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1.
researchsquare; 2024.
Preprint em Inglês | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-3932435.v1

RESUMO

Background Recent studies suggest that neutrophil elastase inhibitor (Sivelestat) may improve pulmonary function and reduce mortality in patients with acute respiratory distress syndrome. We examined the association between receipt of sivelestat and improvement in oxygenation among patients with acute respiratory distress syndrome (ARDS) induced by COVID-19.Methods A large multicentre cohort study of patients with ARDS induced by COVID-19 who had been admitted to intensive care units (ICUs). We used propensity score matching to compare the outcomes of patients treated with sivelestat to those who were not. The differences in continuous outcomes were assessed with the Wilcoxon signed-rank test. Kaplan-Meier method was used to show the 28-day survival curves in the matched cohorts. A log-rank P-test stratified on the matched pairs was used to test the equality of the estimated survival curves. A Cox proportional hazards model that incorporated a robust sandwich-type variance estimator to account for the matched nature of the data was used to estimate hazard ratios (HR). All statistical analyses were performed with SPSS 26.0 and R 4.2.3. A two-sided p-value of < 0.05 was considered statistically significant.Results A total of 387 patients met inclusion criteria, including 259 patients (66.9%) who were treated with sivelestat. In 158 patients matched on the propensity for treatment, receipt of sivelestat was associated with improved oxygenation, decreased Murray lung injury score, increased non-mechanical ventilation time within 28 days, increased alive and ICU-free days within 28 days (HR, 1.85; 95% CI, 1.29 to 2.64; log-rank p < 0.001), shortened ICU stay and ultimately improved survival (HR, 2.78; 95% CI, 1.32 to 5.88; log-rank p = 0.0074).Conclusions Among patients with ARDS induce by COVID-19, sivelestat administration is associated with improved clinical outcomes.


Assuntos
COVID-19 , Síndrome da Fibromatose Hialina , Síndrome do Desconforto Respiratório
2.
biorxiv; 2022.
Preprint em Inglês | bioRxiv | ID: ppzbmed-10.1101.2022.10.10.511541

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains an important health threat. Syncytial formation by infected cells mediated by the SARS-CoV-2 spike protein (SARS-2-S) is a hallmark of COVID-19-associated pathology. Although SARS-CoV-2 infection evokes cellular senescence, as in other viruses, the direct link between SARS-2-S-induced syncytia with senescence in the absence of viral infection and their senescence fate determinants remain unknown. Here, we show that syncytia formed by cells expressing exogenously delivered SARS-2-S exhibited a senescence-like phenotype in vitro and that SARS-2-S mRNA induced senescence phenotype in vivo. Extracellular vesicles (EVs) containing SARS-2-S also induced senescent syncytium formation independent of the de novo synthesis of SARS-2-S. Mechanistically, we show that the accumulation of endogenous dsRNA, partially that whose formation is induced by activation of the unfolded protein response (UPR), in SARS-2-S syncytia triggers RIG-I-MAVS signalling to drive the TNF-α-dependent survival and senescence fate of SARS-2-S syncytia. Our findings suggest that the fusogenic ability of SARS-2-S might contribute to the side effects of particular COVID-19 vaccines or perhaps long COVID-19 syndrome and provide insight into how these effects can be prevented.


Assuntos
Infecções por Coronavirus , Síndrome Respiratória Aguda Grave , COVID-19
3.
researchsquare; 2021.
Preprint em Inglês | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-537089.v1

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces new-onset diabetes and severe metabolic complications of pre-existing diabetes. The pathogenic mechanism underlying this is incompletely understood. Here, we provided evidence linking circulating GP73 with the exaggerated gluconeogenesis triggered by SARS-CoV-2 infection. We found that SARS-CoV-2 infection or glucotoxic conditions increased GP73 production and secretion. Secreted GP73 then trafficked to the liver and kidney to stimulate gluconeogenesis through the cAMP/PKA pathway. By using global phosphoproteomics, we found a drastic remodeling of the PKA kinase hub exerted by GP73. Notably, plasma GP73 levels were elevated and positively correlated with blood glucose in patients with COVID19 and diabetes. Neutralization of circulating GP73 in serum of individuals infected with SARS-CoV-2 or with diabetes reduced excessive gluconeogenesis in cultured hepatocytes, and lowered blood glucose levels in animal models of diabetes. Ablation of GP73 from whole animals has a profound glucose-lowering effect secondary to reduced gluconeogenesis. Thus, GP73 is a key glucogenic hormone contributing to SARS-CoV-2-induced glucose abnormality.


Assuntos
COVID-19
4.
medrxiv; 2021.
Preprint em Inglês | medRxiv | ID: ppzbmed-10.1101.2021.04.30.21256060

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces new-onset diabetes and severe metabolic complications of pre-existing diabetes. The pathogenic mechanism underlying this is incompletely understood. Here, we provided evidence linking circulating GP73 with the exaggerated gluconeogenesis triggered by SARS-CoV-2 infection. We found that SARS-CoV-2 infection or glucotoxic condition increased the cellular secretion of GP73. Secreted GP73 trafficked to the liver and kidney to stimulate gluconeogenesis through cAMP/PKA pathway. By using global phosphoproteomics, we found a drastic remodeling of PKA kinase hub exerted by GP73. Notably, COVID-19 patients showed pathologically elevated plasma GP73, and neutralization of the secreted GP73 inhibited enhanced PKA signaling and glucose production associated with SARS-CoV-2 infection. GP73 blockade also reduced gluconeogenesis and lowered hyperglycemia in type 2 (T2D) diabetic mice. Therefore, our findings provide novel insight into the roles of GP73 as a key glucogenic hormone and mechanistic clues underlying the development of SARS-CoV-induced glucose abnormalities.


Assuntos
Diabetes Mellitus , Síndrome Respiratória Aguda Grave , COVID-19 , Hiperglicemia
5.
biorxiv; 2020.
Preprint em Inglês | bioRxiv | ID: ppzbmed-10.1101.2020.08.13.248872

RESUMO

The recently emerged pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly, leading to a global COVID-19 pandemic. Binding of the viral spike protein (SARS-2-S) to cell surface receptor angiotensin-converting enzyme 2 (ACE2) mediates host cell infection. In the present study, we demonstrate that in addition to ACE2, the S1 subunit of SARS-2-S binds to HDL and that SARS-CoV-2 hijacks the SR-B1-mediated HDL uptake pathway to facilitate its entry. SR-B1 facilitates SARS-CoV-2 entry into permissive cells by augmenting virus attachment. MAb (monoclonal antibody)-mediated blocking of SARS-2-S-HDL binding and SR-B1 antagonists strongly inhibit HDL-enhanced SARS-CoV-2 infection. Notably, SR-B1 is co-expressed with ACE2 in human pulmonary and extrapulmonary tissues. These findings revealed a novel mechanism for SARS-CoV-2 entry and could provide a new target to treat SARS-CoV-2 infection.


Assuntos
COVID-19
6.
medrxiv; 2020.
Preprint em Inglês | medRxiv | ID: ppzbmed-10.1101.2020.04.16.20068528

RESUMO

Abstract The recently emerged pathogenic SARS-coronavirus 2 (SARS-CoV-2) has spread rapidly, leading to a global pandemic. In this study, we show that SARS-CoV-2 infection was associated with clinically significant lower level of HDL cholesterol (HDL-C), which can be used as indicators of disease severity and poor prognosis. Importantly, we found the spike protein of SARS-CoV-2 (SARS-2-S) bound to HDL. Antagonists of HDL receptor-Scavenger receptor class B type I (SR-B1), strongly inhibited SARS-CoV-2 infection. Notably, the lipids transfer function of SR-B1 was indispensable for this inhibition, offering explanations for the reduced serum HDL level observed in COVID-19 patients. Basing on findings here, we speculate that SR-B1-mediated pulmonary HDL-vitamin E uptake could participate in mediating SARS-CoV-2 infection of lung cells, and the unique expression profile of SR-B1 may also affect SARS-CoV-2 cell and tissue tropism. These findings might help to provide further insights into viral transmission, pathological characteristics and reveal therapeutic targets.


Assuntos
COVID-19 , Infecções por Coronavirus
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