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Chhabra KH, Shoemaker R, Herath CB, Thomas MC, Filipeanu CM, Lazartigues E. Molecular dissection of the role of ACE2 in glucose homeostasis. Physiol Rev 2025; 105:935-973. [PMID: 39918873 PMCID: PMC12124467 DOI: 10.1152/physrev.00027.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/17/2024] [Accepted: 01/07/2025] [Indexed: 02/09/2025] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2) was discovered 25 years ago as a negative regulator of the renin-angiotensin system, opposing the effects of angiotensin II. Beyond its well-demonstrated roles in cardiovascular regulation and COVID-19 pathology, ACE2 is involved in a plethora of physiopathological processes. In this review, we summarize the latest discoveries on the role of ACE2 in glucose homeostasis and regulation of metabolism. In the endocrine pancreas, ACE2 is expressed at low levels in β-cells, but loss of its expression inhibits glucose-stimulated insulin secretion and impairs glucose tolerance. Conversely, overexpression of ACE2 improved glycemia, suggesting that recombinant ACE2 might be a future therapy for diabetes. In the skeletal muscle of ACE2-deficient mice a progressive triglyceride accumulation was observed, whereas in diabetic kidney the initial increase in ACE2 is followed by a chronic reduction of expression in kidney tubules and impairment of glucose metabolism. At the intestinal level dysregulation of the enzyme alters the amino acid absorption and intestinal microbiome, whereas at the hepatic level ACE2 protects against diabetic fatty liver disease. Not least, ACE2 is upregulated in adipocytes in response to nutritional stimuli, and administration of recombinant ACE2 decreased body weight and increased thermogenesis. In addition to tissue-specific regulation of ACE2 function, the enzyme undergoes complex cellular posttranslational modifications that are changed during diabetes evolution, with at least proteolytic cleavage and ubiquitination leading to modifications in ACE2 activity. Detailed characterization of ACE2 in a cellular and tissue-specific manner holds promise for improving therapeutic outcomes in diabetes and metabolic disorders.
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Affiliation(s)
- Kavaljit H Chhabra
- Department of Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, Kentucky, United States
| | - Robin Shoemaker
- Department of Pediatrics, University of Kentucky, Lexington, Kentucky, United States
| | - Chandana B Herath
- Department of Medicine, Melbourne Medical School, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
| | - Merlin C Thomas
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Catalin M Filipeanu
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
| | - Eric Lazartigues
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
- Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
- Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
- Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana, United States
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Kayzuka C, Rondon-Pereira VC, Nogueira Tavares C, Pacheco Pachado M, Monica FZ, Tanus-Santos JE, Lacchini R. Epigenetics is involved in the pleiotropic effects of statins. Expert Opin Drug Metab Toxicol 2025; 21:689-701. [PMID: 40208655 DOI: 10.1080/17425255.2025.2491732] [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: 08/31/2024] [Revised: 02/18/2025] [Accepted: 04/07/2025] [Indexed: 04/11/2025]
Abstract
INTRODUCTION Statins have significantly reduced mortality from cardiovascular diseases by lowering serum cholesterol levels. Beyond their lipid-lowering effects, statins improve vascular function, reduce inflammation, decrease reactive oxygen species (ROS) formation, and stabilize atherosclerotic plaques. However, the mechanisms underlying these pleiotropic effects remain unclear. AREA COVERED This narrative review summarizes and discusses epigenetic mechanisms that may explain part of the pleiotropic effects of statins. This approach allows for a reevaluation of statin use beyond its cholesterol-lowering benefits. A structured search was conducted in the PubMed and Scopus databases using specific search terms, including articles published up to August 2024. EXPERT OPINION The pleiotropic effects of statins, including those mediated by the isoprenoid pathway, partially explain their clinical benefits. By inhibiting histone deacetylases (HDACs, the 'erasers') and DNA methyltransferases (DNMTs, the 'writers'), statins promote increased histone acetylation and reduced DNA methylation at gene promoter regions. These epigenetic modifications enhance chromatin accessibility, facilitating gene transcription and protecting the cardiovascular system. Further investigation into these epigenetic mechanisms could support the repositioning of statins for broader therapeutic applications. Statins may have benefits extending beyond their role in managing hypercholesterolemia, as their pleiotropic effects contribute to the prevention of cardiovascular disease-related mortality through mechanisms independent of LDL cholesterol reduction.
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Affiliation(s)
- Cezar Kayzuka
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
- Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, Brazil
| | | | - Cecilia Nogueira Tavares
- Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Mayra Pacheco Pachado
- Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Fabiola Zakia Monica
- Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Jose Eduardo Tanus-Santos
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Riccardo Lacchini
- Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, Brazil
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Visvanathan R, Houghton MJ, Williamson G. Impact of Glucose, Inflammation and Phytochemicals on ACE2, TMPRSS2 and Glucose Transporter Gene Expression in Human Intestinal Cells. Antioxidants (Basel) 2025; 14:253. [PMID: 40227199 PMCID: PMC11939507 DOI: 10.3390/antiox14030253] [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: 01/15/2025] [Revised: 02/05/2025] [Accepted: 02/18/2025] [Indexed: 04/15/2025] Open
Abstract
Inflammation is associated with the pathophysiology of type 2 diabetes and COVID-19. Phytochemicals have the potential to modulate inflammation, expression of SARS-CoV-2 viral entry receptors (angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2)) and glucose transport in the gut. This study assessed the impact of phytochemicals on these processes. We screened 12 phytochemicals alongside 10 pharmaceuticals and three plant extracts, selected for known or hypothesised effects on the SARS-CoV-2 receptors and COVID-19 risk, for their effects on the expression of ACE2 or TMPRSS2 in differentiated Caco-2/TC7 human intestinal epithelial cells. Genistein, apigenin, artemisinin and sulforaphane were the most promising ones, as assessed by the downregulation of TMPRSS2, and thus they were used in subsequent experiments. The cells were then co-stimulated with pro-inflammatory cytokines interleukin-1 beta (IL-1β) and tumour necrosis factor-alpha (TNF-α) for ≤168 h to induce inflammation, which are known to induce multiple pathways, including the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Target gene expression (ACE2, TMPRSS2, SGLT1 (sodium-dependent glucose transporter 1) and GLUT2 (glucose transporter 2)) was measured by droplet digital PCR, while interleukin-1 (IL-6), interleukin-1 (IL-8) and ACE2 proteins were assessed using ELISA in both normal and inflamed cells. IL-1β and TNF-α treatment upregulated ACE2, TMPRSS2 and SGLT1 gene expression. ACE2 increased with the duration of cytokine exposure, coupled with a significant decrease in IL-8, SGLT1 and TMPRSS2 over time. Pearson correlation analysis revealed that the increase in ACE2 was strongly associated with a decrease in IL-8 (r = -0.77, p < 0.01). The regulation of SGLT1 gene expression followed the same pattern as TMPRSS2, implying a common mechanism. Although none of the phytochemicals decreased inflammation-induced IL-8 secretion, genistein normalised inflammation-induced increases in SGLT1 and TMPRSS2. The association between TMPRSS2 and SGLT1 gene expression, which is particularly evident in inflammatory conditions, suggests a common regulatory pathway. Genistein downregulated the inflammation-induced increase in SGLT1 and TMPRSS2, which may help lower the postprandial glycaemic response and COVID-19 risk or severity in healthy individuals and those with metabolic disorders.
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Affiliation(s)
- Rizliya Visvanathan
- Department of Nutrition, Dietetics and Food, BASE Facility, Monash University, Level 1, 264 Ferntree Gully Road, Notting Hill, VIC 3168, Australia
- Victorian Heart Institute, Monash University, Level 2, Victorian Heart Hospital, 631 Blackburn Road, Clayton, VIC 3168, Australia
| | - Michael J. Houghton
- Department of Nutrition, Dietetics and Food, BASE Facility, Monash University, Level 1, 264 Ferntree Gully Road, Notting Hill, VIC 3168, Australia
- Victorian Heart Institute, Monash University, Level 2, Victorian Heart Hospital, 631 Blackburn Road, Clayton, VIC 3168, Australia
| | - Gary Williamson
- Department of Nutrition, Dietetics and Food, BASE Facility, Monash University, Level 1, 264 Ferntree Gully Road, Notting Hill, VIC 3168, Australia
- Victorian Heart Institute, Monash University, Level 2, Victorian Heart Hospital, 631 Blackburn Road, Clayton, VIC 3168, Australia
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Ajoolabady A, Pratico D, Mazidi M, Davies IG, Lip GYH, Seidah N, Libby P, Kroemer G, Ren J. PCSK9 in metabolism and diseases. Metabolism 2025; 163:156064. [PMID: 39547595 DOI: 10.1016/j.metabol.2024.156064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 10/02/2024] [Accepted: 11/05/2024] [Indexed: 11/17/2024]
Abstract
PCSK9 is a serine protease that regulates plasma levels of low-density lipoprotein (LDL) and cholesterol by mediating the endolysosomal degradation of LDL receptor (LDLR) in the liver. When PCSK9 functions unchecked, it leads to increased degradation of LDLR, resulting in elevated circulatory levels of LDL and cholesterol. This dysregulation contributes to lipid and cholesterol metabolism abnormalities, foam cell formation, and the development of various diseases, including cardiovascular disease (CVD), viral infections, cancer, and sepsis. Emerging clinical and experimental evidence highlights an imperative role for PCSK9 in metabolic anomalies such as hypercholesterolemia and hyperlipidemia, as well as inflammation, and disturbances in mitochondrial homeostasis. Moreover, metabolic hormones - including insulin, glucagon, adipokines, natriuretic peptides, and sex steroids - regulate the expression and circulatory levels of PCSK9, thus influencing cardiovascular and metabolic functions. In this comprehensive review, we aim to elucidate the regulatory role of PCSK9 in lipid and cholesterol metabolism, pathophysiology of diseases such as CVD, infections, cancer, and sepsis, as well as its pharmaceutical and non-pharmaceutical targeting for therapeutic management of these conditions.
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Affiliation(s)
- Amir Ajoolabady
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Domenico Pratico
- Alzheimer's Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Mohsen Mazidi
- Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK; King's College London, Department of Twin Research & Genetic Epidemiology, South Wing St Thomas', London, UK; Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Ian G Davies
- School of Sport and Exercise Sciences, Faculty of Science, Liverpool John Moores University, Copperas Hill, Liverpool L3 5AJ, UK
| | - Gregory Y H Lip
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Nabil Seidah
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal), Montreal, QC H2W 1R7, Canada.
| | - Peter Libby
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France; Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
| | - Jun Ren
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
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Liu Y, Lou X. The Bidirectional Association Between Metabolic Syndrome and Long-COVID-19. Diabetes Metab Syndr Obes 2024; 17:3697-3710. [PMID: 39398386 PMCID: PMC11471063 DOI: 10.2147/dmso.s484733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 09/22/2024] [Indexed: 10/15/2024] Open
Abstract
Background The rapid global spread of a new coronavirus disease known as COVID-19 has led to a significant increase in mortality rates, resulting in an unprecedented worldwide pandemic. Methods The impact of COVID-19, particularly its long-term effects, has also had a profound effect on the health and well-being of individuals.Metabolic syndrome increases the risk of heart and brain diseases, presenting a significant danger to human well-being. Purpose The prognosis of long COVID and the progression of metabolic syndrome interact with each other, but there is currently a lack of systematic reports.In this paper, the pathogenesis, related treatment and prognosis of long COVID and metabolic syndrome are systematically reviewed.
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Affiliation(s)
- Yanfen Liu
- Department of Endocrinology at Zhejiang University School of Medicine, Jinhua Hospital, Jinhua, People’s Republic of China
| | - Xueyong Lou
- Department of Endocrinology at Zhejiang University School of Medicine, Jinhua Hospital, Jinhua, People’s Republic of China
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Panduga S, Vasishta S, Subramani R, Vincent S, Mutalik S, Joshi MB. Epidrugs in the clinical management of atherosclerosis: Mechanisms, challenges and promises. Eur J Pharmacol 2024; 980:176827. [PMID: 39038635 DOI: 10.1016/j.ejphar.2024.176827] [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: 05/14/2024] [Revised: 07/03/2024] [Accepted: 07/18/2024] [Indexed: 07/24/2024]
Abstract
Atherosclerosis is a complex and multigenic pathology associated with significant epigenetic reprogramming. Traditional factors (age, sex, obesity, hyperglycaemia, dyslipidaemia, hypertension) and non-traditional factors (foetal indices, microbiome alteration, clonal hematopoiesis, air pollution, sleep disorders) induce endothelial dysfunction, resulting in reduced vascular tone and increased vascular permeability, inflammation and shear stress. These factors induce paracrine and autocrine interactions between several cell types, including vascular smooth muscle cells, endothelial cells, monocytes/macrophages, dendritic cells and T cells. Such cellular interactions lead to tissue-specific epigenetic reprogramming regulated by DNA methylation, histone modifications and microRNAs, which manifests in atherosclerosis. Our review outlines epigenetic signatures during atherosclerosis, which are viewed as potential clinical biomarkers that may be adopted as new therapeutic targets. Additionally, we emphasize epigenetic modifiers referred to as 'epidrugs' as potential therapeutic molecules to correct gene expression patterns and restore vascular homeostasis during atherosclerosis. Further, we suggest nanomedicine-based strategies involving the use of epidrugs, which may selectively target cells in the atherosclerotic microenvironment and reduce off-target effects.
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Affiliation(s)
- Sushma Panduga
- Department of Biochemistry, Palamur Biosciences Private Limited, Hyderabad, 500026, Telangana, India; PhD Program, Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Sampara Vasishta
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Ramamoorthy Subramani
- Department of Biochemistry, Palamur Biosciences Private Limited, Hyderabad, 500026, Telangana, India
| | - Sthevaan Vincent
- Department of Pathology, Palamur Biosciences Private Limited, Hyderabad, 500026, Telangana, India
| | - Srinivas Mutalik
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Manjunath B Joshi
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
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Xi C, Palani C, Takezaki M, Shi H, Horuzsko A, Pace BS, Zhu X. Simvastatin-Mediated Nrf2 Activation Induces Fetal Hemoglobin and Antioxidant Enzyme Expression to Ameliorate the Phenotype of Sickle Cell Disease. Antioxidants (Basel) 2024; 13:337. [PMID: 38539870 PMCID: PMC10968127 DOI: 10.3390/antiox13030337] [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: 01/30/2024] [Revised: 02/26/2024] [Accepted: 03/08/2024] [Indexed: 06/04/2024] Open
Abstract
Sickle cell disease (SCD) is a pathophysiological condition of chronic hemolysis, oxidative stress, and elevated inflammation. The transcription factor Nrf2 is a master regulator of oxidative stress. Here, we report that the FDA-approved oral agent simvastatin, an inhibitor of hydroxymethyl-glutaryl coenzyme A reductase, significantly activates the expression of Nrf2 and antioxidant enzymes. Simvastatin also induces fetal hemoglobin expression in SCD patient primary erythroid progenitors and a transgenic mouse model. Simvastatin alleviates SCD symptoms by decreasing hemoglobin S sickling, oxidative stress, and inflammatory stress in erythroblasts. Particularly, simvastatin increases cellular levels of cystine, the precursor for the biosynthesis of the antioxidant reduced glutathione, and decreases the iron content in SCD mouse spleen and liver tissues. Mechanistic studies suggest that simvastatin suppresses the expression of the critical histone methyltransferase enhancer of zeste homolog 2 to reduce both global and gene-specific histone H3 lysine 27 trimethylation. These chromatin structural changes promote the assembly of transcription complexes to fetal γ-globin and antioxidant gene regulatory regions in an antioxidant response element-dependent manner. In summary, our findings suggest that simvastatin activates fetal hemoglobin and antioxidant protein expression, modulates iron and cystine/reduced glutathione levels to improve the phenotype of SCD, and represents a therapeutic strategy for further development.
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Affiliation(s)
- Caixia Xi
- Department of Pediatrics, Division of Hematology/Oncology, Augusta University, Augusta, GA 30912, USA; (C.X.); (C.P.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA (A.H.)
| | - Chithra Palani
- Department of Pediatrics, Division of Hematology/Oncology, Augusta University, Augusta, GA 30912, USA; (C.X.); (C.P.)
| | - Mayuko Takezaki
- Department of Pediatrics, Division of Hematology/Oncology, Augusta University, Augusta, GA 30912, USA; (C.X.); (C.P.)
| | - Huidong Shi
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA (A.H.)
| | - Anatolij Horuzsko
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA (A.H.)
| | - Betty S. Pace
- Department of Pediatrics, Division of Hematology/Oncology, Augusta University, Augusta, GA 30912, USA; (C.X.); (C.P.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA (A.H.)
| | - Xingguo Zhu
- Department of Pediatrics, Division of Hematology/Oncology, Augusta University, Augusta, GA 30912, USA; (C.X.); (C.P.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA (A.H.)
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Holm A, Graus MS, Wylie-Sears J, Borgelt L, Heng Tan JW, Nasim S, Chung L, Jain A, Sun M, Sun L, Brouillard P, Lekwuttikarn R, Kozakewich H, Qi JY, Teng JC, Mulliken JB, Vikkula M, Francois M, Bischoff J. An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.29.577829. [PMID: 39026886 PMCID: PMC11257613 DOI: 10.1101/2024.01.29.577829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
Infantile hemangioma (IH) is the most common tumor in children and a paradigm for pathological vasculogenesis, angiogenesis and regression. Propranolol is the mainstay of treatment for IH. It inhibits hemangioma vessel formation via a β-adrenergic receptor independent off-target effect of its R(+) enantiomer on the endothelial specific transcription factor sex-determining region Y (SRY) box transcription factor 18 (SOX18). Transcriptomic profiling of patient-derived hemangioma stem cells uncovered the mevalonate pathway (MVP) as a target of R(+) propranolol. Loss of SOX18 function confirmed R(+) propranolol mode of action on the MVP. Functional validation in preclinical IH models revealed that statins - targeting the MVP - are potent inhibitors of hemangioma vessel formation. We propose a novel SOX18-MVP-axis as a central regulator of IH pathogenesis and suggest statin repurposing to treat IH. Our findings reveal novel pleiotropic effects of beta-blockers and statins acting on the SOX18-MVP axis to disable an endothelial specific program in IH, which may impact other scenarios involving pathological vasculogenesis and angiogenesis. Graphical abstract
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Bao X, Liang Y, Chang H, Cai T, Feng B, Gordon K, Zhu Y, Shi H, He Y, Xie L. Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside. Signal Transduct Target Ther 2024; 9:13. [PMID: 38185721 PMCID: PMC10772138 DOI: 10.1038/s41392-023-01690-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 09/27/2023] [Accepted: 10/27/2023] [Indexed: 01/09/2024] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9's potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9's aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.
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Affiliation(s)
- Xuhui Bao
- Institute of Therapeutic Cancer Vaccines, Fudan University Pudong Medical Center, Shanghai, China.
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
- Department of Oncology, Fudan University Pudong Medical Center, Shanghai, China.
- Center for Clinical Research, Fudan University Pudong Medical Center, Shanghai, China.
- Clinical Research Center for Cell-based Immunotherapy, Fudan University, Shanghai, China.
- Department of Pathology, Duke University Medical Center, Durham, NC, USA.
| | - Yongjun Liang
- Center for Medical Research and Innovation, Fudan University Pudong Medical Center, Shanghai, China
| | - Hanman Chang
- Institute for Food Safety and Health, Illinois Institute of Technology, Chicago, IL, USA
| | - Tianji Cai
- Department of Sociology, University of Macau, Taipa, Macau, China
| | - Baijie Feng
- Department of Oncology, Fudan University Pudong Medical Center, Shanghai, China
| | - Konstantin Gordon
- Medical Institute, Peoples' Friendship University of Russia, Moscow, Russia
- A. Tsyb Medical Radiological Research Center, Obninsk, Russia
| | - Yuekun Zhu
- Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Hailian Shi
- Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Zhangjiang Hi-tech Park, Shanghai, China
| | - Yundong He
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
| | - Liyi Xie
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Geiger M, Gorica E, Mohammed SA, Mongelli A, Mengozi A, Delfine V, Ruschitzka F, Costantino S, Paneni F. Epigenetic Network in Immunometabolic Disease. Adv Biol (Weinh) 2024; 8:e2300211. [PMID: 37794610 DOI: 10.1002/adbi.202300211] [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: 06/08/2023] [Revised: 09/08/2023] [Indexed: 10/06/2023]
Abstract
Although a large amount of data consistently shows that genes affect immunometabolic characteristics and outcomes, epigenetic mechanisms are also heavily implicated. Epigenetic changes, including DNA methylation, histone modification, and noncoding RNA, determine gene activity by altering the accessibility of chromatin to transcription factors. Various factors influence these alterations, including genetics, lifestyle, and environmental cues. Moreover, acquired epigenetic signals can be transmitted across generations, thus contributing to early disease traits in the offspring. A closer investigation is critical in this aspect as it can help to understand the underlying molecular mechanisms further and gain insights into potential therapeutic targets for preventing and treating diseases arising from immuno-metabolic dysregulation. In this review, the role of chromatin alterations in the transcriptional modulation of genes involved in insulin resistance, systemic inflammation, macrophage polarization, endothelial dysfunction, metabolic cardiomyopathy, and nonalcoholic fatty liver disease (NAFLD), is discussed. An overview of emerging chromatin-modifying drugs and the importance of the individual epigenetic profile for personalized therapeutic approaches in patients with immuno-metabolic disorders is also presented.
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Affiliation(s)
- Martin Geiger
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Era Gorica
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Shafeeq Ahmed Mohammed
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Alessia Mongelli
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Alessandro Mengozi
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Valentina Delfine
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Frank Ruschitzka
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Sarah Costantino
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
- University Heart Center, University Hospital Zurich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Francesco Paneni
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
- University Heart Center, University Hospital Zurich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
- Department of Research and Education, University Hospital Zurich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
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11
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Zeng J, Wu Q, Xiong S, Lu C, Zhang Z, Huang H, Xiong Y, Luo T. Inhibition of EphA2 protects against atherosclerosis by synergizing with statins to mitigate macrophage inflammation. Biomed Pharmacother 2023; 169:115885. [PMID: 37984301 DOI: 10.1016/j.biopha.2023.115885] [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: 08/20/2023] [Revised: 11/06/2023] [Accepted: 11/13/2023] [Indexed: 11/22/2023] Open
Abstract
Statins are highly prevalent in patients with coronary artery disease. Statins exert their anti-inflammatory effects on the vascular wall and circulating levels of pro-inflammatory cytokines. However, increasing attention revealed the exacerbation of macrophage inflammation induced by statins, and a clear mechanistic explanation of whether the detrimental effects of statins on macrophage inflammatory phenotypes outweigh the beneficial effects is has not yet been established. Here, RNA-sequencing and RT-qPCR analyses demonstrated that statins significantly upregulated EphA2, Nlrp3, IL-1β and TNF-α expression in macrophages. Mechanistically, we found that atorvastatin reduced KLF4 binding to the EphA2 promoter using KLF4-chromatin immunoprecipitation, suppressed HDAC11-mediated deacetylation and subsequently led to enhanced EphA2 transcription. The 4D-label-free proteomics analysis further confirmed the upregulated EphA2 and inflammatory signals. Furthermore, the proinflammatory effect of atorvastatin was neutralized by an addition of recombinant Fc-ephrinA1, a selective Eph receptor tyrosine kinase inhibitor (ALW-II-41-27) or EphA2-silencing adenovirus (siEphA2). In vivo, EphA2 was identified a proatherogenic factor and apoE-/- mice placed on a high-fat diet following gastric gavage with atorvastatin exhibited a consistent elevation in EphA2 expression. We further observed that the transfection with siEphA2 in atorvastatin-treated mice significantly attenuated atherosclerotic plaque formation and abrogated statin-orchestrated macrophages proinflammatory genes expression as compared to that in atorvastatin alone. Increased plaque stability index was also observed following the addition of siEphA2, as evidenced by increased collagen and smooth muscle content and diminished lipid accumulation and macrophage infiltration. The data suggest that blockage of EphA2 provides an additional therapeutic benefit for further improving the anti-atherogenic effects of statins.
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Affiliation(s)
- Jie Zeng
- Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610014, China
| | - Qiao Wu
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Shiqiang Xiong
- Department of Cardiology, the Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan 610031, China
| | - Cong Lu
- Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610014, China
| | - Zheng Zhang
- Department of Cardiology, the Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan 610031, China
| | - Hui Huang
- Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610014, China
| | - Yan Xiong
- Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610014, China
| | - Tiantian Luo
- Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610014, China.
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12
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Dasgupta A, Gangai S, Narayan R, Kapoor S. Mapping the Lipid Signatures in COVID-19 Infection: Diagnostic and Therapeutic Solutions. J Med Chem 2023; 66:14411-14433. [PMID: 37899546 DOI: 10.1021/acs.jmedchem.3c01238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2023]
Abstract
The COVID-19 pandemic ignited research centered around the identification of robust biomarkers and therapeutic targets. SARS-CoV-2, the virus responsible, hijacks the metabolic machinery of the host cells. It relies on lipids and lipoproteins of host cells for entry, trafficking, immune evasion, viral replication, and exocytosis. The infection causes host cell lipid metabolic remodelling. Targeting lipid-based processes is thus a promising strategy for countering COVID-19. Here, we review the role of lipids in the different steps of the SARS-CoV-2 pathogenesis and identify lipid-centric targetable avenues. We discuss lipidome changes in infected patients and their relevance as potential clinical diagnostic or prognostic biomarkers. We summarize the emerging direct and indirect therapeutic approaches for targeting COVID-19 using lipid-inspired approaches. Given that viral protein-targeted therapies may become less effective due to mutations in emerging SARS-CoV-2 variants, lipid-inspired interventions may provide additional and perhaps better means of combating this and future pandemics.
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Affiliation(s)
- Aishi Dasgupta
- Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India
- IIT-Bombay Monash Academy, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Shon Gangai
- School of Chemical and Materials Sciences (SCMS), Institute of Technology Goa, Farmagudi, Ponda, Goa 403401, India
| | - Rishikesh Narayan
- School of Chemical and Materials Sciences (SCMS), Institute of Technology Goa, Farmagudi, Ponda, Goa 403401, India
- School of Interdisciplinary Life Sciences (SILS), Institute of Technology Goa, Farmagudi, Ponda, Goa 403401, India
| | - Shobhna Kapoor
- Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India
- IIT-Bombay Monash Academy, Indian Institute of Technology Bombay, Mumbai 400076, India
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8528, Japan
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13
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Wang CW, Chuang HC, Tan TH. ACE2 in chronic disease and COVID-19: gene regulation and post-translational modification. J Biomed Sci 2023; 30:71. [PMID: 37608279 PMCID: PMC10464117 DOI: 10.1186/s12929-023-00965-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 08/15/2023] [Indexed: 08/24/2023] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2), a counter regulator of the renin-angiotensin system, provides protection against several chronic diseases. Besides chronic diseases, ACE2 is the host receptor for SARS-CoV or SARS-CoV-2 virus, mediating the first step of virus infection. ACE2 levels are regulated by transcriptional, post-transcriptional, and post-translational regulation or modification. ACE2 transcription is enhanced by transcription factors including Ikaros, HNFs, GATA6, STAT3 or SIRT1, whereas ACE2 transcription is reduced by the transcription factor Brg1-FoxM1 complex or ERRα. ACE2 levels are also regulated by histone modification or miRNA-induced destabilization. The protein kinase AMPK, CK1α, or MAP4K3 phosphorylates ACE2 protein and induces ACE2 protein levels by decreasing its ubiquitination. The ubiquitination of ACE2 is induced by the E3 ubiquitin ligase MDM2 or UBR4 and decreased by the deubiquitinase UCHL1 or USP50. ACE2 protein levels are also increased by the E3 ligase PIAS4-mediated SUMOylation or the methyltransferase PRMT5-mediated ACE2 methylation, whereas ACE2 protein levels are decreased by AP2-mediated lysosomal degradation. ACE2 is downregulated in several human chronic diseases like diabetes, hypertension, or lung injury. In contrast, SARS-CoV-2 upregulates ACE2 levels, enhancing host cell susceptibility to virus infection. Moreover, soluble ACE2 protein and exosomal ACE2 protein facilitate SARS-CoV-2 infection into host cells. In this review, we summarize the gene regulation and post-translational modification of ACE2 in chronic disease and COVID-19. Understanding the regulation and modification of ACE2 may help to develop prevention or treatment strategies for ACE2-mediated diseases.
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Affiliation(s)
- Chia-Wen Wang
- Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan, 35053 Taiwan
| | - Huai-Chia Chuang
- Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan, 35053 Taiwan
| | - Tse-Hua Tan
- Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan, 35053 Taiwan
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14
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Xavier DP, Chagas GCL, Gomes LGF, Ferri-Guerra J, Oquet REH. Effects of statin therapy in hospitalized adult COVID-19 patients: a systematic review and meta-analysis of randomized controlled trials. EINSTEIN-SAO PAULO 2023; 21:eRW0351. [PMID: 37341222 DOI: 10.31744/einstein_journal/2023rw0351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 02/07/2023] [Indexed: 06/22/2023] Open
Abstract
INTRODUCTION COVID-19 is associated with endothelial activation and systemic inflammation; consequently, statins can be used in its treatment as they have anti-inflammatory, antithrombotic, and profibrinolytic properties and may interfere with COVID-19 viral entry into cells through disruption of cell membrane lipid rafts. OBJECTIVE We performed a meta-analysis of randomized clinical trials that compared statin therapy to placebo or to standard care in adult patients hospitalized for COVID-19. METHODS We searched the MEDLINE, EMBASE, and Cochrane Library databases for all-cause mortality, hospitalization duration, and admission to the intensive care unit. RESULTS Of the 228 studies reviewed, four studies were included, with a total of 1,231 patients, of whom 610 (49.5%) were treated with statins. There was no significant difference in all-cause mortality (odds ratio [OR] 0.96; 95% confidence interval [95%CI]: 0.61-1.51; p=0.86; I2=13%), duration of hospitalization (mean difference [MD] 0.21; 95%CI: -1.74-2.16; p=0.83; I2=92%), intensive care unit admission (OR= 3.31; 95%CI: 0.13-87.1; p=0.47; I2=84%), need for mechanical ventilation (OR= 1.03; 95%CI: 0.36-2.94; p=0.95; I2=0%), or increase in liver enzyme levels (OR= 0.58; 95%CI: 0.27-1.25; p=0.16; I2=0%) between patients treated with or without statin therapy. CONCLUSION Our findings suggest that in adult patients hospitalized with COVID-19, statin therapy results in no difference in clinical outcomes when compared to outcomes by placebo or standard of care. Prospero database registration: (www.crd.york.ac.uk/prospero) under the number CRD42022338283.
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Affiliation(s)
| | | | | | - Juliana Ferri-Guerra
- Department of Internal Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
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15
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Chen P, Wu M, He Y, Jiang B, He ML. Metabolic alterations upon SARS-CoV-2 infection and potential therapeutic targets against coronavirus infection. Signal Transduct Target Ther 2023; 8:237. [PMID: 37286535 DOI: 10.1038/s41392-023-01510-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 04/18/2023] [Accepted: 05/19/2023] [Indexed: 06/09/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) caused by coronavirus SARS-CoV-2 infection has become a global pandemic due to the high viral transmissibility and pathogenesis, bringing enormous burden to our society. Most patients infected by SARS-CoV-2 are asymptomatic or have mild symptoms. Although only a small proportion of patients progressed to severe COVID-19 with symptoms including acute respiratory distress syndrome (ARDS), disseminated coagulopathy, and cardiovascular disorders, severe COVID-19 is accompanied by high mortality rates with near 7 million deaths. Nowadays, effective therapeutic patterns for severe COVID-19 are still lacking. It has been extensively reported that host metabolism plays essential roles in various physiological processes during virus infection. Many viruses manipulate host metabolism to avoid immunity, facilitate their own replication, or to initiate pathological response. Targeting the interaction between SARS-CoV-2 and host metabolism holds promise for developing therapeutic strategies. In this review, we summarize and discuss recent studies dedicated to uncovering the role of host metabolism during the life cycle of SARS-CoV-2 in aspects of entry, replication, assembly, and pathogenesis with an emphasis on glucose metabolism and lipid metabolism. Microbiota and long COVID-19 are also discussed. Ultimately, we recapitulate metabolism-modulating drugs repurposed for COVID-19 including statins, ASM inhibitors, NSAIDs, Montelukast, omega-3 fatty acids, 2-DG, and metformin.
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Affiliation(s)
- Peiran Chen
- Department of Biomedical Sciences, City University of Hong Kong, HKSAR, Hong Kong, China
| | - Mandi Wu
- Department of Biomedical Sciences, City University of Hong Kong, HKSAR, Hong Kong, China
| | - Yaqing He
- Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, Guangdong, China
| | - Binghua Jiang
- Cell Signaling and Proteomic Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Ming-Liang He
- Department of Biomedical Sciences, City University of Hong Kong, HKSAR, Hong Kong, China.
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16
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Liu C, Shen M, Tan WLW, Chen IY, Liu Y, Yu X, Yang H, Zhang A, Liu Y, Zhao MT, Ameen M, Zhang M, Gross ER, Qi LS, Sayed N, Wu JC. Statins improve endothelial function via suppression of epigenetic-driven EndMT. NATURE CARDIOVASCULAR RESEARCH 2023; 2:467-485. [PMID: 37693816 PMCID: PMC10489108 DOI: 10.1038/s44161-023-00267-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 03/31/2023] [Indexed: 09/12/2023]
Abstract
The pleiotropic benefits of statins in cardiovascular diseases that are independent of their lipid-lowering effects have been well documented, but the underlying mechanisms remain elusive. Here we show that simvastatin significantly improves human induced pluripotent stem cell-derived endothelial cell functions in both baseline and diabetic conditions by reducing chromatin accessibility at transcriptional enhanced associate domain elements and ultimately at endothelial-to-mesenchymal transition (EndMT)-regulating genes in a yes-associated protein (YAP)-dependent manner. Inhibition of geranylgeranyltransferase (GGTase) I, a mevalonate pathway intermediate, repressed YAP nuclear translocation and YAP activity via RhoA signaling antagonism. We further identified a previously undescribed SOX9 enhancer downstream of statin-YAP signaling that promotes the EndMT process. Thus, inhibition of any component of the GGTase-RhoA-YAP-SRY box transcription factor 9 (SOX9) signaling axis was shown to rescue EndMT-associated endothelial dysfunction both in vitro and in vivo, especially under diabetic conditions. Overall, our study reveals an epigenetic modulatory role for simvastatin in repressing EndMT to confer protection against endothelial dysfunction.
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Affiliation(s)
- Chun Liu
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine (Division of Cardiology), Stanford University, Stanford, CA, USA
- These authors contributed equally: Chun Liu, Mengcheng Shen, Wilson L. W. Tan
| | - Mengcheng Shen
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine (Division of Cardiology), Stanford University, Stanford, CA, USA
- These authors contributed equally: Chun Liu, Mengcheng Shen, Wilson L. W. Tan
| | - Wilson L. W. Tan
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine (Division of Cardiology), Stanford University, Stanford, CA, USA
- These authors contributed equally: Chun Liu, Mengcheng Shen, Wilson L. W. Tan
| | - Ian Y. Chen
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine (Division of Cardiology), Stanford University, Stanford, CA, USA
- Medical Service (Cardiology Section), Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
| | - Yu Liu
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine (Division of Cardiology), Stanford University, Stanford, CA, USA
| | - Xuan Yu
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA, USA
| | - Huaxiao Yang
- Department of Biomedical Engineering, University of North Texas, Denton, TX, USA
| | - Angela Zhang
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine (Division of Cardiology), Stanford University, Stanford, CA, USA
- Greenstone Biosciences, Palo Alto, CA, USA
| | - Yanxia Liu
- Department of Bioengineering, Stanford University, Stanford, CA, USA
| | - Ming-Tao Zhao
- Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Mohamed Ameen
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine (Division of Cardiology), Stanford University, Stanford, CA, USA
| | - Mao Zhang
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine (Division of Cardiology), Stanford University, Stanford, CA, USA
| | - Eric R. Gross
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA, USA
| | - Lei S. Qi
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- Sarafan ChEM-H, Standford University, Stanford, CA, USA
- Chan Zuckerberg Biohub–San Francisco, San Francisco, CA, USA
| | - Nazish Sayed
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Division of Vascular Surgery, Department of Surgery, Standford University, Stanford, CA, USA
| | - Joseph C. Wu
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine (Division of Cardiology), Stanford University, Stanford, CA, USA
- Greenstone Biosciences, Palo Alto, CA, USA
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17
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Awosika A, E. Omole A, Adabanya U, Anand N, M. Millis R. Statins and Epigenetics: A Putative Mechanism for Explaining Pleiotropic Effects. STATINS - FROM LIPID-LOWERING BENEFITS TO PLEIOTROPIC EFFECTS 2023. [DOI: 10.5772/intechopen.1001141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
Abstract
Statins remain the most efficient hypolipidemic agent and their use is pivotal in primary, secondary, and tertiary treatment of cardiovascular disease, reducing both morbidity and mortality. Statins target 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes conversion of HMG-CoA to mevalonate, the “committed and rate limiting step” in hepatic production of cholesterol. Genetic predilections for hypercholesterolemia are known to be responsible for substantial morbidity and mortality from cardiovascular disease. Environmental or lifestyle factors such as dietary fat and carbohydrate may also contribute to cardiovascular disease mortality by both genetic and epigenetic mechanisms. Besides lipid-lowering, statins have pleiotropic effects which may contribute to their protection against cardiovascular and several other diseases wherein hypercholesterolemia is a risk factor. Evidence is emerging that the clinical outcomes of many diseases are improved when modifications of environmental or lifestyle factors play integral roles in treatment and preventive prescriptions. This chapter is, therefore, intended to inform physicians and other health care professionals about the environment-gene interactions underlying the main and pleiotropic effects of statins which may be employed to improve the efficacy of statin therapies.
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18
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Shah T, McCarthy M, Nasir I, Archer H, Ragheb E, Kluger J, Kashyap N, Paredes C, Patel P, Lu J, Kandel P, Song C, Khan M, Huang H, Ul Haq F, Ahmad R, Howes C, Cambi B, Lancaster G, Cleman M, Dela Cruz C, Parise H, Lansky A. Colchicine and high-intensity rosuvastatin in the treatment of non-critically ill patients hospitalised with COVID-19: a randomised clinical trial. BMJ Open 2023; 13:e067910. [PMID: 36828654 PMCID: PMC9971831 DOI: 10.1136/bmjopen-2022-067910] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 01/16/2023] [Indexed: 02/26/2023] Open
Abstract
OBJECTIVE To evaluate the effect of colchicine and high-intensity rosuvastatin in addition to standard of care on the progression of COVID-19 disease in hospitalised patients. DESIGN A pragmatic, open-label, multicentre, randomised controlled trial conducted from October 2020 to September 2021. Follow-up was conducted at 30 and 60 days. The electronic medical record was used at all stages of the trial including screening, enrolment, randomisation, event ascertainment and follow-up. SETTING Four centres in the Yale New Haven Health System. PARTICIPANTS Non-critically ill hospitalised patients with COVID-19. INTERVENTIONS Patients were randomised 1:1 to either colchicine plus high-intensity rosuvastatin in addition to standard of care versus standard of care alone. Assigned treatment was continued for the duration of index hospitalisation or 30 days, whichever was shorter. PRIMARY AND SECONDARY OUTCOME MEASURES The prespecified primary endpoint was progression to severe COVID-19 disease (new high-flow or non-invasive ventilation, mechanical ventilation, need for vasopressors, renal replacement therapy or extracorporeal membrane oxygenation, or death) or arterial/venous thromboembolic events (ischaemic stroke, myocardial infarction, deep venous thrombosis or pulmonary embolism) evaluated at 30 days. RESULTS Among the 250 patients randomised in this trial (125 to each arm), the median age was 61 years, 44% were women, 15% were Black and 26% were Hispanic/Latino. As part of the standard of care, patients received remdesivir (87%), dexamethasone (92%), tocilizumab (18%), baricitinib (2%), prophylactic/therapeutic anticoagulation (98%) and aspirin (91%). The trial was terminated early by the data and safety monitoring board for futility. No patients were lost to follow-up due to electronic medical record follow-up. There was no significant difference in the primary endpoint at 30 days between the active arm and standard of care arm (15.2% vs 8.8%, respectively, p=0.17). CONCLUSIONS In this small, open-label, randomised trial of non-critically ill hospitalised patients with COVID-19, the combination of colchicine and rosuvastatin in addition to standard of care did not appear to reduce the risk of progression of COVID-19 disease or thromboembolic events, although the trial was underpowered due to a lower-than-expected event rate. The trial leveraged the power of electronic medical records for efficiency and improved follow-up and demonstrates the utility of incorporating electronic medical records into future trials. TRIAL REGISTRATION NCT04472611.
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Affiliation(s)
- Tayyab Shah
- Yale School of Medicine, New Haven, Connecticut, USA
- Yale New Haven Health System, New Haven, Connecticut, USA
| | - Marianne McCarthy
- Yale School of Medicine, New Haven, Connecticut, USA
- Yale New Haven Health System, New Haven, Connecticut, USA
| | - Irem Nasir
- Yale New Haven Health System, New Haven, Connecticut, USA
- Greenwich Hospital, Greenwich, CT, USA
| | - Herb Archer
- Yale New Haven Health System, New Haven, Connecticut, USA
- Greenwich Hospital, Greenwich, CT, USA
| | - Elio Ragheb
- Yale School of Medicine, New Haven, Connecticut, USA
| | | | - Nitu Kashyap
- Yale School of Medicine, New Haven, Connecticut, USA
- Yale New Haven Health System, New Haven, Connecticut, USA
| | - Carlos Paredes
- Yale School of Medicine, New Haven, Connecticut, USA
- Yale New Haven Health System, New Haven, Connecticut, USA
| | - Prashant Patel
- Yale New Haven Health System, New Haven, Connecticut, USA
- Lawrence & Memorial Hospital, New London, CT, USA
| | - Jing Lu
- Yale School of Medicine, New Haven, Connecticut, USA
| | - Prakash Kandel
- Yale New Haven Health System, New Haven, Connecticut, USA
- Lawrence & Memorial Hospital, New London, CT, USA
| | - Christopher Song
- Yale New Haven Health System, New Haven, Connecticut, USA
- Lawrence & Memorial Hospital, New London, CT, USA
| | - Mustafa Khan
- Yale New Haven Health System, New Haven, Connecticut, USA
- Greenwich Hospital, Greenwich, CT, USA
| | | | - Faheem Ul Haq
- Yale New Haven Health System, New Haven, Connecticut, USA
- Bridgeport Hospital, Bridgeport, CT, USA
| | - Rami Ahmad
- Yale School of Medicine, New Haven, Connecticut, USA
- Yale New Haven Health System, New Haven, Connecticut, USA
| | - Christopher Howes
- Yale New Haven Health System, New Haven, Connecticut, USA
- Greenwich Hospital, Greenwich, CT, USA
| | - Brian Cambi
- Yale New Haven Health System, New Haven, Connecticut, USA
- Lawrence & Memorial Hospital, New London, CT, USA
| | - Gilead Lancaster
- Yale New Haven Health System, New Haven, Connecticut, USA
- Bridgeport Hospital, Bridgeport, CT, USA
| | - Michael Cleman
- Yale New Haven Health System, New Haven, Connecticut, USA
- Greenwich Hospital, Greenwich, CT, USA
| | - Charles Dela Cruz
- Yale School of Medicine, New Haven, Connecticut, USA
- Yale New Haven Health System, New Haven, Connecticut, USA
| | - Helen Parise
- Yale School of Medicine, New Haven, Connecticut, USA
| | - Alexandra Lansky
- Yale School of Medicine, New Haven, Connecticut, USA
- Yale New Haven Health System, New Haven, Connecticut, USA
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19
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Mustafin R. Prospects for the use of statins in antiviral therapy. CLINICAL MICROBIOLOGY AND ANTIMICROBIAL CHEMOTHERAPY 2023; 25:56-67. [DOI: 10.36488/cmac.2023.1.56-67] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Inhibitors of hydroxymethylglutaryl-CoA reductase, in addition to suppressing cholesterol synthesis, have an antiviral effect. Clinical studies have shown antiviral efficacy of statins against COVID-19, HCV, HBV, RSV, HIV, influenza viruses. The ability of statins to inhibit influenza viruses, COVID-19, RSV, HIV, as well as Ebola, Zika, Dengue, Coxsackie, rotaviruses, ADV, HDV, HHV was experimentally confirmed. Statins can also enhance the effects of antiviral drugs, making them more effective in treating infections. Therefore, the use of statins in the complex therapy of viral infections is promising. In addition, the role of influenza viruses, T-cell leukemia and herpesviruses, HIV, HBV, HCV, HPV in the development of atherosclerosis has been identified, so the use of statins in complex treatment is also necessary to correct endothelial dysfunction that occurs under the influence of viruses. Since the activity of retroelements that are evolutionarily related to exogenous viruses increases with aging, it has been suggested that retrotransposons can also be targets for statins. This is evidenced by a change in the expression of non-coding RNAs under the action of statins, since the key sources of non-coding RNAs are retroelements. This property may be an additional factor in the prescription of statins to increase life expectancy, in addition to the prevention and treatment of atherosclerosis, since pathological activation of retroelements are the causes of aging. Viruses, like retroelements, are involved in the pathogenesis of malignant neoplasms, in the treatment of which statins have shown their effectiveness and the ability to enhance the effect of anticancer drugs, overcoming chemoresistance (similar to the potentiation of antiviral drugs). One of the mechanisms of this activity of statins may be their effect on retroelements and viruses.
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20
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Di Simone M, Corsale AM, Lo Presti E, Scichilone N, Picone C, Giannitrapani L, Dieli F, Meraviglia S. Phenotypical and Functional Alteration of γδ T Lymphocytes in COVID-19 Patients: Reversal by Statins. Cells 2022; 11:3449. [PMID: 36359845 PMCID: PMC9656060 DOI: 10.3390/cells11213449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/25/2022] [Accepted: 10/29/2022] [Indexed: 11/06/2022] Open
Abstract
(1) Background: statins have been considered an attractive class of drugs in the pharmacological setting of COVID-19 due to their pleiotropic properties and their use correlates with decreased mortality in hospitalized COVID-19 patients. Furthermore, it is well known that statins, which block the mevalonate pathway, affect γδ T lymphocyte activation. As γδ T cells participate in the inflammatory process of COVID-19, we have investigated the therapeutical potential of statins as a tool to inhibit γδ T cell pro-inflammatory activities; (2) Methods: we harvested peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild clinical manifestations, COVID-19 recovered patients, and healthy controls. We performed ex vivo flow cytometry analysis to study γδ T cell frequency, phenotype, and exhaustion status. PBMCs were treated with Atorvastatin followed by non-specific and specific stimulation, to evaluate the expression of pro-inflammatory cytokines; (3) Results: COVID-19 patients had a lower frequency of circulating Vδ2+ T lymphocytes but showed a pronounced pro-inflammatory profile, which was inhibited by in vitro treatment with statins; (4) Conclusions: the in vitro capacity of statins to inhibit Vδ2+ T lymphocytes in COVID-19 patients highlights a new potential biological function of these drugs and supports their therapeutical use in these patients.
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Affiliation(s)
- Marta Di Simone
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), AUOP Paolo Giaccone, 90127 Palermo, Italy
- Department of Biomedicine, Neuroscience and Advanced Diagnosis (BIND), University of Palermo, 90127 Palermo, Italy
| | - Anna Maria Corsale
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), AUOP Paolo Giaccone, 90127 Palermo, Italy
- Department of Biomedicine, Neuroscience and Advanced Diagnosis (BIND), University of Palermo, 90127 Palermo, Italy
| | - Elena Lo Presti
- National Research Council (CNR), Institute for Biomedical Research and Innovation (IRIB), 90146 Palermo, Italy
| | - Nicola Scichilone
- Division of Respiratory Medicine, AUOP Paolo Giaccone, 90127 Palermo, Italy
- Internal Medicine Department Unit, Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialities Department (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Carmela Picone
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), AUOP Paolo Giaccone, 90127 Palermo, Italy
- Department of Biomedicine, Neuroscience and Advanced Diagnosis (BIND), University of Palermo, 90127 Palermo, Italy
| | - Lydia Giannitrapani
- National Research Council (CNR), Institute for Biomedical Research and Innovation (IRIB), 90146 Palermo, Italy
- Internal Medicine Department Unit, Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialities Department (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Francesco Dieli
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), AUOP Paolo Giaccone, 90127 Palermo, Italy
- Department of Biomedicine, Neuroscience and Advanced Diagnosis (BIND), University of Palermo, 90127 Palermo, Italy
| | - Serena Meraviglia
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), AUOP Paolo Giaccone, 90127 Palermo, Italy
- Department of Biomedicine, Neuroscience and Advanced Diagnosis (BIND), University of Palermo, 90127 Palermo, Italy
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21
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Abiri B, Ahmadi AR, Hejazi M, Amini S. Obesity, Diabetes Mellitus, and Metabolic Syndrome: Review in the Era of COVID-19. Clin Nutr Res 2022; 11:331-346. [PMID: 36381471 PMCID: PMC9633974 DOI: 10.7762/cnr.2022.11.4.331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 10/09/2022] [Accepted: 10/16/2022] [Indexed: 01/24/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now at pandemic levels leading to considerable morbidity and mortality throughout the globe. Patients with obesity, diabetes, and metabolic syndrome (MetS) are mainly susceptible and more probably to get severe side effects when affected by this virus. The pathophysiologic mechanisms for these notions have not been completely known. The pro-inflammatory milieu observed in patients with metabolic disruption could lead to COVID-19-mediated host immune dysregulation, such as immune dysfunction, severe inflammation, microvascular dysfunction, and thrombosis. The present review expresses the current knowledge regarding the influence of obesity, diabetes mellitus, and MetS on COVID-19 infection and severity, and their pathophysiological mechanisms.
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Affiliation(s)
- Behnaz Abiri
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
| | - Amirhossein Ramezani Ahmadi
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran
| | - Mahdi Hejazi
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran 14166-34793, Iran
| | - Shirin Amini
- Department of Nutrition, Shoushtar Faculty of Medical Sciences, Shoushtar 64517-73865, Iran
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22
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Xu Q, Antimisiaris D, Kong M. Statistical methods for assessing drug interactions using observational data. J Appl Stat 2022; 51:298-323. [PMID: 38283050 PMCID: PMC10810670 DOI: 10.1080/02664763.2022.2123460] [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: 10/16/2021] [Accepted: 09/04/2022] [Indexed: 10/14/2022]
Abstract
With advances in medicine, many drugs and treatments become available. On the one hand, polydrug use (i.e. using more than one drug at a time) has been used to treat patients with multiple morbid conditions, and polydrug use may cause severe side effects. On the other hand, combination treatments have been successfully developed to treat severe diseases such as cancer and chronic diseases. Observational data, such as electronic health record data, may provide useful information for assessing drug interactions. In this article, we propose using marginal structural models to assess the average treatment effect and causal interaction of two drugs by controlling confounding variables. The causal effect and the interaction of two drugs are assessed using the weighted likelihood approach, with weights being the inverse probability of the treatment assigned. Simulation studies were conducted to examine the performance of the proposed method, which showed that the proposed method was able to estimate the causal parameters consistently. Case studies were conducted to examine the joint effect of metformin and glyburide use on reducing the hospital readmission for type 2 diabetic patients, and to examine the joint effect of antecedent statins and opioids use on the immune and inflammatory biomarkers for COVID-19 hospitalized patients.
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Affiliation(s)
- Qian Xu
- Department of Bioinformatics and Biostatistics, University of Louisville School of Public Health and Information Sciences, Louisville, KY, USA
- Division of Biometrics and Data Science, Fosun Pharma, Beijing, People's Republic of China
| | - Demetra Antimisiaris
- Department of Health Management and Systems Sciences, University of Louisville School of Public Health and Information Sciences, Louisville, KY, USA
| | - Maiying Kong
- Department of Bioinformatics and Biostatistics, University of Louisville School of Public Health and Information Sciences, Louisville, KY, USA
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23
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Ahmad S, Manzoor S, Siddiqui S, Mariappan N, Zafar I, Ahmad A, Ahmad A. Epigenetic underpinnings of inflammation: Connecting the dots between pulmonary diseases, lung cancer and COVID-19. Semin Cancer Biol 2022; 83:384-398. [PMID: 33484868 PMCID: PMC8046427 DOI: 10.1016/j.semcancer.2021.01.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/08/2020] [Accepted: 01/07/2021] [Indexed: 12/11/2022]
Abstract
Inflammation is an essential component of several respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and acute respiratory distress syndrome (ARDS). It is central to lung cancer, the leading cancer in terms of associated mortality that has affected millions of individuals worldwide. Inflammation and pulmonary manifestations are also the major causes of COVID-19 related deaths. Acute hyperinflammation plays an important role in the COVID-19 disease progression and severity, and development of protective immunity against the virus is greatly sought. Further, the severity of COVID-19 is greatly enhanced in lung cancer patients, probably due to the genes such as ACE2, TMPRSS2, PAI-1 and furin that are commonly involved in cancer progression as well as SAR-CoV-2 infection. The importance of inflammation in pulmonary manifestations, cancer and COVID-19 calls for a closer look at the underlying processes, particularly the associated increase in IL-6 and other cytokines, the dysregulation of immune cells and the coagulation pathway. Towards this end, several reports have identified epigenetic regulation of inflammation at different levels. Expression of several key inflammation-related cytokines, chemokines and other genes is affected by methylation and acetylation while non-coding RNAs, including microRNAs as well as long non-coding RNAs, also affect the overall inflammatory responses. Select miRNAs can regulate inflammation in COVID-19 infection, lung cancer as well as other inflammatory lung diseases, and can serve as epigenetic links that can be therapeutically targeted. Furthermore, epigenetic changes also mediate the environmental factors-induced inflammation. Therefore, a better understanding of epigenetic regulation of inflammation can potentially help develop novel strategies to prevent, diagnose and treat chronic pulmonary diseases, lung cancer and COVID-19.
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Affiliation(s)
- Shama Ahmad
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Shajer Manzoor
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Simmone Siddiqui
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Nithya Mariappan
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Iram Zafar
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Aamir Ahmad
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Aftab Ahmad
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
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24
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Cao X, Zhang M, Li H, Chen K, Wang Y, Yang J. Histone Deacetylase9 Represents the Epigenetic Promotion of M1 Macrophage Polarization and Inflammatory Response via TLR4 Regulation. BIOMED RESEARCH INTERNATIONAL 2022; 2022:7408136. [PMID: 35941971 PMCID: PMC9356872 DOI: 10.1155/2022/7408136] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 06/02/2022] [Accepted: 06/06/2022] [Indexed: 12/05/2022]
Abstract
Atherosclerosis is a chronic inflammatory response mediated by various factors, where epigenetic regulation involving histone deacetylation is envisaged to modulate the expression of related proteins by regulating the binding of transcription factors to DNA, thereby influencing the development of atherosclerosis. The mechanism of atherosclerosis by histone deacetylation is partly known; hence, this project aimed at investigating the role of histone deacetylase 9 (HDAC9) in atherosclerosis. For this purpose, serum was separated from blood samples following clotting and centrifugation from atherosclerotic and healthy patients (n = 40 each), and then, various tests were performed. The results indicated that toll-like receptor 4 (TLR4) was not only positively correlated to the HDAC9 gene, but was also upregulated in atherosclerosis, where it was also significantly upregulated in the atherosclerosis cell model of oxidized low-density lipoprotein-induced macrophages. Conversely, the TLR4 was significantly downregulated in instances of loss of HDAC9 function, cementing the bridging relationship between HDAC9 and macrophage polarization, where the HDAC9 was found to upregulate M1 macrophage polarization which translated into the release of higher content of proinflammatory cytokines such as interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), which tend to significantly decrease following the deletion of TLR4. Hence, this study reports novel relation between epigenetic control and atherosclerosis, which could partly be explained by histone deacetylation.
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Affiliation(s)
- Xi Cao
- Department of Circulatory, Affiliated Center of Shenyang Medical College, Shenyang, Liaoning, China
| | - Man Zhang
- Department of Circulatory, Affiliated Center of Shenyang Medical College, Shenyang, Liaoning, China
| | - Hui Li
- Department of Circulatory, Affiliated Center of Shenyang Medical College, Shenyang, Liaoning, China
| | - Kaiming Chen
- Department of Circulatory, Affiliated Center of Shenyang Medical College, Shenyang, Liaoning, China
| | - Yong Wang
- Central Laboratory of Affiliated Hospital of Shenyang Medical College, Shenyang, Liaoning, China
| | - Jia Yang
- Department of Circulatory, Affiliated Center of Shenyang Medical College, Shenyang, Liaoning, China
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25
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Protective effects of statins on COVID-19 risk, severity and fatal outcome: a nationwide Swedish cohort study. Sci Rep 2022; 12:12047. [PMID: 35835835 PMCID: PMC9282150 DOI: 10.1038/s41598-022-16357-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/08/2022] [Indexed: 12/11/2022] Open
Abstract
The impact of statins on COVID-19 remains unclear. This study aims to investigate whether statin exposure assessed both in the population and in well-defined cohorts of COVID-19 patients may affect the risk and severity of COVID-19 using nationwide Swedish population-based register data. A population ≥ 40 years was selected by age/sex-stratified random sampling from the Swedish population on 1 Jan 2020. COVID-19 outcomes were identified from the SmiNet database, the National Patient Register and/or Cause-of-Death Register and linked with the National Prescribed Drug Register and sociodemographic registers. Statin exposure was defined as any statin prescriptions in the year before index date. In Cox regressions, confounding was addressed using propensity score ATT (Average Treatment effect in the Treated) weighting. Of 572,695 individuals in the overall cohort, 22.3% had prior statin treatment. After ATT weighting, protective effects were observed among statin user for hospitalization and COVID-19 death in the overall cohort and onset cohort. In the hospitalized cohort, statin use was only associated with lower risk for death (HR = 0.86, 95% CI 0.79–0.95), but not ICU admission. Statin-treated individuals appear to have lower COVID-19 mortality than nonusers, whether assessed in the general population, from COVID-19 onset or from hospitalization.
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26
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Gorica E, Mohammed SA, Ambrosini S, Calderone V, Costantino S, Paneni F. Epi-Drugs in Heart Failure. Front Cardiovasc Med 2022; 9:923014. [PMID: 35911511 PMCID: PMC9326055 DOI: 10.3389/fcvm.2022.923014] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 06/17/2022] [Indexed: 11/13/2022] Open
Abstract
Unveiling the secrets of genome's flexibility does not only foster new research in the field, but also gives rise to the exploration and development of novel epigenetic-based therapies as an approach to alleviate disease phenotypes. A better understanding of chromatin biology (DNA/histone complexes) and non-coding RNAs (ncRNAs) has enabled the development of epigenetic drugs able to modulate transcriptional programs implicated in cardiovascular diseases. This particularly applies to heart failure, where epigenetic networks have shown to underpin several pathological features, such as left ventricular hypertrophy, fibrosis, cardiomyocyte apoptosis and microvascular dysfunction. Targeting epigenetic signals might represent a promising approach, especially in patients with heart failure with preserved ejection fraction (HFpEF), where prognosis remains poor and breakthrough therapies have yet to be approved. In this setting, epigenetics can be employed for the development of customized therapeutic approaches thus paving the way for personalized medicine. Even though the beneficial effects of epi-drugs are gaining attention, the number of epigenetic compounds used in the clinical practice remains low suggesting that more selective epi-drugs are needed. From DNA-methylation changes to non-coding RNAs, we can establish brand-new regulations for drug targets with the aim of restoring healthy epigenomes and transcriptional programs in the failing heart. In the present review, we bring the timeline of epi-drug discovery and development, thus highlighting the emerging role of epigenetic therapies in heart failure.
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Affiliation(s)
- Era Gorica
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Pharmacy, University of Pisa, Pisa, Italy
| | - Shafeeq A. Mohammed
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
| | - Samuele Ambrosini
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
| | | | - Sarah Costantino
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Cardiology, University Heart Center, Zurich, Switzerland
| | - Francesco Paneni
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Cardiology, University Heart Center, Zurich, Switzerland
- Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
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27
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Yu S, Qian L, Ma J. Genetic alterations, RNA expression profiling and DNA methylation of HMGB1 in malignancies. J Cell Mol Med 2022; 26:4322-4332. [PMID: 35765707 PMCID: PMC9344825 DOI: 10.1111/jcmm.17454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/31/2022] [Accepted: 06/07/2022] [Indexed: 11/27/2022] Open
Abstract
The high mobility group box 1 (HMGB1) is a potential biomarker and therapeutic target in various human diseases. However, a systematic, comprehensive pan‐cancer analysis of HMGB1 in human cancers remains to be reported. This study analysed the genetic alteration, RNA expression profiling and DNA methylation of HMGB1 in more than 30 types of tumours. It is worth noting that HMGB1 is overexpressed in malignant tissues, including lymphoid neoplasm diffuse large B‐cell lymphoma (DLBC), pancreatic adenocarcinoma (PAAD) and thymoma (THYM). Interestingly, there is a positive correlation between the high expression of HMGB1 and the high survival prognosis of THYM. Finally, this study comprehensively evaluates the genetic variation of HMGB1 in human malignant tumours. As a prospective biomarker of COVID‐19, the role that HMGB1 plays in THYM is highlighted.
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Affiliation(s)
- Shoukai Yu
- Hongqiao International Institue of Medicine & Clinical Research Center, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lingmei Qian
- Hongqiao International Institue of Medicine & Clinical Research Center, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Ma
- Hongqiao International Institue of Medicine & Clinical Research Center, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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28
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Bouillon K, Baricault B, Semenzato L, Botton J, Bertrand M, Drouin J, Dray‐Spira R, Weill A, Zureik M. Association of Statins for Primary Prevention of Cardiovascular Diseases With Hospitalization for COVID-19: A Nationwide Matched Population-Based Cohort Study. J Am Heart Assoc 2022; 11:e023357. [PMID: 35699173 PMCID: PMC9238639 DOI: 10.1161/jaha.121.023357] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 05/03/2022] [Indexed: 12/22/2022]
Abstract
Background There is little evidence on the relationship between statin use and the risk of hospitalization attributable to COVID-19. Methods and Results The French National Healthcare Data System database was used to conduct a matched-cohort study. For each adult aged ≥40 years receiving statins for the primary prevention of cardiovascular diseases, one nonuser was randomly selected and matched for year of birth, sex, residence area, and comorbidities. The association between statin use and hospitalization for COVID-19 was examined using conditional Cox proportional hazards models, adjusted for baseline characteristics, comorbidities, and long-term medications. Its association with in-hospital death from COVID-19 was also explored. All participants were followed up from February 15, 2020, to June 15, 2020. The matching procedure generated 2 058 249 adults in the statin group and 2 058 249 in the control group, composed of 46.6% of men with a mean age of 68.7 years. Statin users had a 16% lower risk of hospitalization for COVID-19 than nonusers (adjusted hazard ratio [HR], 0.84; 95% CI, 0.81-0.88). All types of statins were significantly associated with a lower risk of hospitalization, with the adjusted HR ranging from 0.75 for fluvastatin to 0.89 for atorvastatin. Low- and moderate-intensity statins also showed a lower risk compared with nonusers (HR, 0.78 [95% CI, 0.71-0.86] and HR, 0.84 [95% CI, 0.80-0.89], respectively), whereas high-intensity statins did not (HR, 1.01; 95% CI, 0.86-1.18). We found similar results with in-hospital death from COVID-19. Conclusions Our findings support that the use of statins for primary prevention is associated with lower risks of hospitalization for COVID-19 and of in-hospital death from COVID-19.
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Affiliation(s)
- Kim Bouillon
- EPI‐PHARE Scientific Interest Group in Epidemiology of Health ProductsSaint‐DenisFrance
| | - Bérangère Baricault
- EPI‐PHARE Scientific Interest Group in Epidemiology of Health ProductsSaint‐DenisFrance
| | - Laura Semenzato
- EPI‐PHARE Scientific Interest Group in Epidemiology of Health ProductsSaint‐DenisFrance
| | - Jérémie Botton
- EPI‐PHARE Scientific Interest Group in Epidemiology of Health ProductsSaint‐DenisFrance
- Faculty of PharmacyParis‐Saclay UniversityChâtenay‐MalabryFrance
| | - Marion Bertrand
- EPI‐PHARE Scientific Interest Group in Epidemiology of Health ProductsSaint‐DenisFrance
| | - Jérôme Drouin
- EPI‐PHARE Scientific Interest Group in Epidemiology of Health ProductsSaint‐DenisFrance
| | - Rosemary Dray‐Spira
- EPI‐PHARE Scientific Interest Group in Epidemiology of Health ProductsSaint‐DenisFrance
| | - Alain Weill
- EPI‐PHARE Scientific Interest Group in Epidemiology of Health ProductsSaint‐DenisFrance
| | - Mahmoud Zureik
- EPI‐PHARE Scientific Interest Group in Epidemiology of Health ProductsSaint‐DenisFrance
- Paris‐Saclay UniversityUVSQCESP‐Inserm, Anti‐infective evasion and pharmacoepidemiologyMontigny le BretonneuxFrance
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29
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Mota S, Bensalel J, Park DH, Gonzalez S, Rodriguez A, Gallego-Delgado J. Treatment Reducing Endothelial Activation Protects against Experimental Cerebral Malaria. Pathogens 2022; 11:643. [PMID: 35745497 PMCID: PMC9229727 DOI: 10.3390/pathogens11060643] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 05/25/2022] [Accepted: 05/30/2022] [Indexed: 11/30/2022] Open
Abstract
Cerebral malaria (CM) is the most severe neurological complication of malaria caused by Plasmodium falciparum infection. The available antimalarial drugs are effective at clearing the parasite, but the mortality rate remains as high as 20% of CM cases. At the vascular level, CM is characterized by endothelial activation and dysfunction. Several biomarkers of endothelial activation have been associated with CM severity and mortality, making the brain vascular endothelium a potential target for adjunctive therapies. Statins and Angiotensin II Receptor Blockers (ARBs) are drugs used to treat hypercholesterolemia and hypertension, respectively, that have shown endothelial protective activity in other diseases. Here, we used a combination of a statin (atorvastatin) and an ARB (irbesartan) as adjunctive therapy to conventional antimalarial drugs in a mouse experimental model of CM. We observed that administration of atorvastatin-irbesartan combination decreased the levels of biomarkers of endothelial activation, such as the von Willebrand factor and angiopoietin-1. After mice developed neurological signs of CM, treatment with the combination plus conventional antimalarial drugs increased survival rates of animals 3-4 times compared to treatment with antimalarial drugs alone, with animals presenting lower numbers and smaller hemorrhages in the brain. Taken together, our results support the hypothesis that inhibiting endothelial activation would greatly reduce the CM-associated pathology and mortality.
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Affiliation(s)
- Sabrina Mota
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA; (S.M.); (D.H.P.); (S.G.)
| | - Johanna Bensalel
- Department of Biological Sciences, Lehman College, The City University of New York, Bronx, New York, NY 10468, USA;
- Ph.D. Program in Biology, The Graduate Center, The City University of New York, New York, NY 10016, USA
| | - Do Hee Park
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA; (S.M.); (D.H.P.); (S.G.)
| | - Sandra Gonzalez
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA; (S.M.); (D.H.P.); (S.G.)
| | - Ana Rodriguez
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA; (S.M.); (D.H.P.); (S.G.)
| | - Julio Gallego-Delgado
- Department of Biological Sciences, Lehman College, The City University of New York, Bronx, New York, NY 10468, USA;
- Ph.D. Program in Biology, The Graduate Center, The City University of New York, New York, NY 10016, USA
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30
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Zota IM, Stătescu C, Sascău RA, Roca M, Anghel L, Maștaleru A, Leon-Constantin MM, Ghiciuc CM, Cozma SR, Dima-Cozma LC, Esanu IM, Mitu F. Acute and Long-Term Consequences of COVID-19 on Arterial Stiffness-A Narrative Review. Life (Basel) 2022; 12:781. [PMID: 35743812 PMCID: PMC9224691 DOI: 10.3390/life12060781] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/21/2022] [Accepted: 05/22/2022] [Indexed: 02/07/2023] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global coronavirus (COVID-19) pandemic. Although initially viewed as an acute respiratory illness, COVID-19 is clearly a complex multisystemic disease with extensive cardiovascular involvement. Emerging evidence shows that the endothelium plays multiple roles in COVID-19 physiopathology, as both a target organ that can be directly infected by SARS-CoV-2 and a mediator in the subsequent inflammatory and thrombotic cascades. Arterial stiffness is an established marker of cardiovascular disease. The scope of this review is to summarize available data on the acute and long-term consequences of COVID-19 on vascular function. COVID-19 causes early vascular aging and arterial stiffness. Fast, noninvasive bedside assessment of arterial stiffness could optimize risk stratification in acute COVID-19, allowing for early escalation of treatment. Vascular physiology remains impaired at least 12 months after infection with SARS-CoV-2, even in otherwise healthy adults. This raises concerns regarding the extent of arterial remodeling in patients with preexisting vascular disease and the potential development of a persistent, chronic COVID-19 vasculopathy. Long-term follow up on larger cohorts is required to investigate the reversibility of COVID-19-induced vascular changes and their associated prognostic implications.
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Affiliation(s)
- Ioana Mădălina Zota
- Department of Medical Specialties I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700111 Iași, Romania; (I.M.Z.); (C.S.); (R.A.S.); (M.R.); (L.A.); (A.M.); (M.M.L.-C.); (L.C.D.-C.); (F.M.)
| | - Cristian Stătescu
- Department of Medical Specialties I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700111 Iași, Romania; (I.M.Z.); (C.S.); (R.A.S.); (M.R.); (L.A.); (A.M.); (M.M.L.-C.); (L.C.D.-C.); (F.M.)
| | - Radu Andy Sascău
- Department of Medical Specialties I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700111 Iași, Romania; (I.M.Z.); (C.S.); (R.A.S.); (M.R.); (L.A.); (A.M.); (M.M.L.-C.); (L.C.D.-C.); (F.M.)
| | - Mihai Roca
- Department of Medical Specialties I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700111 Iași, Romania; (I.M.Z.); (C.S.); (R.A.S.); (M.R.); (L.A.); (A.M.); (M.M.L.-C.); (L.C.D.-C.); (F.M.)
| | - Larisa Anghel
- Department of Medical Specialties I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700111 Iași, Romania; (I.M.Z.); (C.S.); (R.A.S.); (M.R.); (L.A.); (A.M.); (M.M.L.-C.); (L.C.D.-C.); (F.M.)
| | - Alexandra Maștaleru
- Department of Medical Specialties I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700111 Iași, Romania; (I.M.Z.); (C.S.); (R.A.S.); (M.R.); (L.A.); (A.M.); (M.M.L.-C.); (L.C.D.-C.); (F.M.)
| | - Maria Magdalena Leon-Constantin
- Department of Medical Specialties I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700111 Iași, Romania; (I.M.Z.); (C.S.); (R.A.S.); (M.R.); (L.A.); (A.M.); (M.M.L.-C.); (L.C.D.-C.); (F.M.)
| | - Cristina Mihaela Ghiciuc
- Pharmacology, Clinical Pharmacology and Algeziology, Department of Morpho-Functional Sciences II, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700111 Iași, Romania
| | - Sebastian Romica Cozma
- Department of Surgery (II), Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700111 Iași, Romania;
| | - Lucia Corina Dima-Cozma
- Department of Medical Specialties I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700111 Iași, Romania; (I.M.Z.); (C.S.); (R.A.S.); (M.R.); (L.A.); (A.M.); (M.M.L.-C.); (L.C.D.-C.); (F.M.)
| | - Irina Mihaela Esanu
- Department of Medical Specialties I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700111 Iași, Romania; (I.M.Z.); (C.S.); (R.A.S.); (M.R.); (L.A.); (A.M.); (M.M.L.-C.); (L.C.D.-C.); (F.M.)
| | - Florin Mitu
- Department of Medical Specialties I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700111 Iași, Romania; (I.M.Z.); (C.S.); (R.A.S.); (M.R.); (L.A.); (A.M.); (M.M.L.-C.); (L.C.D.-C.); (F.M.)
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Abstract
This article reviews the discovery of PCSK9, its structure-function characteristics, and its presently known and proposed novel biological functions. The major critical function of PCSK9 deduced from human and mouse studies, as well as cellular and structural analyses, is its role in increasing the levels of circulating low-density lipoprotein (LDL)-cholesterol (LDLc), via its ability to enhance the sorting and escort of the cell surface LDL receptor (LDLR) to lysosomes. This implicates the binding of the catalytic domain of PCSK9 to the EGF-A domain of the LDLR. This also requires the presence of the C-terminal Cys/His-rich domain, its binding to the secreted cytosolic cyclase associated protein 1, and possibly another membrane-bound "protein X". Curiously, in PCSK9-deficient mice, an alternative to the downregulation of the surface levels of the LDLR by PCSK9 is taking place in the liver of female mice in a 17β-estradiol-dependent manner by still an unknown mechanism. Recent studies have extended our understanding of the biological functions of PCSK9, namely its implication in septic shock, vascular inflammation, viral infections (Dengue; SARS-CoV-2) or immune checkpoint modulation in cancer via the regulation of the cell surface levels of the T-cell receptor and MHC-I, which govern the antitumoral activity of CD8+ T cells. Because PCSK9 inhibition may be advantageous in these processes, the availability of injectable safe PCSK9 inhibitors that reduces by 50% to 60% LDLc above the effect of statins is highly valuable. Indeed, injectable PCSK9 monoclonal antibody or small interfering RNA could be added to current immunotherapies in cancer/metastasis.
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Affiliation(s)
- Nabil G Seidah
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal), Montreal, QC, Canada
| | - Annik Prat
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal), Montreal, QC, Canada
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Wilk-Sledziewska K, Sielatycki PJ, Uscinska N, Bujno E, Rosolowski M, Kakareko K, Sledziewski R, Rydzewska-Rosolowska A, Hryszko T, Zbroch E. The Impact of Cardiovascular Risk Factors on the Course of COVID-19. J Clin Med 2022; 11:2250. [PMID: 35456343 PMCID: PMC9026388 DOI: 10.3390/jcm11082250] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/07/2022] [Accepted: 04/13/2022] [Indexed: 02/06/2023] Open
Abstract
AIM OF THE STUDY The aim of our review is to indicate and discuss the impact of cardiovascular risk factors, such as obesity, diabetes, lipid profile, hypertension and smoking on the course and mortality of COVID-19 infection. BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic is spreading around the world and becoming a major public health crisis. All coronaviruses are known to affect the cardiovascular system. There is a strong correlation between cardiovascular risk factors and severe clinical complications, including death in COVID-19 patients. All the above-mentioned risk factors are widespread and constitute a significant worldwide health problem. Some of them are modifiable and the awareness of their connection with the COVID-19 progress may have a crucial impact on the current and possible upcoming infection. DATA COLLECTION We searched for research papers describing the impact of selected cardiovascular risk factors on the course, severity, complications and mortality of COVID-19 infection form PubMed and Google Scholar databases. Using terms, for example: "COVID-19 cardiovascular disease mortality", "COVID-19 hypertension/diabetes mellitus/obesity/dyslipidemia", "cardiovascular risk factors COVID-19 mortality" and other related terms listed in each subtitle. The publications were selected according to the time of their publications between January 2020 and December 2021. From the PubMed database we obtain 1552 results. Further studies were sought by manually searching reference lists of the relevant articles. Relevant articles were selected based on their title, abstract or full text. Articles were excluded if they were clearly related to another subject matter or were not published in English. The types of articles are mainly randomized controlled trial and systematic review. An additional criterion used by researchers was co-morbidities and age of patients in study groups. From a review of the publications, 105 of them were selected for this work with all subheadings included. Findings and Results: The intention of this review was to summarize current knowledge about comorbidities and development of COVID-19 infection. We tried to focus on the course and mortality of the abovementioned virus disease in patients with concomitant CV risk factors. Unfortunately, we were unable to assess the quality of data in screened papers and studies we choose because of the heterogenicity of the groups. The conducted studies had different endpoints and included different groups of patients in terms of nationality, age, race and clinical status. We decide to divide the main subjects of the research into separately described subtitles such as obesity, lipid profile, hypertension, diabetes, smoking. We believe that the studies we included and gathered are very interesting and show modern and present-day clinical data and approaches to COVID-19 infection in specific divisions of patients.
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Affiliation(s)
- Katarzyna Wilk-Sledziewska
- Department of Internal Medicine and Hypertension, Medical University of Bialystok, 15-540 Bialystok, Poland; (K.W.-S.); (P.J.S.); (N.U.); (E.B.); (M.R.)
| | - Piotr Jan Sielatycki
- Department of Internal Medicine and Hypertension, Medical University of Bialystok, 15-540 Bialystok, Poland; (K.W.-S.); (P.J.S.); (N.U.); (E.B.); (M.R.)
| | - Natalia Uscinska
- Department of Internal Medicine and Hypertension, Medical University of Bialystok, 15-540 Bialystok, Poland; (K.W.-S.); (P.J.S.); (N.U.); (E.B.); (M.R.)
| | - Elżbieta Bujno
- Department of Internal Medicine and Hypertension, Medical University of Bialystok, 15-540 Bialystok, Poland; (K.W.-S.); (P.J.S.); (N.U.); (E.B.); (M.R.)
| | - Mariusz Rosolowski
- Department of Internal Medicine and Hypertension, Medical University of Bialystok, 15-540 Bialystok, Poland; (K.W.-S.); (P.J.S.); (N.U.); (E.B.); (M.R.)
| | - Katarzyna Kakareko
- 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Bialystok, 15-276 Bialystok, Poland; (K.K.); (A.R.-R.); (T.H.)
| | - Rafal Sledziewski
- Department of Radiology, Medical University of Bialystok, 15-276 Bialystok, Poland;
| | - Alicja Rydzewska-Rosolowska
- 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Bialystok, 15-276 Bialystok, Poland; (K.K.); (A.R.-R.); (T.H.)
| | - Tomasz Hryszko
- 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Bialystok, 15-276 Bialystok, Poland; (K.K.); (A.R.-R.); (T.H.)
| | - Edyta Zbroch
- Department of Internal Medicine and Hypertension, Medical University of Bialystok, 15-540 Bialystok, Poland; (K.W.-S.); (P.J.S.); (N.U.); (E.B.); (M.R.)
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Du X, Sun Z, Cao Z, Zhou X, Wang D, Wang K, Li X, Zuo G. Atorvastatin regulates vascular smooth muscle cell phenotypic transformation by epigenetically modulating contractile proteins and mediating Akt/FOXO4 axis. Mol Med Rep 2022; 25:167. [PMID: 35475577 DOI: 10.3892/mmr.2022.12683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 01/14/2022] [Indexed: 11/05/2022] Open
Affiliation(s)
- Xinping Du
- Department of Cardiology, Tianjin Fifth Central Hospital, Tianjin 300450, P.R. China
| | - Zhiyuan Sun
- Department of Cardiology, Tianjin Fifth Central Hospital, Tianjin 300450, P.R. China
| | - Zhongnan Cao
- Department of Cardiology, Tianjin Fifth Central Hospital, Tianjin 300450, P.R. China
| | - Xiuhong Zhou
- Department of Cardiology, Tianjin Fifth Central Hospital, Tianjin 300450, P.R. China
| | - Dong Wang
- Department of Cardiology, Tianjin Fifth Central Hospital, Tianjin 300450, P.R. China
| | - Kuan Wang
- Department of Cardiology, Tianjin Fifth Central Hospital, Tianjin 300450, P.R. China
| | - Xuebin Li
- Department of Cardiology, Tianjin Fifth Central Hospital, Tianjin 300450, P.R. China
| | - Guoxing Zuo
- Department of Cardiology, Tianjin Fifth Central Hospital, Tianjin 300450, P.R. China
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34
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Ghafouri M, Saadati H, Taghavi MR, Azimian A, Alesheikh P, Mohajerzadeh MS, Behnamfar M, Pakzad M, Rameshrad M. Survival of the hospitalized patients with COVID-19 receiving Atorvastatin: a randomized clinical trial. J Med Virol 2022; 94:3160-3168. [PMID: 35274326 PMCID: PMC9088596 DOI: 10.1002/jmv.27710] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 03/04/2022] [Accepted: 03/09/2022] [Indexed: 01/08/2023]
Abstract
As statins decrease the progression of sepsis and its related mortality, this study aimed to evaluate the effect of atorvastatin on survival and symptom improvement in hospitalized patients with COVID‐19. This randomized controlled trial was performed on 156 hospitalized patients with COVID‐19 in Bojnourd city in 2021. Patients were randomly divided into comparison (standard therapy: hydroxychloroquine + Kaletra®) and intervention groups (atorvastatin 20 mg, SD, plus standard therapy). The main outcomes were the rate of symptom improvement, duration of hospitalization, need for intubation, and mortality rate. In this study, seven patients died, two patients (2.6%) in the comparison group and five (6.6%) in the intervention group. The mean hospitalization days (p = 0.001), the pulse rate (p = 0.004), and the frequency of hospitalization in the ICU ward (18.4% vs. 1.3%) were longer and greater in the intervention group. The remission probability in the comparison group was greater (p = 0.0001). The median hospitalization days in the intervention group was longer (p < 0.001) and remission in the comparison group occurred 1.71 times sooner (hazard ratio = 1.70, 95% confidence interval = 1.22–2.38, p = 0.002). Totally, adding atorvastatin to the standard regime in this study increased hospitalization days and imposed negative effects on symptom improvement in hospitalized patients with COVID‐19.
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Affiliation(s)
- Majid Ghafouri
- Department of Internal Medicine, School of Medicine, Vector-borne Diseases Research Center, Imam Hassan Hospital, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Hassan Saadati
- Department of Epidemiology and Biostatistics, School of Health, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Mohammad Reza Taghavi
- Department of Internal Medicine, School of Medicine, Vector-borne Diseases Research Center, Imam Hassan Hospital, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Amir Azimian
- Department of Pathology and Laboratory Sciences, School of Medicine, Vector-borne Diseases Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Peiman Alesheikh
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Mina Sadat Mohajerzadeh
- Department of Radiology and Medical Physics, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Morteza Behnamfar
- Student research committee, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Marzih Pakzad
- Imam Hassan Hospital, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Maryam Rameshrad
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
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Teixeira L, Temerozo JR, Pereira-Dutra FS, Ferreira AC, Mattos M, Gonçalves BS, Sacramento CQ, Palhinha L, Cunha-Fernandes T, Dias SSG, Soares VC, Barreto EA, Cesar-Silva D, Fintelman-Rodrigues N, Pão CRR, de Freitas CS, Reis PA, Hottz ED, Bozza FA, Bou-Habib DC, Saraiva EM, de Almeida CJG, Viola JPB, Souza TML, Bozza PT. Simvastatin Downregulates the SARS-CoV-2-Induced Inflammatory Response and Impairs Viral Infection Through Disruption of Lipid Rafts. Front Immunol 2022; 13:820131. [PMID: 35251001 PMCID: PMC8895251 DOI: 10.3389/fimmu.2022.820131] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 01/25/2022] [Indexed: 12/11/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) is currently a worldwide emergency caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). In observational clinical studies, statins have been identified as beneficial to hospitalized patients with COVID-19. However, experimental evidence of underlying statins protection against SARS-CoV-2 remains elusive. Here we reported for the first-time experimental evidence of the protective effects of simvastatin treatment both in vitro and in vivo. We found that treatment with simvastatin significantly reduced the viral replication and lung damage in vivo, delaying SARS-CoV-2-associated physiopathology and mortality in the K18-hACE2-transgenic mice model. Moreover, simvastatin also downregulated the inflammation triggered by SARS-CoV-2 infection in pulmonary tissue and in human neutrophils, peripheral blood monocytes, and lung epithelial Calu-3 cells in vitro, showing its potential to modulate the inflammatory response both at the site of infection and systemically. Additionally, we also observed that simvastatin affected the course of SARS-CoV-2 infection through displacing ACE2 on cell membrane lipid rafts. In conclusion, our results show that simvastatin exhibits early protective effects on SARS-CoV-2 infection by inhibiting virus cell entry and inflammatory cytokine production, through mechanisms at least in part dependent on lipid rafts disruption.
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Affiliation(s)
- Lívia Teixeira
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Jairo R. Temerozo
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
- National Institute for Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
- National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Filipe S. Pereira-Dutra
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - André Costa Ferreira
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
- National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
- Preclinical Research Laboratory, Universidade Iguaçu (UNIG), Nova Iguaçu, Brazil
| | - Mayara Mattos
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
- National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Barbara Simonson Gonçalves
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Carolina Q. Sacramento
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
- National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Lohanna Palhinha
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Tamires Cunha-Fernandes
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Suelen S. G. Dias
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Vinicius Cardoso Soares
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
- Program of Immunology and Inflammation, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Ester A. Barreto
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Daniella Cesar-Silva
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Natalia Fintelman-Rodrigues
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
- National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Camila R. R. Pão
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Caroline S. de Freitas
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
- National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Patrícia A. Reis
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
- Biochemistry Department, Roberto Alcântara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Eugenio D. Hottz
- Laboratory of Immunothrombosis, Department of Biochemistry, Federal University of Juiz de Fora (UFJF), Minas Gerais, Brazil
| | - Fernando A. Bozza
- National Institute of Infectious Disease Evandro Chagas, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- D’Or Institute for Research and Education, Rio de Janeiro, Brazil
| | - Dumith C. Bou-Habib
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
- National Institute for Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Elvira M. Saraiva
- Laboratory of Immunobiology of Leishmaniasis, Department of Immunology, Paulo de Goes Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Cecília J. G. de Almeida
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - João P. B. Viola
- Program of Immunology and Tumor Biology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil
| | - Thiago Moreno L. Souza
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
- National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Patricia T. Bozza
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
- *Correspondence: Patrícia T. Bozza, ;
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Oyagbemi AA, Ajibade TO, Aboua YG, Gbadamosi IT, Adedapo ADA, Aro AO, Adejumobi OA, Thamahane-Katengua E, Omobowale TO, Falayi OO, Oyagbemi TO, Ogunpolu BS, Hassan FO, Ogunmiluyi IO, Ola-Davies OE, Saba AB, Adedapo AA, Nkadimeng SM, McGaw LJ, Kayoka-Kabongo PN, Yakubu MA, Oguntibeju OO. The therapeutic potential of the novel angiotensin-converting enzyme 2 in the treatment of coronavirus disease-19. Vet World 2021; 14:2705-2713. [PMID: 34903929 PMCID: PMC8654738 DOI: 10.14202/vetworld.2021.2705-2713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 09/13/2021] [Indexed: 01/08/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of coronavirus disease 2019 (COVID-19). This virus has become a global pandemic with unprecedented mortality and morbidity along with attendant financial and economic crises. Furthermore, COVID-19 can easily be transmitted regardless of religion, race, sex, or status. Globally, high hospitalization rates of COVID-19 patients have been reported, and billions of dollars have been spent to contain the pandemic. Angiotensin-converting enzyme (ACE) 2 is a receptor of SARS-CoV-2, which has a significant role in the entry of the virus into the host cell. ACE2 is highly expressed in the type II alveolar cells of the lungs, upper esophagus, stratified epithelial cells, and other tissues in the body. The diminished expressions of ACE2 have been associated with hypertension, arteriosclerosis, heart failure, chronic kidney disease, and immune system dysregulation. Overall, the potential drug candidates that could serve as ACE2 activators or enhance the expression of ACE2 in a disease state, such as COVID-19, hold considerable promise in mitigating the COVID-19 pandemic. This study reviews the therapeutic potential and pharmacological benefits of the novel ACE2 in the management of COVID-19 using search engines, such as Google, Scopus, PubMed, and PubMed Central.
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Affiliation(s)
- Ademola Adetokunbo Oyagbemi
- Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Temitayo Olabisi Ajibade
- Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Yapo Guillaume Aboua
- Department of Health Sciences, Faculty of Health and Applied Sciences, Namibia University of Science and Technology, Private Bag 13388, Namibia
| | | | | | - Abimbola Obemisola Aro
- Department of Agriculture and Animal Health, College of Agriculture and Environmental Sciences, University of South Africa, Florida, South Africa
| | | | - Emma Thamahane-Katengua
- Department of Health Information Management, Botho University, Faculty of Health and Education, Botswana
| | | | - Olufunke Olubunmi Falayi
- Department of Veterinary Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Taiwo Olaide Oyagbemi
- Department of Veterinary Parasitology and Entomology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | | | - Fasilat Oluwakemi Hassan
- Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | | | - Olufunke Eunice Ola-Davies
- Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Adebowale Benard Saba
- Department of Veterinary Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Adeolu Alex Adedapo
- Department of Veterinary Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Sanah Malomile Nkadimeng
- Department of Paraclinical Science, Phytomedicine Programme, University of Pretoria, Faculty of Veterinary Science, Old Soutpan Road, Onderstepoort, 0110, South Africa
| | - Lyndy Joy McGaw
- Department of Paraclinical Science, Phytomedicine Programme, University of Pretoria, Faculty of Veterinary Science, Old Soutpan Road, Onderstepoort, 0110, South Africa
| | - Prudence Ngalula Kayoka-Kabongo
- Department of Agriculture and Animal Health, College of Agriculture and Environmental Sciences, University of South Africa, Florida, South Africa
| | - Momoh Audu Yakubu
- Department of Environmental and Interdisciplinary Sciences, College of Science, Engineering and Technology, Vascular Biology Unit, Center for Cardiovascular Diseases, Texas Southern University, Houston, TX, USA
| | - Oluwafemi Omoniyi Oguntibeju
- Department of Biomedical Sciences, Phytomedicine and Phytochemistry Group, Oxidative Stress Research Centre, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Bellville 7535, South Africa
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Shen L, Qiu L, Wang L, Huang H, Liu D, Xiao Y, Liu Y, Jin J, Liu X, Wang DW, He B, Zhou N. Statin Use and In-hospital Mortality in Patients with COVID-19 and Coronary Heart Disease. Sci Rep 2021; 11:23874. [PMID: 34903765 PMCID: PMC8668894 DOI: 10.1038/s41598-021-02534-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 08/30/2021] [Indexed: 02/08/2023] Open
Abstract
The worsening progress of coronavirus disease 2019 (COVID-19) is attributed to the proinflammatory state, leading to increased mortality. Statin works with its anti-inflammatory effects and may attenuate the worsening of COVID-19. COVID-19 patients were retrospectively enrolled from two academic hospitals in Wuhan, China, from 01/26/2020 to 03/26/2020. Adjusted in-hospital mortality was compared between the statin and the non-statin group by CHD status using multivariable Cox regression model after propensity score matching. Our study included 3133 COVID-19 patients (median age: 62y, female: 49.8%), and 404 (12.9%) received statin. Compared with the non-statin group, the statin group was older, more likely to have comorbidities but with a lower level of inflammatory markers. The Statin group also had a lower adjusted mortality risk (6.44% vs. 10.88%; adjusted hazard ratio [HR] 0.47; 95% CI, 0.29–0.77). Subgroup analysis of CHD patients showed a similar result. Propensity score matching showed an overall 87% (HR, 0.13; 95% CI, 0.05–0.36) lower risk of in-hospital mortality for statin users than nonusers. Such survival benefit of statin was obvious both among CHD and non-CHD patients (HR = 0.30 [0.09–0.98]; HR = 0.23 [0.1–0.49], respectively). Statin use was associated with reduced in-hospital mortality in COVID-19. The benefit of statin was both prominent among CHD and non-CHD patients. These findings may further reemphasize the continuation of statins in patients with CHD during the COVID-19 era.
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Affiliation(s)
- Lan Shen
- Department of Cardiology, Clinical Research Unit, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 200030, China
| | - Lin Qiu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Li Wang
- Department of Geriatrics, School of Medicine, Shanghai Renji Hospital, Shanghai Jiaotong University, Shanghai, 200127, China
| | - Hengye Huang
- School of Public Health, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
| | - Dong Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Ying Xiao
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Yi Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Jingjin Jin
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Xiulan Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Ben He
- Department of Cardiology, Clinical Research Unit, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 200030, China.
| | - Ning Zhou
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China.
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Sharifi Y, Payab M, Mohammadi-Vajari E, Aghili SMM, Sharifi F, Mehrdad N, Kashani E, Shadman Z, Larijani B, Ebrahimpur M. Association between cardiometabolic risk factors and COVID-19 susceptibility, severity and mortality: a review. J Diabetes Metab Disord 2021; 20:1743-1765. [PMID: 34222055 PMCID: PMC8233632 DOI: 10.1007/s40200-021-00822-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/23/2021] [Indexed: 02/08/2023]
Abstract
The novel coronavirus, which began spreading from China Wuhan and gradually spreaded to most countries, led to the announcement by the World Health Organization on March 11, 2020, as a new pandemic. The most important point presented by the World Health Organization about this disease is to better understand the risk factors that exacerbate the course of the disease and worsen its prognosis. Due to the high majority of cardio metabolic risk factors like obesity, hypertension, diabetes, and dyslipidemia among the population over 60 years old and higher, these cardio metabolic risk factors along with the age of these people could worsen the prognosis of the coronavirus disease of 2019 (COVID-19) and its mortality. In this study, we aimed to review the articles from the beginning of the pandemic on the impression of cardio metabolic risk factors on COVID-19 and the effectiveness of COVID-19 on how to manage these diseases. All the factors studied in this article, including hypertension, diabetes mellitus, dyslipidemia, and obesity exacerbate the course of Covid-19 disease by different mechanisms, and the inflammatory process caused by coronavirus can also create a vicious cycle in controlling these diseases for patients.
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Affiliation(s)
- Yasaman Sharifi
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Yaas Diabetes and Metabolic Diseases Research Center, Indiana University School of Medicine, Indianapolis, IN 46202 US
| | - Moloud Payab
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Erfan Mohammadi-Vajari
- Student of Medicine, School of Medicine, Gilan University of Medical Sciences, Rasht, Iran
| | - Seyed Morsal Mosallami Aghili
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farshad Sharifi
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Mehrdad
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Nursing Care Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Elham Kashani
- Department of Obstetrics and Gynecology, Golestan University of Medical Sciences, Golestan, Iran
| | - Zhaleh Shadman
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahbube Ebrahimpur
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Rajtik T, Galis P, Bartosova L, Paulis L, Goncalvesova E, Klimas J. Alternative RAS in Various Hypoxic Conditions: From Myocardial Infarction to COVID-19. Int J Mol Sci 2021; 22:ijms222312800. [PMID: 34884604 PMCID: PMC8657827 DOI: 10.3390/ijms222312800] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/20/2021] [Accepted: 11/24/2021] [Indexed: 12/28/2022] Open
Abstract
Alternative branches of the classical renin–angiotensin–aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor activation. Generally, this branch of the RAS system is described as its non-canonical alternative arm with counterbalancing actions to the classical RAS, conveying vasodilation, anti-inflammatory, anti-remodeling and anti-proliferative effects. The implication of this branch was proposed for many different diseases, ranging from acute cardiovascular conditions, through chronic respiratory diseases to cancer, nonetheless, hypoxia is one of the most prominent common factors discussed in conjugation with the changes in the activity of alternative RAS branches. The aim of this review is to bring complex insights into the mechanisms behind the various forms of hypoxic insults on the activity of alternative RAS branches based on the different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical relevance of studied phenomenon (experimental vs. clinical condition). Moreover, we provide novel insights into the future strategies utilizing the alternative RAS as a diagnostic tool as well as a promising pharmacological target in serious hypoxia-associated cardiovascular and cardiopulmonary diseases.
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Affiliation(s)
- Tomas Rajtik
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (P.G.); (L.B.); (J.K.)
- Correspondence: ; Tel.: +42-12-501-17-391
| | - Peter Galis
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (P.G.); (L.B.); (J.K.)
| | - Linda Bartosova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (P.G.); (L.B.); (J.K.)
| | - Ludovit Paulis
- Institute of Pathophysiology, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Eva Goncalvesova
- Department of Heart Failure, Clinic of Cardiology, National Institute of Cardiovascular Diseases, 831 01 Bratislava, Slovakia;
| | - Jan Klimas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (P.G.); (L.B.); (J.K.)
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Shah T, McCarthy M, Nasir I, Archer H, Ragheb E, Kluger J, Kashyap N, Paredes C, Patel P, Lu J, Kandel P, Song C, Khan M, Ul Haq F, Ahmad R, Howes C, Cambi B, Lancaster G, Cleman M, Dela Cruz CS, Parise H, Lansky A. Design and rationale of the colchicine/statin for the prevention of COVID-19 complications (COLSTAT) trial. Contemp Clin Trials 2021; 110:106547. [PMID: 34461322 PMCID: PMC8397504 DOI: 10.1016/j.cct.2021.106547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/16/2021] [Accepted: 08/25/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Despite improvement in the standard of care (SOC) for hospitalized COVID-19 patients, rates of morbidity and mortality remain high. There continues to be a need for easily available and cost-effective treatments. Colchicine and rosuvastatin are both safe and well-studied medications with anti-inflammatory and other pleiotropic effects that may provide additional benefits to hospitalized COVID-19 patients. METHODS AND RESULTS The Colchicine/Statin for the Prevention of COVID-19 Complications (COLSTAT) trial is a pragmatic, open-label, multicenter, randomized trial comparing the combination of colchicine and rosuvastatin in addition to SOC to SOC alone in hospitalized COVID-19 patients. Four centers in the Yale New Haven Health network will enroll a total of 466 patients with 1:1 randomization. The trial will utilize the electronic health record (Epic® Systems, Verona, Wisconsin, USA) at all stages including screening, randomization, intervention, event ascertainment, and follow-up. The primary endpoint is the 30-day composite of progression to severe COVID-19 disease as defined by the World Health Organization ordinal scale of clinical improvement and arterial/venous thromboembolic events. The secondary powered endpoint is the 30-day composite of death, respiratory failure requiring intubation, and myocardial injury. CONCLUSIONS The COLSTAT trial will provide evidence on the efficacy of repurposing colchicine and rosuvastatin for the treatment of hospitalized COVID-19 patients. Moreover, it is designed to be a pragmatic trial that will demonstrate the power of using electronic health records to improve efficiency and enrollment in clinical trials in an adapting landscape. CLINICAL TRIAL REGISTRATION NCT04472611 (https://clinicaltrials.gov/ct2/show/NCT04472611).
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Affiliation(s)
- Tayyab Shah
- Yale University School of Medicine, New Haven, CT, United States of America; Yale New Haven Health System, CT, United States of America
| | - Marianne McCarthy
- Yale University School of Medicine, New Haven, CT, United States of America; Yale New Haven Health System, CT, United States of America
| | - Irem Nasir
- Yale New Haven Health System, CT, United States of America; Greenwich Hospital, Greenwich, CT, United States of America
| | - Herb Archer
- Yale New Haven Health System, CT, United States of America; Greenwich Hospital, Greenwich, CT, United States of America
| | - Elio Ragheb
- Yale University School of Medicine, New Haven, CT, United States of America
| | - Jonathan Kluger
- Yale University School of Medicine, New Haven, CT, United States of America
| | - Nitu Kashyap
- Yale University School of Medicine, New Haven, CT, United States of America; Yale New Haven Health System, CT, United States of America
| | - Carlos Paredes
- Yale University School of Medicine, New Haven, CT, United States of America; Yale New Haven Health System, CT, United States of America
| | - Prashant Patel
- Yale New Haven Health System, CT, United States of America; Lawrence & Memorial Hospital, New London, CT, United States of America
| | - Jing Lu
- Yale University School of Medicine, New Haven, CT, United States of America; Yale New Haven Health System, CT, United States of America
| | - Prakash Kandel
- Yale New Haven Health System, CT, United States of America; Lawrence & Memorial Hospital, New London, CT, United States of America
| | - Christopher Song
- Yale New Haven Health System, CT, United States of America; Lawrence & Memorial Hospital, New London, CT, United States of America
| | - Mustafa Khan
- Yale New Haven Health System, CT, United States of America; Greenwich Hospital, Greenwich, CT, United States of America
| | - Faheem Ul Haq
- Yale New Haven Health System, CT, United States of America; Bridgeport Hospital, Bridgeport, CT, United States of America
| | - Rami Ahmad
- Yale University School of Medicine, New Haven, CT, United States of America; Yale New Haven Health System, CT, United States of America
| | - Christopher Howes
- Yale New Haven Health System, CT, United States of America; Greenwich Hospital, Greenwich, CT, United States of America
| | - Brian Cambi
- Yale New Haven Health System, CT, United States of America; Lawrence & Memorial Hospital, New London, CT, United States of America
| | - Gilead Lancaster
- Yale New Haven Health System, CT, United States of America; Bridgeport Hospital, Bridgeport, CT, United States of America
| | - Michael Cleman
- Yale New Haven Health System, CT, United States of America; Greenwich Hospital, Greenwich, CT, United States of America
| | - Charles S Dela Cruz
- Yale University School of Medicine, New Haven, CT, United States of America; Yale New Haven Health System, CT, United States of America
| | - Helen Parise
- Yale University School of Medicine, New Haven, CT, United States of America
| | - Alexandra Lansky
- Yale University School of Medicine, New Haven, CT, United States of America; Yale New Haven Health System, CT, United States of America.
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Bailly L, Fabre R, Courjon J, Carles M, Dellamonica J, Pradier C. Obesity, diabetes, hypertension and severe outcomes among inpatients with coronavirus disease 2019: a nationwide study. Clin Microbiol Infect 2021; 28:114-123. [PMID: 34537362 PMCID: PMC8444420 DOI: 10.1016/j.cmi.2021.09.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 09/01/2021] [Accepted: 09/08/2021] [Indexed: 01/08/2023]
Abstract
Objectives Initial studies of individuals with coronavirus disease 2019 (COVID-19) revealed that obesity, diabetes and hypertension were associated with severe outcomes. Subsequently, some authors showed that the risk could vary according to age, gender, co-morbidities and medical history. In a nationwide retrospective cohort, we studied the association between these co-morbidities and patients' requirement for invasive mechanical ventilation (IMV) or their death. Methods All French adult inpatients with COVID-19 admitted during the first epidemic wave (February to September 2020) were included. When patients were diagnosed with obesity, diabetes or hypertension for the first time in 2020, these conditions were considered as incident co-morbidities, otherwise they were considered prevalent. We compared outcomes of IMV and in-hospital death according to obesity, diabetes and hypertension, taking age, gender and Charlson's co-morbidity index score (CCIS) into account. Results A total of 134 209 adult inpatients with COVID-19 were included, half of them had hypertension (n = 66 613, 49.6%), one in four were diabetic (n = 32 209, 24.0%), and one in four were obese (n = 32 070, 23.9%). Among this cohort, IMV was required for 13 596 inpatients, and 19 969 patients died. IMV and death were more frequent in male patients (adjusted oods ratio (aOR) 2.0, 95% CI 1.9–2.1 and aOR 1.5, 95% CI 1.4–1.5, respectively), IMV in patients with co-morbidities (aOR 2.1, 95% CI 2.0–2.2 for CCIS = 2 and aOR 3.0, 95% CI 2.8–3.1 for CCIS ≥5), and death in patients aged 80 or above (aOR 17.0, 95% CI 15.5–18.6). Adjusted on age, gender and CCIS, death was more frequent among inpatients with obesity (aOR 1.2, 95% CI 1.1–1.2) and diabetes (aOR 1.2, 95% CI 1.1–1.2). IMV was more frequently necessary for inpatients with obesity (aOR 1.9, 95% CI 1.8–2.0), diabetes (aOR 1.4, 95% CI 1.3–1.4) and hypertension (aOR 1.7, 95% CI 1.6–1.8). Comparatively, IMV was more often required for patients with the following incident co-morbidities: obesity (aOR 3.5, 95% CI 3.3–3.7), diabetes (aOR 2.0, 95% CI 1.8–2.1) and hypertension (aOR 2.5, 95% CI 2.4–2.6). Conclusions Among 134 209 inpatients with COVID-19, mortality was more frequent among patients with obesity and diabetes. IMV was more frequently necessary for inpatients with obesity, diabetes and hypertension. Patients for whom these were incident co-morbidities were particularly at risk. Specific medical monitoring and vaccination should be priorities for patients with these co-morbidities.
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Affiliation(s)
- Laurent Bailly
- Department of Public Health, University Hospital of Nice, Nice, France; Université Côte d'Azur, CHU Nice, Nice, France.
| | - Roxane Fabre
- Department of Public Health, University Hospital of Nice, Nice, France; CoBTeK Lab, Université Côte d'Azur, Nice, France
| | - Johan Courjon
- Université Côte d'Azur, Inserm, C3M, Nice, France; Department of Infectious Diseases, University Hospital of Nice, Nice, France
| | - Michel Carles
- Université Côte d'Azur, CHU Nice, Nice, France; Department of Infectious Diseases, University Hospital of Nice, Nice, France
| | - Jean Dellamonica
- Université Côte d'Azur, CHU Nice, Nice, France; Médecine Intensive Réanimation, Centre Hospitalier Universitaire de Nice, Nice, France; UR2CA, Unité de Recherche Clinique Côte d'Azur, Université Côte d'Azur, Nice, France
| | - Christian Pradier
- Department of Public Health, University Hospital of Nice, Nice, France; Université Côte d'Azur, CHU Nice, Nice, France
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Choi D, Chen Q, Goonewardena SN, Pacheco H, Mejia P, Smith RL, Rosenson RS. Efficacy of Statin Therapy in Patients with Hospital Admission for COVID-19. Cardiovasc Drugs Ther 2021; 36:1165-1173. [PMID: 34524566 PMCID: PMC8440735 DOI: 10.1007/s10557-021-07263-2] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/07/2021] [Indexed: 12/28/2022]
Abstract
PURPOSE COVID-19 is characterized by dysfunctional immune responses and metabolic derangements, which in some, lead to multi-organ failure and death. Statins are foundational lipid-lowering therapeutics for cardiovascular disease and also possess beneficial immune-modulating properties. Because of these immune-modulating properties, some have suggested their use in COVID-19. We sought to investigate the association between statin use and mortality in patients hospitalized with COVID-19. METHODS Five thousand three hundred seventy-five COVID-19 patients admitted to Mount Sinai Health System hospitals in New York between February 27, 2020, and December 3, 2020, were included in this analysis. Statin use was classified as either non-user, low-to-moderate-intensity user, or high-intensity user. Multivariate Cox proportional hazards models were used to evaluate in-hospital mortality rate. Considered covariates were age, sex, race, and comorbidities. RESULTS Compared to non-statin users, both low-to-moderate-intensity (adjusted hazard ratio; aHR 0.62, 95% confidential intervals; CI 0.51-0.76) and high-intensity statin users (aHR 0.53, 95% CI 0.43-0.65) had a reduced risk of death. Subgroup analysis of 723 coronary artery disease patients showed decreased mortality among high-intensity statin users compared to non-users (aHR 0.51, 95% CI 0.36-0.71). CONCLUSIONS Statin use in patients hospitalized with COVID-19 was associated with a reduced in-hospital mortality. The protective effect of statin was greater in those with coronary artery disease. These data support continued use of statin therapy in hospitalized patients with COVID-19. Clinical trials are needed to prospectively determine if statin use is effective in lowering the mortality in COVID-19 and other viral infections.
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Affiliation(s)
- Daein Choi
- Department of Medicine, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Qinzhong Chen
- Metabolism and Lipids Unit, Cardiovascular Institute, Marie-Josee and Henry R Kravis Center for Cardiovascular Health, Icahn School of Medicine at Mount Sinai, The Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1030, New York, NY, 10029, USA
| | - Sascha N Goonewardena
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Hannah Pacheco
- Metabolism and Lipids Unit, Cardiovascular Institute, Marie-Josee and Henry R Kravis Center for Cardiovascular Health, Icahn School of Medicine at Mount Sinai, The Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1030, New York, NY, 10029, USA
| | - Priscilla Mejia
- Metabolism and Lipids Unit, Cardiovascular Institute, Marie-Josee and Henry R Kravis Center for Cardiovascular Health, Icahn School of Medicine at Mount Sinai, The Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1030, New York, NY, 10029, USA
| | - Robin L Smith
- Clinical Associate Professor, Department of Medicine, Rutgers New Jersey Medical School and the CURA Foundation, New York, NY, USA
| | - Robert S Rosenson
- Metabolism and Lipids Unit, Cardiovascular Institute, Marie-Josee and Henry R Kravis Center for Cardiovascular Health, Icahn School of Medicine at Mount Sinai, The Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1030, New York, NY, 10029, USA.
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Ayeh SK, Abbey EJ, Khalifa BAA, Nudotor RD, Osei AD, Chidambaram V, Osuji N, Khan S, Salia EL, Oduwole MO, Yusuf HE, Lasisi O, Nosakhare E, Karakousis PC. Statins use and COVID-19 outcomes in hospitalized patients. PLoS One 2021; 16:e0256899. [PMID: 34506533 PMCID: PMC8432819 DOI: 10.1371/journal.pone.0256899] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 08/17/2021] [Indexed: 12/21/2022] Open
Abstract
Background There is an urgent need for novel therapeutic strategies for reversing COVID-19-related lung inflammation. Recent evidence has demonstrated that the cholesterol-lowering agents, statins, are associated with reduced mortality in patients with various respiratory infections. We sought to investigate the relationship between statin use and COVID-19 disease severity in hospitalized patients. Methods A retrospective analysis of COVID-19 patients admitted to the Johns Hopkins Medical Institutions between March 1, 2020 and June 30, 2020 was performed. The outcomes of interest were mortality and severe COVID-19 infection, as defined by prolonged hospital stay (≥ 7 days) and/ or invasive mechanical ventilation. Logistic regression, Cox proportional hazards regression and propensity score matching were used to obtain both univariable and multivariable associations between covariates and outcomes in addition to the average treatment effect of statin use. Results Of the 4,447 patients who met our inclusion criteria, 594 (13.4%) patients were exposed to statins on admission, of which 340 (57.2%) were male. The mean age was higher in statin users compared to non-users [64.9 ± 13.4 vs. 45.5 ± 16.6 years, p <0.001]. The average treatment effect of statin use on COVID-19-related mortality was RR = 1.00 (95% CI: 0.99–1.01, p = 0.928), while its effect on severe COVID-19 infection was RR = 1.18 (95% CI: 1.11–1.27, p <0.001). Conclusion Statin use was not associated with altered mortality, but with an 18% increased risk of severe COVID-19 infection.
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Affiliation(s)
- Samuel K. Ayeh
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Enoch J. Abbey
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Banda A. A. Khalifa
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
| | - Richard D. Nudotor
- Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Albert Danso Osei
- Department of Internal Medicine, Medstar Union Memorial Hospital, Baltimore, MD, United States of America
| | - Vignesh Chidambaram
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Ngozi Osuji
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Samiha Khan
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Emmanuella L. Salia
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, United States of America
| | - Modupe O. Oduwole
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Hasiya E. Yusuf
- Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Oluwatobi Lasisi
- Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI, United States of America
| | - Esosa Nosakhare
- Armstrong Institute for Patient Safety and Quality, Johns Hopkins Medicine, Baltimore, MD, United States of America
| | - Petros C. Karakousis
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
- * E-mail:
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COVID-19 and Acute Coronary Syndromes: From Pathophysiology to Clinical Perspectives. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:4936571. [PMID: 34484561 PMCID: PMC8410438 DOI: 10.1155/2021/4936571] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 08/09/2021] [Indexed: 02/08/2023]
Abstract
Acute coronary syndromes (ACS) are frequently reported in patients with coronavirus disease 2019 (COVID-19) and may impact patient clinical course and mortality. Although the underlying pathogenesis remains unclear, several potential mechanisms have been hypothesized, including oxygen supply/demand imbalance, direct viral cellular damage, systemic inflammatory response with cytokine-mediated injury, microvascular thrombosis, and endothelial dysfunction. The severe hypoxic state, combined with other conditions frequently reported in COVID-19, namely sepsis, tachyarrhythmias, anemia, hypotension, and shock, can induce a myocardial damage due to the mismatch between oxygen supply and demand and results in type 2 myocardial infarction (MI). In addition, COVID-19 promotes atherosclerotic plaque instability and thrombus formation and may precipitate type 1 MI. Patients with severe disease often show decrease in platelets count, higher levels of d-dimer, ultralarge von Willebrand factor multimers, tissue factor, and prolongation of prothrombin time, which reflects a prothrombotic state. An endothelial dysfunction has been described as a consequence of the direct viral effects and of the hyperinflammatory environment. The expression of tissue factor, von Willebrand factor, thromboxane, and plasminogen activator inhibitor-1 promotes the prothrombotic status. In addition, endothelial cells generate superoxide anions, with enhanced local oxidative stress, and endothelin-1, which affects the vasodilator/vasoconstrictor balance and platelet aggregation. The optimal management of COVID-19 patients is a challenge both for logistic and clinical reasons. A deeper understanding of ACS pathophysiology may yield novel research insights and therapeutic perspectives in higher cardiovascular risk subjects with COVID-19.
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Kaneko S, Takasawa K, Asada K, Shinkai N, Bolatkan A, Yamada M, Takahashi S, Machino H, Kobayashi K, Komatsu M, Hamamoto R. Epigenetic Mechanisms Underlying COVID-19 Pathogenesis. Biomedicines 2021; 9:1142. [PMID: 34572329 PMCID: PMC8466119 DOI: 10.3390/biomedicines9091142] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/27/2021] [Accepted: 08/31/2021] [Indexed: 12/11/2022] Open
Abstract
In 2019, a novel severe acute respiratory syndrome called coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was reported and was declared a pandemic by the World Health Organization (WHO) in March 2020. With the advancing development of COVID-19 vaccines and their administration globally, it is expected that COVID-19 will converge in the future; however, the situation remains unpredictable because of a series of reports regarding SARS-CoV-2 variants. Currently, there are still few specific effective treatments for COVID-19, as many unanswered questions remain regarding the pathogenic mechanism of COVID-19. Continued elucidation of COVID-19 pathogenic mechanisms is a matter of global importance. In this regard, recent reports have suggested that epigenetics plays an important role; for instance, the expression of angiotensin I converting enzyme 2 (ACE2) receptor, an important factor in human infection with SARS-CoV-2, is epigenetically regulated; further, DNA methylation status is reported to be unique to patients with COVID-19. In this review, we focus on epigenetic mechanisms to provide a new molecular framework for elucidating the pathogenesis of SARS-CoV-2 infection in humans and of COVID-19, along with the possibility of new diagnostic and therapeutic strategies.
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Affiliation(s)
- Syuzo Kaneko
- Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (S.K.); (K.T.); (K.A.); (N.S.); (A.B.); (M.Y.); (S.T.); (H.M.); (K.K.); (M.K.)
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan
| | - Ken Takasawa
- Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (S.K.); (K.T.); (K.A.); (N.S.); (A.B.); (M.Y.); (S.T.); (H.M.); (K.K.); (M.K.)
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan
| | - Ken Asada
- Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (S.K.); (K.T.); (K.A.); (N.S.); (A.B.); (M.Y.); (S.T.); (H.M.); (K.K.); (M.K.)
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan
| | - Norio Shinkai
- Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (S.K.); (K.T.); (K.A.); (N.S.); (A.B.); (M.Y.); (S.T.); (H.M.); (K.K.); (M.K.)
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan
- Department of NCC Cancer Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Amina Bolatkan
- Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (S.K.); (K.T.); (K.A.); (N.S.); (A.B.); (M.Y.); (S.T.); (H.M.); (K.K.); (M.K.)
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan
| | - Masayoshi Yamada
- Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (S.K.); (K.T.); (K.A.); (N.S.); (A.B.); (M.Y.); (S.T.); (H.M.); (K.K.); (M.K.)
- National Cancer Center Hospital, Department of Endoscopy, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Satoshi Takahashi
- Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (S.K.); (K.T.); (K.A.); (N.S.); (A.B.); (M.Y.); (S.T.); (H.M.); (K.K.); (M.K.)
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan
| | - Hidenori Machino
- Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (S.K.); (K.T.); (K.A.); (N.S.); (A.B.); (M.Y.); (S.T.); (H.M.); (K.K.); (M.K.)
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan
| | - Kazuma Kobayashi
- Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (S.K.); (K.T.); (K.A.); (N.S.); (A.B.); (M.Y.); (S.T.); (H.M.); (K.K.); (M.K.)
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan
| | - Masaaki Komatsu
- Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (S.K.); (K.T.); (K.A.); (N.S.); (A.B.); (M.Y.); (S.T.); (H.M.); (K.K.); (M.K.)
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan
| | - Ryuji Hamamoto
- Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (S.K.); (K.T.); (K.A.); (N.S.); (A.B.); (M.Y.); (S.T.); (H.M.); (K.K.); (M.K.)
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan
- Department of NCC Cancer Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
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Diaz-Arocutipa C, Melgar-Talavera B, Alvarado-Yarasca Á, Saravia-Bartra MM, Cazorla P, Belzusarri I, Hernandez AV. Statins reduce mortality in patients with COVID-19: an updated meta-analysis of 147 824 patients. Int J Infect Dis 2021; 110:374-381. [PMID: 34375760 PMCID: PMC8349445 DOI: 10.1016/j.ijid.2021.08.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/22/2021] [Accepted: 08/04/2021] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVES There is conflicting evidence about the efficacy of statin use in regard to clinical outcomes in patients with coronavirus disease 2019 (COVID-19). A systematic review and meta-analysis was performed to examine the effect of statin use on mortality in COVID-19 patients. METHODS The electronic databases were searched, from inception to March 3, 2021. Unadjusted and adjusted effect estimates with their 95% confidence intervals (95% CI) were pooled using random-effects models. RESULTS Twenty-five cohort studies involving 147 824 patients were included. The mean age of the patients ranged from 44.9 to 70.9 years; 57% of patients were male and 43% were female. The use of statins was not associated with mortality when applying the unadjusted risk ratio (uRR 1.16, 95% CI 0.86-1.57; 19 studies). In contrast, meta-analyses of the adjusted odds ratio (aOR 0.67, 95% CI 0.52-0.86; 11 studies) and adjusted hazard ratio (aHR 0.73, 95% CI 0.58-0.91; 10 studies) showed that statins were independently associated with a significant reduction in mortality. Subgroup analyses showed that only chronic use of statins significantly reduced mortality according to the adjusted models. CONCLUSIONS The use of statins was found to be associated with a lower risk of mortality in COVID-19 patients based on adjusted effects of cohort studies. However, randomized controlled trials are still needed to confirm these findings.
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Affiliation(s)
- Carlos Diaz-Arocutipa
- Vicerrectorado de Investigación, Universidad San Ignacio de Loyola, Lima, Peru; Programa de Atencion Domiciliaria - EsSalud, Lima, Peru; Asociación para el Desarrollo de la Investigación Estudiantil en Ciencias de la Salud (ADIECS), Lima, Peru.
| | | | - Ángel Alvarado-Yarasca
- International Research Network in Pharmacology and Precision Medicine, Human Medicine, Universidad San Ignacio de Loyola, Lima, Peru
| | - María M Saravia-Bartra
- International Research Network in Pharmacology and Precision Medicine, Human Medicine, Universidad San Ignacio de Loyola, Lima, Peru
| | - Pedro Cazorla
- International Research Network in Pharmacology and Precision Medicine, Human Medicine, Universidad San Ignacio de Loyola, Lima, Peru; Servicio de Pediatria, Hospital III Suarez-Angamos - EsSalud, Lima, Peru
| | - Iván Belzusarri
- International Research Network in Pharmacology and Precision Medicine, Human Medicine, Universidad San Ignacio de Loyola, Lima, Peru
| | - Adrian V Hernandez
- Vicerrectorado de Investigación, Universidad San Ignacio de Loyola, Lima, Peru; Health Outcomes, Policy, and Evidence Synthesis (HOPES) Group, University of Connecticut School of Pharmacy, Storrs, Connecticut, USA
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Zhang XB, Cheng HJ, Yuan YT, Chen Y, Chen YY, Chiu KY, Zeng HQ. Atorvastatin attenuates intermittent hypoxia-induced myocardial oxidative stress in a mouse obstructive sleep apnea model. Aging (Albany NY) 2021; 13:18870-18878. [PMID: 34289453 PMCID: PMC8351704 DOI: 10.18632/aging.203339] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 07/09/2021] [Indexed: 12/15/2022]
Abstract
Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea (OSA), is associated with various cardiovascular diseases. In the present study, we assessed the effect of the lipid reducing agent atorvastatin on CIH-induced myocardial oxidative stress and apoptosis in a mouse OSA model. Forty-eight C57BL/6J mice were evenly divided among normoxia + vehicle, normoxia + atorvastatin, CIH + vehicle, and CIH + atorvastatin groups. CIH consisted of a hypoxia-reoxygenation cycle in which oxygen concentrations fluctuated from 21% to 6% and back over two minutes for 8 hours each day (30 events/hour). CIH exposure continued for 12 weeks. Atorvastatin (5 mg/kg) was administered from week 6 through the end of the experiment. CIH increased malondialdehyde levels and decreased superoxide dismutase activity, total antioxidant capacity, and nuclear factor erythroid 2-related factor 2 levels in cardiac tissue, indicating a reduction in antioxidant activity. Atorvastatin significantly reversed those effects (p < 0.05). CIH also increased B-cell lymphoma 2-associated protein X and cleaved caspased-3 levels as well as the myocardial apoptotic rate, as indicated by terminal deoxynucleotidyl transferase dUTP nick-end labeling. Atorvastatin had no effect on those changes (p > 0.05). Thus, atorvastatin administration exerts antioxidant but not anti-apoptotic effects after CIH and may therefore have therapeutic potential in OSA patients with cardiovascular comorbidities.
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Affiliation(s)
- Xiao-Bin Zhang
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, Fujian Province, People's Republic of China
| | - Hui-Juan Cheng
- Department of Medical Affairs, Zhongshan Hospital, Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, Fujian Province, People's Republic of China
| | - Ya-Ting Yuan
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, Fujian Province, People's Republic of China
| | - Yan Chen
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, Fujian Province, People's Republic of China
| | - Yi-Yuan Chen
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, Fujian Province, People's Republic of China
| | - Kam Yu Chiu
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, Fujian Province, People's Republic of China
| | - Hui-Qing Zeng
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, Fujian Province, People's Republic of China
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Kiaie N, Gorabi AM, Reiner Ž, Jamialahmadi T, Ruscica M, Sahebkar A. Effects of Statins on Renin-Angiotensin System. J Cardiovasc Dev Dis 2021; 8:80. [PMID: 34357323 PMCID: PMC8305238 DOI: 10.3390/jcdd8070080] [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: 05/19/2021] [Revised: 07/02/2021] [Accepted: 07/05/2021] [Indexed: 12/16/2022] Open
Abstract
Statins, a class of drugs for lowering serum LDL-cholesterol, have attracted attention because of their wide range of pleiotropic effects. An important but often neglected effect of statins is their role in the renin-angiotensin system (RAS) pathway. This pathway plays an integral role in the progression of several diseases including hypertension, heart failure, and renal disease. In this paper, the role of statins in the blockade of different components of this pathway and the underlying mechanisms are reviewed and new therapeutic possibilities of statins are suggested.
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Affiliation(s)
- Nasim Kiaie
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran 1411713138, Iran; (N.K.); (A.M.G.)
| | - Armita Mahdavi Gorabi
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran 1411713138, Iran; (N.K.); (A.M.G.)
| | - Željko Reiner
- Department of Internal Diseases, School of Medicine, University Hospital Center Zagreb, Zagreb University, 10000 Zagreb, Croatia;
| | - Tannaz Jamialahmadi
- Quchan Branch, Department of Food Science and Technology, Islamic Azad University, Quchan 9479176135, Iran;
- Department of Nutrition, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
| | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy;
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
- School of Medicine, The University of Western Australia, Perth 6009, Australia
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
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Yetmar ZA, Chesdachai S, Kashour T, Riaz M, Gerberi DJ, Badley AD, Berbari EF, Tleyjeh IM. Prior Statin Use and Risk of Mortality and Severe Disease From Coronavirus Disease 2019: A Systematic Review and Meta-analysis. Open Forum Infect Dis 2021; 8:ofab284. [PMID: 34258316 PMCID: PMC8244756 DOI: 10.1093/ofid/ofab284] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 05/26/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Statins up-regulate angiotensin-converting enzyme 2, the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), while also exhibiting pleiotropic antiviral, antithrombotic, and anti-inflammatory properties. Uncertainties exist about their effect on the course of SARS-CoV-2 infection. We sought to systematically review the literature and perform a meta-analysis to examine the association between prior statin use and outcomes of patients with coronavirus disease 2019 (COVID-19). METHODS We searched Ovid Medline, Web of Science, Scopus, and the preprint server medRxiv from inception to December 2020. We assessed the quality of eligible studies with the Newcastle-Ottawa quality scale. We pooled adjusted relative risk (aRRs) of the association between prior statin use and outcomes of patients with COVID-19 using the DerSimonian-Laird random-effects model and assessed heterogeneity using the I 2 index. RESULTS Overall, 19 (16 cohorts and 3 case-control) studies were eligible, with a total of 395 513 patients. Sixteen of 19 studies had low or moderate risk of bias. Among 109 080 patients enrolled in 13 separate studies, prior statin use was associated with a lower risk of mortality (pooled aRR, 0.65 [95% confidence interval {CI}, .56-.77], I 2 = 84.1%) and a reduced risk of severe COVID-19 was also observed in 48 110 patients enrolled in 9 studies (pooled aRR, 0.73 [95% CI, .57-.94], I 2 = 82.8%), with no evidence of publication bias. CONCLUSIONS Cumulative evidence suggests that prior statin use is associated with lower risks of mortality or severe disease in patients with COVID-19. These data support the continued use of statins medications in patients with an indication for lipid-lowering therapy during the COVID-19 pandemic.
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Affiliation(s)
- Zachary A Yetmar
- Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Tarek Kashour
- Department of Cardiac Sciences, King Fahad Cardiac Center, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Muhammad Riaz
- Department of Public Health, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | | | - Andrew D Badley
- Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Elie F Berbari
- Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - Imad M Tleyjeh
- Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA
- Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
- Infectious Diseases Section, Department of Medical Specialties, King Fahad Medical City, Riyadh, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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Orlowski S, Mourad JJ, Gallo A, Bruckert E. Coronaviruses, cholesterol and statins: Involvement and application for Covid-19. Biochimie 2021; 189:51-64. [PMID: 34153377 PMCID: PMC8213520 DOI: 10.1016/j.biochi.2021.06.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/01/2021] [Accepted: 06/14/2021] [Indexed: 12/17/2022]
Abstract
The infectious power of coronaviruses is dependent on cholesterol present in the membranes of their target cells. Indeed, the virus enters the infected cell either by fusion or by endocytosis, in both cases involving cholesterol-enriched membrane microdomains. These membrane domains can be disorganized in-vitro by various cholesterol-altering agents, including statins that inhibit cell cholesterol biosynthesis. As a consequence, numerous cell physiology processes, such as signaling cascades, can be compromised. Also, some examples of anti-bacterial and anti-viral effects of statins have been observed for infectious agents known to be cholesterol dependent. In-vivo, besides their widely-reported hypocholesterolemic effect, statins display various pleiotropic effects mediated, at least partially, by perturbation of membrane microdomains as a consequence of the alteration of endogenous cholesterol synthesis. It should thus be worth considering a high, but clinically well-tolerated, dose of statin to treat Covid-19 patients, in the early phase of infection, to inhibit virus entry into the target cells, in order to control the viral charge and hence avoid severe clinical complications. Based on its efficacy and favorable biodisposition, an option would be considering Atorvastatin, but randomized controlled clinical trials are required to test this hypothesis. This new therapeutic proposal takes benefit from being a drug repurposing, applied to a widely-used drug presenting a high efficiency-to-toxicity ratio. Additionally, this therapeutic strategy avoids any risk of drug resistance by viral mutation since it is host-targeted. Noteworthy, the same pharmacological approach could also be proposed to address different animal coronavirus endemic infections that are responsible for heavy economic losses.
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Affiliation(s)
- Stéphane Orlowski
- Institute for Integrative Biology of the Cell (I2BC), CNRS UMR 9198, and CEA / DRF / Institut des Sciences du Vivant Frédéric-Joliot / SB2SM, and Université Paris-Saclay, 91191, Gif-sur-Yvette, Cedex, France.
| | - Jean-Jacques Mourad
- Department of Internal Medicine and ESH Excellence Centre, Groupe Hospitalier Paris Saint-Joseph, Paris, France.
| | - Antonio Gallo
- Department of Endocrinology and Prevention of Cardiovascular Diseases, Institute of Cardiometabolism and Nutrition (ICAN), La Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
| | - Eric Bruckert
- Department of Endocrinology and Prevention of Cardiovascular Diseases, Institute of Cardiometabolism and Nutrition (ICAN), La Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
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