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1.
Front Genet ; 13: 743905, 2022.
Article in English | MEDLINE | ID: covidwho-1775658

ABSTRACT

Aims: This study was aimed to apply a Mendelian randomization design to explore the causal association between coronavirus disease 2019 (COVID-19) and three cardio-cerebrovascular diseases, including atrial fibrillation, ischemic stroke, and coronary artery disease. Methods: Two-sample Mendelian randomization was used to determine the following: 1) the causal effect of COVID-19 on atrial fibrillation (55,114 case participants vs 482,295 control participants), coronary artery disease (34,541 case participants vs 261,984 control participants), and ischemic stroke (34,217 case participants vs 40,611 control participants), which were obtained from the European Bioinformatics Institute, and 2) the causal effect of three cardio-cerebrovascular diseases on COVID-19. The single-nucleotide polymorphisms (SNPs) of COVID-19 were selected from the summary-level genome-wide association study data of COVID-19-hg genome-wide association study (GWAS) meta-analyses (round 5) based on the COVID-19 Host Genetics Initiative for participants with European ancestry. The random-effects inverse-variance weighted method was conducted for the main analyses, with a complementary analysis of the weighted median and Mendelian randomization (MR)-Egger approaches. Results: Genetically predicted hospitalized COVID-19 was suggestively associated with ischemic stroke, with an odds ratio (OR) of 1.049 [95% confidence interval (CI) 1.003-1.098; p = 0.037] in the COVID-19 Host Genetics Initiative GWAS. When excluding the UK Biobank (UKBB) data, our analysis revealed a similar odds ratio of 1.041 (95% CI 1.001-1.082; p = 0.044). Genetically predicted coronary artery disease was associated with critical COVID-19, with an OR of 0.860 (95% CI 0.760-0.973; p = 0.017) in the GWAS meta-analysis and an OR of 0.820 (95% CI 0.722-0.931; p = 0.002) when excluding the UKBB data, separately. Limited evidence of causal associations was observed between critical or hospitalized COVID-19 and other cardio-cerebrovascular diseases included in our study. Conclusion: Our findings provide suggestive evidence about the causal association between hospitalized COVID-19 and an increased risk of ischemic stroke. Besides, other factors potentially contribute to the risk of coronary artery disease in patients with COVID-19, but not genetics.

2.
Front Pharmacol ; 12: 680674, 2021.
Article in English | MEDLINE | ID: covidwho-1389232

ABSTRACT

Liquorice is a traditional medicine. Triterpenoids such as glycyrrhizin and glycyrrhetinic acid are the main active constituents of liquorice. Studies have revealed that these compounds exert inhibitory effects on several viruses, including SARS-CoV-2. The main mechanisms of action of these compounds include inhibition of virus replication, direct inactivation of viruses, inhibition of inflammation mediated by HMGB1/TLR4, inhibition of ß-chemokines, reduction in the binding of HMGB1 to DNA to weaken the activity of viruses, and inhibition of reactive oxygen species formation. We herein review the research progress on the antiviral effects of glycyrrhizin and its derivatives. In addition, we emphasise the significance of exploring unknown antiviral mechanisms, structural modifications, and drug combinations in future studies.

3.
Pregnancy Hypertens ; 26: 17-23, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1364411

ABSTRACT

AIMS: The aim of this study was to apply the Mendelian randomization (MR) design to explore the potential causal association between COVID-19 and the risk of hypertension disorders in pregnancy. METHODS: Our primary genetic instrument comprised 8 single-nucleotide polymorphisms (SNPs) associated with COVID-19 at genome-wide significance. Data on the associations between the SNPs and the risk of hypertension disorders in pregnancy were obtained from study based on a very large cohort of European population. The random-effects inverse-variance weighted method was conducted for the main analyses, with a complementary analysis of the weighted median and MR-Egger approaches. RESULTS: Using IVW, we found that genetically predicted COVID-19 was significantly positively associated with hypertension disorders in pregnancy, with an odds ratio (OR) of 1.111 [95% confidence interval (CI) 1.042-1.184; P = 0.001]. Weighted median regression also showed directionally similar estimates [OR 1.098 (95% CI, 1.013-1.190), P = 0.023]. Both funnel plots and MR-Egger intercepts suggest no directional pleiotropic effects observed. CONCLUSIONS: Our findings provide direct evidence that there is a shared genetic predisposition so that patients infected with COVID-19 may be causally associated with increased risk of hypertension disorders in pregnancy.


Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease , Hypertension/etiology , Mendelian Randomization Analysis/methods , Polymorphism, Single Nucleotide , Risk Assessment/methods , SARS-CoV-2 , COVID-19/complications , COVID-19/epidemiology , Female , Global Health , Humans , Hypertension/epidemiology , Hypertension/genetics , Incidence , Pregnancy , Risk Factors
4.
Int J Mol Sci ; 21(8)2020 Apr 23.
Article in English | MEDLINE | ID: covidwho-825269

ABSTRACT

Our previous study showed that glycyrrhizin (GLY) inhibited porcine epidemic diarrhea virus (PEDV) infection, but the mechanisms of GLY anti-PEDV action remain unclear. In this study, we focused on the anti-PEDV and anti-proinflammatory cytokine secretion mechanisms of GLY. We found that PEDV infection had no effect on toll-like receptor 4 (TLR4) protein and mRNA levels, but that TLR4 regulated PEDV infection and the mRNA levels of proinflammatory cytokines. In addition, we demonstrated that TLR4 regulated p38 phosphorylation but not extracellular regulated protein kinases1/2 (Erk1/2) and c-Jun N-terminal kinases (JNK) phosphorylation, and that GLY inhibited p38 phosphorylation but not Erk1/2 and JNK phosphorylation. Therefore, we further explored the relationship between high mobility group box-1 (HMGB1) and p38. We demonstrated that inhibition of HMGB1 using an antibody, mutation, or knockdown decreased p38 phosphorylation. Thus, HMGB1 participated in activation of p38 through TLR4. Collectively, our data indicated that GLY inhibited PEDV infection and decreased proinflammatory cytokine secretion via the HMGB1/TLR4-mitogen-activated protein kinase (MAPK) p38 pathway.


Subject(s)
Glycyrrhizic Acid/pharmacology , HMGB1 Protein/metabolism , Porcine epidemic diarrhea virus/drug effects , Porcine epidemic diarrhea virus/physiology , Signal Transduction/drug effects , Toll-Like Receptor 4/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Cells, Cultured , Chlorocebus aethiops , Coronavirus Infections/veterinary , Swine , Swine Diseases/metabolism , Swine Diseases/virology , Vero Cells
5.
Lancet ; 395(10236): 1569-1578, 2020 05 16.
Article in English | MEDLINE | ID: covidwho-824547

ABSTRACT

BACKGROUND: No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models. METHODS: We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656. FINDINGS: Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87-1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95-2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early. INTERPRETATION: In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. FUNDING: Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/therapeutic use , Aged , Alanine/adverse effects , Alanine/therapeutic use , Antiviral Agents/adverse effects , Betacoronavirus , COVID-19 , China , Double-Blind Method , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Negative Results , Pandemics , SARS-CoV-2
6.
Int J Med Sci ; 17(14): 2125-2132, 2020.
Article in English | MEDLINE | ID: covidwho-717801

ABSTRACT

Objectives: To present the temporal changes of CT manifestations in COVID-19 patients from a single fangcang shelter hospital and to facilitate the understanding of the disease course. Materials and Methods: This retrospective study included 98 patients (males: females, 43:55, mean year, 49±12 years) with confirmed COVID-19 at Jianghan fangcang shelter hospital admitted between Feb 05, 2020, and Feb 09, 2020, who had initial chest CTs at our hospital. Radiographic features and CT scores were analyzed. Results: A total of 267 CT scans of 98 patients were evaluated. Our study showed a high median total CT score of 7 within the first week from symptom onset, peaked in the 2nd week at 10, followed by persistently high levels of CT score with 9.5, 7 and 7 for the week 3, 4, and >4, respectively, and a prolonged median disease course (30 days, the median interval between the onset of initial symptoms and discharge). Ground-glass opacity (GGO) (58%, 41/71) was the earliest and most frequent finding in week 1. Consolidation (26%, 14/53) and mixed pattern (40%, 21/53) were predominant patterns in 2nd week. GGO and reticular were the main patterns of later phase CT scans in patients with relatively advanced diseases who had longer illness duration (≥4 weeks). Among the 94 CT abnormalities obtained within 3 days from the twice RT-PCR test turned negative, the mixed pattern was mainly presented in patients with disease duration of 2-3 weeks, for GGO and reticular were common during the whole course. Conclusion: Discharged patients from fangcang shelter hospital demonstrated a high extent of lung abnormalities on CT within the first week from symptom onset, peaked at 2nd week, followed by persistence of high levels and a prolonged median disease course. GGO was the predominant pattern in week 1, consolidation and mixed pattern in 2nd week, whereas GGO and reticular patterns in later stages (≥4 weeks).


Subject(s)
Betacoronavirus/isolation & purification , Clinical Laboratory Techniques/statistics & numerical data , Coronavirus Infections/diagnosis , Lung/diagnostic imaging , Pneumonia, Viral/diagnosis , Tomography, X-Ray Computed/statistics & numerical data , Adolescent , Adult , Aged , Betacoronavirus/genetics , COVID-19 , COVID-19 Testing , China/epidemiology , Clinical Laboratory Techniques/methods , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Disease Progression , Female , Humans , Male , Middle Aged , Mobile Health Units , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , RNA, Viral/isolation & purification , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Severity of Illness Index , Young Adult
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