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1.
Cell Metab ; 34(3): 424-440.e7, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1676683

ABSTRACT

Coronavirus disease 2019 (COVID-19) represents a systemic disease that may cause severe metabolic complications in multiple tissues including liver, kidney, and cardiovascular system. However, the underlying mechanisms and optimal treatment remain elusive. Our study shows that impairment of ACE2 pathway is a key factor linking virus infection to its secondary metabolic sequelae. By using structure-based high-throughput virtual screening and connectivity map database, followed with experimental validations, we identify imatinib, methazolamide, and harpagoside as direct enzymatic activators of ACE2. Imatinib and methazolamide remarkably improve metabolic perturbations in vivo in an ACE2-dependent manner under the insulin-resistant state and SARS-CoV-2-infected state. Moreover, viral entry is directly inhibited by these three compounds due to allosteric inhibition of ACE2 binding to spike protein on SARS-CoV-2. Taken together, our study shows that enzymatic activation of ACE2 via imatinib, methazolamide, or harpagoside may be a conceptually new strategy to treat metabolic sequelae of COVID-19.


Subject(s)
COVID-19/drug therapy , Imatinib Mesylate/therapeutic use , Metabolic Diseases/drug therapy , Methazolamide/therapeutic use , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/complications , COVID-19/metabolism , COVID-19/virology , Cells, Cultured , Chlorocebus aethiops , Down-Regulation/drug effects , HEK293 Cells , Human Umbilical Vein Endothelial Cells , Humans , Imatinib Mesylate/pharmacology , Male , Metabolic Diseases/metabolism , Metabolic Diseases/virology , Methazolamide/pharmacology , Mice , Mice, Inbred C57BL , Mice, Obese , Mice, Transgenic , SARS-CoV-2/physiology , Vero Cells , Virus Internalization/drug effects
2.
Lancet Diabetes Endocrinol ; 9(11): 786-798, 2021 11.
Article in English | MEDLINE | ID: covidwho-1586178

ABSTRACT

Up to 50% of the people who have died from COVID-19 had metabolic and vascular disorders. Notably, there are many direct links between COVID-19 and the metabolic and endocrine systems. Thus, not only are patients with metabolic dysfunction (eg, obesity, hypertension, non-alcoholic fatty liver disease, and diabetes) at an increased risk of developing severe COVID-19 but also infection with SARS-CoV-2 might lead to new-onset diabetes or aggravation of pre-existing metabolic disorders. In this Review, we provide an update on the mechanisms of how metabolic and endocrine disorders might predispose patients to develop severe COVID-19. Additionally, we update the practical recommendations and management of patients with COVID-19 and post-pandemic. Furthermore, we summarise new treatment options for patients with both COVID-19 and diabetes, and highlight current challenges in clinical management.


Subject(s)
COVID-19/epidemiology , COVID-19/metabolism , Disease Management , Metabolic Diseases/epidemiology , Metabolic Diseases/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/therapy , Diabetes Mellitus/epidemiology , Diabetes Mellitus/metabolism , Diabetes Mellitus/therapy , Humans , Hypertension/epidemiology , Hypertension/metabolism , Hypertension/therapy , Metabolic Diseases/therapy , Non-alcoholic Fatty Liver Disease/epidemiology , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/therapy , Obesity/epidemiology , Obesity/metabolism , Obesity/therapy
3.
Mol Metab ; 55: 101409, 2022 01.
Article in English | MEDLINE | ID: covidwho-1540868

ABSTRACT

BACKGROUND: Chronic disease appears connected to obesity. However, evidence suggests that chronic metabolic diseases are more specifically related to adipose dysfunction rather than to body weight itself. SCOPE OF REVIEW: Further study of the first generation "insulin sensitizer" pioglitazone and molecules based on its structure suggests that is possible to decouple body weight from the metabolic dysfunction that drives adverse outcomes. The growing understanding of the mechanism of action of these agents together with advances in the pathophysiology of chronic metabolic disease offers a new approach to treat chronic conditions, such as type 2 diabetes, fatty liver disease, and their common organ and vascular sequelae. MAJOR CONCLUSIONS: We hypothesize that treating adipocyte dysfunction with new insulin sensitizers might significantly impact the interface of infectious disease and chronic metabolic disease.


Subject(s)
Chronic Disease/drug therapy , Metabolic Syndrome/drug therapy , Metabolic Syndrome/metabolism , Thiazolidinediones/pharmacology , Adipose Tissue/metabolism , COVID-19 , Diabetes Mellitus, Type 2/metabolism , Humans , Inflammation , Insulin/metabolism , Insulin Resistance , Metabolic Diseases/metabolism , Mitochondria , Non-alcoholic Fatty Liver Disease , Pioglitazone/metabolism
4.
Front Immunol ; 12: 732913, 2021.
Article in English | MEDLINE | ID: covidwho-1504188

ABSTRACT

Obesity prevails worldwide to an increasing effect. For example, up to 42% of American adults are considered obese. Obese individuals are prone to a variety of complications of metabolic disorders including diabetes mellitus, hypertension, cardiovascular disease, and chronic kidney disease. Recent meta-analyses of clinical studies in patient cohorts in the ongoing coronavirus-disease 2019 (COVID-19) pandemic indicate that the presence of obesity and relevant disorders is linked to a more severe prognosis of COVID-19. Given the significance of obesity in COVID-19 progression, we provide a review of host metabolic and immune responses in the immunometabolic dysregulation exaggerated by obesity and the viral infection that develops into a severe course of COVID-19. Moreover, sequela studies of individuals 6 months after having COVID-19 show a higher risk of metabolic comorbidities including obesity, diabetes, and kidney disease. These collectively implicate an inter-systemic dimension to understanding the association between obesity and COVID-19 and suggest an interdisciplinary intervention for relief of obesity-COVID-19 complications beyond the phase of acute infection.


Subject(s)
COVID-19/immunology , COVID-19/metabolism , Obesity/immunology , Obesity/metabolism , COVID-19/complications , Disease Progression , Host-Pathogen Interactions/immunology , Humans , Immunity , Metabolic Diseases/immunology , Metabolic Diseases/metabolism , Obesity/complications , Prognosis , SARS-CoV-2/pathogenicity , Severity of Illness Index
5.
Biomolecules ; 11(5)2021 05 11.
Article in English | MEDLINE | ID: covidwho-1299401

ABSTRACT

Lipoxygenases (LOXs) are lipid metabolizing enzymes that catalyze the di-oxygenation of polyunsaturated fatty acids to generate active eicosanoid products. 12-lipoxygenases (12-LOXs) primarily oxygenate the 12th carbon of its substrates. Many studies have demonstrated that 12-LOXs and their eicosanoid metabolite 12-hydroxyeicosatetraenoate (12-HETE), have significant pathological implications in inflammatory diseases. Increased level of 12-LOX activity promotes stress (both oxidative and endoplasmic reticulum)-mediated inflammation, leading to damage in these tissues. 12-LOXs are also associated with enhanced cellular migration of immune cells-a characteristic of several metabolic and autoimmune disorders. Genetic depletion or pharmacological inhibition of the enzyme in animal models of various diseases has shown to be protective against disease development and/or progression in animal models in the setting of diabetes, pulmonary, cardiovascular, and metabolic disease, suggesting a translational potential of targeting the enzyme for the treatment of several disorders. In this article, we review the role of 12-LOXs in the pathogenesis of several diseases in which chronic inflammation plays an underlying role.


Subject(s)
Arachidonate 12-Lipoxygenase/metabolism , Inflammation/immunology , Metabolic Diseases/immunology , Animals , Arachidonate 12-Lipoxygenase/genetics , Humans , Inflammation/metabolism , Inflammation/pathology , Lipid Metabolism , Metabolic Diseases/metabolism , Metabolic Diseases/pathology , Oxidation-Reduction
6.
Mol Genet Metab ; 132(2): S2-S6, 2021 02.
Article in English | MEDLINE | ID: covidwho-1091577
7.
Clin Sci (Lond) ; 135(3): 535-554, 2021 02 12.
Article in English | MEDLINE | ID: covidwho-1060922

ABSTRACT

The renin-angiotensin system (RAS) has currently attracted increasing attention due to its potential function in regulating energy homeostasis, other than the actions on cellular growth, blood pressure, fluid, and electrolyte balance. The existence of RAS is well established in metabolic organs, including pancreas, liver, skeletal muscle, and adipose tissue, where activation of angiotensin-converting enzyme (ACE) - angiotensin II pathway contributes to the impairment of insulin secretion, glucose transport, fat distribution, and adipokines production. However, the activation of angiotensin-converting enzyme 2 (ACE2) - angiotensin (1-7) pathway, a novel branch of the RAS, plays an opposite role in the ACE pathway, which could reverse these consequences by improving local microcirculation, inflammation, stress state, structure remolding, and insulin signaling pathway. In addition, new studies indicate the protective RAS arm possesses extraordinary ability to enhance brown adipose tissue (BAT) activity and induces browning of white adipose tissue, and consequently, it leads to increased energy expenditure in the form of heat instead of ATP synthesis. Interestingly, ACE2 is the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is threating public health worldwide. The main complications of SARS-CoV-2 infected death patients include many energy metabolism-related chronic diseases, such as diabetes. The specific mechanism leading to this phenomenon is largely unknown. Here, we summarize the latest pharmacological and genetic tools on regulating ACE/ACE2 balance and highlight the beneficial effects of the ACE2 pathway axis hyperactivity on glycolipid metabolism, as well as the thermogenic modulation.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/enzymology , Metabolic Diseases/enzymology , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Energy Metabolism , Humans , Metabolic Diseases/genetics , Metabolic Diseases/metabolism , Metabolic Diseases/virology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Renin-Angiotensin System , SARS-CoV-2/physiology
8.
Microbes Infect ; 23(2-3): 104780, 2021.
Article in English | MEDLINE | ID: covidwho-1039496

ABSTRACT

This review portrays the metabolic consequences of Covid-19 infection at different stages of the clinical syndrome. It also describes how events can change when patients with metabolic problems are infected and the effects that diet and nutrition might play to influence the outcome of infection. We also discuss the types of maneuvers that could be used to reshape metabolic events and question if this approach could be a practical therapy used alone or in combination with other approaches to reduce the burden of Covid-19 infection.


Subject(s)
COVID-19/metabolism , COVID-19/prevention & control , COVID-19/complications , COVID-19/pathology , Diet , Disease Susceptibility/complications , Disease Susceptibility/metabolism , Disease Susceptibility/pathology , Humans , Metabolic Diseases/complications , Metabolic Diseases/immunology , Metabolic Diseases/metabolism , Nutritional Status , Obesity/complications , Obesity/immunology , Obesity/metabolism , SARS-CoV-2/pathogenicity
9.
Curr Neurovasc Res ; 17(5): 765-783, 2020.
Article in English | MEDLINE | ID: covidwho-922756

ABSTRACT

Metabolic disorders that include diabetes mellitus present significant challenges for maintaining the welfare of the global population. Metabolic diseases impact all systems of the body and despite current therapies that offer some protection through tight serum glucose control, ultimately such treatments cannot block the progression of disability and death realized with metabolic disorders. As a result, novel therapeutic avenues are critical for further development to address these concerns. An innovative strategy involves the vitamin nicotinamide and the pathways associated with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and clock genes. Nicotinamide maintains an intimate relationship with these pathways to oversee metabolic disease and improve glucose utilization, limit mitochondrial dysfunction, block oxidative stress, potentially function as antiviral therapy, and foster cellular survival through mechanisms involving autophagy. However, the pathways of nicotinamide, SIRT1, mTOR, AMPK, and clock genes are complex and involve feedback pathways as well as trophic factors such as erythropoietin that require a careful balance to ensure metabolic homeostasis. Future work is warranted to gain additional insight into these vital pathways that can oversee both normal metabolic physiology and metabolic disease.


Subject(s)
Circadian Clocks/genetics , Metabolic Diseases/genetics , Niacinamide/genetics , Sirtuin 1/genetics , TOR Serine-Threonine Kinases/genetics , Animals , Humans , Metabolic Diseases/diagnosis , Metabolic Diseases/metabolism , Niacinamide/metabolism , Sirtuin 1/metabolism , TOR Serine-Threonine Kinases/metabolism
10.
Nat Commun ; 11(1): 5165, 2020 10 14.
Article in English | MEDLINE | ID: covidwho-872694

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) has been identified as the host entry receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the COVID-19 pandemic. ACE2 is a regulatory enzyme of the renin-angiotensin system and has protective functions in many cardiovascular, pulmonary and metabolic diseases. This review summarizes available murine models with systemic or organ-specific deletion of ACE2, or with overexpression of murine or human ACE2. The purpose of this review is to provide researchers with the genetic tools available for further understanding of ACE2 biology and for the investigation of ACE2 in the pathogenesis and treatment of COVID-19.


Subject(s)
Cardiovascular Diseases/pathology , Disease Models, Animal , Lung Diseases/pathology , Peptidyl-Dipeptidase A/metabolism , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/physiology , COVID-19 , Cardiovascular Diseases/metabolism , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Lung Diseases/metabolism , Metabolic Diseases/metabolism , Metabolic Diseases/pathology , Mice , Mice, Mutant Strains , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2
11.
Cardiovasc Diabetol ; 19(1): 164, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-810407

ABSTRACT

BACKGROUND: Cardiometabolic disorders may worsen Covid-19 outcomes. We investigated features and Covid-19 outcomes for patients with or without diabetes, and with or without cardiometabolic multimorbidity. METHODS: We collected and compared data retrospectively from patients hospitalized for Covid-19 with and without diabetes, and with and without cardiometabolic multimorbidity (defined as ≥ two of three risk factors of diabetes, hypertension or dyslipidaemia). Multivariate logistic regression was used to assess the risk of the primary composite outcome (any of mechanical ventilation, admission to an intensive care unit [ICU] or death) in patients with diabetes and in those with cardiometabolic multimorbidity, adjusting for confounders. RESULTS: Of 354 patients enrolled, those with diabetes (n = 81), compared with those without diabetes (n = 273), had characteristics associated with the primary composite outcome that included older age, higher prevalence of hypertension and chronic obstructive pulmonary disease (COPD), higher levels of inflammatory markers and a lower PaO2/FIO2 ratio. The risk of the primary composite outcome in the 277 patients who completed the study as of May 15th, 2020, was higher in those with diabetes (Adjusted Odds Ratio (adjOR) 2.04, 95%CI 1.12-3.73, p = 0.020), hypertension (adjOR 2.31, 95%CI: 1.37-3.92, p = 0.002) and COPD (adjOR 2.67, 95%CI 1.23-5.80, p = 0.013). Patients with cardiometabolic multimorbidity were at higher risk compared to patients with no cardiometabolic conditions (adjOR 3.19 95%CI 1.61-6.34, p = 0.001). The risk for patients with a single cardiometabolic risk factor did not differ with that for patients with no cardiometabolic risk factors (adjOR 1.66, 0.90-3.06, adjp = 0.10). CONCLUSIONS: Patients with diabetes hospitalized for Covid-19 present with high-risk features. They are at increased risk of adverse outcomes, likely because diabetes clusters with other cardiometabolic conditions.


Subject(s)
Betacoronavirus , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Diabetes Mellitus/diagnosis , Diabetes Mellitus/epidemiology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Aged , Aged, 80 and over , COVID-19 , Cardiovascular Diseases/metabolism , Coronavirus Infections/metabolism , Diabetes Mellitus/metabolism , Female , Follow-Up Studies , Humans , Male , Metabolic Diseases/diagnosis , Metabolic Diseases/epidemiology , Metabolic Diseases/metabolism , Middle Aged , Multimorbidity/trends , Pandemics , Pneumonia, Viral/metabolism , Prognosis , Retrospective Studies , Risk Factors , SARS-CoV-2
12.
Nat Metab ; 2(7): 572-585, 2020 07.
Article in English | MEDLINE | ID: covidwho-643353

ABSTRACT

For infectious-disease outbreaks, clinical solutions typically focus on efficient pathogen destruction. However, the COVID-19 pandemic provides a reminder that infectious diseases are complex, multisystem conditions, and a holistic understanding will be necessary to maximize survival. For COVID-19 and all other infectious diseases, metabolic processes are intimately connected to the mechanisms of disease pathogenesis and the resulting pathology and pathophysiology, as well as the host defence response to the infection. Here, I examine the relationship between metabolism and COVID-19. I discuss why preexisting metabolic abnormalities, such as type 2 diabetes and hypertension, may be important risk factors for severe and critical cases of infection, highlighting parallels between the pathophysiology of these metabolic abnormalities and the disease course of COVID-19. I also discuss how metabolism at the cellular, tissue and organ levels might be harnessed to promote defence against the infection, with a focus on disease-tolerance mechanisms, and speculate on the long-term metabolic consequences for survivors of COVID-19.


Subject(s)
Coronavirus Infections/complications , Coronavirus Infections/metabolism , Metabolic Diseases/etiology , Metabolic Diseases/metabolism , Pneumonia, Viral/complications , Pneumonia, Viral/metabolism , COVID-19 , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/physiopathology , Humans , Hypertension/complications , Hypertension/physiopathology , Pandemics , Risk Factors
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