Pathophysiology

Background/Objectives: Diabetic cardiomyopathy (DCM) is a major cardiovascular complication of diabetes mellitus characterized by progressive myocardial remodeling driven by oxidative stress, inflammation, and fibrosis. The interleukin-33 (IL-33)/soluble suppression of tumorigenicity 2 (sST2) signaling axis has recently emerged as an important regulator of cardiac remodeling and a potential therapeutic target in DCM. N-acetylcysteine (NAC) and glycine exhibit complementary antioxidant and anti-inflammatory properties; however, their combined effects on circulating IL-33 and sST2 levels and myocardial structural remodeling in experimental diabetes remain insufficiently investigated. This study evaluated the effects of NAC and glycine, administered alone or in combination, on oxidative stress, inflammatory biomarkers, cardiac morphology, and serum sST2 levels in streptozotocin-induced diabetic rats. Methods: Thirty-four adult Wistar rats were randomly assigned to five groups: healthy controls, untreated diabetic animals, diabetic animals treated with NAC (100 mg/kg/day), glycine (250 mg/kg/day), or combined NAC and glycine for 12 weeks. Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg). Serum concentrations of sST2, IL-33, malondialdehyde (MDA), and superoxide dismutase (SOD) activity were determined. Cardiac remodeling was evaluated by stereological and histopathological analyses. Results: Experimental diabetes significantly increased serum sST2, IL-33, and MDA concentrations and induced marked myocardial remodeling characterized by expansion of the interstitial and perivascular compartments, increased connective tissue deposition, and reduced cardiomyocyte volume density. Both NAC and glycine significantly attenuated these biochemical and structural abnormalities compared with untreated diabetic animals. Treatment effects varied across outcomes. The combined NAC and glycine regimen was associated with particularly pronounced reductions in sST2 and IL-33 and with preservation of myocardial architecture, whereas the magnitude of improvement in oxidative stress markers differed between treatment groups. Conclusions: NAC and glycine, administered either alone or in combination, attenuated several biochemical and structural alterations associated with streptozotocin-induced diabetes. The magnitude of these effects varied across the assessed outcomes, with the combined regimen showing particularly favorable effects on circulating sST2 and IL-33 levels and myocardial structural remodeling, while some oxidative stress parameters showed greater improvement with NAC monotherapy. These outcome-dependent effects highlight the potential complementary actions of NAC and glycine without implying uniform superiority of the combined regimen. Overall, these findings provide an experimental basis for further investigation of NAC- and glycine-based therapeutic approaches for diabetes-associated myocardial remodeling.

Sleep and the gastrointestinal (GI) tract interact in a complex and reciprocal relationship, although the molecular and physiological pathways underlying this interaction remain only partially defined. Communication between the central (CNS) and enteric nervous systems (ENS) spans neural, immune, endocrine, and metabolic pathways, including vagal nerve signaling, the hypothalamic–pituitary–adrenal (HPA) axis, gut-resident microbiota, and circulating microbial metabolites, such as bile acids with neuroinflammatory or neurotransmitter activity. In this narrative review, we synthesize evidence from animal models, observational cohorts, and intervention trials to map this bidirectional axis, focusing on several underexamined modulatory mechanisms including the interaction between the gut microbiome and the glymphatic system, the brain’s perivascular waste-clearance network, which is implicated in the removal of amyloid-β (Aβ) and tau in Alzheimer’s disease; neuroendocrine regulation and sex-related differences in gut microbiome composition and sleep patterns, which may help explain the divergent neurodegenerative disease risks between men and women; and age-related parallel trajectories of microbiome senescence and sleep fragmentation in older adults. We discuss melatonin, cortisol, estrogen, and ghrelin as endocrine mediators linking circadian biology to gut physiology, and we consider how environmental and lifestyle factors further perturb this system. These mechanisms form an integrative framework of the gut–brain–sleep axis and highlight priority directions for mechanistic and translational research, including significant nodes in this pathway where targeted interventions may help cognitive resilience and slow the neurodegenerative disease progression. More research clarifying these mechanisms may help identify the most promising targets, potentially leading to personalized, precision-medicine-based therapeutic strategies.

Coronary microvascular dysfunction (CMD) is an important cause of angina and myocardial ischemia in patients without obstructive coronary artery disease and contributes substantially to the clinical spectrum of angina with non-obstructive coronary arteries (ANOCA) and ischemia with non-obstructive coronary arteries (INOCA). These conditions represent a heterogeneous group of coronary vasomotor disorders in which structural and functional abnormalities of the coronary microcirculation, endothelial dysfunction, coronary vasospasm, and diffuse non-obstructive atherosclerosis may occur alone or in combination. This review summarizes current knowledge on the pathophysiology, diagnosis, and management of CMD in patients with ANOCA and INOCA. We discuss the distinction between ANOCA and INOCA, the principal coronary functional endotypes, and the mechanisms responsible for impaired coronary microvascular function. We also review contemporary diagnostic approaches, including non-invasive imaging and invasive coronary function testing, with emphasis on their complementary roles in identifying the underlying mechanism of ischemia. Current management strategies are presented from a mechanism-based perspective, including lifestyle modification, pharmacological therapy, endotype-guided treatment, and emerging therapeutic approaches. Improved understanding of coronary functional abnormalities has shifted clinical evaluation beyond the exclusion of obstructive coronary artery disease toward identification of the mechanism responsible for persistent symptoms and ischemia. Continued advances in disease phenotyping, coronary function testing, and targeted therapies are expected to support more individualized management and improve outcomes in this diverse patient population.