Diabetic cardiomyopathy (DC) refers to the abnormal myocardial structure and performance induced by diabetes. Although numerous studies have been carried out, the pathophysiological mechanisms of cardiovascular disorders during diabetes have not been fully clarified. Here, we compared the cardiomyopathy of healthy rhesus monkeys and rhesus monkeys with a history of streptozocin induced type 1 diabetes (T1D) over 7 years. Through comparing the cardiac function using echocardiography, and detecting the serum biochemical indexes, and changes of left ventricle (LV), we found that decreased systolic function, higher blood glycosylated hemoglobin A1c (HbA1C) level, hyperglycemia, and hyperlipidemia were early events in diabetic rhesus monkeys. In addition, cardiac histological analysis showed mildly fibrosis and early myocardial hypertrophy, as evidenced by increased Sirius red stained area and cross-sectional area of left ventricle. Transcriptome results revealed that the nutrients metabolism and extracellular matrix related pathways were markedly changed in the left ventricle of diabetic monkeys. Targeted metabolomics and targeted lipid metabolomics further revealed that disturbed amino acid metabolism and lipid accumulation in the LV of diabetic monkeys manifested by accumulated branched chain amino acids (BCAAs) and triglycerides (TAGs), and reduced contents of sphingolipids, glycerophospholipids, cholesteryl esters and carnitines. In conclusion, we reported here for the first time that diabetes lasting for more than 7 years leads to some early pathological changes of myocardium in rhesus monkeys. The cardiac function is mildly compromised and the reprogramming of lipids and amino acids metabolism might play important roles in the progression of DC.

The renin-angiotensin system (RAS) plays a pivotal role in regulating vascular homeostasis, while angiotensin 1-8 (Ang 1-8) traditionally dominates as a vasoconstrictor factor. However, the discovery of angiotensin 1-7 (Ang 1-7) and Ang 1-8 has revealed counter-regulatory mechanisms mediated through endothelial-derived relaxing factors (EDRFs) and endothelial-derived hyperpolarizing factors (EDHFs). This review delves into the vascular actions of Ang 1-7 and Ang 1-8 in both non-diabetes mellitus (non-DM) and diabetes mellitus (DM) conditions, highlighting their effects on vascular endothelial cell (VECs) function as well. In a non-DM vasculature context, Ang 1-8 demonstrate dual effect including vasoconstriction and vasodilation, respectively. Additionally, Ang 1-7 induces vasodilation upon nitric oxide (NO) production as a prominent EDRFs in distinct mechanisms. Further research elucidating the precise mechanisms underlying the vascular actions of Ang 1-7 and Ang 1-8 in DM will facilitate the development of tailored therapeutic interventions aimed at preserving vascular health and preventing cardiovascular complications.

Diabetic cardiomyopathy (DCM) is a cardiac complication specific to individuals with diabetes. It is defined as abnormalities of myocardial structure and function in diabetic patients who do not exhibit any obvious coronary artery disease, hypertensive heart disease, valvular heart disease, or inherited cardiomyopathy. A significant cardiovascular protective factor identified recently is angiotensin-converting enzyme 2 (ACE2), which is a rising star in the renin angiotensin system (RAS) and is responsible for the onset and progression of DCM. Nonetheless, there is not a comprehensive review outlining ACE2's effect on DCM. From the perspective of the pathogenesis of DCM, this review summarizes the myocardial protective role of ACE2 in the aspects of alleviating myocardial structure and dysfunction, correcting energy metabolism disorders, and restoring vascular function. Concurrently, we propose the connections between ACE2 and underlying signaling pathways, including ADAM17, Apelin/APJ, and Nrf2. Additionally, we highlight ACE2-related pharmaceutical treatment options and clinical application prospects for preventing and managing DCM. Further and underlying research is extensively required to completely comprehend the principal pathophysiological mechanism of DCM and the distinctive function of ACE2, switching experimental findings into clinical practice and identifying efficient therapeutic approaches.

High glucose-induced dysfunction of endothelial cells is a critical and initiating factor in the genesis of diabetic vascular complications. Low-magnitude high-frequency vibration (LMHFV) is a non-invasive biophysical intervention. It has been reported that it exhibits protective effects on high glucose-induced osteoblast dysfunction, but little was known on diabetic vascular complications. In this work, we aim to clarify the role of LMHFV on high glucose-induced endothelial dysfunction and hypothesized that the protective effects functioned through adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. We cultured primary murine aortic endothelial cells (MAECs) in normal or HG medium, respectively, before exposing to LMHFV. The tube formation, paracellular permeability assay, and aortic ring sprouting assay showed that the high glucose injured-function of MAECs was improved after LMHFV treatment. The intracellular ROS generation analysis, mitochondrial complex I activities measurement, ATP measurement and mitochondrial membrane potential (MMP), and mitochondrial ROS generation analysis of MAECs indicated that mitochondrial function was restored by LMHFV loading in a high glucose environment. Mechanically, western blot assays showed that AMPK phosphorylation was promoted and mTOR was inhibited in LMHFV-induced endothelial function restoration. After the administration of the AMPK inhibitor, Compound C, these protective effects resulting from LMHFV are reversed. These findings suggest that LMHFV plays a significant role in protecting endothelial cells' function and mitochondrial function in high glucose-induced injured MAECs via AMPK/mTOR signalling.

Hyperuricemia and diabetes mellitus (DM) are prevalent metabolic disorders with high comorbidity, imposing a substantial global public health burden. Their coexistence is not merely additive but synergistic, exacerbating metabolic dysregulation through mechanisms such as insulin resistance and β-cell apoptosis, ultimately establishing a vicious cycle. Both disorders induce acute and chronic damage to vital organs, particularly the cardiovascular, renal systems. Hyperuricemia aggravates diabetic complications, notably diabetic cardiomyopathy, nephropathy and retinopathy via oxidative stress, inflammation, and metabolic dysregulation.Current urate-lowering therapies (ULTs), such as xanthine oxidase inhibitors and urate transporter 1 (URAT1, also known as SLC22A12) antagonists, demonstrate potential benefits in ameliorating diabetic complications but face challenges including safety concerns and dose adjustments. Similarly, several glucose-lowering drugs also exhibit the benefits of improving hyperuricemia. This review summarizes the metabolic crosstalk and therapeutic interplay between hyperuricemia and DM, examines the pathogenic role of uric acid in diabetic complications, and discusses the benefits and challenges of existing ULTs and glucose-lowering drugs in disrupting this cycle of metabolic dysregulation and concurrent organ damage. We hope our findings deepen the comprehension of the intricate metabolic crosstalk between glucose and urate homeostasis, providing novel therapeutic insights for patients with comorbid DM and hyperuricemia.

Stents-assisted coiling (SAC) and flow diverters (FD) are widely used in the endovascular treatment of intracranial aneurysms. However, due to the thrombogenicity of metallic implants, their application may increase the risk of ischemic events. This study aims to evaluate the efficacy of prophylactic tirofiban with dual antiplatelet treatment (DAPT) in unruptured intracranial aneurysms (UIA) patients treated with SAC or FD.

This single center retrospective study included patients with UIAs treated with SAC or FD. Data collected included demographic information, imaging findings, laboratory results, and perioperative complications. Multivariate logistic regression analysis was used to identify independent risk factors for ischemic events. Patients were stratified based on these risk factors, and the efficacy of tirofiban was evaluated across different risk groups.

A total of 420 patients were included in the study, of whom 22(5.2%) experienced ischemic events. Among them, eight patients (3.3%) were in the tirofiban group and 14 patients (8.0%) were in the DAPT (non-tirofiban) group. Multivariate logistic regression identified independent risk factors for ischemic events, including posterior circulation aneurysm (OR: 2.87, 95% CI: 1.06-7.78; P = 0.038) and diabetes (OR: 4.05, 95% CI: 1.50-10.96; P = 0.006). The prophylactic use of tirofiban combined with DAPT can effectively reduce postoperative ischemic events (OR: 0.35, 95% CI: 0.14-0.91; P = 0.032) without increasing the risk of hemorrhage.

This study demonstrates that prophylactic use of tirofiban can effectively reduce postoperative ischemic events in UIA patients receiving SAC or FD treatments without increasing the risk of hemorrhage.

Immune system plays a crucial role in the physiological and pathological regulation of the cardiovascular system. The exploration history and milestones of immune system in cardiovascular diseases (CVDs) have evolved from the initial discovery of chronic inflammation in atherosclerosis to large-scale clinical studies confirming the importance of anti-inflammatory therapy in treating CVDs. This progress has been facilitated by advancements in various technological approaches, including multi-omics analysis (single-cell sequencing, spatial transcriptome et al.) and significant improvements in immunotherapy techniques such as chimeric antigen receptor (CAR)-T cell therapy. Both innate and adaptive immunity holds a pivotal role in CVDs, involving Toll-like receptor (TLR) signaling pathway, nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1/2) signaling pathway, inflammasome signaling pathway, RNA and DNA sensing signaling pathway, as well as antibody-mediated and complement-dependent systems. Meanwhile, immune responses are simultaneously regulated by multi-level regulations in CVDs, including epigenetics (DNA, RNA, protein) and other key signaling pathways in CVDs, interactions among immune cells, and interactions between immune and cardiac or vascular cells. Remarkably, based on the progress in basic research on immune responses in the cardiovascular system, significant advancements have also been made in pre-clinical and clinical studies of immunotherapy. This review provides an overview of the role of immune system in the cardiovascular system, providing in-depth insights into the physiological and pathological regulation of immune responses in various CVDs, highlighting the impact of multi-level regulation of immune responses in CVDs. Finally, we also discuss pre-clinical and clinical strategies targeting the immune system and translational implications in CVDs.

Type 1 Diabetes Mellitus (T1D) is a disease characterized by the destruction of pancreatic beta cells. The subsequent loss of insulin production results in hyperglycemia, muscle wasting, and vascular dysfunction. Due to an inability to appropriately maintain glucose homeostasis, patients afflicted with T1D suffer from increased morbidity and early mortality. Skeletal muscle is the body's largest metabolic reservoir, absorbing significant amounts of glucose from the bloodstream and physical exercise is known to improve and prevent the progression of pathological outcomes, but many T1D patients are unable to exercise at a level that conveys benefit. Thus, directly targeting muscle mass and function may prove beneficial for improving T1D patient outcomes, independent of exercise. A potent negative regulator of skeletal muscle has been identified as being upregulated in T1D patients, namely the myokine myostatin. Our hypothesis is that targeting myostatin (via genetic deletion) will prevent glucose dysfunction in a T1D model, preserve skeletal muscle function, and protect against vascular and renal dysfunction. Our methods utilized adult male mice with (WT) and without myostatin (Myo KO), in combination with the chemical induction of T1D (streptozotocin). Experimental outcomes included the assessment of glucose homeostasis (plasma glucose, HbA1c, IGTT), metabolism, muscle function (in vivo plantarflexion), and skeletal muscle vascular function (ex vivo pressure myography). Our results described systemic benefits from myostatin deletion in the T1D model, independent of insulin, including the following: inhibition of T1D-induced increases in plasma glucose, prevention of functional deficits in muscle performance, and preservation of fluid dynamics. Further, endothelial function was preserved with myostatin deletion. Taken together, these data inform upon the use of myostatin inhibition as a therapeutic target for effective treatment and management of the cardiometabolic and skeletal muscle dysfunction that occurs with T1D.

This study aimed to assess the effect of dapagliflozin on the no-reflow phenomenon in patients with type II diabetes mellitus (T2DM) and acute myocardial infarction (AMI) who underwent percutaneous coronary intervention (PCI).

This single-center, observational cohort study included a total of 829 consecutive T2DM patients who were diagnosed with AMI and underwent PCI within 24 h of the onset of symptoms. Only patients using dapagliflozin (10 mg per day) for more than one year were considered as patients using dapagliflozin. The no-reflow phenomenon was defined as inadequate myocardial perfusion within a segment of the coronary circulation without angiographic evidence of mechanical vessel obstruction, dissection, or residual stenosis after PCI.

Four hundred and thirty-four patients were diagnosed with ST-segment elevation myocardial infarction (STEMI), and 395 patients were diagnosed with non-ST-segment elevation myocardial infarction (NSTEMI). Forward conditional logistic regression analysis demonstrated that the estimated glomerular filtration rate (OR = 0.940, 95% CI: 0.900 to 0.982, p = 0.006), SYNTAX score I (OR = 1.338, 95% CI: 1.179 to 1.520, p < 0.001), and dapagliflozin use (OR = 0.030, 95% CI: 0.004 to 0.228, p = 0.001) were independent predictors of the no-reflow phenomenon in STEMI. However, dapagliflozin use (OR = 0.112, 95% CI: 0.013 to 0.933, p = 0.043) was the only independent predictor of the no-reflow phenomenon in NSTEMI.

Lower rates of the no-reflow phenomenon were observed in T2DM patients taking dapagliflozin, diagnosed with AMI, and underwent PCI. However, this finding requires further investigation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with insulin resistance (IR). However, the prognostic value of different alternative IR surrogates in patients with MASLD remains unclear. This study aimed to evaluate the association between various IR indices and all-cause mortality and cardiovascular mortality in MASLD patients.

A total of 8,753 adults aged ≥ 20 years with MASLD from the National Health and Nutrition Examination Survey (NHANES, 2003-2018) were included, and their mortality data were obtained from the National Death Index (NDI). Insulin resistance surrogates [including the triglyceride-glucose (TyG) index, TyG-body mass index (TyG-BMI), TyG-waist circumference index, TyG-waist-to-height ratio index, and Homeostatic Model Assessment for IR] were stratified into quartiles. Cox proportional hazards models, receiver operating characteristic (ROC) curve analysis, restricted cubic spline (RCS), mediation analyses, and subgroup analyses were used to explore the associations between these indices and all-cause mortality as well as cardiovascular mortality in MASLD patients.

During a median follow-up of 98 months, 1,234 deaths were observed, including 409 cardiovascular disease (CVD)-related deaths. In the fully adjusted model, higher quartiles of TyG-related indices were significantly associated with an increased risk of all-cause mortality in MASLD patients. Furthermore, the TyG-BMI index was associated with both all-cause mortality and CVD mortality [all-cause mortality: HR (95% CI) 2.84 (1.73-4.67), P < 0.001; CVD mortality: HR (95% CI) 5.32 (2.26-12.49), P < 0.001]. The RCS analyses indicated a U-shaped relationship between TyG-BMI and mortality, with a threshold value of 270.49. Subgroup analyses demonstrated that TyG-related indices had stronger associations with mortality in elderly MASLD patients.

Our findings highlight the prognostic value of IR indices, particularly TyG-BMI index, in predicting all-cause mortality and CVD mortality in MASLD patients.

Haploidentical allogeneic hematopoietic cell transplantation (haplo-HCT) using post-transplant cyclophosphamide (PTCY) has become a standard approach for patients lacking HLA-matched donors. While effective in reducing graft-versus-host disease (GVHD), concerns about PTCY-associated cardiovascular toxicity remain. This study investigates the incidence, predictors, and impact of early cardiac events (ECE) in haplo-HCT recipients.

We conducted a retrospective, multicenter analysis of 268 patients with acute myeloid leukemia (AML) treated with anthracycline-based induction regimens and undergoing their first haplo-HCT with PTCY (50 mg/kg/day on days +3 and +4) between 2011 and 2022. ECEs, defined as any new cardiac event within 100 days post-transplant, were analyzed using cumulative incidence functions considering death and relapse as competing risks. Risk factors and the impact on non-relapse mortality (NRM) and overall survival (OS) were assessed via univariate and multivariate regression models.

The median patient age was 57 years (range: 18-79), and pre-transplant comorbidities included hypertension (22.4%), dyslipidemia (13.1%), diabetes mellitus (6.7%), and prior cardiac history (14.2%). ECEs occurred in 23 patients (8.6%) at a median of 19 days post-transplant (IQR: 5-66), with a day +100 cumulative incidence of 8.6% (95% CI: 6.1-12.3). The most frequent complications were pericardial effusion/pericarditis (43.5%), arrhythmias (30.4%), and heart failure (17.4%). Severe ECEs (CTCAE grade 3-4) were observed in 30.4% of cases, and four deaths (17.4%) were directly attributed to ECEs. Univariate analysis identified dyslipidemia (HR: 3.87, p=0.001), hypertension (HR: 2.76, p=0.015), and moderate-severe veno-occlusive disease (HR: 4.94, p=0.002) as significant predictors of ECE. ECEs were associated with lower OS (HR: 1.78, p=0.04) and higher NRM (HR: 2.87, p=0.005).

While the incidence of ECEs following haplo-HCT with PTCY was relatively low, their occurrence significantly worsened transplant outcomes. These findings underscore the importance of cardiovascular risk assessment and structured cardiac monitoring to mitigate complications in haplo-HCT recipients.

Diabetic cardiomyopathy (DCM) is a leading cause of heart failure (HF) among individuals with diabetes, presenting a significant medical challenge due to its complex pathophysiology and the lack of targeted therapies. Pyroptosis, a pro-inflammatory form of programmed cell death (PCD), is the predominant mode of cell death in the primary resident cells involved in DCM. It has been reported to be critical in DCM's onset, progression, and pathogenesis. Non-coding RNAs (ncRNAs), diverse transcripts lacking protein-coding potential, are essential for cellular physiology and the progression of various diseases. Increasing evidence indicates that ncRNAs are pivotal in the pathogenesis of DCM by regulating pyroptosis. This observation suggests that targeting the regulation of pyroptosis by ncRNAs may offer a novel therapeutic approach for DCM. However, a comprehensive review of this topic is currently lacking. Our objective is to elucidate the regulatory role of ncRNAs in pyroptosis associated with DCM and to elucidate the relationships among these factors. Additionally, we explored how ncRNAs influence pyroptosis and contribute to the pathophysiology of DCM. By doing so, we aim to identify new research targets for the clinical diagnosis and treatment of DCM.

Vasculopathy is the most prevalent complication of diabetes. Endothelial damage, a primary contributor to hyperglycemic vascular complications, impacts macro- and micro-vasculatures, causing functional impairment of multiple organs. SETD7 was initially identified as a transcriptional activator based on its ability to methylate histone 3 lysine 4. However, its function in the context of diabetic endothelial dysfunction remains poorly understood. This study aims to elucidate the involvement and underlying mechanisms of SETD7 in diabetic endothelial dysfunction.

SETD7 knockout mice were generated to investigate the effects of SETD7 on Streptozotocin (STZ)-induced hyperglycemia and vascular endothelial injury. Endothelial-specific SETD7 interruption adeno-associated virus (AAV) system was utilized to investigate the effects of SETD7 on diabetic vascular endothelial injury in BKS-DB(Lepr) KO/KO (db/db) mice. In vitro manipulation of SETD7 activation or knockdown was conducted to assess its regulation on the lipid peroxidation, oxidative stress, and cell function of primary rat aortic endothelial cells (RAECs) under high glucose conditions.

Our study revealed that knockout and endothelial deficiency of SETD7 partially restored damaged vascular function and attenuated the inflammatory response caused by high glucose in both STZ-induced and db/db mice. Moreover, SETD7 activation aggravated oxidative stress injury and resulted in profound dysfunction through Glutathione Peroxidase 4 (GPX4)-mediated lipid peroxidation in RAECs. Mechanistically, SETD7 deficiency reduced p53 mono-methylation and blocked FBXO45 transcription, thereby inhibiting the protein degradation of GPX4 and subsequent lipid peroxidation as well as oxidative stress.

In summary, our study demonstrates that SETD7-p53-FBXO45-GPX4 is involved in high glucose-induced oxidative stress injury and exacerbated endothelial dysfunction, which offering great significance for mitigating hyperglycemia-induced endothelial damage.

This study aims to systematically review the risk factors for major adverse cardiovascular events (MACE) in patients with coronary heart disease who have undergone percutaneous coronary intervention (PCI).

Systematic review and meta-analysis.

The Cochrane Library, PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Database, and VIP Database for Chinese Technical Periodicals (VIP) were screened until December 2024.

Case-control studies or cohort studies on the risk factors for MACE in patients with coronary heart disease who underwent PCI. Data extraction and synthesis: The literature review, data extraction, and quality evaluation were conducted by two independent researchers, and the meta-analysis was performed using RevMan 5.4 software.

The main outcome was that MACE occurred during the follow-up period.

A total of 40 articles were included. The meta-analysis erevealed that dyslipidemia (OR = 1.50; 95% CI [1.19, 1.89], p = 0.0007), diabetes mellitus (OR = 1.70; 95% CI [1.43, 2.02], p < 0.00001), hypertension (OR = 1.62; 95% CI [1.35, 1.96], p < 0.0001), history of smoking (OR = 2.08; 95% CI [1.51, 2.85], p < 0.0001), poorer ventricular function (OR = 2.39; 95% CI [2.17-2.64], p < 0.0001), impaired left ventricular ejection fraction (LVEF) (OR = 1.86; 95% CI [1.71-2.03], p < 0.0001), door to balloon (D-to-B) time (OR = 0.61; 95% CI [0.42-0.88]; p = 0.009), thrombolysis in myocardial infarction (TIMI) (OR = 1.41; 95% CI [1.17, 1.70], p = 0.0004), renal dysfunction (OR = 1.82; 95% CI [1.37, 2.43], p < 0.0001), and multi-vessel coronary artery disease (OR = 0.41; 95% CI [0.37, 0.46], p < 0.0001) were significantly associated with MACE after PCI.

The independent risk factors of MACE after PCI are dyslipidemia, hypertension, diabetes mellitus, smoking history, Killip class > II, LVEF ≤40%, D-to-B time >90 min, TIMI flow grade ≤ II, renal insufficiency, and multivessel disease.

Dysglycemia in critically ill patients is associated with endotheliopathy. This relationship may be altered in patients with diabetes.

Dysglycemia is common in critically ill patients and associated with increased mortality. Endotheliopathy is thought to play a role in this relationship; however, evidence is scarce. The aim of this study was to investigate the associations between dysglycemia and endotheliopathy to inform future glycemic management.

This prospective observational study included 577 acutely admitted adult ICU patients at Copenhagen University Hospital-North Zealand, Denmark.

Up to twenty-four hours of patient glycemia was paired with same-day levels of endothelial biomarkers measured after each 24-hour period for three consecutive days. Endotheliopathy was assessed by measurement of Syndecan-1, Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), and soluble thrombomodulin (sTM).

Of the included patients, a total 57.5% were males, median age was 71 yr (interquartile range [IQR], 63-79), and 24.6% had diabetes prior to admission. Median admission time was 5 d (IQR, 3-10). Time above range (TAR) greater than 13.9 mmol/L, but not TAR 10.0-13.9 mmol/L, was associated with increase in sTM (0.01 ng/mL per %-point increase in TAR, p = 0.049) and PECAM-1 (0.01 ng/mL per %-point increase, p = 0.007). Glycemic variability was associated with increases in sTM (0.24 ng/mL per mmol/L increase in sd, p = 0.001 and 0.03 ng/mL per %-point increase in coefficient of variation, p < 0.001). Hypoglycemia 3.0-3.9 mmol/L was associated with increases in sTM (3.0 ng/mL, p < 0.001) and PECAM-1 (1.54 ng/mL, p < 0.001).

In acutely admitted adult ICU patients, hypoglycemia was associated with endotheliopathy regardless of preadmission diabetes status. Hyperglycemia and high glycemic variability were associated with endotheliopathy in patients without diabetes. This suggests different responses to acute dysglycemia in patients with and without diabetes and warrants further investigation in clinical trials.

Diabetes mellitus is a chronic metabolic disorder that affects multiple organs, including the stomach. This research examines the effects of naringin and/or zinc on stomach and pancreatic tissues of streptozotocin-induced diabetic rats. Type 2 diabetes is induced by intraperitoneal injection of nicotinamide and streptozotocin. Three weeks after diabetes induction, rats receive eight weeks of treatment. Malondialdehyde and total antioxidant capacity are estimated colorimetrically. Asprosin and P-selectin levels are assessed via ELISA. Quantitative RT-PCR analysis of nuclear factor kappa B (NF-кB), peroxisome proliferator-activated receptor gamma (PPAR γ), and nuclear factor erythroid 2-related factor 2 (Nrf-2) genes is carried out. Tumor necrosis factor-alpha (TNF-α) is assessed immunohistochemically, and stomach and pancreatic tissues are examined histologically. Combined naringin and zinc treatment significantly reduces gastric Malondialdehyde, serum asprosin, and P-selectin levels in serum, stomach, and pancreas compared to diabetic rats. Additionally, gastric NF-кB expression is significantly lower, while PPAR γ and Nrf-2 expressions are significantly higher compared to diabetic rats. Immunohistochemical analysis and histopathological examination confirm these findings. In conclusion, combined naringin and zinc treatment significantly improves gastric alterations in diabetic rats by reducing oxidative stress and inflammation. Nonetheless, it shows no additional impacts on pancreatic tissue compared to naringin or zinc alone.

Impaired cardiac microvascular function is a significant contributor to diabetic cardiomyopathy. Rnd3 expression is notably downregulated in cardiac microvascular endothelial cells under diabetic conditions. Rnd3 overexpression mitigates diabetic myocardial microvascular injury and improves cardiac function through the Rock1/myosin light chain signaling pathway. Rnd3 facilitates the recruitment and interaction with Trim40 to promote Rock1 ubiquitination, thereby preserving endothelial barrier integrity in the diabetic heart.

Diabetes mellitus-related erectile dysfunction (DMED) is characterized by complicated pathogenesis and unsatisfactory therapeutic remedies. Glycolysis plays an essential role in diabetic complications and whether it is involved in the process of DMED has not been expounded. The aim of this study was to investigate the genetic profiling of glycolysis and explore potential mechanisms for DMED.

Glycolysis-related genes (GRGs) and gene expression matrix of DMED were obtained from the molecular signatures database and gene expression omnibus dataset. Differentially expressed analysis and support vector machine-recursive feature elimination (SVM-RFE) method were both used to obtain hub GRGs. Interactive network and functional enrichment analyses were performed to clarify the associated biological roles of these genes. The expression profile of hub GRGs was validated in cavernous endothelial cells, animals, and clinical patients. The subpopulation distribution of hub GRGs was further identified. In addition, a miRNA-GRGs network was constructed and expression patterns as well as molecular functions of relevant miRNAs were explored and validated. In addition, the relationship between hypoxia and DMED was also uncovered.

Based on the combined analysis, 48 differentially expressed GRGs were obtained. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that these genes were significantly enriched in carbon metabolism and oxidoreductase activities. Then hub GRGs including down-regulated as well as up-regulated genes in DMED were identified ultimately. Among them, ALDOC, ANGPTL4, and CITED2 were well-validated. In addition, 334 glycolysis-related miRNAs were verified and they were involved in endoplasmic reticulum membrane activity, smooth muscle cell differentiation and angiogenesis. After validation of miRNA signature in DMED patients, miR-222-5p, let-7e-5p, miR-184, and miR-122-3p were identified as the promising glycolysis-related miRNA biomarkers in DMED.

We clarified the expression signature of GRGs in DMED based on multi-omics analysis for the first time. It will be significantly important to reveal pathological mechanisms and promising treatments in DMED.

Patients with type 2 diabetes mellitus (T2DM) predominantly experience mortality due to cardiovascular diseases (CVD), particularly in low- and middle-income nations. Among these, heart failure (HF) is the most severe cardiovascular complication in terms of prognosis and management. Despite advancements in individualized glycemic control and cardiovascular risk management, including the development of novel glucose- and lipid-lowering agents, the prevalence of HF in T2DM patients remains persistently high. This indicates that factors beyond hyperglycemia significantly contribute to the heightened risk of HF associated with T2DM. This review examines critical factors influencing CVD risk in T2DM, particularly the roles of reduced heart rate variability (HRV), a marker of autonomic dysfunction, and chronic inflammation, both of which play pivotal roles in HF pathogenesis. Recent evidence highlights the potential of vagus nerve activation to modulate these risk factors, underscoring its capacity to reduce T2DM-related cardiovascular complications. Specifically, we discuss the therapeutic promise of transcutaneous auricular vagus nerve stimulation (taVNS) as a non-invasive intervention to enhance vagal tone, decrease systemic inflammation, and improve cardiovascular outcomes in T2DM. By addressing the interplay among HRV, microvascular disease, and inflammation, this review provides a comprehensive perspective on the potential utility of taVNS in managing HF in T2DM.

Atherosclerosis is a closely related complication of diabetes mellitus (DM), driven by endothelial dysfunction, inflammation, and oxidative stress. The progression of atherosclerosis is accelerated by hyperglycemia, insulin resistance, and hyperlipidemia. Novel antidiabetic agents, SGLT2 inhibitors, and GLP-1 agonists improve glycemic control and offer cardiovascular protection, reducing the risk of major adverse cardiovascular events (MACEs) and heart failure hospitalization. These agents, along with nonsteroidal mineralocorticoid receptor antagonists (nsMRAs), promise to mitigate metabolic disorders and their impact on endothelial function, oxidative stress, and inflammation. This review explores the potential molecular mechanisms through which these drugs may prevent the development of atherosclerosis and cardiovascular disease (CVD), supported by a summary of preclinical and clinical evidence.

Endothelial dysfunction (ED) is characterized by an imbalance between vasodilatory and vasoconstrictive factors, leading to impaired vascular tone, thrombosis, and inflammation. These processes are critical in the development of cardiovascular diseases (CVDs) such as atherosclerosis, hypertension and ischemia/reperfusion injury (IRI). Reduced nitric oxide (NO) production and increased oxidative stress are key contributors to ED. Aging further exacerbates ED through mitochondrial dysfunction and increased oxidative/nitrosative stress, heightening CVD risk. Antioxidant systems like superoxide-dismutase (SOD), glutathione-peroxidase (GPx), and thioredoxin/thioredoxin-reductase (Trx/TXNRD) pathways protect against oxidative stress. However, their reduced activity promotes ED, atherosclerosis, and vulnerability to IRI. Metabolic syndrome, comprising insulin resistance, obesity, and hypertension, is often accompanied by ED. Specifically, hyperglycemia worsens endothelial damage by promoting oxidative stress and inflammation. Obesity leads to chronic inflammation and changes in perivascular adipose tissue, while hypertension is associated with an increase in oxidative stress. The NLRP3 inflammasome plays a significant role in ED, being triggered by factors such as reactive oxygen and nitrogen species, ischemia, and high glucose, which contribute to inflammation, endothelial injury, and exacerbation of IRI. Treatments, such as N-acetyl-L-cysteine, SGLT2 or NLRP3 inhibitors, show promise in improving endothelial function. Yet the complexity of ED suggests that multi-targeted therapies addressing oxidative stress, inflammation, and metabolic disturbances are essential for managing CVDs associated with metabolic syndrome.

Nucleoside diphosphate kinase B (NDPKB) deficiency in endothelial cells (ECs) promotes the activation of the hexosamine biosynthesis pathway (HBP), leading to vascular damage in the retina. The aim of this study was to investigate the consequences of NDPKB deficiency in the mouse heart.

NDPKB deficient mice were used in the study. Echocardiography was employed to assess cardiac function in vivo. Characterization of contractility in hiPSC-derived cardiomyocytes (hiPSC-CMs) was measured with the IonOptix contractility system. Immunoblotting and immunofluorescence were carried out to analyze the expression and localization of proteins in cultured cells and left ventricles (LVs).

NDPKB deficient mice displayed impaired glucose tolerance and increased heart weight compared to controls. Echocardiographic analysis revealed an increase in the diastolic diameter of the left ventricular posterior wall (LVPW), a decrease in the early diastolic mitral valve E and E' wave, and in the ratios of E/A and E'/A' in NDPKB deficient hearts, suggesting cardiac hypertrophy and diastolic dysfunction. In line with cardiac dysfunction, the phosphorylation of myocardial phospholamban (PLN) and the expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) in the NDPKB deficient LVs were significantly reduced. Moreover, the accumulation of collagen, fibronectin as well as the upregulation of transforming growth factor β (TGF-β), were detected in NDPKB deficient LVs. In addition, activation of the HBP and its downstream O-GlcNAc cycle was observed in the LVs and cardiac ECs (CECs) isolated from the NDPKB-/- mice. Furthermore, a bipolar O-GlcNAc regulation was identified in CMs. O-GlcNAc was decreased in NDPKB-depleted CMs, while conditioned medium from NDPKB-depleted ECs significantly increased O-GlcNAc levels, along with contractile and relaxation dysfunction of the hiPSC-CMs, which was attenuated by inhibiting endothelial HBP activation.

Deficiency in NDPKB leads to endothelial activation of the HBP and cardiac dysfunction. Our findings may highlight the crucial role of proper endothelial HBP in maintaining cardiovascular homeostasis.

Diabetic vascular complications (DVCs) are diabetes-induced vascular dysfunction and pathologies, leading to the major causes of morbidity and mortality in millions of diabetic patients worldwide. DVCs are provoked by endothelial dysfunction which is closely coordinated with two important hallmarks: one is the insufficient insulin secretion or insulin resistance, and another is the decrease in intracellular nitric oxide (NO) influenced by dynamic wall shear stress (WSS). Although the intracellular NO dynamics in endothelial cells (ECs) is crucial for endothelial function, the regulation of NO production by dynamic WSS and insulin is still poorly understood. In this study, we have proposed a mathematical model of intracellular NO production in ECs under the stimulation of dynamic WSS combined with insulin. The model integrates simultaneously the biochemical signaling pathways of insulin and the mechanotransduction pathways induced by dynamic WSS. The accuracy and reliability of the model to quantitatively describe NO production in ECs were compared and validated with reported experimental data. According to the validated model, inhibition of protein kinase B (AKT) phosphorylation and Ca2+ influx by dynamic oscillatory WSS disrupts the dual nature of endothelial nitric oxide synthase (eNOS) enzyme activation. This disruption leads to the decrease in NO production and the bimodal disappearance of NO waveforms. Moreover, the results reveal that dynamic WSS combined with insulin promote endothelial NO production through negative synergistic effects, which is resulted from the temporal differences in mechanical and biochemical signaling. In brief, the proposed model elucidates the mechanism of NO generation activated by dynamic WSS combined with insulin, providing a potential target and theoretical framework for future treatment of DVCs.

Diabetic cardiomyopathy, a heart disease resulting from diabetes mellitus, inflicts structural and functional damage to the heart. Recent studies have highlighted the potential role of luteolin, a flavonoid, in mitigating diabetic cardiovascular injuries. The Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is implicated in exacerbating diabetes- and obesity-related complications. Interestingly, luteolin has been shown to inhibit protein tyrosine phosphatases, but it's unclear how SHP2 relates to luteolin's protective effects against diabetic heart disease. Here, we hypothesized that the inhibition of SHP2 signaling could play a role in luteolin's protective action against diabetic heart injury. Diabetes was induced in male Sprague-Dawley rats through a high-fat diet followed by a single intraperitoneal dose of streptozotocin (30 mg/kg). Five weeks post-diabetes induction, these rats were intraperitoneally injected with luteolin at varying doses (5, 10, 20 mg/kg) every other day for an additional 5 weeks. Then cardiac function was assessed, and hearts were isolated for further analysis. We found that luteolin notably improved cardiac function, inhibited cardiac hypertrophy and fibrosis, reduced levels of inflammatory factors and reactive oxygen species, and activated superoxide dismutase. Importantly, luteolin treatment also reduced the expression of SHP2 and phosphorylated signal transducer and activator of transcription 3 (STAT3) in a dose-dependent manner. These findings suggest that luteolin protects the diabetic heart against inflammation, oxidative stress, hypertrophy, and fibrosis, which may relate to down-regulating cardiac SHP2/STAT3 signaling.

Diabetes mellitus (DM) and its various complications, including diabetic nephropathy, retinopathy, neuropathy, cardiovascular disease, and ulcers, pose significant challenges to global health. This review investigates the potential of procyanidins (PCs), a natural polyphenolic compound, in preventing and managing diabetes and its complications. PCs, recognized for their strong antioxidant, anti-inflammatory, and anti-hyperglycemic properties, play a crucial role in reducing oxidative stress and enhancing endothelial function, which are essential for managing diabetic complications. This review elucidates the molecular mechanisms by which PCs improve insulin sensitivity and endothelial health, thereby providing protection against the various complications of diabetes. The comprehensive analysis underscores the promising therapeutic role of PCs in diabetes care, indicating the need for further clinical studies to confirm and leverage their potential in comprehensive diabetes management strategies.

Diabetes mellitus, a pervasive chronic metabolic disorder, is often associated with complications such as impaired wound healing. Various factors, most notably vascular deficiency, govern the wound repair process in diabetic patients, significantly impeding diabetic wound healing; therefore, angiogenesis and its role in diabetic wound repair have emerged as important areas of research. This review aims to delve into the mechanisms of angiogenesis, the effects of diabetes on angiogenesis, and the association between angiogenesis and diabetic wound repair. This will ultimately offer valuable guidance regarding the ideal timing of diabetic wound treatment in a clinical setting.

Interest is increasing in using novel diabetic medications, such as glucagon-like peptide 1 (GLP-1) receptor agonists, to manage coronary artery disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance GLP-1 activity through the same pathway as GLP-1 agonists; however, DPP-4 inhibitors have not been fully evaluated in the setting of ischemic heart disease. We chose to study the DPP-4 inhibitor linagliptin (LIN) in a porcine model of chronic coronary ischemia. Seventeen Yorkshire swine underwent left thoracotomy and ameroid constrictor placement over the left circumflex coronary artery at age 11 weeks. Two weeks thereafter, swine received either vehicle without drug (n = 9) or LIN 2.5 mg (n = 8). Following the elapse of 5 weeks of treatment, swine underwent terminal harvest. LIN significantly increased stroke volume, ejection fraction, cardiac output, and ischemic myocardial perfusion, while decreasing Tau (all P < .05). Trichrome staining showed a marked reduction in ischemic myocardial interstitial and perivascular fibrosis, accompanied by decreased levels of transforming growth factor-β (all P < .05). Apoptosis, measured by terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling staining, was significantly reduced, and accompanied by decreases in apoptosis-inducing factor, BCL2-associated agonist of cell death, caspase-9, and cleaved caspase-9 (all P < .05). Additionally, there were significant increases in phosphoinositide 3-kinase, phospho-protein kinase B, 5' adenosine monophosphate-activated protein kinase, phospho-5' adenosine monophosphate-activated protein kinase, and endothelial nitric oxide synthase, and significant reductions in collagen 18 and angiostatin (all P < .05). LIN significantly improved left ventricular function, cellular survival, and attenuated adverse remodeling, all likely secondary to augmented perfusion ischemic myocardial perfusion. Given that this increased perfusion occurred independently of changes in vascular density, treatment likely resulted in enhanced microvascular reactivity. These benefits warrant further investigation of LIN to fully understand its potential as a therapy for ischemic heart disease. SIGNIFICANCE STATEMENT: Linagliptin significantly improved cardiac cellular survival, left ventricular function, and attenuated adverse myocardial remodeling in a clinically relevant, large animal model of chronic ischemic cardiomyopathy. This warrants further investigation of linagliptin to fully understand its therapeutic potential.

The growing global prevalence of diabetes mellitus (DM), along with its associated complications, continues to rise. When clinically detected most DM complications are irreversible. It is therefore crucial to detect and address these complications early and systematically in order to improve patient care and outcomes. The current clinical practice often prioritizes DM complications by addressing one complication while overlooking others that could occur. It is proposed that the commonly targeted cell types including vascular cells, immune cells, glial cells, and fibroblasts that mediate DM complications, might share early responses to diabetes. In addition, the impact of one complication could be influenced by other complications. Recognizing and focusing on the shared early responses among DM complications, and the impacted cellular constituents, will allow to simultaneously address all DM-related complications and limit adverse treatment impacts. This review explores the current understanding of shared pathological signaling mechanisms among DM complications and recognizes new concepts that will benefit from further investigation in both basic and clinical settings. The ultimate goal is to develop more comprehensive treatment strategies, which effectively impact DM complications in multiple organs and improve patient care and outcomes.

Selenoprotein M (SELENOM) has emerged as a crucial factor in maintaining cellular redox homeostasis and mitigating oxidative damage. This study aims to investigate its protective role in cardiac endothelial cells under hyperglycemic stress, a condition commonly associated with diabetes mellitus and its cardiovascular complications. Diabetic mice model and human umbilical vein endothelial cells (HUVECs) were applied for in vivo and in vitro studies. Results reveal that hyperglycemia significantly downregulates SELENOM expression in both diabetic mouse hearts and primary cultured cardiac endothelial cells. Overexpression of SELENOM in HUVECs mitigated high-glucose-induced FITC-Dextran diffusion and the loss of transendothelial electrical resistance. Additionally, SELENOM overexpression decreased reactive oxygen species (ROS) levels, preserved tight junction protein expression, and maintained cellular structural integrity under hyperglycemic conditions. Furthermore, SELENOM overexpression attenuated high-glucose-induced mitochondrial apoptosis. High-glucose conditions decreased Parkin and increased p62 and Beclin1 expressions. SELENOM overexpression restored Parkin levels and promoted co-localization of LAMP1 and TOMM20. Knockdown of Parkin significantly attenuated these protective effects, suggesting the importance of Parkin in Selenoprotein M-mediated mitophagy. Collectively, these findings suggest that Selenoprotein M enhances Parkin-mediated mitophagy to protect endothelial cells from hyperglycemic stress, offering potential therapeutic insights for diabetic cardiovascular complications.

Endothelial cells are a major contributor to cardiovascular diseases. Studying their function and how they influence pathological processes remains an ongoing area of research. Although primary endothelial cells might be readily available from animals, translating results from these studies can be challenging due to species-dependent differences. A common source of human endothelial cells is human umbilical vein endothelial cells, but these cells might not represent the variety of endothelial cells from various vascular beds. Here we describe a protocol for the isolation and cultivation of endothelial cells from human internal mammary artery remains. These remains are commonly available from coronary artery bypass graft surgeries. The described tissue explant method combined with a magnetic sorting process provided a relatively high yield of endothelial cells that were subsequently passaged and used for studies involving mRNA and protein expression analyses, as well as fluorescence-based immunohistochemistry and patch-clamp electrophysiology. This protocol may help to extend the repertoire of studying human endothelial cells to understand their role and function in health and disease.

Excessive fluoride exposure can lead to health problems, such as fluorosis and neurotoxicity. However, effective therapeutic strategies for neurofluorosis remain elusive due to a limited understanding of the underlying molecular mechanisms. This study aimed to investigate the effects of Tanshinone IIA on spinal cord injury induced by high-fluoride exposure. To identify dysregulated genes associated with ferroptosis, we conducted an intersection analysis between differentially expressed genes in fluoride-treated HOS cells (GSE70719) and ferroptosis-related genes from the FerrDb database. A rat model of fluoride-induced spinal cord injury was established, revealing evidence of aberrant molecular and structural changes. Furthermore, the study demonstrated that Tanshinone IIA restored the altered expression of nine ferroptosis-related genes, eight fluorosis-related inflammatory indicators, and the observed structural changes. Overall, these findings suggest that Tanshinone IIA therapeutic potential in the treatment of fluoride-induced spinal cord injury by inhibiting ferroptosis and inflammation.

Montelukast, a Food and Drug Administration-approved drug for asthma and allergic rhinitis modulates leukotriene (LT) receptors and serves as a critical anti-inflammatory agent. Recent research suggests that the LT signaling pathway targeted by montelukast has broader implications for diseases such as fibrosis, cardiovascular diseases, cancer, cerebrovascular disease, and immune defense. This expanded understanding highlights montelukast's potential for repurposing in conditions involving aberrant stress mechanisms, including ocular diseases marked by inflammation, oxidative stress, ER stress, and apoptosis, among several others. This review delves into montelukast's therapeutic mechanisms across various diseases, draws parallels to ocular conditions, and examines clinical trials and associated adverse effects to underscore the unmet need for cysteinyl LT receptor antagonism by montelukast as an effective therapy for visual deficits.

Cardiovascular disease remains the leading cause of high mortality in individuals with diabetes mellitus. Endothelial injury is a major contributing factor for vascular dysfunction in diabetes. However, the precise mechanisms underlying endothelial cell injury and their heterogeneity in diabetes remains elusive. In this study, single-cell sequencing is performed in heart tissues from leptin receptor knock-out (db/db) diabetic mice at various pathological stages. Through cell cluster identification, differential gene analysis, intercellular communication analysis, pseudo time analysis, and transcription factor analysis, a novel mechanism of cardiac vascular endothelial damage in diabetes is identified. Specifically, a single-cell transcription map of cardiac vascular endothelial cells is presented in db/db mice. Diverse cellular clusters are found to play vital roles under diabetes-induced damage, highlighting crucial transcription factors involved in their regulation. In addition, the essential transcription factor Ets1 is found to protect against vascular endothelial injury in db/db mice. In summary, the work provides a comprehensive understanding of the development of diabetic cardiac vascular endothelial damage and the heterogeneity of the cells involved. These findings offer valuable insights into potential treatments and assessments of diabetic cardiovascular endothelial damage.

Shift work, particularly night shifts, disrupts circadian rhythms and increases stroke risk. This manuscript explores the mechanisms connecting shift work with stroke, focusing on circadian rhythms, hypertension, and diabetes. The circadian system, controlled by different mechanisms including central and peripheral clock genes, suprachiasmatic nuclei (SCN), and pineal gland (through melatonin production), regulates body functions and responds to environmental signals. Disruptions in this system affect endothelial cells, leading to blood pressure issues. Type 2 diabetes mellitus (T2DM) is significantly associated with night shifts, with circadian disturbances affecting glucose metabolism, insulin sensitivity, and hormone regulation. The manuscript examines the relationship between melatonin, insulin, and glucose balance, highlighting pathways that link T2DM to stroke risk. Additionally, dyslipidemia, particularly reduced HDL-c levels, results from shift work and contributes to stroke development. High lipid levels cause oxidative stress, inflammation, and endothelial dysfunction, increasing cerebrovascular risks. The manuscript details the effects of dyslipidemia on brain functions, including disruptions in blood flow, blood-brain barrier integrity, and neural cell death. This comprehensive analysis emphasizes the complex interplay of circadian disruption, hypertension, diabetes, and dyslipidemia in increasing stroke risk among shift workers. Understanding these mechanisms is essential for developing targeted interventions to reduce stroke susceptibility and improve cerebrovascular health in this vulnerable population.

The treatment of diabetic wounds is impaired by the intricate nature of diabetes and its associated complications, necessitating novel strategies. The utilization of mesenchymal stem/stromal cells (MSCs) as a therapeutic modality for chronic and recalcitrant wounds in diabetic patients is an active area of investigation aimed at enhancing its therapeutic potential covering tissue regeneration. The threat posed to the patient and their environment by the presence of a diabetic foot ulcer (DFU) is so significant that any additional therapeutic approach that opens new pathways to halt the progression of local changes, which subsequently lead to a generalized inflammatory process, offers a chance to reduce the risk of amputation or even death. This article explores the potential of MSCs in diabetic foot ulcer treatment, examining their mechanisms of action, clinical application challenges, and future directions for research and therapy.

Diabetes mellitus (DM) induces complex physiological changes in the inner ear environment. This study investigates the roles of oxidative stress (OS) and endoplasmic reticulum stress (ERS) in diabetes-related hearing loss (DRHL) and explores the potential of thioredoxin (Trx) in regulating OS, ERS, and apoptosis-related factors to mitigate the progression of hearing impairment. We conducted auditory and serological assessments in 63 patients with type 2 diabetes and 30 healthy controls. Type 2 diabetes models were induced in wild-type and Trx transgenic (Tg) mice, with auditory brainstem response (ABR) used to evaluate hearing changes. Cochlear tissues were isolated to analyse markers of apoptosis, OS, and ERS. Both patients with diabetes and mouse models exhibited hearing loss, alongside increased serum levels of Trx1, TXNIP, and AOPP, indicating oxidative damage. H&E and succinate dehydrogenase (SDH) staining revealed varying degrees of hair cell loss from the base to the apex of the cochlea in diabetic mice, with decreased expression of the hair cell protein prestin gene. Notably, Tg mice showed significant delay in hearing loss progression. In vitro, advanced glycation end-products (AGEs) induced OS and ERS in cochlear-like HEI-OC1 cells, while Trx overexpression enhanced Nrf2 activity, alleviating AGE-induced cellular stress. In conclusion, Trx exhibits protective effects against DRHL, potentially by enhancing Nrf2/HO-1/SOD2 function to reduce OS and ERS.