Search Results (969)

End-stage chronic kidney disease remains a global challenge, with dialysis and transplantation offering only partial or limited solutions. Recent advances in bioengineering have introduced modular strategies that aim to restore kidney function not by replicating the entire organ, but by rebuilding it one segment at a time. Platforms such as kidney organoids, implantable bioartificial kidneys, 3D-bioprinted tissues, and decellularized scaffolds each target specific nephron functions, from filtration to endocrine signaling. This Perspective examines how these technologies can be integrated into interoperable systems that reflect the nephron’s native structure and functional complexity. We assess translational readiness across key benchmarks, including vascular integration, hormonal responsiveness, immune compatibility, and implantability, and discuss the ethical, regulatory, and design considerations that will shape their clinical future. Collectively, these modular strategies offer a pathway toward more personalized, scalable, and physiologically relevant approaches to kidney replacement. Full article

Environmental pollutants such as heavy metals, endocrine-disrupting chemicals, microplastics, and airborne particulates are increasingly recognized for their potential to influence immune function through epigenetic mechanisms. This review examines conserved pollutant-associated pathways at interfaces of immunity and epigenetics, with particular attention to Toll-like receptor–NF-κB signalling, NLRP3 inflammasome activity, and reactive oxygen species-driven cascades. Evidence from cellular, animal, and epidemiological studies indicates that these pathways may converge on chromatin regulators such as DNA methyltransferases, histone deacetylases, and EZH2, leading to DNA methylation shifts, histone modifications, and altered chromatin accessibility. Pollutants are also reported to modulate non-coding RNAs, including miR-21, miR-155, and several lncRNAs, which can act as intermediaries between cytokine signalling and epigenetic remodelling. Findings from transgenerational models suggest that pollutant-linked immune–epigenetic alterations might persist across generations, raising the possibility of long-term consequences for immune and neurodevelopmental health. Comparative analyses further indicate convergence across diverse pollutant classes, pointing to a shared mechanistic axis of immune–epigenetic disruption. Overall, these insights suggest that pollutant-induced immune–epigenetic signatures may contribute to inflammation, altered immune responses, and heritable disease risks, and their clarification could inform biomarker discovery and future precision approaches in immunotoxicology. Full article

Lead (Pb) is a naturally occurring metal that is environmentally ubiquitous due to industrial activities, such as mining, smelting, and fossil fuel combustion. Exposure to Pb adversely affects the central nervous system, gastrointestinal tract, lungs, liver, bones, and cardiovascular system, leading to a multitude of negative health impacts, such as anemia and neurological disorders. While significant research has focused on the effects of Pb on the nervous and immune systems, Pb’s impact as a reproductive endocrine disruptor remains largely understudied. The first objective of this review was to collate the current literature regarding the effects of Pb on the reproductive system of aquatic species (primarily fish) and agricultural livestock to highlight the ecological significance and impacts on animal health. Literature supports the hypothesis that exposure to Pb can impede reproductive processes by affecting hormone levels, reproductive organ development, and fertility. A second objective of this review was to elucidate putative mechanisms underlying Pb as a reproductive endocrine disruptor using molecular data and computational approaches. Based on transcriptomics data, Pb is hypothesized to perturb key pathways important for hypothalamic–pituitary–gonadal axis functions, such as circadian regulation and estrogen receptor signaling. Given the widespread environmental presence of Pb, understanding these mechanisms is essential for improving risk assessments and protecting animal reproductive health. Full article

Thyroid cancer (TC), the most prevalent endocrine neoplasia, has shown a progressive incidence, highlighting the need for new therapeutic approaches—especially for radioiodine-refractory cases, often associated with mutations in genes such as BRAF, RAS, and TP53. This review proposes a mechanistic model that highlights two interrelated characteristics of the tumor microenvironment (TME): redox imbalance and chronic inflammation, key elements in tumor progression and treatment resistance. Thus, natural phenolic compounds, such as curcumin, quercetin, resveratrol, and epigallocatechin gallate (EGCG), function not as simple antioxidants but as pleiotropic agents that reprogram the TME. A central mechanism of action for these compounds is the modulation of the purinergic axis (CD39/CD73/adenosine), a critical immune-metabolic checkpoint. By selectively inducing lethal oxidative stress in tumor cells, suppressing pro-survival inflammatory pathways—such as that mediated by nuclear factor kappa B (NF-κB)—and destabilizing the immunosuppressive shield conferred by adenosine, certain phytochemicals demonstrate the potential to restore immune surveillance and promote tumor apoptosis. In this context, a critical analysis of the evidence related to targeting purinergic signals becomes essential, since pharmacological reinforcement of this pathway, especially when combined with immunotherapies based on immune checkpoint blockade, emerges as a promising strategy for overcoming therapeutic resistance. Full article

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Although genetic and environmental factors are established contributors, recent research has highlighted the critical role of the gut–brain axis (GBA) in ALS pathogenesis. The GBA is a bidirectional communication network involving neural, immune, and endocrine pathways that connect the gut microbiota with the central nervous system. Dysbiosis in ALS disrupts this axis, leading to increased intestinal permeability, neuroinflammation, and excitotoxicity. Notably, reductions in butyrate-producing bacteria, alterations in microbial metabolites, and enhanced NLRP3 inflammasome activation have been observed in patients with ALS. These changes may precede motor symptoms, suggesting a potential causative role. Interventions targeting the microbiome, such as dietary modulation, have shown promise in delaying disease onset and reducing inflammation. However, the clinical evidence remains limited. Given that gut dysbiosis may precede neurological symptoms, microbiota-targeted therapies offer a novel and potentially modifiable approach to ALS treatment. Understanding the role of GBA in ALS will open new avenues for early diagnosis and intervention. Further clinical trials are required to clarify the causal links and evaluate the efficacy of microbiome-based interventions. Understanding the brain–gut–microbiota axis in ALS could lead to new diagnostic biomarkers and therapeutic strategies. Full article

Objective: To compare the efficacy of exercise modalities for simultaneously improving homeostasis model assessment for insulin resistance (HOMA-IR) and total testosterone in women with polycystic ovary syndrome (PCOS). Methods: We conducted a Bayesian network meta-analysis of 19 randomized controlled trials (n = 808) to evaluate six exercise interventions: yoga, moderate-intensity continuous training (MICT), high-intensity interval training (HIIT), resistance training (RT), combined aerobic-resistance training (CT), and control (CG). Primary outcomes were changes in HOMA-IR and total testosterone, with interventions ranked via surface under the cumulative ranking curve (SUCRA). Results: For HOMA-IR reduction, yoga (SUCRA = 90.73%; SMD = −0.73, 95% CrI: −1.3 to −0.086) and HIIT (SUCRA = 74.12%; SMD = −0.47, 95% CrI: −0.75 to −0.15) demonstrated superior efficacy versus MICT (SUCRA = 50.56%) and CT (SUCRA = 42.29%), while RT was the least effective (SUCRA = 32.53%). For testosterone lowering, yoga was ranked the highest again (SUCRA = 92.46%; SMD = −0.85, 95% CrI: −1.7 to −0.12), followed by MICT (SUCRA = 75.72%; SMD = −0.56, 95% CrI: −0.97 to −0.25) and HIIT (SUCRA = 61.12%; SMD = −0.42, CrI: −0.88 to −0.12). CT and RT showed non-significant effects for both outcomes (p > 0.05). Conclusions: Yoga is the optimal intervention for dual-pathway improvement in PCOS. HIIT and MICT provide outcome-specific benefits (metabolic vs. endocrine), whereas CT and RT necessitate protocol refinement. Systematic review registration: This systematic review and network meta-analysis study was registered in PROSPERO (CRD420251011979). Full article

Iron represents an essential element required for normal physiologic processes throughout organ systems. A vast network of transporters is involved not only in uptake of this element but in processing, oxidation, and recycling to maintain it in a tight balance to avoid excess storage. This complex network of transporters, including heme and ferroportin, among many others, are responsible for facilitating inter-organ tissue iron exchange and availability, contributing to overall heme homeostasis. However, exposure to high levels of iron can overwhelm compensatory mechanisms that result in its accumulation and toxicity. This is the case of patients with genetic diseases such as hemoglobinopathies who suffer from chronic anemia and require, in most instances, a lifetime of red blood cell transfusions to overcome disease crises. Thus, in light of the extensive role of iron in the body, the aim of this review is to present important metabolic pathways involved in iron homeostasis across the cardiovascular, reproductive, hematopoietic, urinary, respiratory, endocrine, and central nervous systems while contrasting these against negative effects caused by iron excess. Full article

This study investigated the molecular mechanisms by which phthalates induce depression, utilizing network toxicology and molecular docking techniques. By integrating the TargetNet, GeneCards, and PharmMapper databases, 658 potential target genes of phthalates were identified. Additionally, 5433 depression-related targets were retrieved from the GeneCards and OMIM databases. Comparative analysis revealed 360 common targets implicated in both phthalate action and depression. A Protein-Protein Interaction (PPI) network was constructed using the STRING database. Subsequently, the CytoHubba plugin (employing the MCC algorithm) within Cytoscape was used to screen the network, identifying the top 20 hub genes. These core genes include AKT1, CASP3, TNF, TP53, BCL2, and IL6, among others. Validation on the GEO dataset (GSE23848) revealed that the expression of multiple core genes was significantly upregulated in patients with depression (p < 0.05). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that phthalates mainly regulate biological processes such as extracellular stimulus response, lipopolysaccharide metabolism, and chemical synaptic transmission. Depression is mediated by the AGE-RAGE signaling pathway (a complication of diabetes), lipids and atherosclerosis, Endocrine resistance, and the PI3K-Akt signaling pathway. Molecular docking confirmed that phthalates have strong binding activity with key targets (CASP3, TNF, TP53, BCL2, IL6). These findings present a novel paradigm for evaluating the health risks posed by environmental pollutants. Full article

Research on the effects of polyunsaturated fatty acids on children’s sleep has made significant advancements. This study explores the unique pathways through which polyunsaturated fatty acids, particularly docosahexaenoic acid and eicosapentaenoic acid from the n-3 series, influence sleep regulation in children. Neurobiologically, docosahexaenoic acid and eicosapentaenoic acid have been shown to bi-directionally modulate neurotransmitters and circadian rhythms via the gut–brain axis, reshaping gut microbiota and affecting brain signaling. In terms of inflammation and immune regulation, this study is the first to confirm that Maresin1, produced from n-3 fatty acids, can inhibit the activation of specific inflammasomes, thereby mitigating the disruptive effects of pro-inflammatory cytokines on sleep. The analysis of clinical applications indicates that newly developed medium- and long-chain triglyceride formulations rich in docosahexaenoic acid exhibit excellent digestive absorption in infants’ gastrointestinal systems, paving the way for new products designed to enhance infant sleep. However, current research has limitations concerning the precise dosing of docosahexaenoic acid, the representativeness of samples, and the overall rigor of study designs. Mechanistically, polyunsaturated fatty acids may exert their effects through various pathways, including neurobiology, inflammation, immune regulation, and endocrine modulation. In clinical studies, different formulations of fish oil show varying safety profiles and bioavailability. Future research should prioritize high-quality studies to clarify how different doses of polyunsaturated fatty acids affect children’s sleep, assess long-term safety, and investigate interactions with other factors, ultimately providing solid theoretical and practical guidance for improving children’s sleep. Full article

Background: Type 2 diabetes (T2D), the most common form of diabetes, is associated with a significantly elevated risk of cardiovascular and cerebrovascular complications. However, circulating metabolic signatures that reliably predict the transition to insulin resistance, and are potentially linked to increased vascular risk, remain incompletely characterized. Rodent models, particularly those induced by a high-fat diet (HFD) combined with low-dose streptozotocin (STZ), are widely used to study the progression of T2D. However, the systemic metabolic shifts associated with this model, especially at the plasma level, are poorly defined. Methods: In this study, we performed untargeted liquid chromatography–mass spectrometry (LC-MS)-based metabolomic profiling on plasma samples from control, HFD-only (obese, insulin-sensitive), and HFD + STZ (obese, insulin-resistant) C57BL/6 mice. Results: In the HFD + STZ cohort, plasma profiles showed a global shift toward lipid classes; depletion of aromatic and branched-chain amino acids (BCAAs); accumulation of phenylalanine-derived co-metabolites, consistent with gut–liver axis dysregulation; elevations in glucose, fructose-6-phosphate, and nucleoside catabolites, indicating impaired glucose handling and heightened nucleotide turnover; increased free fatty acids, reflecting membrane remodeling and lipotoxic stress; and higher cAMP, thyroxine, hydrocortisone, and uric acid, consistent with endocrine and redox imbalance. By contrast, HFD-only mice exhibited elevations in aromatic amino acids and BCAAs relative to controls, a pattern compatible with early obesity-associated adaptation while insulin signaling remained partially preserved. KEGG analysis revealed disturbances in carbohydrate metabolism, amino acid degradation, nucleotide turnover, and hormone-related pathways, and HMDB mapping linked these changes to T2D, obesity, heart failure, and renal dysfunction. Conclusion: Collectively, these findings delineate insulin resistance-specific plasma signatures of metabolic inflexibility and inflammatory stress in the HFD + STZ model, distinguishing it from HFD alone and supporting its utility for mechanistic studies and biomarker discovery. Importantly, this plasma metabolomics study shows that insulin-sensitive and insulin-resistant states exhibit distinct variation in circulating metabolites and cardiovascular risk factors, underscoring the translational value of plasma profiling. Full article

Optic pathway glioma (OPG) is a rare pediatric low-grade glioma, frequently associated with neurofibromatosis type 1 (NF–1), that presents unique therapeutic challenges due to its anatomical location and its potential to impair vision, endocrine function, and developmental trajectories. Current clinical management prioritizes a multidisciplinary, patient-specific approach aimed at tumor control while preserving long-term quality of life. Strategies vary based on clinical presentation, ranging from observation in asymptomatic cases to chemotherapy for progressive or symptomatic tumors. Surgical and radiation options are limited due to potential risks and complications. In recent years, advances in molecular characterization have guided the development of targeted therapies, particularly MEK inhibitors, which demonstrate encouraging efficacy and reduced toxicity profiles. In parallel, investigational therapies including immunotherapy and precision medicine-based approaches are under clinical evaluation. This review provides a synthesis of current standard practices, emerging targeted treatments, and ongoing clinical trials, drawing on relevant literature and expert consensus to inform clinicians and families about available therapeutic options. Literature discussed in this review was identified through a non-systematic search of published articles, clinical trial registries, and authoritative guidelines, with selection based on relevance, clinical significance, and contribution to understanding current and emerging management strategies for OPG. Full article

Type 2 diabetes (T2D) is a complex metabolic disease characterized by chronic hyperglycemia due to insulin resistance and inadequate insulin secretion. Beyond the classically implicated organs, emerging evidence highlights the gut as a central player in T2D pathophysiology through its interactions with metabolic organs. The gut hosts trillions of microbes and enteroendocrine cells that influence inflammation, energy homeostasis, and hormone regulation. Disruptions in gut homeostasis (dysbiosis and increased permeability) have been linked to obesity, insulin resistance, and β-cell dysfunction, suggesting multifaceted “Gut-X axes” contribute to T2D development. We aimed to comprehensively review the evidence for gut-mediated crosstalk with the pancreas, endocrine system, liver, and kidneys in T2D. Key molecular mechanisms (incretins, bile acids, short-chain fatty acids, endotoxins, etc.) were examined to construct an integrated model of how gut-derived signals modulate metabolic and inflammatory pathways across organs. We also discuss clinical implications of targeting Gut-X axes and identify knowledge gaps and future research directions. A literature search (2015–2025) was conducted in PubMed, Scopus, and Web of Science, following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews). Over 150 high-impact publications (original research and review articles from Nature, Cell, Gut, Diabetologia, Lancet Diabetes & Endocrinology, etc.) were screened. Data on gut microbiota, enteroendocrine hormones, inflammatory mediators, and organ-specific outcomes in T2D were extracted. The GRADE framework was used informally to prioritize high-quality evidence (e.g., human trials and meta-analyses) in formulating conclusions. T2D involves perturbations in multiple Gut-X axes. This review first outlines gut homeostasis and T2D pathogenesis, then dissects each axis: (1) Gut–Pancreas Axis: how incretin hormones (GLP-1 and GIP) and microbial metabolites affect insulin/glucagon secretion and β-cell health; (2) Gut–Endocrine Axis: enteroendocrine signals (e.g., PYY and ghrelin) and neural pathways that link the gut with appetite regulation, adipose tissue, and systemic metabolism; (3) Gut–Liver Axis: the role of microbiota-modified bile acids (FXR/TGR5 pathways) and bacterial endotoxins in non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance; (4) Gut–Kidney Axis: how gut-derived toxins and nutrient handling intersect with diabetic kidney disease and how incretin-based and SGLT2 inhibitor therapies leverage gut–kidney communication. Shared mechanisms (microbial SCFAs improving insulin sensitivity, LPS driving inflammation via TLR4, and aryl hydrocarbon receptor ligands modulating immunity) are synthesized into a unified model. An integrated understanding of Gut-X axes reveals new opportunities for treating and preventing T2D. Modulating the gut microbiome and its metabolites (through diet, pharmaceuticals, or microbiota therapies) can improve glycemic control and ameliorate complications by simultaneously influencing pancreatic islet function, hepatic metabolism, and systemic inflammation. However, translating these insights into clinical practice requires addressing gaps with robust human studies. This review provides a state-of-the-art synthesis for researchers and clinicians, underlining the gut as a nexus for multi-organ metabolic regulation in T2D and a fertile target for next-generation therapies. Full article

Secondary metabolites derived from plants, such as flavonoids, alkaloids, and terpenoids, are being increasingly utilized because of their bioactivity and ubiquitous distribution. Although their pharmacological uses and agricultural applications are well studied, their potential role as endocrine-disrupting compounds (EDCs) in non-target environmental organisms is largely unknown. This review aims to update our knowledge on the endocrine-disrupting effects induced by plant-derived metabolites in environmental testing models. We review guidelines and conceptual models for standardized testing approaches used to assess endocrine disruption and identify critical data gaps in the context of mammalian test systems compared to those for environmental species. We also emphasize the known endocrine mechanisms, including the regulation of estrogen and thyroid pathways and their effects on reproduction and hormonal regulation in environmental species. By integrating evidence across diverse biological systems, this work intends to provide a link between toxicological and ecological perspectives on the emerging role of plant-derived metabolites as potential EDCs in natural ecosystems. Importantly, we highlight that an extensive assessment of plant-derived metabolites is required to improve understanding of their ecological hazards and the mechanisms of their effects. Full article

Cancer-associated cachexia is a multifaceted wasting syndrome characterized by progressive loss of skeletal muscle mass, systemic inflammation, and metabolic dysfunction and is particularly prevalent in gastrointestinal cancers. Physical activity has emerged as a promising non-pharmacological intervention capable of attenuating key drivers of cachexia. Exercise modulates inflammatory signaling (e.g., IL-6/STAT3 and TNF-α/NF-κB), enhances anabolic pathways (e.g., IGF-1/Akt/mTOR), and preserves lean body mass and functional capacity. Exercise-induced signaling molecules, known as exerkines, are key mediators of these benefits, which are released during physical activity and act in an autocrine, paracrine, and endocrine manner. However, many of these molecules also exhibit context-dependent effects. While they exert protective, anti-inflammatory, or anabolic actions when transiently elevated after exercise, the same molecules may contribute to cachexia pathogenesis when chronically secreted by tumors or in systemic disease states. The biological effects of a given factor depend on its origin, timing, concentration, and physiological milieu. This review presents recent evidence from clinical and experimental studies to elucidate how physical activity and exerkines may be harnessed to mitigate cancer cachexia, with particular emphasis on gastrointestinal malignancies and their unique metabolic challenges. Full article

Background/Objectives: The aim of this study was to explore the effects of diets with different protein levels on the metabolite composition and metabolic pathways of the longest dorsal muscle of Tibetan pigs, in order to provide a metabolic basis for optimizing the nutritional regulation strategy of Tibetan pigs. Methods: A total of 32 healthy 180-day-old depopulated male Tibetan pigs were randomly divided into four groups and fed diets with protein levels of 10%, 12%, 14%, and 16%, respectively, with a feeding cycle of 8 weeks. The longest dorsal muscle samples were collected, and their metabolic profiles were systematically analyzed by LC-MS non-targeted metabolomics. Results: The TIC plots of the quality control samples were highly overlapped, indicating a stable instrumental detection process and good consistency of sample processing. Principal component analysis and orthogonal partial least squares discriminant analysis revealed significant metabolic differences between groups with different protein levels. A total of multiple differential metabolites was obtained based on VIP value and p-value screening, and Venn diagram analysis revealed a total of 11 metabolites among the three comparative groups, suggesting that they may have key roles in the protein regulation process. Volcano plots further clarified the number and trend of significantly up- and down-regulated metabolites in each group. KEGG pathway enrichment analysis showed that, with the elevation of protein level, the metabolic pathway response showed a tendency of expanding from basal energy metabolism to the complex network of amino acid synthesis, steroidogenesis, endocrine signaling, and detoxification pathways, especially in the high-protein-treated group. Conclusions: The study showed that different protein intake levels could significantly regulate the metabolites and key metabolic pathways in the longest muscle of Tibetan pigs, which provided theoretical support for the scientific formulation of a protein supply program to optimize the quality and growth performance of Tibetan pork. Full article