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Signal Transduct Target Ther ; 6(1): 427, 2021 12 16.
Article in English | MEDLINE | ID: covidwho-1795805


Abnormal glucose and lipid metabolism in COVID-19 patients were recently reported with unclear mechanism. In this study, we retrospectively investigated a cohort of COVID-19 patients without pre-existing metabolic-related diseases, and found new-onset insulin resistance, hyperglycemia, and decreased HDL-C in these patients. Mechanistically, SARS-CoV-2 infection increased the expression of RE1-silencing transcription factor (REST), which modulated the expression of secreted metabolic factors including myeloperoxidase, apelin, and myostatin at the transcriptional level, resulting in the perturbation of glucose and lipid metabolism. Furthermore, several lipids, including (±)5-HETE, (±)12-HETE, propionic acid, and isobutyric acid were identified as the potential biomarkers of COVID-19-induced metabolic dysregulation, especially in insulin resistance. Taken together, our study revealed insulin resistance as the direct cause of hyperglycemia upon COVID-19, and further illustrated the underlying mechanisms, providing potential therapeutic targets for COVID-19-induced metabolic complications.

COVID-19/blood , Hyperglycemia/blood , Insulin Resistance , Lipid Metabolism , Lipids/blood , SARS-CoV-2/metabolism , Adult , Aged , Biomarkers/blood , COVID-19/complications , Female , Humans , Hyperglycemia/etiology , Male , Middle Aged , Retrospective Studies
Cell Metab ; 34(3): 424-440.e7, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1676683


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.

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
Ann Vasc Surg ; 79: 114-121, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1458689


BACKGROUND: Coronavirus disease 2019 (COVID-19) has become a global pandemic which may compromise the management of vascular emergencies. An uncompromised treatment for ruptured abdominal aortic aneurysm (rAAA) during such a health crisis represents a challenge. This study aimed to demonstrate the treatment outcomes of rAAA and the perioperative prevention of cross-infection under the COVID-19 pandemic. METHODS: In cases of rAAA during the pandemic, a perioperative workflow was applied to expedite coronavirus testing and avoid pre-operative delay, combined with a strategy for preventing cross-infection. Data of rAAA treated in 11 vascular centers between January-March 2020 collected retrospectively were compared to the corresponding period in 2018 and 2019. RESULTS: Eight, 12, and 14 rAAA patients were treated in 11 centers in January-March 2018, 2019, and 2020, respectively. An increased portion were treated at local hospitals with a comparable outcome compared with large centers in Guangzhou. With EVAR-first strategy, 85.7% patients with rAAA in 2020 underwent endovascular repair, similar to that in 2018 and 2019. The surgical outcomes during the pandemic were not inferior to that in 2018 and 2019. The average length of ICU stay was 1.8 ± 3.4 days in 2020, tending to be shorter than that in 2018 and 2019, whereas the length of hospital stay was similar among 3 years. The in-hospital mortality of 2018, 2019, and 2020 was 37.5%, 25.0%, and 14.3%, respectively. Three patients undergoing emergent surgeries were suspected of COVID-19, though turned out to be negative after surgery. CONCLUSIONS: Our experience for emergency management of rAAA and infection prevention for healthcare providers is effective in optimizing emergent surgical outcomes during the COVID-19 pandemic.

Aortic Aneurysm, Abdominal/surgery , Aortic Rupture/surgery , COVID-19/prevention & control , Cross Infection/prevention & control , Infection Control , Vascular Surgical Procedures , Aged , Aged, 80 and over , Aortic Aneurysm, Abdominal/diagnosis , Aortic Rupture/diagnosis , COVID-19/diagnosis , COVID-19/transmission , COVID-19/virology , COVID-19 Testing , China , Cross Infection/diagnosis , Cross Infection/transmission , Cross Infection/virology , Emergencies , Female , Humans , Male , Middle Aged , Patient Safety , Retrospective Studies , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome , Vascular Surgical Procedures/adverse effects , Workflow