Diabetic cardiac remodeling involves microvascular dysfunction, inflammatory myeloid responses and fibroblast activation. O-linked beta-N-acetylglucosamine (O-GlcNAc) modification connects nutrient metabolism to protein function within each compartment, but its role in coordinating communication between them remains a hypothesis. This Mini Review evaluates that hypothesis against the available evidence. Diabetic models support causal effects of endothelial O-GlcNAc perturbation on coronary dysfunction, and an arterial endothelial CaMKIIalpha-small-extracellular-vesicle circuit provides evidence for persistent communication with cardiomyocytes after glucose normalization. Macrophage substrate mechanisms and fibroblast contractile responses are drawn partly from other organs or non-diabetic disease. Their relevance is therefore assessed separately from experimental design and human association. We compare O-GlcNAc with parallel AGE-RAGE, oxidative-stress and nutrient-sensing mechanisms, identify limitations of antibody-based and site-level measurements, and address sex as a biological variable. The synthesis supports O-GlcNAc as a candidate intracellular mediator of persistent multicellular remodeling, rather than an established intercellular coordinating signal. A consolidated experimental strategy tests whether endothelial O-GlcNAc is necessary for myeloid recruitment and subsequent fibrosis under matched glycemic conditions, and whether defined endothelial cargo rescues those effects. Cell-, substrate- and time-resolved interventions will be needed to separate pathogenic persistence from adaptive O-GlcNAc responses.

Chronic kidney disease (CKD) is a major global health concern characterized by progressive loss of kidney function and an increased risk of cardiovascular morbidity and mortality. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, initially developed as antihyperglycemic agents for the treatment of type 2 diabetes mellitus (T2DM), have subsequently demonstrated substantial renoprotective effects that extend beyond glycemic control. This systematic review aimed to evaluate current evidence regarding the effects of SGLT-2 inhibitors on CKD progression in adults with and without diabetes. A comprehensive literature search was conducted in PubMed/MEDLINE, Scopus, and Google Scholar from database inception through October 2025. Eligible studies included randomized controlled trials (RCTs), systematic reviews and meta-analyses, and prospective or retrospective observational cohort studies evaluating kidney outcomes, including CKD progression, changes in estimated glomerular filtration rate (eGFR), doubling of serum creatinine, and progression to end-stage kidney disease (ESKD). The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Thirty-two studies met the inclusion criteria, comprising 13 RCTs, eight systematic reviews and meta-analyses, and 11 observational cohort studies. Across randomized trials, SGLT-2 inhibitors consistently reduced CKD progression and major adverse kidney outcomes and slowed the decline in kidney function. Dedicated kidney outcome trials demonstrated substantial reductions in adverse kidney outcomes, while meta-analytic evidence confirmed preservation of kidney function across diverse CKD populations, including individuals without diabetes. Real-world observational studies further supported these findings, demonstrating slower eGFR decline and favorable kidney outcomes in routine clinical practice. SGLT-2 inhibitors were generally well tolerated, and meta-analytic evidence demonstrated a reduced risk of acute kidney injury among patients with CKD. Collectively, the available evidence indicates that SGLT-2 inhibitors substantially slow CKD progression and reduce adverse kidney outcomes across diverse CKD populations, including patients with and without diabetes. Their consistent efficacy and favorable safety profile support their role as cornerstone nephroprotective agents in contemporary CKD management. Further research is warranted to clarify their long-term efficacy and safety in underrepresented populations, particularly patients with advanced CKD and non-albuminuric disease.

Cancer cells have the ability to reprogram their metabolism to meet the proliferative and survival demands. These metabolic alterations involve the formation of many active metabolites associated with epigenetic modifications or remodelling together driving tumourigenesis through self-perpetuating feedback loops. Among the various metabolic stressors, reducing sugars, principally glucose and fructose, lactate, acetyl-CoA, glycolytic intermediates such as 3-deoxyglucosone, glyoxal, polyol pathway metabolites, and methylglyoxal effectively modulate the chromatin remodelling and gene expression. These processes lead to dysregulated DNA methylation and histone modifications involving acetylation, methylation, polysialylation, lactylation, and glycation establishing a tumourigenic environment. Elevated levels of reducing sugars and glycolytic intermediates also contribute to the formation of a large group of reactive molecules termed advanced glycation intermediates (AGIs) and advanced glycation end products (AGEs), which interact with their receptor RAGE to activate signalling cascades resulting in oxidative stress, inflammation, and aberrant gene regulation. Furthermore, the AGE-RAGE axis reprograms cancer metabolism influencing key signalling pathways including PI3K/AKT/mTOR and NF-κB. The epigenetic alterations and metabolic perturbations induced by reducing sugars and non-enzymatic glycation reactions also influence the tumour microenvironment (TME) through extracellular matrix (ECM) remodeling, angiogenesis, and immune evasion. This review elucidates the crosstalk between metabolic reprogramming, AGE-RAGE-mediated signalling, and epigenetic modulation that forms a complex network associated with cancer initiation, progression, and resistance to therapy. Understanding the molecular interplay between these pathways could pave the way for novel metabolic and epigenetic therapeutic strategies aimed at disrupting this vicious cycle and impeding tumour growth.

Using both experimental and in silico approaches, this study aimed to evaluate the phytochemical composition and biological activities of Cistus ladanifer aerial part extracts.

Ischemic stroke remains a leading cause of mortality and long-term neurological disability worldwide, while effective neuroprotective therapies remain limited. Netrin-1 is a multifunctional guidance molecule with neuroprotective properties, and chemically modified mRNA (modRNA) offers a promising platform for transient therapeutic protein expression. However, safe and efficient delivery of modRNA to the ischemic brain remains a major barrier to clinical translation. Here, we engineered Netrin-1 modRNA-loaded extracellular vesicles (EV@mNetrin-1) derived from human umbilical cord mesenchymal stem cells (hUMSCs) and administered them via a noninvasive intranasal route. EV-mediated delivery enabled intracellular translation of Netrin-1 modRNA into protein in neurons and increased Netrin-1 expression in ischemic brain tissue. In vitro, EV@mNetrin-1 significantly reduced neuronal apoptosis and improved neuronal survival following oxygen-glucose deprivation/reoxygenation (OGD/R). In vivo, intranasal administration of EV@mNetrin-1 enhanced brain Netrin-1 expression, reduced infarct volume, improved neurological outcomes, and attenuated neuronal apoptosis in transient middle cerebral artery occlusion (tMCAO) mice. Mechanistically, the neuroprotective effects of EV@mNetrin-1 were associated with DCC-dependent activation of PI3K/AKT signaling. Collectively, these findings demonstrate the therapeutic potential of intranasal EV-mediated Netrin-1 modRNA delivery for ischemic stroke and support the development of RNA therapeutics for central nervous system disorders.