Biology and Life Sciences

Abstract: Hybrid insulin peptides (HIPs) are neoepitopes involved in type 1 diabetes (T1D), but their complete repertoire remains unknown. The vast combinatorial space makes experimental screening unfeasible and requires bioinformatics-based prioritization. We developed a multi-level machine learning pipeline for ranking HIP candidates. First, 36 physicochemical and junction-specific features were computed for a reference library of 240 HIPs with known enzyme-linked immunospot (ELISPOT) reactivity, and a baseline Ridge regression model was trained. Next, all possible HIP candidates with 7–9 amino acid residues per fragment were generated from eight pancreatic β-cell secretory granule source proteins, including insulin chains and C-peptide, islet amyloid polypeptide, chromogranin A, neuropeptide Y, and two secretogranins, yielding 1,057,374 candidates. For each source protein, a local weighted XGBoost (Extreme Gradient Boosting) model was trained using Ridge-score-derived pseudo-labels together with weighted ELISPOT-derived and literature-derived reference HIPs. Finally, anchor-calibrated re-ranking was performed in the global model using cosine similarity to positive anchors (n = 46) and negative anchors (n = 210). The Ridge model achieved 5-fold out-of-fold R² = 0.711 and an area under the receiver operating characteristic curve (AUC) of 0.967. The global model produced a prioritized list of 40 HIP candidates, five per source protein. The highest ranks were observed for candidates with right fragments from neuropeptide Y, secretogranins 1 and 2, islet amyloid polypeptide, and chromogranin A. Candidates carrying the insulin fragment on the right side were systematically down-ranked, suggesting asymmetry in HIP formation. The proposed pipeline reduces the HIPs search space from more than one million sequences to a limited set of candidates for experimental validation and provides a framework adaptable to other chimeric neoepitopes in autoimmunity.

Abstract: Semaglutide and tirzepatide are not approved for type 1 diabetes, and their real-world associations with insulin requirements, metabolic outcomes, and safety remain uncertain. Here we analyzed de-identified federated U.S. EHR data, comparing adults with T1D initiating semaglutide (n=1,424) or tirzepatide (n=578) between Jan 1, 2018, and Dec 31, 2025, with 1:1 propensity-score matched T1D controls without GLP-1RA/tirzepatide exposure (n=2,002). At 12 months mean insulin total daily dose (TDD) percent change was −22.0% (median −9.3%) in the semaglutide subcohort and −19.7% (median −17.2%) in the tirzepatide subcohort versus +10.3% (median +0.4%) in matched controls, widening to −27.4% (median −19.4%) and −25.9% (median −31.5%) versus +10.4% (median −1.1%) in controls at 24 months (all P<0.0001). The rate of patients achieving a ≥10% TDD reduction at 6 months was 51.0% (semaglutide) and 50.3% (tirzepatide) versus 18.4% in controls (both P<0.0001). At 12 months median semaglutide dose was 0.50 mg (Q1, Q3: 0.25, 1.00), with 67.8% of patients above the 0.25 mg starter dose. Median tirzepatide dose was 5.00 mg (Q1, Q3: 2.50, 7.50), with 68.2% of patients above the 2.5 mg starter dose. Stratified analysis of 12-month TDD percent change showed significant heterogeneity by weight-loss category in the semaglutide subcohort with mean TDD reduction of −34.5% in patients losing ≥10% of body weight versus −19.6% in patients with <5% weight loss (P<0.001); semaglutide dose escalation was also associated with mean TDD reduction (1.7–2.4 mg, −31.8%; 0.25 mg, −18.2%; P=0.007) while tirzepatide dose escalation was not significantly associated with TDD reduction (ANOVA P=0.800). At 12 months mean HbA1c percent change from baseline was −4.2% (semaglutide, P<0.0001) and −3.0% (tirzepatide, P=0.007) versus −0.3% in controls and mean body weight percent change was −4.0% and −6.8% versus −0.5% (both P<0.0001). The pre-versus-post 365-day safety profile across 13 prespecified events was gastrointestinal-predominant, with nausea or vomiting increasing by 8.5 percentage points (Benjamini-Hochberg adjusted P [BH P] <0.0001) and smaller increases in hypoglycemia (+3.1 pp, BH P=0.022), constipation (+3.0 pp, BH P=0.003), diarrhea (+2.6 pp, BH P=0.016), decreased appetite (+1.1 pp, BH P=0.016), and acute kidney injury (+1.3 pp, BH P=0.022); diabetic ketoacidosis, severe hypoglycemia, pancreatitis, gallbladder disease, gastroparesis, and retinopathy progression did not change significantly. Among clinical and pharmacologic subgroups, patients with a 6-month TDD reduction of >30% had significantly higher incidence of diabetic ketoacidosis (5.42 events per 100 person-years; BH P=0.034). Across 24 prespecified cardiovascular and renal time-to-event endpoints, exposure to semaglutide or tirzepatide was associated with lower 2-year all-cause mortality (1.4% versus 5.7%; BH P<0.001) and major adverse cardiovascular events (4.2% versus 7.5%; BH P=0.002), with mortality reductions for both drugs individually and a reduction in major adverse cardiovascular events for tirzepatide; no renal endpoint remained significant after multiple-testing correction. In summary, this study demonstrates real-world reductions in daily insulin requirements, HbA1c, and weight in T1D patients after initiation of semaglutide or tirzepatide, motivating prospective evaluation of these therapies as adjunctive therapy in selected T1D adults.

Abstract: Alzheimer’s disease (AD) affects more women than men, and risk rises precipitously during and after the menopausal transition. Estrogen deficiency has been the most prominent hypothesis to explain this sex difference, but increasing evidence also implicates follicle-stimulating hormone (FSH) as an independent contributor to neurodegenerative risk. This narrative review integrates the literature on reproductive aging, AD pathobiology, and sex differences in AD, with an emphasis on endocrine, metabolic, and inflammatory mechanisms relevant to their relationship. PubMed and Google Scholar were searched for peer-reviewed human studies, animal models, and mechanistic investigations published through early 2026, prioritizing primary research and systematic reviews on FSH signaling, ApoE biology, and AD pathophysiology. FSH rises in a graded fashion across the menopausal transition and has been associated with multiple pathways implicated in AD, including C/EBPβ–δ-secretase signaling, mitochondrial function, neuronal glucose metabolism, and autophagic-lysosomal clearance - though the causal directionality of many of these relationships remains to be established in humans. Dysfunction in these interrelated systems has been associated with Aβ accumulation, tau pathology, and chronic neuroinflammation. FSH also appears to influence apolipoprotein biology, particularly ApoE, through actions on lipid metabolism, protein lipidation, and clearance, with downstream effects on Aβ aggregation and inflammatory signaling that differ by ApoE isoform. In addition, reproductive aging is associated with changes in vascular integrity and blood-brain barrier function that may precede classical AD pathology. This review describes the mechanistic pathways through which chronically elevated FSH may contribute to AD risk in women and discusses the potential therapeutic implications of FSH modulation, while acknowledging that much of the current mechanistic evidence derives from preclinical models and requires validation in human populations.

Abstract: Type 2 diabetes mellitus is a highly prevalent, heterogeneous, and progressive chronic disease. In a large proportion of patients, management is based for many years on lifestyle intervention and non-insulin glucose-lowering therapies. This long pre-insulin phase represents a crucial clinical window, in which timely recognition of metabolic deterioration, therapeutic inertia, treatment response, and individual risk trajectories may substantially influence long-term outcomes. However, routine care is still frequently based on intermittent assessments, delayed treatment adaptation, and limited integration of clinical, biochemical, behavioral, and digital data. Artificial intelligence may offer a clinically relevant opportunity to move from reactive management to anticipatory care in non-insulin-treated type 2 diabetes. Rather than replacing clinical judgment or automating treatment decisions, artificial intelligence can support clinicians by identifying hidden patterns, predicting metabolic worsening, stratifying risk, improving the interpretation of glucose data, and personalizing follow-up intensity and therapeutic timing. In this setting, its most meaningful role may be to reduce the silent interval between early deterioration and clinical action. This structured narrative review discusses the rationale, current applications, near-future scenarios, and implementation barriers of artificial intelligence in non-insulin-treated type 2 diabetes. Particular attention is given to advanced interpretation of glycemic data, clinical decision support, prediction of treatment failure, remote monitoring, and the potential integration of multidimensional data into more precise and timely care pathways. The review also emphasizes the need for explainable, clinically validated, equitable, and ethically governed artificial intelligence tools that can be realistically embedded into everyday diabetology practice.

Abstract: Pregnancy is a physiological state of transient, reversible insulin resistance accompanied by major adaptations in glucose and lipid metabolism. Although placental hormones are key drivers of gestational insulin resistance, the mechanisms responsible for the rapid restoration of insulin sensitivity after delivery remain unclear. This review presents a dual-axis model in which fibroblast growth factor 21 (FGF21) and sex hormone–binding globulin (SHBG) represent complementary hepatic pathways regulating maternal metabolic plasticity. During late pregnancy, FGF21 may function as a metabolic resilience factor by promoting fatty acid oxidation, limiting lipid overload, and supporting mitochondrial flexibility through AMPK–PPARα signaling. Reduced SHBG, in contrast, may reflect hepatic insulin resistance and altered HNF4α-dependent transcription. After delivery, restoration of the HNF4α–SHBG axis may indicate recovery of hepatic insulin responsiveness, while persistent adaptive FGF21 signaling may facilitate metabolic reprogramming. Postpartum metabolic resetting may therefore represent an actively regulated process rather than a passive consequence of placental hormone withdrawal. Disruption of FGF21- and SHBG-mediated pathways may contribute to persistent insulin resistance and increased cardiometabolic risk after gestational diabetes. Understanding hepatokine-mediated regulation of maternal metabolic flexibility may provide new insights into risk stratification, early biomarkers, and therapeutic targets for the prevention of type 2 diabetes after pregnancy.

Abstract: Background: Prostaglandin E₂ (PGE₂) is a key lipid mediator involved in inflammation and bone homeostasis. Its systemic production is reliably reflected by 24-hour urinary excretion of PGE₂ (U-PGE₂) and its major metabolite (U-PGEM). However, the physiological association between systemic PGE₂ production, calcium-phosphorus homeostasis and bone turnover markers remains unclear. This study aims to elucidate these relationships in a healthy adult population. Methods: In this multicenter, cross-sectional study, 737 healthy adults underwent standardized 24-hour urine collection. Multivariable linear regression was used to assess independent associations with bone metabolism markers. Restricted cubic spline models were further employed to examine nonlinear relationships. Results: The median 24-hour U-PGE₂ and U-PGEM excretion levels were 133.87 and 246.76 pg/mmol creatinine, respectively, with no significant sex differences (both P>0.05). Multivariable regression analyses revealed that both 24-hour U-PGE₂ and U-PGEM were independently and positively associated with advancing age. Notably, both 24-hour U-PGE₂ and U-PGEM maintained a significant inverse association with serum calcium (Overall P<0.05). Restricted cubic spline analyses further demonstrated a significant non-linear association between both 24-hour U-PGE₂ and U-PGEM and total procollagen type 1 N-propeptide (P1NP; both Overall P<0.05). This relationship was characterized by a steep decline in U-PGE₂ and U-PGEM excretion at lower P1NP concentrations (≤57ng/mL), which subsequently plateaued at higher concentrations (Overall P<0.05). Additionally, U-PGEM exhibited a significant inverse linear association with intact parathyroid hormone (PTH; Overall P<0.05). Conclusions: This study provided valuable insights for clinical determinants of 24-hour U-PGE₂ and U-PGEM in healthy adults and their independent associations with calcium-phosphorus homeostasis and bone turnover markers.

Abstract: This review proposes a systems-level model in which glucocorticoid receptor alpha (GRα) regulates immune effectiveness and phase-specific homeostatic correction during infection and physiological stress. Rather than functioning solely as an anti-inflammatory suppressor, GRα influences pathogen recognition, inflammatory transcriptional programs, mitochondrial metabolism, antimicrobial defense, chromatin accessibility, cytokine responses, tissue adaptation, and resolution processes according to the evolving demands of illness. Within this systems-level model, immune responses exist along a continuum ranging from effective pathogen clearance to maladaptive pathogen-permissive inflammatory states. The review examines the role of GRα signaling in pattern-recognition receptor activation, NF-κB/AP-1 regulation, immunometabolic adaptation, antimicrobial effector function, and immune reprogramming across the Priming, Modulatory, and Restorative phases of homeostatic correction. This systems-level perspective expands current concepts of host defense by emphasizing that immune effectiveness depends not simply on inflammatory activation, but on the coordinated integration of antimicrobial competence, mitochondrial bioenergetics, inflammatory regulation, immune-cell trafficking, vascular and tissue integrity, and reparative adaptation required to maintain systemic stability during severe illness. Improved understanding of GRα-mediated regulation of these adaptive processes may provide a foundation for the development of more mechanism-based therapeutic strategies aimed at restoring immune effectiveness and homeostatic balance during critical illness and severe infection.

Abstract: Bauhinia variegata is a plant with considerable application potential owing to its combined ornamental, edible, aromatic, and medicinal values. However, research on this species remains limited and superficial both domestically and internationally, and systematic investigation of the volatile organic compounds (VOCs) emitted from its flowers is still lacking. Through integrated metabolome and transcriptome analyses, this study provides the first comprehensive characterization of the VOC composition, floral scent profile, key aroma components, and the molecular mechanisms underlying VOC variation during anthesis in Bauhinia variegata floral buds and fully opened flowers. A total of 1,214 volatile compounds were identified across buds and flowers, including 239 odor-active compounds and 37 differential odor-active compounds. Flavor statistics revealed that the floral scent profile of Bauhinia variegata is dominated by fruity, sweet, floral, green, woody, herbal, citrus, phenol, fresh, and spicy. Compared to floral buds, the majority of differential odor-active compounds were markedly up-regulated in fully opened flowers, notably including key floral aroma constituents such as phenylacetaldehyde, rose oxide, beta-ocimene, (Z)-beta-ocimene, 2-methylbenzaldehyde, and melon heptenal. Conversely, (R)-(+)-citronellal, which possesses defensive functions, and the bitter-tasting compound 1-methyl-4-nitro-benzene were significantly down-regulated in flowers, reflecting an ecological strategy shift from a defense-oriented mode at the bud stage to an attraction-oriented mode at anthesis. The up-regulation of Phenylalanine/histidine ammonia-lyase, Acyl-CoA synthetase, and Squalene synthetase genes, together with the down-regulation of Copper amine oxidase, O-methyltransferase, and Aldo/keto reductase genes, synergistically promoted the accumulation of floral aroma compounds such as phenylacetaldehyde and facilitated the floral transition. This study provides an important theoretical foundation for understanding the ecological interactions between Bauhinia variegata floral scent and its pollinators, as well as the molecular mechanisms governing floral scent formation. Furthermore, it contributes to the application of Bauhinia variegata in landscape beautification, edible flower utilization, and fragrance development.

Abstract: A ketogenic diet (KD) is a low-carbohydrate, high-fat dietary approach. Beyond treating neurologic disorders, KD has attracted significant media attention for its 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, cause weight loss, and improve glycaemic control and insulin sensitivity. In particular, the positive effects of KD lower insulin demand and may thereby improve β-cell function. However, the long-term efficacy, safety, and sustainability of KD, especially for diabetes, remain debated. This review offers current insights into the effects of ketogenesis and ketosis and the potential mechanisms underlying them. We examine the metabolic effects of KD in obesity and diabetes, drawing on preclinical and clinical studies, and suggest that combining KD with antidiabetic agents may provide synergistic benefits. We explore how KD alters the composition of the gut microbiota, thereby impacting host metabolism and systemic inflammation. We conclude by highlighting challenges and future directions for optimizing KD-based therapies through personalized nutrition and pharmacological combination treatments.

Abstract: Background: GLP-1 receptor agonists and related incretin-based therapies are effective pharmacological treatments for weight loss in adults with obesity and type 2 diabetes. However, weight regain after treatment discontinuation or attenuation remains a major clinical challenge. Appetite dysregulation may be one mechanism contributing to this regain. Objective: This systematic review aimed to evaluate whether appetite-related changes contribute to weight regain following GLP-1-based weight loss, with particular attention to the distinction between direct post-treatment evidence and indirect evidence from active-treatment studies. Methods: A systematic literature search was conducted in PubMed, Scopus, Embase, and the Cochrane Library for studies published between 2016 and 2026, following PRISMA 2020 guidelines. Eligible studies included adults with obesity, overweight, and/or type 2 diabetes receiving GLP-1 receptor agonists or related incretin-based therapies and reporting appetite-related outcomes, weight outcomes, weight maintenance, or weight regain. Randomized controlled trials, clinical trials, crossover studies, and observational studies were included. Findings were synthesized qualitatively. Results: Eighteen studies published between 2017 and 2026 met the inclusion criteria. Most studies reported that GLP-1-based therapy reduced appetite, hunger, food cravings, energy intake, or dietary intake, while increasing satiety and promoting weight loss during active treatment. Direct appetite measures were commonly reported using visual analogue scales, appetite questionnaires, food craving measures, and energy intake assessments. However, only a small number of studies directly evaluated appetite changes during treatment withdrawal, weight maintenance, or post-treatment weight regain. Therefore, the available evidence supports a plausible mechanistic link between loss of appetite regulation and weight regain, but the evidence remains largely indirect. Conclusion: GLP-1-based therapies consistently improve appetite regulation and promote weight loss during active treatment. However, direct evidence linking post-treatment appetite dysregulation to subsequent weight regain remains limited. Appetite dysregulation should therefore be interpreted as a plausible and clinically relevant contributor, rather than a definitively established causal driver.

Abstract: Background: Women with polycystic ovary syndrome (PCOS) have a substantially increased risk of endometrial cancer (EC), yet the biological mechanisms underpinning this association remain incompletely understood. Insulin-like growth factor (IGF)-associated signaling has been implicated, but existing evidence is conflicting. Methods: This feasibility and hypothesis-generating study combined a small clinical cohort with exploratory transcriptomics, in vitro and in silico analyses. Serum IGF1 and IGFBP-3 were measured in women with PCOS (n = 12 for IGF-1 and n = 6 for IGFBP-3) and controls (n = 24 for IGF1 and n = 7 for IGFBP-3). Pooled serum, stratified by IGF bioactivity, was applied to a human endometrial cancer cell line (HEC1A) to further assess effects on cell viability, cell cycle distribution, and downstream signaling, in addition to exploratory RNA sequencing (n=1 biological replicate per condition). Computational analysis of publicly available endometrial cancer datasets was used to contextualize experimental findings. Results: Serum IGF1 and IGFBP-3 levels did not differ significantly between PCOS and control groups. However, pooled PCOS serum increased EC cell viability and altered cell cycle progression compared with control serum. Pharmacological inhibition of IGF1R partially attenuated these effects, suggesting that IGF-associated pathways may contribute but are unlikely to act in isolation. Exploratory transcriptomic profiling of serum-treated EC cells supported enrichment of IGF-associated metabolic and growth programs (including mTORC1, PI3K/AKT/mTOR, glycolysis and oxidative phosphorylation), consistent with context-dependent modulation rather than IGF-only dependence. In silico analyses demonstrated frequent alterations in PI3K/AKT/mTOR-related genes in endometrial cancer, consistent with pathway-level vulnerability rather than IGF1-specific dependence. Conclusion: As a feasibility study, these findings suggest that PCOS serum contains factors that promote EC cell growth, with partial involvement of IGF signaling. However, multiple metabolic and hormonal pathways are likely to contribute. Larger, better-controlled studies incorporating insulin, sex steroids, and multiple EC models are required before causal inferences can be made.

Abstract: Cytochrome P450 oxidoreductase (POR) is the obligate electron donor for microsomal cytochrome P450 enzymes. Recessive mutations in the POR gene cause POR deficiency (PORD), a severe metabolic disorder characterized by skeletal malformations, ambiguous genitalia, and adrenal insufficiency. Because global POR knockout is embryonically lethal in mammalian models, the mechanistic study of PORD has historically been restricted to reconstituted biochemical assays or non-steroidogenic cellular backgrounds. Here, we describe complete biallelic POR knockout in human adrenal-derived NCI-H295R and human embryonic kidney HEK293T cells using CRISPR/Cas9. Transcriptomic and mass spectrometric steroid profiling of the adrenal clones revealed a blockade in canonical steroidogenesis, characterized by upstream accumulation of pregnenolone and progesterone, and severe depletion of downstream glucocorticoids and mineralocorticoids. Strikingly, knockout cells maintained low-level synthesis of dehydroepiandrosterone (DHEA) despite the complete absence of canonical CYP17A1 catalytic support, providing critical in vitro validation for the activation of alternative, CYP17A1-independent bypass steroidogenic pathways. Furthermore, utilizing the HEK293T platform, we evaluated the functional complementation of clinically relevant variants (A287P, R457H, P228L, and delP399_E401). Notably, the highly prevalent P228L variant exhibited selective preservation of CYP17A1 activity while severely impairing CYP19A1 aromatase function. A direct comparison between episomal overexpression and endogenous CRISPR prime editing of P228L highlighted critical differences in enzyme efficiency under native regulatory control. Finally, we establish a link between POR loss and altered intracellular Fe(II) storage, indicating perturbed ferroptotic susceptibility. These engineered human cell models provide a highly tractable platform for interrogating mutant-specific pharmacogenomics and developing targeted interventions.

Abstract: Castration-resistant prostate cancer (CRPC) survives androgen deprivation, a mechanism widely attributed to autonomous de novo steroidogenesis. Despite the clinical deployment of CYP17A1 inhibitors, the metabolic fidelity of the models underpinning this "tumor-as-gonad" dogma remains controversial. Here, integrating high-resolution liquid chromatography-mass spectrometry with transcriptomics across diverse prostate cancer models, we demonstrate that malignant cell lines universally lack autonomous steroidogenic capacity due to the transcriptional silencing of CYP17A1. Instead, these models operate as high-efficiency precursor "converters" by upregulating HSD3B1 and AKR1C3. Clinical stratification of 844 Prostate Adenocarcinoma patients corroborated this precursor-dependent phenotype. We identify a critical divergence: AR-High tumors rely on oxidative phosphorylation, whereas the transition to an AR-Low state is marked by extensive lineage plasticity. Strikingly, a neuroendocrine plasticity score inversely correlates with AR flux and independently predicts clinical progression (HR=2.41, p=0.024). Our findings redefine CRPC metabolism, dictating a therapeutic shift toward targeting downstream precursor conversion and adaptive lineage plasticity.

Abstract: Evidence suggests that physical activity promotes bone health through mechanical loading and biochemical signaling between bone and muscle tissues. A class of signaling molecules known as exerkines is a key mediator of bone–muscle crosstalk. Although exercise regulates osteokines, the acute exerkine responses across different exercise modalities remain unclear. This randomized repeated-measures crossover study compared acute changes in serum sclerostin (SCL), dickkopf-1 (DKK-1), receptor activator of nuclear factor kappa-B ligand (RANKL), osteopontin (OPN), brain-derived neurotrophic factor (BDNF), irisin, and interleukin 6 (IL-6) following circuit training (CT) (cycle ergometer, push-up, step-ups, medicine ball twist, and front squats with kettlebell for three sets) and traditional resistance (TR) exercise (3 sets 10 repetitions 80% 1RM for leg press, seated cable row, barbell bench press, dumbbell deadlifts, and dumbbell seated shoulder press) in healthy young adults (n=12). Participants performed two protocols separated by 2-week wash-out periods. Blood samples were analyzed before exercise training (pre), immediately post-exercise (IP), and 30 minutes post-exercise (30P) for all exerkines using ELISA. There was a significant interaction between protocol, timepoint, and sex (p=0.038) for SCL levels. There was a significant interaction between protocol, timepoint, and sex for SCL levels (p < 0.05). In males, SCL levels increased from Pre to IP under both training protocols (CT: 0.10 ± 0.02 ng/mL to 0.14 ± 0.02 ng/mL; TR: 0.20 ± 0.02 ng/mL to 0.21 ± 0.02 ng/mL). In both protocols, SCL levels decreased from IP to 30 P (CT: 0.14 ± 0.02 to 0.10 ± 0.01 ng/ml; TR: 0.22 ± 0.02 to 0.17 ± 0.02 ng/ml). In females, SCL levels increased from Pre to IP under both training protocols (CT: 0.03 ± 0.02 ng/mL to 0.06 ± 0.02 ng/mL; TR: 0.07 ± 0.02 ng/mL to 0.13 ± 0.02 ng/mL). There was a significant time effect for OPN and RANKL concentrations. Marginal means for the time point showed that OPN was significantly higher at the Pre time point. Post hoc analyses showed that OPN levels significantly decreased from 30P to Pre (18.84 ± 0.92 to 15.69 ± 1.32 pg/mL) (p=0.08). Similarly, RANKL showed a significant increase from Pre (0.38 ± 0.04 pg/mL) to 30P (0.57 ± 0.06 pg/mL) (p=0.02); otherwise, there were no significant differences between protocols or sexes. Irisin significantly decreased from Pre (28761.73 ± 238.52 pg/mL) to IP (2364.85 ± 243.79 pg/mL) in both protocols (p=0.01). DKK-1, BDNF, and IL-6 levels were only different between protocols (p< 0.01). SCL and BDNF levels were expressed higher in the TR protocol, whereas DKK-1, IL-6, and Irisin levels were expressed higher in the CT protocol. Overall, the findings suggest that SCL, RANKL, OPN, and irisin responded to the exercise bout, while the exerkines did not show meaningful changes over time.

Abstract: Milk quality is crucial for human health, and effective control of the supply chain—including services, processes, and products—is essential to maintain it. This study aimed to compare cholesterol and protein content, phospholipid composition, advanced glycation end products, and somatic cell count in milk from organic and conventional farming systems. Additionally, the impact of short versus long supply chains was evaluated. The results demonstrate that milk from organic farming has a better phos-pholipid and cholesterol composition and also a greater amount of protein than milk derived from traditional farming and that the long supply chain does not significantly change these properties, with the exception of phospholipids. Advanced glycation end products values were significantly higher in long supply chain, both in conventional and biological samples, but the long supply chain had a greater impact especially on the organic product. Finally, somatic cell count results show lower values in organic samples, suggesting particularly effective herd management and animal health protocols in these operations

Abstract: Weight regain following weight loss represents a major challenge in obesity management and is increasingly recognized as a biologically driven process rather than solely a consequence of behavioral non-adherence. A range of physiological adaptations, including reduced energy expenditure, neuroendocrine alterations in appetite regulation, and adipose tissue remodeling, act synergistically to promote weight restoration.In particular, changes in appetite-regulating hormones, such as decreased leptin and increased ghrelin levels, contribute to increased hunger and reduced satiety following weight loss. Additionally, emerging evidence highlights the role of adipose tissue remodeling and metabolic memory in sustaining susceptibility to weight regain.Nutritional factors may play a critical role in modulating these biological mechanisms. Dietary protein, fiber intake, glycemic responses, and overall dietary patterns have been shown to influence appetite regulation through interactions with gut-derived hormones, postprandial metabolism, and central appetite pathways. These effects suggest that dietary composition, beyond caloric restriction alone, may be a key determinant of long-term weight maintenance.Despite growing evidence, findings remain heterogeneous, and the long-term effectiveness of specific dietary strategies is not fully established. Future approaches should focus on integrating nutritional strategies with individual biological responses, including variability in hormonal regulation, metabolic adaptation, and gut–brain signaling.In conclusion, targeting appetite regulation and metabolic adaptation through personalized and sustainable nutritional strategies may represent a promising approach for reducing weight regain and improving long-term outcomes in obesity management.

Abstract: Background: Androgen deprivation therapy (ADT) is widely used in the management of prostate cancer (PCa) and remains a cornerstone of treatment across multiple disease settings. Although ADT con-tributes substantially to disease control, it also induces significant adverse metabolic and body composition changes. These alterations include loss of lean mass, increased fat mass, and deterio-ration in muscle quality, together contributing to a clinical phenotype consistent with sarcopenic obesity (SO). Importantly, ADT-induced SO is characterized not only by reductions in skel-etal muscle mass but also by impaired muscle quality, particularly fatty infiltration of skeletal muscle, or myosteatosis, an underrecognized but defining feature of this syndrome. Methods: This narrative review examines current evidence regarding interventions aimed at mitigating sar-copenic obesity in men treated with ADT for prostate cancer, identifies key gaps in the literature, and proposes a mechanism-driven path forward for intervention development. Results: Several exercise- and nutrition-based interventions have been evaluated in men receiving ADT and demonstrate improvements in selected outcomes such as muscle strength, body composition, and metabolic parameters. However, most studies have been limited by small sample sizes, short intervention durations, and a focus on isolated intervention components. Importantly, muscle quality and intramuscular fat infiltration (myosteatosis), a central component of sarcopenic obesity, have rarely been incorporated as biomarkers or endpoints in intervention trials targeting men re-ceiving ADT. Conclusion: Future interventions designed to mitigate SO and its associated metabolic abnormalities should evaluate comprehensive, bundled strategies initiated early during ADT and sustained long enough to capture clinically meaningful changes. Outcomes should include biomarkers of muscle mass, strength, and quality, including imaging-based measures of myosteatosis, along with metabolic syndrome markers, inflammatory mediators, functional outcomes, adherence, and quality of life. These changes should be correlated with underlying biological mechanisms such as NF-κB signal-ing and pro-inflammatory cytokines. Such data may inform future phase III trials and ultimately support clinical strategies to mitigate ADT-related sarcopenic obesity and its downstream cardi-ometabolic and oncologic consequences.

Abstract: Background: Vitamin K (VK) has emerging roles beyond coagulation, including potential involvement in glucose metabolism. While large cohorts report inverse associations between VK status and incident type 2 diabetes, less is known about its relation-ship with insulin resistance in general populations. Methods: We conducted a cross-sectional analysis of 23,247 adults from the National Health and Nutrition Examination Survey (NHANES) 2001-2018. Dietary VK intake was assessed using a 24-h recall and modeled as energy-adjusted nutrient density (µg/1000 kcal). Fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), fasting glucose, and HbA1c were analyzed using survey-weighted linear regression; models were adjusted for demographic, socioeconomic, lifestyle, and adiposi-ty-related factors. Effect modification by baseline metabolic status was evaluated, and sensitivity analyses assessed robustness. Results: Higher energy-adjusted VK intake was independently associated with lower fasting insulin and HOMA-IR, but not with fasting glucose or HbA1c. Each SD increase in VK intake was associated with 1.4% lower fasting insulin (95% CI -2.4% to -0.4%) and 1.3% lower HOMA-IR (95% CI -2.3% to -0.3%) in fully adjusted models. Associations were attenuated but remained signif-icant after adjustment for adiposity. Effect modification by baseline metabolic status was observed, with stronger associations among normoglycemic individuals. Findings were robust across sensitivity analyses. Conclusions: In this nationally representative sample of U.S. adults, higher VK intake was modestly associated with lower insulin resistance markers. Dietary VK intake may contribute to maintenance of insulin sensitivity, particularly in metabolically intact states. Prospective studies incorporating comprehensive VK biomarkers and dynamic measures of insulin sensitivity are warrant-ed.

Abstract: Obesity is a chronic inflammatory, multifactorial disease characterized by excessive fat accumulation driven by an imbalance between energy intake and energy expenditure. Despite the implementation of public health strategies and individual therapeutic interventions, overweight and obesity affect more than two billion people worldwide. While the distinction between preclinical (PCO) and clinical obesity (CO) has been conceptually established, tools capable of translating this distinction into clinical diagnostics remain lacking. Current approaches typically use quality-of-life questionnaires as outcome measures rather than diagnostic criteria. In this study, we proposed a novel diagnostic framework in which the SF-36 Role-Physical (RP) domain functions as a screening tool to identify CO. We integrated anthropometric criteria (BMI, waist circumference), organ dysfunction (comorbidities), and objectively defined physical limitations (RP domain cutoffs). Results demonstrated that stratifying patients based on this functional model successfully isolated a phenotype characterized by a distinct pro-inflammatory profile. Individuals classified as having CO exhibited significantly increased IL-6 and IL-17A levels compared to PCO and overweight groups, providing biological validation that the SF-36 RP domain can effectively distinguish pathological adiposity from simple weight gain.

Abstract: Type 2 diabetes mellitus (T2DM) is a major driver of cardiovascular disease (CVD), yet current risk stratification tools fail to capture underlying molecular dysregulation. This study aimed to characterize an integrated molecular signature associated with cardiovascular risk in T2DM. A total of 128 individuals (96 T2DM and 32 controls) were evaluated. Circulating miR-34a expression was quantified by RT–qPCR, and protein biomarkers including SIRT1, inflammatory markers (IL-6, TNF-α, hs-CRP), oxidative stress markers (MDA, total antioxidant capacity), and endothelial dysfunction markers (VCAM-1, ICAM-1) were measured by ELISA. Cardiovascular risk was assessed using the Framingham Risk Score. miR-34a expression was significantly elevated in T2DM, particularly in individuals with high cardiovascular risk (p < 0.001). This was accompanied by reduced SIRT1 levels and a progressive increase in inflammatory, oxidative, and endothelial dysfunction markers. Integrated analysis revealed strong correlations between miR-34a upregulation, SIRT1 suppression, and systemic pathophysiological alterations. Multivariate regression identified miR-34a, SIRT1, IL-6, and MDA as independent predictors of high cardiovascular risk. A combined biomarker model demonstrated excellent discriminative performance (AUC = 0.92), outperforming individual markers. These findings support the existence of a coordinated miR-34a/SIRT1-driven molecular axis linking inflammation, oxidative stress, and endothelial dysfunction to cardiovascular risk in T2DM. This integrated biomarker approach may improve risk stratification and support precision cardiometabolic medicine.