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Gai X, Liu F, Chen Y, Zhang B, Zhang Y, Wu Y, Yang S, Chen L, Deng W, Wang Y, Wang S, Yu C, Du J, Zhang Z, Wang J, Zhang H. GOLM1 Promotes Atherogenesis by Activating Macrophage EGFR-ERK Signaling Cascade. Circ Res 2025; 136:848-861. [PMID: 40026146 DOI: 10.1161/circresaha.124.325880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 02/12/2025] [Accepted: 02/19/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND Atherosclerosis is a chronic inflammatory disease. GOLM1 (Golgi membrane protein 1) is an inflammation-responsive protein and a mediator in some inflammation-associated pathological processes. Because we found a positive correlation between GOLM1 expression and atherosclerosis progression by checking the gene expression data set of human atherosclerotic lesions, we explored the potential significance of GOLM1 in atherosclerosis in this study. METHODS GOLM1 levels in serums and lesions of patients with atherosclerosis and mice with atherosclerosis were examined by immunostaining and ELISA. Gain-of-function and loss-of-function approaches were used to study the impacts of GOLM1 in inflammation and atherogenesis of Apoe-/- mice on a Western diet. The effects of GOLM1 on macrophage behaviors were determined by OxLDL (oxidized low-density lipoprotein) uptake assay, single-cell sequencing analysis, global phosphoproteomics analysis, and molecular biological techniques. The therapeutic potential of GOLM1 neutralization for atherosclerosis was evaluated in Apoe-/- mice. RESULTS GOLM1 was elevated in serums and lesions of patients with atherosclerosis and mice with atherosclerosis. Global deletion of GOLM1 ameliorated mouse inflammation and atherosclerosis, while knock-in of GOLM1 exacerbated these pathological manifestations. Furthermore, hepatic GOLM1 deletion reduced circulating GOLM1 and attenuated atherogenesis. Mechanistically, the expression and secretion of GOLM1 were induced in multiple mouse tissues by atherogenic stimulus, leading to the elevation of extracellular GOLM1. Extracellular GOLM1 then stimulated ERK (extracellular signal-regulated kinase) signaling cascade by binding to its putative receptor EGFR (epidermal growth factor receptor) to promote macrophage uptake of LDL (low-density lipoprotein) and enhance the corresponding macrophage immune response. Moreover, neutralizing GOLM1 by an antibody suppressed mouse inflammation and atherogenesis. CONCLUSIONS GOLM1 is an atherogenic mediator and a promising therapeutic target for the intervention of atherosclerotic diseases.
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Affiliation(s)
- Xiaochen Gai
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem (X.G., F.L., B.Z., Y. Wu, S.Y., W.D., H.Z.), Hebei University, Baoding, Hebei, China
| | - Fangming Liu
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem (X.G., F.L., B.Z., Y. Wu, S.Y., W.D., H.Z.), Hebei University, Baoding, Hebei, China
| | - Yixin Chen
- Department of Cardiovascular Surgery, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (Y.C., S.W., C.Y.)
| | - Baohui Zhang
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem (X.G., F.L., B.Z., Y. Wu, S.Y., W.D., H.Z.), Hebei University, Baoding, Hebei, China
- Department of Physiology, School of Life Science, China Medical University, Shenyang, Liaoning, China (B.Z.)
| | - Yinliang Zhang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China (Y.Z.)
| | - Yuting Wu
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem (X.G., F.L., B.Z., Y. Wu, S.Y., W.D., H.Z.), Hebei University, Baoding, Hebei, China
| | - Shuhui Yang
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem (X.G., F.L., B.Z., Y. Wu, S.Y., W.D., H.Z.), Hebei University, Baoding, Hebei, China
| | | | - Weiwei Deng
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem (X.G., F.L., B.Z., Y. Wu, S.Y., W.D., H.Z.), Hebei University, Baoding, Hebei, China
| | - Yuan Wang
- Beijing Anzhen Hospital, Beijing, China (Y. Wang, J.D.)
| | - Shuiyun Wang
- Department of Cardiovascular Surgery, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (Y.C., S.W., C.Y.)
| | - Cuntao Yu
- Department of Cardiovascular Surgery, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (Y.C., S.W., C.Y.)
| | - Jie Du
- Beijing Anzhen Hospital, Beijing, China (Y. Wang, J.D.)
| | - Zhengyi Zhang
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA (Z.Z.)
| | - Jing Wang
- Department of Pathophysiology (J.W.), Hebei University, Baoding, Hebei, China
| | - Hongbing Zhang
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem (X.G., F.L., B.Z., Y. Wu, S.Y., W.D., H.Z.), Hebei University, Baoding, Hebei, China
- Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, College of Life Sciences, Hebei University, Baoding, Hebei, China (H.Z.)
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Sun Y, Shan X, Li M, Niu Y, Sun Z, Ma X, Wang T, Zhang J, Niu D. Autoimmune mechanisms and inflammation in obesity-associated type 2 diabetes, atherosclerosis, and non-alcoholic fatty liver disease. Funct Integr Genomics 2025; 25:84. [PMID: 40205260 DOI: 10.1007/s10142-025-01587-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 04/11/2025]
Abstract
Obesity, characterized by the excessive accumulation of white adipose tissue, is a significant global health burden and a major risk factor for a range of diseases, including malignancies and metabolic disorders. Individuals with high visceral fat content are particularly susceptible to severe complications such as type 2 diabetes, cardiovascular diseases, and liver disorders. However, the pathogenesis of obesity-related metabolic diseases extends beyond simple adiposity. Chronic obesity triggers a prolonged inflammatory response, which leads to tissue fibrosis and sustained organ damage, contributing to multi-organ dysfunction. This review explores the autoimmune mechanisms and inflammatory pathways underlying obesity-induced type 2 diabetes, atherosclerosis, and non-alcoholic fatty liver disease, with an emphasis on their interrelated pathophysiology and the potential for therapeutic interventions.
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Grants
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 32202656, 32402753 National Natural Science Foundation of China
- 32202656, 32402753 National Natural Science Foundation of China
- 32202656, 32402753 National Natural Science Foundation of China
- 32202656, 32402753 National Natural Science Foundation of China
- 32202656, 32402753 National Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- 2021C02068-4 Zhejiang Science and Technology Major Program on Agricultural New Variety Breeding
- 2021C02068-4 Zhejiang Science and Technology Major Program on Agricultural New Variety Breeding
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Affiliation(s)
- Yuanyuan Sun
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Xueting Shan
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Mingyang Li
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Yifan Niu
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Zhongxin Sun
- Department of Plastic, Reconstructive & Hand Microsurgery, Ningbo NO.6 Hospital, Ningbo, 315000, Zhejiang, China
| | - Xiang Ma
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Tao Wang
- Nanjing Kgene Genetic Engineering Co., Ltd, Nanjing, 211300, Jiangsu, China.
| | - Jufang Zhang
- Department of Plastic and Aesthetic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, Zhejiang, China.
| | - Dong Niu
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China.
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Jyotirmaya SS, Rath S, Dandapat J. Redox imbalance driven epigenetic reprogramming and cardiovascular dysfunctions: phytocompounds for prospective epidrugs. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 138:156380. [PMID: 39827814 DOI: 10.1016/j.phymed.2025.156380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/10/2024] [Accepted: 12/16/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND Cardiovascular diseases (CVDs) are the major contributor to global mortality and are gaining incremental attention following the COVID-19 outbreak. Epigenetic events such as DNA methylation, histone modifications, and non-coding RNAs have a significant impact on the incidence and onset of CVDs. Altered redox status is one of the major causative factors that regulate epigenetic pathways linked to CVDs. Various bioactive phytocompounds used in alternative therapies including Traditional Chinese Medicines (TCM) regulate redox balance and epigenetic phenomena linked to CVDs. Phytocompound-based medications are in the limelight for the development of cost-effective drugs with the least side effects, which will have immense therapeutic applications. PURPOSE This review comprehends certain risk factors associated with CVDs and triggered by oxidative stress-driven epigenetic remodelling. Further, it critically evaluates the pharmacological efficacy of phytocompounds as inhibitors of HAT/HDAC and DNMTs as well as miRNAs regulator that lowers the incidence of CVDs, aiming for new candidates as prospective epidrugs. METHODS PRISMA flow approach has been adopted for systematic literature review. Different Journals, computational databases, search engines such as Google Scholar, PubMed, Science Direct, Scopus, and ResearchGate were used to collect online information for literature survey. Statistical information collected from the World Health Organization (WHO) site (https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)) and the American Heart Association of Heart Disease and Stroke reported the international and national status of CVDs. RESULTS The meta-analysis of various studies is elucidated in the literature, shedding light on major risk factors such as socioeconomic parameters, which contribute highly to redox imbalance, epigenetic modulations, and CVDs. Going forward, redox imbalance driven epigenetic regulations include changes in DNA methylation status, histone modifications and non-coding RNAs expression pattern which further regulates global as well as promoter modification of various transcription factors leading to the onset of CVDs. Further, the role of various bioactive compounds used in herbal medicine, including TCM for redox regulation and epigenetic modifications are discussed. Pharmacological safety doses and different phases of clinical trials of these phytocompounds are elaborated on, which shed light on the acceptance of these phytocompounds as prospective drugs. CONCLUSION This review suggests a strong linkage between therapeutic and preventive measures against CVDs by targeting redox imbalance-driven epigenetic reprogramming using phytocompounds as prospective epidrugs. Future in-depth research is required to evaluate the possible molecular mechanisms behind the phytocompound-mediated epigenetic reprogramming and oxidative stress management during CVD progression.
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Affiliation(s)
| | - Suvasmita Rath
- Post-graduate Department of Biotechnology, Utkal University, Bhubaneswar, 751004, Odisha, India.; Centre of Environment, Climate Change and Public Health, Utkal University, Vani Vihar, Bhubaneswar,751004, Odisha, India
| | - Jagneshwar Dandapat
- Post-graduate Department of Biotechnology, Utkal University, Bhubaneswar, 751004, Odisha, India.; Centre of Excellence in Integrated Omics and Computational Biology, Utkal University, Bhubaneswar 751004, Odisha, India..
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Song J, Fang Y, Rao X, Wu L, Zhang C, Ying J, Hua F, Lin Y, Wei G. Beyond conventional treatment: ASGR1 Leading the new era of hypercholesterolemia management. Biomed Pharmacother 2024; 180:117488. [PMID: 39316974 DOI: 10.1016/j.biopha.2024.117488] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/01/2024] [Accepted: 09/20/2024] [Indexed: 09/26/2024] Open
Abstract
Cardiovascular disease (CVD) remains a leading cause of mortality worldwide, with hypercholesterolemia being a major risk factor. Although various lipid-lowering therapies exist, many patients fail to achieve optimal cholesterol control, highlighting the need for novel therapeutic approaches. ASGR1 (asialoglycoprotein receptor 1), predominantly expressed on hepatocytes, has emerged as a key regulator of cholesterol metabolism and low-density lipoprotein (LDL) clearance. This receptor's ability to regulate lipid homeostasis positions it as a promising target for therapeutic intervention in hypercholesterolemia and related cardiovascular diseases. This review critically examines the biological functions and regulatory mechanisms of ASGR1 in cholesterol metabolism, with a focus on its potential as a therapeutic target for hypercholesterolemia and related cardiovascular diseases. By analyzing recent advances in ASGR1 research, this article explores its role in liver-specific pathways, the implications of ASGR1 variants in CVD risk, and the prospects for developing ASGR1-targeted therapies. This review aims to provide a foundation for future research and clinical applications in hypercholesterolemia management.
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Affiliation(s)
- Jiali Song
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China; Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, Jiangxi 330006, PR China
| | - Yang Fang
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China; Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, Jiangxi 330006, PR China
| | - Xiuqin Rao
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China; Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, Jiangxi 330006, PR China
| | - Luojia Wu
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China; Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, Jiangxi 330006, PR China
| | - Chenxi Zhang
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China; Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, Jiangxi 330006, PR China
| | - Jun Ying
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China; Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, Jiangxi 330006, PR China
| | - Fuzhou Hua
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China; Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, Jiangxi 330006, PR China
| | - Yue Lin
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China; Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, Jiangxi 330006, PR China.
| | - Gen Wei
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China; Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, Jiangxi 330006, PR China.
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Mosalmanzadeh N, Pence BD. Oxidized Low-Density Lipoprotein and Its Role in Immunometabolism. Int J Mol Sci 2024; 25:11386. [PMID: 39518939 PMCID: PMC11545486 DOI: 10.3390/ijms252111386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 10/04/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024] Open
Abstract
Modified cholesterols such as oxidized low-density lipoprotein (OxLDL) contribute to atherosclerosis and other disorders through the promotion of foam cell formation and inflammation. In recent years, it has become evident that immune cell responses to inflammatory molecules such as OxLDLs depend on cellular metabolic functions. This review examines the known effects of OxLDL on immunometabolism and immune cell responses in atherosclerosis and several other diseases. We additionally provide context on the relationship between OxLDL and aging/senescence and identify gaps in the literature and our current understanding in these areas.
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Affiliation(s)
| | - Brandt D. Pence
- College of Health Sciences and Center for Nutraceutical and Dietary Supplement Research, University of Memphis, Memphis, TN 38111, USA
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Chait A, Eckel RH, Vrablik M, Zambon A. Lipid-lowering in diabetes: An update. Atherosclerosis 2024; 394:117313. [PMID: 37945448 DOI: 10.1016/j.atherosclerosis.2023.117313] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/11/2023] [Accepted: 09/22/2023] [Indexed: 11/12/2023]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) is accelerated in people with diabetes. Dyslipidemia, hyperglycemia, oxidative stress, and inflammation play a role via a variety of mechanisms operative in the artery wall. In addition, some unique features predispose people with type 1 diabetes to accelerated atherosclerosis. Various organizations have created guidelines that provide advice regarding screening, risk assessment, and roadmaps for treatment to prevent ASCVD in diabetes. Management of dyslipidemia, especially with statins, has proven to be of immense benefit in the prevention of clinical CVD. However, since many patients fail to attain the low levels of low-density lipoproteins (LDL) recommended in these guidelines, supplemental therapy, such as the addition of ezetimibe, bempedoic acid or PCSK9 inhibitors, is often required to reach LDL goals. As a result, the upfront use of combination therapies, particularly a statin plus ezetimibe, is a rational initial approach. The addition to statins of drugs that specifically lower triglyceride levels has not proven beneficial, although the addition of icosapent-ethyl has been shown to be of value, likely by mechanisms independent of triglyceride lowering. Newer treatments in development, including apoC-III and ANGPTL3 inhibitors, seem promising in further reducing apoB-containing lipoproteins.
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Affiliation(s)
- Alan Chait
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, WA, USA
| | - Robert H Eckel
- Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Michal Vrablik
- 3rd Department of Internal Medicine, General University Hospital and 1st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Alberto Zambon
- Department of Medicine - DIMED, University of Padova, and IRCCS Multimedica Milan, Italy.
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Duché G, Sanderson JM. The Chemical Reactivity of Membrane Lipids. Chem Rev 2024; 124:3284-3330. [PMID: 38498932 PMCID: PMC10979411 DOI: 10.1021/acs.chemrev.3c00608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 02/27/2024] [Accepted: 02/28/2024] [Indexed: 03/20/2024]
Abstract
It is well-known that aqueous dispersions of phospholipids spontaneously assemble into bilayer structures. These structures have numerous applications across chemistry and materials science and form the fundamental structural unit of the biological membrane. The particular environment of the lipid bilayer, with a water-poor low dielectric core surrounded by a more polar and better hydrated interfacial region, gives the membrane particular biophysical and physicochemical properties and presents a unique environment for chemical reactions to occur. Many different types of molecule spanning a range of sizes, from dissolved gases through small organics to proteins, are able to interact with membranes and promote chemical changes to lipids that subsequently affect the physicochemical properties of the bilayer. This Review describes the chemical reactivity exhibited by lipids in their membrane form, with an emphasis on conditions where the lipids are well hydrated in the form of bilayers. Key topics include the following: lytic reactions of glyceryl esters, including hydrolysis, aminolysis, and transesterification; oxidation reactions of alkenes in unsaturated fatty acids and sterols, including autoxidation and oxidation by singlet oxygen; reactivity of headgroups, particularly with reactive carbonyl species; and E/Z isomerization of alkenes. The consequences of reactivity for biological activity and biophysical properties are also discussed.
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Affiliation(s)
- Genevieve Duché
- Génie
Enzimatique et Cellulaire, Université
Technologique de Compiègne, Compiègne 60200, France
| | - John M Sanderson
- Chemistry
Department, Durham University, Durham DH1 3LE, United Kingdom
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Yamaji T, Yusoff FM, Kishimoto S, Kajikawa M, Yoshimura K, Nakano Y, Goto C, Harada T, Mizobuchi A, Tanigawa S, Maruhashi T, Higashi Y. Association of cumulative low-density lipoprotein cholesterol exposure with vascular function. J Clin Lipidol 2024; 18:e238-e250. [PMID: 38185588 DOI: 10.1016/j.jacl.2023.12.006] [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: 10/04/2023] [Revised: 12/14/2023] [Accepted: 12/20/2023] [Indexed: 01/09/2024]
Abstract
BACKGROUND The relationship between cumulative low-density lipoprotein cholesterol (LDL-C) exposure and progression of atherosclerosis remains uncertain. OBJECTIVE The aim of this study was to determine the relationship between cumulative LDL-C level and flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID) and the presence of plaque in the common carotid artery (CCA). METHODS This was a cross-sectional study. We measured FMD in 8208 subjects, NID in 1822 subjects, and CCA plaque in 591 subjects who were not taking lipid-lowering drugs. The subjects were divided into four groups based on cumulative LDL-C exposure: <4000 mg·year/dL, 4000-4999 mg·year/dL, 5000-5999 mg·year/dL, and ≥6000 mg·year/dL. RESULTS The odds ratio of the lower quartile of FMD in the cholesterol-year-score <4000 mg·year/dL group was significantly higher than the odds ratios in the other groups. The odds ratio of the lower quartile of NID in the <4000 mg·year/dL group was significantly higher than the odds ratios in the 5000-5999 mg·year/dL and ≥6000 mg·year/dL groups. The odds ratio of the prevalence of CCA plaque in the <4000 mg·year/dL group was significantly higher than that in the ≥6000 mg·year/dL group. CONCLUSIONS Endothelial dysfunction occurred from cumulative LDL-C exposure of 4000 mg·year/dL, vascular smooth muscle dysfunction occurred from cumulative LDL-C exposure of 5000 mg·year/dL, and prevalence of CCA plaque occurred from cumulative LDL-C exposure of 6000 mg·year/dL. CLINICAL TRIAL REGISTRY INFORMATION: http://www.umin.ac.jp (UMIN000012950, UMIN000012951, and UMIN000012952, UMIN000003409).
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Affiliation(s)
- Takayuki Yamaji
- Center for Radiation Disaster Medical Science, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (Drs Yamaji and Higashi); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (Drs Yamaji, Yusoff, Kishimoto, Harada, Mizobuchi, Tanigawa, Maruhashi, and Higashi)
| | - Farina Mohamad Yusoff
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (Drs Yamaji, Yusoff, Kishimoto, Harada, Mizobuchi, Tanigawa, Maruhashi, and Higashi)
| | - Shinji Kishimoto
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (Drs Yamaji, Yusoff, Kishimoto, Harada, Mizobuchi, Tanigawa, Maruhashi, and Higashi)
| | - Masato Kajikawa
- Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan (Drs Kajikawa, Yoshimura, and Higashi)
| | - Kenichi Yoshimura
- Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan (Drs Kajikawa, Yoshimura, and Higashi)
| | - Yukiko Nakano
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan (Dr Nakano)
| | - Chikara Goto
- Hiroshima International University, Hiroshima, Japan (Dr Goto)
| | - Takahiro Harada
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (Drs Yamaji, Yusoff, Kishimoto, Harada, Mizobuchi, Tanigawa, Maruhashi, and Higashi)
| | - Aya Mizobuchi
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (Drs Yamaji, Yusoff, Kishimoto, Harada, Mizobuchi, Tanigawa, Maruhashi, and Higashi)
| | - Shunsuke Tanigawa
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (Drs Yamaji, Yusoff, Kishimoto, Harada, Mizobuchi, Tanigawa, Maruhashi, and Higashi)
| | - Tatsuya Maruhashi
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (Drs Yamaji, Yusoff, Kishimoto, Harada, Mizobuchi, Tanigawa, Maruhashi, and Higashi)
| | - Yukihito Higashi
- Center for Radiation Disaster Medical Science, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (Drs Yamaji and Higashi); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (Drs Yamaji, Yusoff, Kishimoto, Harada, Mizobuchi, Tanigawa, Maruhashi, and Higashi); Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan (Drs Kajikawa, Yoshimura, and Higashi).
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9
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Li K, Song X, Li H, Kuang X, Liu S, Liu R, Li D. Mussel oil is superior to fish oil in preventing atherosclerosis of ApoE -/- mice. Front Nutr 2024; 11:1326421. [PMID: 38410635 PMCID: PMC10894946 DOI: 10.3389/fnut.2024.1326421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 01/24/2024] [Indexed: 02/28/2024] Open
Abstract
Objectives The present study aimed to explore the preventive effect of mussel oil (MO) on atherosclerosis and the potential mechanism in apolipoprotein E-null (ApoE-/-) mice. Methods ApoE-/- mice were fed with a high-fat and high-cholesterol chow and given corn oil (CO), fish oil (FO), MO, or aspirin (ASP, dissolved in CO) by gavage for 12 weeks. The total n-3 polyunsaturated fatty acids (PUFAs) in MO (51.01%) and FO (46.82%) were comparable (mainly C22:6n-3 and C20:5n-3). Wild-type mice were fed with a normal chow and given equivalent CO as health control (CON). Results Compared with the CON group, obvious atherosclerotic plaque appeared at aorta and aortic sinus in the CO group. Compared with the CO group, MO but not FO had a significantly smaller atherosclerotic plaque area in the aorta. The aortic atherosclerotic plaque area was comparable in the MO, CON, and ASP groups. The MO group had a significantly smaller atherosclerotic plaque area, lower lipid deposition, lower contents of smooth muscle cell (SMC), and slightly lower contents of macrophage at the aortic sinus than the FO group. Serum concentrations of IL-1β, NF-κB, and VCAM-1 were comparable in the MO and FO groups and were significantly lower than the CO group. Compared with the CO group, the MO group but not FO group had significantly lower aortic protein levels of p65NF-κB, p38MAPK, and VCAM-1. The aortic protein levels of p-p65NF-κB and p-p38MAPK were significantly lower in the MO group than the FO group. Conclusion In conclusion, MO is more potent than FO in preventing atherosclerosis, and the possible mechanism may be by downregulating p38MAPK/NF-κB signaling pathway, decreasing VCAM-1 and macrophage, and inhibiting proliferation and migration of SMC.
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Affiliation(s)
- Kelei Li
- Institute of Nutrition and Health, Qingdao University, Qingdao, China
- School of Public Health, Qingdao University, Qingdao, China
| | - Xiaolei Song
- Institute of Nutrition and Health, Qingdao University, Qingdao, China
- School of Public Health, Qingdao University, Qingdao, China
| | - Huiying Li
- Institute of Nutrition and Health, Qingdao University, Qingdao, China
- School of Public Health, Qingdao University, Qingdao, China
| | - Xiaotong Kuang
- Institute of Nutrition and Health, Qingdao University, Qingdao, China
- School of Public Health, Qingdao University, Qingdao, China
| | - Shiyi Liu
- Institute of Nutrition and Health, Qingdao University, Qingdao, China
- School of Public Health, Qingdao University, Qingdao, China
| | - Run Liu
- Institute of Nutrition and Health, Qingdao University, Qingdao, China
- School of Public Health, Qingdao University, Qingdao, China
| | - Duo Li
- Institute of Nutrition and Health, Qingdao University, Qingdao, China
- School of Public Health, Qingdao University, Qingdao, China
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10
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Lankin VZ, Sharapov MG, Tikhaze AK, Goncharov RG, Antonova OA, Konovalova GG, Novoselov VI. Dicarbonyl-Modified Low-Density Lipoproteins Are Key Inducers of LOX-1 and NOX1 Gene Expression in the Cultured Human Umbilical Vein Endotheliocytes. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:2125-2136. [PMID: 38462455 DOI: 10.1134/s0006297923120143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/24/2023] [Accepted: 09/26/2023] [Indexed: 03/12/2024]
Abstract
Expression of LOX-1 and NOX1 genes in the human umbilical vein endotheliocytes (HUVECs) cultured in the presence of low-density lipoproteins (LDL) modified with various natural dicarbonyls was investigated for the first time. It was found that among the investigated dicarbonyl-modified LDLs (malondialdehyde (MDA)-modified LDLs, glyoxal-modified LDLs, and methylglyoxal-modified LDLs), the MDA-modified LDLs caused the greatest induction of the LOX-1 and NOX1 genes, as well as of the genes of antioxidant enzymes and genes of proapoptotic factors in HUVECs. Key role of the dicarbonyl-modified LDLs in the molecular mechanisms of vascular wall damage and endothelial dysfunction is discussed.
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Affiliation(s)
- Vadim Z Lankin
- Chazov National Medical Research Center for Cardiology, Moscow, 121552, Russia
| | - Mars G Sharapov
- Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia.
| | - Alla K Tikhaze
- Chazov National Medical Research Center for Cardiology, Moscow, 121552, Russia
| | - Ruslan G Goncharov
- Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
| | - Olga A Antonova
- Chazov National Medical Research Center for Cardiology, Moscow, 121552, Russia
| | - Galina G Konovalova
- Chazov National Medical Research Center for Cardiology, Moscow, 121552, Russia
| | - Vladimir I Novoselov
- Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
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11
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Zhang Q, Du G, Tong L, Guo X, Wei Y. Overexpression of LOX-1 in hepatocytes protects vascular smooth muscle cells from phenotype transformation and wire injury induced carotid neoatherosclerosis through ALOX15. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166805. [PMID: 37468019 DOI: 10.1016/j.bbadis.2023.166805] [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: 10/30/2022] [Revised: 06/16/2023] [Accepted: 07/06/2023] [Indexed: 07/21/2023]
Abstract
Neoatherosclerosis (NA), the main pathological basis of late stent failure, is the main limitation of interventional therapy. However, the specific pathogenesis and treatment remain unclear. In vivo, NA model was established by carotid wire injury and high-fat feeding in ApoE-/- mice. Oxidized low-density lipoprotein receptor-1/lectin-like oxidized low-density lipoprotein receptor-1 (OLR1/LOX-1), a specific receptor for oxidized low-density lipoprotein (ox-LDL), was specifically ectopically overexpressed in hepatocytes by portal vein injection of adeno-associated serotype 8 (AAV8)-thyroid binding globulin (TBG)-Olr1 and the protective effect against NA was examined. In vitro, LOX-1 was overexpressed on HHL5 using lentivirus (LV)-OLR1 and the vascular smooth muscle cells (VSMCs)-HHL5 indirect co-culture system was established to examine its protective effect on VSMCs and the molecular mechanism. Functionally, we found that specific ectopic overexpression of LOX-1 by hepatocytes competitively engulfed and metabolized ox-LDL, alleviating its resulting phenotypic transformation of VSMCs including migration, downregulation of contractile shape markers (smooth muscle α-actin (SMαA) and smooth muscle-22α (SM22α)), and upregulation of proliferative/migratory shape markers (osteopontin (OPN) and Vimentin) as well as foaminess and apoptosis, thereby alleviating NA, which independent of low-density lipoprotein (LDL) lowering treatment (evolocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9)). Mechanistically, we found that overexpression of LOX-1 in hepatocytes competitively engulfed and metabolized ox-LDL through upregulation of arachidonate-15-lipoxygenase (ALOX15), which further upregulated scavenger receptor class B type I (SRBI) and ATP-binding cassette transporter A1 (ABCA1). In conclusion, the overexpression of LOX-1 in liver protects VSMCs from phenotypic transformation and wire injury induced carotid neoatherosclerosis through ALOX15.
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Affiliation(s)
- Qing Zhang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gaohui Du
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lu Tong
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaopeng Guo
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yumiao Wei
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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12
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Lankin VZ, Tikhaze AK, Konovalova GG. Differences in Structural Changes and Pathophysiological Effects of Low-Density Lipoprotein Particles upon Accumulation of Acylhydroperoxy Derivatives in Their Outer Phospholipid Monolayer or upon Modification of Apoprotein B-100 by Natural Dicarbonyls. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:1910-1919. [PMID: 38105208 DOI: 10.1134/s0006297923110196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/20/2023] [Accepted: 09/20/2023] [Indexed: 12/19/2023]
Abstract
Nanoparticles of the lipid-transporting system of the organism, low-density lipoproteins (LDL) of blood plasma, are prone to free radical peroxidation with formation of their main modified forms - oxidized LDL itself (containing hydroperoxy-acyls in phospholipids of the outer layer of particles) and dicarbonyl-modified LDL (apoprotein B-100 in which chemically modified via the Maillard reaction). Based on the study of free radical oxidation kinetics of LDLs, it was found that the existing in the literature designation of "oxidized lipoproteins" is incorrect because it does not reveal the nature of oxidative modification of LDLs. It was shown in this study that the "atherogenic" LDLs (particles of which are actively captured by the cultured macrophages) are not the oxidized LDL (in which LOOH-derivatives of phospholipids are formed by enzymatic oxidation by C-15 lipoxygenase of rabbit reticulocytes), but dicarbonyl-modified LDLs. Important role of the dicarbonyl-modified LDLs in the molecular mechanisms of atherogenesis and endothelial dysfunction is discussed.
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Affiliation(s)
- Vadim Z Lankin
- Chazov National Medical Research Center of Cardiology, Ministry of Health of the Russian Federation, Moscow, 121552, Russia.
| | - Alla K Tikhaze
- Chazov National Medical Research Center of Cardiology, Ministry of Health of the Russian Federation, Moscow, 121552, Russia
| | - Galina G Konovalova
- Chazov National Medical Research Center of Cardiology, Ministry of Health of the Russian Federation, Moscow, 121552, Russia
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13
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Booyani Z, Aryaeian N, Omidi N, Khorasanian AS, Hoseini AF, Nejatian M, Jazayeri S, Morvaridi M. Hesperidin reduces serum levels of triglyceride after coronary artery bypass graft surgery. Food Sci Nutr 2023; 11:7145-7154. [PMID: 37970430 PMCID: PMC10630806 DOI: 10.1002/fsn3.3639] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/28/2023] [Accepted: 08/04/2023] [Indexed: 11/17/2023] Open
Abstract
Hesperidin, as an antioxidant and anti-inflammatory agent, has beneficial effects on cardiovascular diseases. This study aimed to determine the effects of hesperidin supplementation on inflammation, oxidative stress, and lipid profile in depressed coronary artery bypass graft surgery (CABG) patients. Eighty patients after coronary artery bypass graft surgery participated in this clinical trial and were randomly divided into two groups. The intervention group received 200 mg/d pure hesperidin supplement and the second group received placebo for 12 weeks. Both groups continued their usual diet. Serum concentrations of inflammatory and stress oxidative markers (hs-CRP, P-selectin, and ox-LDL) were measured and compared at baseline and the end of the intervention. The changes in serum levels of triglyceride were significantly different between the two groups (p < .05). HDL-c significantly increased in groups but the differences between the two groups were not statistically significant (p > .05). Hesperidin did not affect FBS, other lipid parameters, hs-CRP, P-selectin, and OX-LDL (p > .05). SBP and DBP differences were not statistically significant (p > .05). After 12 weeks of intervention, hesperidin reduced serum levels of triglyceride in depressed post-CABG patients.
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Affiliation(s)
- Zahra Booyani
- Department of Nutrition, School of Public HealthIran University of Medical SciencesTehranIran
| | - Naheed Aryaeian
- Department of Nutrition, School of Public HealthIran University of Medical SciencesTehranIran
| | - Negar Omidi
- Cardiac Primary Prevention Research Centre, Cardiovascular Disesae Research InstituteTehran University of Medical SciencesTehranIran
| | - Atie Sadat Khorasanian
- Department of Nutrition, School of Public HealthIran University of Medical SciencesTehranIran
| | - Agha Fatemeh Hoseini
- Department of Biostatistics, School of HealthIran University of Medical SciencesTehranIran
| | - Mostafa Nejatian
- Department of Cardiac Rehabilitation, Tehran Heart CenterTehran University of Medical SciencesTehranIran
| | - Shima Jazayeri
- Department of Nutrition, School of Public HealthIran University of Medical SciencesTehranIran
| | - Mehrnaz Morvaridi
- Department of Nutrition, School of Public HealthIran University of Medical SciencesTehranIran
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14
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Terao J. Revisiting carotenoids as dietary antioxidants for human health and disease prevention. Food Funct 2023; 14:7799-7824. [PMID: 37593767 DOI: 10.1039/d3fo02330c] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/19/2023]
Abstract
Humans are unique indiscriminate carotenoid accumulators, so the human body accumulates a wide range of dietary carotenoids of different types and to varying concentrations. Carotenoids were once recognized as physiological antioxidants because of their ability to quench singlet molecular oxygen (1O2). In the 1990s, large-scale intervention studies failed to demonstrate that supplementary β-carotene intake reduces the incidence of lung cancer, although its antioxidant activity was supposed to contribute to the prevention of oxidative stress-induced carcinogenesis. Nevertheless, the antioxidant activity of carotenoids has attracted renewed attention as the pathophysiological role of 1O2 has emerged, and as the ability of dietary carotenoids to induce antioxidant enzymes has been revealed. This review focuses on six major carotenoids from fruit and vegetables and revisits their physiological functions as biological antioxidants from the standpoint of health promotion and disease prevention. β-Carotene 9',10'-oxygenase-derived oxidative metabolites trigger increases in the activities of antioxidant enzymes. Lutein and zeaxanthin selectively accumulate in human macular cells to protect against light-induced macular impairment by acting as antioxidants. Lycopene accumulates exclusively and to high concentrations in the testis, where its antioxidant activity may help to eliminate oxidative damage. Dietary carotenoids appear to exert their antioxidant activity in photo-irradiated skin after their persistent deposition in the skin. An acceptable level of dietary carotenoids for disease prevention should be established because they can have deleterious effects as prooxidants if they accumulate to excess levels. Finally, it is expected that the reason why humans are indiscriminate carotenoid accumulators will be understood soon.
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Affiliation(s)
- Junji Terao
- Faculty of Medicine, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
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15
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Ribeiro RM, Vasconcelos SC, Lima PLGDSB, Coelho EF, Oliveira AMN, Gomes EDABM, Mota LDA, Radtke LS, Carvalho MDS, Araújo DABS, Pinheiro MSN, Gama VCDV, Júnior RMM, Braga Neto P, Nóbrega PR. Pathophysiology and Treatment of Lipid Abnormalities in Cerebrotendinous Xanthomatosis: An Integrative Review. Brain Sci 2023; 13:979. [PMID: 37508912 PMCID: PMC10377253 DOI: 10.3390/brainsci13070979] [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: 06/04/2023] [Revised: 06/19/2023] [Accepted: 06/19/2023] [Indexed: 07/30/2023] Open
Abstract
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder caused by pathogenic variants in CYP27A1, leading to a deficiency in sterol 27-hydroxylase. This defect results in the accumulation of cholestanol and bile alcohols in various tissues, including the brain, tendons and peripheral nerves. We conducted this review to evaluate lipid profile abnormalities in patients with CTX. A search was conducted in PubMed, Embase and the Virtual Health Library in January 2023 to evaluate studies reporting the lipid profiles of CTX patients, including the levels of cholestanol, cholesterol and other lipids. Elevated levels of cholestanol were consistently observed. Most patients presented normal or low serum cholesterol levels. A decrease in chenodeoxycholic acid (CDCA) leads to increased synthesis of cholesterol metabolites, such as bile alcohols 23S-pentol and 25-tetrol 3-glucuronide, which may serve as surrogate follow-up markers in patients with CTX. Lipid abnormalities in CTX have clinical implications. Cholestanol deposition in tissues contributes to clinical manifestations, including neurological symptoms and tendon xanthomas. Dyslipidemia and abnormal cholesterol metabolism may also contribute to the increased risk of atherosclerosis and cardiovascular complications observed in some CTX patients.
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Affiliation(s)
| | | | | | | | | | | | | | - Lucas Soares Radtke
- Faculty of Medicine, Federal University of Ceara, Fortaleza 60430-372, Brazil
| | | | | | | | | | | | - Pedro Braga Neto
- Division of Neurology, Department of Clinical Medicine, Federal University of Ceara, Fortaleza 60430-372, Brazil
| | - Paulo Ribeiro Nóbrega
- Division of Neurology, Department of Clinical Medicine, Federal University of Ceara, Fortaleza 60430-372, Brazil
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16
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Sabatino L. Nrf2-Mediated Antioxidant Defense and Thyroid Hormone Signaling: A Focus on Cardioprotective Effects. Antioxidants (Basel) 2023; 12:1177. [PMID: 37371907 DOI: 10.3390/antiox12061177] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 05/24/2023] [Accepted: 05/28/2023] [Indexed: 06/29/2023] Open
Abstract
Thyroid hormones (TH) perform a plethora of actions in numerous tissues and induce an overall increase in metabolism, with an augmentation in energy demand and oxygen expenditure. Oxidants are required for normal thyroid-cell proliferation, as well as for the synthesis of the main hormones secreted by the thyroid gland, triiodothyronine (T3) and thyroxine (T4). However, an uncontrolled excess of oxidants can cause oxidative stress, a major trigger in the pathogenesis of a broad spectrum of diseases, including inflammation and cancer. In particular, oxidative stress is implicated in both hypo- and hyper-thyroid diseases. Furthermore, it is important for the TH system to rely on efficient antioxidant defense, to maintain balance, despite sustained tissue exposure to oxidants. One of the main endogenous antioxidant responses is the pathway centered on the nuclear factor erythroid 2-related factor (Nrf2). The aim of the present review is to explore the multiple links between Nrf2-related pathways and various TH-associated conditions. The main aspect of TH signaling is described and the role of Nrf2 in oxidant-antioxidant homeostasis in the TH system is evaluated. Next, the antioxidant function of Nrf2 associated with oxidative stress induced by TH pathological excess is discussed and, subsequently, particular attention is given to the cardioprotective role of TH, which also acts through the mediation of Nrf2. In conclusion, the interaction between Nrf2 and most common natural antioxidant agents in altered states of TH is briefly evaluated.
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Affiliation(s)
- Laura Sabatino
- Institute of Clinical Physiology, National Research Council, Via Moruzzi 1, 56124 Pisa, Italy
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17
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Kakinuma K, Kakinuma T. Analysis of oxidative stress and antioxidative potential in premature ovarian insufficiency. World J Clin Cases 2023; 11:2684-2693. [PMID: 37214574 PMCID: PMC10198121 DOI: 10.12998/wjcc.v11.i12.2684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/20/2023] [Accepted: 03/23/2023] [Indexed: 04/25/2023] Open
Abstract
BACKGROUND Premature ovarian insufficiency (POI) is characterized by an early decline in ovarian function, inducing secondary amenorrhea. While the cause of POI has not yet been identified, the function of mitochondria in the ovaries and the cytotoxicity associated with reactive oxygen species (ROS) have been implicated in follicle pool depletion and a decline in follicle quality. Recently developed tests have enabled easy measurement of diacron-reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP). The combination of these two tests is used to comprehensively assess oxidative stress in the blood.
AIM To comprehensively assess the oxidative stress of d-ROMs and BAP in POI.
METHODS Participants were classified into two groups: A POI group of 11 women aged < 40 years examined between January 2021 and June 2022 with a history of secondary amenorrhea for at least 4 mo in our hospital and an FSH value of ≥ 40 mIU/mL; and a control group of healthy women of the same age with normal ovarian function in our hospital. Plasma d-ROMs and BAP were measured in both these groups underwent. Differences between groups were assessed using the t-test.
RESULTS The mean age and mean body mass index (BMI) were 35.8 ± 3.0 years and 20.1 ± 1.9 kg/m2 in the control group and 35.8 ± 2.7 years and 19.4 ± 2.5 kg/m2 in the POI group, respectively. The mean gravidity and parity in control and POI groups were 0.6 ± 0.7 and 0.4 ± 0.5 and 0.6 ± 0.9 and 0.3 ± 0.5, respectively. The two groups did not differ significantly in terms of mean age, BMI, gravidity, or parity. The d-ROMs level was significantly higher in the POI group than in the control group (478.2 ± 58.7 vs 341.1 ± 35.1 U.CARR; P < 0.001); however, the BAP level did not significantly differ between the two groups (2078.5 ± 157.4 vs 2029.0 ± 186.4 μmol/L). The oxidase stress index (d-ROMs/BAP × 100) was significantly higher in the POI group than in the control group (23.7 ± 3.3 vs 16.5 ± 2.1; P < 0.001).
CONCLUSION Oxidative stress was significantly greater in the POI group than in the control group, suggesting oxidative stress as a factor that can serve as a POI biomarker.
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Affiliation(s)
- Kaoru Kakinuma
- Department of Obstetrics and Gynecology, International Health and Welfare Hospital, Nasushiobara 327-2763, Japan
| | - Toshiyuki Kakinuma
- Department of Obstetrics and Gynecology, International Health and Welfare Hospital, Nasushiobara 327-2763, Japan
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18
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de Mello Barros Pimentel MV, Bertolami A, Fernandes LP, Barroso LP, Castro IA. Could a lipid oxidative biomarker be applied to improve risk stratification in the prevention of cardiovascular disease? Biomed Pharmacother 2023; 160:114345. [PMID: 36753953 DOI: 10.1016/j.biopha.2023.114345] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/26/2023] [Accepted: 01/29/2023] [Indexed: 02/08/2023] Open
Abstract
There is significant evidence demonstrating the influence of oxidative stress on atherosclerosis and cardiovascular diseases (CVD). However, oxidative biomarkers have not been applied to follow patients under primary or secondary prevention. Many factors can explain this paradox: the higher complexity of the methods applied to quantify oxidative markers, the high variability observed among the studies, the lack of reference values, and the weak correlation with clinical endpoints. This review presents the role of the major reactive oxygen species (ROS) involved in cardiovascular pathophysiology and how they can be neutralized by endogenous and exogenous antioxidants based on classical and recent studies, highlighting the importance of the secondary products of fatty acid oxidation as potential biomarkers. Furthermore, we discuss the great variability of oxidative stress biomarkers, using as an example data obtained from 55 studies. Among the molecules directly formed from lipid oxidation, such as malondialdehyde (MDA), oxidized LDL (oxLDL), and isoprostanes (F2-IsoP), and those associated with general oxidative conditions (ferric-reducing antioxidant power (FRAP), superoxide dismutase (SOD), glutathione (GSH)), MDA was the most lipid biomarker evaluated in the treatments and proved to be an independent factor compared with traditional markers used in the algorithms to stratify the patient's risk. Finally, this review suggests four steps to follow, aiming to include MDA in the algorithms applied to estimate CVD risk.
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Affiliation(s)
| | - Adriana Bertolami
- Dyslipidemia Medical Section, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil
| | - Lígia Prestes Fernandes
- LADAF, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Lúcia Pereira Barroso
- Department of Statistics, Institute of Mathematics and Statistics, University of São Paulo, São Paulo, Brazil
| | - Inar Alves Castro
- LADAF, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil; Food Research Center (FoRC), CEPID-FAPESP, Research Innovation and Dissemination Centers São Paulo Research Foundation, São Paulo 05468-140, Brazil.
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Guha Ray A, Odum OP, Wiseman D, Weinstock A. The diverse roles of macrophages in metabolic inflammation and its resolution. Front Cell Dev Biol 2023; 11:1147434. [PMID: 36994095 PMCID: PMC10041730 DOI: 10.3389/fcell.2023.1147434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 02/14/2023] [Indexed: 03/14/2023] Open
Abstract
Macrophages are one of the most functionally diverse immune cells, indispensable to maintain tissue integrity and metabolic health. Macrophages perform a myriad of functions ranging from promoting inflammation, through inflammation resolution to restoring and maintaining tissue homeostasis. Metabolic diseases encompass a growing list of diseases which develop from a mix of genetics and environmental cues leading to metabolic dysregulation and subsequent inflammation. In this review, we summarize the contributions of macrophages to four metabolic conditions-insulin resistance and adipose tissue inflammation, atherosclerosis, non-alcoholic fatty liver disease and neurodegeneration. The role of macrophages is complex, yet they hold great promise as potential therapies to address these growing health concerns.
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Affiliation(s)
| | | | | | - Ada Weinstock
- Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, United States
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Papadea P, Skipitari M, Kalaitzopoulou E, Varemmenou A, Spiliopoulou M, Papasotiriou M, Papachristou E, Goumenos D, Onoufriou A, Rosmaraki E, Margiolaki I, Georgiou CD. Methods on LDL particle isolation, characterization, and component fractionation for the development of novel specific oxidized LDL status markers for atherosclerotic disease risk assessment. Front Med (Lausanne) 2023; 9:1078492. [PMID: 36687450 PMCID: PMC9851470 DOI: 10.3389/fmed.2022.1078492] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 12/05/2022] [Indexed: 01/06/2023] Open
Abstract
The present study uses simple, innovative methods to isolate, characterize and fractionate LDL in its main components for the study of specific oxidations on them that characterize oxidized low-density lipoprotein (oxLDL) status, as it causatively relates to atherosclerosis-associated cardiovascular disease (CVD) risk assessment. These methods are: (a) A simple, relatively time-short, low cost protocol for LDL isolation, to avoid shortcomings of the currently employed ultracentrifugation and affinity chromatography methodologies. (b) LDL purity verification by apoB100 SDS-PAGE analysis and by LDL particle size determination; the latter and its serum concentration are determined in the present study by a simple method more clinically feasible as marker of CVD risk assessment than nuclear magnetic resonance. (c) A protocol for LDL fractionation, for the first time, into its main protein/lipid components (apoB100, phospholipids, triglycerides, free cholesterol, and cholesteryl esters), as well as into LDL carotenoid/tocopherol content. (d) Protocols for the measurement, for the first time, of indicative specific LDL component oxidative modifications (cholesteryl ester-OOH, triglyceride-OOH, free cholesterol-OOH, phospholipid-OOH, apoB100-MDA, and apoB100-DiTyr) out of the many (known/unknown/under development) that collectively define oxLDL status, which contrasts with the current non-specific oxLDL status evaluation methods. The indicative oxLDL status markers, selected in the present study on the basis of expressing early oxidative stress-induced oxidative effects on LDL, are studied for the first time on patients with end stage kidney disease on maintenance hemodialysis, selected as an indicative model for atherosclerosis associated diseases. Isolating LDL and fractionating its protein and main lipid components, as well as its antioxidant arsenal comprised of carotenoids and tocopherols, paves the way for future studies to investigate all possible oxidative modifications responsible for turning LDL to oxLDL in association to their possible escaping from LDL's internal antioxidant defense. This can lead to studies to identify those oxidative modifications of oxLDL (after their artificial generation on LDL), which are recognized by macrophages and convert them to foam cells, known to be responsible for the formation of atherosclerotic plaques that lead to the various CVDs.
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Affiliation(s)
| | | | | | | | | | - Marios Papasotiriou
- Department of Nephrology, General University Hospital of Patras, Patras, Greece,Marios Papasotiriou,
| | | | - Dimitrios Goumenos
- Department of Nephrology, General University Hospital of Patras, Patras, Greece
| | - Anny Onoufriou
- Department of Microbiology, General University Hospital of Patras, University of Patras Medical School, Patras, Greece
| | | | | | - Christos D. Georgiou
- Department of Biology, University of Patras, Patras, Greece,*Correspondence: Christos D. Georgiou,
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21
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Calderón-Torres CM, Ortiz-Reyes AE, Murguía-Romero M. Oxidative Damage by 3-nitrotyrosine in Young Adults with Obesity: Its Implication in Chronic and Contagious Diseases. Curr Mol Med 2023; 23:358-364. [PMID: 35331110 DOI: 10.2174/1566524022666220324114027] [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: 11/12/2021] [Revised: 01/07/2022] [Accepted: 02/09/2022] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Cellular damage by oxidation occurs in numerous chronic diseases, such as obesity, type II diabetes, cardiovascular disease, nonalcoholic fatty liver, etc. The oxidized compound 3-nitrotyrosine is a marker of oxidative stress and protein oxidation damage. OBJECTIVE The article aims to assess whether 3-nitrotyrosine levels are higher in young people with obesity than in the same population without obesity. METHODS Anthropometry and blood chemistry analyses were performed on 24 young Mexican participants (18-30 years old), categorized into two groups based on their waist circumference: Withobesity (≥ 80 cm women; ≥ 90 cm men) and without-obesity (<80 cm women; <90 cm men). Additionally, 3-nitrotyrosine blood values were quantified by ELISA. RESULTS Except for HDL-cholesterol, the mean values of lipids increased in women and men with obesity (p<0.05), and 3-nitrotyrosine concentration (nM/μg total protein) was higher by 60% in the group with-obesity compared to the group without-obesity, both for women (66.21 ± 23.85 vs. 40.69 ± 16.25, p<0.05) and men (51.72 ± 20.56 vs. 30.52 ± 5.21, p<0.05). CONCLUSION Oxidative damage measured by compound 3-nitrotyrosine was higher in the group with obesity than in the group without obesity, which, if not controlled, could lead to a chronic oxidative condition and thereby to a degree of cellular aging with adverse health effects.
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Affiliation(s)
- Claudia Marissa Calderón-Torres
- Facultad de Estudios Superiores Iztacala, Unidad de Biomedicina, Universidad Nacional Autónoma de México. Ave. de Los Barrios #1, Tlalnepantla, 54090 Estado de México, Mexico
| | - Ana E Ortiz-Reyes
- Facultad de Estudios Superiores Iztacala, Unidad de Biomedicina, Universidad Nacional Autónoma de México. Ave. de Los Barrios #1, Tlalnepantla, 54090 Estado de México, Mexico
| | - Miguel Murguía-Romero
- Instituto de Biología, Universidad Nacional Autónoma de México, Circuito Zona Deportiva s/n, Ciudad Universitaria, Coyoacán, 04510 Ciudad de México, Mexico
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22
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Lankin VZ, Tikhaze AK, Melkumyants AM. Malondialdehyde as an Important Key Factor of Molecular Mechanisms of Vascular Wall Damage under Heart Diseases Development. Int J Mol Sci 2022; 24:ijms24010128. [PMID: 36613568 PMCID: PMC9820205 DOI: 10.3390/ijms24010128] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 12/12/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
This mini review is devoted to a specific issue: the role of malondialdehyde (MDA)-a secondary product of free radical lipid peroxidation-in the molecular mechanisms of the formation of primary atherosclerotic vascular wall lesions. The principal difference between this review and the available literature is that it discusses in detail the important role in atherogenesis not of "oxidized" LDL (i.e., LDL particles containing lipohydroperoxides), but of LDL particles chemically modified by the natural low-molecular weight dicarbonyl MDA. To confirm this, we consider the data obtained by us earlier, indicating that "atherogenic" are not LDL oxidized as a result of free radical lipoperoxidation and containing lipohydroperoxy derivatives of phospholipids in the outer layer of particles, but LDL whose apoprotein B-100 has been modified due to the chemical reaction of terminal lysine residue amino groups of the apoB-100 with the aldehyde groups of the MDA (Maillard reaction). In addition, we present our original data proving that MDA injures endothelial glycocalyx that suppress the ability of the endothelium to control arterial tone according to changes in wall shear stress. In summary, this mini review for the first time exhaustively discloses the key role of MDA in atherogenesis.
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23
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Colletti A, Fratter A, Pellizzato M, Cravotto G. Nutraceutical Approaches to Dyslipidaemia: The Main Formulative Issues Preventing Efficacy. Nutrients 2022; 14:nu14224769. [PMID: 36432457 PMCID: PMC9696395 DOI: 10.3390/nu14224769] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/29/2022] [Accepted: 11/04/2022] [Indexed: 11/16/2022] Open
Abstract
Currently, the nutraceutical approach to treat dyslipidaemia is increasing in use, and in many cases is used by physicians as the first choice in the treatment of patients with borderline values. Nutraceuticals represent an excellent opportunity to treat the preliminary conditions not yet showing the pathological signs of dyslipidaemia. Their general safety, the patient's confidence, the convincing proof of efficacy and the reasonable costs prompted the market of new preparations. Despite this premise, many nutraceutical products are poorly formulated and do not meet the minimum requirements to ensure efficacy in normalizing blood lipid profiles, promoting cardiovascular protection, and normalizing disorders of glycemic metabolism. In this context, bioaccessibility and bioavailability of the active compounds is a crucial issue. Little attention is paid to the proper formulations needed to improve the overall bioavailability of the active molecules. According to these data, many products prove to be insufficient to ensure full enteric absorption. The present review analysed the literature in the field of nutraceuticals for the treatment of dyslipidemia, focusing on resveratrol, red yeast rice, berberine, and plant sterols, which are among the nutraceuticals with the greatest formulation problems, highlighting bioavailability and the most suitable formulations.
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Affiliation(s)
- Alessandro Colletti
- Department of Science and Drug Technology, University of Turin, 10124 Turin, Italy
- Italian Society of Nutraceutical Formulators (SIFNut), 31033 Treviso, Italy
| | - Andrea Fratter
- Italian Society of Nutraceutical Formulators (SIFNut), 31033 Treviso, Italy
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35122 Padua, Italy
| | - Marzia Pellizzato
- Italian Society of Nutraceutical Formulators (SIFNut), 31033 Treviso, Italy
| | - Giancarlo Cravotto
- Department of Science and Drug Technology, University of Turin, 10124 Turin, Italy
- Italian Society of Nutraceutical Formulators (SIFNut), 31033 Treviso, Italy
- Correspondence: ; Tel.: +39-011-670-7103
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24
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Labarrere CA, Kassab GS. Glutathione: A Samsonian life-sustaining small molecule that protects against oxidative stress, ageing and damaging inflammation. Front Nutr 2022; 9:1007816. [PMID: 36386929 PMCID: PMC9664149 DOI: 10.3389/fnut.2022.1007816] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 10/12/2022] [Indexed: 11/26/2022] Open
Abstract
Many local and systemic diseases especially diseases that are leading causes of death globally like chronic obstructive pulmonary disease, atherosclerosis with ischemic heart disease and stroke, cancer and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 19 (COVID-19), involve both, (1) oxidative stress with excessive production of reactive oxygen species (ROS) that lower glutathione (GSH) levels, and (2) inflammation. The GSH tripeptide (γ- L-glutamyl-L-cysteinyl-glycine), the most abundant water-soluble non-protein thiol in the cell (1-10 mM) is fundamental for life by (a) sustaining the adequate redox cell signaling needed to maintain physiologic levels of oxidative stress fundamental to control life processes, and (b) limiting excessive oxidative stress that causes cell and tissue damage. GSH activity is facilitated by activation of the Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) redox regulator pathway, releasing Nrf2 that regulates expression of genes controlling antioxidant, inflammatory and immune system responses. GSH exists in the thiol-reduced (>98% of total GSH) and disulfide-oxidized (GSSG) forms, and the concentrations of GSH and GSSG and their molar ratio are indicators of the functionality of the cell. GSH depletion may play a central role in inflammatory diseases and COVID-19 pathophysiology, host immune response and disease severity and mortality. Therapies enhancing GSH could become a cornerstone to reduce severity and fatal outcomes of inflammatory diseases and COVID-19 and increasing GSH levels may prevent and subdue these diseases. The life value of GSH makes for a paramount research field in biology and medicine and may be key against systemic inflammation and SARS-CoV-2 infection and COVID-19 disease. In this review, we emphasize on (1) GSH depletion as a fundamental risk factor for diseases like chronic obstructive pulmonary disease and atherosclerosis (ischemic heart disease and stroke), (2) importance of oxidative stress and antioxidants in SARS-CoV-2 infection and COVID-19 disease, (3) significance of GSH to counteract persistent damaging inflammation, inflammaging and early (premature) inflammaging associated with cell and tissue damage caused by excessive oxidative stress and lack of adequate antioxidant defenses in younger individuals, and (4) new therapies that include antioxidant defenses restoration.
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25
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Unravelling mechanisms of protein and lipid oxidation in mayonnaise at multiple length scales. Food Chem 2022; 402:134417. [DOI: 10.1016/j.foodchem.2022.134417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 09/09/2022] [Accepted: 09/25/2022] [Indexed: 11/19/2022]
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26
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Oxidised Low-Density Lipoprotein-Induced Platelet Hyperactivity—Receptors and Signalling Mechanisms. Int J Mol Sci 2022; 23:ijms23169199. [PMID: 36012465 PMCID: PMC9409144 DOI: 10.3390/ijms23169199] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 07/26/2022] [Accepted: 08/09/2022] [Indexed: 11/17/2022] Open
Abstract
Dyslipidaemia leads to proatherogenic oxidative lipid stress that promotes vascular inflammation and thrombosis, the pathologies that underpin myocardial infarction, stroke, and deep vein thrombosis. These prothrombotic states are driven, at least in part, by platelet hyperactivity, and they are concurrent with the appearancxe of oxidatively modified low-density lipoproteins (LDL) in the circulation. Modified LDL are heterogenous in nature but, in a general sense, constitute a prototype circulating transporter for a plethora of oxidised lipid epitopes that act as danger-associated molecular patterns. It is well-established that oxidatively modified LDL promote platelet activation and arterial thrombosis through a number of constitutively expressed scavenger receptors, which transduce atherogenic lipid stress to a complex array of proactivatory signalling pathways in the platelets. Stimulation of these signalling events underlie the ability of modified LDL to induce platelet activation and blunt platelet inhibitory pathways, as well as promote platelet-mediated coagulation. Accumulating evidence from patients at risk of arterial thrombosis and experimental animal models of disease suggest that oxidised LDL represents a tangible link between the dyslipidaemic environment and increased platelet activation. The aim of this review is to summarise recent advances in our understanding of the pro-thrombotic signalling events induced in platelets by modified LDL ligation, describe the contribution of individual platelet scavenger receptors, and highlight potential future challenges of targeting these pathways.
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27
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Dicarbonyl-Dependent Modification of LDL as a Key Factor of Endothelial Dysfunction and Atherosclerotic Vascular Wall Damage. Antioxidants (Basel) 2022; 11:antiox11081565. [PMID: 36009284 PMCID: PMC9405452 DOI: 10.3390/antiox11081565] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/02/2022] [Accepted: 08/10/2022] [Indexed: 12/05/2022] Open
Abstract
The review presents evidence that the main damage to the vascular wall occurs not from the action of “oxidized” LDL, which contain hydroperoxy acyls in the phospholipids located in their outer layer, but from the action of LDL particles whose apoprotein B-100 is chemically modified with low molecular weight dicarbonyls, such as malondialdehyde, glyoxal, and methylglyoxal. It has been argued that dicarbonyl-modified LDL, which have the highest cholesterol content, are particularly “atherogenic”. High levels of dicarbonyl-modified LDL have been found to be characteristic of some mutations of apoprotein B-100. Based on the reviewed data, we hypothesized a common molecular mechanism underlying vascular wall damage in atherosclerosis and diabetes mellitus. The important role of oxidatively modified LDL in endothelial dysfunction is discussed in detail. In particular, the role of the interaction of the endothelial receptor LOX-1 with oxidatively modified LDL, which leads to the expression of NADPH oxidase, which in turn generates superoxide anion radical, is discussed. Such hyperproduction of ROS can cause destruction of the glycocalyx, a protective layer of endotheliocytes, and stimulation of apoptosis in these cells. On the whole, the accumulated evidence suggests that carbonyl modification of apoprotein B-100 of LDL is a key factor responsible for vascular wall damage leading to atherogenesis and endothelial dysfunction. Possible ways of pharmacological correction of free radical processes in atherogenesis and diabetogenesis are also discussed.
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28
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Aftermath of AGE-RAGE Cascade in the pathophysiology of cardiovascular ailments. Life Sci 2022; 307:120860. [PMID: 35940220 DOI: 10.1016/j.lfs.2022.120860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 07/20/2022] [Accepted: 08/01/2022] [Indexed: 11/21/2022]
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29
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Fonseca FA, Izar MC. Role of Inflammation in Cardiac Remodeling After Acute Myocardial Infarction. Front Physiol 2022; 13:927163. [PMID: 35837017 PMCID: PMC9274081 DOI: 10.3389/fphys.2022.927163] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 06/08/2022] [Indexed: 11/13/2022] Open
Abstract
Atherosclerosis is defined as an inflammatory disease. Low-grade inflammation is present in all phases of the cardiovascular continuum, since the establishment of cardiovascular risk factors and ischemic heart disease until cardiovascular events, such as myocardial infarction, heart failure and death. Not all inflammatory pathways are linked to cardiovascular outcomes, and thus, not all anti-inflammatory approaches decrease cardiovascular events. The most common cause of ventricular remodeling and heart failure is ischemic heart disease. Biomarkers such as high-sensitivity C-reactive protein can identify individuals at risk of major cardiovascular complications, but this biomarker has no causal effect on cardiovascular disease. On the other hand, interleukin 6 appears to be causally associated with cardiovascular disease. CANTOS was the first proof of concept study showing that anti-inflammatory therapy reduces major cardiovascular outcomes. Based on many anti-inflammatory trials, only therapies acting on the NLRP3 inflammasome, or interleukin 1beta, showed benefits on cardiovascular disease. Ventricular remodeling, particularly after myocardial infarction seems also influenced by the intensity of inflammatory responses, suggesting that anti-inflammatory therapies may reduce the residual cardiovascular risk. Inflammasome (NLRP3) activation, subtypes of lymphocytes, interleukin 6, and some inflammatory biomarkers, are associated with larger infarct size and impaired ventricular function after myocardial infarction. Cardiovascular risk factors commonly present in patients with myocardial infarction, and advanced age are associated with higher inflammatory activity.
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30
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Lu Y, Cui X, Zhang L, Wang X, Xu Y, Qin Z, Liu G, Wang Q, Tian K, Lim KS, Charles CJ, Zhang J, Tang J. The Functional Role of Lipoproteins in Atherosclerosis: Novel Directions for Diagnosis and Targeting Therapy. Aging Dis 2022; 13:491-520. [PMID: 35371605 PMCID: PMC8947823 DOI: 10.14336/ad.2021.0929] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 09/28/2021] [Indexed: 11/20/2022] Open
Abstract
Dyslipidemia, characterized by a high level of lipids (cholesterol, triglycerides, or both), can increase the risk of developing and progressing atherosclerosis. As atherosclerosis progresses, the number and severity of aterial plagues increases with greater risk of myocardial infarction, a major contributor to cardiovascular mortality. Atherosclerosis progresses in four phases, namely endothelial dysfunction, fatty streak formation, lesion progression and plaque rupture, and eventually thrombosis and arterial obstruction. With greater understanding of the pathological processes underlying atherosclerosis, researchers have identified that lipoproteins play a significant role in the development of atherosclerosis. In particular, apolipoprotein B (apoB)-containing lipoproteins have been shown to associate with atherosclerosis. Oxidized low-density lipoproteins (ox-LDLs) also contribute to the progression of atherosclerosis whereas high-density lipoproteins (HDL) contribute to the removal of cholesterol from macrophages thereby inhibiting the formation of foam cells. Given these known associations, lipoproteins may have potential as biomarkers for predicting risk associated with atherosclerotic plaques or may be targets as novel therapeutic agents. As such, the rapid development of drugs targeting lipoprotein metabolism may lead to novel treatments for atherosclerosis. A comprehensive review of lipoprotein function and their role in atherosclerosis, along with the latest development of lipoprotein targeted treatment, is timely. This review focuses on the functions of different lipoproteins and their involvement in atherosclerosis. Further, diagnostic and therapeutic potential are highlighted giving insight into novel lipoprotein-targetted approaches to treat atherosclerosis.
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Affiliation(s)
- Yongzheng Lu
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, China.,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, China.
| | - Xiaolin Cui
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) group, Department of Orthopedic Surgery, University of Otago, Christchurch 8011, New Zealand.,Department of Bone and Joint, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
| | - Li Zhang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, China.,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, China.
| | - Xu Wang
- Department of Medical Record Management, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Yanyan Xu
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, China.,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, China.
| | - Zhen Qin
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, China.,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, China.
| | - Gangqiong Liu
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, China.,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, China.
| | - Qiguang Wang
- National Engineering Research Centre for Biomaterials, Sichuan University, Chengdu, Sichuan, China.
| | - Kang Tian
- Department of Bone and Joint, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
| | - Khoon S Lim
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) group, Department of Orthopedic Surgery, University of Otago, Christchurch 8011, New Zealand.
| | - Chris J Charles
- Christchurch Heart Institute, Department of Medicine, University of Otago Christchurch, Christchurch 8011, New Zealand
| | - Jinying Zhang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, China.,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, China.
| | - Junnan Tang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, China.,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, China.,Correspondence should be addressed to: Dr. Junnan Tang, Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
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31
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Patten DA, Wilkinson AL, O'Keeffe A, Shetty S. Scavenger Receptors: Novel Roles in the Pathogenesis of Liver Inflammation and Cancer. Semin Liver Dis 2022; 42:61-76. [PMID: 34553345 PMCID: PMC8893982 DOI: 10.1055/s-0041-1733876] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The scavenger receptor superfamily represents a highly diverse collection of evolutionarily-conserved receptors which are known to play key roles in host homeostasis, the most prominent of which is the clearance of unwanted endogenous macromolecules, such as oxidized low-density lipoproteins, from the systemic circulation. Members of this family have also been well characterized in their binding and internalization of a vast range of exogenous antigens and, consequently, are generally considered to be pattern recognition receptors, thus contributing to innate immunity. Several studies have implicated scavenger receptors in the pathophysiology of several inflammatory diseases, such as Alzheimer's and atherosclerosis. Hepatic resident cellular populations express a diverse complement of scavenger receptors in keeping with the liver's homeostatic functions, but there is gathering interest in the contribution of these receptors to hepatic inflammation and its complications. Here, we review the expression of scavenger receptors in the liver, their functionality in liver homeostasis, and their role in inflammatory liver disease and cancer.
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Affiliation(s)
- Daniel A. Patten
- National Institute for Health Research Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Alex L. Wilkinson
- National Institute for Health Research Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Ayla O'Keeffe
- National Institute for Health Research Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Shishir Shetty
- National Institute for Health Research Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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Pierce G, Deniset J, Resch C, Mourin M, Dibrov E, Dibrov P. The evidence for a role of bacteria and viruses in cardiovascular disease. SCRIPTA MEDICA 2022. [DOI: 10.5937/scriptamed53-37418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Inflammation plays a critical role in atherosclerosis and cardiovascular disease. Bacteria and viruses are major causative agents of inflammation in the body which normally develops as a response to infection. It is a logical extention, therefore, to believe bacterial and viral infections may be involved in a variety of presentations of cardiovascular diseases. The purpose of this review is to describe the data and conclusions to date on the involvement of these infectious agents in the induction of cardiovascular disease. The review also discusses the various specific bacteria and viruses that have been implicated in cardiovascular disease and the mechanisms, if known, that these agents induce cardiovascular disease.
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33
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Glycated apolipoprotein B decreases after bariatric surgery in people with and without diabetes: A potential contribution to reduction in cardiovascular risk. Atherosclerosis 2022; 346:10-17. [DOI: 10.1016/j.atherosclerosis.2022.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 12/19/2021] [Accepted: 01/13/2022] [Indexed: 11/17/2022]
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34
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Yuan M, Han S, Jia Y, Feng J, Liu D, Su Z, Liu X. Statins Are Associated with Improved Survival of Patients with Gastric Cancer: A Systematic Review and Meta-Analysis. Int J Clin Pract 2022; 2022:4938539. [PMID: 35685487 PMCID: PMC9158792 DOI: 10.1155/2022/4938539] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 11/17/2022] Open
Abstract
Statins are associated with gastric cancer (GC) risk. The present study aimed to clarify the efficacy of statins on the overall survival (OS) benefits in patients with GC. Publications were retrieved from PubMed, Embase, and the Cochrane Library as of April 2022. Data from the eligible cohort, case-control studies, and randomized control trials (RCTs) were extracted for the meta-analysis. Hazard ratio (HR) and 95% confidence intervals (CI) were used to assess the association between statins users and OS in GC patients. Subgroup analysis was performed based on the study design (prospective vs. retrospective). A total of 6 studies encompassing 5693 GC patients were included. Statins added to the standard treatment prolonged the patient's OS outcome (HR (95% CI): 0.72 (0.53-0.97), p = 0.032; I 2 = 88.0%, p heterogeneity < 0.001). A prospective study did not find any statistically significant difference in OS between statins users vs. nonstatin users (HR (95% CI): 0.92 (0.68-1.26), p = 0.614; I 2 = 11.7%, p heterogeneity = 0.322), whereas the retrospective studies showed prolonged OS in statins users (HR (95% CI): 0.63 (0.42-0.961), p = 0.032; I 2 = 94.6%, p heterogeneity < 0.001). Statin users had significantly improved OS compared to nonstatin users in GC treatment. This long-term survival benefit was only observed in the pooled analysis of retrospective studies but not in prospective studies.
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Affiliation(s)
- Mingjie Yuan
- Department of Clinical Laboratory, Binzhou Medical University, Yantai, Shandong, China
| | - Shuyi Han
- Department of Laboratory, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Department of Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Yanfei Jia
- Department of Laboratory, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Department of Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Jiankai Feng
- Department of Clinical Laboratory, Binzhou Medical University, Yantai, Shandong, China
| | - Duanrui Liu
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Zhenguo Su
- Department of Clinical Laboratory, Binzhou Medical University, Yantai, Shandong, China
| | - Xiangdong Liu
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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35
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Sphingolipids and Cholesterol. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1372:1-14. [DOI: 10.1007/978-981-19-0394-6_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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36
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Yang H, Li H, Chen W, Mei Z, Yuan Y, Wang X, Chu L, Xu Y, Sun Y, Li D, Gao H, Zhan B, Li H, Yang X. Therapeutic Effect of Schistosoma japonicum Cystatin on Atherosclerotic Renal Damage. Front Cell Dev Biol 2021; 9:760980. [PMID: 34901005 PMCID: PMC8656285 DOI: 10.3389/fcell.2021.760980] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/11/2021] [Indexed: 01/15/2023] Open
Abstract
Atherosclerosis is a chronic inflammation of the arterial vessel wall driven by lipid metabolism disorders. Although helminthic infection and their derivatives have been identified to attenuate the chronic inflammatory diseases, the immunomodulatory effect of recombinant Schistosoma japonicum cystatin (rSj-Cys) on metabolic diseases and atherosclerosis has not been reported. In this study, we investigated the therapeutic efficacy of rSj-Cys on atherosclerotic renal damage and explored the related immunological mechanism. The results demonstrated that treatment with rSj-Cys significantly reduced body weight gain, hyperlipidemia, and atherosclerosis induced by the high-fat diet in apoE–/– mice. The treatment of rSj-Cys also significantly improved kidney functions through promoting macrophage polarization from M1 to M2, therefore inhibiting M1 macrophage–induced inflammation. The possible mechanism underlying the regulatory effect of rSj-Cys on reducing atherosclerosis and atherosclerotic renal damage is that rSj-Cys stimulates regulatory T cell and M2 macrophage polarization that produce regulatory cytokines, such as interleukin 10 and transforming growth factor β. The therapeutic effect of rSj-Cys on atherosclerotic renal damage is possibly through inhibiting the activation of TLR2/Myd88 signaling pathway. The results in this study provide evidence for the first time that Schistosoma-derived cystatin could be developed as a therapeutic agent to treat lipid metabolism disorder and atherosclerosis that threats million lives around the world.
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Affiliation(s)
- Huijuan Yang
- Department of Nephrology, First Affiliated Hospital of Bengbu Medical College, Bengbu, China.,Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China
| | - Hongqi Li
- Department of Gerontology, Anhui Provincial Hospital, First Affiliated Hospital of University of Science and Technology of China, Hefei, China
| | - Weidong Chen
- Department of Nephrology, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Zhijie Mei
- Department of Urology, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yuan Yuan
- Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China.,Basic Medical College of Bengbu Medical College, Bengbu, China
| | - Xiaoli Wang
- Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China.,Basic Medical College of Bengbu Medical College, Bengbu, China
| | - Liang Chu
- Second Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yu Xu
- Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China.,Basic Medical College of Bengbu Medical College, Bengbu, China
| | - Yan Sun
- Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China.,Basic Medical College of Bengbu Medical College, Bengbu, China
| | - Dingru Li
- Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China.,Basic Medical College of Bengbu Medical College, Bengbu, China
| | - Hongyu Gao
- Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China.,Basic Medical College of Bengbu Medical College, Bengbu, China
| | - Bin Zhan
- National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Huihui Li
- Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China.,Basic Medical College of Bengbu Medical College, Bengbu, China
| | - Xiaodi Yang
- Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China.,Basic Medical College of Bengbu Medical College, Bengbu, China
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37
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Jia J, Zhang H, Liang X, Dai Y, Liu L, Tan K, Ma R, Luo J, Ding Y, Ke C. Application of Metabolomics to the Discovery of Biomarkers for Ischemic Stroke in the Murine Model: a Comparison with the Clinical Results. Mol Neurobiol 2021; 58:6415-6426. [PMID: 34532786 DOI: 10.1007/s12035-021-02535-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 08/16/2021] [Indexed: 12/20/2022]
Abstract
Ischemic stroke (IS) is a major cause of mortality and disability worldwide. However, the pathogenesis of IS remains unknown, and methods for early prediction and diagnosis of IS are lacking. Metabolomics can be applied to biomarker discovery and mechanism exploration of IS by exploring metabolic alterations. In this review, 62 IS metabolomics studies in the murine model published from January 2006 to December 2020 in the PubMed and Web of Science databases were systematically reviewed. Twenty metabolites (e.g., lysine, phenylalanine, methionine, tryptophan, leucine, lactate, serine, N-acetyl-aspartic acid, and glutathione) were reported consistently in more than two-third murine studies. The disturbance of metabolic pathways, such as arginine biosynthesis; alanine, aspartate and glutamate metabolism; aminoacyl-tRNA biosynthesis; and citrate cycle, may be implicated in the development of IS by influencing the biological processes such as energy failure, oxidative stress, apoptosis, and glutamate toxicity. The transient middle cerebral artery occlusion model and permanent middle cerebral artery occlusion model exhibit both common and distinct metabolic patterns. Furthermore, five metabolites (proline, serine, LysoPC (16:0), uric acid, glutamate) in the blood sample and 7 metabolic pathways (e.g., alanine, aspartate, and glutamate metabolism) are shared in animal and clinical studies. The potential biomarkers and related pathways of IS in the murine model may facilitate the biomarker discovery for early diagnosis of IS and the development of novel therapeutic targets.
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Affiliation(s)
- Jinjing Jia
- Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, People's Republic of China
| | - Hangyao Zhang
- Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, People's Republic of China
| | - Xiaoyi Liang
- Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, People's Republic of China
| | - Yuning Dai
- Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, People's Republic of China
| | - Lihe Liu
- Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, People's Republic of China
| | - Kaiwen Tan
- Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, People's Republic of China
| | - Ruohan Ma
- Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, People's Republic of China
| | - Jiahuan Luo
- Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, People's Republic of China
| | - Yi Ding
- Department of Preventive Medicine, College of Clinical Medicine, Suzhou Vocational Health College, Suzhou, 215009, People's Republic of China
| | - Chaofu Ke
- Department of Epidemiology and Biostatistics, School of Public Health, Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, People's Republic of China.
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38
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Leigh JH, Park HJ, Chun SM, Min YS, Choi M. Association of Atopic Dermatitis with Dyslipidemia in Adolescents: A Cross-Sectional Study. Ann Dermatol 2021; 33:483-485. [PMID: 34616137 PMCID: PMC8460476 DOI: 10.5021/ad.2021.33.5.483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 04/07/2021] [Accepted: 04/13/2021] [Indexed: 11/12/2022] Open
Affiliation(s)
- Ja-Ho Leigh
- Department of Rehabilitation Medicine, Workers' Compensation and Welfare Service Incheon Hospital, Incheon, Korea.,Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hee Jae Park
- Department of Dermatology, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Seong-Min Chun
- Department of Physical Medicine and Rehabilitation, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Yu-Sun Min
- Department of Rehabilitation Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.,Department of Rehabilitation Medicine, Kyungpook National University Hospital, Daegu, Korea
| | - Mira Choi
- Department of Dermatology, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
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Ducatez F, Mauhin W, Boullier A, Pilon C, Pereira T, Aubert R, Benveniste O, Marret S, Lidove O, Bekri S, Tebani A. Parsing Fabry Disease Metabolic Plasticity Using Metabolomics. J Pers Med 2021; 11:jpm11090898. [PMID: 34575675 PMCID: PMC8468728 DOI: 10.3390/jpm11090898] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 09/03/2021] [Accepted: 09/05/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Fabry disease (FD) is an X-linked lysosomal disease due to a deficiency in the activity of the lysosomal α-galactosidase A (GalA), a key enzyme in the glycosphingolipid degradation pathway. FD is a complex disease with a poor genotype–phenotype correlation. FD could involve kidney, heart or central nervous system impairment that significantly decreases life expectancy. The advent of omics technologies offers the possibility of a global, integrated and systemic approach well-suited for the exploration of this complex disease. Materials and Methods: Sixty-six plasmas of FD patients from the French Fabry cohort (FFABRY) and 60 control plasmas were analyzed using liquid chromatography and mass spectrometry-based targeted metabolomics (188 metabolites) along with the determination of LysoGb3 concentration and GalA enzymatic activity. Conventional univariate analyses as well as systems biology and machine learning methods were used. Results: The analysis allowed for the identification of discriminating metabolic profiles that unambiguously separate FD patients from control subjects. The analysis identified 86 metabolites that are differentially expressed, including 62 Glycerophospholipids, 8 Acylcarnitines, 6 Sphingomyelins, 5 Aminoacids and 5 Biogenic Amines. Thirteen consensus metabolites were identified through network-based analysis, including 1 biogenic amine, 2 lysophosphatidylcholines and 10 glycerophospholipids. A predictive model using these metabolites showed an AUC-ROC of 0.992 (CI: 0.965–1.000). Conclusion: These results highlight deep metabolic remodeling in FD and confirm the potential of omics-based approaches in lysosomal diseases to reveal clinical and biological associations to generate pathophysiological hypotheses.
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Affiliation(s)
- Franklin Ducatez
- Department of Metabolic Biochemistry, Normandie University, UNIROUEN, INSERM U1245, CHU Rouen, 76000 Rouen, France; (F.D.); (C.P.); (R.A.); (S.B.)
- Department of Neonatal Pediatrics, Intensive Care, and Neuropediatrics, Normandie University, UNIROUEN, INSERM U1245, CHU Rouen, 76000 Rouen, France;
| | - Wladimir Mauhin
- Department of Internal Medicine, Groupe Hospitalier Diaconesses Croix Saint Simon, Site Avron & UMRS 974, 75013 Paris, France; (W.M.); (O.L.)
| | - Agnès Boullier
- MP3CV-UR7517, CURS-Université de Picardie Jules Verne, Avenue de la Croix Jourdain, 80054 Amiens, France;
- Laboratoire de Biochimie CHU Amiens-Picardie, Avenue de la Croix Jourdain, 80054 Amiens, France
| | - Carine Pilon
- Department of Metabolic Biochemistry, Normandie University, UNIROUEN, INSERM U1245, CHU Rouen, 76000 Rouen, France; (F.D.); (C.P.); (R.A.); (S.B.)
| | - Tony Pereira
- CHU Rouen, Institut de Biologie Clinique, 76000 Rouen, France;
| | - Raphaël Aubert
- Department of Metabolic Biochemistry, Normandie University, UNIROUEN, INSERM U1245, CHU Rouen, 76000 Rouen, France; (F.D.); (C.P.); (R.A.); (S.B.)
| | - Olivier Benveniste
- Department of Internal Medicine, Hôpital Pitié-Salpêtrière & INSERM U 974, 75013 Paris, France;
| | - Stéphane Marret
- Department of Neonatal Pediatrics, Intensive Care, and Neuropediatrics, Normandie University, UNIROUEN, INSERM U1245, CHU Rouen, 76000 Rouen, France;
| | - Olivier Lidove
- Department of Internal Medicine, Groupe Hospitalier Diaconesses Croix Saint Simon, Site Avron & UMRS 974, 75013 Paris, France; (W.M.); (O.L.)
| | - Soumeya Bekri
- Department of Metabolic Biochemistry, Normandie University, UNIROUEN, INSERM U1245, CHU Rouen, 76000 Rouen, France; (F.D.); (C.P.); (R.A.); (S.B.)
| | - Abdellah Tebani
- Department of Metabolic Biochemistry, Normandie University, UNIROUEN, INSERM U1245, CHU Rouen, 76000 Rouen, France; (F.D.); (C.P.); (R.A.); (S.B.)
- Correspondence:
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40
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Kiechl SJ, Staudt A, Stock K, Gande N, Bernar B, Hochmayr C, Winder B, Geiger R, Griesmacher A, Anliker M, Kiechl S, Kiechl‐Kohlendorfer U, Knoflach M, Pechlaner R, for the Early Vascular Ageing (EVA) Study Group AsareMandyBock‐BartlManuelaBohlMaximilianKlingenschmidJuliaKothmayerMartinaMarxerJuliaPircherMaximilianReiterCarmenSchreinerChristina. Predictors of Carotid Intima-Media Thickness Progression in Adolescents-The EVA-Tyrol Study. J Am Heart Assoc 2021; 10:e020233. [PMID: 34482715 PMCID: PMC8649517 DOI: 10.1161/jaha.120.020233] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Background Cardiovascular disease depends on the duration and time course of risk factor exposure. Previous reports on risk factors of progression of carotid intima-media thickness (cIMT) in the young were mostly restricted to high-risk populations or susceptible to certain types of bias. We aimed to unravel a risk factor signature for early vessel pathology based on repeated ultrasound assessments of the carotid arteries in the general population. Methods and Results Risk factors were assessed in 956 adolescents sampled from the general population with a mean age of 15.8±0.9 years, 56.2% of whom were female. cIMT was measured at baseline and on average 22.5±3.4 months later by high-resolution ultrasound. Effects of baseline risk factors on cIMT progression were investigated using linear mixed models with multivariable adjustment for potential confounders, which yielded significant associations (given as increase in cIMT for a 1-SD higher baseline level) for alanine transaminase (5.5 μm; 95% CI: 1.5-9.5), systolic blood pressure (4.7 μm; 0.3-9.2), arterial hypertension (9.5 μm, 0.2-18.7), and non-high-density (4.5 μm; 0.7-8.4) and low-density lipoprotein cholesterol (4.3 μm; 0.5-8.1). Conclusions Systolic blood pressure, arterial hypertension, low-density and non-high-density lipoprotein cholesterol, and alanine transaminase predicted cIMT progression in adolescents, even though risk factor levels were predominantly within established reference ranges. These findings reemphasize the necessity to initiate prevention early in life and challenge the current focus of guideline recommendations on high-risk youngsters. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03929692.
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Affiliation(s)
- Sophia J. Kiechl
- Department of NeurologyMedical University of InnsbruckInnsbruckAustria,VASCageResearch Centre on Vascular Ageing and StrokeInnsbruckAustria
| | - Anna Staudt
- Department of Pediatrics IIMedical University of InnsbruckInnsbruckAustria
| | - Katharina Stock
- Department of Pediatrics IIMedical University of InnsbruckInnsbruckAustria,Department of Pediatrics IIIMedical University of InnsbruckInnsbruckAustria
| | - Nina Gande
- Department of Pediatrics IIMedical University of InnsbruckInnsbruckAustria
| | - Benoît Bernar
- Department of Pediatrics IIMedical University of InnsbruckInnsbruckAustria,Department of Pediatrics IMedical University of InnsbruckInnsbruckAustria
| | - Christoph Hochmayr
- Department of Pediatrics IIMedical University of InnsbruckInnsbruckAustria
| | - Bernhard Winder
- Department of Pediatrics IIMedical University of InnsbruckInnsbruckAustria,VASCageResearch Centre on Vascular Ageing and StrokeInnsbruckAustria
| | - Ralf Geiger
- Department of Pediatrics IIIMedical University of InnsbruckInnsbruckAustria
| | - Andrea Griesmacher
- Central Institute of Clinical Chemistry and Laboratory MedicineMedical University of InnsbruckInnsbruckAustria
| | - Markus Anliker
- Central Institute of Clinical Chemistry and Laboratory MedicineMedical University of InnsbruckInnsbruckAustria
| | - Stefan Kiechl
- Department of NeurologyMedical University of InnsbruckInnsbruckAustria,VASCageResearch Centre on Vascular Ageing and StrokeInnsbruckAustria
| | | | - Michael Knoflach
- Department of NeurologyMedical University of InnsbruckInnsbruckAustria
| | - Raimund Pechlaner
- Department of NeurologyMedical University of InnsbruckInnsbruckAustria
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41
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Xu S, Chaudhary O, Rodríguez-Morales P, Sun X, Chen D, Zappasodi R, Xu Z, Pinto AFM, Williams A, Schulze I, Farsakoglu Y, Varanasi SK, Low JS, Tang W, Wang H, McDonald B, Tripple V, Downes M, Evans RM, Abumrad NA, Merghoub T, Wolchok JD, Shokhirev MN, Ho PC, Witztum JL, Emu B, Cui G, Kaech SM. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8 + T cells in tumors. Immunity 2021; 54:1561-1577.e7. [PMID: 34102100 PMCID: PMC9273026 DOI: 10.1016/j.immuni.2021.05.003] [Citation(s) in RCA: 429] [Impact Index Per Article: 107.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 03/03/2021] [Accepted: 05/04/2021] [Indexed: 01/21/2023]
Abstract
A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36-/- T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.
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Affiliation(s)
- Shihao Xu
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Omkar Chaudhary
- Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06510, USA
| | - Patricia Rodríguez-Morales
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Xiaoli Sun
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Dan Chen
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Roberta Zappasodi
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Ziyan Xu
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA
| | - Antonio F M Pinto
- Mass Spectrometry Core for Proteomics and Metabolomics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - April Williams
- The Razavi Newman Integrative Genomics and Bioinformatics Core Facility, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Isabell Schulze
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Yagmur Farsakoglu
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Siva Karthik Varanasi
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Jun Siong Low
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA; Fondazione per l'istituto di ricerca in biomedicina, Bellinzona, Switzerland
| | - Wenxi Tang
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Haiping Wang
- Department of Fundamental Oncology, Ludwig Institute for Cancer Research at University of Lausanne, Lausanne, Switzerland
| | - Bryan McDonald
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Victoria Tripple
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Michael Downes
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Ronald M Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Nada A Abumrad
- Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Taha Merghoub
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Jedd D Wolchok
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Maxim N Shokhirev
- The Razavi Newman Integrative Genomics and Bioinformatics Core Facility, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Ping-Chih Ho
- Department of Fundamental Oncology, Ludwig Institute for Cancer Research at University of Lausanne, Lausanne, Switzerland
| | - Joseph L Witztum
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Brinda Emu
- Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06510, USA
| | - Guoliang Cui
- T Cell Metabolism Group (D140), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany.
| | - Susan M Kaech
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
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Ashry NA, Abdеlaziz RR, Suddеk GM, Saleh MA. Canagliflozin ameliorates aortic and hepatic dysfunction in dietary-induced hypercholesterolemia in the rabbit. Life Sci 2021; 280:119731. [PMID: 34144054 DOI: 10.1016/j.lfs.2021.119731] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/05/2021] [Accepted: 06/08/2021] [Indexed: 01/14/2023]
Abstract
AIMS Canagliflozin is an antidiabetic agent which lowers blood glucose levels by inhibiting the glucose reabsorption machinery in the proximal tubules. There have not been conducted any study on its direct impact on hypercholesterolemia and associated vascular disorders independently of blood glucose lowering activity. MATERIALS AND METHODS Rabbits were arranged in 3 groups: Group 1 (Control): regular rabbit chow; Group 2 (HCD): 1% cholesterol-enriched chow was given to rabbits for 4 weeks; Group 3 (HCD-CANA): 1% cholesterol-enriched chow was fed to rabbits concurrently with canagliflozin (10 mg/kg/day, orally) for 4 weeks. At the end of experiment, blood and tissue samples were obtained for biochemical, histological, immunohistochemical, and vascular reactivity assessment. KEY FINDINGS When statistically compared to Control (P < 0.05), HCD showed a significant increase in the serum triglycerides, low-density lipoprotein, total cholesterol, C-reactive protein, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase. Furthermore, a significant decrease was seen in both liver and aortic levels of glutathione peroxidase and superoxide dismutase concurrently with a significant elevation in malondialdehyde levels. Aortic levels of nitrate/nitrite ratio were significantly elevated. Acetylcholine-induced relaxation was impaired as the Emax decreased significantly in aortae. Moreover, a significant increase was seen in the level of aortic intima/media ratio. Canagliflozin treatment significantly improved vascular function, lipid profile and inflammation and reduced liver injury. SIGNIFICANCE Our data suggest that SGLT-2 inhibition via canagliflozin not only possesses an antihyperglycemic activity, but also improves hypercholesterolemia, vascular and liver function in dietary-induced hypercholesterolemia in the rabbit.
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Affiliation(s)
- Nora A Ashry
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 33516, Egypt
| | - Rania R Abdеlaziz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 33516, Egypt
| | - Ghada M Suddеk
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 33516, Egypt
| | - Mohamed A Saleh
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 33516, Egypt.
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Structure and Dynamics of Oxidized Lipoproteins In Vivo: Roles of High-Density Lipoprotein. Biomedicines 2021; 9:biomedicines9060655. [PMID: 34201176 PMCID: PMC8229488 DOI: 10.3390/biomedicines9060655] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/03/2021] [Accepted: 06/04/2021] [Indexed: 01/30/2023] Open
Abstract
Oxidative modification of lipoproteins is implicated in the occurrence and development of atherosclerotic lesions. Earlier studies have elucidated on the mechanisms of foam cell formation and lipid accumulation in these lesions, which is mediated by scavenger receptor-mediated endocytosis of oxidized low-density lipoprotein (oxLDL). Mounting clinical evidence has supported the involvement of oxLDL in cardiovascular diseases. High-density lipoprotein (HDL) is known as anti-atherogenic; however, recent studies have shown circulating oxidized HDL (oxHDL) is related to cardiovascular diseases. A modified structure of oxLDL, which was increased in the plasma of patients with acute myocardial infarction, was characterized. It had two unique features: (1) a fraction of oxLDL accompanied oxHDL, and (2) apoA1 was heavily modified, while modification of apoB, and the accumulation of oxidized phosphatidylcholine (oxPC) and lysophosphatidylcholine (lysoPC) was less pronounced. When LDL and HDL were present at the same time, oxidized lipoproteins actively interacted with each other, and oxPC and lysoPC were transferred to another lipoprotein particle and enzymatically metabolized rapidly. This brief review provides a novel view on the dynamics of oxLDL and oxHDL in circulation.
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Lawrence GD. Perspective: The Saturated Fat-Unsaturated Oil Dilemma: Relations of Dietary Fatty Acids and Serum Cholesterol, Atherosclerosis, Inflammation, Cancer, and All-Cause Mortality. Adv Nutr 2021; 12:647-656. [PMID: 33693484 PMCID: PMC8166560 DOI: 10.1093/advances/nmab013] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/23/2020] [Accepted: 01/21/2021] [Indexed: 12/27/2022] Open
Abstract
PUFAs are known to regulate cholesterol synthesis and cellular uptake by multiple mechanisms that do not involve SFAs. Polymorphisms in any of the numerous proteins involved in cholesterol homeostasis, as a result of genetic variation, could lead to higher or lower serum cholesterol. PUFAs are susceptible to lipid peroxidation, which can lead to oxidative stress, inflammation, atherosclerosis, cancer, and disorders associated with inflammation, such as insulin resistance, arthritis, and numerous inflammatory syndromes. Eicosanoids from arachidonic acid are among the most powerful mediators that initiate an immune response, and a wide range of PUFA metabolites regulate numerous physiological processes. There is a misconception that dietary SFAs can cause inflammation, although endogenous palmitic acid is converted to ceramides and other cell constituents involved in an inflammatory response after it is initiated by lipid mediators derived from PUFAs. This article will discuss the many misconceptions regarding how dietary lipids regulate serum cholesterol, the fact that all-cause death rate is higher in humans with low compared with normal or moderately elevated serum total cholesterol, the numerous adverse effects of increasing dietary PUFAs or carbohydrate relative to SFAs, as well as metabolic conversion of PUFAs to SFAs and MUFAs as a protective mechanism. Consequently, dietary saturated fats seem to be less harmful than the proposed alternatives.
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Affiliation(s)
- Glen D Lawrence
- Department of Chemistry and Biochemistry, Long Island University, Brooklyn, NY, USA
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Paul N, Sarkar R, Sarkar S. Zinc protoporphyrin-trimethylamine-N-oxide complex involves cholesterol oxidation causing atherosclerosis. J Biol Inorg Chem 2021; 26:367-374. [PMID: 33713182 DOI: 10.1007/s00775-021-01861-z] [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: 12/03/2020] [Accepted: 03/05/2021] [Indexed: 01/25/2023]
Abstract
Metabolism of food protein by gut microbes produce trimethylamine which on oxidation by hepatic flavin-containing monooxygenases is transformed to trimethylamine-N-oxide (TMAO). TMAO has recently been implicated as a biomarker for atherosclerosis. TMAO, as (CH3)3N+-O-), is ionic and so a hydrophilic molecule that is freely available in blood plasma. For the effective interaction with lipid-soluble molecules, TMAO should be phase transferred to the lipid site. We show that the free TMAO is effectively bonded to zinc protoporphyrin IX dimethyl ester [ZnPPDME] to yield [TMAOZnPPDME] using phase transfer reaction. The zinc protoporphyrin IX, [ZnPP], in general, available in blood may form [TMAOZnPP] complex. The nature of such interaction between TMAO and [ZnPP] has been structurally shown using a model complex, [TMAOZnTPP] (TPP = tetraphenylporphyrin). These complexes readily move from the polar plasma to the non-polar (lipid) site to act as the oxo-transfer agent to oxidize cholesterol causing atherosclerosis. Chromatographic and circular dichroism (CD) studies show that either TMAO or [ZnPP] alone cannot oxidize cholesterol. Free TMAO bonded with zinc-protoporphyrin IX, [ZnPP], in blood plasma as [TMAOZnPP] is transported to the lipid site and this is the reacting species to oxidize cholesterol causing atherosclerosis.
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Affiliation(s)
- Navendu Paul
- Department of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, West Bengal, 711103, India
| | - Rudra Sarkar
- Department of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, West Bengal, 711103, India
| | - Sabyasachi Sarkar
- Department of Chemistry and Applied Chemistry, Ramakrishna Mission Vidyamandira, Belurmath, West Bengal, 711202, India.
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Piceatannol inhibits pyroptosis and suppresses oxLDL-induced lipid storage in macrophages by regulating miR-200a/Nrf2/GSDMD axis. Biosci Rep 2021; 40:226337. [PMID: 32886103 PMCID: PMC7494992 DOI: 10.1042/bsr20201366] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 09/01/2020] [Accepted: 09/03/2020] [Indexed: 02/07/2023] Open
Abstract
As a major bioactive compound from grapes, piceatannol (PIC) has been reported to exert anti-atherosclerotic activity in various studies. Nevertheless, the mechanism underlying the effect of piceatannol against atherosclerosis (AS) is elusive. Our study identified miR-200a/Nrf2/GSDMD signaling pathway as critical mediators in the effect of piceatannol on macrophages. In the present study, we confirmed that treatment of piceatannol repressed the oxLDL-induced lipid storage in macrophages. Compared with control group, piceatannol inhibited TG storage and the activity of caspase1. It is noting that in response to oxLDL challenge, piceatannol abated the pyroptosis in RAW264.7 cells, with a decreased expression of caspase1, gasdermin D (GSDMD), IL-18, IL-1β and NLRP3. Moreover, we investigated the role of microRNA (miR)-200a/Nrf2 signaling pathway in the effect of piceatannol. The results declared that after transfection of si-miR-200a or si-Nrf2 plasmids, the effects of piceatannol on macrophages were converted, including lipid storage and pyroptosis. Importantly, si-miR-200a plasmid reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), indicating that miR-200a acted as an enhancer of Nrf2 in macrophages. Collectively, our findings demonstrate that piceatannol exerts anti-atherosclerotic activity on RAW264.7 cells by regulating miR-200a/Nrf2/GSDMD signaling. The present study is the first time to identify miR-200a as a candidate target in AS and declared an association between miR-200a and pyroptosis, which provides a novel therapy for the treatment of AS.
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Abstract
PURPOSE OF REVIEW Cadmium has been recognized as a potential risk factor for cardiovascular disease (CVD). We present a review of cadmium toxicity, its effect on cellular activities, and a summary of reported association between environmental cadmium exposure and CVD. We also discuss the possible therapeutic benefit of cadmium chelation. RECENT FINDINGS Experimental data suggest that cadmium affects several signaling pathways which may lead to endothelial dysfunction and vascular tissue damage, promoting atherosclerosis. This is further supported by epidemiological studies that have shown an association of even low-level cadmium exposure with an increased risk of clinical cardiovascular events. The Trial to Assess Chelation Therapy (TACT) provided inferential evidence for the cardiovascular benefit of treating toxic metal burden. However, at the present time, there is no direct evidence, but suggestive findings from clinical trials indicating that removal of cadmium from body stores may be associated with improved cardiovascular outcomes. An evolving body of evidence supports environmental cadmium exposure as a pro-atherosclerosis risk factor in CVD; however, the mechanisms for the proatherogenic effect of cadmium are still not completely understood. Further studies in translational toxicology are needed to fill the knowledge gaps regarding the molecular mechanisms of cadmium toxicity and the promotion of atherosclerosis.
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Alajbegovic A, Holmberg J, Daoud F, Rippe C, Kalliokoski G, Ekman M, Daudi S, Ragnarsson S, Swärd K, Albinsson S. MRTFA overexpression promotes conversion of human coronary artery smooth muscle cells into lipid-laden foam cells. Vascul Pharmacol 2021; 138:106837. [PMID: 33516965 DOI: 10.1016/j.vph.2021.106837] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/22/2020] [Accepted: 01/21/2021] [Indexed: 01/26/2023]
Abstract
OBJECTIVE Smooth muscle cells contribute significantly to lipid-laden foam cells in atherosclerotic plaques. However, the underlying mechanisms transforming smooth muscle cells into foam cells are poorly understood. The purpose of this study was to gain insight into the molecular mechanisms regulating smooth muscle foam cell formation. APPROACH AND RESULTS Using human coronary artery smooth muscle cells we found that the transcriptional co-activator MRTFA promotes lipid accumulation via several mechanisms, including direct transcriptional control of LDL receptor, enhanced fluid-phase pinocytosis and reduced lipid efflux. Inhibition of MRTF activity with CCG1423 and CCG203971 significantly reduced lipid accumulation. Furthermore, we demonstrate enhanced MRTFA expression in vascular remodeling of human vessels. CONCLUSIONS This study demonstrates a novel role for MRTFA as an important regulator of lipid homeostasis in vascular smooth muscle cells. Thus, MRTFA could potentially be a new therapeutic target for inhibition of vascular lipid accumulation.
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Affiliation(s)
- Azra Alajbegovic
- Department of Experimental Medical Science, Lund University, Sweden.
| | - Johan Holmberg
- Department of Experimental Medical Science, Lund University, Sweden
| | - Fatima Daoud
- Department of Experimental Medical Science, Lund University, Sweden
| | - Catarina Rippe
- Department of Experimental Medical Science, Lund University, Sweden
| | | | - Mari Ekman
- Department of Experimental Medical Science, Lund University, Sweden
| | - Sébastien Daudi
- Department of Clinical Science, Lund University, Lund, Sweden
| | | | - Karl Swärd
- Department of Experimental Medical Science, Lund University, Sweden
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Tea consumption and its effects on primary and secondary prevention of coronary artery disease: Qualitative synthesis of evidence from randomized controlled trials. Clin Nutr ESPEN 2021; 41:77-87. [PMID: 33487310 DOI: 10.1016/j.clnesp.2020.11.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/27/2020] [Accepted: 11/10/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS There is a general interest in understanding how the consumption of tea impacts cardiovascular function in individuals at risk of developing cardiovascular disease (CVD). The current review focuses on evidence from randomized controlled trials (RCTs) reporting on associations between tea consumption and endothelial function, in the primary and secondary prevention of coronary artery disease (CAD). METHODS PubMed, EMBASE, and Google Scholar databases/search engines were used to identify eligible studies. Included studies had to report on the impact of tea supplementation of endothelial function or CAD related markers. In addition to flow-mediated dilation (FMD), makers of oxidative stress and inflammation such as oxidized low-density lipoprotein and C-reactive protein were considered as determinants of endothelial function. A total of 34 RCTs met the inclusion criteria, and these reported on the impact of tea consumption on endothelial function in individuals at risk of CVD or patients with CAD. RESULTS The current qualitative synthesis of literature demonstrates that beyond enhancing nitric oxide bioavailability and lowering blood pressure, regular consumption of tea and its active ingredients such as epigallocatechin gallate may be beneficial in reducing markers of oxidative stress and inflammation. Moreover, the reduction of oxidized low-density lipoprotein and C-reactive protein levels, could be a sign of improved endothelial function in individuals at increased risk of developing CVD. CONCLUSIONS The cumulative evidence also suggests that the development of epigallocatechin gallate as a nutraceutical or enriching foods with this bioactive compound could be a feasible strategy to improve endothelial function and lower CVD-risk. However, well-designed RCTs are still necessary to confirm long-term benefits of tea consumption on vascular health.
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Ulfig A, Leichert LI. The effects of neutrophil-generated hypochlorous acid and other hypohalous acids on host and pathogens. Cell Mol Life Sci 2021; 78:385-414. [PMID: 32661559 PMCID: PMC7873122 DOI: 10.1007/s00018-020-03591-y] [Citation(s) in RCA: 138] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 06/21/2020] [Accepted: 07/01/2020] [Indexed: 12/15/2022]
Abstract
Neutrophils are predominant immune cells that protect the human body against infections by deploying sophisticated antimicrobial strategies including phagocytosis of bacteria and neutrophil extracellular trap (NET) formation. Here, we provide an overview of the mechanisms by which neutrophils kill exogenous pathogens before we focus on one particular weapon in their arsenal: the generation of the oxidizing hypohalous acids HOCl, HOBr and HOSCN during the so-called oxidative burst by the enzyme myeloperoxidase. We look at the effects of these hypohalous acids on biological systems in general and proteins in particular and turn our attention to bacterial strategies to survive HOCl stress. HOCl is a strong inducer of protein aggregation, which bacteria can counteract by chaperone-like holdases that bind unfolding proteins without the need for energy in the form of ATP. These chaperones are activated by HOCl through thiol oxidation (Hsp33) or N-chlorination of basic amino acid side-chains (RidA and CnoX) and contribute to bacterial survival during HOCl stress. However, neutrophil-generated hypohalous acids also affect the host system. Recent studies have shown that plasma proteins act not only as sinks for HOCl, but get actively transformed into modulators of the cellular immune response through N-chlorination. N-chlorinated serum albumin can prevent aggregation of proteins, stimulate immune cells, and act as a pro-survival factor for immune cells in the presence of cytotoxic antigens. Finally, we take a look at the emerging role of HOCl as a potential signaling molecule, particularly its role in neutrophil extracellular trap formation.
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Affiliation(s)
- Agnes Ulfig
- Ruhr University Bochum, Institute for Biochemistry and Pathobiochemistry-Microbial Biochemistry, Universitätsstrasse 150, 44780, Bochum, Germany
| | - Lars I Leichert
- Ruhr University Bochum, Institute for Biochemistry and Pathobiochemistry-Microbial Biochemistry, Universitätsstrasse 150, 44780, Bochum, Germany.
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