|
1
|
Fitzpatrick-Schmidt T, Dasa V, Leonardi C, Ferguson TF, Welsh DA, Molina PE, Ronis MJJ, Edwards S. Intersection of alcohol use, pain symptoms, and negative affect in total knee arthroplasty patients and people with HIV. THE JOURNAL OF PAIN 2025; 32:105446. [PMID: 40403859 DOI: 10.1016/j.jpain.2025.105446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 05/13/2025] [Accepted: 05/15/2025] [Indexed: 05/24/2025]
Abstract
Alcohol is a well-known analgesic, although excessive alcohol use can lead to hyperalgesia and heightened negative affect. This cross-sectional study examined associations between alcohol use, self-reported pain, and negative affective symptoms in two distinct cohorts of patients vulnerable to chronic pain: individuals undergoing total knee arthroplasty (TKA) surgery and a cohort of people with HIV (PWH). Participants were enrolled in two clinical studies: a retrospective study of patients undergoing TKA and a longitudinal study of PWH, the New Orleans Alcohol Use in HIV (NOAH) cohort. Based on the Alcohol Use Disorders Identification Test - Consumption (AUDIT-C) score, participants in both cohorts were stratified as alcohol drinkers (AUDIT-C ≥ 1) or non-drinkers (AUDIT-C < 1). In the NOAH cohort, pain intensity and interference were assessed using the 36-Item Short Form Survey (SF-36). In the TKA cohort, self-reported pain was quantified using the Pain Intensity and Pain Interference items from the Patient-Reported Outcomes Measurement Information System® (PROMIS-29) and the Knee Osteoarthritis and Outcomes Score (KOOS) Pain scores. Alcohol drinkers reported fewer pain symptoms compared to non-drinkers across both cohorts, and females with HIV reported more pain compared to males with HIV. Furthermore, pain symptoms were associated with increased anxiety and depression symptoms in both cohorts, and in PWH these associations appeared stronger in drinkers compared to non-drinkers. These findings suggest that although alcohol may offer some analgesic benefits, patients should be cautioned about its use for self-medication, as it may increase risk for pain-related negative affective comorbidities. PERSPECTIVE: Alcohol can both relieve and exacerbate pain. The current study discovered that ongoing alcohol use was associated with fewer self-reported pain symptoms but appeared to increase associations between pain and negative affective symptoms in two vulnerable cohorts. Findings support cautioning patients against the recurring use of alcohol for pain management.
Collapse
Affiliation(s)
- Taylor Fitzpatrick-Schmidt
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Vinod Dasa
- Department of Orthopedics, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Claudia Leonardi
- School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Tekeda F Ferguson
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - David A Welsh
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Patricia E Molina
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Martin J J Ronis
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Scott Edwards
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
| |
Collapse
|
|
2
|
Chen S, Dan L, Xiang L, He Q, Hu D, Gao Y. The role of gut flora-driven Th cell responses in preclinical rheumatoid arthritis. J Autoimmun 2025; 154:103426. [PMID: 40300482 DOI: 10.1016/j.jaut.2025.103426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 03/24/2025] [Accepted: 04/22/2025] [Indexed: 05/01/2025]
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder with an immune pathogenesis that evolves over decades. Preclinical RA (PreRA) represents a dynamic immune phase preceding clinical RA, marked by the loss of autoimmune tolerance, the appearance of tissue-invasive effector T cells, and the production of autoantibodies (such as antibodies against citrullinated proteins and rheumatoid factors). Extensive research has demonstrated that gut microbiota influence mucosal T-cell responses, driving the progression of PreRA through multiple mechanisms, including altered intestinal permeability, gene-environment interactions, bacterial antigenic specificity, molecular mimicry, and metabolite production. Environmental risk factors such as smoking, hormonal changes, and high-sodium (Na) diets, may contribute to RA pathogenesis via the gut microbiome. The next challenge in RA research lies in developing therapeutic strategies to intervene during the asymptomatic autoimmune phase, where dietary adjustments, natural compounds, probiotics, and other approaches could effectively modulate gut flora to prevent or delay RA onset.
Collapse
Affiliation(s)
- Shuanglan Chen
- Department of Rheumatology and Immunology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Lijuan Dan
- Department of Infection, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Li Xiang
- Department of Rheumatology and Immunology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Qingman He
- Department of Rheumatology and Immunology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Dongsen Hu
- Sichuan Jinxin Xi'nan Women's and Children's Hospital Co., Ltd, Chengdu, 610023, China
| | - Yongxiang Gao
- Department of Rheumatology and Immunology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| |
Collapse
|
|
3
|
Rodolfi S, Selmi C. Environmental factors and rheumatic diseases. Best Pract Res Clin Rheumatol 2025:102053. [PMID: 40140341 DOI: 10.1016/j.berh.2025.102053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 02/26/2025] [Indexed: 03/28/2025]
Abstract
The pathogenesis and pathophysiology of rheumatic diseases is complex and relies on the interaction of different factors. The common view is that the pathological autoimmunity develops in genetically predisposed individuals upon exposure to an environmental trigger. This highlights the importance of recognizing and deconstructing the effects of environmental agents in rheumatic diseases. Several factors have been identified in the last decades, with detrimental or protective effects, impacting not only on disease onset, but also on its natural history. Cigarette smoking has been identified as one of the strongest environmental risk factors, being associated with disease development and severity for several rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and spondyloarthropathies. Moreover, other airborne pollutants, such as silica, solvents, asbestos and metals are recognized risk factors for rheumatic diseases. The effect of some other agents is however not straightforward, of which a remarkable example is alcohol consumption. Alcohol has been associated with both pro- and anti-inflammatory effects, exerting a variable effect on rheumatic diseases depending on quantity and frequency of consumption, as well as sex and ethnicity. Similarly, ultraviolet light exposure has been associated with a higher risk of SLE but lower risk of RA. The relationship between microbial exposure and autoimmunity is also complex: while some infectious agents increase the risk of rheumatic diseases, it is widely accepted that less exposure to microbial agents, particularly during immune system development, increases the risk of autoimmunity. Furthermore, in recent years the spotlight has switched to the human microbiome, as alterations in organ-specific microbiome composition are anticipated to be early participants in the onset of immune-mediated illnesses. The aim of this review is to highlight the most relevant environmental factors and their role in Rheumatology, with a specific focus on proposed pathophysiological effect and correlation with clinical outcomes.
Collapse
Affiliation(s)
- Stefano Rodolfi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Carlo Selmi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy.
| |
Collapse
|
|
4
|
Terracina S, Caronti B, Lucarelli M, Francati S, Piccioni MG, Tarani L, Ceccanti M, Caserta M, Verdone L, Venditti S, Fiore M, Ferraguti G. Alcohol Consumption and Autoimmune Diseases. Int J Mol Sci 2025; 26:845. [PMID: 39859557 PMCID: PMC11766456 DOI: 10.3390/ijms26020845] [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: 11/26/2024] [Revised: 12/31/2024] [Accepted: 01/04/2025] [Indexed: 01/27/2025] Open
Abstract
Alcohol is the second-most misused substance after tobacco. It has been identified as a causal factor in more than 200 diseases and 5.3% of all deaths and is associated with significant behavioral, social, and economic difficulties. As alcohol consumption may modulate the immune system's regulatory mechanisms to avoid attacking the body's tissues, it has been proven to play a dichotomic role in autoimmune diseases (ADs) based on the quantity of consumption. In this review, we report updated evidence on the role of alcohol in ADs, with a focus on alcohol addiction and the human biological immune system and the relationship between them, with alcohol as a risk or protective factor. Then, in this narrative review, we report the main evidence on the most studied ADs where alcohol represents a key modulator, including autoimmune thyroiditis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, diabetes, allergic rhinitis, and primary biliary cholangitis. Alcohol at low-moderate dosages seems mostly to have a protective role in these diseases, while at higher dosages, the collateral risks surpass possible benefits. The specific mechanisms by which low-to-moderate alcohol intake relieves AD symptoms are not yet fully understood; however, emerging studies suggest that alcohol may have a systemic immunomodulatory effect, potentially altering the balance of anti-inflammatory innate and adaptive immune cells, as well as cytokines (via the NF-κB or NLRP3 pathways). It might influence the composition of the gut microbiome (increasing amounts of beneficial gut microbes) and the production of their fatty acid metabolites, such as short-chain fatty acids (SCFAs) and polyunsaturated fatty acids (PUFAs), as well as elevated concentrations of acetate, high-density lipoprotein (HDL), and nitric oxide (NO). Unfortunately, a definite acceptable daily intake (ADI) of ethanol is complicated to establish because of the many mechanisms associated with alcohol consumption such that despite the interesting content of these findings, there is a limit to their applicability and risks should be weighed in cases of alcoholic drinking recommendations. The aim of future studies should be to modulate those beneficial pathways involved in the alcohol-protective role of ADs with various strategies to avoid the risks associated with alcohol intake.
Collapse
Affiliation(s)
- Sergio Terracina
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy; (S.T.); (M.L.); (S.F.)
| | - Brunella Caronti
- Department of Human Neurosciences, Sapienza University Hospital of Rome, 00185 Rome, Italy
| | - Marco Lucarelli
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy; (S.T.); (M.L.); (S.F.)
- Pasteur Institute, Cenci Bolognetti Foundation, Sapienza University of Rome, 00161 Rome, Italy
| | - Silvia Francati
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy; (S.T.); (M.L.); (S.F.)
| | - Maria Grazia Piccioni
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00161 Rome, Italy; (M.G.P.); (L.T.)
| | - Luigi Tarani
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00161 Rome, Italy; (M.G.P.); (L.T.)
| | - Mauro Ceccanti
- SITAC, Società Italiana per il Trattamento dell’Alcolismo e le sue Complicanze, 00185 Rome, Italy;
| | - Micaela Caserta
- Institute of Molecular Biology and Pathology (IBPM-CNR), 00161 Rome, Italy; (M.C.); (L.V.)
| | - Loredana Verdone
- Institute of Molecular Biology and Pathology (IBPM-CNR), 00161 Rome, Italy; (M.C.); (L.V.)
| | - Sabrina Venditti
- Department of Biology and Biotechnologies “Charles Darwin”, Sapienza University of Rome, 00161 Rome, Italy;
| | - Marco Fiore
- Institute of Biochemistry and Cell Biology (IBBC-CNR), c/o Department of Sensory Organs, Sapienza University of Rome, 00161 Rome, Italy
| | - Giampiero Ferraguti
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy; (S.T.); (M.L.); (S.F.)
| |
Collapse
|
|
5
|
Ma K, Miao L, Li B, Yu W, Liu F, Liu K, Li Y, Huang C, Yang Z. Mechanism of action of Nrf2 and its related natural regulators in rheumatoid arthritis. J Orthop Surg Res 2024; 19:759. [PMID: 39543632 PMCID: PMC11566362 DOI: 10.1186/s13018-024-05221-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 10/29/2024] [Indexed: 11/17/2024] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis that can lead to joint deformities. To date, more than 18 million individuals worldwide have been diagnosed with RA, making it one of the most prevalent autoimmune diseases globally and posing a significant threat to public health and safety. Due to the complex pathogenesis of the disease, which involves autoimmunity, genetics, inflammation and oxidative stress in the body's tissues, the current drug therapy generally targets a single molecule, and effective and efficient drugs involving multiple levels and targets are lacking; thus, there is an urgent need for high-quality research and treatment in this field. Nuclear transcription factor erythroid 2-associated factor 2 (Nrf2) plays a crucial role in cellular resistance to oxidative stress and electrophilic attacks and is a potential pharmacological target for chronic disease treatment. While currently no drugs that target Nrf2 have been approved specifically for RA treatment, such an approach holds great significance. In recent years, the use of natural products to treat RA and other chronic conditions has become increasingly widespread because of their superior efficacy and minimal side effects. Therefore, this article provides a review of the mechanism of Nrf2 in RA and summarizes natural products that target Nrf2 and its associated pathways in the treatment of RA, aiming to offer new insights and strategies for the prevention and management of RA.
Collapse
Affiliation(s)
- Ke Ma
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Lili Miao
- Department of Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Bo Li
- Department of Orthopaedics, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Wenfei Yu
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Fengzhao Liu
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Kun Liu
- Department of Orthopaedics, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Yang Li
- Department of Orthopaedics, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Chengcheng Huang
- Department of Endocrinology, Shandong University of Traditional Chinese Medicine Affiliated Hospital, Jinan, 250014, Shandong, China
| | - Zhenguo Yang
- Department of Orthopaedics, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China.
| |
Collapse
|
|
6
|
He K, Huang H. The Significant Role of Alcohol in the Relationship between C-Reactive Protein and Self-Reported Osteoarthritis. J Nutr 2024; 154:600-609. [PMID: 38219865 DOI: 10.1016/j.tjnut.2024.01.009] [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: 11/14/2023] [Revised: 12/31/2023] [Accepted: 01/09/2024] [Indexed: 01/16/2024] Open
Abstract
BACKGROUND Despite the known inflammatory nature of osteoarthritis (OA) and the established role of C-reactive protein (CRP) as an inflammation marker, the influence of alcohol consumption on the CRP-OA relationship remains uncertain, with previous research providing conflicting results. OBJECTIVES This study aims to examine the potential moderating effect of alcohol on the association between CRP concentrations and self-reported OA. METHODS We conducted a cross-sectional study involving 50,259 participants, all data collected from NHANES between 2005-2010 and 2015-2018. A multivariable logistic regression model was used to analyze the relationship between CRP and OA. RESULTS We found a nonsignificant positive association between CRP concentration and prevalence of self-reported OA after adjusting for covariates in the raw dataset or 5 multiple imputed datasets. In the stratified analysis by alcohol drinking, for every 10 mg/L higher in CRP concentration, the prevalence of self-reported OA was higher by 13 % in nondrinkers (P = 0.007, adjusted for covariates). Conversely, for every 10 mg/L higher in CRP concentration, the prevalence of self-reported OA was lower by 59 % in drinkers (P = 0.005, adjusted for covariates). Furthermore, we discovered that the directions of the association between CRP concentrations (10 mg/L) and prevalence of self-reported OA [odds ratio (OR) < 1 in the drinking subgroup and OR > 1 in the no-drinking subgroup] were stable in both the main and sensitivity analyses. The significant interaction between CRP concentration and alcohol drinking on the prevalence of self-reported OA was shown in most of our analyses (P-interaction < 0.05). CONCLUSION Alcohol consumption may be an interaction factor between CRP and self-reported OA. To our knowledge, our findings are the first to highlight the importance of incorporating analysis of alcohol consumption differences into future studies of CRP and self-reported OA.
Collapse
Affiliation(s)
- Kaiyin He
- Department of Clinical Nutrition, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, P. R. China
| | - Hao Huang
- Department of Pain Management, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, P. R. China.
| |
Collapse
|
|
7
|
Hübner M, Zaiss MM, Azizov V. Double-edged sword: Alcohol's effect on rheumatoid arthritis and beyond. Joint Bone Spine 2024; 91:105626. [PMID: 37543136 DOI: 10.1016/j.jbspin.2023.105626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 07/21/2023] [Indexed: 08/07/2023]
Affiliation(s)
- Michel Hübner
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander- University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Mario M Zaiss
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander- University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
| | - Vugar Azizov
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander- University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| |
Collapse
|
|
8
|
Jin L, Zhang Z, Pan P, Zhao Y, Zhou M, Liu L, Zhai Y, Wang H, Xu L, Mei D, Zhang H, Yang Y, Hua J, Zhang X, Zhang L. Low-dose ethanol consumption inhibits neutrophil extracellular traps formation to alleviate rheumatoid arthritis. Commun Biol 2023; 6:1088. [PMID: 37884797 PMCID: PMC10603044 DOI: 10.1038/s42003-023-05473-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 10/17/2023] [Indexed: 10/28/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Ethanol consumption has been reported to reduce morbidity in RA patients, but the mechanism behind it remains unclear. Our results showed that Muribaculaceae was predominant in the gut microbiota of mice after ethanol treatment, and the levels of microbiota metabolite acetate were increased. Acetate reduced arthritis severity in collagen-induced arthritis (CIA) mice, which was associated with a decrease in the articular neutrophils and the myeloperoxidase-deoxyribonucleic acid complex in serum. Meanwhile, in vitro experiments confirmed that acetate affected neutrophil activity by acting on G-protein-coupled receptor 43, which reduced endoplasmic reticulum stress in neutrophils and inhibited neutrophil extracellular traps formation. Furthermore, exogenous acetate reversed CIA mice with exacerbated gut microbial disruption, further confirming that the effect of gut microbial metabolite acetate on neutrophils in vivo is crucial for the immune regulation. Our findings illuminate the metabolic and cellular mechanisms of the gut-joint axis in the regulation of autoimmune arthritis, and may offer alternative avenues to replicate or induce the joint-protective benefits of ethanol without associated detrimental effects.
Collapse
Affiliation(s)
- Lin Jin
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, Anhui, China
- Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui, China
| | - Ziwei Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, Anhui, China
- Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui, China
| | - Pin Pan
- Department of orthopedics, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, Anhui, China
| | - Yuchen Zhao
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, Anhui, China
- Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui, China
| | - Mengqi Zhou
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, Anhui, China
- Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui, China
| | - Lianghu Liu
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, Anhui, China
- Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui, China
| | - Yuanfang Zhai
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, Anhui, China
- Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui, China
| | - Han Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, Anhui, China
- Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui, China
| | - Li Xu
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, Anhui, China
- Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui, China
| | - Dan Mei
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, Anhui, China
- Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui, China
| | - Han Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, Anhui, China
- Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui, China
| | - Yining Yang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, Anhui, China
- Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui, China
| | - Jinghan Hua
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, Anhui, China
- Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui, China
| | - Xianzheng Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China.
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, Anhui, China.
- Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui, China.
| | - Lingling Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China.
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, Anhui, China.
- Anti-inflammatory Immune Drugs Collaborative Innovation Center, Hefei, 230032, Anhui, China.
| |
Collapse
|
|
9
|
Azizov V, Hübner M, Frech M, Hofmann J, Kubankova M, Lapuente D, Tenbusch M, Guck J, Schett G, Zaiss MM. Alcohol-sourced acetate impairs T cell function by promoting cortactin acetylation. iScience 2023; 26:107230. [PMID: 37485352 PMCID: PMC10362326 DOI: 10.1016/j.isci.2023.107230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 02/28/2023] [Accepted: 06/23/2023] [Indexed: 07/25/2023] Open
Abstract
Alcohol is among the most widely consumed dietary substances. Excessive alcohol consumption damages the liver, heart, and brain. Alcohol also has strong immunoregulatory properties. Here, we report how alcohol impairs T cell function via acetylation of cortactin, a protein that binds filamentous actin and facilitates branching. Upon alcohol consumption, acetate, the metabolite of alcohol, accumulates in lymphoid organs. T cells exposed to acetate, exhibit increased acetylation of cortactin. Acetylation of cortactin inhibits filamentous actin binding and hence reduces T cell migration, immune synapse formation and activation. While mutated, acetylation-resistant cortactin rescues the acetate-induced inhibition of T cell migration, primary mouse cortactin knockout T cells exhibited impaired migration. Acetate-induced cytoskeletal changes effectively inhibited activation, proliferation, and immune synapse formation in T cells in vitro and in vivo in an influenza infection model in mice. Together these findings reveal cortactin as a possible target for mitigation of T cell driven autoimmune diseases.
Collapse
Affiliation(s)
- Vugar Azizov
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Michel Hübner
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Michael Frech
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Jörg Hofmann
- Division of Biochemistry, Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Marketa Kubankova
- Max Planck Institute for the Science of Light & Max Planck Zentrum für Physik und Medizin, Erlangen, Germany
| | - Dennis Lapuente
- Institute of Clinical and Molecular Virology, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Matthias Tenbusch
- Institute of Clinical and Molecular Virology, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Jochen Guck
- Max Planck Institute for the Science of Light & Max Planck Zentrum für Physik und Medizin, Erlangen, Germany
| | - Georg Schett
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Mario M. Zaiss
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| |
Collapse
|
|
10
|
Tsofack Ngueguim F, Kamkumo Gounoue R, Hubert Donfack J, Manefen Simo S, Jouonzo J, Ngapout Fifen R, Djomeni Dzeufiet PD, Dimo T. Chromolaena odorata (L.) R. M. King and H. Robinson Leaves Aqueous Extract Improves the Femoral Head in Ethanol-Induced Osteonecrosis in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2023; 2023:5436771. [PMID: 37416805 PMCID: PMC10322325 DOI: 10.1155/2023/5436771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 05/28/2023] [Accepted: 06/07/2023] [Indexed: 07/08/2023]
Abstract
Chronic alcohol consumption damages bone formation and causes bone pathology, including osteonecrosis of the femoral head. The aim of this work was to evaluate the effects of the leaf aqueous extract of Chromolaena odorata (C. odorata) on the femoral head in ethanol-induced osteonecrosis in rats. Animals received alcohol (40°) at 3 g/kg for 12 weeks. A group of animals were sacrificed to attest to the instalment of osteonecrosis by using histopathological analysis. The remaining animals received alcohol concomitantly with the plant extract (150, 300, or 600 mg/kg) or diclofenac (1 mg/kg) for 28 additional days. At the end of the experimental period, biochemical parameters including total cholesterol, triglycerides, calcium, alkaline phosphatase (ALP), reduced glutathione (GSH), malondialdehyde (MDA), nitrite, superoxide dismutase (SOD), and catalase activities were measured. Histopathological and histomorphometry analyses of femurs were also assessed. The administration of alcohol, irrespective of the experimental period, induced a significant increase in total cholesterol (p < 0.05) and triglyceride (p < 0.01) and a decrease in ALP (p < 0.05) and calcium (p < 0.05-p < 0.001) levels. Intoxicated animals showed an alteration in oxidative stress parameters accompanied by a significant drop in bone cortical thickness and density with necrosis and marked bone resorption. The concomitant administration of the plant with ethanol reversed the alcohol-induced bone defect, characterized by the improvement of the lipid profile (p < 0.001), bone calcium concentration (p < 0.05), bone ALP activity (p < 0.001), oxidative stress parameters, improved cortical bone thickness (p < 0.01), and bone density (p < 0.05). These results are supported by the absence of bone resorption with an obvious effect at a dose of 300 mg/kg. The pharmacological effect of the extract on ethanol-induced osteonecrosis of the femoral head is probably due to its osteogenic, hypolipidemic, and antioxidant properties, justifying its use in Cameroonian folk medicine for articulation and bone pain management.
Collapse
Affiliation(s)
- Florence Tsofack Ngueguim
- Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé 1, P.O. Box 812, Yaoundé, Cameroon
| | - Raceline Kamkumo Gounoue
- Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé 1, P.O. Box 812, Yaoundé, Cameroon
| | - Jean Hubert Donfack
- Department of Pharmaceutical Sciences, Faculty of Medicine and Pharmaceutical Sciences, University of Dschang, P.O. Box 96, Dschang, Cameroon
| | - Sandra Manefen Simo
- Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé 1, P.O. Box 812, Yaoundé, Cameroon
| | - Josiane Jouonzo
- Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé 1, P.O. Box 812, Yaoundé, Cameroon
| | - Rodrigue Ngapout Fifen
- Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé 1, P.O. Box 812, Yaoundé, Cameroon
| | - Paul Desire Djomeni Dzeufiet
- Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé 1, P.O. Box 812, Yaoundé, Cameroon
| | - Théophile Dimo
- Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé 1, P.O. Box 812, Yaoundé, Cameroon
| |
Collapse
|
|
11
|
Alfredsson L, Klareskog L, Hedström AK. Disease Activity and Health-Related Quality of Life Among Patients With Rheumatoid Arthritis With Different Alcohol Consumption Habits. Arthritis Rheumatol 2023; 75:872-878. [PMID: 36629408 DOI: 10.1002/art.42442] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 12/16/2022] [Accepted: 01/05/2023] [Indexed: 01/12/2023]
Abstract
OBJECTIVE Multiple studies have found a relationship between alcohol consumption and disease activity in rheumatoid arthritis (RA), although reverse causation has been suggested to explain the association. We aimed to study the relationship between alcohol consumption and disease activity, disease progression, and health-related quality of life in patients with RA. METHODS We followed up 1,228 patients with newly diagnosed RA from a population-based case-control study, Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Drinkers and non-drinkers were compared to evaluate risk of unfavorable outcomes regarding disease activity and health-related quality of life. Odds ratios with 95% confidence intervals were calculated using logistic regression models. RESULTS Non-drinkers at baseline had higher disease activity and estimated their pain as more severe compared to drinkers. At 1 year of follow-up, non-drinkers reported higher swollen and tender joint counts and experienced more pain and fatigue, lower global health scores, and lower health-related quality of life. The inverse relationship between alcohol consumption and RA-specific outcomes was also observed when comparing drinkers and non-drinkers who had not changed their alcohol consumption habits at or after the year of disease onset. Those who stopped drinking postbaseline experienced higher disease activity, more pain, and lower health-related quality of life at 1 year of follow-up, compared to drinkers, although there was no difference in disease activity at baseline between drinkers who continued versus discontinued drinking. Our findings argue against bias due to reverse causation. CONCLUSION Alcohol consumption was associated with lower disease activity and higher health-related quality of life in RA patients in a dose-dependent manner.
Collapse
Affiliation(s)
- Lars Alfredsson
- Institute of Environmental Medicine, Karolinska Institutet, and Centre for Occupational and Environmental Medicine, Region Stockholm, Stockholm, Sweden
| | - Lars Klareskog
- Division of Rheumatology, Department of Medicine, Karolinska Institutet at Karolinska University Hospital, Solna, Stockholm, Sweden
| | - Anna Karin Hedström
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
12
|
Wang L, Song L, Ma J, Wang H, Li Y, Huang D. Alcohol induces apoptosis and autophagy in microglia BV-2 cells. Food Chem Toxicol 2023; 177:113849. [PMID: 37217066 DOI: 10.1016/j.fct.2023.113849] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/06/2023] [Accepted: 05/19/2023] [Indexed: 05/24/2023]
Abstract
Alcohol (ethanol) has proven to be toxic to nearly all organs, with the brain being one of the principal targets. As one of the important components of the brain's blood-brain barrier (BBB) and central nervous system, the state of microglia may be associated with some symptoms of alcohol intoxication. In the present study, microglia BV-2 cells were exposed to various concentrations of alcohol for 3 or 12 h, imitating different stages of drunkenness after alcohol use, respectively. From the perspective of the autophagy-phagocytosis axis, our findings show that alcohol alters autophagy levels or promotes apoptosis in BV-2 cells. The current study adds to the understanding of the action mechanisms of alcohol neurotoxicity. We anticipate that this study will increase public awareness of alcohol's negative effects and contribute to the creation of novel alcoholism treatment approaches.
Collapse
Affiliation(s)
- Luchen Wang
- State Key Laboratory of Food Science and Technology, International Institute of Food Innovation, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, 235 Nanjing East Road, Nanchang, 330047, China
| | - Lingmin Song
- State Key Laboratory of Food Science and Technology, International Institute of Food Innovation, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, 235 Nanjing East Road, Nanchang, 330047, China
| | - Juan Ma
- State Key Laboratory of Food Science and Technology, International Institute of Food Innovation, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, 235 Nanjing East Road, Nanchang, 330047, China
| | - Huimei Wang
- State Key Laboratory of Food Science and Technology, International Institute of Food Innovation, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, 235 Nanjing East Road, Nanchang, 330047, China
| | - Yingzhi Li
- State Key Laboratory of Food Science and Technology, International Institute of Food Innovation, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, 235 Nanjing East Road, Nanchang, 330047, China
| | - Danfei Huang
- State Key Laboratory of Food Science and Technology, International Institute of Food Innovation, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, 235 Nanjing East Road, Nanchang, 330047, China.
| |
Collapse
|
|
13
|
Attur M, Scher JU, Abramson SB, Attur M. Role of Intestinal Dysbiosis and Nutrition in Rheumatoid Arthritis. Cells 2022; 11:2436. [PMID: 35954278 PMCID: PMC9368368 DOI: 10.3390/cells11152436] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/11/2022] Open
Abstract
Rheumatoid arthritis is a chronic systemic immune-mediated disease caused by genetic and environmental factors. It is often characterized by the generation of autoantibodies that lead to synovial inflammation and eventual multi-joint destruction. A growing number of studies have shown significant differences in the gut microbiota composition of rheumatoid arthritis (RA) patients compared to healthy controls. Environmental factors, and changes in diet and nutrition are thought to play a role in developing this dysbiosis. This review aims to summarize the current knowledge of intestinal dysbiosis, the role of nutritional factors, and its implications in the pathogenesis of rheumatoid arthritis and autoimmunity. The future direction focuses on developing microbiome manipulation therapeutics for RA disease management.
Collapse
Affiliation(s)
- Malavikalakshmi Attur
- Drexel University College of Medicine, Drexel University, Philadelphia, PA 19129, USA
| | - Jose U Scher
- Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY 10003, USA
| | - Steven B. Abramson
- Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY 10003, USA
| | - Mukundan Attur
- Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY 10003, USA
| |
Collapse
|
|
14
|
Venetsanopoulou AI, Alamanos Y, Voulgari PV, Drosos AA. Epidemiology of rheumatoid arthritis: genetic and environmental influences. Expert Rev Clin Immunol 2022; 18:923-931. [PMID: 35904251 DOI: 10.1080/1744666x.2022.2106970] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a chronic systemic disease characterized by articular involvement and extra-articular manifestations. The incidence and prevalence of the disease vary across populations, and there is an ongoing debate on whether a change of RA occurrence over time exists or is due to methodological issues and other biases. Moreover, the disease's onset is related to an interaction of genetic and environmental factors that influence its expression. AREAS COVERED This review explores the latest knowledge on RA epidemiology and the possible risk factors associated with its presentation to identify potential warning signs that may in the future help disease management. EXPERT OPINION Current epidemiological evidence suggests a significant impact of smoking, sex hormones, and lifestyle status in RA occurrence. However, the association between these variables has not yet been thoroughly studied. Still, their effect must be interpreted as they may present subsequently integral indicators for a more rational approach of the disease.
Collapse
Affiliation(s)
- Aliki I Venetsanopoulou
- Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
| | - Yannis Alamanos
- Institute of Epidemiology, Preventive Medicine and Public Health, Corfu, Greece
| | - Paraskevi V Voulgari
- Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
| | - Alexandros A Drosos
- Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
| |
Collapse
|
|
15
|
Arleevskaya M, Takha E, Petrov S, Kazarian G, Renaudineau Y, Brooks W, Larionova R, Korovina M, Valeeva A, Shuralev E, Mukminov M, Kravtsova O, Novikov A. Interplay of Environmental, Individual and Genetic Factors in Rheumatoid Arthritis Provocation. Int J Mol Sci 2022; 23:ijms23158140. [PMID: 35897715 PMCID: PMC9329780 DOI: 10.3390/ijms23158140] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/18/2022] [Accepted: 07/19/2022] [Indexed: 02/05/2023] Open
Abstract
In this review, we explore systemization of knowledge about the triggering effects of non-genetic factors in pathogenic mechanisms that contribute to the development of rheumatoid arthritis (RA). Possible mechanisms involving environmental and individual factors in RA pathogenesis were analyzed, namely, infections, mental stress, sleep deprivation ecology, age, perinatal and gender factors, eating habits, obesity and smoking. The non-genetic factors modulate basic processes in the body with the impact of these factors being non-specific, but these common challenges may be decisive for advancement of the disease in the predisposed body at risk for RA. The provocation of this particular disease is associated with the presence of congenital loci minoris resistentia. The more frequent non-genetic factors form tangles of interdependent relationships and, thereby, several interdependent external factors hit one vulnerable basic process at once, either provoking or reinforcing each other. Understanding the specific mechanisms by which environmental and individual factors impact an individual under RA risk in the preclinical stages can contribute to early disease diagnosis and, if the factor is modifiable, might be useful for the prevention or delay of its development.
Collapse
Affiliation(s)
- Marina Arleevskaya
- Central Research Laboratory, Kazan State Medical Academy, 420012 Kazan, Russia; (E.T.); (S.P.); (G.K.); (R.L.); (M.K.); (A.V.); (E.S.); (M.M.)
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia;
- Correspondence: ; Tel.: +7-89172-886-679; Fax: +7-843-238-5413
| | - Elena Takha
- Central Research Laboratory, Kazan State Medical Academy, 420012 Kazan, Russia; (E.T.); (S.P.); (G.K.); (R.L.); (M.K.); (A.V.); (E.S.); (M.M.)
| | - Sergey Petrov
- Central Research Laboratory, Kazan State Medical Academy, 420012 Kazan, Russia; (E.T.); (S.P.); (G.K.); (R.L.); (M.K.); (A.V.); (E.S.); (M.M.)
- Institute of Environmental Sciences, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Gevorg Kazarian
- Central Research Laboratory, Kazan State Medical Academy, 420012 Kazan, Russia; (E.T.); (S.P.); (G.K.); (R.L.); (M.K.); (A.V.); (E.S.); (M.M.)
| | - Yves Renaudineau
- Department of Immunology, CHU Toulouse, INSERM U1291, CNRS U5051, University Toulouse IIII, 31000 Toulouse, France;
| | - Wesley Brooks
- Department of Chemistry, University of South Florida, Tampa, FL 33620, USA;
| | - Regina Larionova
- Central Research Laboratory, Kazan State Medical Academy, 420012 Kazan, Russia; (E.T.); (S.P.); (G.K.); (R.L.); (M.K.); (A.V.); (E.S.); (M.M.)
| | - Marina Korovina
- Central Research Laboratory, Kazan State Medical Academy, 420012 Kazan, Russia; (E.T.); (S.P.); (G.K.); (R.L.); (M.K.); (A.V.); (E.S.); (M.M.)
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia;
| | - Anna Valeeva
- Central Research Laboratory, Kazan State Medical Academy, 420012 Kazan, Russia; (E.T.); (S.P.); (G.K.); (R.L.); (M.K.); (A.V.); (E.S.); (M.M.)
| | - Eduard Shuralev
- Central Research Laboratory, Kazan State Medical Academy, 420012 Kazan, Russia; (E.T.); (S.P.); (G.K.); (R.L.); (M.K.); (A.V.); (E.S.); (M.M.)
- Institute of Environmental Sciences, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Malik Mukminov
- Central Research Laboratory, Kazan State Medical Academy, 420012 Kazan, Russia; (E.T.); (S.P.); (G.K.); (R.L.); (M.K.); (A.V.); (E.S.); (M.M.)
- Institute of Environmental Sciences, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Olga Kravtsova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia;
| | - Andrey Novikov
- Mathematical Center, Sobolev Instiute of Mathematics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia;
| |
Collapse
|
|
16
|
Aloke C, Ohanenye IC, Aja PM, Ejike CECC. Phytochemicals from medicinal plants from African forests with potentials in rheumatoid arthritis management. J Pharm Pharmacol 2022; 74:1205-1219. [PMID: 35788356 DOI: 10.1093/jpp/rgac043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 06/04/2022] [Indexed: 11/13/2022]
Abstract
OBJECTIVES Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammation, pain, and cartilage and bone damage. There is currently no cure for RA. It is however managed using nonsteroidal anti-inflammatory drugs, corticosteroids and disease-modifying anti-rheumatic drugs, often with severe side effects. Hidden within Africa's lush vegetation are plants with diverse medicinal properties including anti-RA potentials. This paper reviews the scientific literature for medicinal plants, growing in Africa, with reported anti-RA activities and identifies the most abundant phytochemicals deserving research attention. A search of relevant published scientific literature, using the major search engines, such as Pubmed/Medline, Scopus, Google Scholar, etc. was conducted to identify medicinal plants, growing in Africa, with anti-RA potentials. KEY FINDINGS Twenty plants belonging to 17 families were identified. The plants are rich in phytochemicals, predominantly quercetin, rutin, catechin, kaempferol, etc., known to affect some pathways relevant in RA initiation and progression, and therefore useful in its management. SUMMARY Targeted research is needed to unlock the potentials of medicinal plants by developing easy-to-use technologies for preparing medicines from them. Research attention should focus on how best to exploit the major phytochemicals identified in this review for the development of anti-RA 'green pharmaceuticals'.
Collapse
Affiliation(s)
- Chinyere Aloke
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, Alex Ekwueme Federal University, Ndufu-Alike, Ebonyi State, Nigeria.,Protein Structure-Function and Research Unit, School of Molecular and Cell Biology, Faculty of Science, University of the Witwatersrand, Braamfontein 2050, Johannesburg, South Africa
| | - Ikenna C Ohanenye
- School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa Ontario Canada
| | - Patrick M Aja
- Department of Biochemistry, Faculty of Science, Ebonyi State University Abakaliki, Ebonyi State, Nigeria
| | - Chukwunonso E C C Ejike
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, Alex Ekwueme Federal University, Ndufu-Alike, Ebonyi State, Nigeria
| |
Collapse
|
|
17
|
Malmhäll-Bah E, Andersson KME, Erlandsson MC, Akula MK, Brisslert M, Wiel C, El Zowalaty AE, Sayin VI, Bergö MO, Bokarewa MI. Rho-GTPase dependent leukocyte interaction generates pro-inflammatory thymic Tregs and causes arthritis. J Autoimmun 2022; 130:102843. [PMID: 35643017 DOI: 10.1016/j.jaut.2022.102843] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/13/2022] [Accepted: 05/13/2022] [Indexed: 12/23/2022]
Abstract
Conditional mutation of protein geranylgeranyltransferase type I (GGTase-I) in macrophages (GLC) activates Rho-GTPases and causes arthritis in mice. Knocking out Rag1 in GLC mice alleviates arthritis which indicates that lymphocytes are required for arthritis development in those mice. To study GLC dependent changes in the adaptive immunity, we isolated CD4+ T cells from GLC mice (CD4+GLCs). Spleen and joint draining lymph nodes (dLN) CD4+GLCs exhibited high expression of Cdc42 and Rac1, which repressed the caudal HOXA proteins and activated the mechanosensory complex to facilitate migration. These CDC42/RAC1 rich CD4+GLCs presented a complete signature of GARP+NRP1+IKZF2+FOXP3+ regulatory T cells (Tregs) of thymic origin. Activation of the β-catenin/Lef1 axis promoted a pro-inflammatory Th1 phenotype of Tregs, which was strongly associated with arthritis severity. Knockout of Cdc42 in macrophages of GLC mice affected CD4+ cell biology and triggered development of non-thymic Tregs. Knockout of Rac1 and RhoA had no such effects on CD4+ cells although it alleviated arthritis in GLC mice. Disrupting macrophage and T cell interaction with CTLA4 fusion protein reduced the Th1-driven inflammation and enrichment of thymic Tregs into dLNs. Antigen challenge reinforced the CD4+GLC phenotype in non-arthritic heterozygote GLC mice and increased accumulation of Rho-GTPase expressing thymic Tregs in dLNs. Our study demonstrates an unexpected role of macrophages in stimulating the development of pro-inflammatory thymic Tregs and reveal activation of Rho-GTPases behind their arthritogenic phenotype.
Collapse
Affiliation(s)
- Eric Malmhäll-Bah
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Box 480, 40530, Gothenburg, Sweden
| | - Karin M E Andersson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Box 480, 40530, Gothenburg, Sweden
| | - Malin C Erlandsson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Box 480, 40530, Gothenburg, Sweden; Rheumatology Clinic, Sahlgrenska University Hospital, Gröna Stråket 16, 41346, Gothenburg, Sweden
| | - Murali K Akula
- Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 40530, Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Mikael Brisslert
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Box 480, 40530, Gothenburg, Sweden
| | - Clotilde Wiel
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden
| | - Ahmed E El Zowalaty
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
| | - Volkan I Sayin
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden
| | - Martin O Bergö
- Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 40530, Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Biosciences and Nutrition, Karolinska Institute, 14183, Huddinge, Sweden
| | - Maria I Bokarewa
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Box 480, 40530, Gothenburg, Sweden; Rheumatology Clinic, Sahlgrenska University Hospital, Gröna Stråket 16, 41346, Gothenburg, Sweden.
| |
Collapse
|
|
18
|
Yu XH, Bo L, Cao RR, Yang YQ, He P, Lei SF, Deng FY. Systematic Evaluation of Rheumatoid Arthritis Risk by Integrating Lifestyle Factors and Genetic Risk Scores. Front Immunol 2022; 13:901223. [PMID: 35874719 PMCID: PMC9299428 DOI: 10.3389/fimmu.2022.901223] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/07/2022] [Indexed: 11/13/2022] Open
Abstract
Background Effective identification of high-risk rheumatoid arthritis (RA) individuals is still a challenge. Whether the combined effects of multiple previously reported genetic loci together with lifestyle factors can improve the prediction of RA risk remains unclear. Methods Based on previously reported results and a large-scale Biobank dataset, we constructed a polygenic risk score (PRS) for RA to evaluate the combined effects of the previously identified genetic loci in both case-control and prospective cohorts. We then evaluated the relationships between several lifestyles and RA risk and determined healthy lifestyles. Then, the joint effects of healthy lifestyles and genetic risk on RA risk were evaluated. Results We found a positive association between PRS and RA risk (OR = 1.407, 95% confidence interval (CI) = 1.354~1.463; HR = 1.316, 95% CI = 1.257~1.377). Compared with the low genetic risk group, the group with intermediate or high genetic risk had a higher risk (OR = 1.347, 95% CI = 1.213~1.496; HR = 1.246, 95% CI = 1.108~1.400) (OR = 2.169, 95% CI = 1.946~2.417; HR = 1.762, 95% CI = 1.557~1.995). After adjusting for covariates, we found protective effects of three lifestyles (no current smoking, regular physical activity, and moderate body mass index) on RA risk and defined them as healthy lifestyles. Compared with the individuals with low genetic risks and favorable lifestyles, those with high genetic risks and unfavorable lifestyles had as high as OR of 4.637 (95%CI = 3.767~5.708) and HR of 3.532 (95%CI = 2.799~4.458). Conclusions In conclusion, the integration of PRS and lifestyles can improve the prediction of RA risk. High RA risk can be alleviated by adopting healthy lifestyles but aggravated by adopting unfavorable lifestyles.
Collapse
Affiliation(s)
- Xing-Hao Yu
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| | - Lin Bo
- Department of Rheumatology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Rong-Rong Cao
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| | - Yi-Qun Yang
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| | - Pei He
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| | - Shu-Feng Lei
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| | - Fei-Yan Deng
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| |
Collapse
|
|
19
|
Hart AP, Laufer TM. A review of signaling and transcriptional control in T follicular helper cell differentiation. J Leukoc Biol 2022; 111:173-195. [PMID: 33866600 DOI: 10.1002/jlb.1ri0121-066r] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
T follicular helper (Tfh) cells are a critical component of adaptive immunity and assist in optimal Ab-mediated defense. Multiple effector functions of Tfh support germinal center B cell survival, Ab class switching, and plasma cell maturation. In the past 2 decades, the phenotype and functional characteristics of GC Tfh have been clarified allowing for robust studies of the Th subset including activation signals and environmental cues controlling Tfh differentiation and migration during an immune response. A unique, 2-step differentiation process of Tfh has been proposed but the mechanisms underlying transition between unstable Tfh precursors and functional mature Tfh remain elusive. Likewise, newly identified transcriptional regulators of Tfh development have not yet been incorporated into our understanding of how these cells might function in disease. Here, we review the signals and downstream transcription factors that shape Tfh differentiation including what is known about the epigenetic processes that maintain Tfh identity. It is proposed that further evaluation of the stepwise differentiation pattern of Tfh will yield greater insights into how these cells become dysregulated in autoimmunity.
Collapse
Affiliation(s)
- Andrew P Hart
- Division of Rheumatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Terri M Laufer
- Division of Rheumatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Rheumatology, Department of Medicine, Corporal Michael C. Crescenz VA Medical Center, Philadelphia, PA, 19104, USA
| |
Collapse
|
|
20
|
Hedenstierna L, Bellocco R, Ye W, Adami HO, Åkerstedt T, Trolle Lagerros Y, Hedström AK. Effects of alcohol consumption and smoking on risk for RA: results from a Swedish prospective cohort study. RMD Open 2021; 7:rmdopen-2020-001379. [PMID: 33414179 PMCID: PMC7797247 DOI: 10.1136/rmdopen-2020-001379] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 10/22/2020] [Accepted: 12/10/2020] [Indexed: 12/16/2022] Open
Abstract
Objective Several, but not all studies, have shown a dose-dependent inverse association with alcohol consumption and rheumatoid arthritis (RA), whereas smoking is an established risk factor for RA. We aimed to study the association between alcohol consumption and RA incidence and investigate a potential interaction between alcohol and smoking habits, regarding RA incidence. Methods We used a prospective cohort study, based on 41 068 participants with detailed assessment of alcohol intake, smoking and potential confounders at baseline in 1997. We ascertained a total of 577 incident cases of RA during a mean of 17.7 years of follow-up through linkage to nationwide and essentially complete databases. Multivariate Cox proportional hazards models were used to estimate HR with 95% CI. Interaction on the additive scale between alcohol and smoking was estimated by calculating the attributable proportion due to interaction (AP). Results Overall, alcohol consumption was associated with a 30% reduced incidence of RA (HR 0.69, 95% CI 0.55 to 0.86) with a dose–response relationship (p value for trend <0.001) which remained significant after stratification by age and smoking habits. The positive association between smoking and RA incidence was reduced with increasing alcohol consumption (p value for trend <0.001). A synergistic effect was observed between alcohol and smoking (AP 0.40, 95% CI 0.15 to 0.64), indicating that 40% of the cases among the double exposed are due to the interaction per se. Conclusions Our findings suggest an inverse association between alcohol consumption and RA incidence, and a synergistic effect between alcohol and smoking.
Collapse
Affiliation(s)
- Louise Hedenstierna
- Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden .,Center of Rheumatology, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden
| | - Rino Bellocco
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Hans-Olov Adami
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Clinical Effectiveness Group, Institute of Health and Society, University of Oslo, Oslo, Norway
| | - Torbjörn Åkerstedt
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Stress Research, Stockholm University, Stockholm University, Stockholm, Sweden
| | - Ylva Trolle Lagerros
- Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.,Center for Obesity, Academic Specialst Center, Stockholm Health Services, Stockholm, Sweden
| | - Anna Karin Hedström
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
21
|
Disease Differentiation and Monitoring of Anti-TNF Treatment in Rheumatoid Arthritis and Spondyloarthropathies. Int J Mol Sci 2021; 22:ijms22147389. [PMID: 34299006 PMCID: PMC8307996 DOI: 10.3390/ijms22147389] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 07/03/2021] [Accepted: 07/07/2021] [Indexed: 01/16/2023] Open
Abstract
Rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) are comprehensive immunological disorders. The treatment of these disorders is limited to ameliorating the symptoms and improving the quality of life of patients. In this study, serum samples from RA, AS, and PsA patients were analyzed with metabolomic tools employing the 1H NMR method in combination with univariate and multivariate analyses. The results obtained in this study showed that the changes in metabolites were the highest for AS > RA > PsA. The study demonstrated that the time until remission or until low disease activity is achieved is shortest (approximately three months) for AS, longer for RA and longest for PsA. The statistically common metabolite that was found to be negatively correlated with the healing processes of these disorders is ethanol, which may indicate the involvement of the gut microflora and/or the breakdown of malondialdehyde as a cell membrane lipid peroxide product.
Collapse
|
|
22
|
Turk JN, Zahavi ER, Gorman AE, Murray K, Turk MA, Veale DJ. Exploring the effect of alcohol on disease activity and outcomes in rheumatoid arthritis through systematic review and meta-analysis. Sci Rep 2021; 11:10474. [PMID: 34006854 PMCID: PMC8131728 DOI: 10.1038/s41598-021-89618-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/14/2021] [Indexed: 12/15/2022] Open
Abstract
To evaluate the effects of alcohol consumption on disease activity in rheumatoid arthritis. EMBASE, Pubmed, the Cochrane Library, and Web of Science were searched until July 29, 2020. English language studies that reported disease activity outcomes in rheumatoid arthritis were included. Studies were excluded if they were reviews, case reports, had fewer than 20 patients, or reported on prevalence but not disease activity in RA. Forest plots were used to determine pooled mean difference and were generated on RevMan5.3. Linear regression was used to determine correlations between alcohol and antibody status, gender, and smoking status. The search identified 4126 citations of which 14 were included. The pooled mean difference in DAS28 (95% CI) was 0.34 (0.24, 0.44) (p < 10−5) between drinkers and non-drinkers with lower DAS28 in non-drinkers, 0.33 (0.05, 0.62) (p = 0.02) between heavy drinkers and non-drinkers with lower DAS28 in heavy drinkers, and 0.00 (− 0.30, 0.30) (p = 0.98) between low- and high-risk drinkers.
The mean difference of HAQ assessments was significantly different between those who drink alcohol compared to those who do not, with drinkers reporting lower HAQ scores (0.3 (0.18, 0.41), p < 10−5). There was no significant correlation between drinking and gender, smoking status, or antibody positivity. Alcohol consumption is associated with lower disease activity and self-reported health assessment in rheumatoid arthritis. However, drinking has no correlation with smoking, gender, or antibody status.
Collapse
Affiliation(s)
| | | | - Aine E Gorman
- Department of Rheumatology, Saint Vincent's University Hospital, Dublin 4, Ireland.,EULAR Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, Dublin, Ireland
| | - Kieran Murray
- Department of Rheumatology, Saint Vincent's University Hospital, Dublin 4, Ireland.,EULAR Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, Dublin, Ireland
| | - Matthew A Turk
- Department of Rheumatology, Saint Vincent's University Hospital, Dublin 4, Ireland. .,EULAR Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, Dublin, Ireland.
| | - Douglas J Veale
- Department of Rheumatology, Saint Vincent's University Hospital, Dublin 4, Ireland.,EULAR Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, Dublin, Ireland
| |
Collapse
|
|
23
|
Albrecht K, Zink A. [If smoking, then also drinking? : New aspects on the influence of alcohol and smoking on the risk for rheumatoid arthritis]. Z Rheumatol 2021; 80:563-564. [PMID: 33880617 DOI: 10.1007/s00393-021-01004-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/30/2021] [Indexed: 11/25/2022]
Affiliation(s)
- Katinka Albrecht
- Programmbereich Epidemiologie und Versorgungsforschung, Deutsches Rheuma-Forschungszentrum Berlin, Charitéplatz 1, 10117, Berlin, Deutschland.
| | - Angela Zink
- Programmbereich Epidemiologie und Versorgungsforschung, Deutsches Rheuma-Forschungszentrum Berlin, Charitéplatz 1, 10117, Berlin, Deutschland
| |
Collapse
|
|
24
|
Azizov V, Zaiss MM. Alcohol Consumption in Rheumatoid Arthritis: A Path through the Immune System. Nutrients 2021; 13:1324. [PMID: 33923766 PMCID: PMC8072698 DOI: 10.3390/nu13041324] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/14/2021] [Accepted: 04/15/2021] [Indexed: 12/27/2022] Open
Abstract
Benefits and harms of different components of human diet have been known for hundreds of years. Alcohol is one the highest consumed, abused, and addictive substances worldwide. Consequences of alcohol abuse are increased risks for diseases of the cardiovascular system, liver, and nervous system, as well as reduced immune system function. Paradoxically, alcohol has also been a consistent protective factor against the development of autoimmune diseases such as type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis (RA). Here, we focused on summarizing current findings on the effects of alcohol, as well as of its metabolites, acetaldehyde and acetate, on the immune system and RA. Heavy or moderate alcohol consumption can affect intestinal barrier integrity, as well as the microbiome, possibly contributing to RA. Additionally, systemic increase in acetate negatively affects humoral immune response, diminishing TFH cell as well as professional antigen-presenting cell (APC) function. Hence, alcohol consumption has profound effects on the efficacy of vaccinations, but also elicits protection against autoimmune diseases. The mechanism of alcohol's negative effects on the immune system is multivariate. Future studies addressing alcohol and its metabolite acetate's effect on individual components of the immune system remains crucial for our understanding and development of novel therapeutic pathways.
Collapse
Affiliation(s)
- Vugar Azizov
- Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany;
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Mario M. Zaiss
- Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany;
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| |
Collapse
|
|
25
|
The pre-clinical phase of rheumatoid arthritis: From risk factors to prevention of arthritis. Autoimmun Rev 2021; 20:102797. [PMID: 33746022 DOI: 10.1016/j.autrev.2021.102797] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 01/29/2021] [Indexed: 02/06/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease considered as a multistep process spanning from the interaction of genetic (e.g., shared epitope or non-HLA loci), environmental and behavioral risk factors (e.g., smoking) leading to breaking immune tolerance and autoimmune processes such as the production of autoantibodies (e.g., antibodies against citrullinated proteins ACPA or rheumatoid factors, RF), development of the first symptoms without clinical arthritis, and, finally, the manifestation of arthritis. Despite the typical joint involvement in established RA, the pathogenesis of the disease likely begins far from joint structures: in the lungs or periodontium in association with citrullination, intestinal microbiome, or adipose tissue, which supports normal findings in synovial tissue in ACPA+ patients with arthralgia. The presence of ACPA is detectable even years before the first manifestation of RA. The pre-clinical phase of RA is the period preceding clinically apparent RA with ACPA contributing to the symptoms without subclinical inflammation. While the combination of ACPA and RF increases the risk of progression to RA by up to 10 times, increasing numbers of novel autoantibodies are to be investigated to contribute to the increased risk and pathogenesis of RA. With growing knowledge about the course of RA, new aspiration emerges to cure and even prevent RA, shifting the "window of opportunity" to the pre-clinical phases of RA. The clinical definition of individuals at risk of developing RA (clinically suspect arthralgia, CSA) makes it possible to unify these at-risk individuals' clinical characteristics for "preventive" treatment in ongoing clinical trials using mostly biological or conventional synthetic disease-modifying drugs. However, the combination of symptoms, laboratory, and imaging biomarkers may be the best approach to select the correct target at-risk population. The current review aims to explore different phases of RA and discuss the potential of (non)pharmacological intervention aiming to prevent RA.
Collapse
|
|
26
|
Kim SK, Bae J, Choe JY. The relationship between alcohol consumption and knee osteoarthritis in Korean population over 50 years-old: Results from Korea National Health and Nutrition Examination Survey. Medicine (Baltimore) 2021; 100:e24746. [PMID: 33578626 PMCID: PMC10545239 DOI: 10.1097/md.0000000000024746] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/19/2020] [Accepted: 01/16/2021] [Indexed: 12/29/2022] Open
Abstract
ABSTRACT There is still debate regarding the pathogenic relationship between alcohol intake and osteoarthritis (OA). This study investigated the association between alcohol consumption and knee OA in a Korean population.Among 8058 subjects who participated in the Korea National Health and Nutrition Examination Survey (KNHANES) 2012, a total of 2917 subjects over the age of 50 and taken plain radiography was included in this analysis. Knee OA was classified based on the Kellgren-Lawrence (K-L) grading scale. Multivariate logistic regression analyses were used to evaluate the odds ratios (ORs) and 95% confidence intervals (CIs) of variables for knee OA (K-L grade ≥ 2).There were 1022 subjects with knee OA (29.2%). Subjects with knee OA tended to have lower daily alcohol intake (g/day) than did those without knee OA (10.4 [6.2-14.6] vs. 15.8 [12.8-18.8], P = .04). Similarly, those with knee OA demonstrated less makgeolli intake than did those without knee OA (P = .002). Subjects who consumed >0.6 g/day of beer also demonstrated less knee OA than did those who consumed <0.6 g/day of beer (OR 0.68, 95% CI 0.46-0.99). However, knee OA was not associated with the categories of alcohol consumption amount (g/day), including total daily alcohol intake (g/day), soju daily intake (g/day), and makgeolli daily intake (g/day) (P > .05 of all).Alcohol consumption was negatively associated with prevalence of knee OA in a Korean population. This preliminary observation will need to be confirmed in future studies.
Collapse
Affiliation(s)
- Seong-Kyu Kim
- Division of Rheumatology, Department of Internal Medicine
| | - Jisuk Bae
- Department of Preventive Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea
| | - Jung-Yoon Choe
- Division of Rheumatology, Department of Internal Medicine
| |
Collapse
|
|
27
|
Caslin B, Mohler K, Thiagarajan S, Melamed E. Alcohol as friend or foe in autoimmune diseases: a role for gut microbiome? Gut Microbes 2021; 13:1916278. [PMID: 34224314 PMCID: PMC8259720 DOI: 10.1080/19490976.2021.1916278] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 03/16/2021] [Accepted: 04/01/2021] [Indexed: 02/07/2023] Open
Abstract
Alcohol is well known for promoting systemic inflammation and aggravating multiple chronic health conditions. Thus, alcohol may also be expected to serve as a risk factor in autoimmune diseases. However, emerging data from human and animal studies suggest that alcohol may in fact be protective in autoimmune diseases. These studies point toward alcohol's complex dose-dependent relationship in autoimmune diseases as well as potential modulation by duration and type of alcohol consumption, cultural background and sex. In this review, we will explore alcohol's pro- and anti-inflammatory properties in human and animal autoimmune diseases, including autoimmune diabetes, thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, experimental autoimmune encephalomyelitis and multiple sclerosis. We will also discuss potential mechanisms of alcohol's anti-inflammatory effects mediated by the gut microbiome.
Collapse
Affiliation(s)
- Blaine Caslin
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, United States
| | - Kailey Mohler
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, United States
| | - Shreya Thiagarajan
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, United States
| | - Esther Melamed
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, United States
| |
Collapse
|
|
28
|
Alpízar-Rodríguez D, Finckh A, Gilbert B. The Role of Nutritional Factors and Intestinal Microbiota in Rheumatoid Arthritis Development. Nutrients 2020; 13:nu13010096. [PMID: 33396685 PMCID: PMC7823566 DOI: 10.3390/nu13010096] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 12/10/2020] [Accepted: 12/11/2020] [Indexed: 02/07/2023] Open
Abstract
Evidence about the role of nutritional factors and microbiota in autoimmune diseases, and in rheumatoid arthritis (RA) in particular, has grown in recent years, however many controversies remain. The aim of this review is to summarize the role of nutrition and of the intestinal microbiota in the development of RA. We will focus on selected dietary patterns, individual foods and beverages that have been most consistently associated with RA or with the occurrence of systemic autoimmunity associated with RA. We will also review the evidence for a role of the intestinal microbiota in RA development. We propose that diet and digestive microbiota should be considered together in research, as they interact and may both be the target for future preventive interventions in RA.
Collapse
Affiliation(s)
- Deshiré Alpízar-Rodríguez
- Research Unit, Colegio Mexicano de Reumatología, Mexico City 04318, Mexico
- Correspondence: ; Tel.: +52-55-2525-1853
| | - Axel Finckh
- Department of Rheumatology, Geneva University Hospitals, 1206 Geneva, Switzerland; (A.F.); (B.G.)
| | - Benoît Gilbert
- Department of Rheumatology, Geneva University Hospitals, 1206 Geneva, Switzerland; (A.F.); (B.G.)
| |
Collapse
|
|
29
|
Eloff E, Martinsson K, Ziegelasch M, Cedergren J, Reckner Å, Skogh T, Karlsson L, Ärlemalm A, Borggreven NV, Trouw LA, Kastbom A. Autoantibodies are major predictors of arthritis development in patients with anti-citrullinated protein antibodies and musculoskeletal pain. Scand J Rheumatol 2020; 50:189-197. [PMID: 33243072 DOI: 10.1080/03009742.2020.1818820] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Objectives: Predictors of arthritis development are highly warranted among patients with anti-citrullinated protein antibodies (ACPAs) and musculoskeletal symptoms to optimize clinical management. We aimed to identify clinical and laboratory predictors of arthritis development, including biochemically assessed alcohol consumption, among ACPA-positive patients with musculoskeletal pain.Method: 82 ACPA-positive individuals with musculoskeletal pain but no clinical arthritis were followed for a median of 72 months (interquartile range 57-81 months). We evaluated the prognostic value of baseline clinical and laboratory factors including smoking, symptom duration, age, gender, shared epitope, rheumatoid factor (RF), anti-carbamylated protein antibodies, ACPA levels, erythrocyte sedimentation rate, C-reactive protein levels, tender joint count, patient-reported general well-being, 28-joint Disease Activity Score, and alcohol consumption as measured by phosphatidyl ethanol (PEth) levels in whole blood.Results: During follow-up, 48% developed at least one arthritis. Multivariable analysis revealed an increased risk of arthritis development with RF positivity [hazard ratio (HR) = 2.3, 95% confidence interval (CI) 1.1-4.8, p = 0.028] and higher ACPA levels (HR = 1.0, 95% CI 1.000-1.001, p = 0.002). High levels of RF (HR = 4.4, 95% CI 1.7-11) entailed the highest HR in this ACPA-positive population. Neither clinical characteristics nor alcohol consumption measured by PEth conferred significant prognostic value.Conclusions: ACPA levels and concurrent presence of RF are independent predictors of arthritis development among ACPA-positive patients with musculoskeletal pain. The results are compatible with a dose-response relationship between RA-related autoantibodies and risk of arthritis development.
Collapse
Affiliation(s)
- E Eloff
- Department of Rheumatology, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - K Martinsson
- Department of Rheumatology, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - M Ziegelasch
- Department of Rheumatology, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - J Cedergren
- Department of Rheumatology, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Å Reckner
- Department of Rheumatology, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - T Skogh
- Department of Rheumatology, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - L Karlsson
- Department of Clinical Pharmacology, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - A Ärlemalm
- Department of Clinical Pharmacology, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - N V Borggreven
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - L A Trouw
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - A Kastbom
- Department of Rheumatology, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| |
Collapse
|
|
30
|
Klareskog L, Rönnelid J, Saevarsdottir S, Padyukov L, Alfredsson L. The importance of differences; On environment and its interactions with genes and immunity in the causation of rheumatoid arthritis. J Intern Med 2020; 287:514-533. [PMID: 32176395 DOI: 10.1111/joim.13058] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 02/03/2020] [Accepted: 02/25/2020] [Indexed: 12/19/2022]
Abstract
The current review uses rheumatoid arthritis (RA) as a prominent example for how studies on the interplay between environmental and genetic factors in defined subsets of a disease can be used to formulate aetiological hypotheses that subsequently can be tested for causality using molecular and functional studies. Major discussed findings are that exposures to airways from many different noxious agents including cigarette smoke, silica dust and more interact with major susceptibility genes, mainly HLA-DR genetic variants in triggering antigen-specific immune reactions specific for RA. We also discuss how several other environmental and lifestyle factors, including microbial, neural and metabolic factors, can influence risk for RA in ways that are different in different subsets of RA.The description of these processes in RA provides the best example so far in any immune-mediated disease of how triggering of immunity at one anatomical site in the context of known environmental and genetic factors subsequently can lead to symptoms that precede the classical inflammatory disease symptoms and later contribute also to the classical RA joint inflammation. The findings referred to in the review have led to a change of paradigms for very early therapy and prevention of RA and to efforts towards what we have named 'personalized prevention'. We believe that the progress described here for RA will be of relevance for research and practice also in other immune-mediated diseases.
Collapse
Affiliation(s)
- L Klareskog
- From the, Division of Rheumatology, Department of Medicine, Karolinska Institutet and Karolinska University Hospital (Solna), Stockholm, Sweden
| | - J Rönnelid
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - S Saevarsdottir
- Division of Clinical Epidemiology, Department of Medicine, Karolinska Institutet and Karolinska University Hospital (Solna), Stockholm, Sweden.,Faculty of Medicine, School of Health Sciences, University of Iceland, Karolinska Institutet, Stockholm, Sweden
| | - L Padyukov
- From the, Division of Rheumatology, Department of Medicine, Karolinska Institutet and Karolinska University Hospital (Solna), Stockholm, Sweden
| | - L Alfredsson
- Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
31
|
Ethanol consumption inhibits T FH cell responses and the development of autoimmune arthritis. Nat Commun 2020; 11:1998. [PMID: 32332730 PMCID: PMC7181688 DOI: 10.1038/s41467-020-15855-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 03/26/2020] [Indexed: 11/09/2022] Open
Abstract
Alcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (TFH) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice have reduced Bcl6 and PD-1 expression as well as IL-21 production by TFH cells, preventing proper spatial organization of TFH cells to form TFH:B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and tolerance-inducing effect of alcohol consumption. Moderate consumption of alcohol is associated with protection from some autoimmune diseases. Here the authors show that ethanol and its metabolite acetate can protect mice from collagen-induced arthritis and provide evidence that the mechanism of this effect might be via inhibition of the effector function of T follicular helper cells.
Collapse
|
|
32
|
Ishikawa Y, Terao C. The Impact of Cigarette Smoking on Risk of Rheumatoid Arthritis: A Narrative Review. Cells 2020; 9:cells9020475. [PMID: 32092988 PMCID: PMC7072747 DOI: 10.3390/cells9020475] [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] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/10/2020] [Accepted: 02/11/2020] [Indexed: 12/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and subsequent proliferation of synovial tissues, which eventually leads to cartilage and bone destruction without effective treatments. Anti-citrullinated cyclic peptide/protein antibody (ACPA) and rheumatoid factor (RF) are two main characteristic autoantibodies found in RA patients and are associated with unfavorable disease outcomes. Although etiologies and causes of the disease have not been fully clarified yet, it is likely that interactive contributions of genetic and environmental factors play a main role in RA pathology. Previous works have demonstrated several genetic and environmental factors as risks of RA development and/or autoantibody productions. Among these, cigarette smoking and HLA-DRB1 are the well-established environmental and genetic risks, respectively. In this narrative review, we provide a recent update on genetic contributions to RA and the environmental risks of RA with a special focus on cigarette smoking and its impacts on RA pathology. We also describe gene–environmental interaction in RA pathogenesis with an emphasis on cigarette smoking and HLA-DRB1.
Collapse
Affiliation(s)
- Yuki Ishikawa
- Section for Immunobiology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA;
- Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
| | - Chikashi Terao
- Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
- Clinical Research Center, Shizuoka General Hospital, 4 Chome-27-1 Kitaando, Aoi Ward, Shizuoka 420-8527, Japan
- Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
- Correspondence: ; Tel.: +81-(0)45-503-9121
| |
Collapse
|
|
33
|
Metabonomic-Transcriptome Integration Analysis on Osteoarthritis and Rheumatoid Arthritis. Int J Genomics 2020; 2020:5925126. [PMID: 31976312 PMCID: PMC6961787 DOI: 10.1155/2020/5925126] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Accepted: 11/20/2019] [Indexed: 12/11/2022] Open
Abstract
Purpose This study is aimed at exploring the potential metabolite/gene biomarkers, as well as the differences between the molecular mechanisms, of osteoarthritis (OA) and rheumatoid arthritis (RA). Methods Transcriptome dataset GSE100786 was downloaded to explore the differentially expressed genes (DEGs) between OA samples and RA samples. Meanwhile, metabolomic dataset MTBLS564 was downloaded and preprocessed to obtain metabolites. Then, the principal component analysis (PCA) and linear models were used to reveal DEG-metabolite relations. Finally, metabolic pathway enrichment analysis was performed to investigate the differences between the molecular mechanisms of OA and RA. Results A total of 976 DEGs and 171 metabolites were explored between OA samples and RA samples. The PCA and linear module analysis investigated 186 DEG-metabolite interactions including Glycogenin 1- (GYG1-) asparagine_54, hedgehog acyltransferase- (HHAT-) glucose_70, and TNF receptor-associated factor 3- (TRAF3-) acetoacetate_35. Finally, the KEGG pathway analysis showed that these metabolites were mainly enriched in pathways like gap junction, phagosome, NF-kappa B, and IL-17 pathway. Conclusions Genes such as HHAT, GYG1, and TRAF3, as well as metabolites including glucose, asparagine, and acetoacetate, might be implicated in the pathogenesis of OA and RA. Metabolites like ethanol and tyrosine might participate differentially in OA and RA progression via the gap junction pathway and phagosome pathway, respectively. TRAF3-acetoacetate interaction may be involved in regulating inflammation in OA and RA by the NF-kappa B and IL-17 pathway.
Collapse
|
|
34
|
Sun Z, Yang T, Wang Y, Li C, Yang Y, Wang D, Guo J, Shi T, Wang Y, Qu Y, Wei Q, Feng C. Propionic acid abrogates the deleterious effects of cerebral ischemic reperfusion injury through nuclear factor-κb signaling in mice. Pharmacogn Mag 2020. [DOI: 10.4103/pm.pm_306_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
|
|
35
|
Le Daré B, Lagente V, Gicquel T. Ethanol and its metabolites: update on toxicity, benefits, and focus on immunomodulatory effects. Drug Metab Rev 2019; 51:545-561. [PMID: 31646907 DOI: 10.1080/03602532.2019.1679169] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
This article summarizes recent experimental and epidemiological data on the toxic and beneficial effects of ethanol and its metabolites (acetaldehyde), and focuses on their immunomodulatory effects. The section dealing with the toxic effects of alcohol focuses on its chronic toxicity (liver disorders, carcinogenic effects, cardiovascular disorders, neuropsychic disorders, addiction and withdrawal syndrome, hematologic disorders, reprotoxicity, osteoporosis) although acute toxicity is considered. The role of oxidative metabolism of ethanol by alcohol dehydrogenase, cytochrome P450 2E1, and aldehyde dehydrogenase, as well as the impact of genetic polymorphism in its physiopathology are also highlighted. The section dealing with the beneficial effects of low to moderate alcohol consumption (on cardiovascular system, diabetes, the nervous system and sensory organs, autoimmune diseases, and rheumatology) highlights the importance of anti-inflammatory and immunomodulatory effects in these observations. This knowledge, enriched by a focus on the immunomodulatory effects of ethanol and its metabolites, in particular on the NLRP3 inflammasome pathway, might facilitate the development of treatments that can reduce ethanol's harmful effects or accentuate its beneficial effects.
Collapse
Affiliation(s)
- Brendan Le Daré
- Univ Rennes, INSERM, INRA, Institut NuMeCan (Nutrition, Metabolisms and Cancer), Rennes, France.,Pharmacy Unit, Pontchaillou University Hospital, Rennes, France.,Forensic and Toxicology Laboratory, Pontchaillou University Hospital, Rennes, France
| | - Vincent Lagente
- Univ Rennes, INSERM, INRA, Institut NuMeCan (Nutrition, Metabolisms and Cancer), Rennes, France
| | - Thomas Gicquel
- Univ Rennes, INSERM, INRA, Institut NuMeCan (Nutrition, Metabolisms and Cancer), Rennes, France.,Forensic and Toxicology Laboratory, Pontchaillou University Hospital, Rennes, France
| |
Collapse
|
|
36
|
Abstract
OBJECTIVE To examine whether alcohol intake is causally associated with rheumatoid arthritis (RA). METHODS We performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We used the publicly available summary statistics of alcohol intake frequency from the UK Biobank genome-wide association studies (GWASs; n = 336,965) as the exposure and a GWAS meta-analysis of 5539 autoantibody-positive RA patients and 20,169 controls as the outcome. RESULTS We selected 24 single nucleotide polymorphisms (SNPs) associated with alcohol intake frequency at genome-wide significance as instrumental variables (IVs) to improve inference, 16 of which were inversely associated with RA. The IVW method showed no evidence of a causal association between alcohol intake and RA (beta = 0.218, SE = 0.213, p = 0.306). The MR-Egger regression revealed that directional pleiotropy was unlikely to bias the result (intercept = 0.027, p = 0.292). The MR-Egger analysis and the weighted median approach showed no causal association between alcohol intake and RA (beta = -0.778, SE = 0.947, p = 0.420 and beta = -0.286, SE = 0.302, p = 0.344, respectively). Cochran's Q test did not indicate heterogeneity between IV estimates based on the individual variants, and results from a "leave-one-out" analysis demonstrated that no single SNP was driving the IVW point estimate. CONCLUSION The MR analysis does not support a causal inverse association between alcohol intake and RA occurrence.
Collapse
Affiliation(s)
- S-C Bae
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea (Republic of)
| | - Y H Lee
- Department of Rheumatology, Korea University College of Medicine, 73, Inchon-ro, Seongbuk-gu, Seoul, Korea (Republic of).
| |
Collapse
|
|
37
|
Hedström AK, Hössjer O, Klareskog L, Alfredsson L. Interplay between alcohol, smoking and HLA genes in RA aetiology. RMD Open 2019; 5:e000893. [PMID: 31168412 PMCID: PMC6525609 DOI: 10.1136/rmdopen-2019-000893] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 03/12/2019] [Accepted: 03/27/2019] [Indexed: 02/07/2023] Open
Abstract
Objectives The relationship between alcohol consumption and risk for rheumatoid arthritis (RA) is incompletely understood. We aimed to determine the influence of alcohol on anticitrullinated protein antibody (ACPA) positive and ACPA-negative RA and investigate potential interactions between alcohol consumption, smoking and the presence of human leucocyte antigen (HLA)-DRB1-shared epitope (SE). Methods A Swedish population-based case–control study with incident cases of RA was used (3353 cases, 2836 matched controls). Subjects with different HLA-DRB1-SE status, smoking and alcohol consumption were compared regarding risk of ACPA-positive and ACPA-negative RA, by calculating OR with 95% CI employing logistic regression. Interaction on the additive scale between alcohol, HLA-DRB1-SE and smoking was estimated by calculating the attributable proportion (AP) due to interaction. Results Compared with non-drinking, low and moderate alcohol consumption was dose dependently associated with a reduced risk of ACPA-positive and ACPA-negative RA. Independent of smoking habits, non-drinking and the presence of HLA-DRB1-SE interacted to increase the risk of ACPA-positive RA. Among HLA-DRB1-SE positive subjects, there was also a significant interaction between non-drinking and smoking with regard to risk for ACPA-positive RA. A three-way interaction was observed between alcohol, smoking and HLA-DRB1-SE with regard to risk for ACPA-positive RA (AP 0.7, 95% CI 0.6 to 0.8) that remained significant when the influence from the two-way interactions was removed (AP 0.4, 95% CI 0.2 to 0.6). Conclusions Our findings emphasize the need to investigate complex interactions between several environmental and genetic factors in order to better understand the etiology of RA. Whereas of great interest in an aetiological perspective, the finding of a protective role of alcohol on risk for RA must, however, be interpreted with caution in a clinical and public health perspective.
Collapse
Affiliation(s)
- Anna Karin Hedström
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Instititute of Environmental Medicine, Karolinska Institutet, Stockhom, Sweden
| | - Ola Hössjer
- Department of Mathematics, Stockholm university, Stockholm, Sweden
| | - Lars Klareskog
- Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Lars Alfredsson
- Instititute of Environmental Medicine, Karolinska Institutet, Stockhom, Sweden
| |
Collapse
|
|
38
|
Sageloli F, Quesada JL, Fautrel B, Salliot C, Gaudin P, Baillet A. Moderate alcohol consumption is associated with increased radiological progression in women, but not in men, with early rheumatoid arthritis: results from the ESPOIR cohort (Étude et Suivi des Polyarthrites Indifférenciées Récentes). Scand J Rheumatol 2018; 47:440-446. [PMID: 29774784 DOI: 10.1080/03009742.2018.1437216] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVE We conducted this study to determine whether alcohol consumption influences radiological progression in early rheumatoid arthritis (RA). METHOD Patients fulfilling the European League Against Rheumatism/American College of Rheumatology 2010 criteria in the early arthritis cohort ESPOIR (Étude et Suivi des Polyarthrites Indifférenciées Récentes) were included in this study. Alcohol consumption was collected at baseline and at each visit. We classified alcohol consumption into three groups: abstinent (0 g/day), moderate (≤ 20 g/day for women, ≤ 30 g/day for men), and abuse (> 20 g/day for women, > 30 g/day for men). The primary outcome was the occurrence of radiological progression, defined as an increase ≥ 5 points in the total Sharp/van der Heijde score. We investigated whether alcohol consumption is predictive of radiological progression at 1, 3, and 5 years by univariate and multivariate analysis adjusted for age, baseline erosion, rheumatoid factor, anti-citrullinated peptide antibody, smoking status, body mass index, and treatment with leflunomide or methotrexate and biologics. RESULTS The study included 596 patients. When considering the influence of gender on the interaction between alcohol consumption and radiological progression, we showed a deleterious effect of moderate consumption in women [odds ratio (OR) = 1.73, 95% confidence interval (CI) 1.01; 2.96, p = 0.045] and a trend towards a protective effect of moderate consumption in men (OR = 0.50, 95% CI 0.21; 1.16, p = 0.106) in multivariate analysis. CONCLUSION Our data suggest a deleterious effect of moderate consumption of alcohol on radiological progression in women, but not in men, with early RA.
Collapse
Affiliation(s)
- F Sageloli
- a Department of Rheumatology , Grenoble Alpes University Hospital , Grenoble , France
| | - J L Quesada
- b Clinical Investigation Center , Grenoble Alpes University Hospital , Grenoble , France.,c Scientific Department of the Clinical Research Delegation , Grenoble Alpes University Hospital , Grenoble , France
| | - B Fautrel
- d Department of Rheumatology , Pitie Salpetriere Hospital , Paris , France
| | - C Salliot
- e Department of Rheumatology , University Hospital Orléans , Orléans , France
| | - P Gaudin
- a Department of Rheumatology , Grenoble Alpes University Hospital , Grenoble , France.,f Department of Rheumatology , Hopital Sud, Grenoble Teaching Hospital , Echirolles , France
| | - A Baillet
- a Department of Rheumatology , Grenoble Alpes University Hospital , Grenoble , France.,f Department of Rheumatology , Hopital Sud, Grenoble Teaching Hospital , Echirolles , France
| |
Collapse
|
|
39
|
Luo Z, Liu Y, Liu Y, Chen H, Shi S, Liu Y. Cellular and molecular mechanisms of alcohol-induced osteopenia. Cell Mol Life Sci 2017; 74:4443-4453. [PMID: 28674727 PMCID: PMC11107754 DOI: 10.1007/s00018-017-2585-y] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 05/24/2017] [Accepted: 06/27/2017] [Indexed: 02/07/2023]
Abstract
Alcoholic beverages are widely consumed, resulting in a staggering economic cost in different social and cultural settings. Types of alcohol consumption vary from light occasional to heavy, binge drinking, and chronic alcohol abuse at all ages. In general, heavy alcohol consumption is widely recognized as a major epidemiological risk factor for chronic diseases and is detrimental to many organs and tissues, including bones. Indeed, recent findings demonstrate that alcohol has a dose-dependent toxic effect in promoting imbalanced bone remodeling. This imbalance eventually results in osteopenia, an established risk factor for osteoporosis. Decreased bone mass and strength are major hallmarks of osteopenia, which is predominantly attributed not only to inhibition of bone synthesis but also to increased bone resorption through direct and indirect pathways. In this review, we present knowledge to elucidate the epidemiology, potential pathogenesis, and major molecular mechanisms and cellular effects that underlie alcoholism-induced bone loss in osteopenia. Novel therapeutic targets for correcting alcohol-induced osteopenia are also reviewed, such as modulation of proinflammatory cytokines and Wnt and mTOR signaling and the application of new drugs.
Collapse
Affiliation(s)
- Zhenhua Luo
- Laboratory of Tissue Regeneration and Immunology, Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No. 4, Beijing, 100050, People's Republic of China
| | - Yao Liu
- Liaoning Province Key Laboratory of Oral Disease, 117 Nanjing North Street, Shenyang, 110002, People's Republic of China
| | - Yitong Liu
- Laboratory of Tissue Regeneration and Immunology, Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No. 4, Beijing, 100050, People's Republic of China
| | - Hui Chen
- Liaoning Province Key Laboratory of Oral Disease, 117 Nanjing North Street, Shenyang, 110002, People's Republic of China
| | - Songtao Shi
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, USA
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology, Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No. 4, Beijing, 100050, People's Republic of China.
| |
Collapse
|
|
40
|
Ng HP, Jennings S, Wang J, Molina PE, Nelson S, Wang G. Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory Response. Front Immunol 2017. [PMID: 28638383 PMCID: PMC5461336 DOI: 10.3389/fimmu.2017.00661] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Acute alcohol exposure suppresses cell inflammatory response. The underlying mechanism has not been fully defined. Here we report that alcohol was able to activate glucocorticoid receptor (GR) signaling in the absence of glucocorticoids (GCs) and upregulated glucocorticoid-induced leucine zipper (gilz), a prominent GC-responsive gene. Such a non-canonical activation of GR was not blocked by mifepristone, a potent GC competitor. The proximal promoter of gilz, encompassing five GC-responsive elements (GREs), was incorporated and tested in a luciferase reporter system. Deletion and/or mutation of the GREs abrogated the promoter responsiveness to alcohol. Thus, the GR–GRE interaction transduced the alcohol action on gilz. Alcohol induced GR nuclear translocation, which was enhanced by the alcohol dehydrogenase inhibitor fomepizole, suggesting that it was alcohol, not its metabolites, that engendered the effect. Gel mobility shift assay showed that unliganded GR was able to bind GREs and such interaction withstood clinically relevant levels of alcohol. GR knockout via CRISPR/Cas9 gene targeting or GILZ depletion via small RNA interference diminished alcohol suppression of cell inflammatory response to LPS. Thus, a previously unrecognized, non-canonical GR activation of gilz is involved in alcohol modulation of cell immune response.
Collapse
Affiliation(s)
- Hang Pong Ng
- Alcohol and Drug Abuse Center, Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Scott Jennings
- Alcohol and Drug Abuse Center, Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Jack Wang
- Alcohol and Drug Abuse Center, Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Patricia E Molina
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Steve Nelson
- Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Guoshun Wang
- Alcohol and Drug Abuse Center, Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| |
Collapse
|
|
41
|
Cellular and molecular perspectives in rheumatoid arthritis. Semin Immunopathol 2017; 39:343-354. [PMID: 28508153 DOI: 10.1007/s00281-017-0633-1] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Accepted: 04/17/2017] [Indexed: 12/13/2022]
Abstract
Synovial immunopathology in rheumatoid arthritis is complex involving both resident and infiltrating cells. The synovial tissue undergoes significant neovascularization, facilitating an influx of lymphocytes and monocytes that transform a typically acellular loose areolar membrane into an invasive tumour-like pannus. The microvasculature proliferates to form straight regularly-branching vessels; however, they are highly dysfunctional resulting in reduced oxygen supply and a hypoxic microenvironment. Autoantibodies such as rheumatoid factor and anti-citrullinated protein antibodies are found at an early stage, often before arthritis has developed, and they have been implicated in the pathogenesis of RA. Abnormal cellular metabolism and mitochondrial dysfunction thus ensue and, in turn, through the increased production of reactive oxygen species actively induce inflammation. Key pro-inflammatory cytokines, chemokines and growth factors and their signalling pathways, including nuclear factor κB, Janus kinase-signal transducer, are highly activated when immune cells are exposed to hypoxia in the inflamed rheumatoid joint show adaptive survival reactions by activating. This review attempts to highlight those aberrations in the innate and adaptive immune systems including the role of genetic and environmental factors, autoantibodies, cellular alterations, signalling pathways and metabolism that are implicated in the pathogenesis of RA and may therefore provide an opportunity for therapeutic intervention.
Collapse
|
|
42
|
Environmental factors and hormones in the development of rheumatoid arthritis. Semin Immunopathol 2017; 39:461-468. [PMID: 28451785 DOI: 10.1007/s00281-017-0624-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 04/02/2017] [Indexed: 12/22/2022]
Abstract
The etiopathogenesis of rheumatoid arthritis (RA) is partially understood. Genetic, environmental, and hormonal factors and their interactions are considered to play an important role on disease development. The relative contribution of environmental factors to RA development is probably larger than previously thought. The aim of this review is to appraise robust evidence about the role of environmental and hormonal risk factors for RA. We will discuss inhaled pollutants, nutritional habits, infectious, hormonal, and reproductive factors. As some of these factors are potentially modifiable, understanding their impact on RA development opens new opportunities for potential interventions and disease prevention.
Collapse
|
|
43
|
Chang W, Bai J, Tian S, Ma M, Li W, Yin Y, Deng R, Cui J, Li J, Wang G, Zhang P, Tao K. Autophagy protects gastric mucosal epithelial cells from ethanol-induced oxidative damage via mTOR signaling pathway. Exp Biol Med (Maywood) 2017; 242:1025-1033. [PMID: 28056554 DOI: 10.1177/1535370216686221] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Alcohol abuse is an important cause of gastric mucosal epithelial cell injury and gastric ulcers. A number of studies have demonstrated that autophagy, an evolutionarily conserved cellular mechanism, has a protective effect on cell survival. However, it is not known whether autophagy can protect gastric mucosal epithelial cells against the toxic effects of ethanol. In the present study, gastric mucosal epithelial cells (GES-1 cells) and Wistar rats were treated with ethanol to detect the adaptive response of autophagy. Our results demonstrated that ethanol exposure induced gastric mucosal epithelial cell damage, which was accompanied by the downregulation of mTOR signaling pathway and activation of autophagy. Suppression of autophagy with pharmacological agents resulted in a significant increase of GES-1 cell apoptosis and gastric mucosa injury, suggesting that autophagy could protect cells from ethanol toxicity. Furthermore, we evaluated the cellular oxidative stress response following ethanol treatment and found that autophagy induced by ethanol inhibited generation of reactive oxygen species and degradation of antioxidant and lipid peroxidation. In conclusion, these findings provide evidence that ethanol can activate autophagy via downregulation of the mTOR signaling pathway, serving as an adaptive mechanism to ameliorate oxidative damage induced by ethanol in gastric mucosal epithelial cells. Therefore, modifying autophagy may provide a therapeutic strategy against alcoholic gastric mucosa injury. Impact statement The effect and mechanism of autophagy on ethanol-induced cell damage remain controversial. In this manuscript, we report the results of our study demonstrating that autophagy can protect gastric mucosal epithelial cells against ethanol toxicity in vitro and in vivo. We have shown that ethanol can activate autophagy via downregulation of the mTOR signaling pathway, serving as an adaptive mechanism to ameliorate ethanol-induced oxidative damage in gastric mucosal epithelial cells. This study brings new and important insights into the mechanism of alcoholic gastric mucosal injury and may provide an avenue for future therapeutic strategies.
Collapse
Affiliation(s)
- Weilong Chang
- 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China.,2 Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, People's Republic of China
| | - Jie Bai
- 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Shaobo Tian
- 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Muyuan Ma
- 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Wei Li
- 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Yuping Yin
- 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Rui Deng
- 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Jinyuan Cui
- 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Jinjin Li
- 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Guobin Wang
- 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Peng Zhang
- 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Kaixiong Tao
- 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| |
Collapse
|
|
44
|
Kc R, Voigt R, Li X, Forsyth CB, Ellman MB, Summa KC, Turek FW, Keshavarzian A, Kim JS, Im HJ. Induction of Osteoarthritis-like Pathologic Changes by Chronic Alcohol Consumption in an Experimental Mouse Model. Arthritis Rheumatol 2015; 67:1678-80. [PMID: 25708245 DOI: 10.1002/art.39090] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Revised: 01/31/2015] [Accepted: 02/19/2015] [Indexed: 12/19/2022]
Affiliation(s)
- Ranjan Kc
- Rush University Medical Center, Chicago, IL
| | | | - Xin Li
- Rush University Medical Center, Chicago, IL
| | | | - Michael B Ellman
- Rush University Medical Center, Chicago, IL.,Panorama Orthopedics, Denver, CO
| | | | | | - Ali Keshavarzian
- Rush University Medical Center, Chicago, IL.,Utrecht University, Utrecht, The Netherlands
| | | | - Hee-Jeong Im
- Rush University Medical Center, Chicago, IL.,University of Illinois, Chicago, IL
| |
Collapse
|
|
45
|
Li J, Zhang FQ, Du ZN, Cai T, Cai PS, Fan L. Protective effect of HO-1 transfection against ethanol-induced osteoblast damage. ACTA ACUST UNITED AC 2015; 35:374-377. [DOI: 10.1007/s11596-015-1440-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Revised: 03/30/2015] [Indexed: 11/25/2022]
|
|
46
|
Santana APM, Tavares BM, Lucetti LT, Gouveia FS, Ribeiro RA, Soares PMG, Sousa EHS, Lopes LGF, Medeiros JVR, Souza MHLP. The nitric oxide donor cis-[Ru(bpy)2(SO3)NO](PF6) increases gastric mucosa protection in mice--involvement of the soluble guanylate cyclase/K(ATP) pathway. Nitric Oxide 2015; 45:35-42. [PMID: 25681154 DOI: 10.1016/j.niox.2015.02.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2014] [Revised: 01/28/2015] [Accepted: 02/01/2015] [Indexed: 10/24/2022]
Abstract
Here, we have evaluated the protective effect of the NO donor cis-[Ru(bpy)2(SO3)NO](PF6) (FOR0810) in experimental models of gastric damage induced by naproxen or ethanol in mice, and the involvement of soluble guanylate cyclase (sGC) and ATP-sensitive K(+) channels (KATP) in these events. Swiss mice were pre-treated with saline, ODQ (a soluble guanylate cyclase inhibitor; 10 mg kg(-1)) or glibenclamide (a KATP channels blocker; 10 mg kg(-1)). After either 30 min or 1 h, FOR0810 (3 mg kg(-1)) was administered. At the end of 30 min, the animals received naproxen (300 mg kg(-1)) by gavage. After 6 h, the animals were sacrificed and gastric damage, myeloperoxidase (MPO) activity, and TNF-α and IL-1β gastric concentrations were evaluated. In addition, the effects of FOR0810 on naproxen-induced mesenteric leukocyte adherence were determined by intravital microscopy. Other groups, were pre-treated with saline, ODQ or glibenclamide. After either 30 min or 1 h, FOR0810 was administered. At the end of 30 min, the animals received 50% ethanol by gavage. After 1 h, the animals were sacrificed, and gastric damage, gastric reduced glutathione (GSH) concentration and malondialdehyde (MDA) levels were determined. In naproxen-induced gastric damage, FOR0810 prevented gastric injury, decreased gastric MPO activity and leukocyte adherence, associated with a decrease in TNFα and IL-1β gastric concentrations. FOR0810 also prevented ethanol-induced gastric damage by increase in GSH levels and decrease in MDA levels. ODQ and glibenclamide completely reversed FOR0810's ability to prevent gastric damage by either naproxen or ethanol. We infer that FOR0810 prevented gastric damage through the activation of both sGC and KATP channels, which triggered a decrease in both free radical and cytokine production via the blocking of neutrophil adhesion and infiltration.
Collapse
Affiliation(s)
- Ana Paula M Santana
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Bruno M Tavares
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Larisse T Lucetti
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Florêncio S Gouveia
- Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Ronaldo A Ribeiro
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Pedro M G Soares
- Department of Morphology, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Eduardo H S Sousa
- Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Luiz G F Lopes
- Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Jand-Venes R Medeiros
- Department of Biotechnology and Biodiversity Center Research, Federal University of Piauí, Parnaíba, PI, Brazil
| | - Marcellus H L P Souza
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil.
| |
Collapse
|
|
47
|
Stenberg P, Roth B. Zinc is the modulator of the calcium-dependent activation of post-translationally acting thiol-enzymes in autoimmune diseases. Med Hypotheses 2015; 84:331-5. [PMID: 25660831 DOI: 10.1016/j.mehy.2015.01.022] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2013] [Accepted: 01/15/2015] [Indexed: 01/08/2023]
Abstract
UNLABELLED Post-translational modifications of proteins can generate antigenic conformations that may cause autoimmune diseases in persons with specific HLA-haplotypes. Monocytes and macrophages, attracted to an inflamed site, can release post-translationally acting enzymes, such as transglutaminases and peptidylarginine deiminases. In vivo, the activation of these enzymes is crucial for the further course of event. Our hypothesis is that zinc modulates the activation of these calcium-dependent thiol-enzymes. Persons with celiac disease carry antibodies against deamidated dietary gluten and against transglutaminase type 2. Similarly, antibodies against citrulline-containing peptides and against peptidylarginine deiminase are detected in patients with rheumatoid arthritis. Thus, in two major autoimmune diseases, antibodies are detected against post-translationally modified proteins and against the thiol-enzymes responsible for catalyzing the modifications. In vitro, physiological concentrations of zinc reversibly inhibit the calcium-dependent activation of transglutaminases. Zinc attenuates the calcium-induced increase in affinity between transglutaminase 2 and serum from patients with celiac disease. Peptidylarginine deiminases are also inhibited by zinc. Moreover, zinc is rapidly redistributed in animals when an infection is induced. This pathway starting with an unspecific inflammation and ending up with an immune reaction against a specific tissue constitutes a theme with variations in other autoimmune diseases, such as dermatitis herpetiformis, multiple sclerosis, and type 1 diabetes. Inhibitors against transglutaminases and peptidylarginine deiminases have a great pharmacological potential. Interestingly, a large portion of the population may have been exposed to such an inhibitor. The primary metabolite of ethanol, acetaldehyde, can probably function as an irreversible inhibitor of these enzymes by forming a hemithioacetal with the thiol group of the active site. Not surprisingly, epidemiological studies have shown that alcohol is beneficial in rheumatoid arthritis. We predict that a similar situation will be observed in multiple sclerosis. The affinity of chelators such as EDTA and EGTA for Zn(2+) is three orders of magnitude greater than that for Ca(2+). This frequently overlooked complication imposes problems in biomedical research since a restoration of the zinc level can never be achieved in a blood sample which has been anti-coagulated by calcium chelators. The new synthetic direct thrombin inhibitors may offer a better way of preventing coagulation in vitro. CONCLUSIONS Post-translational modifications are of potential interest in autoimmune diseases. The in vivo activation of calcium-dependent thiol-enzymes catalyzing these alterations, such as the transglutaminases and the peptidylarginine deiminases, is crucial for this pathway. According to our hypothesis, zinc is the modulator of this key function.
Collapse
Affiliation(s)
- Pål Stenberg
- Lund University, Department of Clinical Sciences Malmö, Clinical Coagulation Research Unit, Skåne University Hospital, S-205 02 Malmö, Sweden.
| | - Bodil Roth
- Lund University, Department of Clinical Sciences Malmö, Internal Medicine, Skåne University Hospital, S-205 02 Malmö, Sweden
| |
Collapse
|
|
48
|
Kim GT. Diet and Folk Medicines for Rheumatic Diseases. JOURNAL OF RHEUMATIC DISEASES 2015. [DOI: 10.4078/jrd.2015.22.1.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Geun-Tae Kim
- Division of Rheumatology, Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
| |
Collapse
|
|
49
|
The epidemiology of alcohol consumption and multiple sclerosis: a review. Neurol Sci 2014; 36:189-96. [DOI: 10.1007/s10072-014-2007-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 11/06/2014] [Indexed: 12/14/2022]
|
|
50
|
Laurent AJ, Bindslev N, Johansson B, Berg L. Synergistic effects of ethanol and isopentenyl pyrophosphate on expansion of γδ T cells in synovial fluid from patients with arthritis. PLoS One 2014; 9:e103683. [PMID: 25090614 PMCID: PMC4121167 DOI: 10.1371/journal.pone.0103683] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 04/29/2014] [Indexed: 01/03/2023] Open
Abstract
Low to moderate ethanol consumption has been associated with protective effects in autoimmune diseases such as rheumatoid arthritis, RA. An expansion of γδ T cells induced by isopentenyl pyrophosphate, IPP, likewise seems to have a protective role in arthritis. The aim of this project was to test the hypothesis that low doses of ethanol can enhance IPP-induced expansion of synovial fluid γδ T cells from patients with arthritis and may thereby potentially account for the beneficial effects of ethanol on symptoms of the arthritic process. Thus, mononuclear cells from synovial fluid (SF) from 15 patients with arthritis and from peripheral blood (PB) from 15 healthy donors were stimulated with low concentrations of ethanol and IPP for 7 days in vitro. IPP in combination with ethanol 0.015%, 2.5 mM, equivalent to the decrease per hour in blood ethanol concentration due to metabolism, gave a significantly higher fractional expansion of SF γδ T cells compared with IPP alone after 7 days (ratio 10.1+/-4.0, p<0.0008, n = 12) in patients with arthritis. Similar results were obtained for PB γδ T cells from healthy controls (ratio 2.0+/-0.4, p<0.011, n = 15). The augmented expansion of γδ T cells in SF is explained by a higher proliferation (p = 0.0034, n = 11) and an increased survival (p<0.005, n = 11) in SF cultures stimulated with IPP plus ethanol compared to IPP alone. The synergistic effects of IPP and ethanol indicate a possible allosteric effect of ethanol. Similar effects could be seen when stimulating PB with ethanol in presence of risedronate, which has the ability to increase endogenous levels of IPP. We conclude that expansion of γδ T cells by combinatorial drug effects, possibly in fixed-dose combination, FDC, of ethanol in the presence of IPP might give a protective role in diseases such as arthritis.
Collapse
MESH Headings
- Adult
- Aged
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/immunology
- Arthritis, Rheumatoid/pathology
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Drug Synergism
- Ethanol/pharmacology
- Etidronic Acid/analogs & derivatives
- Etidronic Acid/pharmacology
- Etidronic Acid/therapeutic use
- Female
- Hemiterpenes/pharmacology
- Humans
- Interferon-gamma/biosynthesis
- Lymphocyte Activation/drug effects
- Male
- Middle Aged
- Models, Biological
- Organophosphorus Compounds/pharmacology
- Phenotype
- Receptors, Antigen, T-Cell, alpha-beta/metabolism
- Receptors, Antigen, T-Cell, gamma-delta/metabolism
- Risedronic Acid
- Synovial Fluid/cytology
- Synovial Fluid/drug effects
- Synovial Fluid/immunology
- T-Lymphocyte Subsets/drug effects
Collapse
Affiliation(s)
- Agneta J. Laurent
- Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- * E-mail:
| | - Niels Bindslev
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Björn Johansson
- Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Louise Berg
- Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|