Effects of Quercetin on Uric Acid Metabolism

Background and Objective: High blood uric acid (hyperuricemia) is a common phenomenon in populations with hypertension, hyperglycemia, obesity and/or dyslipidemia. This study was to investigate the effects of quercetin supplementation on blood uric acid level and the biochemical mechanism behind it. Methods: A pilot trial confirmed the delivery of quercetin from a supplement tablet in healthy males (n=6). Randomised, double-blind, cross-over, placebo-controlled 4-week dietary intervention trial with the same supplement tablet containing 500 mg quercetin d-1 was conducted in selected healthy males (n=22, with higher blood uric acid but within normal range). Changes of uric acid and glucose were analysed in fasting blood plasma at 0, 2 and 4 weeks. Plasma metabolomics were profiled by 1H-NMR. Where quercetin and its metabolites may affect in the pathway of uric acid metabolism was investigated in vitro and ex vivo. Results: At the end of the 4-week trial, plasma uric acid levels were significantly reduced (mean change -26.5 µM, 95% CI -7.6 to -45.5, P = 0.008, n=22), as were diastolic blood pressures in normotensive subjects (-3.1 mm Hg, -0.5 to -5.8, P = 0.048, n=10). Paired plasma 1H-NMR spectrum showed lowered glutamine (P = 0.008), acetoacetate (P = 0.005) and lactate (P = 0.03) after quercetin treatment. A dose-dependent inhibition of quercetin, quercetin-3'-O-sulfate and 3,4-dihydroxyphenylacetic acid on xanthine oxidase in vitro and a mild inhibitory effect of quercetin on plasma adenosine deaminase was found. Conclusions: Quercetin supplementation can maintain blood uric acid level and blood pressure within a low-risk range. It is probably a result of regulated purine metabolism by quercetin, its microbial derivatives and their metabolites

Elevated circulating PCSK9 level is associated with 28-day mortality in patients with sepsis: a prospective cohort study

Abstract Objectives Pro-protein convertase subtilisin/kexin 9 (PCSK9) decreases the clearance of the pathogenic lipids, supporting the potential role of PCSK9 in the prognosis of sepsis. Methods In this prospective cohort study, patients with sepsis were consecutively recruited from 1 to 2020 to 30 September 2021 at the First People’s Hospital of Huaihua, China. All the eligible patients were categorized into low-PCSK9 and high-PCSK9 groups, based on their PCSK9 levels at admission. Time-dependent receiver operating characteristic curves and Cox proportional hazards regression were used to evaluate the association between PCSK9 level and 28-day mortality of sepsis. Results Of the 203 enrolled patients, 56 (27.59%) died during the 28-day follow-up. The PCSK9 level was positively related to the C-reactive protein level. The cut-off point of PCSK9 levels for 28-day mortality risk was 370 ng/ml. Through comparison between high-PCSK9 (> 370 ng/ml) with low-PCSK9 (≤ 370 ng/ml) groups, the adjusted HR for mortality was 2.56 (95% CI: 1.25–5.23, p = 0.01). Conclusions The 28-day mortality of sepsis increased significantly as the baseline circulating PCSK9 level exceeded 370 ng/ml, indicating circulating PCSK9 levels may be a potential biomarker to predict the prognosis of sepsis

D2I and F9Y Mutations in the NS1 Protein of Influenza A Virus Affect Viral Replication via Regulating Host Innate Immune Responses

Influenza A viruses (IAV) modulate host antiviral responses to promote viral growth and pathogenicity. The non-structural (NS1) protein of influenza A virus has played an indispensable role in the inhibition of host immune responses, especially in limiting interferon (IFN) production. In this study, random site mutations were introduced into the NS1 gene of A/WSN/1933 (WSN, H1N1) via an error prone PCR to construct a random mutant plasmid library. The NS1 random mutant virus library was generated by reverse genetics. To screen out the unidentified NS1 functional mutants, the library viruses were lung-to-lung passaged in mice and individual plaques were picked from the fourth passage in mice lungs. Sanger sequencing revealed that eight different kinds of mutations in the NS1 gene were obtained from the passaged library virus. We found that the NS1 F9Y mutation significantly enhanced viral growth in vitro (MDCK and A549 cells) and in vivo (BALB/c mice) as well as increased virulence in mice. The NS1 D2I mutation attenuated the viral replication and pathogenicity in both in vitro and in vivo models. Further studies demonstrated that the NS1 F9Y mutant virus exhibited systematic and selective inhibition of cytokine responses as well as inhibited the expression of IFN. In addition, the expression levels of innate immunity-related cytokines were significantly up-regulated after the rNS1 D2I virus infected A549 cells. Collectively, our results revealed that the two mutations in the N-terminal of the NS1 protein could alter the viral properties of IAV and provide additional evidence that the NS1 protein is a critical virulence factor. The two characterized NS1 mutations may serve as potential targets for antiviral drugs as well as attenuated vaccine development