Towards Neuro-CoViD-19.

CoViD-19 is the current pandemic caused by the Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2). Infection by SARS-CoV-2 occurs via the binding of its S protein to the angiotensin-converting enzyme-2 receptor (ACE2-R). S binding to ACE2-R leads to a drop in ACE2, a homolog of angiotensin converting enzyme (ACE). In the central nervous system (CNS), ACE mediates neuroinflammation, neurodegeneration and neurotoxicity responsible for several CNS disorders. ACE2 counteracts the damaging effects of ACE on CNS neurons. SARS-CoV-2 can directly access the CNS via the circulation or via cranial nerve I and the olfactory bulb. Inactivation of ACE2 following binding of SARS-CoV-2 S protein to ACE2-R in situ might blunt ACE2-moderating effects upon ACE CNS neurotoxicity and neurodegeneration. Here, we propose a neurobiological mechanism directly involving SARS-CoV-2 binding to ACE2-R in the etiology of putative Neuro-CoViD-19.

Mechanisms of Atrial Fibrillation in Covid-19

Atrial fibrillation (AF) is the most frequent form of cardiac arrhythmia in COVID-19 infected patients. The occurrence of AF paroxysms is often associated with the acute period of infection in time. At the same time, the pathophysiological mechanisms of the occurrence of AF associated with COVID-19 remain insufficiently studied. The review considers the available literature data on the influence of factors such as reduced availability of angiotensin-converting enzyme 2 receptors, interaction of the virus with the cluster of differentiation 147 and sialic acid, increased inflammatory signaling, "cytokine storm", direct viral damage to the endothelium, electrolyte and acid-alkaline balance in the acute phase of severe illness and increased sympathetic activity.Copyright © Autors 2023.

Progress on cross-species infection mechanism of 2019-nCoV and antiviral drug research.

2019-nCoV has a up to 96% homology with the gene sequence of a bat coronavirus. By comparing its 7 conserved non-structural proteins, it is found that 2019-nCoV belongs to SARS related coronaviruses(SARSr-CoV). The receptor for 2019-nCoV entering cells is the same as that for SARSr-CoV, and angiotensin-converting enzyme 2 (ACE2) is a common cross-genus receptor. This article first elaborates the interspecies transmission and genetic variation, then briefly discusses the receptors on the surface of human cells (such as ACE2 and APP4), which cause human infection and encode five proteins in the viral genome, therefore are important targets for development of antiviral drugs. The article reviews eight promising anti-coronavirus drugs, including three anti-HIV drugs (Lopinavir/Ritonavir, Danoprevir/Ritonavir, Darunavir), two anti-Ebola virus drugs (Remdesivir, Galidesivir), two anti-influenza virus drugs (Arbidol, Favipiravir) and one anti-malarial drug (chloroquine phosphate). Among them, Remdesivir, Abidol and Favipiravir have strong inhibitory effects on 2019-nCoV, they may be the most promising drugs under investigation.Copyright © 2020 by the Chinese Medical Association.

Progress on cross-species infection mechanism of 2019-nCoV and antiviral drug research.

2019-nCoV has a up to 96% homology with the gene sequence of a bat coronavirus. By comparing its 7 conserved non-structural proteins, it is found that 2019-nCoV belongs to SARS related coronaviruses(SARSr-CoV). The receptor for 2019-nCoV entering cells is the same as that for SARSr-CoV, and angiotensin-converting enzyme 2 (ACE2) is a common cross-genus receptor. This article first elaborates the interspecies transmission and genetic variation, then briefly discusses the receptors on the surface of human cells (such as ACE2 and APP4), which cause human infection and encode five proteins in the viral genome, therefore are important targets for development of antiviral drugs. The article reviews eight promising anti-coronavirus drugs, including three anti-HIV drugs (Lopinavir/Ritonavir, Danoprevir/Ritonavir, Darunavir), two anti-Ebola virus drugs (Remdesivir, Galidesivir), two anti-influenza virus drugs (Arbidol, Favipiravir) and one anti-malarial drug (chloroquine phosphate). Among them, Remdesivir, Abidol and Favipiravir have strong inhibitory effects on 2019-nCoV, they may be the most promising drugs under investigation.Copyright © 2020 by the Chinese Medical Association.

Progress on cross-species infection mechanism of 2019-nCoV and antiviral drug research.

2019-nCoV has a up to 96% homology with the gene sequence of a bat coronavirus. By comparing its 7 conserved non-structural proteins, it is found that 2019-nCoV belongs to SARS related coronaviruses(SARSr-CoV). The receptor for 2019-nCoV entering cells is the same as that for SARSr-CoV, and angiotensin-converting enzyme 2 (ACE2) is a common cross-genus receptor. This article first elaborates the interspecies transmission and genetic variation, then briefly discusses the receptors on the surface of human cells (such as ACE2 and APP4), which cause human infection and encode five proteins in the viral genome, therefore are important targets for development of antiviral drugs. The article reviews eight promising anti-coronavirus drugs, including three anti-HIV drugs (Lopinavir/Ritonavir, Danoprevir/Ritonavir, Darunavir), two anti-Ebola virus drugs (Remdesivir, Galidesivir), two anti-influenza virus drugs (Arbidol, Favipiravir) and one anti-malarial drug (chloroquine phosphate). Among them, Remdesivir, Abidol and Favipiravir have strong inhibitory effects on 2019-nCoV, they may be the most promising drugs under investigation.Copyright © 2020 by the Chinese Medical Association.

Evaluation of the Association between Multilobar Involvement and ACE Inhibitor Use in SARS-CoV-2 Patients

Aim: Angiotensin-converting enzyme 2 (ACE2) acts not only as an enzyme but also as a thought to be central receptor by which severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters host cells. Angiotensin-converting enzyme inhibitors (ACEIs) are thought to $1 are central to SARS-CoV-2 progression. However, its effect on clinical outcomes is still not fully explained. In this study, we investigated the effects of ACEIs use on pulmonary computed tomography findings. Method(s): The data of the patients who were hospitalized for SARS-CoV-2 pneumonia and were using medications for the diagnosis of hypertension from 20th March to 20th June 2020 were evaluated retrospectively. Patients were divided into 2 groups patients using ACEIs and not using ACEIs. Result(s): The study was conducted with 107 patients. Mild cases without signs of pneumonia were excluded from this study. Moderate cases were accepted as patients with symptoms related to the respiratory system and pneumonia detected on imaging. SpO2<=93%, >=30 breaths/min respiratory rate, and patients who developed respiratory failure, mechanical ventilator need, shock, or multiorgan failure were included in the severe and critically ill cases group. Severe and critical cases were evaluated as a single group. When the radiological images of the patients were examined, it was remarkable that multilobar findings were less common in the ACEIs using group (p<0.001). At the clinical end point, mortality rates in patients using ACEIs (12.7%) were significantly lower than patients without using ACEIs (32.7%). Conclusion(s): In our study, we showed that SARS-CoV-2 progresses with less multilobar involvement in pulmonary computed tomography in patients using ACEI.Copyright © 2023 by The Medical Bulletin of Istanbul Haseki Training and Research Hospital The Medical Bulletin of Haseki published by Galenos Yayinevi.

In Silico Protein Folding Prediction of COVID-19 Mutations and Variants.

With its fast-paced mutagenesis, the SARS-CoV-2 Omicron variant has threatened many societies worldwide. Strategies for predicting mutagenesis such as the computational prediction of SARS-CoV-2 structural diversity and its interaction with the human receptor will greatly benefit our understanding of the virus and help develop therapeutics against it. We aim to use protein structure prediction algorithms along with molecular docking to study the effects of various mutations in the Receptor Binding Domain (RBD) of the SARS-CoV-2 and its key interactions with the angiotensin-converting enzyme 2 (ACE-2) receptor. The RBD structures of the naturally occurring variants of SARS-CoV-2 were generated from the WUHAN-Hu-1 using the trRosetta algorithm. Docking (HADDOCK) and binding analysis (PRODIGY) between the predicted RBD sequences and ACE-2 highlighted key interactions at the Receptor-Binding Motif (RBM). Further mutagenesis at conserved residues in the Original, Delta, and Omicron variants (P499S and T500R) demonstrated stronger binding and interactions with the ACE-2 receptor. The predicted T500R mutation underwent some preliminary tests in vitro for its binding and transmissibility in cells; the results correlate with the in-silico analysis. In summary, we suggest conserved residues P499 and T500 as potential mutation sites that could increase the binding affinity and yet do not exist in nature. This work demonstrates the use of the trRosetta algorithm to predict protein structure and future mutations at the RBM of SARS-CoV-2, followed by experimental testing for further efficacy verification. It is important to understand the protein structure and folding to help develop potential therapeutics.

SARS-CoV-2 Invasion and Pathological Links to Prion Disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 disease, is a highly infectious and transmissible viral pathogen that continues to impact human health globally. Nearly ~600 million people have been infected with SARS-CoV-2, and about half exhibit some degree of continuing health complication, generically referred to as long COVID. Lingering and often serious neurological problems for patients in the post-COVID-19 recovery period include brain fog, behavioral changes, confusion, delirium, deficits in intellect, cognition and memory issues, loss of balance and coordination, problems with vision, visual processing and hallucinations, encephalopathy, encephalitis, neurovascular or cerebrovascular insufficiency, and/or impaired consciousness. Depending upon the patient's age at the onset of COVID-19 and other factors, up to ~35% of all elderly COVID-19 patients develop a mild-to-severe encephalopathy due to complications arising from a SARS-CoV-2-induced cytokine storm and a surge in cytokine-mediated pro-inflammatory and immune signaling. In fact, this cytokine storm syndrome:&nbsp;(i) appears to predispose aged COVID-19 patients to the development of other neurological complications, especially those who have experienced a more serious grade of COVID-19 infection; (ii) lies along highly interactive and pathological pathways involving SARS-CoV-2 infection that promotes the parallel development and/or intensification of progressive and often lethal neurological conditions, and (iii) is strongly associated with the symptomology, onset, and development of human prion disease (PrD) and other insidious and incurable neurological syndromes. This commentary paper will evaluate some recent peer-reviewed studies in this intriguing area of human SARS-CoV-2-associated neuropathology and will assess how chronic, viral-mediated changes to the brain and CNS contribute to cognitive decline in PrD and other progressive, age-related neurodegenerative disorders.

The Prevalence and Pathophysiology of Chemical Sense Disorder Caused by the Novel Coronavirus.

Emerging viral infections are a ceaseless challenge and remain a global public health concern. The world has not yet come back to normal from the devastating effects of the highly contagious and pathogenic novel coronavirus, or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Olfactory and taste dysfunction is common in patients infected by the novel coronavirus. In light of the emergence of different coronavirus variants, it is important to update the prevalence and pathophysiology of these side effects. In this review, articles published on the prevalence of olfactory and taste dysfunction from coronavirus disease (COVID-19) and their possible pathophysiologic mechanisms have been reviewed and reported. The modulatory role of different SARS-CoV-2 variants on the chemical senses is then described. The clinical relevance of chemical sense disorder and its long-term morbidity and management is also discussed.

Role of SARS-CoV-2 in Modifying Neurodegenerative Processes in Parkinson's Disease: A Narrative Review.

The COVID-19 pandemic, caused by SARS-CoV-2, continues to impact global health regarding both morbidity and mortality. Although SARS-CoV-2 primarily causes acute respiratory distress syndrome (ARDS), the virus interacts with and influences other organs and tissues, including blood vessel endothelium, heart, gastrointestinal tract, and brain. We are learning much about the pathophysiology of SARS-CoV-2 infection; however, we are just beginning to study and understand the long-term and chronic health consequences. Since the pandemic's beginning in late 2019, older adults, those with pre-existing illnesses, or both, have an increased risk of contracting COVID-19 and developing severe COVID-19. Furthermore, older adults are also more likely to develop the neurodegenerative disorder Parkinson's disease (PD), with advanced age as the most significant risk factor. Thus, does SARS-CoV-2 potentially influence, promote, or accelerate the development of PD in older adults? Our initial focus was aimed at understanding SARS-CoV-2 pathophysiology and the connection to neurodegenerative disorders. We then completed a literature review to assess the relationship between PD and COVID-19. We described potential molecular and cellular pathways that indicate dopaminergic neurons are susceptible, both directly and indirectly, to SARS-CoV-2 infection. We concluded that under certain pathological circumstances, in vulnerable persons-with-Parkinson's disease (PwP), SARS-CoV-2 acts as a neurodegenerative enhancer to potentially support the development or progression of PD and its related motor and non-motor symptoms.

Clinical Characterization and Possible Pathological Mechanism of Acute Myocardial Injury in COVID-19.

COVID-19 is a respiratory disease that can cause damage to multiple organs throughout the body. Cardiovascular complications related to COVID-19 mainly include acute myocardial injury, heart failure, acute coronary syndrome, arrhythmia, myocarditis. Among them, myocardial injury is the most common complication in COVID-19 hospitalized patients, and is associated with poor prognosis such as death and arrhythmias. There is a continuous relationship between myocardial injury and the severity of COVID-19. The incidence of myocardial injury is higher in critically ill patients and dead patients, and myocardial injury is more likely to occur in the elderly critically ill patients with comorbidities. Myocardial injury is usually accompanied by more electrocardiogram abnormalities, higher inflammation markers and more obvious echocardiographic abnormalities. According to reports, COVID-19 patients with a history of cardiovascular disease have a higher in-hospital mortality, especially in the elder patients. At present, the mechanism of myocardial injury in COVID-19 is still unclear. There may be direct injury of myocardial cells, systemic inflammatory response, hypoxia, prethrombotic and procoagulant state, myocardial interstitial fibrosis, interferon-mediated immune response and coronary artery plaque instability and other related factors, and angiotensin-converting enzyme-2 receptor may play a key role in the myocardial injury in COVID-19.

Human serum from SARS-CoV-2-vaccinated and COVID-19 patients shows reduced binding to the RBD of SARS-CoV-2 Omicron variant.

BACKGROUND: The COVID-19 pandemic is caused by the betacoronavirus SARS-CoV-2. In November 2021, the Omicron variant was discovered and immediately classified as a variant of concern (VOC), since it shows substantially more mutations in the spike protein than any previous variant, especially in the receptor-binding domain (RBD). We analyzed the binding of the Omicron RBD to the human angiotensin-converting enzyme-2 receptor (ACE2) and the ability of human sera from COVID-19 patients or vaccinees in comparison to Wuhan, Beta, or Delta RBD variants. METHODS: All RBDs were produced in insect cells. RBD binding to ACE2 was analyzed by ELISA and microscale thermophoresis (MST). Similarly, sera from 27 COVID-19 patients, 81 vaccinated individuals, and 34 booster recipients were titrated by ELISA on RBDs from the original Wuhan strain, Beta, Delta, and Omicron VOCs. In addition, the neutralization efficacy of authentic SARS-CoV-2 wild type (D614G), Delta, and Omicron by sera from 2× or 3× BNT162b2-vaccinated persons was analyzed. RESULTS: Surprisingly, the Omicron RBD showed a somewhat weaker binding to ACE2 compared to Beta and Delta, arguing that improved ACE2 binding is not a likely driver of Omicron evolution. Serum antibody titers were significantly lower against Omicron RBD compared to the original Wuhan strain. A 2.6× reduction in Omicron RBD binding was observed for serum of 2× BNT162b2-vaccinated persons. Neutralization of Omicron SARS-CoV-2 was completely diminished in our setup. CONCLUSION: These results indicate an immune escape focused on neutralizing antibodies. Nevertheless, a boost vaccination increased the level of anti-RBD antibodies against Omicron, and neutralization of authentic Omicron SARS-CoV-2 was at least partially restored. This study adds evidence that current vaccination protocols may be less efficient against the Omicron variant.

Digestive system and severe acute respiratory syndrome coronavirus 2: New era of microbiome study and gastrointestinal tract manifestations during the coronavirus disease-19 pandemic

The main topic of this review article is the study of gastrointestinal disorders that were accompanying the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although SARS-CoV-2 primarily causes lung infection through binding to angiotensin-converting enzyme 2 (ACE2) receptors, intestinal epithelial cells, especially enterocytes of the small intestine, also express ACE2 receptors. Viral RNA and viral particles can be observed in feces for more than 30 days. It is also known that a respiratory viral infection causes disturbances in the gut microbiota. Diets, environmental factors, and genetics play an important role in the formation of the gut microbiota, which can affect the immune system. The diversity of the gut microbiota diminishes with age, which means that the fact that coronavirus disease (COVID-19) has proved to be mostly fatal in older patients further indicates the role that gut microbiota may play in this disease. It is, therefore, plausible that the gut microbiota could be a new therapeutic target and that probiotics could also have a role in the management of the patients affected by COVID-19. © 2021 Alibek Kossumov, Karakoz Mussabay, Astghik Pepoyan, Vardan Tsaturyan, Ketevan Sidamonidze, David Tsereteli, Adil Supiyev, Samat Kozhakhmetov, Laura Chulenbayeva, Marat Dusmagambetov, Massimo Pignatelli, Zhaxybay Zhumadilov, Francesco Marotta, Almagul Kushugulova.

Coronavirus disease 2019 gastrointestinal and liver manifestations in adults: A review.

Coronavirus disease 2019 (COVID-19) is an important health problem that has a serious adverse impact on the global economy and healthcare systems. The virus is not only involved in the respiratory system, but also causes other systemic effects as well as several gastrointestinal and liver issues. Evidence has shown direct viral invasion into the gastrointestinal tissue and supporting vascular network, causing various manifestations such as diarrhea, nausea, gastrointestinal bleeding, and abnormal liver function tests. The degree of gastrointestinal injury, especially in terms of liver involvement, is correlated with disease severity. There is no specific treatment for gastrointestinal involvement, and the symptoms can be managed with supportive therapy. Moreover, increased liver decompensation and mortality can be found in COVID-19-infected patients with coexisting liver disease. As the virus can be identified in gastrointestinal contents, endoscopic procedures during the pandemic should be carefully selected and proper protection strategies should be encouraged to prevent viral transmission.

Angiotensin-converting enzyme 2 gene expression in human male urological tissues: implications for pathogenesis and virus transmission pathways.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection occurs through binding and internalization of the viral spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell membrane. Pathological changes are caused by damage and failure of vital organs that express high levels of ACE2, including the lungs, the heart and the kidneys. The aim of this study was to investigate ACE2 gene expression in the human male urogenital tract using a public database. METHODS: A search of transcriptomic datasets from a database to investigate ACE2 gene expression in human urogenital tract tissue. RESULTS: The gene expression profile demonstrated that ACE2 gene expression was higher in human kidney cortex and testis than human lung tissue. The gene expression profile demonstrated that ACE2 gene expression in the human bladder and prostate was comparable to human lung tissue. CONCLUSIONS: Male urogenital tissues are directly susceptible to SARS-CoV-2 infection through the expression of ACE2. Moreover, the SARS-Cov-2/ACE2 interaction may disturb the male genital and reproductive functions.

A Computational Approach to Evaluate the Combined Effect of SARS-CoV-2 RBD Mutations and ACE2 Receptor Genetic Variants on Infectivity: The COVID-19 Host-Pathogen Nexus.

SARS-CoV-2 infectivity is largely determined by the virus Spike protein binding to the ACE2 receptor. Meanwhile, marked infection rate differences were reported between populations and individuals. To understand the disease dynamic, we developed a computational approach to study the implications of both SARS-CoV-2 RBD mutations and ACE2 polymorphism on the stability of the virus-receptor complex. We used the 6LZG PDB RBD/ACE2 3D model, the mCSM platform, the LigPlot+ and PyMol software to analyze the data on SARS-CoV-2 mutations and ACE variants retrieved from GISAID and Ensembl/GnomAD repository. We observed that out of 351 RBD point mutations, 83% destabilizes the complex according to free energy (ΔΔG) differences. We also spotted variations in the patterns of polar and hydrophobic interactions between the mutations occurring in 15 out of 18 contact residues. Similarly, comparison of the effect on the complex stability of different ACE2 variants showed that the pattern of molecular interactions and the complex stability varies also according to ACE2 polymorphism. We infer that it is important to consider both ACE2 variants and circulating SARS-CoV-2 RBD mutations to assess the stability of the virus-receptor association and evaluate infectivity. This approach might offers a good molecular ground to mitigate the virus spreading.

Experimental Evidence for Enhanced Receptor Binding by Rapidly Spreading SARS-CoV-2 Variants.

Rapidly spreading new variants of SARS-CoV-2 carry multiple mutations in the viral spike protein which attaches to the angiotensin converting enzyme 2 (ACE2) receptor on host cells. Among these mutations are amino acid changes N501Y (lineage B.1.1.7, first identified in the UK), and the combination N501Y, E484K, K417N (B.1.351, first identified in South Africa), all located at the interface on the receptor binding domain (RBD). We experimentally establish that RBD containing the N501Y mutation results in 7-fold stronger binding to the hACE2 receptor than wild type RBD. The E484K mutation only slightly enhances the affinity for the receptor, while K417N attenuates affinity. As a result, RBD from B.1.351 containing all three mutations binds 3-fold stronger to hACE2 than wild type RBD but 2-fold weaker than N501Y. However, the recently emerging double mutant E484K/N501Y binds even stronger than N501Y. The independent evolution of lineages containing mutations with different effects on receptor binding affinity, viral transmission and immune evasion underscores the importance of global viral genome surveillance and functional characterization.

Pathophysiological mechanisms underlying gastrointestinal symptoms in patients with COVID-19.

Gastrointestinal (GI) symptoms, such as diarrhea, abdominal pain, vomiting, and anorexia, are frequently observed in patients with coronavirus disease 2019 (COVID-19). However, the pathophysiological mechanisms connecting these GI symptoms to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections remain elusive. Previous studies indicate that the entry of SARS-CoV-2 into intestinal cells leads to downregulation of angiotensin converting enzyme 2 (ACE2) receptors resulting in impaired barrier function. While intestinal ACE2 functions as a chaperone for the amino acid transporter B0AT1, the B0AT1/ACE2 complex within the intestinal epithelium acts as a regulator of gut microbiota composition and function. Alternations to the B0AT1/ACE2 complex lead to microbial dysbiosis through increased local and systemic immune responses. Previous studies have also suggested that altered serotonin metabolism may be the underlying cause of GI disorders involving diarrhea. The findings of elevated plasma serotonin levels and high fecal calprotectin in COVID-19 patients with diarrhea indicate that the viral infection evokes a systemic inflammatory response that specifically involves the GI. Interestingly, the elevated proinflammatory cytokines correlate with elevated serotonin and fecal calprotectin levels further supporting the evidence of GI inflammation, a hallmark of functional GI disorders. Moreover, the finding that rectal swabs of COVID-19 patients remain positive for SARS-CoV-2 even after the nasopharynx clears the virus, suggests that viral replication and shedding from the GI tract may be more robust than that of the respiratory tract, further indicating fecal-oral transmission as another important route of viral spread. This review summarized the evidence for pathophysiological mechanisms (impaired barrier function, gut inflammation, altered serotonin metabolism and gut microbiota dysbiosis) underlying the GI symptoms in patients with COVID-19.

Expression of the SARS-CoV-2 receptorACE2 in human heart is associated with uncontrolled diabetes, obesity, and activation of the renin angiotensin system.

BACKGROUND: Diabetic and obese patients are at higher risk of severe disease and cardiac injury in corona virus 2 (SARS-CoV-2) infections. Cellular entry of SARS-CoV-2 is mainly via the angiotensin-converting enzyme 2 (ACE2) receptor, which is highly expressed in normal hearts. There is a disagreement regarding the effect of factors such as obesity and diabetes on ACE2 expression in the human heart and whether treatment with renin-angiotensin system inhibitors or anti-diabetic medications increases ACE2 expression and subsequently the susceptibility to infection. We designed this study to elucidate factors that control ACE2 expression in human serum, human heart biopsies, and mice. METHODS: Right atrial appendage biopsies were collected from 79 patients that underwent coronary artery bypass graft (CABG) surgery. We investigated the alteration in ACE2 mRNA and protein expression in heart tissue and serum. ACE2 expression was compared with clinical risk factors: diabetes, obesity and different anti-hypertensive or anti-diabetic therapies. WT or db/db mice were infused with Angiotensin II (ATII), treated with different anti-diabetic drugs (Metformin, GLP1A and SGLT2i) were also tested. RESULTS: ACE2 gene expression was increased in diabetic hearts compared to non-diabetic hearts and was positively correlated with glycosylated hemoglobin (HbA1c), body mass index (BMI), and activation of the renin angiotensin system (RAS), and negatively correlated with ejection fraction. ACE2 was not differentially expressed in patients who were on angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) prior to the operation. We found no correlation between plasma free ACE2 and cardiac tissue ACE2 expression. Transmembrane serine protease 2 (TMPRSS2), metalloprotease ADAM10 and ADAM17 that facilitate viral-ACE2 complex entry and degradation were increased in diabetic hearts. ACE2 expression in mice was increased with ATII infusion and attenuated following anti-diabetic drugs treatment. CONCLUSION: Patients with uncontrolled diabetes or obesity with RAS activation have higher ACE2 expressions therefore are at higher risk for severe infection. Since ACEi or ARBs show no effect on ACE2 expression in the heart further support their safety.