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Wally ME, Aly MH. Gastroprotective Effect of Linagliptin on Indomethacin-Induced Gastric Ulceration in Mice: Crosstalk Between Oxidative Stress and Inflammasome Pathways. ACS Pharmacol Transl Sci 2025; 8:808-818. [PMID: 40109745 PMCID: PMC11915470 DOI: 10.1021/acsptsci.4c00695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 02/20/2025] [Accepted: 02/25/2025] [Indexed: 03/22/2025]
Abstract
The clinical efficacy of indomethacin, a nonsteroidal anti-inflammatory drug, is hindered by its high ulcerogenic potential. Linagliptin, a dipeptidyl peptidase-4 inhibitor, has demonstrated anti-inflammatory properties through NLRP3 inflammasome modulation; however, its possible antiulcerogenic effect remains unclear. This study aimed to examine the potential prophylactic effect of linagliptin against indomethacin-induced gastric ulcers with a focus on NLRP3 inflammasome signaling. Gastric ulcers were induced using indomethacin and compared to pretreatment with linagliptin or the standard prophylactic omeprazole. Gastric injury was confirmed by gross morphology, ulcer scoring, and histopathological assessments. Additionally, redox status markers glutathione reductase (GSH), malondialdehyde (MDA), and Nrf2/Keap-1/HO-1 were evaluated in the gastric tissue. Immunohistochemical analysis of pNF-κB, NLRP3, and Caspase-1 inflammasome parameters was also conducted. Finally, measurement of gastric levels of Gasdermin-D was performed, as well as immunohistochemical and gene expression of IL-1β. Pretreatment with linagliptin suppressed all features of mucosal damage as well as inflammatory cell infiltration. The antioxidant effect of linagliptin was evident in low MDA, high GSH gastric levels, and high immunohistochemical reactivity of gastric tissues against Nrf2 and HO-1 antibodies, as well as low gastric levels of keap1. The overly active inflammasome pathway observed in indomethacin-induced ulcerated samples was reinstated by linagliptin, as seen in the suppression of pNF-κB, NLRP3, Caspase-1, and IL-1β immunohistochemical reactivity as well as Gasdermin-D levels. Our study showed that NLRP3 inflammasome contributes to the pathogenesis of indomethacin-mediated gastric injury and that linagliptin exhibits a protective effect against indomethacin-induced gastric ulcers, possibly through activation of the Nrf2/HO-1 antioxidant pathway and inhibition of the NLRP3 inflammasome axis.
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Affiliation(s)
- Maha E Wally
- Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt
- Health Research Center of Excellence; Drug Research and Development Group, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt
| | - Mohamed H Aly
- Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt
- Health Research Center of Excellence; Drug Research and Development Group, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt
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Li F, Zhao P, Zhao L, Bai L, Su Q, Feng Y, Ma W, Zhu J, Yang J, Zhang S. Colchicine Alleviates Interstitial Lung Disease in an Experimental Autoimmune Myositis Murine Model by Inhibiting the Formation of Neutrophil Extracellular Traps. Inflammation 2024:10.1007/s10753-024-02220-1. [PMID: 39688740 DOI: 10.1007/s10753-024-02220-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 12/08/2024] [Accepted: 12/11/2024] [Indexed: 12/18/2024]
Abstract
Our previous study has shown that neutrophil extracellular traps (NETs) were associated with idiopathic inflammatory myopathy-related interstitial lung disease (IIM-ILD). Colchicine plays an anti-inflammatory role mainly by inhibiting the activity and chemotaxis of neutrophils. This study aims to verify therapeutic effects and mechanism of colchicine in IIM-ILD. 20 experimental autoimmune myositis (EAM) model mice were randomly divided into EAM group, colchicine groups (1, 2 mg/kg) and Cl-amidine group (positive control), five mice in the control group received sham modeling procedure. After 5 weeks, the mice were sacrificed to evaluate the degree of pulmonary interstitial lesions and the formation of NETs. Human neutrophils were pretreated with colchicine (40 nmol/L) and stimulated to form NETs. Human pulmonary microvascular endothelial cells (HPMECs) were pretreated with colchicine and stimulated with NETs, and markers of inflammation and pyroptosis were detected. Pathological staining of lung tissue showed that severity of ILD and NETs infiltration were significantly alleviated in colchicine groups (P < 0.01) and in the Cl-amidine group (P < 0.01), and the serum level of NETs was also significantly decreased in colchicine groups (P < 0.05) and in the Cl-amidine group (P < 0.05). Colchicine intervention significantly attenuated PMA-induced NETs formation in vitro (P < 0.0001). Colchicine intervention significantly reduced marker expressions of inflammasome and pyroptosis in HPMECs stimulated by NETs and in the lung tissue of EAM mice. Colchicine can alleviate ILD in EAM mice by inhibiting NETs formation, inflammasome activation and endothelial cell pyroptosis. These findings provide a basis for targeting NETs and colchicine administration in the treatment of myositis-associated ILD.
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Affiliation(s)
- Feifei Li
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Peipei Zhao
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Liangtao Zhao
- Cuiying Biomedical Research Center, the Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Ling Bai
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Qiyan Su
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Yingyue Feng
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Wenlan Ma
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Jiarui Zhu
- Cuiying Biomedical Research Center, the Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Jumei Yang
- Cuiying Biomedical Research Center, the Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Sigong Zhang
- Department of Rheumatology and Immunology, the Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China.
- The Gansu Clinical Medical Research Center for Rheumatic and Immunological Diseases, Lanzhou, 730030, Gansu, China.
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Li Y, Qiang R, Cao Z, Wu Q, Wang J, Lyu W. NLRP3 Inflammasomes: Dual Function in Infectious Diseases. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:407-417. [PMID: 39102612 PMCID: PMC11299487 DOI: 10.4049/jimmunol.2300745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 06/11/2024] [Indexed: 08/07/2024]
Abstract
The Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome has been the most distinctive polymer protein complex. After recognizing the endogenous and exogenous danger signals, NLRP3 can cause inflammation by pyroptosis and secretion of mature, bioactive forms of IL-1β and IL-18. The NLRP3 inflammasome is essential in the genesis and progression of infectious illnesses. Herein, we provide a comprehensive review of the NLRP3 inflammasome in infectious diseases, focusing on its two-sided effects. As an essential part of host defense with a protective impact, abnormal NLRP3 inflammasome activation, however, result in a systemic high inflammatory response, leading to subsequent damage. In addition, scientific evidence of small molecules, biologics, and phytochemicals acting on the NLRP3 inflammasome has been reviewed. We believe that the NLRP3 inflammasome helps us understand the pathological mechanism of different stages of infectious diseases and that inhibitors targeting the NLRP3 inflammasome will become a new and valuable research direction for the treatment of infectious diseases.
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Affiliation(s)
- Yanbo Li
- Department of Infectious Diseases, Guang’anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing
| | - Rui Qiang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine Shunyi Hospital, Beijing, China
| | - Zhengmin Cao
- Department of Infectious Diseases, Guang’anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing
| | - Qingjuan Wu
- Department of Infectious Diseases, Guang’anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing
| | - Jiuchong Wang
- Department of Infectious Diseases, Guang’anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing
| | - Wenliang Lyu
- Department of Infectious Diseases, Guang’anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing
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Guan J, Abudouaini H, Lin K, Yang K. Emerging insights into the role of IL-1 inhibitors and colchicine for inflammation control in type 2 diabetes. Diabetol Metab Syndr 2024; 16:140. [PMID: 38918878 PMCID: PMC11197348 DOI: 10.1186/s13098-024-01369-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/30/2024] [Indexed: 06/27/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM), a prevalent chronic metabolic disorder, is closely linked to persistent low-grade inflammation, significantly contributing to its development and progression. This review provides a comprehensive examination of the inflammatory mechanisms underlying T2DM, focusing on the role of the NLRP3 inflammasome and interleukin-1β (IL-1β) in mediating inflammatory responses. We discuss the therapeutic potential of IL-1 inhibitors and colchicine, highlighting their mechanisms in inhibiting the NLRP3 inflammasome and reducing IL-1β production. Recent studies indicate that these agents could effectively mitigate inflammation, offering promising avenues for the prevention and management of T2DM. By exploring the intricate connections between metabolic disturbances and chronic inflammation, this review underscores the need for novel anti-inflammatory strategies to address T2DM and its complications.
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Affiliation(s)
- Jianbin Guan
- Honghui-Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Haimiti Abudouaini
- Honghui-Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Kaiyuan Lin
- Honghui-Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.
| | - Kaitan Yang
- Honghui-Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.
- Truma Rehabilitation Department, Honghui-Hospital，Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.
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Vecchié A, Bonaventura A, Golino M, Thomas G, Abbate A. Novel Therapeutic Insights Into the Treatment of Pericarditis: Targeting the Innate Immune System. J Cardiovasc Pharmacol 2024; 83:377-383. [PMID: 38422218 DOI: 10.1097/fjc.0000000000001553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 02/12/2024] [Indexed: 03/02/2024]
Abstract
ABSTRACT Acute pericarditis is characterized by pericardial inflammation that can be treated with anti-inflammatory drugs. A considerable percentage of patients develops recurrent pericarditis with several relapses. In developed countries, the idiopathic form is the most frequent and has a high risk of recurrences. Two pathophysiological mechanisms have been described for idiopathic recurrent pericarditis: autoimmune and autoinflammatory. The autoimmune mechanism is more frequently encountered in patients with rheumatologic disorders, especially systemic lupus erythematosus. The innate immune system plays a central role in the pathophysiology of pericarditis, especially in the autoinflammatory phenotype. Current evidence highlights the central role played by interleukin 1 and NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) in idiopathic recurrent pericarditis. Accordingly, interleukin 1 blockers have been approved for the treatment of this condition. Neutrophils are likely to be important in such setting; however, their role has only been partially investigated. In the present review, we have collected the current knowledge on the role of innate immune system in pericarditis pathophysiology and how this can be used to provide targeted treatments for patients with recurrent pericarditis.
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Affiliation(s)
| | - Aldo Bonaventura
- Department of Internal Medicine, ASST Sette Laghi, Varese, Italy
| | - Michele Golino
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA
- Department of Medicine and Surgery, University of Insubria, Varese, Italy; and
| | - Georgia Thomas
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA
| | - Antonio Abbate
- Robert M. Berne Cardiovascular Research Center and Division of Cardiology, Department of Internal Medicine, Heart and Vascular Center, University of Virginia, Charlottesville, VA
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Yeh JJ, Liw PX, Wong YS, Kao HM, Lee CH, Lin CL, Kao CH. The effect of colchicine on cancer risk in patients with immune-mediated inflammatory diseases: a time-dependent study based on the Taiwan's National Health Insurance Research Database. Eur J Med Res 2024; 29:245. [PMID: 38649928 PMCID: PMC11034118 DOI: 10.1186/s40001-024-01836-1] [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: 12/22/2023] [Accepted: 04/10/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND To determine the effect of colchicine on cancer risk in patients with the immune-mediated inflammatory diseases (IMIDs)-related to colchicine use. METHODS This is a time-dependent propensity-matched general population study based on the National Health Insurance Research Database (NHIRD) of Taiwan. We identified the IMIDs patients (n = 111,644) newly diagnosed between 2000 and 2012 based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)-274,712, 135, 136.1, 279.49, 518.3, 287.0, 696.0, 696.1, 696.8, 420, 429.4, 710.0, 710.1, 710.3, 710.4, 714.0, 720, 55.0, 55.1, 55.9, 556. INCLUSION CRITERIA aged ≧ 20 years, if a patient had at least these disease diagnosis requirements within 1 year of follow-up, and, these patients had at least two outpatient visits or an inpatient visit. After propensity-matched according to age, sex, comorbidities, medications and index date, the IMIDs patients enter into colchicine users (N = 16,026) and colchicine nonusers (N = 16,026). Furthermore, time-dependent Cox models were used to analyze cancer risk in propensity-matched colchicine users compared with the nonusers. The cumulative cancer incidence was analyzed using Cox proportional regression analysis. We calculated adjusted hazard ratios (aHRs) and their 95% confidence intervals (95% CIs) for cancer after adjusting for sex, age, comorbidities, and use of medicine including acetylcysteine, medication for smoking cessation such as nicotine replacement medicines (the nicotine patch) and pill medicines (varenicline), anti-inflammatory drugs and immunosuppressant drugs. RESULTS Comparing the colchicine nonusers, all cancer risk were mildly attenuated, the (aHR (95% CI)) of all cancer is (0.84 (0.55, 0.99)). Meanwhile, the colchicine users were associated with the lower incidence of the colorectal cancer, the (aHRs (95% CI)) is (0.22 (0.19, 0.89)). Those aged < 65 years and male/female having the colchicine users were associated with lower risk the colorectal cancer also. Moreover, the colchicine > 20 days use with the lower aHR for colorectal cancer. CONCLUSION Colchicine was associated with the lower aHR of the all cancer and colorectal cancer formation in patients with the IMIDs.
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Affiliation(s)
- Jun-Jun Yeh
- Department of Family Medicine, Chest Medicine, Geriatric Medicine and Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
| | - Pei-Xuan Liw
- Department of Family Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Yi-Sin Wong
- Department of Family Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Husan-Min Kao
- Department of Geriatric Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Chia-Hsun Lee
- Department of Medical Education, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Cheng-Li Lin
- College of Medicine, China Medical University, Taichung, Taiwan
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Hung Kao
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung, 404, Taiwan.
- Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan.
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan.
- Artificial Intelligence Center, China Medical University Hospital, Taichung, Taiwan.
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Zhou X, Qin M, He L, Zhang Y, Liu A, Chen D, Pan H. Geraniin restricts inflammasome activation and macrophage pyroptosis by preventing the interaction between ASC and NLRP3 to exert anti-inflammatory effects. Int Immunopharmacol 2024; 129:111656. [PMID: 38340422 DOI: 10.1016/j.intimp.2024.111656] [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: 11/02/2023] [Revised: 01/24/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024]
Abstract
Geraniin, a chemical component of the traditional Chinese medicine geranii herba, possesses anti-inflammatory and anti-oxidative activities. However, its anti-inflammatory role in managing NLRP3 inflammasome and pyroptosis remains to be elucidated. To investigate the anti-inflammation mechanism of geraniin, LPS-primed macrophages were incubated with classical activators of NLRP3 inflammasome (such as ATP, Nigericin, or MSU crystals), and MSU crystals were injected into the ankle joints of mice to establish an acute gouty arthritis model. The propidium iodide (PI) staining results showed that geraniin could restrain cell death in the ATP- or nigericin-stimulated bone marrow-derived macrophages (BMDMs). Geraniin decreased the release of lactate dehydrogenase (LDH) and interleukin (IL)-1β from cytoplasm to cell supernatant. Geraniin also inhibited the expression of caspase-1 p20, IL-1β in cell supernatant and N-terminal of gasdermin D (GSDMD-NT) while blocking the oligomerization of ASC to form speck. The inhibitory effects of geraniin on caspase-1 p20, IL-1β, GSDMD-NT, and ASC speck were not observed in NLRP3 knockout (NLRP3-/-) BMDMs. Hence, the resistance of geraniin to inflammasome and pyroptosis was contingent upon NLRP3 presence. Geraniin reduced reactive oxygen species (ROS) production and maintained mitochondrial membrane potential while preventing interaction between ASC and NLRP3 protein. Additionally, geraniin diminished MSU crystal-induced mouse ankle joint swelling and IL-1β expression. Geraniin blocked the recruitment of neutrophils and macrophages to the synovium of joints. Our results demonstrate that geraniin prevents the assembly of ASC and NLRP3 through its antioxidant effect, thereby inhibiting inflammasome activation, pyroptosis, and IL-1β release to provide potential insights for gouty arthritis targeted therapy.
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Affiliation(s)
- Xiaoyi Zhou
- Department of Human Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; Research Centre for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Minyan Qin
- Department of Human Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; Research Centre for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Leran He
- Department of Human Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; Research Centre for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Ying Zhang
- Research Centre for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Aijun Liu
- Research Centre for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Dongfeng Chen
- Department of Human Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; Research Centre for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Hao Pan
- Department of Human Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; Research Centre for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China.
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Zhan Y, Yue H, Zhao X, Tang J, Wu Z. Colchicine in atrial fibrillation: are old trees in bloom? Front Physiol 2023; 14:1260774. [PMID: 37916222 PMCID: PMC10616799 DOI: 10.3389/fphys.2023.1260774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 09/26/2023] [Indexed: 11/03/2023] Open
Abstract
Colchicine is a widely used drug that was originally used to treat gout and rheumatic diseases. In recent years, colchicine has shown high potential in the cardiovascular field. Atrial fibrillation (AF) is a cardiovascular disease with a high incidence. One of the most frequent complications following cardiovascular surgery is postoperative atrial fibrillation (POAF), which affects patient health and disease burden. This article reviews the research status of colchicine in AF and summarizes the relevant progress.
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Affiliation(s)
- Yujia Zhan
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Honghua Yue
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Xueshan Zhao
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Juan Tang
- Acupuncture and Moxibustion School of Teaching, Hospital of Chengdu, University of Traditional Chinese Medicine, Tianjin, China
- Key Laboratory of Emergency and Trauma, Ministry of Education, Hainan Medical University, Haikou, China
| | - Zhong Wu
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
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Zhang Q, Liu W, Li Q, Zeng Y, Wu M, Wu T, Guo S, Wang L, Zhao D, Yi D, Hou Y. Protective effects and mechanisms of N-acetylcysteine on indomethacin-induced intestinal injury in a porcine model. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 262:115173. [PMID: 37356397 DOI: 10.1016/j.ecoenv.2023.115173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 06/09/2023] [Accepted: 06/19/2023] [Indexed: 06/27/2023]
Abstract
This study aimed to investigate the effect of N-acetylcysteine (NAC) on indomethacin (IDMT)-induced intestinal injury in a piglet model and explore the underlying molecular mechanisms. Piglets were randomly divided into 3 treatment groups: (1) control group; (2) IDMT group; (3) NAC+IDMT group. The results showed that NAC administration significantly increased the average daily gain of piglets, attenuated the intestine hyperemia, and restored normal jejunal morphology. Further studies indicated that NAC administration significantly increased plasma citrulline concentration and jejunal villin expression, but decreased the content of proinflammatory cytokines in plasma and jejunum of IDMT-stimulated piglets. NAC administration selectively decreased the proportion of eosinophils but not neutrophils in plasma. Furthermore, NAC administration significantly increased the activities of superoxide dismutase and catalase in plasma but decreased the concentrations of hydrogen peroxide (plasma) and malondialdehyde (plasma and jejunum), as well as the activity of myeloperoxidase (jejunum) when comparing NAC+IDMT group with IDMT group. Gene Ontology analysis showed that the significantly enriched molecular function term was "ubiquitin-like protein ligase binding" for NAC+IDMT versus IDMT differentially regulated genes. In the biological process category, differentially regulated genes of NAC+IDMT versus IDMT were mainly enriched in immune-related terms. The major enrichments for differentially regulated proteins (DRPs) of NAC+IDMT versus IDMT were terms involved in lipid metabolism and immune response. KEGG pathway enrichment analysis showed that "arginine biosynthesis" was a significant enrichment term for the DRPs of NAC+IDMT versus IDMT. Further studies demonstrated that NAC administration up-regulated argininosuccinate synthase 1 mRNA expression and down-regulated arginase mRNA expression in the jejunum of IDMT-stimulated piglets. Moreover, the content of nitric oxide was restored to a normal level with the reduction of nitric oxide synthase activity. NAC administration ameliorated intestinal injury in IDMT-challenged piglets by enhancing antioxidant and anti-inflammatory functions and modulating arginine metabolism in the small intestine.
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Affiliation(s)
- Qian Zhang
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Wenkai Liu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China; Huanggang Academy of Agricultural Sciences, Huanggang 438000, China
| | - Qian Li
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Yitong Zeng
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Mengjun Wu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Tao Wu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Shuangshuang Guo
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Lei Wang
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Di Zhao
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Dan Yi
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
| | - Yongqing Hou
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
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Jones D, Spirito A, Sartori S, Smith KF, Pivato CA, Chiarito M, Cao D, Nicolas J, Beerkens F, Edens M, Pileggi B, Sen A, Zhang Z, Vogel B, Sweeny J, Baber U, Dangas G, Sharma SK, Kini A, Mehran R. PROGNOSTIC VALUE OF HIGH-SENSITIVITY C-REATIVE PROTEIN AMONG CHRONIC KIDNEY DISEASE PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION. J Cardiol 2023:S0914-5087(23)00108-9. [PMID: 37187289 DOI: 10.1016/j.jjcc.2023.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 05/03/2023] [Accepted: 05/09/2023] [Indexed: 05/17/2023]
Abstract
BACKGROUND Data on the prognostic value of high-sensitivity C-reactive protein (hs-CRP) levels in patients with chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI) are limited. METHODS Patients undergoing PCI at a tertiary center from January 2012 to December 2019 were included. CKD was defined as a glomerular filtration rate (GFR) <60 mL/min/1.73m2 and elevated hs-CRP was defined as >3 mg/L. Acute myocardial infarction (MI), acute heart failure, neoplastic disease, patients undergoing hemodialysis, or hs-CRP >10 mg/L were exclusion criteria. The primary outcome was major adverse cardiac events (MACE), a composite of all-cause death, MI, and target vessel revascularization at 1-year after PCI. RESULTS Out of 12,410 patients, 3,029 (24.4%) had CKD. Elevated hs-CRP levels were found in 31.8% of CKD and 25.8% of non-CKD patients. At 1 year, MACE occurred in 87 (11.0%) CKD patients with elevated hs-CRP and 163 (9.5%) with low hs-CRP (adj. HR 1.26, 95% CI 0.94-1.68); among non-CKD patients, in 200 (10%) and 470 (8.1%), respectively (adj. HR 1.21, 95% CI 1.00-1.45). Hs-CRP was associated with an increased risk of all-cause death in both CKD (Adj. HR 1.92, 95% CI 1.07-3.44) and no-CKD patients (adj. HR 3.02, 95% CI 1.74-5.22). There was no interaction between hs-CRP and CKD. CONCLUSIONS Among patients undergoing PCI without acute MI, elevated hs-CRP values were not associated with a higher risk of MACE at 1 year, but with increased mortality hazards irrespective of the CKD status. The prognostic value of hs-CRP was consistent in patients with or without CKD.
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Affiliation(s)
- Davis Jones
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alessandro Spirito
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Samantha Sartori
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kenneth F Smith
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Carlo Andrea Pivato
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Milan, Italy
| | - Mauro Chiarito
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Humanitas Research Hospital IRCCS, Rozzano-, Milan, Milan, Italy
| | - Davide Cao
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Johny Nicolas
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Frans Beerkens
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Madison Edens
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Brunna Pileggi
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Cardiopneumonology, Heart Institute of the University of Sao Paulo, Sao Paulo, Brazil
| | - Ananya Sen
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Zhongjie Zhang
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Birgit Vogel
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joseph Sweeny
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Usman Baber
- Department of Cardiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - George Dangas
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Samin K Sharma
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Annapoorna Kini
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Roxana Mehran
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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11
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Lin XL, Shi YN, Cao YL, Tan X, Zeng YL, Luo ST, Li YM, Qin L, Xia BH, Fu RG, Lin LM, Li K, Cao D, Zeng JG, Liao DF. Sanguinarine protects against indomethacin-induced small intestine injury in rats by regulating the Nrf2/NF-κB pathways. Front Pharmacol 2022; 13:960140. [PMID: 36304153 PMCID: PMC9593053 DOI: 10.3389/fphar.2022.960140] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 09/27/2022] [Indexed: 12/04/2022] Open
Abstract
In recent years, small intestine as a key target in the treatment of Inflammatory bowel disease caused by NSAIDs has become a hot topic. Sanguinarine (SA) is one of the main alkaloids in the Macleaya cordata extracts with strong pharmacological activity of anti-tumor, anti-inflammation and anti-oxidant. SA is reported to inhibit acetic acid-induced colitis, but it is unknown whether SA can relieve NSAIDs-induced small intestinal inflammation. Herein, we report that SA effectively reversed the inflammatory lesions induced by indomethacin (Indo) in rat small intestine and IEC-6 cells in culture. Our results showed that SA significantly relieved the symptoms and reversed the inflammatory lesions of Indo as shown in alleviation of inflammation and improvement of colon macroscopic damage index (CMDI) and tissue damage index (TDI) scores. SA decreased the levels of TNF-α, IL-6, IL-1β, MDA and LDH in small intestinal tissues and IEC-6 cells, but increased SOD activity and ZO-1 expression. Mechanistically, SA dose-dependently promoted the expression of Nrf2 and HO-1 by decreasing Keap-1 level, but inhibited p65 phosphorylation and nuclear translocation in Indo-treated rat small intestine and IEC-6 cells. Furthermore, in SA treated cells, the colocalization between p-p65 and CBP in the nucleus was decreased, while the colocalization between Nrf2 and CBP was increased, leading to the movement of gene expression in the nucleus to the direction of anti-inflammation and anti-oxidation. Nrf2 silencing blocked the effects of SA. Together our results suggest that SA can significantly prevent intestinal inflammatory lesions induced by Indo in rats and IEC-6 cells through regulation of the Nrf2 pathway and NF-κBp65 pathway.
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Affiliation(s)
- Xiu-lian Lin
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Ya-ning Shi
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Yu-ling Cao
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Xi Tan
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Ya-ling Zeng
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Shi-teng Luo
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Ya-mei Li
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Li Qin
- Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Bo-hou Xia
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Rong-geng Fu
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Li-mei Lin
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Kai Li
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Deliang Cao
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China
- *Correspondence: Deliang Cao, ; Jian-guo Zeng, ; Duan-fang Liao,
| | - Jian-guo Zeng
- Hunan Key Laboratory of Traditional Chinese Veterinary Medicine, Hunan Agricultural University, Changsha, Hunan, China
- *Correspondence: Deliang Cao, ; Jian-guo Zeng, ; Duan-fang Liao,
| | - Duan-fang Liao
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha, Hunan, China
- *Correspondence: Deliang Cao, ; Jian-guo Zeng, ; Duan-fang Liao,
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High Neutrophil-to-Lymphocyte Ratio Facilitates Cancer Growth-Currently Marketed Drugs Tadalafil, Isotretinoin, Colchicine, and Omega-3 to Reduce It: The TICO Regimen. Cancers (Basel) 2022; 14:cancers14194965. [PMID: 36230888 PMCID: PMC9564173 DOI: 10.3390/cancers14194965] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/03/2022] [Accepted: 10/03/2022] [Indexed: 11/22/2022] Open
Abstract
Simple Summary Several elements that are composed of, or related to, neutrophils, have been shown to inhibit strong immune responses to cancer and promote cancers’ growth. This paper presents the collected data showing these elements and how their coordinated actions as an ensemble facilitate growth in the common cancers. The paper goes on to present a drug regimen, TICO, designed to reduce the cancer growth enhancing effects of the neutrophil related elements. TICO uses four already marketed, readily available generic drugs, repurposed to inhibit neutrophil centered growth facilitation of cancer. Abstract This paper presents remarkably uniform data showing that higher NLR is a robust prognostic indicator of shorter overall survival across the common metastatic cancers. Myeloid derived suppressor cells, the NLRP3 inflammasome, neutrophil extracellular traps, and absolute neutrophil count tend to all be directly related to the NLR. They, individually and as an ensemble, contribute to cancer growth and metastasis. The multidrug regimen presented in this paper, TICO, was designed to decrease the NLR with potential to also reduce the other neutrophil related elements favoring malignant growth. TICO is comprised of already marketed generic drugs: the phosphodiesterase 5 inhibitor tadalafil, used to treat inadequate erections; isotretinoin, the retinoid used for acne treatment; colchicine, a standard gout (podagra) treatment; and the common fish oil supplement omega-3 polyunsaturated fatty acids. These individually impose low side effect burdens. The drugs of TICO are old, cheap, well known, and available worldwide. They all have evidence of lowering the NLR or the growth contributing elements related to the NLR when clinically used in general medicine as reviewed in this paper.
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13
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Li K, Cheng X, Jin R, Han T, Li J. The influence of different proton pump inhibitors and potassium-competitive acid blockers on indomethacin-induced small intestinal injury. J Gastroenterol Hepatol 2022; 37:1935-1945. [PMID: 35938741 DOI: 10.1111/jgh.15973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 07/18/2022] [Accepted: 08/03/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM The influence of gastric acid inhibitors (GAIs) on nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy is controversial. Herein, the influences of different GAIs on NSAID-induced intestinal injury and the underlying mechanisms are clarified. METHODS Indomethacin (IND; 10 mg/kg/day) was administered to mice to induce small intestinal injury. Disease activity was examined macroscopically and histologically. The permeability of small intestine was evaluated by measuring plasma lipopolysaccharide levels. 16S rDNA sequencing was performed to determine the composition of intestinal flora. RESULTS Among the four GAIs, ilaprazole (IPZ) significantly attenuated IND-induced small intestinal injury and maintained the integrity of the mucosal barrier. Omeprazole (OPZ) and vonoprazan (VPZ) ameliorated ulceration without significant differences, while rabeprazole (RPZ) failed to protect against the injury. To explore the potential mechanism, we investigated changes in the gut microbiota mediated by GAIs. After 5-day administration, GAIs significantly altered the composition of the gut microbiota. The IND group had a significant decrease in alpha diversity compared with the control group, and this decrease was reversed by OPZ and IPZ treatment, respectively. After IPZ treatment, the community membership was more assembled in the control group than the IND group. Further, we found that Lactobacillus was significantly increased in the groups of OPZ, IPZ, and VPZ, while Bacteroides was significantly increased in the RPZ group. CONCLUSION Our results indicated that GAIs have different influences on the mucosal barrier, possibly by altering the composition of intestinal microbiota, and the impacts mediated by various GAIs in the IND-induced intestinal damage model seem different.
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Affiliation(s)
- Kemin Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaoyun Cheng
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Rui Jin
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Taotao Han
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jingnan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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14
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Puleo MG, Miceli S, Di Chiara T, Pizzo GM, Della Corte V, Simonetta I, Pinto A, Tuttolomondo A. Molecular Mechanisms of Inflammasome in Ischemic Stroke Pathogenesis. Pharmaceuticals (Basel) 2022; 15:1168. [PMID: 36297283 PMCID: PMC9612213 DOI: 10.3390/ph15101168] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 09/01/2022] [Accepted: 09/13/2022] [Indexed: 11/16/2022] Open
Abstract
Ischemic stroke (also called cerebral ischemia) is one of the leading causes of death and severe disability worldwide. NLR inflammasomes play a crucial role in sensing cell damage in response to a harmful stimuli and modulating the inflammatory response, promoting the release of pro-inflammatory cytokines such as IL-18 and IL-1β following ischemic injury. Therefore, a neuroprotective effect is achieved by inhibiting the expression, assembly, and secretion of inflammasomes, thus limiting the extent of brain detriment and neurological sequelae. This review aims to illustrate the molecular characteristics, expression levels, and assembly of NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin-domain-containing 3) inflammasome, the most studied in the literature, in order to discover promising therapeutic implications. In addition, we provide some information regarding the contribution of NLRP1, NLRP2, and NLRC4 inflammasomes to ischemic stroke pathogenesis, highlighting potential therapeutic strategies that require further study.
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Affiliation(s)
| | | | | | | | | | | | | | - Antonino Tuttolomondo
- Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialties, “G. D’Alessandro”, University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy
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15
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Jiang Y, Zhao T, Zhou X, Xiang Y, Gutierrez‐Castrellon P, Ma X. Inflammatory pathways in COVID-19: Mechanism and therapeutic interventions. MedComm (Beijing) 2022; 3:e154. [PMID: 35923762 PMCID: PMC9340488 DOI: 10.1002/mco2.154] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/01/2022] [Accepted: 06/02/2022] [Indexed: 02/05/2023] Open
Abstract
The 2019 coronavirus disease (COVID-19) pandemic has become a global crisis. In the immunopathogenesis of COVID-19, SARS-CoV-2 infection induces an excessive inflammatory response in patients, causing an inflammatory cytokine storm in severe cases. Cytokine storm leads to acute respiratory distress syndrome, pulmonary and other multiorgan failure, which is an important cause of COVID-19 progression and even death. Among them, activation of inflammatory pathways is a major factor in generating cytokine storms and causing dysregulated immune responses, which is closely related to the severity of viral infection. Therefore, elucidation of the inflammatory signaling pathway of SARS-CoV-2 is important in providing otential therapeutic targets and treatment strategies against COVID-19. Here, we discuss the major inflammatory pathways in the pathogenesis of COVID-19, including induction, function, and downstream signaling, as well as existing and potential interventions targeting these cytokines or related signaling pathways. We believe that a comprehensive understanding of the regulatory pathways of COVID-19 immune dysregulation and inflammation will help develop better clinical therapy strategies to effectively control inflammatory diseases, such as COVID-19.
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Affiliation(s)
- Yujie Jiang
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduPR China
| | - Tingmei Zhao
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduPR China
| | - Xueyan Zhou
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduPR China
| | - Yu Xiang
- Department of BiotherapyState Key Laboratory of Biotherapy Cancer CenterWest China HospitalSichuan UniversityChengduPR China
| | - Pedro Gutierrez‐Castrellon
- Center for Translational Research on Health Science Hospital General Dr. Manuel Gea GonzalezMinistry of HealthMexico CityMexico
| | - Xuelei Ma
- Department of BiotherapyState Key Laboratory of Biotherapy Cancer CenterWest China HospitalSichuan UniversityChengduPR China
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16
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Sun C, Zhao H, Han Y, Wang Y, Sun X. The Role of Inflammasomes in COVID-19: Potential Therapeutic Targets. J Interferon Cytokine Res 2022; 42:406-420. [PMID: 35984324 DOI: 10.1089/jir.2022.0061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The coronavirus 2019 disease (COVID-19) pandemic has caused massive morbidity and mortality worldwide. In severe cases, it is mainly associated with acute pneumonia, cytokine storm, and multi-organ dysfunction. Inflammasomes play a primary role in various pathological processes such as infection, injury, and cancer. However, their role in COVID-19-related complications has not been explored. In addition, the role of underlying medical conditions on COVID-19 disease severity remains unclear. Therefore, this review expounds on the mechanisms of inflammasomes following COVID-19 infection and provides recent evidence on the potential double-edged sword effect of inflammasomes during COVID-19 pathogenesis. The assembly and activation of inflammasomes are critical for inducing effective antiviral immune responses and disease resolution. However, uncontrolled activation of inflammasomes causes excessive production of proinflammatory cytokines (cytokine storm), increased risk of acute respiratory distress syndrome, and death. Therefore, discoveries in the role of the inflammasome in mediating organ injury are key to identifying therapeutic targets and treatment modifications to prevent or reduce COVID-19-related complications.
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Affiliation(s)
- Chen Sun
- Department of Clinical Medicine, School of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Hangyuan Zhao
- Department of Clinical Medicine, School of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yunze Han
- Department of Clinical Medicine, School of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yiqing Wang
- Department of Clinical Medicine, School of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Xiao Sun
- Department of Basic Medical Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
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17
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Li X, Zhang Z, Wang Z, Gutiérrez-Castrellón P, Shi H. Cell deaths: Involvement in the pathogenesis and intervention therapy of COVID-19. Signal Transduct Target Ther 2022; 7:186. [PMID: 35697684 PMCID: PMC9189267 DOI: 10.1038/s41392-022-01043-6] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/18/2022] [Accepted: 05/26/2022] [Indexed: 02/06/2023] Open
Abstract
The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has dramatically influenced various aspects of the world. It is urgent to thoroughly study pathology and underlying mechanisms for developing effective strategies to prevent and treat this threatening disease. It is universally acknowledged that cell death and cell autophagy are essential and crucial to maintaining host homeostasis and participating in disease pathogenesis. At present, more than twenty different types of cell death have been discovered, some parts of which have been fully understood, whereas some of which need more investigation. Increasing studies have indicated that cell death and cell autophagy caused by coronavirus might play an important role in virus infection and pathogenicity. However, the knowledge of the interactions and related mechanisms of SARS-CoV-2 between cell death and cell autophagy lacks systematic elucidation. Therefore, in this review, we comprehensively delineate how SARS-CoV-2 manipulates diverse cell death (including apoptosis, necroptosis, pyroptosis, ferroptosis, and NETosis) and cell autophagy for itself benefits, which is simultaneously involved in the occurrence and progression of COVID-19, aiming to provide a reasonable basis for the existing interventions and further development of novel therapies.
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Affiliation(s)
- Xue Li
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Ziqi Zhang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Zhenling Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Ke Yuan 4th Road, Gao Peng Street, Chengdu, Sichuan, 610041, People's Republic of China
| | - Pedro Gutiérrez-Castrellón
- Center for Translational Research on Health Science, Hospital General Dr. Manuel Gea Gonzalez. Ministry of Health, Calz. Tlalpan 4800, Col. Secc. XVI, 14080, Mexico city, Mexico.
| | - Huashan Shi
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.
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18
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Hirano S, Higashimori A, Nagami Y, Nadatani Y, Tanigawa T, Ominami M, Fukunaga S, Otani K, Hosomi S, Tanaka F, Kamata N, Taira K, Watanabe T, Fujiwara Y. Pirfenidone prevents esophageal stricture by inhibiting nucleotide binding oligomerization domain like receptor protein 3 inflammasome activation. J Gastroenterol Hepatol 2022; 37:1096-1106. [PMID: 35434849 DOI: 10.1111/jgh.15861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 03/21/2022] [Accepted: 04/11/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Esophageal injury often results in a scar, leading to refractory strictures. The NLRP3 inflammasome activates caspase-1, causing the maturation of interleukin (IL)-1β. Here, we aimed to investigate the preventive effect of pirfenidone (PFD), an antifibrotic drug, on esophageal stricture after ulcer healing and studied its mechanism by focusing on the activation of the NLRP3 inflammasome. METHODS Esophageal ulcers were induced in rats via the local application of acetic acid in the serosa. PFD was intraperitoneally administered to the rats 3 days after ulcer induction. The effect of PFD on esophageal stricture after ulcer healing was assessed by esophagography on day 9. The protein levels of mature caspase-1 and IL-1β were assessed by western blotting. RESULTS The ulcers fully developed 3 days after induction and were almost scarred by day 9 with severe strictures. PFD promoted ulcer healing and attenuated fibrotic collagen in the submucosa by suppressing the increase in NLRP3, cleaved caspase-1, and mature IL-1β expression, improving stricture rate (PFD vs vehicle = 55% vs 81%). Exogenous IL-1β abolished the therapeutic effects of PFD on ulcer healing and stricture formation. Furthermore, NLRP3 and caspase-1 inhibitors mimicked the effects of PFD on ulcer healing and stricture formation, with suppression of the increase in cleaved caspase-1 and mature IL-1β proteins and expression of fibrosis-related molecules including transforming growth factor (TGF)-β1. CONCLUSION The NLRP3 inflammasome promotes esophageal stricture formation following ulcer healing, and PFD exerts potential prophylactic activity against strictures, possibly via the inhibition of the NLRP3/IL-1β/TGF-β1 axis.
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Affiliation(s)
- Shinji Hirano
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Akira Higashimori
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuaki Nagami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yuji Nadatani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.,Department of Premier Preventive Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tetsuya Tanigawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.,Department of Gastroenterology, Osaka City Juso Hospital, Osaka, Japan
| | - Masaki Ominami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shusei Fukunaga
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koji Otani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shuhei Hosomi
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Fumio Tanaka
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Noriko Kamata
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koichi Taira
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Toshio Watanabe
- Department of Premier Preventive Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuhiro Fujiwara
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Lin WY, Li LH, Hsiao YY, Wong WT, Chiu HW, Hsu HT, Peng YJ, Ho CL, Chernikov OV, Cheng SM, Yang SP, Hua KF. Repositioning of the Angiotensin II Receptor Antagonist Candesartan as an Anti-Inflammatory Agent With NLRP3 Inflammasome Inhibitory Activity. Front Immunol 2022; 13:870627. [PMID: 35669789 PMCID: PMC9163344 DOI: 10.3389/fimmu.2022.870627] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/25/2022] [Indexed: 11/29/2022] Open
Abstract
Aberrant activation of the NLRP3 inflammasome promotes the pathogenesis of many inflammatory diseases. The development of the NLRP3 inflammasome inhibitors from existing drugs for new therapeutic purposes is becoming more important. Candesartan is an angiotensin II receptor antagonist widely used as a blood pressure-lowering drug; however, the inhibitory potential of candesartan on the NLRP3 inflammasome has not yet been investigated. We demonstrated that candesartan significantly inhibited the NLRP3 inflammasome and pyroptosis in macrophages. Mechanistic analysis revealed that candesartan inhibited the expression of NLRP3 and proIL-1β by suppressing NF-κB activation and reducing the phosphorylation of ERK1/2 and JNK1/2. Candesartan reduced mitochondrial damage and inhibited the NLRP3 inflammasome assembly by suppressing NLRP3 binding to PKR, NEK7 and ASC. In addition, candesartan inhibited IL-1β secretion partially through autophagy induction. Furthermore, oral administration of candesartan reduced peritoneal neutrophil influx, NLRP3 and ASC expression in peritoneal cells, and lavage fluid concentrations of active caspase-1, IL-1β, IL-6 and MCP-1 in uric acid crystal-injected mice. These results indicated that candesartan has board anti-inflammatory effects and has the potential to be repositioned to ameliorate inflammatory diseases or NLRP3-associated complications.
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Affiliation(s)
- Wen-Yu Lin
- Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Lan-Hui Li
- Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Ya-Yun Hsiao
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Wei-Ting Wong
- Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan
| | - Hsiao-Wen Chiu
- Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan
| | - Hsien-Ta Hsu
- Division of Neurosurgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
- School of Medicine, Bu ddhist Tzu Chi University, Hualien, Taiwan
| | - Yi-Jen Peng
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chen-Lung Ho
- Division of Wood Cellulose, Taiwan Forestry Research Institute, Taipei, Taiwan
| | - Oleg V. Chernikov
- G.B. Elyakov Pacific Institute, Bioorganic Chemistry of the Far-Eastern Branch of the Russian Academy of Sciences (FEB RAS), Vladivostok, Russia
| | - Shu-Meng Cheng
- Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Shih-Ping Yang
- Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Kuo-Feng Hua
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- *Correspondence: Kuo-Feng Hua,
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20
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Abdel-Aziz AM, Ibrahim YF, Ahmed RF, Mohamed ASM, Welson NN, Abdelzaher WY. Potential role of carvedilol in intestinal toxicity through NF-κB/iNOS/COX-2/TNF-α inflammatory signaling pathway in rats. Immunopharmacol Immunotoxicol 2022; 44:613-620. [PMID: 35506611 DOI: 10.1080/08923973.2022.2072327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND The increased use of indomethacin (IND) is associated with gastrointestinal injury. This research aims to investigate the effects of a beta-blocker, carvedilol (CAR) on a rat model of IND-induced acute intestinal damage and clarify the probable underlying protective mechanisms. MATERIALS AND METHODS Twenty-four male Wistar rats were divided into four groups. Control group: given vehicles; CAR-treated group: given 10 mg/kg/day CAR PO daily by gastric gavage for 10 consecutive days; IND-treated group: given a single Sc dose of 10 mg/kg IND at the end of the ninth day of the experiment; combined CAR/IND-treated group: given both IND and CAR. RESULTS In the rats that received IND, severe intestinal histopathological changes together with oxidative and nitrosative intestinal stress were present biochemically and immunohistochemically. Obvious inflammatory and tissue damage were represented by the significant intestinal increases in TNF-α, COX-2, and caspase-3 together with the elevated expression of VCAM-1 adhesion molecules. Intestinal gene expression of NF-kB and COX-2 was also increased. Pretreatment with CAR significantly reversed the IND-induced intestinal toxic manifestations. CONCLUSION CAR has beneficial intestinal protective effects. Its ameliorative action is conferred through its antioxidant, antinitrosative, anti-inflammatory, and antiapoptotic properties.
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Affiliation(s)
| | - Yasmine F Ibrahim
- Department of Pharmacology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Rasha Fouad Ahmed
- Department of Medical Biochemistry, Faculty of Medicine, Minia University, Minia, Egypt
| | | | - Nermeen N Welson
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
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21
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Nappi F, Bellomo F, Avtaar Singh SS. Insights into the Role of Neutrophils and Neutrophil Extracellular Traps in Causing Cardiovascular Complications in Patients with COVID-19: A Systematic Review. Biomedicines 2022; 11:2460. [PMID: 35566589 PMCID: PMC9855935 DOI: 10.3390/biomedicines11010113] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 04/24/2022] [Accepted: 04/25/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 virus has resulted in significant mortality and burdening of healthcare resources. While initially noted as a pulmonary pathology, subsequent studies later identified cardiovascular involvement with high mortalities reported in specific cohorts of patients. While cardiovascular comorbidities were identified early on, the exact manifestation and etiopathology of the infection remained elusive. This systematic review aims to investigate the role of inflammatory pathways, highlighting several culprits including neutrophil extracellular traps (NETs) which have since been extensively investigated. METHOD A search was conducted using three databases (MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations and EMBASE). Data from randomized controlled trials (RCT), prospective series, meta-analyses, and unmatched observational studies were considered for the processing of the algorithm and treatment of inflammatory response during SARS-CoV-2 infection. Studies without the SARS-CoV-2 Infection period and case reports were excluded. RESULTS A total of 47 studies were included in this study. The role of the acute inflammatory response in the propagation of the systemic inflammatory sequelae of the disease plays a major part in determining outcomes. Some of the mechanisms of activation of these pathways have been highlighted in previous studies and are highlighted. CONCLUSION NETs play a pivotal role in the pathogenesis of the inflammatory response. Despite moving into the endemic phase of the disease in most countries, COVID-19 remains an entity that has not been fully understood with long-term effects remaining uncertain and requiring ongoing monitoring and research.
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Affiliation(s)
- Francesco Nappi
- Department of Cardiac Surgery, Centre Cardiologique du Nord of Saint-Denis, 93200 Saint-Denis, France
| | - Francesca Bellomo
- Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy
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22
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Wei Y, Yang L, Pandeya A, Cui J, Zhang Y, Li Z. Pyroptosis-Induced Inflammation and Tissue Damage. J Mol Biol 2022; 434:167301. [PMID: 34653436 PMCID: PMC8844146 DOI: 10.1016/j.jmb.2021.167301] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 09/23/2021] [Accepted: 10/05/2021] [Indexed: 02/07/2023]
Abstract
Programmed cell deaths are pathways involving cells playing an active role in their own destruction. Depending on the signaling system of the process, programmed cell death can be divided into two categories, pro-inflammatory and non-inflammatory. Pyroptosis is a pro-inflammatory form of programmed cell death. Upon cell death, a plethora of cytokines are released and trigger a cascade of responses from the neighboring cells. The pyroptosis process is a double-edged sword, could be both beneficial and detrimental in various inflammatory disorders and disease conditions. A physiological outcome of these responses is tissue damage, and sometimes death of the host. In this review, we focus on the inflammatory response triggered by pyroptosis, and resulting tissue damage in selected organs.
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Affiliation(s)
- Yinan Wei
- Department of Chemistry, College of Arts and Sciences, University of Kentucky, Lexington, KY, USA.
| | - Ling Yang
- Department of Chemistry, College of Arts and Sciences, University of Kentucky, Lexington, KY, USA
| | - Ankit Pandeya
- Department of Chemistry, College of Arts and Sciences, University of Kentucky, Lexington, KY, USA
| | - Jian Cui
- Department of Chemistry, College of Arts and Sciences, University of Kentucky, Lexington, KY, USA
| | - Yan Zhang
- Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, KY, USA.,Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou,China
| | - Zhenyu Li
- Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, KY, USA.
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23
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Chen Y, Zhang H, Chen Y, Li M, Luo W, Liu Y, Fu Y, Xia H, Xu C, Jiang Y, Wu Y. Colchicine may become a new cornerstone therapy for coronary artery disease: a meta-analysis of randomized controlled trials. Clin Rheumatol 2022; 41:1873-1887. [PMID: 35138464 DOI: 10.1007/s10067-022-06050-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 12/14/2021] [Accepted: 01/01/2022] [Indexed: 12/30/2022]
Abstract
PURPOSE Colchicine is an ancient anti-inflammatory drug. In recent years, an increasing number of studies have shown that colchicine improves the prognosis of patients with coronary artery disease (CAD), while other studies have reported the opposite. The aim of this study was to evaluate the relative efficacy and safety of colchicine in treating CAD. METHODS PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov were searched from inception to 20 October 2020 for randomized controlled trials (RCTs) comparing colchicine and placebo in patients with CAD. The primary outcomes were the primary composite outcomes of cardiovascular death, myocardial infarction (MI), ischemic stroke, or ischemia-driven coronary revascularization after colchicine administration. The secondary outcomes were cardiovascular death, death from any cause, noncardiac death, MI, ischemic stroke, coronary revascularization, gastrointestinal (GI) symptoms, and the different effects of colchicine in acute and chronic CAD. We assessed the pooled odds ratio (OR) of all-cause and cardiovascular mortality for CAD in fixed-effects models, the pooled risk ratio (RR) of the primary composite outcomes, MI, ischemic stroke, and ischemia-driven coronary revascularization in fixed-effects models and the pooled RR of GI symptoms in random-effects models. The Cochrane risk of bias tool was used to assess the risk of bias in the included RCTs. FINDINGS Eleven of the 894 identified studies (n = 12,899 patients) were included (6501 subjects in the colchicine group; 6389 subjects in the control group). The colchicine group had significantly lower pooled RRs of the primary composite outcomes (0.73, 95% confidence interval (CI) 0.64-0.84, P < 0.0001), MI (0.77, 95% CI 0.64-0.92, P = 0.004), ischemic stroke (0.47, 95% CI 0.30-0.76, P = 0.002), and ischemia-driven coronary revascularization (0.77, 95% CI 0.66-0.89, P = 0.0007), while the pooled RR of adverse GI events (2.15 95% CI 1.40-3.31, P = 0.0005) was significantly higher. Colchicine had a lower pooled RR of ischemic stroke (0.28, 95% CI 0.12-0.65, P = 0.003) for patients with acute compared with chronic CAD. IMPLICATIONS Colchicine treatment significantly decreased the risk of primary cardiovascular composite outcomes, MI, ischemic stroke, and ischemia-driven coronary revascularization in CAD patients but increased adverse GI events. There was no significant difference in all-cause mortality, cardiovascular mortality, and non-cardiovascular death between the colchicine and control groups. Colchicine performs better in acute CAD patients with ischemic stroke than chronic CAD patients. Colchicine might be a new treatment for patients with CAD.
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Affiliation(s)
- Yi Chen
- Department of Cardiovascular Medicine, Donghu District, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Hongzhou Zhang
- Department of Cardiovascular Medicine, Donghu District, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Yuxin Chen
- Department of Cardiovascular Medicine, Donghu District, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Meng Li
- Department of Cardiovascular Medicine, Donghu District, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Wei Luo
- Department of Cardiovascular Medicine, Donghu District, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Yue Liu
- Department of Cardiovascular Medicine, Donghu District, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Yang Fu
- Department of Cardiovascular Medicine, Donghu District, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Huasong Xia
- Department of Cardiovascular Medicine, Donghu District, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Cong Xu
- Department of Cardiovascular Medicine, Donghu District, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Yu Jiang
- Department of Cardiovascular Medicine, Donghu District, The First Affiliated Hospital of Nanchang University, No. 17, Yongzhengwai Road, Nanchang, 330006, Jiangxi, China
| | - Yanqing Wu
- Department of Cardiovascular Medicine, Donghu District, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, 330006, Jiangxi, China.
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Abstract
Purpose of Review Pericarditis is a generally benign disease, although complications and/or recurrences may occur in up to 30% of cases. New evidence on the pathophysiology of the disease has accumulated in recent years. Recent Findings Recently, it has been shown that the activation of the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome is central in the pathophysiology of pericarditis. These findings derive from clinical data, an experimental animal model of acute pericarditis supporting a role for the NLRP3 inflammasome in pericarditis, and from indirect evidence of inhibitors of NLRP3 inflammasome in clinical trials. Summary Pericarditis is regarded as a stereotypical response to an acute damage of the mesothelial cells of the pericardial layers. NLRP3 inflammasome, a macromolecular structure sensing damage and releasing pro-inflammatory cytokines, is centrally involved as it releases interleukin (IL)-1β, whose auto-induction feeds an autoinflammatory disease, mostly responsible for recurrences. Colchicine, an inhibitor of NLRP3 inflammasome formation, and IL-1-targeted therapies, such as anakinra and rilonacept, were found to effectively blunt the acute inflammation and reduce the risk for recurrences.
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25
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Pascual-Figal DA, Roura-Piloto AE, Moral-Escudero E, Bernal E, Albendín-Iglesias H, Pérez-Martínez MT, Noguera-Velasco JA, Cebreiros-López I, Hernández-Vicente Á, Vázquez-Andrés D, Sánchez-Pérez C, Khan A, Sánchez-Cabo F, García-Vázquez E. Colchicine in Recently Hospitalized Patients with COVID-19: A Randomized Controlled Trial (COL-COVID). Int J Gen Med 2021; 14:5517-5526. [PMID: 34539185 PMCID: PMC8445096 DOI: 10.2147/ijgm.s329810] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 08/20/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Colchicine has been proposed as a potential therapy in coronavirus disease 2019 (COVID-19) due to their anti-inflammatory actions. METHODS The COL-COVID study was a prospective, randomized, controlled and open-label clinical trial that compared colchicine added to standard treatment vs standard treatment in hospitalized COVID-19 patients that do not need mechanical ventilatory support. Colchicine was initiated within the first 48 hours of admission at a 1.5 mg loading dose, followed by 0.5 mg b.i.d. for one week and 0.5 mg per day for 28 days. The study endpoints were clinical status (7-points WHO ordinal scale) and inflammatory biomarkers (IL-6 and CRP). RESULTS A total of 103 patients (51±12 years, 52% male) were randomly allocated to colchicine arm (n=52) and control arm (n=51). At day 28, all patients in the colchicine group were alive and discharged, whereas in the control group, two patients died in-hospital and one patient remained hospitalized. Clinical improvement in terms of changes on WHO scale at day 14 and 28 and time to 1-point clinical improvement did not differ between the two groups. Clinical deterioration (increase of at least 1-point in WHO scale) was observed in a higher proportion of cases in colchicine group (13.8%) vs control group (5.8%) (p=0.303); after adjustment by baseline risk factors and concomitant therapies, colchicine therapy was associated with a lower risk of clinical deterioration (p=0.030). Inflammatory biomarkers CRP and IL-6 concentrations course did not differ between the two arms. CONCLUSION In hospitalized COVID-19 patients, colchicine treatment neither improved the clinical status, nor the inflammatory response, over the standard treatment. Nevertheless, a preventive effect for further clinical deterioration might be possible. TRIAL REGISTRATION NCT04350320.
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Affiliation(s)
- Domingo A Pascual-Figal
- Cardiology Department, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, (CIBERCV), Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Aychel E Roura-Piloto
- Infectious Diseases and Internal Medicine Department, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
| | - Encarnación Moral-Escudero
- Infectious Diseases and Internal Medicine Department, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
| | - Enrique Bernal
- Infectious Diseases and Internal Medicine Department, Hospital Universitario Reina Sofia, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
| | - Helena Albendín-Iglesias
- Infectious Diseases and Internal Medicine Department, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
| | - M Teresa Pérez-Martínez
- Cardiology Department, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
| | - Jose Antonio Noguera-Velasco
- Clinical Biochemistry Department, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
| | - Iria Cebreiros-López
- Clinical Biochemistry Department, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
| | - Álvaro Hernández-Vicente
- Cardiology Department, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
| | - David Vázquez-Andrés
- Cardiology Department, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
| | - Carmen Sánchez-Pérez
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, (CIBERCV), Madrid, Spain
| | - Amjad Khan
- Department of Chemistry, University of Oxford, Oxford, UK
| | | | - Elisa García-Vázquez
- Infectious Diseases and Internal Medicine Department, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
| | - On behalf of the COL-COVID Investigators
- Cardiology Department, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, (CIBERCV), Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Infectious Diseases and Internal Medicine Department, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
- Infectious Diseases and Internal Medicine Department, Hospital Universitario Reina Sofia, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
- Clinical Biochemistry Department, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
- Department of Chemistry, University of Oxford, Oxford, UK
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Otani K, Watanabe T, Higashimori A, Nadatani Y, Nagami Y, Taira K, Inui K, Fujiwara Y. Effects of Colchicine on NSAID-Induced Severe Small Intestinal Damage: A Pilot Study. Digestion 2021; 102:803-808. [PMID: 33202409 DOI: 10.1159/000511255] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 08/31/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND We previously reported that nonsteroidal anti-inflammatory drugs (NSAIDs) induced small intestinal damage through nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-dependent interleukin-1β secretion in mice. Our further study demonstrated that colchicine, a therapeutic agent for gout, significantly suppressed NSAID-induced small intestinal damage by inhibiting NLRP3 inflammasome activation in mice. However, clinical efficacy of colchicine for NSAID-induced small intestinal damage has not been established. OBJECTIVES We examined the clinical efficacy of colchicine in patients with NSAID-induced severe small intestinal damage as an animal-to-human translational research. METHODS This is a single-center, single-arm, prospective pilot study. From February 2017 to March 2019, we performed video capsule endoscopy (VCE) to screen 10 patients who took NSAIDs continuously for more than 3 months, and 7 of those with severe small intestinal damage were enrolled. Participants were treated with oral colchicine 0.5 mg twice daily for 8 weeks and thereafter followed up with blood tests and VCE. RESULTS After 8 weeks of colchicine treatment, complete healing was achieved in 4 patients (57.1%), and the median number of small erosions decreased significantly from 7.0 (range, 5.0-10.5) to 0.0 (range, 0.0-2.3) (p = 0.031). One patient withdrew due to diarrhea, and 5 patients revealed slightly elevated liver enzymes during the study. No other adverse events including changes in blood tests and clinical symptoms were observed. CONCLUSIONS Colchicine treatment achieved a high rate of complete healing in patients with NSAID-induced severe small intestinal damage.
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Affiliation(s)
- Koji Otani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Toshio Watanabe
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan,
| | - Akira Higashimori
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yuji Nadatani
- Department of Premier Preventive Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuaki Nagami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koichi Taira
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kentaro Inui
- Department of Orthopaedic Surgery, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan
| | - Yasuhiro Fujiwara
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
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27
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Das B, Sarkar C, Rawat VS, Kalita D, Deka S, Agnihotri A. Promise of the NLRP3 Inflammasome Inhibitors in In Vivo Disease Models. Molecules 2021; 26:4996. [PMID: 34443594 PMCID: PMC8399941 DOI: 10.3390/molecules26164996] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/28/2021] [Accepted: 08/10/2021] [Indexed: 12/26/2022] Open
Abstract
Nucleotide-binding oligomerization domain NOD-like receptors (NLRs) are conserved cytosolic pattern recognition receptors (PRRs) that track the intracellular milieu for the existence of infection, disease-causing microbes, as well as metabolic distresses. The NLRP3 inflammasome agglomerates are consequent to sensing a wide spectrum of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Certain members of the NLR family have been documented to lump into multimolecular conglomerates called inflammasomes, which are inherently linked to stimulation of the cysteine protease caspase-1. Following activation, caspase-1 severs the proinflammatory cytokines interleukin (IL)-1β and IL-18 to their biologically active forms, with consequent commencement of caspase-1-associated pyroptosis. This type of cell death by pyroptosis epitomizes a leading pathway of inflammation. Accumulating scientific documentation has recorded overstimulation of NLRP3 (NOD-like receptor protein 3) inflammasome involvement in a wide array of inflammatory conditions. IL-1β is an archetypic inflammatory cytokine implicated in multiple types of inflammatory maladies. Approaches to impede IL-1β's actions are possible, and their therapeutic effects have been clinically demonstrated; nevertheless, such strategies are associated with certain constraints. For instance, treatments that focus on systemically negating IL-1β (i.e., anakinra, rilonacept, and canakinumab) have been reported to result in an escalated peril of infections. Therefore, given the therapeutic promise of an NLRP3 inhibitor, the concerted escalated venture of the scientific sorority in the advancement of small molecules focusing on direct NLRP3 inflammasome inhibition is quite predictable.
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Affiliation(s)
- Biswadeep Das
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Virbhadra Road, Rishikesh 249203, Uttarakhand, India;
| | - Chayna Sarkar
- Department of Clinical Pharmacology & Therapeutics, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences (NEIGRIHMS), Mawdiangdiang, Shillong 793018, Meghalaya, India;
| | - Vikram Singh Rawat
- Department of Psychiatry, All India Institute of Medical Sciences (AIIMS), Virbhadra Road, Rishikesh 249203, Uttarakhand, India;
| | - Deepjyoti Kalita
- Department of Microbiology, All India Institute of Medical Sciences (AIIMS), Virbhadra Road, Rishikesh 249203, Uttarakhand, India; (D.K.); (S.D.)
| | - Sangeeta Deka
- Department of Microbiology, All India Institute of Medical Sciences (AIIMS), Virbhadra Road, Rishikesh 249203, Uttarakhand, India; (D.K.); (S.D.)
| | - Akash Agnihotri
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Virbhadra Road, Rishikesh 249203, Uttarakhand, India;
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Li Y, Zhang Y, Lu J, Yin Y, Xie J, Xu B. Anti-inflammatory mechanisms and research progress of colchicine in atherosclerotic therapy. J Cell Mol Med 2021; 25:8087-8094. [PMID: 34312998 PMCID: PMC8419170 DOI: 10.1111/jcmm.16798] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/17/2021] [Accepted: 07/10/2021] [Indexed: 12/13/2022] Open
Abstract
Inflammatory responses play a vital role in the onset and development of atherosclerosis, and throughout the entire process of the chronic disease. The inflammatory responses in atherosclerosis are mainly mediated by the NLRP3 inflammasome and its downstream inflammatory factors. As a powerful anti‐inflammatory medicine, colchicine has a history of more than 200 years in clinical application and is the first‐choice treatment for immune diseases such as gout and familial Mediterranean fever. In atherosclerosis, colchicine can inhibit the assembly and activation of NLRP3 inflammasome via various mechanisms to effectively reduce the expression of inflammatory factors, thereby reducing the inflammation. Recent clinical trials show that a low dose of colchicine (0.5 mg per day) has a certain protective effect in stable angina patients or those with acute myocardial infarction after PCI. This article summarizes and discusses the mechanisms of colchicine in the treatment of atherosclerosis and the latest research progress.
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Affiliation(s)
- Yuyu Li
- Department of Cardiology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, School of Medicine, Nanjing University, Nanjing, China
| | - Yuxin Zhang
- Institution of Translational Medicine, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jianrong Lu
- Department of Cardiology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, School of Medicine, Nanjing University, Nanjing, China
| | - Yong Yin
- Department of Cardiology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, School of Medicine, Nanjing University, Nanjing, China
| | - Jun Xie
- Department of Cardiology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, School of Medicine, Nanjing University, Nanjing, China
| | - Biao Xu
- Department of Cardiology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, School of Medicine, Nanjing University, Nanjing, China
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29
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Zhao N, Di B, Xu LL. The NLRP3 inflammasome and COVID-19: Activation, pathogenesis and therapeutic strategies. Cytokine Growth Factor Rev 2021; 61:2-15. [PMID: 34183243 PMCID: PMC8233448 DOI: 10.1016/j.cytogfr.2021.06.002] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 06/14/2021] [Accepted: 06/14/2021] [Indexed: 12/12/2022]
Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits a wide spectrum of clinical presentations, ranging from asymptomatic cases to severe pneumonia or even death. In severe COVID-19 cases, an increased level of proinflammatory cytokines has been observed in the bloodstream, forming the so-called “cytokine storm”. Generally, nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation intensely induces cytokine production as an inflammatory response to viral infection. Therefore, the NLRP3 inflammasome can be a potential target for the treatment of COVID-19. Hence, this review first introduces the canonical NLRP3 inflammasome activation pathway. Second, we review the cellular/molecular mechanisms of NLRP3 inflammasome activation by SARS-CoV-2 infection (e.g., viroporins, ion flux and the complement cascade). Furthermore, we describe the involvement of the NLRP3 inflammasome in the pathogenesis of COVID-19 (e.g., cytokine storm, respiratory manifestations, cardiovascular comorbidity and neurological symptoms). Finally, we also propose several promising inhibitors targeting the NLRP3 inflammasome, cytokine products and neutrophils to provide novel therapeutic strategies for COVID-19.
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Affiliation(s)
- Ni Zhao
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China
| | - Bin Di
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China.
| | - Li-Li Xu
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China.
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30
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Liberale L, Montecucco F, Schwarz L, Lüscher TF, Camici GG. Inflammation and cardiovascular diseases: lessons from seminal clinical trials. Cardiovasc Res 2021; 117:411-422. [PMID: 32666079 DOI: 10.1093/cvr/cvaa211] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/29/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022] Open
Abstract
Inflammation has been long regarded as a key contributor to atherosclerosis. Inflammatory cells and soluble mediators play critical roles throughout arterial plaque development and accordingly, targeting inflammatory pathways effectively reduces atherosclerotic burden in animal models of cardiovascular (CV) diseases. Yet, clinical translation often led to inconclusive or even contradictory results. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) followed by the Colchicine Cardiovascular Outcomes Trial (COLCOT) were the first two randomized clinical trials to convincingly demonstrate the effectiveness of specific anti-inflammatory treatments in the field of CV prevention, while other phase III trials-including the Cardiovascular Inflammation Reduction Trial one using methotrexate-were futile. This manuscript reviews the main characteristics and findings of recent anti-inflammatory Phase III trials in cardiology and discusses their similarities and differences in order to get further insights into the contribution of specific inflammatory pathways on CV outcomes. CANTOS and COLCOT demonstrated efficacy of two anti-inflammatory drugs (canakinumab and colchicine, respectively) in the secondary prevention of major adverse CV events (MACE) thus providing the first confirmation of the involvement of a specific inflammatory pathway in human atherosclerotic CV disease (ASCVD). Also, they highlighted the NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome-related pathway as an effective therapeutic target to blunt ASCVD. In contrast, other trials interfering with a number of inflammasome-independent pathways failed to provide benefit. Lastly, all anti-inflammatory trials underscored the importance of balancing the risk of impaired host defence with an increase in infections and the prevention of MACE in CV patients with residual inflammatory risk.
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Affiliation(s)
- Luca Liberale
- Center for Molecular Cardiology, University of Zurich, 12 Wagistrasse, 8952 Schlieren, Switzerland
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
| | - Fabrizio Montecucco
- IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy
- First Clinic of Internal Medicine, Department of Internal Medicine, Centre of Excellence for Biomedical Research (CEBR), University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
| | - Lena Schwarz
- Center for Molecular Cardiology, University of Zurich, 12 Wagistrasse, 8952 Schlieren, Switzerland
| | - Thomas F Lüscher
- Center for Molecular Cardiology, University of Zurich, 12 Wagistrasse, 8952 Schlieren, Switzerland
- Royal Brompton and Harefield Hospitals and Imperial College, London, UK
| | - Giovanni G Camici
- Center for Molecular Cardiology, University of Zurich, 12 Wagistrasse, 8952 Schlieren, Switzerland
- Department of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8092 Zurich, Switzerland
- Department of Research and Education, University Hospital Zurich, Rämistrasse 100, 8092, Zurich, Switzerland
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31
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Bahadoram M, Keikhaei B, Saeedi-Boroujeni A, Mahmoudian-Sani MR. Chloroquine/hydroxychloroquine: an inflammasome inhibitor in severe COVID-19? NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 394:997-1001. [PMID: 33416933 PMCID: PMC7792551 DOI: 10.1007/s00210-020-02034-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 11/26/2020] [Indexed: 12/01/2022]
Abstract
Chloroquine and hydroxychloroquine belong to the aminoquinoline drugs. Studies revealed that chloroquine and hydroxychloroquine shows antagonism activity against COVID-19 under laboratory conditions. ARDS and ALI are conditions that occur in patients with COVID-19 as the main pathological complications of cytokine storm. Inflammasomes play a key role in the pathogenesis of many diseases associated with destructive inflammation. NLRP3 inflammasome has been shown to play a key role in the pathogenesis of viral diseases. The possible role of NLRP3 inflammasome inhibitors in the treatment of COVID-19 has been considered. We surveyed the potential inhibitory effect of chloroquine and hydroxychloroquine on inflammasome. Studies indicate that one of the possible anti-inflammatory mechanisms of chloroquine and hydroxychloroquine is inhibition of the activity of NLRP3 inflammasome.
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Affiliation(s)
- Mohammad Bahadoram
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Bijan Keikhaei
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Saeedi-Boroujeni
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,ImmunologyToday, Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mohammad-Reza Mahmoudian-Sani
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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32
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Wang X, Tang Q, Hou H, Zhang W, Li M, Chen D, Gu Y, Wang B, Hou J, Liu Y, Cao H. Gut Microbiota in NSAID Enteropathy: New Insights From Inside. Front Cell Infect Microbiol 2021; 11:679396. [PMID: 34295835 PMCID: PMC8290187 DOI: 10.3389/fcimb.2021.679396] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 06/10/2021] [Indexed: 12/15/2022] Open
Abstract
As a class of the commonly used drugs in clinical practice, non-steroidal anti-inflammatory drugs (NSAIDs) can cause a series of adverse events including gastrointestinal injuries. Besides upper gastrointestinal injuries, NSAID enteropathy also attracts attention with the introduction of capsule endoscopy and double balloon enteroscopy. However, the pathogenesis of NSAID enteropathy remains to be entirely clarified. Growing evidence from basic and clinical studies presents that gut microbiota is a critical factor in NSAID enteropathy progress. We have reviewed the recent data about the interplay between gut microbiota dysbiosis and NSAID enteropathy. The chronic medication of NSAIDs could change the composition of the intestinal bacteria and aggravate bile acids cytotoxicity. Meanwhile, NSAIDs impair the intestinal barrier by inhibiting cyclooxygenase and destroying mitochondria. Subsequently, intestinal bacteria translocate into the mucosa, and then lipopolysaccharide released from gut microbiota combines to Toll-like receptor 4 and induce excessive production of nitric oxide and pro-inflammatory cytokines. Intestinal injuries present in the condition of intestinal inflammation and oxidative stress. In this paper, we also have reviewed the possible strategies of regulating gut microbiota for the management of NSAID enteropathy, including antibiotics, probiotics, prebiotics, mucosal protective agents, and fecal microbiota transplant, and we emphasized the adverse effects of proton pump inhibitors on NSAID enteropathy. Therefore, this review will provide new insights into a better understanding of gut microbiota in NSAID enteropathy.
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Affiliation(s)
- Xianglu Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Qiang Tang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Huiqin Hou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Wanru Zhang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Mengfan Li
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Danfeng Chen
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Yu Gu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Jingli Hou
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
- *Correspondence: Hailong Cao, ; Jingli Hou, ; Yangping Liu,
| | - Yangping Liu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
- *Correspondence: Hailong Cao, ; Jingli Hou, ; Yangping Liu,
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
- *Correspondence: Hailong Cao, ; Jingli Hou, ; Yangping Liu,
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Dupuis J, Sirois MG, Rhéaume E, Nguyen QT, Clavet-Lanthier MÉ, Brand G, Mihalache-Avram T, Théberge-Julien G, Charpentier D, Rhainds D, Neagoe PE, Tardif JC. Colchicine reduces lung injury in experimental acute respiratory distress syndrome. PLoS One 2020; 15:e0242318. [PMID: 33264297 PMCID: PMC7710059 DOI: 10.1371/journal.pone.0242318] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 10/30/2020] [Indexed: 12/28/2022] Open
Abstract
The acute respiratory distress syndrome (ARDS) is characterized by intense dysregulated inflammation leading to acute lung injury (ALI) and respiratory failure. There are no effective pharmacologic therapies for ARDS. Colchicine is a low-cost, widely available drug, effective in the treatment of inflammatory conditions. We studied the effects of colchicine pre-treatment on oleic acid-induced ARDS in rats. Rats were treated with colchicine (1 mg/kg) or placebo for three days prior to intravenous oleic acid-induced ALI (150 mg/kg). Four hours later they were studied and compared to a sham group. Colchicine reduced the area of histological lung injury by 61%, reduced lung edema, and markedly improved oxygenation by increasing PaO2/FiO2 from 66 ± 13 mmHg (mean ± SEM) to 246 ± 45 mmHg compared to 380 ± 18 mmHg in sham animals. Colchicine also reduced PaCO2 and respiratory acidosis. Lung neutrophil recruitment, assessed by myeloperoxidase immunostaining, was greatly increased after injury from 1.16 ± 0.19% to 8.86 ± 0.66% and significantly reduced by colchicine to 5.95 ± 1.13%. Increased lung NETosis was also reduced by therapy. Circulating leukocytosis after ALI was not reduced by colchicine therapy, but neutrophils reactivity and CD4 and CD8 cell surface expression on lymphocyte populations were restored. Colchicine reduces ALI and respiratory failure in experimental ARDS in relation with reduced lung neutrophil recruitment and reduced circulating leukocyte activation. This study supports the clinical development of colchicine for the prevention of ARDS in conditions causing ALI.
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Affiliation(s)
- Jocelyn Dupuis
- Montreal Heart Institute Research Center, Montreal, Quebec, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Martin G. Sirois
- Montreal Heart Institute Research Center, Montreal, Quebec, Canada
- Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Eric Rhéaume
- Montreal Heart Institute Research Center, Montreal, Quebec, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Quang T. Nguyen
- Montreal Heart Institute Research Center, Montreal, Quebec, Canada
| | | | - Genevieve Brand
- Montreal Heart Institute Research Center, Montreal, Quebec, Canada
| | | | | | | | - David Rhainds
- Montreal Heart Institute Research Center, Montreal, Quebec, Canada
| | | | - Jean-Claude Tardif
- Montreal Heart Institute Research Center, Montreal, Quebec, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
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34
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Hu L, Chen H, Zhang X, Feng Z, Zhang H, Meng Q. Rosiglitazone ameliorates radiation-induced intestinal inflammation in rats by inhibiting NLRP3 inflammasome and TNF-α production. JOURNAL OF RADIATION RESEARCH 2020; 61:842-850. [PMID: 32876675 PMCID: PMC7674707 DOI: 10.1093/jrr/rraa062] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 07/08/2020] [Indexed: 02/05/2023]
Abstract
Radiation-induced acute intestinal injury is a common and serious occurrence following abdominal and pelvic irradiation. The Nod-like receptor protein 3 (NLRP3)-dependant inflammasome and inflammation activation is crucial in this process. In a pre-experimental design of radiation-induced intestinal injury, we found that rosiglitazone inhibited caspase-1 which is a key marker of inflammasome activation. The purpose of the present study was to clarify the inhibitory effect of rosiglitazone on the NLRP3 inflammasome both in vivo and in vitro. Radiation-induced intestinal injury after rosiglitazone treatment, and the expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), caspase-1 and NLRP3 in a radiation-induced intestinal injury model in a rat and macrophages were observed. We found that rosiglitazone ameliorated radiation-induced intestinal injury in rats by suppressing the expression of caspase-1, NLRP3, IL-1β and TNF-α. Treatment with rosiglitazone in vitro reduced the expression of NLRP3, and the NLRP3 activator monosodium urate (MSU) reversed the inhibition of IL-1β and TNF-α by rosiglitazone in macrophages. MSU reversed the protective effect of rosiglitazone on radiation-induced intestinal injury in rats by reversing the rosiglitazone-induced inhibition of IL-1β and TNF-α. Taken together, these findings indicate that the peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates radiation-induced intestine inflammation in rats via inhibiting the induction of the NLRP3-dependent inflammasome in macrophages.
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Affiliation(s)
- Liqiong Hu
- Department of Intensive Care Unit of Guangzhou Red Cross hospital, Medical College, Jinan University, Guangzhou 51000, China
| | - Hao Chen
- Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, China
| | | | - Zhencheng Feng
- Guangzhou institute of traumatic surgery, Guangzhou Red Cross hospital, Medical College, Jinan University, Guangzhou 510000, China
| | - Haifeng Zhang
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 51000, China
| | - Qingqi Meng
- Guangzhou institute of traumatic surgery, Guangzhou Red Cross hospital, Medical College, Jinan University, Guangzhou 510000, China
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Bertocchi I, Foglietta F, Collotta D, Eva C, Brancaleone V, Thiemermann C, Collino M. The hidden role of NLRP3 inflammasome in obesity-related COVID-19 exacerbations: Lessons for drug repurposing. Br J Pharmacol 2020; 177:4921-4930. [PMID: 32776354 PMCID: PMC7436458 DOI: 10.1111/bph.15229] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/17/2020] [Accepted: 08/02/2020] [Indexed: 02/07/2023] Open
Abstract
COVID-19, the illness caused by SARS-CoV-2, has a wide-ranging clinical spectrum that, in the worst-case scenario, involves a rapid progression to severe acute respiratory syndrome and death. Epidemiological data show that obesity and diabetes are among the main risk factors associated with high morbidity and mortality. The increased susceptibility to SARS-CoV-2 infection documented in obesity-related metabolic derangements argues for initial defects in defence mechanisms, most likely due to an elevated systemic metabolic inflammation ("metaflammation"). The NLRP3 inflammasome is a master regulator of metaflammation and has a pivotal role in the pathophysiology of either obesity or diabetes. Here, we discuss the most recent findings suggesting contribution of NLRP3 inflammasome to the increase in complications in COVID-19 patients with diabesity. We also review current pharmacological strategies for COVID-19, focusing on treatments whose efficacy could be due, at least in part, to interference with the activation of the NLRP3 inflammasome. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.
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Affiliation(s)
- Ilaria Bertocchi
- Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Italy.,University of Turin, Neuroscience Institute of the Cavalieri-Ottolenghi Foundation, Orbassano (TORINO), Italy
| | - Federica Foglietta
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Debora Collotta
- Department of Drug Science and Technology, University of Turin, Turin, Italy
| | - Carola Eva
- Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Italy.,University of Turin, Neuroscience Institute of the Cavalieri-Ottolenghi Foundation, Orbassano (TORINO), Italy
| | | | - Christoph Thiemermann
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Massimo Collino
- Department of Drug Science and Technology, University of Turin, Turin, Italy
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Yang M, Lv H, Liu Q, Zhang L, Zhang R, Huang X, Wang X, Han B, Hou S, Liu D, Wang G, Hou J, Yu B. Colchicine Alleviates Cholesterol Crystal-Induced Endothelial Cell Pyroptosis through Activating AMPK/SIRT1 Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9173530. [PMID: 32733639 PMCID: PMC7378601 DOI: 10.1155/2020/9173530] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 05/20/2020] [Indexed: 12/11/2022]
Abstract
Cholesterol crystal- (CC-) induced endothelial cell inflammation and pyroptosis play an important role in the development of cardiovascular diseases, especially in atherosclerosis (AS). Increasing evidence suggests that cholesterol crystals are known to be a pivotal pathological marker of atherosclerotic plaque vulnerability. As a classical nonspecific anti-inflammatory drug, colchicine has been widely used in the treatment of acute gout. However, whether colchicine could alleviate CC-induced endothelial cell injury and the related mechanisms remains to be addressed. In this study, the protective effect of colchicine on human umbilical vein endothelial cells (HUVECs) was confirmed. Our results revealed that after cotreatment with colchicine and cholesterol crystals in endothelial cells, the uptake of cholesterol crystals was significantly decreased, the cell viability was obviously increased, and the release of lactate dehydrogenase (LDH) and the number of pyroptotic cells decreased significantly; then, the expression of NLRP3 inflammasome-related proteins and various inflammatory factors was also visibly suppressed; moreover, as a potent activator of NLRP3 inflammasome, the intracellular ROS level was clearly reduced, while mitochondrial membrane potential improved significantly. In addition, the expression levels of AMP-dependent kinase (AMPK) pathway-related proteins as well as various antioxidant enzymes were elevated notably in varying degrees. However, the above effects of colchicine were completely offset by the treatment of siRNA targeting AMPKα and Sirtuin1 (SIRT1). Therefore, we conclude that colchicine plays a crucial role in alleviating the intracellular inflammatory response and NLRP3 inflammation activation, attenuating the levels of cellular oxidative stress and pyroptosis in endothelial cells via regulating AMPK/SIRT1 signaling, which may be a concrete mechanism for the secondary prevention of cardiovascular diseases.
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Affiliation(s)
- Mengyue Yang
- The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, Heilongjiang 150086, China
- Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Hang Lv
- The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, Heilongjiang 150086, China
- Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Qi Liu
- The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, Heilongjiang 150086, China
- Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Lu Zhang
- Department of Cardiology, The Affiliated Cardiovascular Hospital of Xiamen University, Xiamen, Fujian 316006, China
| | - Ruoxi Zhang
- The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, Heilongjiang 150086, China
- Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Xingtao Huang
- The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, Heilongjiang 150086, China
- Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Xuedong Wang
- The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, Heilongjiang 150086, China
- Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Baihe Han
- The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, Heilongjiang 150086, China
- Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Shenglong Hou
- The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, Heilongjiang 150086, China
- Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Dandan Liu
- The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, Heilongjiang 150086, China
- Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Gang Wang
- The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, Heilongjiang 150086, China
- Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Jingbo Hou
- The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, Heilongjiang 150086, China
- Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Bo Yu
- The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, Heilongjiang 150086, China
- Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
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Pan H, Lin Y, Dou J, Fu Z, Yao Y, Ye S, Zhang S, Wang N, Liu A, Li X, Zhang F, Chen D. Wedelolactone facilitates Ser/Thr phosphorylation of NLRP3 dependent on PKA signalling to block inflammasome activation and pyroptosis. Cell Prolif 2020; 53:e12868. [PMID: 32656909 PMCID: PMC7507381 DOI: 10.1111/cpr.12868] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 06/14/2020] [Accepted: 06/15/2020] [Indexed: 12/13/2022] Open
Abstract
Objectives Wedelolactone exhibits regulatory effects on some inflammatory diseases. However, the anti‐inflammatory mechanism of wedelolactone has not been entirely unravelled. Therefore, the present study focuses on investigating the mechanism of wedelolactone on NLRP3 inflammasome in macrophages and its influence on MSU‐induced inflammation. Materials and Methods BMDM, J774A.1 and PMA‐differentiated THP‐1 macrophages were primed with LPS and then stimulated with ATP or nigericin or MSU crystal in the presence or absence of wedelolactone. The cell lysates and supernatants were collected to detect NLRP3 inflammasome components such as NLRP3, ASC and caspase 1, as well as pyroptosis and IL‐1β production. In addition, the anti‐inflammatory effects of wedelolactone on MSU‐induced peritonitis and arthritis mice were also evaluated. Results We found that wedelolactone broadly inhibited NLRP3 inflammasome activation and pyroptosis and IL‐1β secretion. Wedelolactone also block ASC oligomerization and speck formation. The inhibitory effects of wedelolactone were abrogated by PKA inhibitor H89, which also attenuated wedelolactone‐enhanced Ser/Thr phosphorylation of NLRP3 at PKA‐specific sites. Importantly, wedelolactone could abate MSU‐induced IL‐1β production and neutrophils migration into peritoneal cavity, and reduced caspase 1 (p20) and IL‐1β expression in the joint tissue of MSU‐induced arthritis. Conclusion Our results indicate that wedelolactone promotes the Ser/Thr phosphorylation of NLRP3 to inhibit inflammasome activation and pyroptosis partly through potentiating PKA signalling, thus identifying its potential use for treating MSU‐induced peritonitis and gouty arthritis.
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Affiliation(s)
- Hao Pan
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, P.R China.,Dongguan & Guangzhou University of Chinese Medicine Cooperative Academy of Mathematical Engineering for Chinese Medicine, Dongguan, P.R China
| | - Yuqing Lin
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, P.R China
| | - Jianping Dou
- Department of Human Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, P.R China
| | - Zhen Fu
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, P.R China
| | - Yanqing Yao
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, P.R China
| | - Shanyu Ye
- Department of Human Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, P.R China
| | - Saixia Zhang
- Center for Experimental Teaching, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, P.R China
| | - Neng Wang
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, P.R China
| | - Aijun Liu
- Center for Experimental Teaching, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, P.R China
| | - Xican Li
- School of Chinese Herbal Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R China
| | - Fengxue Zhang
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, P.R China
| | - Dongfeng Chen
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, P.R China.,Department of Human Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, P.R China
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Awad AS, Elariny HA, Sallam AS. The possible protective effect of colchicine against liver damage induced by renal ischemia-reperfusion injury: role of Nrf2 and NLRP3 inflammasome. Can J Physiol Pharmacol 2020; 98:849-854. [PMID: 32640174 DOI: 10.1139/cjpp-2020-0230] [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] [Indexed: 01/20/2023]
Abstract
Ischemia-reperfusion injury (IRI) induces an inflammatory response and production of reactive oxygen species, which affects the organs remote to the sites of renal IR. However, remote effects of renal IRI on the liver need further investigations. Renal injury associated with liver disease is a common clinical problem. Colchicine is an established drug for microtubule stabilization that may reduce tissue injury and has antioxidant and antiinflammatory effects. The aim of the present study was (i) to assess the hepatic changes after induction of renal IRI, (ii) to explore the possible protective effect of colchicine on liver injury following renal IRI, and (iii) to investigate the possible mechanisms underlying the potential effect. Forty rats were randomly divided into four groups: sham operation group, colchicine-treated group, IR group, and colchicine-treated IR group. Colchicine treatment improved liver function (ALT/AST) after renal IRI, decreased hepatic oxidative stress and cell apoptosis by reducing hepatic MDA, upregulating hepatic total antioxidant capacity, Nrf2, and HO-1. Furthermore, colchicine inhibited inflammatory responses by downregulating hepatic NLRP3 inflammasome, IL-1β, and caspase-1. Colchicine attenuates renal IRI-induced liver injury in rats. This effect may be due to reducing inflammation and oxidative stress markers.
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Affiliation(s)
- Azza Sayed Awad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Hemat A Elariny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Amany Said Sallam
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Menoufia University, Menofia, Egypt
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Liang Y, Zhou HF, Tong M, Chen L, Ren K, Zhao GJ. Colchicine inhibits endothelial inflammation via NLRP3/CRP pathway. Int J Cardiol 2020; 294:55. [PMID: 31522718 DOI: 10.1016/j.ijcard.2019.06.070] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 06/25/2019] [Indexed: 01/13/2023]
Affiliation(s)
- Yin Liang
- Department of Histology and Embryology, Guilin Medical University, Guilin, Guangxi 541004, China; Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, China
| | - Hui-Fang Zhou
- Department of Histology and Embryology, Guilin Medical University, Guilin, Guangxi 541004, China; Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, China
| | - Min Tong
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Lu Chen
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Kun Ren
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
| | - Guo-Jun Zhao
- Department of Histology and Embryology, Guilin Medical University, Guilin, Guangxi 541004, China.
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40
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Shah A. Novel Coronavirus-Induced NLRP3 Inflammasome Activation: A Potential Drug Target in the Treatment of COVID-19. Front Immunol 2020; 11:1021. [PMID: 32574259 PMCID: PMC7248552 DOI: 10.3389/fimmu.2020.01021] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 04/28/2020] [Indexed: 12/18/2022] Open
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Watanabe T, Fujiwara Y, Chan FKL. Current knowledge on non-steroidal anti-inflammatory drug-induced small-bowel damage: a comprehensive review. J Gastroenterol 2020; 55:481-495. [PMID: 31865463 PMCID: PMC7188723 DOI: 10.1007/s00535-019-01657-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 12/10/2019] [Indexed: 02/04/2023]
Abstract
Recent advances in small-bowel endoscopy such as capsule endoscopy have shown that non-steroidal anti-inflammatory drugs (NSAIDs) frequently damage the small intestine, with the prevalence rate of mucosal breaks of around 50% in chronic users. A significant proportion of patients with NSAIDs-induced enteropathy are asymptomatic, but some patients develop symptomatic or complicated ulcers that need therapeutic intervention. Both inhibition of prostaglandins due to the inhibition of cyclooxygenases and mitochondrial dysfunction secondary to the topical effect of NSAIDs play a crucial role in the early process of injury. As a result, the intestinal barrier function is impaired, which allows enterobacteria to invade the mucosa. Gram-negative bacteria and endogenous molecules coordinate to trigger inflammatory cascades via Toll-like receptor 4 to induce excessive expression of cytokines such as tumor necrosis factor-α and to activate NLRP3 inflammasome, a multiprotein complex that processes pro-interleukin-1β into its mature form. Finally, neutrophils accumulate in the mucosa, resulting in intestinal ulceration. Currently, misoprostol is the only drug that has a proven beneficial effect on bleeding small intestinal ulcers induced by NSAIDs or low-dose aspirin, but its protection is insufficient. Therefore, the efficacy of the combination of misoprostol with other drugs, especially those targeting the innate immune system, should be assessed in the next step.
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Affiliation(s)
- Toshio Watanabe
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan.
| | - Yasuhiro Fujiwara
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Francis K L Chan
- Department of Medicine and Therapeutics, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China
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42
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Affiliation(s)
- Davide Cao
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York (D.C., M.C., R.M.)
| | - Mauro Chiarito
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York (D.C., M.C., R.M.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele – Milan, Italy (M.C.)
| | - Roxana Mehran
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York (D.C., M.C., R.M.)
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43
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Jia L, Chen H, Yang J, Fang X, Niu W, Zhang M, Li J, Pan X, Ren Z, Sun J, Pan LL. Combinatory antibiotic treatment protects against experimental acute pancreatitis by suppressing gut bacterial translocation to pancreas and inhibiting NLRP3 inflammasome pathway. Innate Immun 2019; 26:48-61. [PMID: 31615312 PMCID: PMC6974879 DOI: 10.1177/1753425919881502] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gut bacterial translocation following impaired gut barrier is a critical
determinant of initiating and aggravating acute pancreatitis (AP). Antibiotic
combination (ABX; vancomycin, neomycin and polymyxin b) is capable of reducing
gut bacteria, but its efficacy in AP prevention and the underlying mechanism
have not been investigated yet. AP was induced in BALB/c mice by caerulein (CAE)
hyperstimulation. We found that ABX supplementation attenuated the severity of
AP as evidenced by reduced pancreatic oedema and myeloperoxidase activity. The
protective effect was also confirmed by improved histological morphology of the
pancreas and decreased pro-inflammatory markers (IL-1β, TNF-α, MCP-1) in
pancreas. ABX administration inhibits the activation of colonic TLR4/NLRP3
inflammasome pathway. Subsequently, down-regulated NLRP3 resulted in decreased
colonic pro-inflammation (IL-1β, IL-6, MCP-1) and enhanced gut physical barrier
as evidenced by up-regulation of tight junction proteins including occludin,
claudin-1 and ZO-1, as well as improved histological morphology of the colon.
Together, combinatory ABX therapy inhibited the translocation of gut bacteria to
pancreas and its amplification effects on pancreatic inflammation by inhibiting
the pancreatic NLRP3 pathway, and inhibiting intestinal-pancreatic inflammatory
responses. The current study provides the basis for potential clinical
application of ABX in AP.
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Affiliation(s)
- Lingling Jia
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Hao Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Jun Yang
- Public Health Research Center and Department of General Surgery, Affiliated Hospital of Jiangnan University
| | - Xin Fang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Wenying Niu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Ming Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Jiahong Li
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Xiaohua Pan
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Zhengnan Ren
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Jia Sun
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Li-Long Pan
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, P. R. China
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Koc K, Cerig S, Ucar S, Colak S, Bakir M, Erol HS, Yildirim S, Hosseinigouzdagani M, Simsek Ozek N, Aysin F, Fehim Kocpinar E, Budak H, Geyikoglu F. Gastroprotective effects of oleuropein and thymol on indomethacin-induced gastric ulcer in Sprague-Dawley rats. Drug Chem Toxicol 2018; 43:441-453. [PMID: 30426792 DOI: 10.1080/01480545.2018.1530261] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ethnopharmacological studies demonstrated that thymol (Thym) and oleuropein (Ole) have therapeutic potential for gastric ulcers. The molecular mechanism underlying the gastroprotective effects of these compounds have not been elucidated yet especially for their individual and combination use at high dose. Therefore, this study was conducted to explore their gastroprotective mechanisms on indomethacin (Indo)-induced gastric ulcer model. Ole (50,100, 250, and 500 mg/kg) and Thym (50,100, 200, and 500 mg/kg) were orally administered to the rats 10 min before the induction of ulcer with Indo. The combination of 500 mg/kg doses of Ole and Thym were applied. The gastric mucosa was evaluated histopathologically. Moreover, TAC/TOS, tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), endothelial nitric oxide synthase (eNOS), and caspase-3 levels were assessed by ELISA and the caspase-3 and TNF-α expressions were quantified by qRT-PCR. Indo-induced histopathological changes while Ole and Thym pretreatment prevented these effects. Unlike the 500 mg/kg dose of Ole treatment, the 500 mg/kg dose of Thym administration enhanced these damages. The decreased TAC, PGE2 levels and increased TOS, eNOS, TNF-α, caspase-3 levels were obtained in Indo group. However, these changes were reversed by Ole and Thym groups except the 500 mg/kg dose of Thym and the combination treatment groups. Similar trends were observed in the caspase-3 and TNF-α expression levels. These results demonstrated that enhanced inflammation, oxidant/antioxidant imbalance, and apoptotic activities were occurred in Indo, 500 mg/kg dose of Thym and the combination treatment groups while not in the other groups. The findings demonstrated the gastroprotective ability of Ole and low doses of Thym in gastric ulcer models.
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Affiliation(s)
- Kubra Koc
- Department of Biology, Faculty of Science, Ataturk University, Erzurum, Turkey
| | - Salim Cerig
- Department of Biology, Faculty of Science, Ataturk University, Erzurum, Turkey
| | - Serap Ucar
- Department of Biology, Faculty of Science, Ataturk University, Erzurum, Turkey
| | - Suat Colak
- Department of Biology, Erzincan University, Erzincan, Turkey
| | - Murat Bakir
- Department of Biology, Faculty of Science, Ataturk University, Erzurum, Turkey
| | - Huseyin Serkan Erol
- Department of Biochemistry, Faculty of Veterinary, Ataturk University, Erzurum, Turkey
| | - Serkan Yildirim
- Department of Pathology, Faculty of Veterinary, Ataturk University, Erzurum, Turkey
| | | | - Nihal Simsek Ozek
- Department of Biology, Faculty of Science, Ataturk University, Erzurum, Turkey
| | - Ferhunde Aysin
- Department of Biology, Faculty of Science, Ataturk University, Erzurum, Turkey.,East Anatolian High Technology Research and Application Center (DAYTAM), Ataturk University, Erzurum, Turkey
| | - Enver Fehim Kocpinar
- Department of Medical Laboratory, Techniques Vocational School of Health Services, Alparslan University, Mus, Turkey
| | - Harun Budak
- Department of Molecular Biology and Genetics, Faculty of Science, Ataturk University, Erzurum, Turkey
| | - Fatime Geyikoglu
- Department of Biology, Faculty of Science, Ataturk University, Erzurum, Turkey
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Martínez GJ, Celermajer DS, Patel S. The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation. Atherosclerosis 2018; 269:262-271. [DOI: 10.1016/j.atherosclerosis.2017.12.027] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 12/18/2017] [Accepted: 12/19/2017] [Indexed: 12/22/2022]
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Abstract
Inflammasome signalling is an emerging pillar of innate immunity and has a central role in the regulation of gastrointestinal health and disease. Activation of the inflammasome complex mediates both the release of the pro-inflammatory cytokines IL-1β and IL-18 and the execution of a form of inflammatory cell death known as pyroptosis. In most cases, these mediators of inflammation provide protection against bacterial, viral and protozoal infections. However, unchecked inflammasome activities perpetuate chronic inflammation, which underpins the molecular and pathophysiological basis of gastritis, IBD, upper and lower gastrointestinal cancer, nonalcoholic fatty liver disease and obesity. Studies have also highlighted an inflammasome signature in the maintenance of gut microbiota and gut-brain homeostasis. Harnessing the immunomodulatory properties of the inflammasome could transform clinical practice in the treatment of acute and chronic gastrointestinal and extragastrointestinal diseases. This Review presents an overview of inflammasome biology in gastrointestinal health and disease and describes the value of experimental and pharmacological intervention in the treatment of inflammasome-associated clinical manifestations.
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Baicalein ameliorates TNBS-induced colitis by suppressing TLR4/MyD88 signaling cascade and NLRP3 inflammasome activation in mice. Sci Rep 2017; 7:16374. [PMID: 29180692 PMCID: PMC5703971 DOI: 10.1038/s41598-017-12562-6] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 09/12/2017] [Indexed: 12/27/2022] Open
Abstract
Baicalein (5,6,7-trihydroxyflavone), a predominant bioactive component isolated from the root of Scutellaria baicalensis Georgi, has established potent anti-inflammatory activity via multi-targeted mechanisms. However, little is known about the effect of baicalein on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, which shares pathology related to human Crohn’s disease (CD). The present study demonstrated that baicalein alleviated the severity of TNBS-induced colitis in mice by decreasing the activity of myeloperoxidase (MPO) and the expression of pro-inflammatory mediators. The decline in the activation of nuclear factor-kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) correlated with a decrease in the expression of mucosal toll-like receptor 4 (TLR4) and its adaptor myeloid differentiation factor 88 (MyD88). In vitro, baicalein down-regulated the TLR4/MyD88 signaling cascades (NF-κB and MAPKs) in lipopolysaccharide (LPS)-stimulated macrophages. At the upstream level, baicalein bound to the hydrophobic region of the myeloid differentiation protein-2 (MD-2) pocket and inhibited the formation of the LPS-induced MD-2/TLR4 complex. Furthermore, baicalein reduced NOD-like receptor 3 (NLRP3) inflammasome activation and downstream interleukin-1β expression in a dose-dependent manner. Our study provided evidence for the first time that baicalein attenuated TNBS-induced colitis, at least in part, via inhibition of TLR4/MyD88 signaling cascade as well as inactivation of NLRP3 inflammasome.
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48
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Inflammasomes and intestinal inflammation. Mucosal Immunol 2017; 10:865-883. [PMID: 28401932 DOI: 10.1038/mi.2017.19] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Accepted: 02/19/2017] [Indexed: 02/04/2023]
Abstract
The inflammasome is a cytosolic multi-protein innate immune rheostat, sensing a variety of endogenous and environmental stimuli, and regulating homeostasis or damage control. In the gastrointestinal tract, inflammasomes orchestrate immune tolerance to microbial and potentially food-related signals or drive the initiation of inflammatory responses to invading pathogens. When inadequately regulated, intestinal inflammasome activation leads to a perpetuated inflammatory response leading to immune pathology and tissue damage. In this review, we present the main features of the predominant types of inflammasomes participating in intestinal homeostasis and inflammation. We then discuss current controversies and open questions related to their functions and implications in disease, highlighting how pathological inflammasome over-activation or impaired function impact gut homeostasis, the microbiome ecosystem, and the propensity to develop gut-associated diseases. Collectively, understanding of the molecular basis of intestinal inflammasome signaling may be translated into clinical manipulation of this fundamental pathway as a potential immune modulatory therapeutic intervention.
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Brucella Melitensis 16M Regulates the Effect of AIR Domain on Inflammatory Factors, Autophagy, and Apoptosis in Mouse Macrophage through the ROS Signaling Pathway. PLoS One 2016; 11:e0167486. [PMID: 27907115 PMCID: PMC5132199 DOI: 10.1371/journal.pone.0167486] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 11/15/2016] [Indexed: 01/18/2023] Open
Abstract
Brucellosis is a highly contagious zoonosis caused by Brucella. Brucella can invade and persist inside host cells, which results in chronic infection. We constructed AIR interference and overexpression lentiviruses to acquire AIR interference, overexpression, and rescue stable expression cell lines. We also established a Brucella melitensis 16M-infected macrophage model, which was treated with either the vehicle control or NAC (ROS scavenger N-acetylcysteine (NAC) for 0, 3, 6, 12, and 24 h. Confocal laser microscopy, transmission electron microscopy, fluorescence quantitative PCR, flow cytometry, ELISA, and Western blot were used to detect inflammation, cell autophagy and apoptosis-related protein expression levels, ROS levels, and the distribution of mitochondria. It was found that after interference and overexpression of AIR, ROS release was significantly changed, and mitochondria became abnormally aggregated. B. melitensis 16M activated the NLRP3/AIM2 inflammatory complex, and induced RAW264.7 cells to secrete IL-1β and IL-18 through the ROS pathway. B. melitensis 16M also altered autophagy-related gene expression, increased autophagy activity, and induced cell apoptosis through the ROS pathway. The results showed that after B. melitensis 16M infection, ROS induced apoptosis, inflammation, and autophagy while AIR inhibited autophagosome maturation and autophagy initiation. Autophagy negatively regulated the activation of inflammasomes and prevented inflammation from occurring. In addition, mitophagy could promote cell apoptosis.
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