Poor serum uric acid control increases risk for developing hypertension: a retrospective cohort study in China.

Background: Serum uric acid (SUA) has been suggested as a contributor of hypertension. However, reports on the relationship between changes in SUA and hypertension are limited. Hence, we aimed to investigate the potential impact of SUA, especially its change over time, on hypertension incidence. Methods: This dynamic cohort included 6052 participants without hypertension at baseline. Participants were categorized into six grades based on whether baseline SUA was high and whether changes in SUA progressed to hyperuricemia or decreased to normal levels. Grades 1 to 6 represented the participants' SUA control from best to worst. Logistic regression and restricted cubic spline (RCS) models were used to explore the association of the grades of SUA control and hypertension incidence. Results: During a median follow-up of 6 years, 2550 (42.1%) participants developed hypertension. After adjusting confounding factors, compared to grade 1 with the best control of SUA, the odds ratios for grades 2 to 6 with worse control were 1.347 (1.109-1.636), 1.138 (0.764-1.693), 1.552 (1.245-1.934), 1.765 (1.170-2.663), and 2.165 (1.566-2.993), respectively. RCS indicated a linear correlation between the risk of hypertension and changes in SUA, and an elevated risk in participants with baseline hyperuricemia. Subgroup analyses showed that grades of SUA control had an interaction with systolic (P = 0.003) and diastolic blood pressure (P < 0.001). Sensitivity analyses further determined the robustness of the result that participants with poor SUA control have a higher risk of developing hypertension. Conclusion: Poor SUA control, an increase in SUA over time, rises the risk of developing hypertension regardless of whether the initial SUA is normal or not. Initial hyperuricemia will exacerbate this risk. Effective SUA control should be an important measure for primary prevention of hypertension.

Electrochemically Driven C4-Selective Decyanoalkylation of Cyanopyridines with Unactivated Alkyl Bromides Enabling C(sp3)-C(sp2) Coupling.

With cyanopyridines and alkyl bromides as coupling partners, an electrochemically driven C4-selective decyanoalkylation has been established to access diverse 4-alkylpyridines in one step. The reaction proceeds through the single electron reduction/radical-radical coupling tandem process under mild electrolytic conditions, achieving the cleavage of the C(sp2)-CN bond and the formation of C(sp3)-C(sp2). The practicality of this protocol is illustrated by no sacrificial anodes, a broad substrate scope, and gram-scale synthesis.

Design, Synthesis, and Antitumor Efficacy of Substituted 2-Amino[1,2,4]triazolopyrimidines and Related Heterocycles as Dual Inhibitors for Microtubule Polymerization and Janus Kinase 2.

Preclinical and clinical studies have demonstrated the synergistic effect of microtubule-targeting agents in combination with Janus kinase 2 (JAK2) inhibitors, prompting the development of single agents with enhanced therapeutic efficacy by dually inhibiting tubulin polymerization and JAK2. Herein, we designed and synthesized a series of substituted 2-amino[1,2,4]triazolopyrimidines and related heterocycles as dual inhibitors for tubulin polymerization and JAK2. Most of these compounds exhibited potent antiproliferative activity against the selected cancer cells, with compound 7g being the most active. This compound effectively inhibits both tubulin assembly and JAK2 activity. Furthermore, phosphorylated compound 7g (i.e., compound 7g-P) could efficiently convert to compound 7g in vivo. Compound 7g, whether it was administered directly or in the form of a phosphorylated prodrug (i.e., compound 7g-P), significantly inhibited the growth of A549 xenografts in nude mice. The present findings strongly suggest that compound 7g represents a promising chemotherapeutic agent with high antitumor efficacy.

A fluorescent screening method for optimization of conotoxin expression in Pichia pastoris.

Conotoxins are small cysteine-rich peptides secreted by the Conus venom glands, which act on ion channels or membrane receptors with high specificity and potency. Conotoxins are invaluable sources for neuroscience research and drug leads, but their application is hindered by the limited successes in quantitative engineering using either chemical or biotechnological approaches. Here, we explore the Pichia pastoris to express 23 selected conopeptides using a GFP-based fluorescence screen. We found that, in a protease-deficient strain PichiaPink™ Strain 4 (ade2 prb1 pep4), most of the recombinant conopeptides were expressed as two major folding variants including a compact form that was somehow resistant to reduction and high temperature. The GFP-αTxIA was the only one displaying a single band that showed a dose-dependent neurotoxicity on larvae of the insect Plutella xylostella, with a 48-h LD50 lower than 1.12 pmol mg-1 body weight. Furthermore, the recombinant αTxIA after cleavage from the fusion was able to inhibit cell proliferation of the LYCT and HEK293T cell lines with an appearance IC50 of 341 ± 8 and 235 ± 15 nM, respectively. This screening method is straightforward and easy to scale up, providing a versatile tool for further optimization of conotoxin production in the yeast cell.

Diagnostic performance of circulating exosomes in human cancer: A meta-analysis.

BACKGROUND: Cancer has become a public health problem with high morbidity and mortality. Recent publications have shown that exosomes can be used as potential diagnostic biomarkers of cancer. However, the diagnostic accuracy and reliability of circulating exosomes remain unclear. The present meta-analysis was conducted to comprehensively summarize the overall diagnostic performance of circulating exosomes for cancer. METHODS: Eligible studies published up to June 27, 2019, on PubMed, Embase, and Cochrane Library were selected for the meta-analysis. All statistical analyses were performed by STATA 15.1 statistical software and Meta-DiSc 1.4. Quality Assessment for Studies of Diagnostic Accuracy 2 tool was used to access the quality of included studies. A bivariate mixed-effects model was applied to calculate the diagnostic indexes from included studies. RESULTS: A total of 5924 participants comprising 3161 cases and 2763 controls from 42 eligible studies were analyzed. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the area under the curve with 95% confidence intervals (95% CI) were as follows: 0.79 (0.75-0.82), 0.81 (0.78-0.84), 4.1 (3.5-4.8), 0.26 (0.22-0.31), 16 (12-21), and 0.87 (0.84-0.89), respectively. Sensitivity analysis suggested no study exclusively contributed to the heterogeneity, and Deeks' funnel plot asymmetry test indicated no potential publication bias (P = .09). CONCLUSIONS: The meta-analysis indicated that circulating exosomes could serve as effective and minimally invasive biomarkers for diagnosis of cancer, especially in patients with hepatocellular carcinoma or ovarian cancer, serum-based samples and exosomal proteins.

A nomogram for predicting 5-year incidence of type 2 diabetes in a Chinese population.

PURPOSE: To develop a nomogram for predicting 5-year incidence of type 2 diabetes (T2D) in Chinese adults. METHODS: This is a retrospective cohort study from a prospectively collected database. We included a total 32,766 adults free of T2D at baseline with a median follow-up of 3 years. Univariate and multivariate Cox regression analyses were applied to identify independent predictors. A nomogram was constructed to predict 5-year incident rate of T2D based on the multivariate analysis results. Harrell's C-indexes and calibration plots were used to evaluate the accuracy of the nomogram in both internal and external validations. RESULTS: The overall prevalence of T2D was 2.1%. Participants were randomly divided into a training set (n = 21,844) and a validation set (n = 10,922). After multivariate analysis in the training set, age, sex, BMI, hypertension, dyslipidemia, smoking status, and family history were found as risk predictors and integrated into the nomogram. Harrell's C-indexes were 0.815 (95% CI: 0.797-0.834) and 0.779 (95% CI: 0.747-0.811) in the training and validation sets, respectively. The calibration plots demonstrated good agreement between the estimated probability and the actual observation. CONCLUSION: Our nomogram could be a simple and reliable tool for predicting 5-year risk of developing T2D in high-risk Chinese. Through the model, early identifying high-risk individuals is helpful for timely intervention to reduce the incidence of T2D.