Diabetic cardiomyopathy represents a significant and irreversible chronic cardiovascular complication among diabetic patients. The condition is characterised by early diastolic dysfunction, myocardial fibrosis, cardiac hypertrophy, systolic dysfunction, and other complex pathophysiological events that ultimately lead to heart failure. Untargeted metabolomic analysis represents a powerful tool for the discovery of novel biomarkers. It can not only reveal the metabolic disorder model of diabetic cardiomyopathy, and find specific biomarkers, but also help analyse its pathogenesis and provide new clues for developing treatment strategies. Nevertheless, the precise mechanisms that give rise to diabetic cardiomyopathy remain unclear. In this study, we established a rat model of diabetic cardiomyopathy. We evaluated the model using various established methods, including fasting glucose, glycated hemoglobin, insulin resistance index, cardiac histopathology, and cardiac ultrasound. We then proceeded to identify diabetic cardiomyopathy serum biomarkers by untargeted metabolomics. The potential metabolic pathways of the multiple metabolic differentials were mainly related to amino acid metabolism and arachidonic acid metabolism. Two common metabolites, 5-OxoETE and D-Glutamine, were identified through various cross-comparisons. These two metabolites have good diagnostic ability, especially between DCM vs. CTR, DCM vs. NDCM, and NDCM vs. CTR. These findings may provide new insights into the study of DCM.

Type 2 diabetes is a significant risk factor for cardiovascular disease, particularly coronary heart disease, heart failure, and diabetic cardiomyopathy. Diabetic cardiomyopathy, characterized by heart dysfunction in the absence of coronary artery disease or hypertension, is triggered by various mechanisms, including hyperinsulinemia, insulin resistance, and inflammation. At the cellular level, increased insulin resistance leads to an imbalance in lipid and glucose metabolism, causing oxidative stress, mitochondrial dysfunction, and excess production of reactive oxygen species (ROS). This disrupts normal heart function, leading to fibrosis, hypertrophy, and cardiac remodeling. In diabetic patients, the excessive accumulation of fatty acids, advanced glycation end products (AGEs), and other metabolic disturbances further contribute to endothelial dysfunction and inflammatory responses. This inflammatory environment promotes structural damage, apoptosis, and calcium-handling abnormalities, resulting in heart failure. Additionally, diabetes increases the risk of arrhythmias, such as atrial fibrillation, which worsens cardiac outcomes. New insights into these molecular mechanisms have led to improvements in diabetes management, focusing on mitigating complications and understanding the cellular processes involved. Recent therapeutic advances, such as SGLT-2 inhibitors, have shown promise in addressing the energy imbalance and cardiac dysfunction seen in diabetic cardiomyopathy, offering new hope for better cardiovascular outcomes.

Cardiomyopathies comprise a heterogeneous group of cardiac disorders characterized by structural and functional abnormalities in the absence of significant coronary artery disease, hypertension, valvular disease, or congenital defects. Major subtypes include hypertrophic, dilated, arrhythmogenic, and stress-induced cardiomyopathies. Oxidative stress (OS), resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, has emerged as a key contributor to the pathogenesis of these conditions. ROS-mediated injury drives inflammation, protease activation, mitochondrial dysfunction, and cardiomyocyte damage, thereby promoting cardiac remodeling and functional decline. Although numerous studies implicate OS in cardiomyopathy progression, the precise molecular mechanisms remain incompletely defined. This review provides an updated synthesis of current findings on OS-related signaling pathways across cardiomyopathy subtypes, emphasizing emerging therapeutic targets within redox-regulatory networks. A deeper understanding of these mechanisms may guide the development of targeted antioxidant strategies to improve clinical outcomes in affected patients.

In diabetes mellitus, dysregulated glucose and lipid metabolism lead to diabetic cardiomyopathy (DCM) by imparting pathological myocardial remodeling and cellular injury. Accelerated glycation, oxidative stress, and activated inflammatory pathways culminate in cardiac fibrosis and hypertrophy in DCM. The regulatory effects of l-Arginine (L-Arg) have been elucidated in the pathological changes of DCM, including myocardial fibrosis, hypertrophy, and apoptosis, by inhibiting glycation and oxidative stress-induced inflammation. Disturbed L-Arg metabolism and decreased intracellular L-Arg pool are correlated with the progression of DCM; therefore, L-Arg supplementation has been prescribed for various cardiovascular dysfunctions. This review expands the therapeutic potential of L-Arg supplementation in DCM by elucidating its molecular mechanism of action and exploring potential clinical outcomes.

Among noncommunicable diseases, cardiovascular disease (CVD) is the leading cause of mortality and morbidity. In China, diabetes is renowned for its high incidence rate, and the body roundness index (BRI) is an emerging indicator for assessing obesity, particularly abdominal obesity. High BRI may lead to new-onset CVD events. However, the relationships between the BRI and new-onset CVD in individuals with or without diabetes remain unclear.

Data for this analysis were extracted from the China Health and Retirement Longitudinal Study (CHARLS). Our research utilized a cohort that was meticulously assessed over a period from 2011 to 2018, encompassing a comprehensive follow-up of 17,708 participants. Ultimately, this study focused on a subset of 6,737 individuals aged 45 years or older. Methodological approaches include Cox regression, Kaplan-Meier survival analysis, restricted cubic splines (RCS) analysis, receiver operating characteristic (ROC) curve analysis, subgroup analysis, and mediation analysis to explore the relationships of interest.

This study included 6,737 participants, all of whom were above the age of 45. Our findings revealed that within this demographic group, 1,481 (22.0%) patients experienced new-onset CVD. The Kaplan-Meier survival analysis further revealed that the group characterized by non-diabetes mellitus (Non-DM) had the lowest cumulative incidence of CVD compared with the diabetes mellitus (DM) group. Multivariate Cox regression revealed that in the fully adjusted model (Model 3) (HR = 1.122, 95% CI = 1.080 to 1.167), BRI was associated with the risk of CVD in the Non-DM group during the three-wave follow-up. RCS analysis revealed a positive, linear-like dose‒dependent relationship between BRI and new-onset CVD in Non-DM patients (P = 0.007, P for nonlinearity = 0.938). Smoking could affect the ability of the BRI to predict the incidence rate of CVD in the total population and in the population without diabetes (P interaction = 0.007). Moreover, the mediating effect of the BRI on new-onset CVD among diabetic patients was particularly pronounced in the long term, exceeding 4 years.

Our findings demonstrate a significant association between the BRI and CVD risk in non-diabetic individuals, with diabetes influencing the incidence and risk of new-onset CVD in middle-aged and elderly Chinese populations through the BRI playing a mediating role. As an obesity indicator, the BRI provides a valuable tool for early detection and intervention of CVD.

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Oxidative stress refers to an imbalance between oxidative capacity and antioxidant capacity, leading to oxidative damage to proteins, lipids, and DNA, which can result in cell senescence or death. It is closely associated with the occurrence and development of various diseases, including cardiovascular diseases, nephropathy, malignant tumors, neurodegenerative diseases, hypertension, diabetes, and inflammatory diseases. Curcumin is a natural polyphenol compound of β-diketone, which has a wide range of pharmacological activities such as anti-inflammatory, antibacterial, anti-oxidative stress, anti-tumor, anti-fibrosis, and hypolipidemic, demonstrating broad research and development value. It has a wide range of biological targets and can bind to various endogenous biomolecules. Additionally, it maintains the redox balance primarily by scavenging ROS, enhancing the activity of antioxidant enzymes, inhibiting lipid peroxidation, and chelating metal ions. This paper systematically describes the antioxidative stress mechanisms of curcumin from the perspective of signaling pathways, focusing on the Keap1-Nrf2/ARE, NF-κB, NOX, MAPK and other pathways. The study also discusses potential pathway targets and the complex crosstalk among these pathways, aiming to provide insights for further research on curcumin's antioxidant mechanisms and its clinical applications.

Myocardial ischemia/reperfusion (I/R) injury is a major global health problem with high rates of mortality and disability, which is more severe in patients with diabetes. Substantial researches have documented that diabetic myocardium are more susceptible to I/R injury, but many current intervention strategies against myocardial I/R injury have limited effectiveness in diabetic hearts. Caveolin-3 (Cav-3) is the signature protein of caveolae and serves as a signal integration and transduction platform in the plasma membrane of cardiomyocytes, which plays a vital role in myocardial functions, metabolism and protection of multiple conditioning strategies against I/R injury. Nevertheless, numerous studies have revealed that the expression of Cav-3 is impaired in diabetic hearts, which contributes to increased vulnerability of myocardium to I/R injury and resistance to protective conditioning strategies. In this review, we outline the basic structure and function of Cav-3, emphatically present the unique role of Cav-3 as a signal integration and transduction element in diabetic myocardial I/R injury and discuss its therapeutic perspective in strategies against myocardial I/R injury in diabetes.

Diabetic cardiomyopathy (DCM) is one of the common diabetic microangiopathy in clinical practice. In the early stage of the disease, there are no obvious clinical symptoms. In the middle and late stages, MF, arrhythmia, and even heart failure may occur, affecting the life and health of patients. MF, as one of the pathological features of DCM at the end stage, is the key factor of poor prognosis leading to ventricular wall stiffness and heart failure, which affects the clinical process and outcome of patients. The development of MF in a high glucose environment involves multiple complex fibrogenic pathways that work together to activate fibroblasts, thereby promoting MF. Indeed, aberrant activation of cardiac fibroblasts (CFs) is a key factor in MF. Therefore, inhibiting the activation of CFs may become a new strategy for the treatment of DCM. Previous studies have shown that Chinese herbal medicine (CHM) has potential in the treatment of DCM. In this review, we first introduced the physiology and function of CFs and discussed the conditions for the pathological activation of CFs in the process of diabetes, and then systematically summarized the effects of CHM on the activation of CFs by controlling the production of advanced glycosylation end products, oxidative stress and inflammation. This review will illustrate the potential of CHM to inhibit the activation of CFs and provide new ideas for the treatment of DCM.

Diabetes mellitus (DM) is a multifaceted disorder with a pandemic spread and a remarkable burden of cardiovascular mortality and morbidity. Diabetic cardiomyopathy (DBCM) has been increasingly recognized as the development of cardiac dysfunction, which is accompanied by heart failure (HF) symptoms in the absence of obvious reasons like ischemic heart disease, hypertension, or valvulopathies. Several pathophysiological mechanisms have been proposed, including metabolic disorders (e.g., glycation products), oxidative stress, low-grade inflammation, mitochondrial dysfunction, etc., which should guide the development of new therapeutic strategies. Up to now, HF treatment has not differed between patients with and without diabetes, which limits the expected benefits despite the high cardiovascular risk in the former group. However, DBCM patients may require different management, which prioritize anti-diabetic medications or testing other novel therapies. This review aims to appraise the challenges and prospectives of the individualized pharmaceutical therapy for DBCM.

Diabetes is a primary contributor to diabetic cardiomyopathy (DbCM), which is marked by metabolic imbalances such as elevated blood glucose and lipid levels, leading to significant structural and functional alterations in the myocardium. Elevated free fatty acids (FFAs) and hyperglycemia play critical roles in DbCM development, with FFAs inducing insulin resistance in cardiomyocytes and promoting lipid accumulation, resulting in oxidative stress and fibrosis. Current research suggests that glucagon-like peptide-1 (GLP-1) receptor agonists may effectively mitigate DbCM, although an effective treatment for this condition remains elusive, and the precise mechanisms of this protective effect are not fully understood.

In this study, we aimed to replicate diabetic glucolipotoxic conditions by treating differentiated H9c2 cells with high glucose and free fatty acids. Additionally, a diabetic cardiomyopathy model was induced in mice through high-fat diets. Both in vitro and in vivo models were used to investigate the protective effects of liraglutide on cardiomyocytes and elucidate its underlying molecular mechanisms.

Our findings indicate that liraglutide significantly reduces lipid droplet (LD) formation and myocardial fibrosis, as evidenced by decreased expression of fibrosis markers, including TGF-β1 and collagen types I and III. Liraglutide also enhanced AMP-activated protein kinase (AMPK) activation, which improved mitochondrial function, increased antioxidant gene expression, enhanced insulin signaling, and reduced oxidative stress.

These results demonstrate the potential therapeutic role of liraglutide in managing diabetes-related cardiac complications, offering a comprehensive approach to improving cardiac outcomes in patients with diabetes.

IntroductionDiabetic cardiomyopathy (DCM) is a complication of diabetes mellitus (DM) that can lead to heart failure and increase the risk of mortality. Pedunculoside (PE), a novel triterpenoid saponin, exhibits anti-inflammatory and anti-oxidative stress (OS) properties. However, its role in DCM remains unexplored.MethodsDCM models were established and treated with PE or the Nrf2 inhibitor (ML385). In vitro, cell function was evaluated using CCK-8, flow cytometry, qRT-PCR, and ELISA. In vivo, fasting blood glucose and insulin levels in rats were measured. The effects of PE on DCM were assessed using HE staining, TUNEL staining, and corresponding kits. Additionally, Nrf2/HO-1 pathway proteins were analyzed by western blot.ResultsLow doses of PE (2.5, 5, 10, and 20 μM) did not affect the viability of H9c2 cells. PE (10 and 20 μM) improved cell viability and prevented apoptosis, inflammation, and OS in high glucose (HG)-stimulated H9c2 cells. PE also upregulated Nrf2 in the nucleus and enhanced HO-1 and NQO1 expression in HG-treated H9c2 cells. Furthermore, the Nrf2 inhibitor (ML385) reversed PE's protective effects on HG-induced cell injury. In vivo, PE reduced blood glucose, increased insulin, alleviated myocardial injury, inhibited apoptosis, decreased levels of inflammatory factors and OS, and upregulated Nrf2, HO-1, and NQO1 in DCM model rats.DiscussionPE alleviates DCM injury by activating the Nrf2/HO-1 pathway. These findings support the potential therapeutic application of PE in DCM.

Vascular smooth muscle cells (VSMCs) undergo metabolic pathway transitions, including aerobic glycolysis, fatty acid oxidation, and amino acid metabolism, which are important for their function. Metabolic dysfunction in VSMCs can lead to age-related vascular diseases. O-GlcNAcylation, a nutrient-dependent posttranslational modification linked specifically to glucose metabolism, plays an important role in this context. Magnolia kobus DC. (MK), derived from the flower buds of Magnolia biondii, is known for its anticancer, anti-allergy, and anti-inflammatory properties. However, the role of O-GlcNAcylation in VSMCs under aging and the association between MK and O-GlcNAc remain unclear. Therefore, the present study aimed to determine the effects of O-GlcNAc on VSMC proliferation, along with the expression of MOF (males absent on the first, KAT8) and its correlation with the efficacy of MK. The results showed that aging and O-GlcNAc induction increased the expression levels of O-GlcNAc, O-GlcNAc transferase (OGT), ataxia telangiectasia mutated (ATM) protein, and MOF in mouse vascular smooth muscle cells (MOVAS) and aorta tissue. Transfection with OGT siRNA reduced the expression of MOF and OGT, indicating that OGT regulates MOF and influences cell proliferation. MK treatment reduced the expression of OGT, ATM, and MOF, which was correlated with O-GlcNAc levels. These findings suggest that O-GlcNAcylation is important for VSMC homeostasis and may be a novel target for vascular diseases. Thus, MK exhibits potential as a new drug candidate for treating vascular diseases by modulating O-GlcNAcylation and MOF interactions.

Diabetes is a complex condition with a rising global incidence, and its impact is equally evident in pediatric practice. Regardless of whether we are dealing with type 1 or type 2 diabetes, the development of complications following the onset of the disease is inevitable. Consequently, contemporary medicine must concentrate on understanding the pathophysiological mechanisms driving systemic decline and on finding ways to address them. We are particularly interested in the effects of oxidative stress on target cells and organs, such as pancreatic islets, the retina, kidneys, and the neurological or cardiovascular systems. Our goal is to explore, using the latest data from international scientific databases, the relationship between oxidative stress and the development or persistence of systemic damage associated with diabetes in children. Additionally, we highlight the beneficial roles of antioxidants such as vitamins, minerals, polyphenols, and other bioactive molecules; in mitigating the pathogenic cascade, detailing how they intervene and their bioactive properties. As a result, our study provides a comprehensive exploration of the key aspects of the oxidative stress-antioxidants-pediatric diabetes triad, expanding understanding of their significance in various systemic diseases.

Fibrosis is the outcome of any abnormal tissue repair process that results in normal tissue replacement with scar tissue, leading to persistent tissue damage and cellular injury. During the process of fibrosis, many cytokines and chemokines are involved, and their activities are controlled by post-translational modifications, especially SUMOylation and NEDDylation. Both these modifications entail a three-step process of activation, conjugation, and ligation that involves three kinds of enzymes, namely, E1 activating, E2 conjugating, and E3 ligase enzymes. SUMOylation participates in organ fibrosis by modulating FXR, PML, TGF-β receptor I, Sirt3, HIF-1α, and Sirt1, while NEDDylation influences organ fibrosis by regulating cullin3, NIK, SRSF3, and UBE2M. Further investigations exhibit the therapeutic potentials of SUMOylation/NEDDylation activators and inhibitors against organ fibrosis, especially ginkgolic acid in SUMOylation and MLN4924 in NEDDylation. These results demonstrate the therapeutic effects of SUMOylation and NEDDylation against organ fibrosis and highlight their activators as well as inhibitors as potential candidates. In the future, deeper investigations of SUMOylation and NEDDylation are needed to identify novel substrates against organ fibrosis; moreover, clinical investigations are needed to determine the therapeutic effects of their activators and inhibitors that can benefit patients. This review highlights that SUMOylation and NEDDylation function as potential therapeutic targets for organ fibrosis.

Fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) and constitutes a central pathophysiological process that underlies tissue dysfunction, across organs, in multiple chronic diseases and during aging. Myocardial fibrosis is a key contributor to dysfunction and failure in numerous diseases of the heart and is a strong predictor of poor clinical outcome and mortality. The excess structural and matricellular ECM proteins deposited by cardiac fibroblasts, is found between cardiomyocytes (interstitial fibrosis), in focal areas where cardiomyocytes have died (replacement fibrosis), and around vessels (perivascular fibrosis). Although myocardial fibrosis has important clinical prognostic value, access to cardiac tissue biopsies for histological evaluation is limited. Despite challenges with sensitivity and specificity, cardiac magnetic resonance imaging (CMR) is the most applicable diagnostic tool in the clinic, and the scientific community is currently actively searching for blood biomarkers reflecting myocardial fibrosis, to complement the imaging techniques. The lack of mechanistic insights into specific pro- and anti-fibrotic molecular pathways has hampered the development of effective treatments to prevent or reverse myocardial fibrosis. Development and implementation of anti-fibrotic therapies is expected to improve patient outcomes and is an urgent medical need. Here, we discuss the importance of the ECM in the heart, the central role of fibrosis in heart disease, and mechanistic pathways likely to impact clinical practice with regards to diagnostics of myocardial fibrosis, risk stratification of patients, and anti-fibrotic therapy.

Diabetic cardiomyopathy (DCM) represents a critical complication of Diabetes mellitus (DM), characterized by structural and functional changes in the myocardium independent of coronary artery disease or hypertension. Emerging evidence highlights the significant roles of phytochemicals, particularly astilbin and apigenin, in modulating key molecular pathways implicated in DCM. This review synthesizes current mechanistic insights and therapeutic potential of these compounds, focusing on their interactions with AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptors (PPARs), O-linked N-acetylglucosamine (O-GlcNAc), sodium-glucose co-transporter 2 (SGLT2), protein kinase C (PKC), nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) pathways. Astilbin and apigenin have demonstrated the ability to improve cardiac function, mitigate oxidative stress, and reduce inflammatory responses in diabetic conditions. By activating AMPK and PPARs, these flavonoids enhance glucose uptake and fatty acid oxidation, contributing to improved metabolic homeostasis. Their inhibition of O-GlcNAcylation, SGLT2 activity, and PKC signaling further attenuates hyperglycemia-induced cellular damage. Additionally, suppression of NF-κB, MAPK, and JNK pathways by astilbin and apigenin results in reduced pro-inflammatory cytokine production and apoptotic cell death. Collectively, these interactions position astilbin and apigenin as promising therapeutic agents for ameliorating DCM, offering novel avenues for treatment strategies aimed at modulating multiple pathogenic pathways.

Cancer cells maintain high levels of reactive oxygen species (ROS) to drive their growth, but ROS can trigger cell death through oxidative stress and DNA damage. To survive enhanced ROS levels, cancer cells activate their antioxidant defenses. One such defense is MTH1, an enzyme that prevents the incorporation of oxidized nucleotides into DNA, thus preventing DNA damage and allowing cancer to proliferate. MTH1 levels are often elevated in many cancers, and thus, inhibiting MTH1 is an attractive strategy for suppressing tumor growth and metastasis. Targeted MTH1 inhibition can induce DNA damage in cancer cells, exploiting their vulnerability to oxidative stress and selectively targeting them for destruction. Targeting MTH1 is promising for cancer treatment because normal cells have lower ROS levels and are less dependent on these pathways, making the approach both effective and specific to cancer. This review aims to investigate the potential of MTH1 as a therapeutic target, especially in cancer treatment, offering detailed insights into its structure, function, and role in disease progression. We also discussed various MTH1 inhibitors that have been developed to selectively induce oxidative damage in cancer cells, though their effectiveness varies. In addition, this review provide deeper mechanistic insights into the role of MTH1 in cancer prevention and oxidative stress management in various diseases.

The purpose of this study was to investigate the mechanism of EMP1 action in high glucose (HG)-induced H9c2 cardiac cell pyroptosis and oxidative injury. Rat cardiomyocytes H9c2 were exposed to 33 mM glucose for 24, 48, or 72 h to induce cytotoxicity. EMP1-siRNA, NLRP3 agonist Nigericin, and pcNDA-RAS were used to treat H9c2 cells under HG conditions. Cell Counting Kit (CCK)-8 assay showed that cell proliferation was decreased following HG induction, which was rescued by EMP1 knockdown. Our results also suggested that EMP1 siRNA transfection significantly decreased the apoptosis and pyroptosis of HG-induced cells, as indicated by the reduction of NLRP3 IL-1β, ASC, GSDMD, cleaved-caspase1 and cleaved-caspase3 levels in HG-induced H9c2 cells. In addition, EMP1 knockdown alleviated HG-induced mitochondrial damage and oxidative stress in H9c2 cells. NLRP3 activation reversed the inhibitory effects of EMP1 knockdown on pyroptosis and oxidative stress in HG-induced H9c2 cells. Mechanistically, we found that EMP1 knockdown suppressed the RAS/RAF/MAPK signaling pathway in HG-induced H9c2 cells. RAS overexpression blocked the protective effect of EMP1 knockdown on HG-induced H9c2 cell apoptosis, pyroptosis, and oxidative injury. Our findings suggest that EMP1 knockdown treatment might provide a novel therapy for diabetic cardiomyopathy.

Diabetes is a chronic metabolic disorder characterized by elevated blood glucose levels. This study aimed to analyze the changes underlying heterogeneities and communication properties of CMs in diabetes mellitus (DM).

GSE213337 dataset was retrieved from NCBI Gene Expression Omnibus, containing the single-cell RNA sequencing data of hearts from the control and streptozotocin-induced diabetic mice. GSEA and GSVA were used to explore the function enrichment of DEGs in CM. Cell communication analysis was carried out to study the altered signals and significant ligand-receptor interactions.

Seventeen cell types were identified between DM and the controls. The increasing ratio of CM suggested the occurrence of diabetes induces potential pathological changes of CM proliferation. A total of 1144 DEGs were identified in CM. GSEA and GSVA analysis indicated the enhancing lipid metabolism involving in DM. The results of cell communication analysis suggested that high glucose activated the ability of CM receiving fibroblast and LEC, while inhibited the capacity of receiving ECC and pericyte. Furthermore, GAS and ANGPTL were significantly decreased under DM, which was consistent with the results of GSEA and GSVA. Finally, the ligand-receptor interactions such as vegfc-vegfr2, angptl1 were changes in CM.

The CM showed the significant heterogeneities in DM, which played an important role in myocardial fibrosis induce by hyperglycemia.

Hypoxic injury is a critical pathological factor in the development of various cardiovascular diseases, such as congenital heart disease, myocardial infarction, and heart failure. Mitochondrial quality control is essential for protecting cardiomyocytes from hypoxic damage. Under hypoxic conditions, disruptions in mitochondrial homeostasis result in excessive reactive oxygen species (ROS) production, imbalances in mitochondrial dynamics, and initiate pathological processes including oxidative stress, inflammatory responses, and apoptosis. Targeted interventions to enhance mitochondrial quality control, such as coenzyme Q10 and statins, have shown promise in mitigating hypoxia-induced mitochondrial dysfunction. These treatments offer potential therapeutic strategies for hypoxia-related cardiovascular diseases by regulating mitochondrial fission and fusion, restoring mitochondrial biogenesis, reducing ROS production, and promoting mitophagy.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that has alarmingly increased in incidence in recent decades. One of the most serious complications of T2DM is diabetic cardiomyopathy (DCM), an often underrecognized yet severe condition that is a leading cause of mortality among diabetic patients. In the early stages of DCM, patients typically show no symptoms and maintain normal systolic and diastolic left ventricle function, making early detection challenging. Currently available clinical markers are often not specific enough to detect the early stage of DCM. Conventional biomarkers of cardiac mechanical stress and injury, such as natriuretic peptides (NPs) and cardiac troponin I (cTnI), have shown limited predictive value for patients with T2DM. NPs have proven efficacy in detecting diastolic dysfunction in diabetic patients when used alongside 2D echocardiography, but their utility as biomarkers is limited to symptomatic individuals. While cTnI is a reliable indicator of general cardiac damage, it is not specific to cardiac injury caused by high glucose levels or T2DM. This underscores the need for research into biomarkers that can enable early diagnosis and management of DCM to reduce mortality rates. Promising novel biomarkers that showed good performance in detecting diastolic dysfunction or heart failure in diabetic patients include galectin-3, ST2, FGF-21, IGFBP-7, GDF-15, and TGF-β. This review summarizes the current understanding of DCM biomarkers, aiming to generate new ideas for the early recognition and treatment of DCM by exploring related pathophysiological mechanisms.

Diabetic cardiomyopathy (DCM) is a kind of myocardial disease that occurs in diabetes patients and cannot be explained by hypertensive heart disease, coronary atherosclerotic heart disease and other heart diseases. Its pathogenesis may be closely related to programmed cell death, oxidative stress, intestinal microbes and micro-RNAs. The excessive activation of mineralocorticoid receptors (MR) in DCM can cause damage to the heart and kidneys. The third-generation non-steroidal mineralocorticoid receptor antagonist (MRA), finerenone, can effectively block MR, thus playing a role in protecting the heart and kidneys. This review mainly introduces the classification of MRA, and the mechanism of action, applications and limitations of finerenone in DCM, in order to provide reference for the study of treatment plans for DCM patients.

This editorial introduces the potential of targeting macrophage function for diabetic cardiomyopathy (DCM) treatment by dipeptidyl peptidase-4 (DPP-4) inhibitors. Zhang et al studied teneligliptin, a DPP-4 inhibitor used for diabetes management, and its potential cardioprotective effects in a diabetic mouse model. They suggested teneligliptin administration may reverse established markers of DCM, including cardiac hypertrophy and compromised function. It also inhibited the NLRP3 inflammasome and reduced inflammatory cytokine production in diabetic mice. Macrophages play crucial roles in DCM pathogenesis. Chronic hyperglycemia disturbs the balance between pro-inflammatory (M1) and anti-inflammatory (M2) macrophages, favoring a pro-inflammatory state contributing to heart damage. Here, we highlight the potential of DPP-4 inhibitors to modulate macrophage function and promote an anti-inflammatory environment. These compounds may achieve this by elevating glucagon-like peptide-1 levels and potentially inhibiting the NLRP3 inflammasome. Further studies on teneligliptin in combination with other therapies targeting different aspects of DCM could be suggested for developing more effective treatment strategies to improve cardiovascular health in diabetic patients.

Infiltration of monocyte-derived macrophages plays a crucial role in cardiac remodeling and dysfunction. The serum and glucocorticoid-inducible protein kinase 3 (SGK3) is a downstream factor of PI3K signaling, regulating various biological processes via an AKT-independent signaling pathway. SGK3 has been implicated in cardiac remodeling. However, the contribution of macrophagic SGK3 to hypertensive cardiac remodeling remains unclear. A cardiac remodeling model was established by angiotensin II (Ang II) infusion in SGK3-Lyz2-CRE (f/f, +) and wild-type mice to assess the function of macrophagic SGK3. Additionally, a co-culture system of SGK3-deficient or wild-type macrophages and neonatal rat cardiomyocytes (CMs) or neonatal rat fibroblasts (CFs) was established to evaluate the effects of SGK3 and the underlying mechanisms. SGK3 levels were significantly elevated in both peripheral blood mononuclear cells and serum from patients with heart failure. Macrophage SGK3 deficiency attenuated Ang II-induced macrophage infiltration, myocardial hypertrophy, myocardial fibrosis, and mitochondrial oxidative stress. RNA sequencing suggested Ndufa13 as the candidate gene in the effect of SGK3 on Ang II-induced cardiac remolding. Downregulation of Ndufa13 in CMs and CFs prevented the suppression of cardiac remodeling caused by SGK3 deficiency in macrophages. Mechanistically, the absence of SGK3 led to a reduction in IL-1β secretion by inhibiting the NLRP3/Caspase-1/IL-1β pathway in macrophages, consequently suppressing upregulated Ndufa13 expression and mitochondrial oxidative stress in CMs and CFs. This study provides new evidence that SGK3 is a potent contributor to the pathogenesis of hypertensive cardiac remodeling, and targeting SGK3 in macrophages may serve as a potential therapy for cardiac remodeling.

The purpose of the study is to elucidate whether irisin is a promising predictive biomarker for kidney-related events in patients with T2DM and concomitant asymptomatic HF. We prospectively enrolled 146 T2DM patients who had either evidence of structural cardiac abnormality or elevated levels of N-terminal brain natriuretic pro-peptide (NT-proBNP) > 125 pmol/mL and followed them for 52 weeks. Structural cardiac abnormalities were used as the minimum from the following criteria: abnormal left ventricular (LV) global longitudinal strain (GLS) < -16%, LV hypertrophy, left atrial volume index > 34 mL/m2, abnormal ratio of early transmitral diastolic filling velocity/early mitral annular velocity ≥ 13 units. All the patients underwent echocardiographic and Doppler examinations by two blinded, highly experienced echocardiographers. NT-proBNP, irisin, TNF-alpha, and hs-CRP were quantified in the serum at baseline, at 26 weeks, and at the end of the study. The kidney-related outcomes consisted of an eGFR reduction by 40% from baseline, or end-stage kidney disease, or kidney replacement therapy. We found that levels of irisin at baseline < 4.15 ng/mL and/or its decrease > 20% from baseline in T2DM patients predicted kidney-related events better than baseline levels/dynamic NT-proBNP and the use of SGLT2 inhibitors. In conclusion, we established that a low baseline level of irisin and its 20% decrease correlated with newly kidney-related events in T2DM patients with asymptomatic HFpEF/HFmrEF.

Sepsis-induced myocardial injury (SIMI) may be associated with insufficient mitophagy in cardiomyocytes, but the exact mechanism involved remains unknown. Sirtuin 3 (Sirt3) is mainly found in the mitochondrial matrix and is involved in repairing mitochondrial function through means such as the activation of autophagy. Previously, we demonstrated that the annexin-A1 small peptide (ANXA1sp) can promote Sirt3 expression in mitochondria. In this study, we hypothesized that the activation of Sirt3 by ANXA1sp induces mitophagy, thereby providing a protective effect against SIMI in mice.

A mouse model of SIMI was established via cecal ligation and puncture. Intraperitoneal injections of ANXA1sp, 3TYP, and 3MA were administered prior to modeling. After successful modeling, IL-6, TNF-α, CK-MB, and CTn-I levels were measured; cardiac function was assessed using echocardiography; myocardial mitochondrial membrane potential, ROS, and ATP production were determined; myocardial mitochondrial ultrastructure was observed using transmission electron microscopy; and the expression levels of Sirt3 and autophagy-related proteins were detected using western blotting.

ANXA1sp significantly reduced serum IL-6, TNF-α, CK-MB, and CTn-I levels; decreased myocardial ROS production; increased mitochondrial membrane potential and ATP synthesis; and improved myocardial mitochondrial ultrastructure in septic mice. Furthermore, ANXA1sp promoted Sirt3 expression and activated the AMPK-mTOR pathway to induce myocardial mitophagy. These protective effects of ANXA1sp were reversed upon treatment with the Sirt3 blocker, 3-TYP.

ANXA1sp can reverse SIMI, and the underlying mechanism may be related to the activation of the AMPK-mTOR pathway following upregulation of Sirt3 by ANXA1sp, which, in turn, induces autophagy.

Early dietary patterns potentially influence the health status and lifespan throughout adulthood and the entire lifespan. However, dietary behaviors are difficult for everyone to control during adolescence. It is even more important to study the effects of interventions of early dietary patterns on the lifespan under arbitrary feeding conditions. The research involves observing the survival status and lifespan of rats from weaning to adulthood with three different dietary patterns (a high-carbohydrate diet (HC), a high-protein diet (HP), and a high-fat diet (HF)) under ad libitum feeding conditions. The administration of high-carbohydrate diets leads to a significant extension of both median and maximum survival times (P < 0.05) in Wistar rats. Furthermore, it markedly enhanced the spatial memory capacity, mitigated the occurrence of liver and kidney pathological outcomes in elderly rats, and increased the abundance of gut microbiota improving amino acid metabolism. Additionally, feeding rats a high-carbohydrate diet improved glutathione (GSH) synthesis and recycling and activated the expression and upregulation of the lifespan-related proteins Foxo3a/Sirt3 and the key metabolic enzyme GPX-4. The high-carbohydrate diet from weaning to adulthood may potentially extend the lifespan by enhancing rat systemic glutathione synthesis, recycling, and improving the redox state pathway.

Diabetic cardiomyopathy (DCM) is a myocardial-specific microvascular disease caused by diabetes that affects the structure and function of the heart and is considered to be the leading cause of morbidity and death in patients with diabetes. Currently, there is no specific treatment or preventive drug for DCM, and there is an urgent need to develop new drugs to treat DCM. Traditional Chinese medicine (TCM) has rich experience in the treatment of DCM, and its characteristics of multi-target, multi-pathway, multi-component, and few side effects can effectively deal with the complexity and long-term nature of DCM. Growing evidence suggests that myocardial fibrosis, inflammation, oxidative stress, apoptosis, cardiac hypertrophy, and advanced glycation end product deposition were the main pathologic mechanisms of DCM. According to the pathological mechanism of DCM, this study revealed the potential of metabolites and prescriptions in TCM against DCM from the perspective of signaling pathways. The results showed that TGF-β/Smad, NF-κB, PI3K/AKT, Nrf2, AMPK, NLRP3, and Wnt/β-catenin signaling pathways were the key signaling pathways for TCM treatment of DCM. The aim of this study was to summarize and update the signaling pathways for TCM treatment of DCM, to screen potential targets for drug candidates against DCM, and to provide new ideas and more experimental evidence for the clinical use of TCM treatment of DCM.

Diabetic cardiomyopathy is a serious complication of obesity with type 2 diabetes and is a major cause of mortality. Metabolic surgery, such as duodenal-jejunal bypass (DJB), can effectively improve diabetic cardiomyopathy; however, the underlying mechanisms remain elusive. Oxidative stress is one of the pivotal mechanisms of diabetic cardiomyopathy. Our objective was to investigate the effect and potential mechanisms of DJB on oxidative stress in the heart of diabetic cardiomyopathy rats.

High-fat diet combined with intraperitoneal injection of streptozotocin was used to establish diabetic cardiomyopathy rats. DJB was performed on diabetic cardiomyopathy rats, and high glucose and palmitate were used to simulate diabetic cardiomyopathy in H9C2 cells in vitro. Sera from different groups of rats were used for experiments in vivo and in vitro.

DJB effectively improved oxidative stress and activated the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway to increase endothelial nitric oxide synthase (eNOS) phosphorylation level and the expression of antioxidative system-related proteins and genes in the heart of diabetic cardiomyopathy rats. AMPK agonists and serum from DJB rats activated the AMPK pathway to increase eNOS phosphorylation level and the expression of antioxidative system-related proteins and genes and decreased the content of reactive oxygen species in H9C2 cells, but this improvement was almost eliminated by the addition of AMPK inhibitors.

DJB activates eNOS and enhances the antioxidant system by activating the AMPK pathway-and not solely by improving blood glucose-to improve oxidative stress in the heart of diabetic cardiomyopathy rats.

Cardiovascular diseases (CVD) persist as a prominent cause of mortality worldwide, with oxidative stress constituting a pivotal contributory element. The oxidative modification of guanosine, specifically 8-oxoguanine, has emerged as a crucial biomarker for oxidative stress, providing novel insights into the molecular underpinnings of CVD. 8-Oxoguanine can be directly generated at the DNA (8-oxo-dG) and RNA (8-oxo-G) levels, as well as at the free nucleotide level (8-oxo-dGTP or 8-oxo-GTP), which are produced and can be integrated through DNA replication or RNA transcription. When exposed to oxidative stress, guanine is more readily produced in RNA than in DNA. A burgeoning body of research surrounds 8-oxoguanine, exhibits its accumulation playing a pivotal role in the development of CVD. Therapeutic approaches targeting oxidative 8-Oxoguanine damage to DNA and RNA, encompassing the modulation of repair enzymes and the development of small molecule inhibitors, are anticipated to enhance CVD management. In conclusion, we explore the noteworthy elevation of 8-oxoguanine levels in patients with various cardiac conditions and deliberate upon the formation and regulation of 8-oxo-dG and 8-oxo-G under oxidative stress, as well as their function in CVD.

Hypertrophic cardiomyopathy (HCM) is a heart condition characterized by cellular and metabolic dysfunction, with mitochondrial dysfunction playing a crucial role. Although the direct relationship between genetic mutations and mitochondrial dysfunction remains unclear, targeting mitochondrial dysfunction presents promising opportunities for treatment, as there are currently no effective treatments available for HCM. This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews guidelines. Searches were conducted in databases such as PubMed, Embase, and Scopus up to September 2023 using "MESH terms". Bibliographic references from pertinent articles were also included. Hypertrophic cardiomyopathy (HCM) is influenced by ionic homeostasis, cardiac tissue remodeling, metabolic balance, genetic mutations, reactive oxygen species regulation, and mitochondrial dysfunction. The latter is a common factor regardless of the cause and is linked to intracellular calcium handling, energetic and oxidative stress, and HCM-induced hypertrophy. Hypertrophic cardiomyopathy treatments focus on symptom management and complication prevention. Targeted therapeutic approaches, such as improving mitochondrial bioenergetics, are being explored. This includes coenzyme Q and elamipretide therapies and metabolic strategies like therapeutic ketosis. Understanding the biomolecular, genetic, and mitochondrial mechanisms underlying HCM is crucial for developing new therapeutic modalities.

Diabetic heart disease (DHD) is a serious complication in patients with diabetes. Despite numerous studies on the pathogenic mechanisms and therapeutic targets of DHD, effective means of prevention and treatment are still lacking. The pathogenic mechanisms of DHD include cardiac inflammation, insulin resistance, myocardial fibrosis, and oxidative stress. Macrophages, the primary cells of the human innate immune system, contribute significantly to these pathological processes, playing an important role in human disease and health. Therefore, drugs targeting macrophages hold great promise for the treatment of DHD. In this review, we examine how macrophages contribute to the development of DHD and which drugs could potentially be used to target macrophages in the treatment of DHD.

Toll-like receptors (TLRs) are inflammatory triggers and belong to a family of pattern recognition receptors (PRRs) that are central to the regulation of host protective adaptive immune responses. Activation of TLRs in innate immune myeloid cells directs lymphocytes to produce the most appropriate effector responses to eliminate infection and maintain homeostasis of the body's internal environment. Inappropriate TLR stimulation can lead to the development of general autoimmune diseases as well as chronic and acute inflammation, and even cancer. Therefore, TLRs are expected to be targets for therapeutic treatment of inflammation-related diseases, autoimmune diseases, microbial infections, and human cancers. This review summarizes the recent discoveries in the molecular and structural biology of TLRs. The role of different TLR signaling pathways in inflammatory diseases, autoimmune diseases such as diabetes, cardiovascular diseases, respiratory diseases, digestive diseases, and even cancers (oral, gastric, breast, colorectal) is highlighted and summarizes new drugs and related clinical treatments in clinical trials, providing an overview of the potential and prospects of TLRs for the treatment of TLR-related diseases.

Diabetes mellitus is a non-communicable metabolic disease hallmarked by chronic hyperglycemia caused by beta-cell failure. Diabetic complications affect the vasculature and result in macro- and microangiopathies, which account for a significantly increased morbidity and mortality. The rising incidence and prevalence of diabetes is a major global health burden. There are no feasible strategies for beta-cell preservation available in daily clinical practice. Therefore, patients rely on antidiabetic drugs or the application of exogenous insulin. Glutaredoxins (Grxs) are ubiquitously expressed and highly conserved members of the thioredoxin family of proteins. They have specific functions in redox-mediated signal transduction, iron homeostasis and biosynthesis of iron-sulfur (FeS) proteins, and the regulation of cell proliferation, survival, and function. The involvement of Grxs in chronic diseases has been a topic of research for several decades, suggesting them as therapeutic targets. Little is known about their role in diabetes and its complications. Therefore, this review summarizes the available literature on the significance of Grxs in diabetes and its complications. In conclusion, Grxs are differentially expressed in the endocrine pancreas and in tissues affected by diabetic complications, such as the heart, the kidneys, the eye, and the vasculature. They are involved in several pathways essential for insulin signaling, metabolic inflammation, glucose and fatty acid uptake and processing, cell survival, and iron and mitochondrial metabolism. Most studies describe significant changes in glutaredoxin expression and/or activity in response to the diabetic metabolism. In general, mitigated levels of Grxs are associated with oxidative distress, cell damage, and even cell death. The induced overexpression is considered a potential part of the cellular stress-response, counteracting oxidative distress and exerting beneficial impact on cell function such as insulin secretion, cytokine expression, and enzyme activity.

Diabetes is a prevalent disease, primarily characterized by high blood sugar (hyperglycemia). Significantly higher rates of myocardial dysfunction have been noted in individuals with diabetes, even in those without coronary artery disease or high blood pressure (hypertension). Numerous molecular mechanisms have been identified through which diabetes contributes to the pathology of diabetic cardiomyopathy, which presents as cardiac hypertrophy and fibrosis. At the cellular level, oxidative stress and inflammation in cardiomyocytes are triggered by hyperglycemia. Although males are generally more likely to develop cardiovascular disease than females, diabetic males are less likely to develop diabetic cardiomyopathy than are diabetic females. One reason for these differences may be the higher levels of serum testosterone in males compared with females. Although testosterone appears to protect against cardiomyocyte oxidative stress and exacerbate hypertrophy, its role in inflammation and fibrosis is much less clear. Additional preclinical and clinical studies will be required to delineate testosterone's effect on the diabetic heart.

Diabetic cardiomyopathy (DCM) is the development of myocardial dysfunction in patients with diabetes despite the absence of comorbidities such as hypertension, atherosclerosis or valvular defect. The cardiovascular complications of poorly controlled diabetes are very well illustrated by the U.K. Prospective Diabetes Study (UKPDS), which showed a clear association between increasing levels of glycated hemoglobin and the development of heart failure (HF). The incidence of HF in patients with diabetes is projected to increase significantly, which is why its proper diagnosis and treatment is so important. Providing appropriate therapy focusing on antidiabetic and hypolipemic treatment with the consideration of pharmacotherapy for heart failure reduces the risk of CMD and reduces the incidence of cardiovascular complications. Health-promoting changes made by patients such as a low-carbohydrate diet, regular exercise and weight reduction also appear to be important in achieving appropriate outcomes. New hope for the development of therapies for DCM is offered by novel methods using stem cells and miRNA, which, however, require more thorough research to confirm their efficacy.

Diabetic cardiomyopathy (DCM) is closely related to ferroptosis, a new type of cell death that mainly manifests as intracellular iron accumulation and lipid peroxidation. Paeoniflorin (PA) helps to improve impaired glucose tolerance, influences the distribution of the intestinal flora, and induces significant resistance to ferroptosis in several models. In this study, we found that PA improved cardiac dysfunction in mice with DCM by alleviating myocardial damage, resisting oxidative stress and ferroptosis, and changing the community composition and structure of the intestinal microbiota. Metabolomics analysis revealed that PA-treated fecal microbiota transplantation affected metabolites in DCM mice. Based on in vivo and in vitro experiments, 11,12-epoxyeicosatrienoic acid (11,12-EET) may serve as a key contributor that mediates the cardioprotective and antiferroptotic effects of PA-treated fecal microbiota transplantation (FMT) in DCM mice.NEW & NOTEWORTHY This study demonstrated for the first time that paeoniflorin (PA) exerts protective effects in diabetic cardiomyopathy mice by alleviating myocardial damage, resisting ferroptosis, and changing the community composition and structure of the intestinal microbiota, and 11,12-epoxyeicosatrienoic acid (11,12-EET) may serve as a key contributor in its therapeutic efficacy.

Increased reactive oxygen species (ROS) and oxidative stress response lead to cardiomyocyte hypertrophy and apoptosis, which play crucial roles in the pathogenesis of heart failure. The purpose of current research was to explore the role of antioxidant N-acetylcysteine (NAC) on cardiomyocyte dysfunction and the underlying molecular mechanisms.

Compared with control group without NAC treatment, NAC dramatically inhibited the cell size of primary cultured neonatal rat cardiomyocytes (NRCMs) tested by immunofluorescence staining and reduced the expression of representative markers associated with hypertrophic, fibrosis and apoptosis subjected to phenylephrine administration examined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Moreover, enhanced ROS expression was attenuated, whereas activities of makers related to oxidative stress response examined by individual assay Kits, including total antioxidation capacity (T-AOC), glutathione peroxidase (GSH-Px), and primary antioxidant enzyme Superoxide dismutase (SOD) were induced by NAC treatment in NRCMs previously treated with phenylephrine. Mechanistically, we noticed that the protein expression levels of phosphorylated phosphatidylinositol 3-kinase (PI3K) and AKT were increased by NAC stimulation. More importantly, we identified that the negative regulation of NAC in cardiomyocyte dysfunction was contributed by PI3K/AKT signaling pathway through further utilization of PI3K/AKT inhibitor (LY294002) or agonist (SC79).

Collected, NAC could attenuate cardiomyocyte dysfunction subjected to phenylephrine, partially by regulating the ROS-induced PI3K/AKT-dependent signaling pathway.