The respiratory epithelium acts as the airway's first physical barrier against invading pathogens, mainly relying on mucociliary clearance (MCC) and apical junctional complexes (tight junctions/TJs and adherens junctions/AJs) for barrier function. Primary airway epithelial cells cultured in the air-liquid interface (ALI) system can well mimic these characteristics in vitro. This study established and characterized well-differentiated ALI-cultured goat airway epithelial cells (ALI-GAECs), and developed a CPIV3 infection model therein, verifying the apical infection and release of CPIV3 in ALI-GAECs. CPIV3 infection impaired the barrier function of ALI-GAECs, as reflected by decreased trans-epithelial electrical resistance (TEER), increased FITC-Dextran permeability, and reorganization of the ZO-1 and F-actin meshwork. Mechanistically, RT-qPCR and Western blot analyses demonstrated that CPIV3 downregulated major TJ proteins (ZO-1, occludin, claudin-1) while upregulated the expression of proinflammatory cytokines (TNF-α, IL-1β, IL-4, IL-6). The NF-κB signaling pathway, but not the MAPK pathways, was activated upon viral infection. Treatment with the NF-κB inhibitor BAY 11-7082 partially restored the expression of TJ proteins and proinflammatory cytokines. Collectively, the activation of the NF-κB pathway and subsequent production of proinflammatory cytokines is responsible for CPIV3-induced TJ disruption. In addition, the developed ALI-GAECs model provides a valuable in vitro tool for investigating the pathogenesis of CPIV3 and other caprine respiratory pathogens.

Myocardial injury and adverse remodeling following acute myocardial infarction (MI) drive heart failure progression, in which cardiomyocyte pyroptosis plays a critical pathogenic role. Bone morphogenetic protein 7 (BMP7) exerts anti-fibrotic and anti-inflammatory effects; however, its role in regulating pyroptosis during post-infarction cardiac repair remains unclear. We found that plasma BMP7 levels were markedly reduced in patients with chronic MI, showing a positive association with left ventricular ejection fraction and a negative correlation with myocardial fibrosis quantified by late gadolinium enhancement cardiac magnetic resonance imaging. In a mouse MI model, cardiomyocyte-specific BMP7 overexpression or exogenous BMP7 supplementation preserved cardiac function, reduced infarct size, and attenuated fibrosis and pyroptosis, whereas pharmacological inhibition of BMP7 with DMH-1 aggravated myocardial dysfunction and fibrosis. In primary neonatal rat ventricular myocytes, hypoxia induced BMP7 downregulation with increased pyroptosis, which was reversed by recombinant BMP7, while siRNA-mediated BMP7 knockdown further promoted pyroptotic death. BMP7 also suppressed the transition of cardiac fibroblasts into myofibroblasts. Mechanistically, BMP7 suppressed NF-κB p65 nuclear translocation, thereby limiting NLRP3 inflammasome activation and reducing pyroptosis. These findings identify BMP7 as a cardioprotective factor mitigating myocardial injury and remodeling after MI through NF-κB/NLRP3 inhibition, suggesting BMP7 as a potential therapeutic target for preventing heart failure. Schematic illustration of the protective role of BMP7 against post-myocardial infarction injury through inhibition of NF-κB/NLRP3-mediated cardiomyocyte pyroptosis and fibroblast activation

BackgroundThe Cardiometabolic Index (CMI) serves as a measurable indicator capable of concurrently reflecting the presence of metabolic disorders and the status of central obesity. The aim of this study is to evaluate the association between the CMI and the risk of developing major adverse cardiovascular events (MACEs) and all-cause mortality in patients with type 2 diabetes mellitus (T2DM).MethodsThis post-hoc analysis included 10,094 participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and the ACCORD Follow-up study with baseline CMI data. The natural logarithm (ln) of each CMI measurement was computed. Univariate and multivariate Cox proportional hazard regression analyses were conducted to examine the relationship between CMI and the risk of MACEs and all-cause mortality. The incremental predictive value of CMI was further assessed.ResultsOver a median follow-up period of 8.82 years, 1,791 (17.74%) participants experienced MACEs, and 1,914 (18.96%) all-cause mortality were recorded. After adjusting for traditional cardiovascular risk factors, multivariate Cox proportional hazards regression analysis demonstrated a significant association between CMI and the risk of MACEs and all-cause mortality. Incorporating CMI into the conventional risk model improved the predictive efficacy for MACEs and all-cause mortality.ConclusionsElevated CMI is associated with an increased risk of MACEs and all-cause mortality in patients with T2DM. Furthermore, CMI improves the predictive performance for MACEs and all-cause mortality risk in this patient population.

Respiratory diseases induced by Mycoplasma species, mainly Mycoplasma capricolum subsp. capripneumoniae (Mccp) and Mycoplasma ovipneumonia (Mo), pose a major threat to goat/sheep farming. This study investigated the biological characteristics and antimicrobial susceptibility of Mccp isolates that suddenly spread extensively in China in the first half of 2024. A total of 34 Mccp isolates were obtained from goats with suspected contagious caprine pleuropneumonia (CCPP) across multiple provinces during 2024-2025. All isolates were purified and confirmed via a PCR targeting the arcD gene and exhibited characteristic "fried egg" colony morphology. Phylogenetic analysis based on the arcD gene and multi-locus sequence analysis (MLSA) of eight genetic loci revealed that the circulating strains shared high homology and belonged to Group 1 within Lineage 1, which showed a close genetic relationship with isolates from Qatar and the United Arab Emirates, while differing from previously reported strains in China. Antimicrobial susceptibility testing against nine antimicrobial drugs indicated that the Mccp isolates generally exhibited low resistance levels. However, some strains showed reduced susceptibility to florfenicol and lincomycin. These findings highlight the emergence of a genetically distinct Mccp lineage in China and underscore the importance of ongoing surveillance, strain characterization, and prudent antimicrobial use in CCPP control.

Mycoplasma ovipneumoniae is a primary causative agent of pneumonia in ruminants, causing chronic non-progressive pneumonia in domestic sheep and goats, but leading to higher morbidity and mortality in bighorn sheep and wild small ruminants. This disease has become a widespread epidemic, resulting in significant losses to the sheep industry. In this study, we evaluated the immunogenicity and initial protective effects of four antigenic proteins of M. ovipneumoniae, namely Eno, EF-Tu, Ulad, and T4SS. These proteins were used to immunize BALB/c mice either individually or in a combination (rProteins group). The mice were intranasally infected with 109 CCU50/mL M. ovipneumoniae strain NJ01 twice, on days 28 and 30 after immunization. Among the four recombinant proteins, rEno demonstrated the most promising results in terms of inducing specific humoral and cellular immune responses. It also resulted in the lowest lung lesion scores and the lowest M. ovipneumoniae loads in the lungs and bronchoalveolar lavage fluid (BALF). Compared to the other three proteins, rEno provided superior protection. Furthermore, the rEno vaccine significantly reduced the inflammatory response in the lungs of mice, as evidenced by the evaluation of pro-inflammatory cytokines. The expression of IL-1β and NF-κB was significantly reduced, while the expression of IL-4 was significantly increased. In conclusion, the rEno vaccine elicited a favorable immunological response and conferred protection against M. ovipneumoniae. This finding presents a novel approach to controlling the global spread of this pathogen.

Macrophages are considered the first line of defence against Mycoplasma pneumoniae infection in sheep, and their polarization significantly affects lung tissue damage and remodelling. Here, we collected sheep bronchoalveolar lavage fluid (BALF) 28 days after infection with Mycoplasma ovipneumoniae (MO). RNA-seq analysis revealed a significant increase in peptidyl arginine deiminase 2 (PADI2) expression in the MO group, and upregulated genes were significantly enriched in the “FoxO signalling pathway” and “AMPK signalling pathway”. Immunohistofluorescence (IHF) staining revealed a significant increase in the number of macrophages, which were widely distributed in the alveolar cavity, in the MO infection group, and PADI2 was also positively expressed in the macrophages. In bone marrow-derived macrophages (BMDMs) isolated in vitro, inhibiting the expression of PADI2 induced infected macrophages to polarize towards alternatively activated (AAM, M2) macrophages. Moreover, the expression levels of the anti-inflammatory gene IL10 and tissue repair-related genes such as vascular endothelial growth factor alpha (VEGFA), transforming growth factor-β (TGF-β), and hepatocyte growth factor (HGF) significantly increased. In an in vitro coculture system, inhibition of PADI2 expression in BMDMs reduced apoptotic and intracellular reactive oxygen species (ROS) levels in lung fibroblasts. Interestingly, correlation analysis between the tracheal MO load and PADI2 expression in the bronchoalveolar lavage fluid of naturally infected MO sheep revealed that the higher the MO load was, the greater the PADI2 expression. A dual luciferase reporter assay confirmed that this process may be regulated by the transcription factor SP3. These results contribute to the understanding of the polarization state of macrophages after mycoplasma infection and to the preliminary exploration of PADI2 as an effective target to enhance host defence against MO infection. Targeting PADI2 to promote the polarization of M2 macrophages provides a promising approach for treating MO infection or preparing anti-Mycoplasma pneumonia gene-edited sheep.

BACKGROUND:Although recent studies have reported the reliability of triglyceride-glucose index (TyG) as a biomarker for evaluation of insulin resistance, the research exploring the association of TyG-body mass index (BMI) with major cardiovascular outcomes and all-cause mortality among the type 2 diabetes mellitus (T2DM) population remains scarce. AIM:To ascertain whether TyG-BMI correlates with cardiovascular outcomes and mortality risk in individuals diagnosed with T2DM. METHODS:Data were drawn from the ACCORD trial and its subsequent follow-up (ACCORDION), which together included 10190 participants. To evaluate the associations of TyG-BMI with future cardiovascular outcomes and overall mortality risk among T2DM patients, Cox's proportional-hazards model was employed. Non-linear associations and thresholds were investigated by performing restricted cubic spline regression, fitting smooth curves, and conducting piecewise regression. Additionally, we examined whether the above findings were robust through interaction and subgroup analyses. The robustness of results was further verified by a series of sensitivity assessments. Through the area under the receiver operating characteristic curve estimation, the incremental predictive power of TyG-BMI beyond conventional risk factors was also evaluated. RESULTS:Applying multivariable Cox regression analysis, we identified a significant correlation of TyG-BMI with both cardiovascular outcomes and overall mortality. Specifically, after adjusting for multiple confounders, the cardiovascular mortality, congestive heart failure (CHF) and overall mortality risks in the highest TyG-BMI quartile were 1.74, 2.65 and 1.42 times greater, respectively, when compared to the lowest quartile. The analysis revealed that TyG-BMI was linked nonlinearly to both types of mortality, while a two-stage linear regression discerned inflection points at 252.77 for cardiovascular mortality and 245.90 for overall mortality. TyG-BMI was found to correlate positively with future CHF. Additionally, introducing TyG-BMI into conventional prediction models resulted in a substantial improvement of their predictability for cardiovascular outcomes and overall mortality when compared to incorporating TyG or BMI alone. CONCLUSION:Among T2DM individuals, a higher TyG-BMI is linked strongly to elevated risks of cardiovascular outcomes and overall mortality, highlighting its utility as a predictive marker for these risks.

Increasing antibiotic resistance in Mycoplasma hyopneumoniae (Mhp) necessitates alternative treatments. Piper sarmentosum extracts (PSE) and guava extracts (GE) show promise due to their antimicrobial and antioxidant properties. This study evaluates the combined in vitro effects of PSE and GE against Mhp and their antioxidant activities. Anti-Mhp activity was assessed using microdilution minimum inhibitory concentration (MIC) and synergy via fractional inhibitory concentration index (FICI), while antioxidant capacity was measured with 2,2'-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and ferric reducing antioxidant power (FRAP) assays for individual extracts, and a 1:1 mixture (based on the results of FICI). Phytochemical profiling used high performance liquid chromatography (HPLC) to quantify main six bioactive compounds. HPLC showed PSE contained vitexin-2-O-rhamnoside (8.58 mg/g) and pellitorine (3.31 mg/g); GE had quercetin-3-O-glucuronide (6.85 mg/g), quercetin (3.72 mg/g), isoquercitrin (0.51 mg/g), and avicularin (1.37 mg/g). PSE (MIC 0.78 mg/mL) and GE (MIC 0.39 mg/mL) exhibited anti-Mhp effects, with their 1:1 combination being additive (FICI=0.75) and reducing MIC to 0.195 mg/mL. This mix also enhanced antioxidant activity by 9.0% in ABTS and 27.0% in FRAP assays. The 1:1 combination of PSE and GE demonstrated superior anti-Mhp activity (additive effect) and enhanced antioxidant properties (synergistic effect) compared to the individual extracts. These findings highlight the potential of these extracts as phytopharmaceutical agents.

BACKGROUND AND AIM:Recent studies have identified the weight-adjusted waist index (WWI) as a novel anthropometric measure strongly associated with metabolic diseases and mortality. However, it remains unclear whether cumulative exposure to WWI influences the risk of all-cause mortality among patients with type 2 diabetes mellitus (T2DM).This study aims to assess how baseline WWI and cumulative WWI are linked to all-cause mortality in patients with T2DM and their predictive value. METHODS AND RESULTS:This study used data from the ACCORD/ACCORDION clinical trial. Baseline WWI and cumulative WWI were calculated for the first three follow-up visits. The Kaplan-Meier survival curve and the Cox proportional hazards regression model were employed to investigate the relationship between WWI and all-cause mortality. RCS and smooth curve fitting techniques were employed to find possible nonlinear associations. Predictive ability was assessed via AUC, NRI, and IDI. Over 6.61 median follow-up years, 1274 deaths occurred. Each 1-unit increase in baseline and cumulative WWI raised mortality risk by 15 % (HR = 1.15, 95 % CI: 1.06-1.24) and 8 % (HR = 1.08, 95 % CI: 1.05-1.11), respectively. Highest WWI quartiles had 1.29-fold (baseline) and 1.49-fold (cumulative) higher mortality risks. Cumulative WWI showed a linear association with mortality risk, while baseline WWI exhibited a U-shaped relationship (inflection point: 10.236). Cumulative WWI had superior predictive ability. CONCLUSIONS:WWI independently predicts mortality in T2DM patients, with cumulative WWI being more stable and predictive. WWI may serve as an additional factor to be considered for long-term risk stratification and personalized management in T2DM.

BACKGROUND Recent studies have indicated that triglyceride glucose (TyG)-waist height ratio (WHtR) and TyG-waist circumference (TyG-WC) are effective indicators for evaluating insulin resistance. However, research on the association in TyG-WHtR, TyG-WC, and the risk and prognosis of major adverse cardiovascular events (MACEs) in type 2 diabetes mellitus (T2DM) cases are limited. AIM To clarify the relation in TyG-WHtR, TyG-WC, and the risk of MACEs and overall mortality in T2DM patients. METHODS Information for this investigation was obtained from Action to Control Cardiovascular Risk in Diabetes (ACCORD)/ACCORD Follow-On (ACCORDION) study database. The Cox regression model was applied to assess the relation among TyG-WHtR, TyG-WC and future MACEs risk and overall mortality in T2DM cases. The RCS analysis was utilized to explore the nonlinear correlation. Subgroup and interaction analyses were conducted to prove the robustness. The receiver operating characteristic curves were applied to analysis the additional predicting value of TyG-WHtR and TyG-WC. RESULTS After full adjustment for confounding variables, the highest baseline TyG-WHtR cohort respectively exhibited a 1.353-fold and 1.420-fold higher risk for MACEs and overall mortality, than the lowest quartile group. Similarly, the highest baseline TyG-WC cohort showed a 1.314-fold and 1.480-fold higher risk for MACEs and overall mortality, respectively. Each 1 SD increase in TyG-WHtR was significantly related to an 11.7% increase in MACEs and a 14.9% enhance in overall mortality. Each 1 SD increase in TyG-WC corresponded to an 11.5% in MACEs and a 16.6% increase in overall mortality. Including these two indexes in conventional models significantly improved the predictive power for MACEs and overall mortality. CONCLUSION TyG-WHtR and TyG-WC were promising predictors of MACEs and overall mortality risk in T2DM cases.

Monomethyl fumarate (MMF), the active metabolite of dimethyl fumarate, an immunomodulatory drug approved for multiple sclerosis and psoriasis, has emerging potential in ischemic heart disease. We investigated whether MMF can attenuate myocardial infarction (MI) injury and delineated the underlying mechanisms, focusing on hydroxycarboxylic acid receptor 2 (HCAR2, also known as GPR109A) and PI3K/Akt signaling. In a mouse MI model induced by permanent left anterior descending coronary artery ligation, MMF administration prior to ischemia significantly preserved left ventricular function and reduced cardiomyocyte apoptosis compared with untreated MI. Echocardiography and pressure–volume loop analyses demonstrated higher ejection fraction and cardiac output in MMF-treated MI mice, accompanied by attenuation of adverse ventricular remodeling. TUNEL staining and analysis of apoptotic markers showed that MMF decreased myocardial cell death and caspase-3 activation in vivo, while concomitantly upregulating HCAR2 expression and enhancing Akt phosphorylation in ischemic myocardium. In vitro, MMF protected HL-1 cardiomyocytes from CoCl₂-induced hypoxic injury, improving cell viability and reducing apoptosis, as evidenced by fewer TUNEL-positive cells and a lower Bax/Bcl-2 ratio compared with hypoxia alone. Pharmacological inhibition of Gi-coupled signaling with pertussis toxin or siRNA-mediated knockdown of HCAR2 abolished MMF’s cytoprotective effects and blunted MMF-induced Akt phosphorylation, and PI3K/Akt pathway inhibition eliminated MMF’s anti-apoptotic benefits in vitro. Collectively, these findings demonstrate that MMF markedly reduces ischemic cardiomyocyte injury via an HCAR2-dependent mechanism involving activation of the pro-survival PI3K/Akt pathway, establishing a novel cardioprotective role for MMF and supporting its translational potential as a therapeutic strategy to mitigate acute MI injury.

This study investigates the association between a novel index, TyG-WWI (triglyceride-glucose-weight-adjusted waist index), and cardiovascular outcomes and total mortality (TM) in patients with type 2 diabetes mellitus (T2DM), and evaluates its predictive value. Data from 10,092 participants in the ACCORD/ACCORDION trials were analyzed using Cox regression, restricted cubic splines (RCS), and smooth curve fitting (SCF). Subgroup and sensitivity analyses tested robustness. Predictive ability was assessed using area under curve (AUC), net reclassification index (NRI), and integrated discrimination improvement(IDI). Higher TyG-WWI was significantly associated with increased risk of major adverse cardiovascular events (MACEs), major coronary heart disease (CHD), congestive heart failure (CHF), and total mortality (TM). Per 1-SD increase in TyG-WWI, risks rose by 11% for MACEs, 8% for major-CHD, 28% for CHF, and 12% for TM. RCS and SCF identified a nonlinear association with TM, with a turning point observed at a TyG-WWI value of 96.574. Subgroup and sensitivity analyses confirmed result stability. TyG-WWI outperformed TyG alone in predictive accuracy. A significant positive linear association exists between TyG-WWI and adverse cardiovascular outcomes in T2DM patients, while a U-shaped relationship is observed with TM. TyG-WWI is an independent predictor of future cardiovascular outcomes and TM in T2DM patients.Trial registration number NCT00000620, Clinical Trial URLs: https://clinicaltrials.gov/ct2/show/NCT00000620 , Registration Date: 1999-10-27.

Mycoplasma pneumonia is a chronic respiratory disease that seriously affects the health of sheep. To date, little information is available about the damage caused by Mycoplasma ovipneumoniae (MO) pneumonia to host lungs. Here, after sheep were infected with MO for 28 days, severe inflammatory reactions and pathological damage occurred. By using single-cell RNA sequencing (scRNA-seq), all the transcriptome changes in 11 cell types in sheep lung tissue were systematically analyzed, and the key biological processes regulating inflammation and immunity were identified. Moreover, we constructed both intercellular communication models and differential expression maps of key regulatory genes for each cell subgroup. We also specifically focused on the response of T cell subpopulations and neutrophils to MO infection. Long-term infection may affect an organism's immune response, inhibit intercellular communication, and highlight the important role of the cyclophilin A (CypA) and macrophage migration inhibitory factor (MIF) pathways in intercellular communication. Notably, MO infection decreased the toxicity of CD8 effector T cells and depleted regulatory T cells, thus inhibiting normal cell function. Subsequently, emphasis was placed on the important role of the neutrophil marker gene S100A9 in promoting neutrophil clearance of MO through activation of the ERK signaling pathway and reactive oxygen species (ROS) burst in vitro. These results contribute to understanding the progression of MO infection in the lungs and provide a rich database on the molecular basis of the response to different cell types in MO infection.

With the rapid development of cattle industry, bovine viral diarrhea virus (BVDV) is becoming widespread in China, which causes serious economic losses to the industry. Effective vaccination and viral surveillance are critical for the prevent and control of BVDV infection. In the present study, the immunogenic domain of E2 protein of BVDV-1 was expressed by prokaryotic pET-28a vector. Monoclonal antibodies (mAbs) against E2 protein were prepared and systemically examined by western blot, immunofluorescence assay, blocking ELISA (bELISA) and virus neutralization test (VNT). The mAb 1E2B3, which showed good reactivity and neutralizing activity to BVDV-1 strains, was selected for ELISA establishment. After a series of screening and optimization, a novel bELISA for highly sensitive and specific detection of BVDV-1 antibodies was established, using HRP-labeled 1E2B3 and recombinant E2 protein. ROC analysis of 91 positive and 84 negative reference bovine serum samples yielded the area under the curve (AUC) of 0.9903. A diagnostic specificity of 96.43 % and a sensitivity of 95.6 % were achieved when the cutoff value was set at 24.31 %. There was no cross reaction to the positive sera of classical swine fever virus (CSFV), BVDV-2, border disease virus (BDV), bovine parainfluenza virus type 3 (BPIV3), infectious bovine rhinotracheitis virus (IBRV), foot-and-mouth disease virus (FMDV), Mycoplasma bovis (M.bovis) and Brucella. The total agreement rate of bELISA with VNT was 93.96 % (249/265). In addition, the result of bELISA was positively correlated with neutralizing antibody titer, and the bELISA could well distinguish the serum samples before and after BVDV vaccination. These results indicate that the established bELISA in this study is specific, sensitive, simple and convenient, which provides technical support for the vaccine efficacy evaluation, prevention and control of BVD in the future.

Doxorubicin induces myocardial injury and fibrosis. Still, no effective interventions are available. AP39 is an H2S donor that explicitly targets mitochondria. This study investigated whether AP39 could improve doxorubicin-induced myocardial fibrosis. Doxorubicin induced significant myocardial fibrosis while suppressing mitophagy-related proteins and elevating pyroptosis-related proteins. Conversely, AP39 reverses these effects, enhancing mitophagy and inhibiting pyroptosis. In vitro experiments revealed that AP39 inhibited H9c2 cardiomyocyte pyroptosis, improved doxorubicin-induced impairment of mitophagy, reduced ROS levels, ameliorated the mitochondrial membrane potential, and upregulated AMPK-ULK1-FUNDC1 expression. In contrast, AMPK inhibitor (dorsomorphin) and ULK1 inhibitor (SBI-0206965) reversed AP39 antagonism of doxorubicin-induced FUNDC1-mediated impairment of mitophagy and secondary cardiomyocyte pyroptosis. These results suggest that mitochondria-targeted H2S can antagonize doxorubicin-induced pyroptosis and impaired mitophagy in cardiomyocytes via AMPK-ULK1-FUNDC1 and ameliorated myocardial fibrosis and remodeling.

Mycoplasma hyopneumoniae(Mhp)and Mycoplasma ovip-neumoniae(Mo),similar to Mycoplasma pneumoniae(Mp),initiate a chronic respiratory infection with concomitant pulmonary disease,causing substantial harm worldwide.1 A mouse model with genetic consistency helped to elucidate the unknown pathogenic mechanism of respiratory myco-plasmas in large animals and humans.

AimsThe efficacy of intensive blood pressure (BP) control remains controversial, and the variability of HbA1c was a risk factor for macrovascular events in patients with type 2 diabetes. We investigated whether the HbA1c variability modifies the efficacy of intensive BP control. MethodsData from the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) trial was utilized. K-means clustering was used to cluster patients into three groups based on the HbA1c variability score and baseline HbA1c values. Cox proportional hazard models and generalized linear models were used to measure the subgroup differences in intensive BP control treatment effects. The primary outcome was a composite of nonfatal myocardial infarction (MI), stroke, or death from cardiovascular causes. ResultsIn patients with low HbA1c variability rather than medium or high HbA1c variability, intensive BP control reduced the risk of the primary outcome on a relative scale (HR 0.60, 95%CI 0.40-0.90, p interaction was 0.03), non-fatal MI (HR 0.61, 95% CI 0.37-1.00, p interaction was 0.04) and stroke (HR 0.19, 95%CI 0.05-0.64, p interaction was 0.02) or absolute scale. Regardless of the variability group, intensive BP control did not reduce the risk of cardiovascular or all-cause mortality (p interaction >0.05) both on relative and absolute risk scales. ConclusionHbA1c variability had effect on the efficacy of intensive BP control and intensive BP control brought a significant macrovascular benefit in patients with type 2 diabetes and low HbA1c variability.

Context The urinary albumin to creatinine ratio (UACR) is a widely used indicator of albuminuria and has predictive value for adverse cardiovascular events. Objective To evaluate the correlation between the UACR and the risk of developing major adverse cardiovascular events (MACEs) and total mortality in patients with type 2 diabetes mellitus (T2DM). Methods This post hoc analysis included 10 171 participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and the ACCORD follow-up study (ACCORDION) with baseline UACR data. The natural logarithm (ln) of each UACR measurement was calculated. Univariate and multivariate Cox proportional hazard regression analyses were conducted to examine the association between the UACR and the risk of MACEs and total mortality. The additional predictive value of UACR was further evaluated. Similar methods were used to analyze the correlation between the UACR and MACEs and total mortality within the normal range. Results During a median follow-up period of 8.83 years, 1808 (17.78%) participants experienced MACEs, and there were 1934 (19.01%) total deaths. After adjusting for traditional cardiovascular risk factors, the multivariate analysis revealed a significant association between the UACR and the risk of MACEs and total mortality. The inclusion of UACR in the conventional risk model enhanced the predictive efficacy for MACEs and total mortality. Conclusion An elevated UACR is associated with a higher risk of MACEs and total mortality in patients with T2DM, even when it falls within the normal range. The UACR improves prediction of MACE and total mortality risk in patients with T2DM.

AIM:To explore the association between the non-high-density lipoprotein cholesterol (HDL-C)/HDL-C ratio (NHHR) and the risk of major adverse cardiovascular events (MACEs) and overall mortality in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS:NHHR, calculated as (total cholesterol - HDL-C)/HDL-C, was evaluated in 10,188 participants. Cox proportional hazard regression models were employed to assess the association of NHHR with future risk of MACEs and overall mortality. Restricted cubic spline analysis, smooth curve fitting and piecewise regression models were utilized to explore the non-linear correlation and establish the threshold. Subgroup and interaction analyses verified the robustness of the findings. The area under the receiver operating characteristic area under the curve assessed the additional predictive value of NHHR beyond conventional risk factors. RESULTS:After adjusting for confounding factors, each 1-unit increase in NHHR was associated with a 12% increased risk of MACEs (hazard ratio [HR]: 1.12, 95% confidence interval [CI]: 1.07-1.16; p < 0.0001), a 5% increase in overall mortality (HR: 1.05, 95% CI: 1.01-1.10; p = 0.0256), a 10% increase in cardiovascular disease mortality (HR 1.10, 95% CI: 1.03-1.18; p = 0.0074), an 12% increase in non-fatal myocardial infarction (HR: 1.12, 95% CI: 1.05-1.18; p = 0.0002), and an 11% increase in non-fatal stroke (HR: 1.11, 95% CI: 1.02-1.20; p = 0.0123). Analyses showed a non-linear relationship between NHHR and MACEs in patients with T2DM (non-linearity p < 0.001). A two-stage linear regression model identified a threshold for MACEs at 6.28. Integration NHHR into the conventional model significantly enhanced predictive accuracy for MACEs. CONCLUSIONS:NHHR is a predictor of the risk of developing MACEs and overall mortality in patients with T2DM, with higher NHHR values independently associated with increased future MACE risks after full adjustment for confounders.

Diabetic cardiomyopathy (DCM) contributes significantly to the heightened mortality rate observed among diabetic patients, with myocardial fibrosis (MF) being a pivotal element in the disease's progression. Hydrogen sulfide (H2S) has been shown to mitigate MF, but the specific underlying mechanisms have yet to be thoroughly understood. A connection has been established between the evolution of DCM and the incidence of cardiomyocyte pyroptosis. Our research offers insights into H2S protective impact and its probable mode of action against DCM, analyzed through the lens of MF. In this study, a diabetic rat model was developed using intraperitoneal injections of streptozotocin (STZ), and hyperglycemia-stimulated cardiomyocytes were employed to replicate the cellular environment of DCM. There was a marked decline in the expression of cystathionine γ-lyase (CSE), a catalyst for H2S synthesis, in both the STZ-induced diabetic rats and hyperglycemia-stimulated cardiomyocytes. Experimental results in vivo indicated that H2S ameliorates MF and enhances cardiac functionality in diabetic rats by mitigating cardiomyocyte pyroptosis. In vitro assessments highlighted the induction of cardiomyocyte pyroptosis and the subsequent decline in cell viability under hyperglycemic conditions. However, the administration of sodium hydrosulfide (NaHS) curtailed cardiomyocyte pyroptosis and augmented cell viability. In contrast, propargylglycine (PAG), a CSE inhibitor, reversed the effects rendered by NaHS administration. Additional exploration indicated that the mitigating effect of H2S on cardiomyocyte pyroptosis is modulated through the ROS/NLRP3 pathway. In essence, our findings corroborate the potential of H2S in alleviating MF in diabetic subjects. This therapeutic effect is likely attributable to the regulation of cardiomyocyte pyroptosis via the ROS/NLRP3 pathway. This discovery furnishes a prospective therapeutic target for the amelioration and management of MF associated with diabetes.