Cardiomyocyte senescence drives cardiovascular disease, underscoring the need to define its molecular mechanisms. The role of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel in this process remains unclear, particularly regarding its expression and function. Atrial tissues were collected from patients with sinus rhythm or atrial fibrillation (AF) of varying durations. CFTR was downregulated in AF patients and negatively correlated with p16, p21, and p53. Myocardial aging models were established using D-galactose (D-gal) in both mice and neonatal mouse cardiomyocytes (CMs). In both animal and cellular models, D-gal increased SA-β-gal positivity and senescence markers while decreasing CFTR. Overexpressing CFTR reduced D-gal-induced elevations in p16, p21, p53, and malondialdehyde (MDA), and restored superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities. Mechanistically, CFTR alleviates mitochondrial oxidative stress damage by enhancing plasma membrane Ca2+ ATPase (PMCA) activity to reduce cytoplasmic Ca2+ levels. Furthermore, we identified USP45 as a direct binding partner of CFTR, which deubiquitinates CFTR by specifically targeting K48-linked chains and the K688 residue. CFTR knockdown exacerbated D-gal-induced senescence and mitochondrial oxidative stress, which was rescued by USP45 overexpression. In conclusion, this study reveals a novel mechanism in which USP45-mediated deubiquitination of CFTR mitigates cardiomyocyte senescence and mitochondrial oxidative stress, offering a targeted intervention against age-related cardiovascular diseases.

ObjectiveTo investigate the risk factors for all-cause mortality of previously untreated pulmonary tuberculosis patients complicated by hypertension and construct a predictive model.MethodsWe retrospectively analyzed the clinical data of inpatients with previously untreated pulmonary tuberculosis complicated by hypertension from 2019 to 2021 in Changsha Central Hospital. Patients’ survival status and cardiovascular events were collected through telephone follow-up. LASSO regression was utilized to screen predictive variables, and binary logistic regression identified mortality risk factors. A predictive nomogram model was developed using R software, and its precision and reliability were verified.ResultsAmong the 1,014 patients, there were 100 (9.86%) deaths and 82 (8.09%) cardiovascular events. LASSO regression screened out 13 predictive variables. Multivariate logistic regression analysis revealed that smoking history, sputum bacteriology, pleural effusion, coronary heart disease, and chronic kidney disease were independent risk factors. Based on the training set data, a nomogram prognostic model was developed, showing an AUC of 0.712 (95% CI: 0.777-0.847), with 50.0% sensitivity and 84.3% specificity. The model’s fit was confirmed through internal and external validations.ConclusionThe prediction model constructed in this study has high predictive ability and satisfactory clinical efficacy, and can provide an effective individualized prediction tool for assessing all-cause mortality risk in patients with previously untreated pulmonary tuberculosis complicated by hypertension.

Purpose:To analyze the factors affecting patients' prognoses based on the community acquired-bloodstream infection patient data from 2017 to 2021. Patients and Methods:The data of 940 patients were retrieved, having at least one positive bilateral blood culture within 48 hours of hospitalization, and grouped into survivor and non-survivor groups. The clinical characteristics, laboratory results, causative pathogen and other indicators were collected and compared, and risk factors were identified by applying Cox proportional hazard regression model to the data. Results:Community acquired-bloodstream infection is most commonly caused by Escherichia coli, Klebsiella species and Staphylococcus hominis. Among the total of 940 selected patients, 52 (5.5%) died during hospitalization. The demographic parameters like age and gender, clinical protocols like maintenance hemodialysis, glucocorticoid use during hospitalization, catheter placement, procaicitonin, total protein, albumin, creatinine, uric acid contents and Sequential Organ Failure Assessment scores were significantly different between the survivor and non-survivor groups. The survival analysis results revealed that age (HR=1.02, 95% CI: 1.00-1.05, P=0.002), glucocorticoid use during hospitalization (HR=3.69, 95% CI: 1.62-8.37, P=0.021) and Sequential Organ Failure Assessment score (HR=1.10, 95% CI: 1.03-1.18, P=0.004) might be the risk factors affecting 30-day mortality in patients with community acquired-bloodstream infection. Conclusion:The identified risk factors may help guide clinical treatment protocol for patients with community acquired-bloodstream infection, providing more effective treatment strategy selection with improved clinical outcomes.

Purpose: Myocardial ischemic reperfusion injury (MIRI) is a crucial clinical problem globally.The molecular mechanisms of MIRI need to be fully explored to develop new therapeutic methods.Galangin (Gal), which is a natural flavonoid extracted from Alpinia Officinarum Hance and Propolis, possesses a wide range of pharmacological activities, but its effects on MIRI remain unclear.This study aimed to determine the pharmacological effects of Gal on MIRI.Methods: C57BL/6 mice underwent reperfusion for 3 h after 45 min of ischemia, and neonatal rat cardiomyocytes (NRCs) subjected to hypoxia and reoxygenation (HR) were cultured as in vivo and in vitro models.Echocardiography and TTC-Evans Blue staining were performed to evaluate the myocardial injury.Transmission electron microscope and JC-1 staining were used to validate the mitochondrial function.Additionally, Western blot detected ferroptosis markers, including Gpx4, FTH, and xCT.Results: Gal treatment alleviated cardiac myofibril damage, reduced infarction size, improved cardiac function, and prevented mitochondrial injury in mice with MIRI.Gal significantly alleviated HR-induced cell death and mitigated mitochondrial membrane potential reduction in NRCs.Furthermore, Gal significantly inhibited ferroptosis by preventing iron overload and lipid peroxidation, as well as regulating Gpx4, FTH, and xCT expression levels.Moreover, Gal up-regulated nuclear transcriptive factor Nrf2 in HR-treated NRCs.Nrf2 inhibition by Brusatol abolished the protective effect of Gal against ferroptosis.Conclusion: This study revealed that Gal alleviates myocardial ischemic reperfusion-induced ferroptosis by targeting Nrf2/Gpx4 signaling pathway.

The purpose of this trial was to evaluate the pharmacokinetics (PK), bioequivalence (BE), and safety of 2 preparations of hydroxychloroquine (200-mg tablet) under fasting and fed conditions. A total of 180 subjects (fasting condition: n = 80; fed condition: n = 100) were randomly enrolled in this randomized, open, single-dose, single-cycle parallel phase Ⅰ clinical study. Under the 2 conditions, the subjects were randomly administered the test (T) or reference (R) tablet, both at a dose of 200 mg (1 tablet). Liquid chromatography-tandem mass spectrometry was used to determine the concentration of hydroxychloroquine in healthy subjects after oral administration of the T or R preparation to evaluate the PK characteristics. In this trial, the T and R preparations of hydroxychloroquine were bioequivalent under both conditions within the range of 80%-125%. No serious adverse events (SAEs) were found in the safety assessments for either condition, and all adverse events (AEs) were mild, except for 2 moderate AEs in the fed condition, indicating good safety.

Sacubitril/valsartan is a commonly used medicine for treating heart failure (HF) patients, but the treatment effects significantly vary. Neprilysin (NEP) and carboxylesterase 1 (CES1) play an important role in the efficacy of sacubitril/valsartan. The purpose of this study was to explore the relationship between NEP and CES1 gene polymorphisms and the efficacy and safety of sacubitril/valsartan treatment in HF patients. Genotyping of 10 single nucleotide polymorphisms (SNPs) of the NEP and CES1 genes in 116 HF patients was performed by the Sequenom MassARRAY method, and logistic regression and haplotype analysis were used to evaluate the associations between SNPs and the clinical efficacy and safety of sacubitril/valsartan in HF patients. A total of 116 Chinese patients with HF completed the whole trial, and T variations in rs701109 in NEP gene were an independent risk factor (P = 0.013, OR = 3.292, 95

OBJECTIVE To evaluate the pharmacokinetics (PK), safety, and bioequivalence of two formulations of apixaban in healthy Chinese subjects under fasting and fed conditions. MATERIALS AND METHODS A single-center, randomized, open, single-dose, two-period crossover PK study was carried out under fasting and fed conditions in 64 healthy subjects enrolled in either the fasting (36 subjects) or the fed (28 subjects) arms of the study. Subjects received a single oral dose of 2.5 mg apixaban tablets as test (T) or reference (R) formulation. The primary PK parameters determined were the area under the plasma concentration-time curve from zero to t and ∞ (AUC0-t and AUC0-∞) and the maximal plasma concentration (Cmax). Safety was assessed mainly from the occurrence of adverse events (AEs). RESULTS A single drop-out in the fed arm of the trial was excluded from the statistical evaluation. The 90% confidence intervals (CIs) for the geometric mean ratio (GMR) for T/R using AUC0-t were 95.4 - 100.9% and 97.8 - 103.8%, and for AUC0-∞ were 95.3 - 100.6% and 98.3 - 104.3% under fasting (36 subjects) and fed (27 subjects) conditions, respectively. Similarly, the 90% CIs for Cmax were 94.6 - 103.1% and 88.8 - 102.0% under fasting (36 subjects) and the fed (27 subjects) conditions, respectively. Therefore, the 90% CIs for the T/R AUC and Cmax ratios were within the standard range for bioequivalence (80.0 - 125.0%). There were no serious adverse events (SAEs). CONCLUSION The test and reference 2.5 mg apixaban tablets were bioequivalent and both showed good tolerability and safety.

Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM. The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018–September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval. Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28–63) vs. 56 days (IQR 28–84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035). Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.