Causal associations between type 1 diabetes and COVID-19 infection and prognosis: a two-sample Mendelian randomization study.

INTRODUCTION: It has been suggested that type 1 diabetes was associated with increased COVID-19 morbidity and mortality. However, their causal relationship is still unclear. Herein, we performed a two-sample Mendelian randomization (MR) to investigate the causal effect of type 1 diabetes on COVID-19 infection and prognosis. RESEARCH DESIGN AND METHODS: The summary statistics of type 1 diabetes were obtained from two published genome-wide association studies of European population, one as a discovery sample including 15 573 cases and 158 408 controls, and the other data as a replication sample consisting of 5913 cases and 8828 controls. We first performed a two-sample MR analysis to evaluate the causal effect of type 1 diabetes on COVID-19 infection and prognosis. Then, reverse MR analysis was conducted to determine whether reverse causality exists. RESULTS: MR analysis results showed that the genetically predicted type 1 diabetes was associated with higher risk of severe COVID-19 (OR=1.073, 95% CI: 1.034 to 1.114, pFDR=1.15×10-3) and COVID-19 death (OR=1.075, 95% CI: 1.033 to 1.119, pFDR=1.15×10-3). Analysis of replication dataset showed similar results, namely a positive association between type 1 diabetes and severe COVID-19 (OR=1.055, 95% CI: 1.029 to 1.081, pFDR=1.59×10-4), and a positively correlated association with COVID-19 death (OR=1.053, 95% CI: 1.026 to 1.081, pFDR=3.50×10-4). No causal association was observed between type 1 diabetes and COVID-19 positive, hospitalized COVID-19, the time to the end of COVID-19 symptoms in the colchicine treatment group and placebo treatment group. Reverse MR analysis showed no reverse causality. CONCLUSIONS: Type 1 diabetes had a causal effect on severe COVID-19 and death after COVID-19 infection. Further mechanistic studies are needed to explore the relationship between type 1 diabetes and COVID-19 infection and prognosis.

A comparative study of spike protein of SARS-CoV-2 and its variant Omicron (B.1.1.529) on some immune characteristics.

The emergence of Omicron variant raises great concerns because of its rapid transmissibility and its numerous mutations in spike protein (S-protein). S-protein can act as a pathogen-associated molecular pattern and complement activator as well as antigen. We compared some immune characteristics of trimer S-proteins for wild type (WT-S) and B.1.1.529 Omicron (Omicron-S) to investigate whether the mutations have affected its pathogenicity and antigenic shift. The results indicated that WT-S and Omicron-S directly activated nuclear factor-κB (NF-κB) and induced the release of pro-inflammatory cytokines in macrophages, but the actions of Omicron-S were weaker. These inflammatory reactions could be abrogated by a Toll-like receptor 4 antagonist TAK-242. Two S-proteins failed to induce the production of antiviral molecular interferon-ß. In contrast to pro-inflammatory effects, the ability of two S-proteins to activate complement was comparable. We also compared the binding ability of two S-proteins to a high-titer anti-WT-receptor-binding domain antibody. The data showed that WT-S strongly bound to this antibody, while Omicron-S was completely off-target. Collectively, the mutations of Omicron have a great impact on the pro-inflammatory ability and epitopes of S-protein, but little effect on its ability to activate complement. Addressing these issues can be helpful for more adequate understanding of the pathogenicity of Omicron and the vaccine breakthrough infection.

Flavonoids for Treating Viral Acute Respiratory Tract Infections: A Systematic Review and Meta-Analysis of 30 Randomized Controlled Trials.

BACKGROUND: This meta-analysis aimed to investigate the efficacy and safety of flavonoids in treating viral acute respiratory tract infections (ARTIs). METHODS: Randomized controlled trials (RCTs) were entered into meta-analyses performed separately for each indication. Efficacy analyses were based on changes in disease-specific symptom scores. Safety was analyzed based on the pooled data from all eligible trials, by comparing the incidence of adverse events between flavonoids and the control. RESULTS: In this study, thirty RCTs (n = 5,166) were included. In common cold, results showed that the flavonoids group decreased total cold intensity score (CIS), the sum of sum of symptom intensity differences (SSID) of CIS, and duration of inability to work vs. the control group. In influenza, the flavonoids group improved the visual analog scores for symptoms. In COVID-19, the flavonoids group decreased the time taken for alleviation of symptoms, time taken for SARS-CoV-2 RT-PCR clearance, the RT-PCR positive subjects at day 7, time to achievement of the normal status of symptoms, patients needed oxygen, patients hospitalized and requiring mechanical ventilation, patients in ICU, days of hospitalization, and mortality vs. the control group. In acute non-streptococcal tonsillopharyngitis, the flavonoids group decreased the tonsillitis severity score (TSS) on day 7. In acute rhinosinusitis, the flavonoids group decreased the sinusitis severity score (SSS) on day 7, days off work, and duration of illness. In acute bronchitis, the flavonoids group decreased the bronchitis severity score (BSS) on day 7, days off work, and duration of illness. In bronchial pneumonia, the flavonoids group decreased the time to symptoms disappearance, the level of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). In upper respiratory tract infections, the flavonoids group decreased total CIS on day 7 and increased the improvement rate of symptoms. Furthermore, the results of the incidence of adverse reactions did not differ between the flavonoids and the control group. CONCLUSION: Results from this systematic review and meta-analysis suggested that flavonoids were efficacious and safe in treating viral ARTIs including the common cold, influenza, COVID-19, acute non-streptococcal tonsillopharyngitis, acute rhinosinusitis, acute bronchitis, bronchial pneumonia, and upper respiratory tract infections. However, uncertainty remains because there were few RCTs per type of ARTI and many of the RCTs were small and of low quality with a substantial risk of bias. Given the limitations, we suggest that the conclusions need to be confirmed on a larger scale with more detailed instructions in future studies.Systematic Review Registration: inplasy.com/inplasy-2021-8-0107/, identifier: INPLASY20218010.

Isodeoxyelephantopin, a sesquiterpene lactone from Elephantopus scaber Linn., inhibits pro-inflammatory mediators' production through both NF-κB and AP-1 pathways in LPS-activated macrophages.

Isodeoxyelephantopin (IDET) has been identified as an anti-tumor natural constituent whose anti-tumor activity and mechanism have been widely investigated. Since the occurrence and development of cancer usually accompany with inflammation, and tumor signaling shares many components with inflammation signaling, the agents with anti-tumor activity are likely to possess anti-inflammation potential. Thus, the current study aims to demonstrate the anti-inflammatory activity along with the underlying mechanism of IDET in lipopolysaccharide (LPS)-primed macrophages. By using Griess method and ELISA, we found that in both bone marrow derived macrophages and alveolar macrophage cell line, IDET, at relatively low concentrations (0.75, 1.5 and 3 µM), could inhibit LPS-induced expression of various pro-inflammatory mediators including nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS), interleukin (IL)-6, monocyte chemotactic protein-1 (MCP-1) and IL-1ß. Meanwhile, in activated MH-S cells, the inhibitory action of IDET on mRNA expression levels of these cytokines was also detected using qPCR. Mechanistically, the effects of IDET on two key inflammatory signalings, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) pathways, were determined in LPS-activated MH-S cells by reporter gene along with western blot assays. On the one hand, IDET suppressed NF-κB signaling via down-regulating phosphorylation and degradation of inhibitor of NF-κB (IκB)-α and the subsequent p65 translocation. On the other hand, IDET dampened AP-1 signaling through attenuating phosphorylation of both c-jun N-terminal kinase 1/2 (JNK1/2) and extracellular signal regulated kinase 1/2 (ERK1/2). Our study indicates that IDET might be a promising constituent from the anti-inflammatory herb Elephantopus scaber Linn. in mitigating inflammatory conditions, especially respiratory inflammation.