viability via autophagy. The induction of apoptosis by high concentrations of glucosamine was significantly exacerbated by 3-MA, whereas the promotion of cell proliferation by low concentrations of glucosamine was significantly suppressed by 3-MA. Autophagy was examined by western blot detection of autophagy-related proteins including LC3, Beclin-1, and SQSTM1/p62 and by immunofluorescence analysis of autophagosomes. Glucosamine activated autophagy in a time- and concentration-dependent manner. Investigation of the underlying mechanism showed that glucosamine inhibited the phosphorylation of m-TOR in a concentration-dependent manner within 48 h, and rapamycin significantly inhibited the phosphorylation of m-TOR. These results demonstrated that glucosamine promoted hFOB1.19 cell proliferation and increased autophagy by inhibiting the m-TOR pathway, suggesting its potential as a therapeutic agent for osteoporosis.
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Affiliation(s)
- Chen Lv
- Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Lu Wang
- Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Xiongbai Zhu
- Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Wenjun Lin
- Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Xin Chen
- Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Zhengxiang Huang
- Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Lintuo Huang
- Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Shengwu Yang
- Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
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Cai L, Chen WN, Li R, Liu MM, Lei C, Li CM, Qiu YY. Acetazolamide protects rat articular chondrocytes from IL-1β-induced apoptosis by inhibiting the activation of NF-κB signal pathway. Can J Physiol Pharmacol 2018; 96:1104-1111. [PMID: 30067070 DOI: 10.1139/cjpp-2018-0334] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Because the excessive apoptosis of articular chondrocytes contributes to extracellular matrix (ECM) loss and cartilage damage in rheumatoid arthritis (RA), inhibiting chondrocyte apoptosis might be a promising strategy for RA. Aquaporin1 (AQP1) is overexpressed in RA cartilage and synovial tissues, and play a vital pathogenic role in RA development. Particularly, we previously reported that acetazolamide (AZ) as an AQP1 inhibitor suppressed secondary inflammation and promoted ECM production in cartilage of adjuvant-induced arthritis rats. Here, we investigated the antiapoptotic effect of AZ on interleukin-1β (IL-1β)-induced apoptosis, a classic in vitro model of chondrocyte apoptosis. AZ treatment could inhibit IL-1β-induced apoptosis, evidenced by increasing cell viability, relieving apoptotic nuclear morphology, decreasing apoptosis rates, and restoring mitochondrial membrane potential. Additionally, AZ reversed IL-1β-induced decrease of Bcl-2 protein and reduced IL-1β-induced increases of Bax and caspase 3 protein, accompanied by inhibiting IκBα degradation and phosphorylation in cytoplasm, reducing NF-κB p65 protein level in nucleus and preventing NF-κB p65 translocation from cytoplasm to nucleus. In conclusion, our findings indicated that AZ could effectively attenuate IL-1β-induced chondrocyte apoptosis mediated by regulating the protein levels of apoptosis-related genes and inhibiting the activation of NF-κB signal pathway, suggesting that AZ might be of potential clinical interest in RA treatment.
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Affiliation(s)
- Li Cai
- a Department of Pathology, School of Basic Medicine, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China
| | - Wei-Na Chen
- b School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China
| | - Rong Li
- b School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China.,c School of Pharmacy, Macau University of Science and Technology, Avenida Wai Long Road, Macau, China
| | - Ming-Ming Liu
- b School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China
| | - Chao Lei
- b School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China
| | - Chun-Mei Li
- b School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui Province, China
| | - Yuan-Ye Qiu
- c School of Pharmacy, Macau University of Science and Technology, Avenida Wai Long Road, Macau, China
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Omolekulo TE, Areola ED, Badmus OO, Michael OS, Kim I, Olatunji LA. Inhibition of adenosine deaminase and xanthine oxidase by valproic acid abates hepatic triglyceride accumulation independent of corticosteroids in female rats treated with estrogen-progestin. Can J Physiol Pharmacol 2018; 96:1092-1103. [PMID: 30001502 DOI: 10.1139/cjpp-2018-0231] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Elevated circulating uric acid has been postulated to play an important pathophysiological role in estrogen-progestin combined oral contraceptive (COC)-induced hypertension and endothelial dysfunction. We hypothesized that disruption of glucoregulation and liver triglyceride (TG) accumulation induced by COC use would be abated by valproic acid (VPA) treatment through suppression of adenosine deaminase (ADA) and xanthine oxidase (XO) activities. Female Wistar rats aged 9-10 weeks were treated with a combination of estrogen-progestin COC steroids (1.0 μg ethinylestradiol and 5.0 μg levonorgestrel; p.o.) with or without VPA (100.0 mg/kg; p.o.) daily for 6 weeks. The result shows that the disrupted glucoregulation and associated elevated hepatic ADA activity, plasma and hepatic XO activity, uric acid (UA), TG/HDL-cholesterol, total cholesterol, and malondialdehyde induced by COC treatment were attenuated by VPA treatment. However, VPA did not have any effect on plasma aldosterone, corticosterone, ADA, circulating and hepatic free fatty acid. Our results demonstrate that suppression of plasma and hepatic XO activities, along with hepatic ADA activity and UA by VPA treatment, protects against disrupted glucoregulation and increased liver TG by COC independent of elevated corticosteroids. The findings imply that VPA would provide protection against the development of cardiometabolic disorder via inhibition of the ADA/XO/UA-mediated pathway.
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Affiliation(s)
- Tolulope Eniola Omolekulo
- a HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Emmanuel Damilare Areola
- a HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Olufunto Olayinka Badmus
- a HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.,b Department of Public Health, Kwara State University, Malete, Nigeria
| | - Olugbenga Samuel Michael
- a HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.,c Cardiometabolic Research Unit, Department of Physiology, College of Health Sciences, Bowen University, Iwo, Nigeria
| | - Inkyeom Kim
- d Cardiovascular Research Institute and Department of Pharmacology, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Lawrence Aderemi Olatunji
- a HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
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Li X, Wang J, Song X, Wu H, Guo P, Jin Z, Wang C, Tang C, Wang Y, Zhang Z. Ketamine ameliorates ischemia-reperfusion injury after liver autotransplantation by suppressing activation of Kupffer cells in rats. Can J Physiol Pharmacol 2018; 96:886-892. [PMID: 29975111 DOI: 10.1139/cjpp-2018-0046] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
This study aimed to investigate the protective effects of ketamine against hepatic ischemia-reperfusion (I/R) injury by suppressing activation of Kupffer cells (KCs) in rat liver autotransplantation. Male Sprague-Dawley rats were randomized into 3 groups (n = 10 each). Group I, the sham group, received saline. Group II received saline and underwent orthotopic liver autotransplantation (OLAT). Group III received 10 mg/kg ketamine and underwent OLAT. Blood samples were obtained at 3, 6, 12, and 24 h after I/R, and following ALT, AST, LDH, IL-6, TNF-α, IL-1β, and IL-10 in serum were detected. Model rats were sacrificed at the indicated time points and the graft liver tissues were evaluated histologically. KCs were isolated from rat liver tissues, and inflammatory products and proteins of NF-κB signaling pathway were detected using quantitative RT-PCR and Western blotting. Our results showed that ketamine significantly decreased ALT, AST, LDH, IL-6, TNF-α, and IL-1β levels and increased IL-10 level. Furthermore, ketamine alleviated the histopathology changes, by less KC infiltration and lower hepatocyte apoptosis. Moreover, activity of NF-κB signaling pathway in KCs was suppressed. In addition, production of pro- and anti-inflammatory factors is consistent with the results in tissues. Ketamine ameliorated I/R injury after liver transplantation by suppressing activation of KCs in rats.
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Affiliation(s)
- Xinyi Li
- a Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Jin Wang
- a Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Xuemin Song
- a Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Huisheng Wu
- a Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Peipei Guo
- a Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Zhao Jin
- a Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Chengyao Wang
- a Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Chaoliang Tang
- b Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China; Department of Anesthesiology, The First Affiliated Hospital of USTC; Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Yanlin Wang
- a Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Zongze Zhang
- a Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
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