Search Results (286)

Objective: Diabetes mellitus (DM) is a major metabolic disorder associated with hyper-glycemia and oxidative stress. Traditional medicinal plants remain important sources of bioactive compounds with potential antidiabetic activity. Salacia reticulata and Caralluma tuberculata are two important medicinal plants that have been reported to have antidiabetic effects. The growing burden of type 2 diabetes and the need for therapies that address both hyperglycemia and oxidative stress underscore the necessity to investigate these two medicinal plants. Therefore, the current study evaluated the antihyperglycemic, antioxidant, and protective effects of Salacia reticulata and Caralluma tuberculata in an alloxan-induced diabetic female rat model. Methods: Ethanolic extracts of S. reticulata and C. tuberculata were characterized by total phenolic content (TPC), total flavonoid content (TFC), DPPH radical-scavenging assay, and UPLC–MS/MS metabolite profiling. Female Wistar rats (n = 42) were randomly assigned to seven groups (n = 6/group), including normal control, diabetic control, extract-treated non-diabetic groups, diabetic extract-treated groups, and a metformin-treated diabetic group. Diabetes was induced by alloxan (130 mg/kg), followed by oral treatment for 8 days with extracts or metformin (500 mg/kg/day). Fasting blood glucose, oral glucose tolerance, serum malondialdehyde (MDA), antioxidant markers (SOD1, GSH, and CAT), and liver and kidney histopathology were assessed. Results: Both plant extracts significantly reduced fasting blood glucose compared with baseline, with S. reticulata showing a greater reduction (22.8%) than C. tuberculata (12.3%), and a response comparable to metformin (27.4%). Diabetic rats exhibited increased MDA and reduced antioxidant enzyme activities. C. tuberculata significantly lowered MDA levels and increased SOD1 activity, suggesting moderate antioxidant effects, whereas S. reticulata showed higher phenolic and flavonoid contents and the highest DPPH scavenging activity. UPLC–MS/MS identified 33 compounds in S. reticulata and 24 in C. tuberculata. Histopathological findings supported improvement of diabetes-associated renal and hepatic damage. Conclusions: Within the eight-day experimental period, both extracts demonstrated significant acute antidiabetic and antioxidant effects with distinct redox–metabolic profiles. However, further long-term studies are recommended to evaluate their sustained efficacy, safety, and potential as complementary therapeutic agents for diabetes management. Full article

Background: Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) usually coexist and are related to increased morbidity and mortality. Cardiovascular benefits have been demonstrated by drugs such as sodium-glucose cotransporter-2 inhibitors (SGLT2i) and GLP-1 receptor agonists including the dual GIP/GLP-1 receptor agonist tirzepatide (collectively, incretin-based therapies); however, their relative effectiveness in patients with concomitant AF and HFpEF remains undefined. Methods: We conducted a retrospective, propensity score-matched cohort study utilizing the TriNetX Global Collaborative Network. Adults with AF or atrial flutter with a diagnosis of HFpEF who initiated incretin-based therapies (GLP-1 receptor agonists or dual GLP-1/GIP receptor agonists) or SGLT2i were included; index medication was required to be initiated within 30 days of a qualifying AF/HFpEF diagnosis. 1:1 matching was performed based on baseline medications, demographics, and comorbidities. Co-primary outcomes were all-cause mortality, inpatient visits, and emergency department (ED) visits at 1 year. Secondary outcomes included myocardial infarction, ischemic stroke, acute kidney injury, transient ischemic attack, major adverse cardiovascular events (MACE; all-cause mortality/MI/stroke composite), and AF-related procedures. Agent-specific subgroup analyses were performed for semaglutide and tirzepatide separately. Sensitivity analyses were conducted at 6 months and 2 years. Results: 7624 patients were included in each cohort after matching (mean age: 70.8 years; 52% women). At 1 year, incretin-based therapy was associated with lower all-cause mortality (5.3% vs. 7.3%, HR 0.721, 95% CI 0.634–0.820; p < 0.001), fewer inpatient visits (30.0% vs. 37.4%, HR 0.743, 95% CI 0.702–0.787; p < 0.001), and no statistically significant difference in ED visits (27.0% vs. 28.0%; HR 0.946, 95% CI 0.888–1.007; p = 0.081) compared with SGLT2i. Incretin-based therapy was also associated with lower risk of MACE (HR 0.709), acute kidney injury (HR 0.751), myocardial infarction (HR 0.583), catheter ablation (HR 0.685), and electrical cardioversion (HR 0.472). No significant differences were observed in ischemic stroke or transient ischemic attack. These findings were broadly consistent at 6-month and 2-year follow-up, and directionally consistent in agent-specific subgroup analyses of semaglutide and tirzepatide. Conclusions: In this large propensity-matched cohort of patients with AF and HFpEF, initiation of incretin-based therapy (GLP-1 receptor agonists or dual GLP-1/GIP receptor agonists) was associated with lower all-cause mortality, fewer inpatient visits, and reduced cardiovascular events compared with SGLT2i. These findings, while subject to observational limitations, suggest potential benefits of incretin-based therapy in this high-risk population and support the need for prospective comparative trials. Full article

A ketogenic diet (KD) is a low-carbohydrate, high-fat dietary approach. Beyond treating neurologic disorders, KDs have attracted significant media attention for their potential to improve obesity and diabetes. The diet induces a metabolic shift from glucose toward fatty acid oxidation and ketone body production. This shift leads to ketosis, which may reduce hunger, partly through the anorexigenic effects of ketone bodies, thereby contributing to weight loss and improved metabolic parameters, including glycaemic control and insulin sensitivity. In particular, the positive effects of KDs lower insulin demand and may thereby improve β-cell function. However, the long-term efficacy, safety, and sustainability of KDs, especially for diabetes, remain debated. This review offers current insights into the effects of ketogenesis and ketosis, as well as the potential mechanisms underlying them. We explore the metabolic effects of KDs in obesity and diabetes, drawing on preclinical and clinical studies, and suggest that combining KDs with antidiabetic agents may provide synergistic benefits. However, combining KDs with these pharmacotherapies, particularly SGLT-2 inhibitors, requires careful clinical supervision because of potential risks, including euglycaemic diabetic ketoacidosis. We explore how a KD alters the composition of the gut microbiota, thereby affecting host health. We conclude by highlighting challenges and future directions for optimising KD-based therapies and by outlining the limitations of the current review. Full article

Introduction: Fish and humans share evolutionarily conserved pathways regulating lipid metabolism. However, the effects of pharmaceuticals on lipid homeostasis in fish remain poorly understood, particularly regarding mechanistic lipid dysregulation and its implications for fish physiology and environmental toxicology. While hypolipidemic drugs such as statins have been shown to modulate lipid metabolism in teleosts, other lipid-lowering agents, including cholesterol absorption inhibitors, remain largely unexplored. Additionally, synthetic hormones have been shown to interfere with lipid regulation, although their effects—particularly those of progestins—remain poorly characterized. Objective: This study aimed to explore the mechanistic lipid disruptions induced by potential hypo- and hyperlipidemic modulating pharmaceuticals in brown trout juveniles exposed to subchronic pharmacological conditions. Methodology: Juvenile brown trout were exposed via intramuscular injection every 72 h for 28 days and allocated into six experimental groups (n = 12 per group): control (C; 0.7% NaCl), solvent control (SC; 0.7% NaCl, 0.9% ethanol, 0.1% dimethyl sulfoxide), atorvastatin (ATV; 0.3 µg·g⁻¹), ezetimibe (EZB; 0.3 µg·g⁻¹), 17α-ethinylestradiol (EE2; 2 µg·g⁻¹), and levonorgestrel (LNG; 0.1 µg·g⁻¹). All concentrations represented pharmacological doses. On day 28, the fish were euthanized and sampled. Endpoints included biometric measurements, blood lipid profiling, serum biochemistry, and hepatic lipid accumulation. Results: ATV fish displayed greater body length, whereas EE2 increased liver weight and hepatosomatic index. EE2 reduced high-density lipoproteins and increased low-density lipoproteins, while atorvastatin reduced low-density lipoproteins. EE2 exposure also increased albumin levels and decreased glucose concentrations. Furthermore, EE2 significantly enhanced hepatic lipid deposition. Conclusions: The hyperlipidemic effects of EE2 were the most pronounced, whereas ATV produced the strongest hypolipidemic responses, consistent with its known effects in humans, and also influenced biometry. These findings provide a robust foundation for understanding how pharmaceuticals influence lipid metabolism and related physiological processes such as growth in fish, with relevance for both fish physiology research and environmental toxicology. Full article

Alzheimer’s disease (AD) and metabolic syndrome often occur together, sharing characteristics such as insulin resistance, dyslipidemia, and chronic inflammation. Metabolic dysfunction frequently precedes cognitive decline, indicating that early intervention might alter the disease’s progression. We investigated whether the GLP-1 receptor agonist semaglutide (SMGL) influences metabolic impairment and AD pathology in an AD mouse model. Male and female 5xFAD and wild-type (WT) mice on regular (RD) or high-fat diets (HFD) were administered SMGL for 13 weeks. SMGL-treated groups exhibited significant, context-dependent effects. In metabolically challenged 5xFAD HFD mice, treatment led to reduced body weight, improved glucose tolerance, normalized cholesterol levels, and a restored balance of adiponectin and leptin. These improvements were associated with reduced Aβ40 and Aβ42 levels, restored GLP-1 receptor expression, increased synaptophysin and βIII-tubulin levels, and enhanced spatial memory. SMGL also decreased Iba1 and CD68 immunoreactivity in the hippocampus and cortex, reduced macrophage infiltration, and lowered CD36 expression in visceral adipose tissue (VAT), indicating coordinated anti-inflammatory effects. WT RD mice showed minimal metabolic responses and a modest decline in Y-maze performance, suggesting that excessive GLP-1 receptor activation may disrupt neuronal homeostasis when metabolic status is normal. SMGL acts as a context-specific metabolic and neuroprotective agent, offering the greatest benefits under conditions of metabolic dysfunction. These findings in a preclinical model suggest that targeting early metabolic disturbances provides a testable hypothesis for attenuating AD-related neurodegeneration, though further translational studies are required. Full article

Background/Objectives: Type 2 Diabetes Mellitus (T2DM) is characterized by insulin resistance and chronic hyperglycemia, which significantly impair vascular function. In experimental T2DM models, the vascular endothelium is compromised, showing decreased vasodilator responses. Vitamin D3 has emerged as a promising intervention for improving glycemic parameters and restoring endothelial function. This study evaluated the effects of vitamin D3 (0.25 and 0.50 µg/kg/day) administered for 4 and 8 weeks on the ex vivo aortic vascular reactivity of T2DM rats. Methods: T2DM was induced in male Wistar rats via a high-fat, normoprotein diet and streptozotocin (30 mg/kg, i.p.). Groups included normal control, diabetic control, metformin, and vitamin D3 (0.25 or 0.50 µg/kg/day). Following 4 or 8 weeks of treatment, thoracic aortic segments were isolated for ex vivo vascular reactivity studies to assess responses to vasoconstrictor and vasorelaxant agents. Results: Vitamin D3 treatment improved glycemic profiles; the 0.25 µg/kg dose reduced fasting glucose, while the 0.50 µg/kg dose lowered glycated hemoglobin at 8 weeks. Endothelium-dependent relaxation induced by acetylcholine was significantly increased in diabetic rats treated with vitamin D3 at both doses over 4 weeks compared to diabetic controls. Moreover, vitamin D3 prevented the attenuation of maximal contractile responses to phenylephrine observed in untreated diabetic rats at 8 weeks. Conclusions: Vitamin D3 supplementation restores endothelial function and improves vascular reactivity in an experimental T2DM model. These findings suggest that vitamin D3 may mitigate vascular complications by enhancing vasorelaxation and maintaining contractile integrity. Full article

Three medium-chain fatty acids (MCFAs), namely decanoic acid, octanoic acid, and hexanoic acid, were identified in ozonated sunflower oil (OSO) using high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC/MS). All three MCFAs exhibited strong in vitro antioxidant activity to enhance high-density lipoprotein (HDL)-associated paraoxonase and protected low-density lipoproteins (LDL) from oxidative damage caused by Cu²⁺ ions. Consistently, MCFAs displayed substantial cellular antioxidant activity and minimized carboxymethyllysine (CML)-induced reactive oxygen species (ROS) generation and apoptotic cell death in zebrafish embryos. In adult zebrafish, MCFAs treatment mitigated CML-induced acute death and swimming abnormalities, and substantially augmented plasma sulfhydryl content, ferric ion reduction ability (FRA), and paraoxonase (PON)-like activity. Also, MCFA-treated zebrafish showed lower blood glucose, total cholesterol (TC) and triglycerides (TG) with raising HDL cholesterol levels. The MCFAs showed substantial inhibition of hepatic ROS generation, neutrophil efflux, interleukin (IL)-6 production, and steatosis, leading to hepatoprotection against CML-triggered adversity. Consistent with hepatic histology results, reduced plasma hepatic function biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were observed in MCFA-treated groups than in the CML-treated group. In the kidney, MCFA treatment effectively reduced oxidative stress and cellular senescence and protected against kidney damage induced by exposure to CML. The study concludes the presence of three MCFAs in the OSO, which serve as functional antioxidants and anti-inflammatory agents, accounting for its diverse pharmacological properties. Full article

Chronic kidney disease (CKD) is a major global health burden associated with substantially increased risks of morbidity and mortality. Cardiovascular disease remains the leading cause of death across all stages of CKD. Over the past few decades, several pharmacologic therapies—including renin–angiotensin system inhibitors, sodium–glucose cotransporter-2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, and lipid-lowering agents—have demonstrated substantial cardio-nephroprotective benefits and are recommended in international guidelines. However, real-world implementation of these therapies remains incomplete, and emerging evidence highlights important sex-based disparities in prescribing patterns. Although CKD is more prevalent in women worldwide, women with CKD are consistently less likely than men to receive guideline-directed cardioprotective and nephroprotective medications. This treatment gap spans both traditional therapies, such as angiotensin-converting enzyme inhibitors and statins, and newer agents with proven outcome benefits. Women are less likely to initiate treatment, less likely to receive high-intensity or target doses, and less likely to achieve recommended blood pressure and lipid goals. Importantly, the presence of CKD attenuates the usual female survival advantage, and the relative excess cardiovascular risk associated with CKD may be particularly pronounced in women. The under-prescription of cardio-renal therapies in women with CKD reflects a complex interplay of factors. These include older age at presentation, higher reported rates of adverse drug reactions, concerns regarding tolerability and safety in advanced kidney disease, therapeutic inertia, underestimation of cardiovascular risk, and persistent underrepresentation of women in clinical trials. Biological differences in pharmacokinetics and pharmacodynamics, as well as structural and system-level barriers, further contribute to inequities in care. Addressing these disparities requires improved risk recognition, sex-informed prescribing practices, enhanced representation of women in clinical research, and implementation strategies that incorporate sex-disaggregated performance metrics. Reducing treatment gaps is essential to improving cardiovascular and renal outcomes and to achieving equitable, precision-based care for women with CKD. Full article

Coronary microvascular dysfunction (CMD) has emerged as a crucial contributor to cardiovascular morbidity and mortality, particularly in patients with ischemia and non-obstructive coronary arteries (INOCA). The condition arises from a complex interplay of structural and functional abnormalities within the small coronary vessels, driven by underlying molecular mechanisms including endothelial nitric oxide synthase (eNOS) uncoupling, oxidative stress, and chronic inflammation. Lipid metabolism plays a central role in this pathology, especially in the setting of elevated low-density lipoprotein cholesterol (LDL-C). Furthermore, the protective capacity of high-density lipoprotein (HDL) is increasingly understood to depend on its functionality rather than absolute levels, as it can become dysfunctional and pro-inflammatory in pathological states. Emerging evidence has identified lipoprotein(a) [Lp(a)] and triglyceride-rich lipoproteins as significant, independent contributors to microvascular injury. Comprehensive clinical assessment of microvascular dysfunction therefore requires integration of advanced lipid profiling, including apolipoprotein B (ApoB), [Lp(a)], and the triglyceride-glucose (TyG) index with invasive and non-invasive measures of coronary flow reserve to more precisely stratify risk. In this narrative review, we synthesize current observational, mechanistic, and early interventional data linking diverse lipid phenotypes to coronary microvascular dysfunction. We propose a concept of lipid-driven CMD endotypes, such as ApoB-/particle overload, dysfunctional HDL, Lp(a)-mediated risk, and metabolic/TyG-high states, and map these to a practical, mechanism-informed management framework. While intensive LDL-C lowering with high-intensity statins and combination therapy remains guideline-directed care for high-risk patients, evidence for dedicated microvascular benefit from newer lipid and cardiometabolic agents is still largely hypothesis-generating. A personalized approach that aligns lipid phenotyping, CMD endotyping, and existing guideline-based therapies may help refine risk assessment and inform future trials. Full article

Plants of the genus Salacia (Celastraceae) have long been used in traditional medical systems of South and Southeast Asia for the management of diabetes and related metabolic disorders. Modern phytochemical and pharmacological studies have confirmed the antidiabetic potential of several Salacia species, leading to the identification of a distinctive group of sulfur-containing sugars as their principal bioactive constituents. Salacinol, neosalacinol, kotalanol, neokotalanol, and related analogues represent a novel class of thiosugar sulfonium compounds that act as potent and selective α-glucosidase inhibitors, providing a clear mechanistic basis for their glucose-lowering effects. Simpler thiosugars, such as 5-thiomannose, further contribute to the overall metabolic activity of Salacia extracts and may serve as biosynthetic or functional precursors. Beyond Salacia, sulfur-containing natural products are widespread in nature and perform diverse biological roles. In particular, the genus Allium is well known for producing organosulfur compounds, including thioethers and polysulfides, which exhibit antidiabetic, hypolipidemic, antioxidant, and cardioprotective activities. In a different context, sulfur-containing hopanes have been identified in sediments and petroleum as products of early diagenetic sulfurization of bacterial hopanoids. Although these compounds have been studied primarily as geochemical biomarkers, recent QSAR/PASS analyses suggest that sulfur hopanes may also possess biologically relevant activities, particularly related to metabolic and cardiovascular regulation. Recent PASS-based QSAR evaluations of Salacia-derived thiosugars and sulfur hopanes predict significant antidiabetic activity, including potential type 2 diabetes-related pharmacological effects, supported by predicted α-glucosidase inhibitory, hypoglycemic, hepatic, and gastrointestinal activities. Collectively, these findings highlight sulfur-containing natural products from both plant and sedimentary sources as chemically diverse yet functionally convergent scaffolds with promising potential for the development of functional foods and therapeutic agents targeting metabolic disorders. Full article

The global population is ageing due to increased life expectancy, and the prevalence of diabetes is proportionally increasing. With advancing age, diabetes in older people is a complex condition due to associated morbidities and geriatric syndromes. As a result, the management of diabetes in old age is challenging. Due to the wide heterogeneity of older people, diabetes management in this age group should be personalised. While strict targets are accepted in fit individuals, relaxed targets should be considered in patients with multiple morbidities and a high risk of hypoglycaemia. The development of frailty changes the metabolic profile of older people, and their insulin resistance and diabetes trajectory, which will have an impact on the choice of glucose-lowering agents and the goals of therapy. For example, intensive therapy, the use of SGLT-2 inhibitors and GLP-1RA, and tight targets should be continued in frail, sarcopenic, obese individuals due to their increased insulin resistance and cardiovascular risk. On the other hand, relaxed targets and deintensification of therapy should be considered in anorexic, malnourished, frail individuals with significant weight loss due to their low insulin resistance, low prevalence of cardiovascular risk factors, and high risk of hypoglycaemia. Annual reviews of older people with diabetes should include screening for frailty, depression and dementia for early diagnosis, and appropriate interventions. The introduction of continuous glucose monitoring is increasingly used in older people with diabetes and has the potential to reduce the incidence of hypoglycaemia. With the expectation of a continued increase in the prevalence of older people with diabetes, the use of mobile health may allow care delivery on a wider scale without the need for face-to-face appointments. In addition, there is a promising scope for artificial intelligence to achieve better diabetes outcomes. Future research is still required to expand the use of these technologies in older age groups. Full article

The interest in the use of phytochemicals and herbal medicines for the treatment of acne vulgaris has grown steadily over recent decades. The research on the secondary metabolites and biological properties of bearberry (Arctostaphylos uva-ursi (L.) Spreng.) has been intensified in recent years, but the range of bacterial strains tested, many of which are highly relevant to human health, remains very limited. Therefore, the aim of this study was to evaluate the chemical composition and the antioxidant, antimicrobial, and cytotoxic activities of water and ethanolic bearberry leaf extracts. Compared with the ethanolic extract, the water extract was characterized by higher concentrations of arbutin, hydroquinone, corilagin, and hyperoside and the absence of ursolic acid and oleanolic acid. However, it exhibited lower total phenolic content and reduced levels of penta-O-galloyl-β-d-glucose (PGG). The ethanolic extract of bearberry leaves showed higher antioxidant activity and the most favorable overall biological properties. The therapeutic index (TI) values for the water and ethanolic extracts, respectively, were as follows: Cutibacterium acnes ATCC 11827 (10.70; 21.57), Propionibacterium acnes PCM 2334 (10.70; 43.13), P. acnes PCM (5.33; 21.57), Staphylococcus aureus ATCC 25923 (10.70; 21.57), and S. epidermidis ATCC 12228 (5.33; 10.78). The present findings further support the medicinal and cosmetic use of A. uva-ursi and highlight its potential as a source of natural antibacterial agents for acne treatment. Full article

Background/Objectives: Metformin has been proposed as a potential treatment for hyperprolactinemia irrespective of etiology. Previous studies suggest that vitamin D deficiency attenuates the prolactin-lowering effect of metformin in women. This study examined whether vitamin D status modifies the effects of this agent on prolactin and other anterior pituitary hormones in men with iatrogenic hyperprolactinemia. Methods: Seventy-five adult men with antipsychotic-induced hyperprolactinemia and type 2 diabetes or prediabetes were enrolled. Participants were assigned to three equal groups based on vitamin D status and supplementation: vitamin D-naive men with sufficient levels (group 1), vitamin D-naive men with deficiency (group 2), and men with sufficient vitamin D levels receiving oral supplementation for at least six months (group 3). All participants received metformin (3 g/day) for six months. Plasma 25-hydroxyvitamin D, markers of glucose metabolism, total and monomeric prolactin, TSH, gonadotropins, ACTH, testosterone, and IGF-1 were measured at baseline and after treatment. Results: Baseline characteristics were comparable among groups except for 25-hydroxyvitamin D levels. Seventy participants completed the study. Metformin improved glycemic control and insulin sensitivity in all groups, with greater effects in men with sufficient vitamin D status. Reductions in total and monomeric prolactin were observed only in groups 1 and 3 and were associated with baseline prolactin concentrations and pretreatment 25-hydroxyvitamin D levels. These changes were accompanied by modest increases in LH and testosterone, and improvements in sexual functioning. Vitamin D levels and other hormonal parameters remained unchanged. The magnitude of the metformin effect did not differ between groups 1 and 3. Conclusions: Adequate vitamin D status is necessary for metformin to reduce prolactin levels in men with iatrogenic hyperprolactinemia. Full article

Stroke remains a major cause of morbidity and mortality worldwide. Although reperfusion therapies and secondary prevention have advanced, the global stroke burden continues to rise, driven by increasing rates of hypertension and diabetes mellitus. Type 2 diabetes (T2DM) increases the risk of acute ischemic stroke (AIS) through mechanisms involving chronic hyperglycemia, endothelial dysfunction, inflammation, and accelerated atherogenesis. In recent years, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising agents for cardiovascular and cerebrovascular risk reduction in patients with T2DM. Beyond their glucose-lowering properties, GLP-1RAs improve blood pressure regulation and lipid metabolism, as mentioned in the 2025 AHA Journal guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults. Emerging preclinical and clinical evidence indicates that GLP-1RAs also provide direct neurovascular protection by stabilizing the blood–brain barrier, modulating neuroinflammation, and promoting neuronal survival. These mechanisms may reduce ischemic injury, improve recovery after stroke, and protect against cognitive decline. Major cardiovascular outcome trials have demonstrated significant reductions in major adverse cardiovascular events and, to a lesser degree, non-fatal stroke among patients receiving GLP-1RAs. This narrative review evaluates current evidence on the neurovascular, cardiometabolic, and anti-inflammatory actions of GLP-1RAs and their potential role in mitigating stroke risk and promoting cerebrovascular health. Additionally, it highlights gaps in the literature, explores clinical and guideline implications, and outlines future directions for integrating GLP-1RA therapy into comprehensive stroke prevention and recovery strategies. Full article

Diabetic neuropathy is a frequent and disabling complication of diabetes, encompassing distal symmetric polyneuropathy and cardiovascular autonomic neuropathy, both associated with reduced quality of life and increased cardiovascular risk. Beyond its traditional interpretation as a direct consequence of chronic hyperglycaemia, oxidative stress has emerged as a central integrative mechanism linking metabolic overload, inflammation, mitochondrial dysfunction, and microvascular injury to progressive neural damage. These processes converge within the neurovascular unit, promoting a self-perpetuating cycle of axonal degeneration, impaired nerve perfusion and altered neuronal excitability. This narrative review synthesises experimental and clinical evidence on oxidative stress-related pathways implicated in diabetic neuropathy, including hyperglycaemia-activated metabolic routes, mitochondrial dysfunction, endoplasmic reticulum stress, and chronic inflammatory signalling. Classical antioxidant and mitochondrial-supportive interventions are evaluated alongside pleiotropic glucose-lowering agents, with particular emphasis on sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, integrating mechanistic insights with biomarker and clinical outcome data. Conventional antioxidant strategies, such as α-lipoic acid, acetyl-L-carnitine, coenzyme Q10 and N-acetylcysteine, show reproducible benefits on neuropathic symptoms and oxidative stress markers, but evidence for sustained structural or disease-modifying effects remains limited. In contrast, incretin-based therapies and sodium–glucose cotransporter-2 inhibitors exert broader pleiotropic actions by attenuating oxidative and inflammatory signalling, improving mitochondrial homeostasis and endothelial function, with emerging evidence for modest but consistent neurophysiological and autonomic benefits. Overall, oxidative stress emerges as a key mechanistic hub in diabetic neuropathy. Future progress will depend on mechanism-aligned, neuropathy-specific clinical trials incorporating multidimensional endpoints and validated biomarkers. Full article