Objective. The objective of this study was to investigate the involved mechanisms of advanced glycation end product‐ (AGE‐) exacerbated atherosclerosis (AS). Methods. Toll‐like receptor 4 (TLR4) inhibitor was administrated to type 2 diabetes mellitus (T2DM) AS rats. Atherosclerotic plaque, M1 macrophage infiltration, and VSMCs phenotypes were evaluated. AGE‐exposed primary macrophages were treated with specific siRNAs knocking down receptor for AGEs (RAGE) and TLR4. Phenotypes of M1 macrophage and VSMCs were identified by fluorescent stains. Contact and noncontact coculture models were established. VSMCs and macrophages were cocultured in these models. ELISA was used to detect inflammatory cytokine concentrations. Relative mRNA expression levels were determined by real‐time PCR. Relative protein expression and phosphorylation levels were evaluated by Western blots assays. Results. TLR4 inhibitor treatment significantly reduced arterial stenosis, infiltration of M1 polarized macrophages, and contractile‐to‐synthetic phenotype conversion of VSMCs in DM AS animals. RAGE and TLR4 silencing dramatically reduced AGE‐induced macrophage M1 polarization, inflammatory cytokine secretion, and RAGE/TLR4/forkhead box protein C2 (FOXC2)/signaling which inhibited delta‐like ligand 4 (Dll4) expression in macrophages. AGE‐treated macrophages induced VSMC phenotypic conversion via activating Notch pathway in a contact coculture model rather than a noncontact model. The VSMC phenotypic conversion induction capability of macrophages was attenuated by RAGE and TLR4 silencing. Conclusions. AGEs induced activation of RAGE/TLR4/FOXC2 signaling, which featured macrophage with Dll4 high expression during M1 polarization. These macrophages promoted contractile‐synthetic phenotypic conversion of VSMCs through the Dll4/Notch pathway after direct cell‐to‐cell contacts.

Background: Epidemiological evidence of the associations between metal exposure and gout-related outcomes (including serum uric acid [SUA], hyperuricemia and gout) is scarce. The aim of the study is to investigate the associations of metal exposure with SUA, hyperuricemia and gout in general adults.Methods: In this study, the exposure to five blood metals (mercury, manganese, lead, cadmium and selenium) of general adults was analyzed based on the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018 (n = 14,871). Linear, logistic and weighted quantile sum (WQS) regression models were applied to examine the associations of blood metals with gout-related outcomes. Possible dose-response relationships were analyzed through restricted cubic spline regression.Results: Compared with the lowest quartile of blood metals, mercury (quartile 2 and 4), lead (quartile 2, 3, and 4) and selenium (quartile 2 and 4) were found to be positively correlated with SUA and hyperuricemia. Higher levels of mercury and lead were associated with gout, but only those in the fourth quartile had statistical significance (OR [95%CI]: 1.39 [1.10-1.75] and 1.905 [1.41-2.57]) respectively). The WQS index of the blood metals was independently correlated with SUA (β [95%CI]: 0.17 [0.13-0.20]), hyperuricemia (OR [95%CI]: 1.29 [1.16-1.42]) and gout (OR [95%CI]: 1.35 [1.15-1.58]). Among them, lead was the most heavily weighted component (weight = 0.589 for SUA, 0.482 for hyperuricemia, and 0.527 for gout). In addition, restricted cubic spline regression models showed a linear association of lead with the prevalence of hyperuricemia and gout.Conclusion: Our results suggested that blood metal mixtures were positively associated with gout-related outcomes, with the greatest effect coming from lead.

Background and aims: Flavonoids are a class of secondary plant metabolites that have been shown to have multiple health benefits, including antioxidant and anti-inflammatory. This study was to explore the association between dietary flavonoid consumption and the prevalence of chronic respiratory diseases (CRDs) in adults. Methods and results: The six main types of flavonoids, including isoflavones, anthocyanidins, flavan-3-ols, flavanones, flavones, and flavonols, were obtained from the National Health and Nutrition Examination Survey (NHANES) 2007–2010 and 2017–2018 by the two 24-h recall interviews. The prevalence of CRDs, including asthma, emphysema, and chronic bronchitis, was determined through a self-administered questionnaire. The analysis included 15,753 participants aged 18 years or older who had completed a diet history interview. After adjustment for potential confounders, the inverse link was found with total flavonoids, anthocyanidins, flavanones, and flavones, with an OR (95%CI) of 0.86 (0.75–0.98), 0.84 (0.72–0.97), 0.80(0.69–0.92), and 0.85(0.73–0.98) for the highest group compared to the lowest group. WQS regression revealed that the mixture of flavonoids was negatively linked with the prevalence of CRDs (OR = 0.88 [0.82–0.95], P < 0.01), and the largest effect was mainly from flavanones (weight = 0.41). In addition, we found that flavonoid intake was negatively linked with inflammatory markers, and systemic inflammation significantly mediated the associations of flavonoids with CRDs, with a mediation rate of 12.64% for CRP (P < 0.01). Conclusion: Higher flavonoid intake was related with a lower prevalence of CRDs in adults, and this relationship may be mediated through systemic inflammation.

Cardiovascular health (CVH) is a key determinant of mortality, but the comparative effectiveness of different CVH metrics remains uncertain. Life’s Simple 7 (LS7) evaluates seven domains: smoking, body mass index, physical activity, total cholesterol, blood pressure, fasting glucose, and diet. Life’s Essential 8 (LE8) adds sleep health, while Life’s Crucial 9 (LC9) further includes mental health. This study aimed to assess whether the additional components in LE8 and LC9 enhance mortality prediction compared to LS7. Data from 22,382 participants in the NHANES 2005–2018 were analyzed. Cox proportional hazards regression models were used to evaluate the associations between the scores of these metrics and all-cause, cardio-cerebrovascular disease (CCD), and CVD mortality. The predictive performance of each metric was assessed via receiver operating characteristic (ROC) curves and area under the curve (AUC) values. The participants had a mean age of 45.23 ± 0.23 years, and 51.53% were female. During a median follow-up of 7.75 (4.42–11.08) years, there were 1,483 all-cause deaths, 405 CCD deaths, and 337 CVD deaths. Compared with participants with LS7 scores ≤ 4, those with scores ≥ 11 had a 65% (HR = 0.35 [0.25–0.50]) lower risk of all-cause mortality, a 66% (HR = 0.34 [0.16–0.73]) lower risk of CCD mortality, and a 61% (HR = 0.39 [0.18–0.85]) lower risk of CVD mortality. Similar trends were observed for LE8 and LC9. The AUC for LS7 (0.68 [0.66–0.70]) was slightly greater than that for LE8 (0.67 [0.65–0.69], P = 0.007) and LC9 (0.67 [0.65–0.69], P = 0.019) in predicting all-cause mortality at 5 years; however, the overall predictive performance was nearly identical across all three metrics. Furthermore, the addition of LS7 (AUC = 0.84 [0.82–0.86], P < 0.001), LE8 (AUC = 0.84 [0.82–0.86], P < 0.001), and LC9 (AUC = 0.84 [0.83–0.86], P < 0.001) to the baseline model (AUC = 0.83 [0.82–0.85]) significantly improved all-cause mortality predictions at 5 years; however, the actual gains in predictive performance were marginal. LS7, LE8, and LC9 all predict mortality effectively. Given its simpler scoring and fewer components, LS7 demonstrates comparable predictive performance to LE8 and LC9, making it a more practical tool for clinical and public health applications.

Aims Sarcolipin (SLN) is a key regulator of sarcoplasmic reticulum calcium‐ATPase (SERCA)2a, which handles intracellular calcium re‐uptake. This study was aimed to investigate the involvement of SLN in post‐myocardial infarction (MI) heart failure (HF) in diabetes. Methods and results Diabetes/MI rat models were established. Altered SLN expression in diabetic hearts was screened out by microarray. A myocardiotropic viral vector was used to deliver siRNA to silence SLN. DNA methylation was evaluated by bisulfite sequencing. Cardiac functions were evaluated by invasive haemodynamic examinations. The SERCA2a activity, cytoplasmic calcium concentration ([Ca²⁺]_i), calcium spark, and myocyte contraction were detected. Correlation between HF and diabetes was analysed in a cohort consisted of 101 ST‐segment elevated myocardial infarction (STEMI) patients between 2017 and 2019 [53.54 ± 4.64 years old; 61.4% male gender; HbA1c% 6.15 ± 2.00; and left ventricular ejection fraction (LVEF%) 40.64 ± 3.20%]. SLN expression was evaluated in left ventricular tissue sample from six STEMI patients complicated with diabetes and six STEMI patients without diabetes. Expressions of DNA methyltransferase 1a and DNA methyltransferase 3 were reduced in diabetic hearts, leading to down‐regulation of SLN promoter methylation, resulting in increased SLN expression in rats. Impaired heart systolic functions were found in experimental diabetic MI rats, which were attenuated by SLN silencing. SERCA2a activity reduction and [Ca²⁺]_i elevation were attenuated by SLN silencing in diabetic animal hearts and high‐glucose incubated primary myocytes. SLN silencing suppressed calcium sparks and improved contraction and sarcoplasmic reticulum calcium re‐uptake in high‐glucose incubated primary myocytes. Expression of SLN was up‐regulated in LV sampled from STEMI patients complicated with diabetes compared with non‐diabetic ones (P < 0.05). LVEF% was reduced in STEMI patients complicated with diabetes compared with non‐diabetic ones (P < 0.01). HbA1c% and LVEF% was related (r = −0.218, P = 0.028). Increased HbA1c% was correlated with reduced LVEF% after adjustment for age, sex, body mass index, cigarette smoking, creatinine, UA, low density lipoprotein, K⁺, Na⁺, and troponin I (adjusted odds ration = 0.75, 95% confidence interval 0.62–0.90, P = 0.002). Conclusions Diabetes increases the vulnerability of STEMI patients to post‐MI HF by down‐regulating SLN promoter methylation, which further regulates SERCA2a activity via increasing cardiac SLN expression.

Objective: To study the general efficacy of hydromorphone as a systemic analgesic in postoperative pain management following single-port video-assisted thoracoscopic surgery (VATS) and to explore the optimal administration regimen. Methods: A prospective, randomized, double-blind study was designed and conducted in a tertiary hospital. In total, 157 valid patients undergoing single-port VATS were randomly allocated into three groups. A total of 53 patients received morphine bolus only for postoperative analgesia (Group Mb); 51 patients received a hydromorphone background infusion plus bolus (Group Hb + i), and 53 patients received a hydromorphone bolus only (Group Hb). The primary outcomes were patient-reported static and dynamic pain levels; the secondary outcomes included side effects, sleep quality, and recovery indexes. Results: Patients in Group Hb + i experienced lower pain intensity (approximately 10 out of 100 on the visual analog scale) in both static pain and dynamic pain in the days following surgery (P<0.01), better sleep quality during the first night only (P=0.002), and a higher satisfaction level than those in the other two groups (P=0.006). A comparison of these variables in Group Mb and Group Hb resulted in no significant differences. Lastly, side effects and recovery indexes remained the same among bolus-only groups and bolus-plus-background-infusion groups. Conclusion: There is no advantage to administering hydromorphone over morphine using bolus only mode. Within 24 h after surgery, a background infusion should be considered as a part of a standard protocol for patient-controlled intravenous analgesia. At 24 h after surgery, the background infusion should be adjusted in accordance with patient preferences and pain intensity.