Psychological stress can cause or exacerbate irritable bowel syndrome (IBS). According to the Rome V framework, functional gastrointestinal disorders, including IBS, are classified as gut-brain interaction disorders. These disorders involve information processing by the central nervous system. Therefore, to understand IBS pathophysiology, it is necessary to focus on the central neural circuits regulating visceral sensation and colorectal motility. In this review, we first outline the autonomic outflow that controls the colorectum and then focus on descending neural pathways that modulate spinal visceral sensory processing and colorectal autonomic outflow, as well as the hypothalamic, midbrain, limbic, and cortical regions that regulate these processes. Finally, we outline their effects within the context of stress.

Ultraviolet B (UVB) irradiation, with wavelengths ranging from 290 to 320 nm, represents a biologically active fraction of solar irradiation that reaches the Earth's surface and exerts significant effects on human skin. Due to its high energy, UVB penetrates the epidermis and directly interacts with cellular components, particularly DNA, leading to the formation of photoproducts such as cyclobutane pyrimidine dimers. In parallel, UVB exposure induces the generation of reactive oxygen species, promoting oxidative stress and damage to lipids, proteins, and genetic material. These events activate key intracellular signaling pathways, including NF-κB and MAPKs, resulting in the production of pro-inflammatory mediators that amplify cutaneous inflammation. In addition to classical inflammatory and oxidative mechanisms, emerging evidence highlights the role of neuroimmune interactions in the skin, involving crosstalk between nerve endings, neuropeptides, and immune cells, which contributes to the regulation of local immune responses following UVB exposure. The integration of these processes plays a central role in the pathophysiology of UVB-induced skin damage and in the development of skin diseases. This review will discuss the molecular and cellular mechanisms underlying the cutaneous response triggered by UVB irradiation, with emphasis on inflammation, oxidative stress, and neuroimmune communication. Additionally, current and emerging therapeutic strategies based on pathophysiology mechanisms, including antioxidant agents, anti-inflammatory compounds, and photoprotective approaches, will be discussed to highlight potential avenues for improved prevention and treatment of UVB-induced skin damage.

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.

Background: Pheochromocytoma is a highly vascular neuroendocrine tumor with variable biological behavior. Reliable biomarkers reflecting tumor aggressiveness remain limited. This study evaluated apelin and vascular endothelial growth factor (VEGF) expression in pheochromocytoma and their associations with histopathological prognostic parameters. Methods: This retrospective single-center study included 20 pheochromocytoma patients and 18 normal adrenal medulla controls. Apelin and VEGF expression were evaluated immunohistochemically using the immunoreactivity score (IRS). Associations between IRS values and Pheochromocytoma of the Adrenal Gland Scaled Score (PASS), Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP) score, Ki-67 index, tumor size, clinicopathological characteristics, and individual PASS components were analyzed. Results: Apelin IRS was significantly lower in pheochromocytoma than in normal adrenal medulla (median 0 vs. 4, p = 0.001), whereas VEGF IRS was significantly higher (median 6 vs. 2, p < 0.001). Tumors with PASS ≥ 4 had significantly lower apelin IRS than those with PASS < 4 (p = 0.001). Apelin IRS was inversely correlated with PASS (r = -0.874, p < 0.001), GAPP score (r = -0.618, p = 0.004), and Ki-67 (r = -0.560, p = 0.010). Lower apelin expression was also associated with diffuse growth pattern, central/confluent necrosis, and tumor cell spindling. VEGF IRS showed no significant association with PASS, GAPP score, Ki-67, tumor size, or individual PASS components. Conclusions: Reduced apelin immunoreactivity was associated with unfavorable histopathological features in pheochromocytoma, whereas increased VEGF immunoreactivity was not associated with the evaluated histopathological risk parameters. These exploratory findings suggest that apelin may be a candidate tissue marker; however, its clinical and prognostic relevance requires further investigation in larger multicenter studies.

Introduction: Inflammation is a central component of the biological processes involved in orthopedic interventions, whether performed for acute traumatic injuries or chronic non-traumatic conditions. Cytokines play major roles in modulating these responses; however, data describing cytokine activity in bone marrow, particularly during orthopedic procedures, remain limited. This study aimed to examine variations in cytokine levels in traumatic and non-traumatic orthopedic surgeries by analyzing simultaneous bone marrow and plasma samples. Methods: This single-center prospective observational study with exploratory objectives included skeletally mature patients undergoing urgent surgery for acute traumatic fractures or planned surgery for chronic non-traumatic degenerative orthopedic conditions. Bone-marrow and peripheral plasma samples were collected simultaneously intraoperatively. All samples were tested in duplicate for interleukin-8 (IL-8), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-4 (IL-4), interleukin-1 receptor antagonist (IL-1RA), and tumor necrosis factor-α (TNF-α) using developmental ELISA kits. Cytokine levels were compared between traumatic and non-traumatic groups and between bone-marrow and plasma samples. Results: Nineteen participants were included, providing 19 bone-marrow samples and 15 plasma samples, with the number of available measurements varying among cytokines. Bone-marrow IL-10 was detected in three of five available traumatic samples and in none of the eight available non-traumatic samples (unadjusted p = 0.035; false-discovery-rate-adjusted q = 0.178). Plasma IL-1RA concentrations were higher in traumatic than in non-traumatic patients (median 2828.00 versus 1269.00 pg/mL; unadjusted p = 0.038; q = 0.178). Bone-marrow IL-8 also showed higher concentrations in traumatic patients and approached the unadjusted significance threshold (p = 0.053; q = 0.178). No comparison remained statistically significant after FDR correction. Discussion: Bone-marrow IL-10 detection and plasma IL-1RA concentrations showed nominal between-group differences that did not remain statistically significant after multiple-comparison adjustment. Although preliminary and hypothesis-generating, these observations identify potentially informative local and systemic cytokine patterns and highlight the value of further investigating bone-marrow cytokine responses in orthopedic trauma.

Background: Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of select hematologic malignancies and is increasingly being explored for non-oncological indications, including autoimmune diseases and persistent infectious diseases. This systematic review synthesized current evidence on CAR T cell and CAR-Treg approaches beyond oncology, with emphasis on therapeutic targets, translational and clinical outcomes, safety, and implementation barriers. Methods: The review followed PRISMA 2020 guidelines. PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, ClinicalTrials.gov, and major trial registries were searched for studies published from 1 January 2010 to 31 March 2026. Eligible studies included clinical, preclinical, and translational investigations of CAR T cell or CAR-Treg strategies in autoimmune or infectious diseases. Results: Because of heterogeneity in disease indications, CAR constructs, endpoints, and study designs, findings were synthesized descriptively. The strongest early clinical signals were observed with B cell-directed CAR T cell therapy for severe, refractory autoimmune diseases, particularly systemic lupus erythematosus, systemic sclerosis, and inflammatory myopathies. Infectious disease applications, mainly HIV and hepatitis B, showed preliminary safety, persistence, and partial antiviral activity, but durable pathogen eradication remains unproven. Conclusion: Overall, CAR T cell therapy beyond oncology is promising but remains preliminary, requiring standardized reporting, long-term safety monitoring, scalable manufacturing, and carefully defined risk-benefit thresholds. Human clinical evidence was interpreted separately from preclinical and mechanistic evidence, and clinical conclusions were based primarily on human studies.

Modern abdominal wall hernia surgery is centered on the biomechanics of the fascial-aponeurotic framework and on intra-abdominal pressure (IAP) control; neuromuscular regulation of the wall remains outside perioperative planning. This review reframes the abdominal wall as a coordinated neuromuscular system and outlines a framework in which ventral herniation is hypothesized to represent a compensatory response to altered regulation of elevated IAP, while discoordinated contraction of the muscular layers is proposed as a potential predisposing factor. A structured literature search was performed in PubMed/MEDLINE, Embase and the Cochrane Library from inception to March 2026 across four thematic blocks: basal tone and innervation, spinal pathology and coordination, skeletal muscle memory, and electromyographic and clinical models of denervation. Synthesis followed SANRA criteria. This is not a formal systematic review or meta-analysis. Basal tone of the abdominal muscles is individual and depends on spinal innervation, lifestyle, comorbidity, and hernia duration; obstructive pulmonary disease yields a hypertonic phenotype, and persistent meteorism a hypotonic one. In a patient predisposed to herniation, elevated IAP may be partially accommodated through redistribution of abdominal contents; within the proposed framework, herniation is hypothesized to function as a pressure-relief mechanism. Discoordination of the muscular layers may reduce the capacity of the abdominal wall to adapt to rapid or unfamiliar loading, potentially contributing to hernia formation in predisposed patients. Six meta-analyses of preoperative botulinum toxin type A confirm lateral muscle elongation; none assessed basal-tone recovery after toxin washout. Each hernia patient presents with an individual neuromuscular phenotype shaped by basal tone, intermuscular coordination and muscle memory. The proposed framework complements mechano-fascial concepts with a neurophysiological dimension and provides a hypothesis-generating rationale for investigating phenotype-tailored prehabilitation and postoperative rehabilitation. Prospective electromyographic mapping with functional maneuvers is the immediate research priority.

Sodium glucose cotransporter-2 inhibitors (SGLT2is) have rapidly evolved from glucose-lowering agents to multifaceted therapies with significant renoprotective and cardioprotective potential. Although originally developed to inhibit glucose reabsorption within the renal proximal tubule for the treatment of Type 2 diabetes mellitus (T2DM), growing evidence indicates that SGLT2is exert broad systemic actions extending beyond glycemic control. Among this drug class, dapagliflozin has emerged as a clinically important agent with pleiotropic effects involving renal hemodynamics, inflammatory signaling, mitochondrial function, fibrosis regulation, and cellular stress adaptation. This review outlines the historical progression from the discovery of phlorizin to the development of highly selective modern SGLT2 inhibitors while emphasizing mechanistic insights gained from experimental and clinical studies of dapagliflozin. In addition to the established effects on sodium-glucose transport, dapagliflozin modulates multiple epithelial transport proteins including NHE3, NaPi-2a, NCC, and NCX1, highlighting complex regulatory effects on sodium handling and tubular electrolyte transport. Emerging evidence further demonstrates that dapagliflozin suppresses inflammatory and profibrotic pathways involving YAP/TAZ, STAT1, TGF-β, NLRP3, and NF-KB signaling. Restoration of tubuloglomerular feedback, attenuation of oxidative stress, and preservation of mitochondrial function also appear to contribute substantially to the renoprotective actions of SGLT2 inhibition. Beyond the kidney, dapagliflozin and related SGLT2is exert cardioprotective effects through coordinated improvements in cardiac energetics, inflammatory regulation, and hemodynamic function. Emerging studies additionally suggest potential pulmonary benefits, including reductions in inflammatory signaling, pulmonary edema, and respiratory complications. Collectively, these findings support a shift in understanding SGLT2is from targeted metabolic therapies to broader regulators of cellular and organ function. Continued investigation into the glucose-independent mechanisms of dapagliflozin may reveal additional therapeutic applications across chronic metabolic, cardiovascular, and inflammatory diseases.

Non-communicable diseases remain the dominant cause of adult morbidity and mortality, yet cardiometabolic, vascular and renal risk may originate before birth. This structured narrative review critically evaluates human evidence linking pregnancy-related exposures, placental pathophysiology and later offspring health within a maternal-placental-fetal-life-course framework. Evidence published from 2020 to 2026 was emphasised, while seminal earlier cohorts were retained when they provided uniquely long follow-up or direct placental measurements. The most consistent associations concern maternal obesity, gestational diabetes, excessive gestational weight gain and hypertensive disorders, which are linked with higher offspring blood pressure, greater adiposity and adverse glucose-insulin profiles. Human placental studies implicate vascular malperfusion, altered nutrient transport, inflammatory and oxidative signalling, endocrine function and epigenetic regulation. Few studies, however, have measured the prenatal exposure, a specific placental phenotype and a long-term offspring outcome within the same longitudinal design; most proposed placental pathways are supported by convergent evidence or biological plausibility rather than demonstrated mediation. Preterm birth and fetal growth restriction are clinically observable, etiologically heterogeneous sentinel phenotypes, not obligatory mediators. Placental and offspring epigenetic signatures, telomere biology and mitochondrial function represent distinct domains of biological embedding; their causal and prognostic significance remains uncertain. Longitudinal studies integrating maternal exposures, placental histopathology and molecular phenotypes, fetal organ development, childhood cardiometabolic trajectories and adult clinical outcomes are needed to determine whether, and under what circumstances, the placenta plays an intermediary role rather than merely serving as a marker of an adverse pregnancy environment.

Background/Objectives: Microplastics (MPs) are increasingly reported in human reproductive tissues and fluids, but detection alone does not establish tissue injury or disease. Recent reviews have synthesised occurrence, reproductive toxicity, placental transfer, fertility, and pregnancy outcomes. The unresolved problem is that occurrence, model-response, lesion-comparison, clinical-association, and causal evidence are not interchangeable. This review asks what minimum evidence is required for an MP finding in the female genital tract (FGT) or fetoplacental continuum to become lesion-relevant and where inference must stop. Methods: We performed a critical narrative search of PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar from database inception through 10 July 2026. The final synthesis comprised 59 sources: 28 primary studies, 24 reviews or systematic syntheses, and 7 regulatory, consensus, or professional-guidance documents.. Methodological recommendations were graded as claim-essential, context-dependent, or exploratory and as routine, specialised, or research-intensive. Results: The distinct contribution is an FGT-specific mechanistic and claim-to-evidence architecture rather than another environmental or reproductive-toxicity catalogue. We propose an ordered, claim-calibrated evidence ladder linking external exposure, internal dose, reproductive-fluid burden, spatial localisation, lesion response, and clinically annotated phenotype. The framework specifies the minimum evidence for occurrence, localisation, lesion, clinical, and causal claims and provides explicit stopping and downgrading rules rather than treating all desirable measurements as mandatory. The FGT Lesion Atlas is a compartment-by-compartment map of prioritised, non-exhaustive endpoints and sampling requirements. The FGT Lesionome is a cross-compartment synthesis of recurring barrier-receptivity, stromal-fibrotic, vascular-perfusion, immune-microbiome, endocrine-steroidogenic, and particle-cargo axes. An integrated hypothesis-generating pathway links systemic or local exposure, internal and target-compartment burden, physicochemical conditioning in reproductive-fluid microenvironments, particle or particle-associated-constituent interaction with compartment-specific cells and matrices, the six response axes, physiological dysfunction, and clinically annotated outcomes. A reproductive-fluid model, an assisted-reproductive-technology sentinel sequence, and an FGT Microplastic Pathology Reporting Checklist rank study elements by evidentiary necessity, feasibility, and interpretive consequence. Conclusions: The framework is hypothesis-generating, not a validated causal map or a universal core outcome set. It separates essential validity safeguards from context-dependent best practices and exploratory endpoints. Human reproductive and fetoplacental disease causation remains unproven without contamination-controlled sampling, polymer confirmation, spatial co-localisation with lesions, temporality, exposure-response assessment, confounder control, replication, and appropriately powered, temporally informative clinical outcomes.

Background/Objectives: The increasing therapeutic use of cannabinoid-based formulations highlights the need to better characterize their safety profile, particularly in organs involved in xenobiotic elimination, such as the kidneys. This study evaluated the renal effects of cannabidiol (CBD) and Δ[9]-tetrahydrocannabinol (Δ[9]-THC) nanoemulsions following subchronic oral administration in male Wistar rats. Methods: Forty animals (n = 8/group) were randomly allocated into five groups: vehicle control (Licuri oil + Pluronic[®] F127), CBD 2.5 mg/kg, CBD 5 mg/kg, CBD+THC 2.5 mg/kg, and CBD+THC 5 mg/kg. Treatments were administered daily by oral gavage for 21 consecutive days. Kidney samples were analyzed by histopathology and immunohistochemistry (Ki-67, GST-P, and cleaved caspase-3). Results: High-dose groups (5 mg/kg) exhibited marked histopathological alterations, including tubular and glomerular damage, hemorrhagic areas, inflammatory infiltration, and necrosis. These groups also showed increased Ki-67 and cleaved caspase-3 immunoexpression compared to controls. GST-P expression was significantly increased only in the CBD 5 mg/kg group. No significant changes were observed in the low-dose groups. Conclusions: These findings suggest dose-dependent morphological and molecular alterations in renal tissue associated with cannabinoid nanoemulsion exposure under experimental conditions.

Background/Objectives: Oxidative stress is a major contributor to the pathogenesis of cardiovascular diseases, including hypertension, ischemic cardiomyopathy, and heart failure. MicroRNAs (miRNAs) have been extensively investigated in various contexts, and some of them have been identified to play a role in cardiovascular disease. This narrative review focuses on miR-103 and miR-155, two miRNAs implicated in the modulation of oxidative stress and cardiovascular remodeling. Methods: The following queries were used in PubMed since inception until May 2026: (("miR-155" OR "microRNA-155" OR miR155) AND ("oxidative stress" OR ROS OR "reactive oxygen species") AND ("cardiovascular disease" OR cardiovascular OR cardiac OR heart OR vascular)); (("miR-103" OR "microRNA-103" OR miR103) AND ("oxidative stress" OR ROS OR "reactive oxygen species") AND ("cardiovascular disease" OR cardiovascular OR cardiac OR heart OR vascular)). Results: A total of seven citations for miR-103 and 79 citations for miR-155 were identified. Reviews and papers about diseases other than those on cardiac/vascular involvement were excluded. miR-155 emerges as a potential regulator of inflammatory-redox signaling, whereas miR-103 appears more closely linked to cell fate and metabolic pathways. In both cases, available evidence supports a context-dependent role that challenges simplistic classification as pro- or antioxidant miRNAs. Conclusions: Available evidence suggests that both miR-103 and miR-155 are important regulators of oxidative stress-related pathways in cardiovascular disease. Nevertheless, the context-dependent effects observed across different cardiovascular disorders raise concerns regarding the safety of systemic miRNA modulation-based therapeutic strategies. Future studies should clarify the determinants of this context-dependent behavior and identify the specific conditions under which these miRNAs exert protective or harmful effects, which might pave the way for the development of miRNA-based therapeutic strategies targeting oxidative stress and cardiovascular remodeling.