Search Results (11,610)

Diabetic retinopathy (DR) reflects retinal microvascular injury and systemic immune-metabolic stress, and most public DR transcriptomic datasets lack paired microbiome/metabolomic profiles. We used gutMGene v2.0 as a curated microbe/metabolite–host gene prior and integrated it with peripheral blood transcriptomics from GSE221521. Candidate genes were refined by weighted gene co-expression network analysis (WGCNA), repeated resampling, cross-dataset assessment, mechanism scoring, peripheral blood mononuclear cell (PBMC) single-cell localization and filamin A (FLNA)-centered single-cell gene regulatory network (GRN) virtual knockout. The gutMGene prior contained 238 host genes; 15 DR-associated genes overlapped this prior, and WGCNA retained ten candidate gut microbe and microbial metabolite-related genes (GMMRGs): FLNA, AKT1, IRAK1, BCL10, CDK6, CTSD, JUP, CXCL1, CXCR2 and IL4R. Resampling prioritized FLNA as the most consistent candidate. Cross-dataset assessment localized the strongest signal to type 2 diabetes (T2D) PBMCs, retinal endothelial cells and advanced proliferative diabetic retinopathy with diabetic macular edema (PDR + DME) retinal tissue, with weaker separation in whole blood, broad retinal tissue and six-donor type 1 diabetes (T1D) PBMCs. FLNA virtual knockout predicted cell-context-dependent perturbation of immune-related transcriptional programs, including IL4R in DR B cells and CTSD in DR monocytes/NK cells. This prior-guided study identifies FLNA within a ten-gene GMMRG set as a circulating host-response signal that links curated microbe/metabolite–host records to immune-vascular and cytoskeletal remodeling in DR. Full article

Age-associated metabolic dysfunction is commonly defined by abnormalities in adiposity, glucose regulation, lipid metabolism, and blood pressure. Although clinically useful, these criteria do not fully capture the biological heterogeneity that explains why older adults with similar metabolic profiles may follow divergent trajectories toward type 2 diabetes, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease, frailty or multimorbidity. This narrative Review summarizes clinical, translational, and mechanistic evidence on the biological processes that shape metabolic aging, with particular emphasis on inflammaging, immunosenescence, cellular senescence, oxidative stress, mitochondrial dysfunction, adipose tissue dysfunction, endothelial injury, and inflammation-related microRNAs. We first discuss how chronic low-grade inflammation and immune remodeling alter the interpretation of conventional metabolic syndrome components in older adults. We then review redox imbalance and mitochondrial stress as amplifiers of insulin resistance, lipid injury, vascular dysfunction, and tissue remodeling. The review also examines inflammation-related microRNAs, including circulating and extracellular-vesicle-associated miRNAs, as post-transcriptional regulators that may connect inflammatory, metabolic, and redox pathways. Finally, we discuss how conventional metabolic markers may be integrated with inflammatory mediators, oxidative-stress indicators, adipokines, endothelial and senescence-related markers, and miRNA profiles to improve biological interpretation of metabolic risk. Within this context, we present the Inflammaging–Redox–InflammamiR Axis as a conceptual framework for organizing these overlapping mechanisms rather than as an established diagnostic or causal model. The proposed biomarker tiers and candidate risk phenotypes are author-derived, hypothesis-generating constructs intended to guide future longitudinal and interventional research. Clinical translation will require standardized assays, longitudinal validation, external replication, and intervention studies. Full article

Cardiometabolic residual risk in type 2 diabetes mellitus (T2D) persists despite major advances in glucose-lowering therapy, lipid management, blood pressure control, weight reduction, and organ-protective strategies. This residual burden should not be interpreted solely as the consequence of incomplete achievement of conventional therapeutic targets, but rather as the clinical expression of persistent molecular activity involving multiple interconnected organs and pathways. Insulin resistance, metaflammation, oxidative stress, mitochondrial dysfunction, lipotoxicity, endothelial impairment, hepatic metabolic dysregulation, renal inflammation, fibrotic remodeling, and metabolic memory interact within a dynamic network linking adipose tissue, liver, kidney, immune cells, and vasculature. In this review, we discuss the biochemical and molecular drivers of cardiometabolic residual risk in T2D, with particular emphasis on impaired insulin receptor substrate/PI3K/Akt signaling, stress-kinase activation, NLRP3 inflammasome priming and assembly, MASLD-related lipotoxicity and fibrogenesis, podocyte and tubular injury, endothelial nitric oxide synthase uncoupling, AGE-RAGE signaling, and thrombo-inflammatory vascular injury. These pathways explain why biological vulnerability may persist even when conventional clinical parameters appear adequately controlled. We also examine the role of translational biomarkers and simple clinical indices, including TyG-derived indices, adiposity markers, hepatic steatosis and fibrosis scores, albuminuria, eGFR, and lipid-related markers, as accessible windows into active biological pathways. Finally, we review how contemporary therapeutic strategies may modulate selected components of this residual-risk network. A pathway-centered interpretation of T2D may support more precise residual-risk phenotyping and help move cardiometabolic care beyond isolated target control toward mechanism-based prevention. This review further links these mechanisms to the contemporary cardiovascular–kidney–metabolic (CKM) framework, as defined by the 2026 AHA/ACC/ADA/ASN CKM Guideline, and disaggregates the underlying molecular network into organ-specific pathway cascades that make the causal relationships between metabolic, inflammatory, hepatic, renal, and vascular injury more explicit. Full article

Background/Objectives: Diabetes mellitus type 2 (T2DM) is often associated with hypertension, necessitating treatment with combinations of medications that address both glycemic control and blood pressure. Whether commonly co-prescribed antihypertensives modify the glycemic efficacy of a sulfonylurea remains insufficiently characterized in controlled preclinical models. Methods: One hundred adult male Wistar rats were allocated to ten parallel groups (n = 10): healthy and diabetic untreated controls; glimepiride, bisoprolol or amlodipine monotherapy (in healthy and diabetic animals); and the diabetic combinations glimepiride+bisoprolol and glimepiride+amlodipine. T2DM was induced with a high-fat diet plus low-dose streptozotocin (35 mg/kg, i.p.) and confirmed by fasting blood glucose ≥ 200 mg/dL. Glycated hemoglobin (HbA1c) was measured weekly for 11 weeks. Non-parametric inference (Kruskal–Wallis, Dunn’s with Bonferroni correction, Mann–Whitney U, Wilcoxon signed-rank) was complemented by Random Forest regression and PCA/K-means clustering. Results: Week-11 HbA1c differed markedly across groups (Kruskal–Wallis H = 94.3, p < 0.001). Glimepiride + bisoprolol achieved near-normal control (4.37% ± 0.15), statistically indistinguishable from healthy groups (p ≥ 0.33), and was the only diabetic regimen with a declining trajectory (−0.66 percentage points; Wilcoxon p = 0.004). Adding either antihypertensive to glimepiride did not worsen glycemic control. Amlodipine monotherapy did not attenuate hyperglycemia (8.47% ± 0.20), approaching that of untreated diabetic controls (9.31% ± 0.18), consistent with the absence of intrinsic glucose-lowering activity. All agents showed pronounced disease-state dependence (healthy–diabetic divergence 2.33–3.13 points). Random Forest prediction was accurate (R² = 0.985), and unsupervised clustering separated effective from ineffective regimens, corroborating the statistical findings. Conclusions: In this model, bisoprolol co-administration enhanced and amlodipine co-administration preserved glimepiride-mediated glycemic control. Glimepiride+bisoprolol emerged as the most effective regimen, supporting cardioselective β-blockade as a metabolically favorable antihypertensive partner for sulfonylurea therapy and warranting clinical confirmation. More broadly, these results provide a preclinical, evidence-based rationale for selecting metabolically favorable antihypertensives in patients with coexisting T2DM and hypertension, with the potential to improve glycemic outcomes and reduce the risk of adverse drug–disease interactions during combination therapy. Full article

Obesity is a major global health problem and is closely associated with a broad range of metabolic disorders, including metabolic syndrome (MetS), dyslipidemia, hypertension, atherosclerosis, type 2 diabetes mellitus, and cardiovascular disease. The gut microbiota plays a central role in maintaining intestinal epithelial integrity, regulating glucose and lipid metabolism, and modulating immune function. Through the gut–brain axis, it also contributes to appetite regulation and energy homeostasis by influencing the release of anorexigenic hormones. Dysbiosis, including alterations in the relative abundance of major bacterial phyla such as Firmicutes and Bacteroidetes, has been associated with increased intestinal permeability, metabolic endotoxemia, and chronic low-grade inflammation, all of which may contribute to the development of obesity and insulin resistance. Diets rich in plant-derived fiber can beneficially shape gut microbiota composition. Bacterial fermentation of dietary fiber produces short-chain fatty acids (SCFAs), including butyrate, acetate, and propionate, which contribute to intestinal barrier integrity, inflammatory regulation, immune regulation, and metabolic homeostasis. Overall, the interaction between gut microbiota, diet, and host metabolic pathways represents a promising field for therapeutic and nutritional interventions aimed at preventing and managing MetS and metabolic diseases. Full article

Cardiac tamponade in pregnancy is an exceptional maternal–fetal emergency in which physiological tachycardia, hypervolaemia and dependent oedema mask the classical signs of tamponade. Corynebacterium amycolatum is a non-diphtherial, Gram-positive coryneform commensal of human skin and mucosa that is increasingly recognised as a true invasive pathogen, although pericardial infection has rarely, if ever, been reported. We aimed to describe the diagnostic and decompression strategy in such a case. We report a 29-year-old woman at 30 + 4 weeks of gestation with class III obesity (pre-pregnancy body mass index 36 kg/m²), pregnancy-induced hypertension and diet-controlled type 2 diabetes referred after a routine echocardiogram suggested tamponade despite preserved haemodynamic compensation. Transthoracic echocardiography demonstrated a large circumferential pericardial effusion with diastolic right-atrial and right-ventricular collapse, a plethoric inferior vena cava and respiratory mitral-inflow variation. Severe maternal obesity superimposed on advanced gestation degraded the acoustic windows, elevated the diaphragm, displaced the heart anteriorly and brought the gravid uterus into the subxiphoid corridor, rendering percutaneous pericardiocentesis prohibitively hazardous. After multidisciplinary heart-team review, a left anterior mini-thoracotomy with pleuro-pericardial window evacuated approximately 1000 mL of fluid. Aerobic culture yielded C. amycolatum (MALDI-TOF), with histological pericarditis and a consistent antibiogram; autoimmune, viral and neoplastic causes were excluded, although blood cultures and extended viral testing were not performed. Targeted intravenous cefazolin was given, and the patient delivered a healthy term neonate at 39 weeks, with a normal 7-month echocardiogram. To the best of our knowledge, this is among the first reported cases of C. amycolatum pericardial tamponade in pregnancy. Because blood cultures and molecular confirmation of pericardial involvement were not obtained, a contaminant or incidental role for the organism cannot be entirely excluded, and the causal attribution should be regarded as probable rather than definitive. The case highlights heart-team-based individualised decompression and the cautious microbiological interpretation of organisms traditionally regarded as commensals. Full article

Background: Osteoprotegerin (OPG) is best known for regulating bone remodeling, vascular calcification, apoptosis, and immune responses. Recent studies also suggest that OPG may play an important role in diabetic microvascular complications such as diabetic retinopathy (DR). Objectives: The aim of our cross-sectional case–control study was to assess the relationship between the OPG variants (rs2073618 and rs3134069) and DR in a large cohort of subjects with type 2 diabetes (T2DM). Methods: A total of 1554 subjects with T2DM were enrolled in this cross-sectional case–control study: 577 with DR and 977 without DR. Genotyping was performed using StepOne Real-Time PCR with TaqMan genotyping assays. Results: Our data indicated that the prevalence of the C minor allele was significantly higher among patients with DR and type 2 diabetes in both polymorphisms. Furthermore, individuals carrying the CC genotype of the rs2073618 had a 1.42-fold increased likelihood of DR, while carriers of the CC or CA genotypes of the rs3134069 exhibited a 1.55-fold higher likelihood of DR. Conclusions: Taken together with existing evidence, these results suggest that OPG polymorphisms may be involved in the development of DR. Full article

Background/Objectives: Diabetes-related stigma decreases treatment motivation. While subjective financial burden is a known barrier, the impact of actual medical costs on stigma remains unclear. We investigated the relationship between annual outpatient medical costs (total and out-of-pocket) and stigma in type 2 diabetes to explore whether this association might be more closely related to direct financial hardship or underlying treatment complexity. Methods: In a cross-sectional study, we evaluated stigma in 232 outpatients using the Kanden Institute Stigma Scale (KISS). Patients scoring ≥20 formed the high stigma group (n = 59). Annual medical costs were extracted from electronic hospital claims. We examined associations between medical costs and high stigma using multivariable logistic regression and restricted cubic spline (RCS) models. Results: Adjusted for sex and age, higher total medical cost (per 10,000 JPY/year) was significantly associated with high stigma (odds ratio [OR] = 1.03, 95% confidence interval [CI]: 1.01–1.05, p < 0.01). However, this significance was attenuated after additionally adjusting for HbA1c and antidiabetic agent count (OR = 1.02, 95% CI: 1.00–1.04, p = 0.05). RCS analysis confirmed this dose–response association disappeared upon adjusting for treatment intensity. Notably, out-of-pocket costs showed no significant association with high stigma in any fully adjusted models (OR = 1.03, 95% CI: 0.95–1.11, p = 0.45). Conclusions: While total medical costs are associated with high stigma, the attenuation of this relationship after adjusting for clinical factors suggests that this association may be closely intertwined with the psychosocial burden of treatment complexity, such as polypharmacy and insulin injections, rather than acting solely through direct economic pain from out-of-pocket expenses. Clinicians should prioritize shared decision-making to mitigate psychological distress when intensifying treatment. Full article

Background: Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, characterised by sensory dysfunction and progressive loss of small nerve fibres. Corneal nerves are among the earliest fibres affected and may serve as sensitive markers for early detection and therapeutic intervention. Sitagliptin and celery seed extract have demonstrated anti-hyperglycaemic and neuroprotective properties in experimental diabetes; however, their effects on corneal nerve morphology and function remain unknown. Purpose: The present study aimed to investigate the effects of sitagliptin and celery seed extract on corneal nerve morphology, corneal sensitivity, and sensory behaviour in a high-fat diet, streptozotocin-induced rat model of type 2 diabetes. Methods: Male Sprague Dawley rats (n = 24) were used to induce type 2 diabetes by combining a high-fat diet with streptozotocin. Diabetic rats were treated with sitagliptin (30 mg/kg per day for 4 weeks) or celery seed extract (100 mg/kg per day for 4 weeks). Fasting blood glucose levels were measured throughout the monitoring period. Corneal nerve fibre parameters, including corneal nerve fibre length (CNFL), density (CNFD), and tortuosity, were assessed in βIII-tubulin-stained whole-mount corneas. Corneal sensitivity was measured with the Cochet–Bonnet esthesiometer. Sensory behaviour was evaluated using hot- and cold-water tail immersion and an acetone drop test. Results: Diabetes significantly reduced the CNFL (39.8 ± 4.7 vs. normal: 71.7 ± 7.3 mm/mm²; p < 0.05) and CNFD (7.1 ± 0.9 vs. normal: 10.6 ± 1.2%; p < 0.05) and increased corneal nerve tortuosity (5.8 ± 0.2 vs. normal: 5.1 ± 0.2; p < 0.05). Both sitagliptin and celery seed extract significantly increased the CNFL (68.8 ± 4.5 and 65.8 ± 6.5 mm/mm², respectively) compared to the untreated diabetic group. Tortuosity was significantly decreased in both the sitagliptin (4.3 ± 0.1) and celery seed extract (4.9 ± 0.1) groups compared with the untreated diabetic group. However, the CNFD showed only a modest increase after either treatment. A significant decrease in corneal sensitivity was also observed in rats following diabetes induction (5.8 ± 0.1 in normal vs. 4.5 ± 0.1 cm in diabetic rats; p < 0.05). This was rescued with sitagliptin and celery seed extract treatment (5.5 ± 0.1 and 5.3 ± 0.1 cm, respectively; p < 0.05). Compared with the non-diabetic controls, diabetic rats showed significantly shorter withdrawal latencies in both the hot- (3.9 ± 0.3 vs. 7.6 ± 1.1 s) and cold-water tests (4.3 ± 0.5 vs. 8.1 ± 0.9 s), indicating thermal sensitivity. By contrast, diabetic rats showed a significantly longer response time in the acetone drop test (8.0 ± 0.7 vs. 3.6 ± 0.4 s), indicating altered cold sensitivity (p < 0.05) for all responses. Treatment with sitagliptin and celery seed extract significantly reversed these changes, as evidenced by increased withdrawal latency in the cold-water test and decreased response time in the acetone drop test. However, this improvement was not significant in the hot-water test. Conclusions: Sitagliptin and celery seed extract restored corneal nerve architecture, corneal sensitivity, and sensory dysfunction in diabetic rats, suggesting the therapeutic potential for DPN. Full article

Background/Objectives: Dietary patterns characterized by excess saturated fat intake contribute to obesity, type 2 diabetes, and cardiac metabolic dysfunction. Ceramides, bioactive sphingolipids synthesized in response to nutrient overload, have emerged as key molecular mediators linking dietary lipid composition to alterations in cardiac metabolic signaling. This review aims to integrate current evidence on diet-induced ceramide remodeling and its impact on intracellular pathways regulating cardiac metabolism. Methods: We analyzed experimental and clinical studies investigating the effects of high-fat and Western-type diets on myocardial ceramide synthesis, lipidomic remodeling, and downstream signaling pathways. Evidence from animal models, genetic and pharmacological interventions, nutritional studies, and circulating biomarker analyses was examined to delineate mechanistic and translational insights. Results: Saturated fatty acid excess, particularly palmitate, activates the de novo ceramide synthesis pathway in the myocardium, promoting accumulation of specific ceramide species. This remodeling impairs insulin signaling through Akt inhibition, protein phosphatase 2A activation, and PKCζ-dependent mechanisms, contributing to cardiac metabolic inflexibility. Ceramides further disrupt mitochondrial function by altering electron transport chain activity, increasing reactive oxygen species production, and modulating mitophagy and apoptotic signaling. Lipidomic studies highlight species-specific effects, with C16-ceramides frequently associated with adverse metabolic and cardiovascular outcomes, whereas very-long-chain ceramides may exert distinct functional roles. Circulating ceramide profiles have also been linked to diet-associated cardiovascular risk. Conclusions: Diet-induced ceramide remodeling represents a central molecular axis connecting dietary lipid excess to altered cardiac metabolic signaling. Targeting sphingolipid metabolism through nutritional or pharmacological strategies may offer novel opportunities for preventing and managing diet-associated cardiac dysfunction. Full article

γ-Cyclodextrin (γ-CD) is a cyclic oligosaccharide with high aqueous solubility, low toxicity, and a large internal cavity that enables inclusion complex formation with selected bioactive compounds. Beyond its established role as a pharmaceutical and food excipient, emerging evidence suggests that γ-CD may influence metabolic regulation through interactions with the gut microbiota, microbial fermentation products, and host metabolic signaling pathways. This review synthesizes current evidence on the effects of γ-CD on short-chain fatty acid production, lipid homeostasis, glycemic control, and obesity- and type 2 diabetes-related metabolic disturbances. Particular attention is given to the gut–metabolism axis, SCFA-mediated GPCR signaling, microbial taxa potentially involved in γ-CD fermentation, and the relative contribution of prebiotic-like effects versus lipid-binding mechanisms. Available data indicate that γ-CD may modulate microbial composition and metabolic outcomes, but most evidence derives from in vitro experiments, animal models, and limited human studies. Therefore, the clinical relevance of γ-CD remains insufficiently established. Future studies should include well-designed human trials, standardized doses, multi-omics analyses, and direct comparisons between native and modified cyclodextrins to clarify whether γ-CD can be translated into nutritional or therapeutic strategies for metabolic disorders. Full article

Background and Objectives: Oral health is a key but often overlooked component of healthy aging and functional wellbeing in older adults. Population aging, multimorbidity, and social determinants of health interact in order to shape oral disease patterns, particularly in primary care settings. Understanding age- and sex-specific distributions of oral diseases is essential for informing integrated public health strategies aimed at promoting healthy aging. Materials and Methods: We conducted a cross-sectional population-based analysis using the SIMEF primary care database, including 7386 adults aged 60 years and older, who were attended between January and December 2022. Oral diseases were identified using ICD-10 codes K00–K14. Prevalence estimates were calculated by life decade and sex. Associations were assessed using chi-square tests and sex-stratified analyses. Results: The overall prevalence of oral diseases was 5.2%, with a significant and progressive decline across age groups, from 6.5% in sexagenarians to 1.6% in nonagenarians (p < 0.001). The most prevalent conditions were disorders of teeth and supporting structures (2.6%, 95% confidence interval [95% CI] 2.3–3.0), dentofacial anomalies (2.2%, 95% CI 1.8–2.5), and dental caries (1.7%, 95% CI 1.4–2.0). Women showed a slightly higher prevalence of selected oral and mucosal conditions. Among older adults with oral diseases (n = 384), the most frequent comorbidities were hypertension (40.4% 95% CI 35.7–45.3), type 2 diabetes (29.2% 95% CI 24.7–33.8), and dyslipidemia (21.1% 95% CI 17.2–25.3), with marked sex-specific differences in endocrine, urinary, musculoskeletal, and mental health conditions. Conclusions: Oral disease burden in older adults decreases with advancing age but remains strongly linked to cardiometabolic and systemic comorbidities, reflecting shared risk factors relevant to healthy aging. The observed age- and sex-specific patterns underscore the need to integrate oral health into primary care and public health policies targeting aging populations, supporting comprehensive and equitable strategies for healthy longevity. Full article

Background/Objectives: Suboptimal dietary patterns are among the leading modifiable contributors to global morbidity and mortality, particularly in cardiovascular disease, type 2 diabetes mellitus (T2DM), obesity, metabolic syndrome, and hypertension. Digital nutrition platforms have emerged to improve adherence to evidence-based dietary strategies; however, many systems lack structured optimization, processing-aware nutrient profiling, and explainable artificial intelligence (AI) mechanisms. The integration of large language models (LLMs) into digital health introduces conversational personalization but also risks hallucination and unsafe outputs without constraint enforcement. This study aimed to describe the system development, architecture, database infrastructure, optimization algorithms, explainability enforcement, and digital health implications of NutriSteppe-AI, a chatbot-first LLM-driven system for personalized health menu generation constrained by deterministic nutrient logic and processing-aware scoring. Methods: NutriSteppe-AI integrates: (1) a multi-source structured nutrient database of 20,000 food products with up to 130 tracked nutrients; (2) energy requirement estimation using the revised Harris-Benedict equation; (3) linear programming-based multi-objective optimization; (4) a Healthy Food Index (HFI; 0.5–5.0 scale) incorporating NOVA processing classification penalties; (5) traffic-light nutrient gating; and (6) a constrained LLM orchestration layer governed by structured API contracts. Algorithmic validation was performed using 10,000 simulated user profiles spanning diverse age, anthropometric, activity, dietary exclusion, and budget parameters. Results: The system achieved 96.8% full constraint satisfaction with macronutrient mean absolute errors of 11.60% (energy), 18.86% (protein), 16.26% (fat), and 20.91% (carbohydrates). Incorporating NOVA processing penalties reduced ultra-processed food HFI scores by 0.73 points (p < 0.001). Median optimized menu HFI improved from 3.6 to 4.3. Median system latency was 1.8 s. Explainability validation confirmed 100% deterministic alignment with zero hallucinated numeric claims. Conclusions: NutriSteppe-AI demonstrates that LLM-driven nutrition chatbots can achieve deterministic, explainable, and clinically aligned performance when governed by structured optimization, processing-aware scoring, and explainability enforcement. This architecture provides scalable digital health infrastructure for cardiometabolic disease prevention in diverse populations. Full article

Skeletal muscle is increasingly recognized as a dynamic secretory organ capable of translating contractile, metabolic, mechanical and inflammatory stimuli into systemic biological signals. Among these signals, myokines and myokine-associated exerkines mediate communication between skeletal muscle and distant organs, influencing glucose and lipid metabolism, immune regulation, bone remodeling, neuroplasticity, vascular function and tissue regeneration. Representative mediators considered include IL-6, IL-15, myostatin, follistatin, decorin, FNDC5/irisin, FGF21, myonectin/CTRP15, BDNF, cathepsin B, SPARC, apelin and extracellular-vesicle cargo. However, current evidence remains fragmented across individual molecules, exercise modalities, sampling windows, assay platforms and disease contexts. This narrative mechanistic review proposes the concept of the “myokine adaptome” as an integrated, context-dependent signaling network through which skeletal muscle contributes to systemic homeostasis in health and disease. We synthesize evidence on cellular triggers of myokine release, including AMPK-PGC-1α signaling, mTORC1-dependent mechanical sensing, calcium flux, redox signaling, inflammatory pathways and extracellular-vesicle-mediated communication. We further examine how exercise modality, aging, obesity, type 2 diabetes, sarcopenia, osteoporosis, cardiovascular disease, COPD, cancer/cachexia and chronic inflammation reshape myokine production and target-organ responsiveness. The central argument is that myokine biology should be interpreted not as a catalog of isolated mediators, but as a dynamic adaptive code defined by signal amplitude, temporal pattern, molecular composition, delivery route and recipient-tissue sensitivity. Its novelty is operational rather than nominal: it requires source confidence, temporal kinetics, co-signal context, delivery route and functional decoding to be evaluated together. This framework may improve biomarker design, disease-specific exercise prescription and therapeutic strategies aimed at restoring adaptive muscle–organ communication. The framework is further strengthened by testable predictions concerning adaptive pulsatility, modality-specific signatures, source attribution, recovery quality, disease-specific decoding and the superiority of multi-marker panels over single-molecule readouts. Full article

Incretin-based therapies have transformed the management of obesity and type 2 diabetes mellitus (T2DM). Established agents—the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) semaglutide and liraglutide, and the dual GIP/GLP-1 receptor agonist tirzepatide—are now widely used, while a diverse pipeline of multi-receptor agents is advancing through late-phase development. GLP-1 receptors are expressed in several oral and other craniofacial tissues, raising the question of how these drugs affect oral health. This narrative review (PubMed, EMBASE, Scopus, Web of Science, Cochrane Library, ClinicalTrials.gov; January 2010–June 2026) integrates mechanistic studies, randomised controlled trials, pharmacovigilance data, society guidance, and the patient-facing phenomena increasingly raised in the dental chair. Preclinical and limited clinical evidence suggests that GLP-1 RAs may attenuate periodontal inflammation, while their effects on alveolar bone remain uncertain, reflecting both direct receptor and indirect metabolic influences. Concurrently, gastrointestinal adverse effects (nausea, vomiting, belching), reduced fluid intake, and possible salivary changes underlie a cluster of patient-reported complaints colloquially termed “Ozempic mouth”, “Ozempic teeth”, and “Ozempic breath”, alongside the facial soft-tissue changes seen in “Ozempic face”. Human oral-health-endpoint data remain scarce; much evidence is preclinical, indirect, or derived from case-level or pharmacovigilance reports. The oral cavity is nonetheless a plausible direct target of incretin pharmacotherapy and a practical monitoring site for tolerability. Dental practitioners should proactively manage the oral consequences of these agents, and validated oral health endpoints should be incorporated into future incretin trials. Full article