Objectives:Myocardial ischaemia and remodelling are major contributors to the progression and mortality of coronary artery disease (CAD). Previous studies have shown immune cell alterations in CAD patients, but their characteristics and associations with myocardial ischaemia and remodelling remain unclear. Methods:We compared immune cell changes among patients without CAD, those with CAD and those with CAD and heart failure (HF). Results:We found a progressive reduction in circulating mucosal-associated invariant T (MAIT) cells across the three patient groups. MAIT cells exhibited increased expression of activation markers (CD69 and PD-1) and cytotoxic molecules (such as granzyme B). The features of MAIT cells were correlated positively with worsening clinical indicators of myocardial ischaemia and remodelling, including the Gensini score, cTnI, NT-proBNP, LVEF and E/e'. Additionally, the reduction, activation and cytotoxicity of MAIT cells were associated with indicators of myocardial fibrosis (sST2, Gal-3, PICP and PIIINP), a central pathological mechanism of myocardial remodelling. Finally, we preliminarily explored potential triggers for MAIT cell abnormalities in CAD patients and found that impaired intestinal barrier function and increased circulating bacterial antigens may contribute to these changes. Conclusions:During CAD progression, we observed a decrease in circulating MAIT cells. Enhanced activation and cytotoxicity of MAIT cells are associated with myocardial ischaemia and remodelling in CAD patients with heart failure, potentially triggered by gut microbial leakage. Our findings suggest a novel strategy for monitoring and intervention in disease progression.

Contrast-induced acute kidney injury (CIAKI) is a common complication after contrast media administration. Growing evidences implicate microRNA (miR)-30c has a key role in renal diseases. This study aimed to investigate the role and mechanism of miR-30c in CIAKI. CIAKI rat models were established using tail vein injection of omnipaque. MiR-30c was significantly downregulated in CIAKI models both in vivo and in vitro, concomitant with increased cell apoptosis and deteriorated renal injury. Meanwhile, the cell apoptosis, renal dysfunction and renal injury under contrast exposure were alleviated after overexpression of miR-30c. Mechanistically, we demonstrated that miR-30c directly targeted SOCS1, whose downregulation reduced contrast-induced HK-2 cell apoptosis. Furthermore, the upregulation of SOCS1 abolish the protective effect of the overexpression of miR-30c on contrast-induced cell apoptosis. In summary, overexpression of miR-30c inhibited renal tubular epithelial cell apoptosis and mitigated CIAKI via inhibiting the gene of SOCS1.

Background: Peritoneal fibrosis is a serious complication of long-term peritoneal dialysis (PD) and abdominal surgeries, yet effective treatments remain elusive. Given the known roles of mucosal-associated invariant T (MAIT) cells in immune responses and fibrotic diseases, we investigated their involvement in PD-induced peritoneal fibrosis to identify potential therapeutic targets. Methods: We employed single-cell RNA sequencing (scRNA-seq) and flow cytometry to characterize the activation and function of peritoneal MAIT cells in patients undergoing long-term PD. Our investigation focused on the molecular pathways activated by these cells, particularly the MHC class I–related protein 1 (MR1)-mediated interaction with mesothelial cells and subsequent activation of the mTORC1 signaling pathway. We further assessed the impact of inhibiting MAIT cells on fibrogenesis using both in vitro models and Mr1 knockout mice. Results: Our study revealed that long-term PD significantly enhanced the activation of MAIT cells, particularly the pro-inflammatory MAIT17 subtype. These activated cells contributed to peritoneal fibrogenesis by binding to the MR1 receptor on mesothelial cells, which triggered hyperglycolysis through the mTORC1 pathway, ultimately leading to fibrogenesis. Notably, we demonstrated that blocking the MR1-MAIT interaction, either through genetic knockout or pharmacological inhibition with acetyl-6-formylpterin (Ac-6-FP), effectively mitigated fibrosis. Conclusions: This study identified MAIT cells as crucial drivers of PD-induced peritoneal fibrosis.

Background:The growing obesity epidemic highlights the need to understand how various obesity phenotypes affect myocardial structure and increase non-ischaemic cardiomyopathy (NICM) incidence. The aim of this study was to investigate the causal effect of eight obesity-related traits on NICM and 16 cardiac MRI parameters. Potential mediators between obesity and NICM were also investigated. Methods:Two-sample Mendelian randomisation was used to explore the causal relationship between eight obesity-related traits and NICM and assess their impact on cardiac MRI indicators. The study also used validation dataset analysis and multivariable Mendelian randomisation to ensure robustness, and mediation Mendelian randomisation analysis to identify metabolic markers as potential mediators. Results:All eight obesity-related traits demonstrated a causal relationship with NICM, with the relationship between BMI and NICM persisting after adjustment for LDL cholesterol, urate level and hypertension (HTN). These traits also influenced arterial and cardiac structure and function, especially with regard to left ventricular mass. HTN was identified as a significant mediator, with a mediation effect ratio of 31%. Conclusion:There is a robust causal association between obesity and NICM, and with abnormalities in myocardial structure and function. HTN emerges as a pivotal mediator in the obesity-NICM pathway, underscoring the critical role of managing obesity and HTN in preventing NICM progression.

BACKGROUND:Contrast-induced acute kidney injury (CI-AKI) continues to pose a pressing clinical challenge during invasive cardiovascular procedures due to the limited availability of preventative strategies. We aimed to demonstrate that irisin, a myokine induced by exercise, protects against CI-AKI by inhibiting the cGAS-STING inflammatory pathway. METHODS AND RESULTS:We explored the relationship between serum irisin levels and CI-AKI incidence in patients administered the contrast media iohexol. Notably, lower serum irisin levels were strongly associated with an increased incidence of CI-AKI following contrast media administration. To establish a causal link between serum irisin levels and CI-AKI, we utilised a mouse model that simulates exercise by overexpressing muscle-specific PGC-1α. This approach showed a significant reduction in tubular injury and mitochondrial dysfunction induced by iohexol via cGAS/STING suppression, thereby diminishing inflammation. Mechanistically, irisin was found to inhibit the activation of cGAS/STING, preventing double stranded DNA (dsDNA) leakage and reducing inflammation in tubular epithelial cells (TECs). Pharmacological inhibition of STING further corroborated these observations. Moreover, we identified integrin complex αV/β5 as the irisin receptor on TECs, which is essential for irisin-mediated suppression of cGAS-STING signalling and resolution of inflammation. CONCLUSIONS:Our data position irisin as a crucial factor in muscle‒kidney crosstalk, inhibiting cGAS-STING signalling and preventing dsDNA leakage via integrin αV/β5 in TECs, thus mitigating tubular injury and inflammation. These data underscore the potential of irisin as both a predictive biomarker for CI-AKI and a promising candidate for preventative strategies against CI-AKI. HIGHLIGHTS:Irisin mediated muscle-kidney crosstalk mitigated tubular injury and inflammation. Irisin inhibited the cGAS-STING signalling activation via integrin αV/β5 in tubular epithelial cells. Irisin was a predictive biomarker and a promising candidate for CI-AKI.

Peritoneal dialysis (PD), as a renal replacement therapy, relies heavily on the structural and functional integrity of the peritoneum. In some patients, however, the peritoneum may undergo adverse remodeling and fibrotic thickening, resulting in treatment failure. Here, a previously unrecognized metabolic-epigenetic mechanism contributing to peritoneal fibrogenesis is uncovered, wherein lactate accumulation in injured peritoneal mesothelial cells promotes histone H3K18 lactylation and transcriptional activation of macrophage-recruiting chemokine CCL2. In a mouse model of peritoneal fibrosis induced by chlorhexidine gluconate (CG) or PD fluid, the administration of extracellular vesicles derived from human bone marrow mesenchymal stem cells (MSC-EVs) significantly ameliorates histological and functional changes in the peritoneum. Single-cell RNA sequencing reveals that MSC-EVs attenuate mesothelial-macrophage crosstalk by suppressing CCL2 signaling. Mechanistically, MSC-EVs reprogram glycolytic metabolism in mesothelial cells, reduce lactate production, and inhibit H3K18 lactylation-dependent transcriptional activation of CCL2. Pharmacologic blockade of lactate production recapitulates the protective effects of MSC-EVs. These findings suggest that lactate-induced histone lactylation is a key driver of peritoneal fibrosis, positioning MSC-EVs as a promising cell-free therapeutic strategy for targeting metabolic-epigenetic inflammation in serosal injury.

Background: Deposition of adipose tissue may have a promoting role in the development of diabetic complications. This study is aimed at investigating the relationship between adipose tissue thickness and risk of contrast‐induced nephropathy (CIN) in patients with Type 2 diabetes mellitus (T2DM). Methods: A total of 603 T2DM patients undergoing percutaneous coronary angiography or angioplasty with suspicious or confirmed stable coronary artery disease were enrolled in this study. The thicknesses of perirenal fat (PRF), subcutaneous fat (SCF), intraperitoneal fat (IPF), and epicardial fat (ECF) were measured by color Doppler ultrasound, respectively. The association of various adipose tissues with CIN was analyzed. Results: Seventy‐seven patients (12.8%) developed CIN in this cohort. Patients who developed CIN had significantly thicker PRF (13.7 ± 4.0 mm vs. 8.9 ± 3.6 mm, p < 0.001), slightly thicker IPF ( p = 0.046), and similar thicknesses of SCF ( p = 0.782) and ECF ( p = 0.749) compared to those who did not develop CIN. Correlation analysis showed that only PRF was positively associated with postoperation maximal serum creatinine (sCr) ( r = 0.18, p = 0.012), maximal absolute change in sCr ( r = 0.33, p < 0.001), and maximal percentage of change in sCr ( r = 0.36, p < 0.001). In receiver operating characteristic (ROC) analysis, the area under the curve (AUC) of PRF (0.809) for CIN was significantly higher than those of SCF (0.490), IPF (0.594), and ECF (0.512). Multivariate logistic regression analysis further confirmed that thickness of PRF, rather than other adipose tissues, was independently associated with the development of CIN after adjusted for confounding factors (odds ratio (OR) = 1.53, 95% CI: 1.38–1.71, p < 0.001). Conclusions: PRF is independently associated with the development of CIN in T2DM patients undergoing coronary catheterization.

Background The relationship between remnant cholesterol (RC) and atrial fibrillation (AF) remains unclear. Objective The purpose of this study was to comprehensively explore the association between RC characteristics and new-onset AF. Methods Data from 5 follow-up visits of the ARIC (Atherosclerosis Risk in Communities) study were analyzed. RC were multidimensionally evaluated in 4 characteristics: baseline level, variability, cumulative exposure, and trajectory. Baseline RC was obtained from the initial visit (V1), and new-onset AF was monitored in V2 to V5 (cohort 1, n = 14,450). RC variability, cumulative RC, and RC trajectory were calculated by RC values gathered from V1 to V3, and new-onset AF was monitored in V4 and V5 (cohort 2, n = 11,012). Participants were divided into 4 groups based on quartiles or trajectories. Cox proportional hazards analyses were used to investigate the relationship between RC characteristics and AF. Results Following median follow-up of 22.39 years in cohort 1 and 16.71 years in cohort 2, a total of 1993 AF events in cohort 1 and 1571 in cohort 2 were identified. Participants with the highest quartile exhibited an elevated risk of new-onset AF, with the multivariable-adjusted hazard ratios of 1.16 (P = .039) for baseline RC and 1.30 (P < .001) for RC variability. Although the highest quartile of cumulative RC (P = .241) and the high-increasing trajectory (P = .210) did not demonstrate a statistically significant association with AF occurrence, they indicate a trend toward heightened risk. Conclusion Our findings reveal that higher levels of RC, particularly at baseline and in variability, are associated with an increased risk of AF.

Objective: Lipotoxicity is a well-established contributor to cardiomyocyte death and heart damage, with ferroptosis being identified as a crucial death mode in cardiomyocyte disease. This study aims to explore the potential role and mechanism of ferroptosis in lipotoxicity-induced myocardial injury. Methods: Eight-week high-fat diet (HFD) Sprague-Dawley rat and H9c2 cardiomyocytes treated with palmitic acid (PA) were established for an in vivo and in vitro lipotoxic model. Ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) were used to inhibit ferroptosis. Myocardial-specific stimulator of interferon genes (STING) knockdown rat (Stingmyo-KD) with HFD was further introduced. Rat cardiac structure and function, cell viability, the level of lipid peroxidation, malondialdehyde (MDA), glutathione (GSH), mitochondrial function, ferroptosis-related proteins, and STING pathway-related proteins in H9c2 cells/myocardium were detected. Results: HFD rats with a ferroptosis inhibitor showed improved cardiac structure and function, reduced lipid peroxidation, and restored GSH, which was further confirmed in H9c2 cell. The time-dependent activation of the STING pathway following PA stimulation was observed. Knockdown of the expression of STING could reduce PA-induced cell death, lipid peroxidation, and MDA levels while restoring the GSH. In addition, both HFD Stingmyo-KD rats and HFD rats with systematic inhibition by the STING inhibitor exhibited mitigating lipotoxicity-induced myocardial ferroptosis and reducing myocardial injury. Innovation and Conclusion: These findings suggest that lipotoxicity can induce ferroptosis in cardiomyocytes through the activation of the STING pathway, providing new targets and strategies for the treatment of lipotoxicity cardiomyopathy. Antioxid. Redox Signal. 42, 184-198.

BackgroundType 2 diabetes mellitus (T2DM) is associated with decreased heart rate variability (HRV) with an unclear intermediate mechanism. This study aimed to conduct mediation analysis to explore the impact of various adipose tissues on the relationship between T2DM and HRV.MethodsA total of 380 participants were enrolled for analysis, including 249 patients with T2DM and 131 non-diabetic controls. The thicknesses of four adipose tissues (subcutaneous, extraperitoneal, intraperitoneal, and epicardial) were measured by abdominal ultrasound or echocardiography respectively. HRV was assessed by 24-hour Holter for monitoring both frequency domain indices (LF, HF, and LF/HF) and time domain indices (SDNN, SDANN, SDNN index, rMSSD and pNN50). Mediation analysis was used toexamine whether adipose tissues mediated the relationship between T2DM and each index of HRV. Then, a latent variable - HRV burden - was constructed by structural equation model with selected HRV indices to comprehensively assess the whole HRV.ResultsCompared to non-diabetic controls, patients with T2DM exhibited a significant reduction in indices of HRV, and a remarkable increase in the thicknesses of extraperitoneal, intraperitoneal, and epicardial adipose tissues. Mediation analysis found significant indirect effects of T2DM on six indices of HRV, including HF, SDNN, SDANN, SDNN index, rMSSD, and pNN50, which was mediated by epicardial adipose tissue rather than other adipose tissues, with the mediation proportions of 64.21%, 16.38%, 68.33%, 24.34%, 24.10% and 30.51%, respectively. Additionally, epicardial adipose tissue partially mediated the relationship between T2DM and reduced HRV burden (24.26%), which composed by SDNN, SDNN index, rMSSD, and pNN50.ConclusionEpicardial adipose tissue partially mediated the relationship between T2DM and reduced HRV, which reinforces the value of targeting heart-specific visceral fat to prevent cardiac autonomic neuropathy in diabetes.

BACKGROUND:12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) has shown potential in protecting against heart disease, but its relationship with atrial fibrillation (AF) remains unknown. METHODS:Coronary sinus (CS) and femoral vein blood samplings were synchronously collected from AF and non-AF subjects (paroxysmal supraventricular tachycardia or idiopathic premature ventricular complexes) who underwent catheter ablation. First, untargeted metabolomic profiling was performed in a discovery cohort (including 12 AF and 12 non-AF subjects) to identify the most promising CS or femoral vein metabolite. Then, the selected metabolite was further measured in a validation cohort (including 119 AF and 103 non-AF subjects) to confirm its relationship with left atrium remodeling and 1-year postablation recurrence of AF. Finally, the biological function of the selected metabolite was validated in a rapid-paced cultured HL-1 atrial cardiomyocytes model. RESULTS:Metabolomic analysis identified CS 12,13-diHOME as the most pronounced change metabolite correlated with left atrium remodeling in the discovery cohort. In the validation cohort, CS 12,13-diHOME was significantly lower in patients with AF than non-AF controls (84.32±20.13 versus 96.24±23.56 pg/mL; P<0.01), and associated with worse structural, functional, and electrical remodeling of left atrium. Multivariable regression analyses further demonstrated that decreased CS 12,13-diHOME was an independent predictor of 1-year postablation recurrence of AF (odds ratio, 0.754 [95% CI, 0.648-0.920]; P=0.005). Biological function validations showed that 12,13-diHOME treatment significantly protect the cell viability, improved the expression of MHC (myosin heavy chain) and Cav1.2 (L-type calcium channel α1c), and attenuated mitochondrial damage in the rapid-paced cultured HL-1 cardiomyocytes model. CONCLUSIONS:CS metabolite 12,13-diHOME is decreased in patients with AF and can serve as a novel biomarker for left atrium remodeling.

Background Type 1 diabetes (T1D) is a significant risk factor for a range of cardiovascular diseases. Nonetheless, the causal relationship between T1D and non-ischemic cardiomyopathy (NICM) remains to be elucidated. Furthermore, the mechanisms responsible for the progression from T1D to NICM have not been definitively characterized. Objective The aim of this study was to conduct a Mendelian randomization (MR) study to investigate the causal effects of T1D and its complications on the development of NICM. Additionally, this study aimed to conduct a mediation analysis to identify potential mediators within this correlation. Methods Genetic variants were used as instrumental variables for T1D. The summary data for T1D were obtained from two genome-wide association study datasets. The summary data for T1D with complications and NICM were obtained from the Finnish database. Two-sample MR, multivariable MR and mediation MR were conducted in this study. Results The study revealed a causal association between T1D, T1D with complications, and NICM (with odds ratios of 1.02, 95% CI 1.01–1.04, p = 1.17e-04 and 1.03, 95% CI 1.01–1.05, p = 3.15e-3). Even after adjusting for confounding factors such as body mass index and hypertension, T1D remained statistically significant (with odds ratio of 1.02, 95% CI 1.01–1.04, p = 1.35e-4). Mediation analysis indicated that monokine induced by gamma interferon may play a mediating role in the pathogenesis of T1D-NICM (mediation effect indicated by odds ratio of 1.005, 95% CI 1.001–1.01, p = 4.9e-2). Conclusion The study demonstrates a causal relationship between T1D, its complications, and NICM. Additionally, monokine induced by gamma interferon may act as a potential mediator in the pathogenesis of T1D-NICM.

Peritoneal fibrosis progression is regarded as a significant cause of the loss of peritoneal function, markedly limiting the application of peritoneal dialysis (PD). However, the pathogenesis of peritoneal fibrosis remains to be elucidated. Tissue-derived extracellular vesicles (EVs) change their molecular cargos to adapt the environment alteration, mediating intercellular communications and play a significant role in organ fibrosis. Hence, we performed, for the first time, four-dimensional label-free quantitative liquid chromatography-tandem mass spectrometry proteomic analyses on EVs from normal peritoneal tissues and PD-induced fibrotic peritoneum in mice. We demonstrated the alterations of EV concentration and protein composition between normal control and PD groups. A total of 2339 proteins containing 967 differentially expressed proteins were identified. Notably, upregulated proteins in PD EVs were enriched in processes including response to wounding and leukocyte migration, which participated in the development of fibrosis. In addition, EV proteins of the PD group exhibited unique metabolic signature compared with those of the control group. The glycolysis-related proteins increased in PD EVs, while oxidative phosphorylation and fatty acid metabolism-related proteins decreased. We also evaluated the effect of cell-type specificity on EV proteins, suggesting that mesothelial cells mainly cause the alterations in the molecular composition of EVs. Our study provided a useful resource for further validation of the key regulator or therapeutic target of peritoneal fibrosis.

Progressive peritoneal fibrosis and the loss of peritoneal function often emerged in patients undergoing long-term peritoneal dialysis (PD), resulting in PD therapy failure. Varieties of cell-cell communications among peritoneal cells play a significant role in peritoneal fibrogenesis. Extracellular vesicles (EVs) have been confirmed to involve in intercellular communication by transmitting proteins, nucleic acids or lipids. However, their roles and functional mechanisms in peritoneal fibrosis remain to be determined. Using integrative analysis of EV proteomics and single-cell RNA sequencing, we characterized the EVs isolated from PD patient's effluent and revealed that mesothelial cells are the main source of EVs in PD effluent. We demonstrated that transforming growth factor-β1 (TGF-β1) can substitute for PD fluid to stimulate mesothelial cells releasing EVs, which in turn promoted fibroblast activation and peritoneal fibrogenesis. Blockade of EVs secretion by GW4869 or Rab27a knockdown markedly suppressed PD-induced fibroblast activation and peritoneal fibrosis. Mechanistically, injured mesothelial cells produced EVs containing high level of integrin-linked kinase (ILK), which was delivered to fibroblast and activated them via p38 MAPK signalling pathway. Clinically, the expression of ILK was up-regulated in fibrotic peritoneum of patients undergoing long-term PD. The percentage of ILK positive EVs in PD effluent correlated with peritoneal dysfunction and the degree of peritoneal damage. Our study highlights that peritoneal EVs mediate communications between mesothelial cells and fibroblasts to initiate peritoneal fibrogenesis. Targeting EVs or ILK could provide a novel therapeutic strategy to combat peritoneal fibrosis.

Background Atrial fibrillation (AF) and heart failure (HF) frequently coexist because of their similar pathological basis. However, whether sodium-glucose cotransporter 2 inhibitor (SGLT2i), a novel class of anti-HF medication, decreases the risk of AF in HF patients remains unclear. Objectives The aim of this study was to assess the relationship between SGLT2i and AF in HF patients. Methods A meta-analysis of randomized controlled trails evaluating the effects of SGLT2i on AF in HF patients was performed. PubMed and ClinicalTrails.gov were searched for eligible studies until 27 November 2022. The risk of bias and quality of evidence were assessed through the Cochrane tool. Pooled risk ratio of AF for SGLT2i versus placebo in eligible studies was calculated. Results A total of 10 eligible RCTs examining 16,579 patients were included in the analysis. AF events occurred in 4.20% (348/8292) patients treated with SGLT2i, and in 4.57% (379/8287) patients treated with placebo. Meta-analysis showed that SGLT2i did not significantly reduce the risk of AF (RR 0.92; 95% CI 0.80–1.06; p = 0.23) in HF patients when compared to placebo. Similar results remained in the subgroup analyses, regardless of the type of SGLT2i, the type of HF, and the duration of follow-up. Conclusions Current evidences showed that SGLT2i may have no preventive effects on the risk of AF in patients with HF. Translational perspective Despite HF being one of the most common heart diseases and conferring increased risk for AF, affective prevention of AF in HF patients is still unresolved. The present meta-analysis demonstrated that SGLT2i may have no preventive effects on reducing AF in patients with HF. How to effectively prevent and early detect the occurrence of AF is worth discussing.

Chronic inflammation is involved in the development of heart failure (HF) in type 2 diabetes mellitus (T2DM). However, reliable and easily accessible biomarker of subclinical left cardiac remodeling and dysfunction remains a challenge.Overall, 1020 patients with T2DM without overt HF were enrolled from May 2019 to April 2020. Monocyte to high-density lipoprotein ratio (MHR) was calculated by blood monocyte count divided by high-density lipoprotein cholesterol. Left cardiac structure and function were assessed using transthoracic echocardiography. Univariate and multivariate linear regression analyses were used to estimate the association of MHR (Lg transferred) with echocardiographic parameters. We found that septal wall thickness (SWT), left ventricular internal end-diastole dimension (LVIDd), and left ventricular mass index (LVMI) raised with increasing MHR (P = 0.002 for SWT, P < 0.001 for LVIDd, and P = 0.001 for LVMI). Declined trends were shown in ejection fraction (EF) (P = 0.016), E velocity (P = 0.037), E/A ratio (P = 0.009), and tissue Doppler e' (P < 0.001), and elevating trend was observed in E/e' (P < 0.001). In multivariate regression analysis, MHR (Lg transferred) was positively associated with LVIDd (β = 0.031; P = 0.016), LVMI (β = 0.073; P = 0.014), and E/e' (β = 0.331; P < 0.001), whereas it was negatively associated with EF (β = -0.086; P = 0.007), E/A (β = -0.072; P = 0.009), and e' (β = -0.332; P < 0.001).MHR could be a practical biomarker for indicating subclinical cardiac remodeling and dysfunction in T2DM, due to low cost and easy availability.

Abstract Purpose: Mitophagy reduces mitochondrial dysfunction and accumulation of reactive oxygen species (ROS) to prevent myocardial injury in diabetic cardiomyopathy (DCM). Accumulated studies have confirmed that metformin enhances autophagy to maintain mitochondrial homeostasis and scavenge ROS. However, whether and how metformin regulates mitophagy in cardiomyocytes remain unclear. Methods: Diabetic cardiomyopathy was modeled in H9c2 Cardiomyocytes treated with high glucose (30 mM) . Then high Glucose-stimulated H9C2 cells were exposed to metformin, AMPKα inhibitor and Sirt1 inhibitor for 24 h. Mitochondrial dysfunction and mitophagy were detected by fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA), mitochondrial membrane potential(MMP), flow cytometry and western blot. Resluts: We found that the protein expression of Parkin, ROS level, and mitochondrial membrane potential showed dynamic changes in H9C2 cells under the stimulation of high glucose. Importantly, metformin enhanced mitophagy, scavenged ROS, improved mitochondrial function and inhibited apoptosis in H9C2 cells treated with high glucose. Mechanistically, metformin increased the protein expression of p-AMPKα, Sirt1, Parkin, and LC3-II in H9C2 cells after a high glucose challenge. Depletion of AMPKα and Sirt1 abolished the increase of protein levels of Parkin and LC3-II and mitophagy levels induced by metformin. Conclusion: Our data indicated that metformin improves mitochondrial dysfunction of H9C2 cells under hyperglycemia by activating AMPKα/Sirt1/Parkin-mediated mitophagy, which provides novel evidence for the treatment of DCM.

Background: Inflammatory activation and immune infiltration play important roles in the pathologic process of heart failure (HF). The current study is designed to investigate the immune infiltration and identify related biomarkers in heart failure patients due to ischemic cardiomyopathy. Methods: Expression data of HF due to ischemic cardiomyopathy (CM) samples and non-heart failure (NF) samples were downloaded from gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) between CM and NF samples were identified. Single sample gene set enrichment analysis (ssGSEA) was performed to explore the landscape of immune infiltration. Weighted gene co-expression network analysis (WGCNA) was applied to screen the most relevant module associated with immune infiltration. The diagnostic values of candidate genes were evaluated by receiver operating curves (ROC) curves. The mRNA levels of potential biomarkers in the peripheral blood mononuclear cells (PBMCs) isolated from 10 CM patients and 10 NF patients were analyzed to further assess their diagnostic values. Results: A total of 224 DEGs were identified between CM and NF samples in GSE5406, which are mainly enriched in the protein processing and extracellular matrix related biological processes and pathways. The result of ssGSEA showed that the abundance of dendritic cells (DC), mast cells, natural killer (NK) CD56dim cells, T cells, T follicular helper cells (Tfh), gammadelta T cells (Tgd) and T helper 2 (Th2) cells were significantly higher, while the infiltration of eosinophils and central memory T cells (Tcm) were lower in CM samples compared to NF ones. Correlation analysis revealed that Calumenin (CALU) and palladin (PALLD) were negatively correlated with the abundance of DC, NK CD56dim cells, T cells, Tfh, Tgd and Th2 cells, but positively correlated with the level of Tcm. More importantly, CALU and PALLD were significantly lower in PBMCs from CM patients compared to NF ones. Conclusion: Our study revealed that CALU and PALLD are potential biomarkers associated with immune infiltration in heart failure due to ischemic cardiomyopathy.

BACKGROUND:Accumulating evidence has indicated that dysregulation of microRNAs (miRNAs) contributes to the tumorigenesis of prostate cancer (PCa). Nevertheless, the role of miR-593-3p in the development of PCa remains unclear. The objective of this study was to investigate the role and mechanisms of miR-593-3p in PCa cells.METHODS:RT-PCR was used to detect the expression levels of miR-593-3p. CCK-8, colony formation, spheroid formation and transwell assays were performed to examine the proliferation, migration and invasion of C4-2, DU145 and RWPE-1 cells. And then, transcriptome sequencing, dual-luciferase reporter assay and Western blot were taken to identify the target gene and downstream mechanisms of miR-593-3p.RESULTS:Here, we found that miR-593-3p promoted PCa cell proliferation, colony formation, spheroid formation, migration and invasion. Further mechanistic studies revealed that miR-593-3p possessed binding sites of ADIPOR1 3'-UTR and played an important role in 5'-AMP-activated protein kinase (AMPK) signaling pathway and epithelial-mesenchymal transition (EMT) process. In addition, the transfection of si-ADIPOR1 also enhanced the PCa cell proliferation and invasion.CONCLUSION:Our study provides an empirical investigation of miR-593-3p, which exerts oncogenic function through targeting ADIPOR1 in PCa cells.

Background: Hyperhomocysteinemia is a risk factor for contrast-induced nephropathy. Folic acid can attenuate such nephropathies in rats. The protective effect of folic acid against contrast-induced nephropathy has not been studied in humans. We aimed to investigate the effect of folic acid on the incidence of contrast-induced nephropathy (CIN) after coronary catheterization in patients with hyperhomocysteinemia.Methods: This was a single-center, prospective, double-blind, randomized controlled trial (ClinicalTrials.gov, NCT02444013). In total, 412 patients (mean age: 65 ± 12 years, 268 male) with plasma homocysteine ≥15 μM, who underwent coronary arteriography (CAG) or percutaneous coronary intervention (PCI) from May 2015 to August 2018, were enrolled. Patients were randomly assigned to two groups: a treatment group (n = 203), taking 5 mg of folic acid (orally, three times/day) immediately after enrollment and for 72 h after operation, and a control group (n = 209), taking placebo. Contrast-induced nephropathy was defined as an increase in serum creatinine of >25% or 44 μM within 48 or 72 h after contrast medium administration.Results: In total, 50 (12%) patients developed CIN after 48 h after catheterization, including 16 (8%) in the treatment group and 34 (16%) in the control group (P = 0.009). Meanwhile, 53 (13%) patients developed CIN after 72 h of CAG/PCI, including 18 (9%) in the treatment group and 35 (17%) in the control group (P = 0.017). The incidence of contrast-induced nephropathy in the treatment group was lower than that in the control group (P = 0.017). Logistic regression analysis confirmed that administration of folic acid was a protective factor against contrast-induced nephropathy (RD = 0.0788, 95%CI: 0.0105–0.1469, P = 0.019). We found no serious adverse events associated with folic acid. No death or hemodialysis occurred in either group.Conclusions: Perioperative administration of folic acid attenuates the incidence of contrast-induced nephropathy after coronary catheterization in patients with hyperhomocysteinemia.Clinical Trial Registration:ClinicalTrials.gov, identifier [NCT02444013].