Search Results (2,508)

Background: Polybacterial infections associated with periodontitis are increasingly linked to systemic vascular complications, yet the underlying endothelial mechanisms remain unclear. This study investigated how a consortium of red-complex bacteria (Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola) and orange complex (Fusobacterium nucleatum) affects oxidative stress, inflammation, metabolism, and apoptosis in endothelial cells, and whether L-Sepiapterin [a tetrahydrobiopterin (BH4) precursor via salvage pathway] or bardoxolone methyl (CDDO-Me) [a potent nuclear factor erythroid 2-related factor 2 (Nrf2) activator)] could provide protection. Methods: Human umbilical vein endothelial cells (HUVECs) were infected for 12–72 h and treated with L-Sepiapterin or CDDO-Me. Nitric oxide (NO), BH4, and reactive oxygen species (ROS) levels were quantified, and mRNA expression of key genes regulating nitric oxide synthase activity, antioxidant defense, inflammation (TLR4/NF-κB, cytokines), metabolism (PI3K-AKT-PEA-15), and apoptosis (FAS–caspase pathway) was analyzed. Results: Infection markedly reduced NO and BH4, elevated ROS, activated TLR4/NF-κB and proinflammatory cytokines, disrupted PI3K/AKT signaling, and triggered endothelial apoptosis. Treatments with L-Sepiapterin and CDDO-Me restored NO bioavailability, reduced oxidative and inflammatory responses, normalized metabolic gene expression, and attenuated apoptosis, with CDDO-Me showing more promising effects. This study provides the mechanistic insight linking periodontal polybacterial infection to endothelial dysfunction and metabolic impairment such as diabetes, suggesting that redox-modulating strategies such as L-Sepiapterin and CDDO-Me may help prevent vascular damage associated with periodontal disease. Full article

Endometriosis involves oestrogen-dependent chronic inflammation and the abnormal proliferation of ectopic endometrial tissue. Conventional hormonal therapies suppress systemic oestrogen, but do not fully address local oxidative and inflammatory signalling. This review provides a mechanistic synthesis of recent molecular evidence. This evidence is on four FDA-recognized (Food and Drug Administration) medicinal plants. These are Curcuma longa, Zingiber officinale, Glycyrrhiza glabra, and Silybum marianum. The review highlights their capacity to modulate key intracellular pathways. These pathways are implicated in endometriosis. The review covers the integration of phytochemical-specific actions within NF-κB- (nuclear factor kappa-light-chain-enhancer of activated B cells), COX-2-(Cyclooxygenase-2), PI3K/Akt-(PI3K/Akt signaling pathway), Nrf2/ARE-(Nuclear factor erythroid 2–related factor 2) and ERβ-(Estrogen receptor beta) mediated networks, which jointly regulate cytokine secretion, apoptosis, angiogenesis and redox balance in endometrial lesions. Curcumin downregulates COX-2 and aromatase while activating Nrf2 signalling, shogaol from ginger suppresses prostaglandin synthesis and induces caspase-dependent apoptosis, isoliquiritigenin from liquorice inhibits HMGB1-TLR4–NF-κB (High Mobility Group Box 1, Toll-like receptor 4) activation, and silymarin from milk thistle reduces IL-6 (Interleukin-6) and miR-155 (microRNA-155) expression while enhancing antioxidant capacity. Together, these phytochemicals demonstrate pharmacodynamic complementarity with hormonal agents by targeting local inflammatory and oxidative circuits rather than systemic endocrine axes. This mechanistic framework supports the rational integration of phytotherapy into endometriosis management and identifies redox-inflammatory signalling nodes as future translational targets. Full article

Uterine leiomyosarcoma (uLMS) is a rare, highly aggressive malignancy of uterine smooth muscle, associated with early metastasis, frequent recurrence, and poor prognosis. Accurate preoperative diagnosis remains difficult given that clinical and radiologic features often overlap with benign leiomyomas, and no reliable biomarkers are currently available. This review summarizes recent evidence on the role of microRNAs (miRNAs) in the biology and clinical management of uLMS. Literature from molecular and translational studies was examined to identify dysregulated miRNAs, their target pathways, and potential diagnostic and therapeutic applications. uLMS displays a characteristic miRNA profile, including downregulation of tumor-suppressive miRNAs such as the miR-29 and miR-200 families and upregulation of oncogenic miRNAs including miR-21 and the miR-183~96~182 cluster, leading to activation of PI3K/AKT/mTOR signaling and epithelial–mesenchymal transition (EMT). Circulating and tissue miRNAs show promise as minimally invasive biomarkers for differentiating uLMS from leiomyomas, predicting prognosis, and guiding therapy. Emerging therapeutic approaches aim to restore the tumor-suppressive miRNAs or inhibit oncogenic ones using mimics or antagomiRs. Overall miRNAs represent critical regulators of uLMS pathogenesis and hold significant potential for precision diagnosis, prognostication, and targeted therapy, though larger validation studies and improved delivery systems are required before clinical translation. Full article

Cancer progression in skeletal muscle (SkM) is very rare, and mechanisms remain unclear. This study assessed the potential of SkM (myocyte)-derived EVs (C2C12-EVs) as anti-cancer agents. Using murine in vitro models, we showed that following treatment with C2C12-EVs, lung carcinoma cells failed to colonise SkM cells, and that C2C12-EVs selectively exerted apoptosis on cancer cells. Uptake of C2C12-EVs by carcinoma cells caused changes in lysosomal function and mitochondrial membrane properties inducing cell death with elevated caspase 3 and 9. The C2C12-EVs also inhibited cell proliferation, affecting cell cycle arrest at S phase and inhibited cell migration. Proteomic analysis of C2C12-EV cargoes highlighted functional enrichment pathways involved in lysozyme function, HIF-1 and PI3K-Akt signalling, regulation of actin cytoskeleton, pyruvate metabolism, platelet activation, and protein processing in ER. Decorin, a muscle cell-specific cytokine released from myocytes in response to stress, was significantly enriched in C2C12-EVs and may contribute to C2C12-EVs’ inhibitory activity on cancer cells. C2C12-EVs may suppress cancer and potentially be used as therapeutic agents for cancer metastasis. Full article

Glioblastoma (GBM), formerly referred to as glioblastoma multiforme, represents the most prevalent and aggressive form of glioma, predominantly affecting the aging population. Despite considerable advances in recent years in elucidating its pathogenesis and developing novel immunotherapeutic approaches, the overall survival rate for patients with this central nervous system (CNS) neoplasm remains dismally low. Consequently, there is an urgent and unmet need to identify and characterize additional therapeutic targets that could be employed synergistically with existing treatment modalities to enhance both survival outcomes and quality of life. Among the emerging areas of investigation, substantial interest has been directed toward aging-associated molecular signaling mechanisms that also constitute key oncogenic pathways in GBM. These include aberrant growth factor signaling, hyperactivation of the PI3K/AKT/mTOR axis, and inactivation of critical tumor suppressor pathways such as p53 and retinoblastoma (RB). The dysregulation of these signaling cascades results in profound disturbances of essential cellular homeostatic processes, notably autophagy and cellular senescence, which are intimately involved in both tumor initiation and progression. This review aims to delineate the complex interplay between autophagy and cellular senescence within the context of aging-related GBM pathogenesis. Furthermore, it explores the relevant intracellular signaling transduction mechanisms that govern these processes and discusses prospective therapeutic strategies. Full article

Cryptorchidism, characterized by undescended testes, is associated with infertility and increased cancer risk through complex, multifactorial pathophysiological mechanisms involving interconnected alterations in testicular microenvironment, including but not limited to elevated temperature, hormonal dysregulation, altered vascular perfusion, and immune responses. These factors interact synergistically to drive testicular pathology. Using a surgically induced bilateral cryptorchid mouse model established at postnatal day 21 (PND21), we investigated phase-specific pathological mechanisms through analyses at prepubertal (PND35) and sexually mature (PND70) phases. Our transcriptome analysis revealed distinct molecular signatures at different developmental phases, with prepubertal cryptorchid testes showing 2570 differentially expressed genes predominantly enriched in immunoproteasome components and inflammatory pathways, while sexually mature testes exhibited 883 differentially expressed genes primarily related to extracellular matrix (ECM) remodeling and oncogenic pathways. Prepubertal molecular changes indicated immunoproteasome activation and inflammatory responses, whereas mature-phase alterations were characterized by ECM reorganization and fibrotic remodeling. Functional analysis demonstrated prepubertal enrichment in spermatogenesis regulation and interferon responses, while mature-phase signatures were associated with apoptosis, epithelial–mesenchymal transition, and inflammatory signaling cascades. Phase-specific oncogenic pathway correlations revealed distinct mechanisms: metabolic reprogramming and epigenetic regulation in prepubertal testes versus structural remodeling and invasion-related pathways in mature testes. Molecular validation confirmed elevated PI3K-Akt and NF-κB signaling at both developmental phases, identifying these as potential therapeutic targets. This first phase-resolved characterization of cryptorchidism pathology provides insights into developmental phase-specific mechanisms and suggests timing-dependent therapeutic strategies. Although differing from human congenital cryptorchidism in developmental timing and etiology, our surgically induced model recapitulates anatomical testicular malposition with multiple inseparable pathophysiological alterations, and the identified molecular signatures reflect integrated responses to the complex cryptorchid microenvironment. Full article

Astaxanthin has attracted considerable interest, owing to its potent antioxidant and pigmentation properties. To investigate its effects of astaxanthin on body color variation in Lutjanus erythropterus, fish were divided into a control group and a treatment group fed an astaxanthin-supplemented diet. Body color parameters, growth performance, and liver antioxidant enzyme activities were measured at the end of the experiment. Tissues, including skin, intestine, liver, and blood, were subsequently collected for transcriptome sequencing. The results demonstrate that the astaxanthin-treatment group exhibited significantly enhanced body coloration alongside improved body length, body weight, and specific growth rate compared to the control group (p < 0.05). Specifically regarding the red–green value (a*), the treatment group showed significantly higher values on the ventral skin, dorsal skin, and gill cover (p < 0.05). The yellow–blue (b*) and lightness (L*) values were also significantly elevated in the ventral skin and gill cover (p < 0.05), although no significant differences were observed in the dorsal skin (p > 0.05). The skin was identified as the tissue with the highest total carotenoid content. Astaxanthin supplementation enhanced liver antioxidant capacity, evidenced by significantly elevated total superoxide dismutase (T-SOD) activity and significantly reduced malondialdehyde (MDA) levels in the treatment group (p < 0.05). Catalase (CAT) activity did not differ significantly between groups (p > 0.05). Transcriptomic analysis identified several coloration-associated genes, such as bco1, bco2, gstt1, and gstz1. It also revealed significant enrichment in key metabolic pathways (fatty acid, cholesterol, and retinol metabolism) and signaling pathways (PPAR and PI3K-Akt). Furthermore, the expression of multiple solute-carrier family members and apolipoproteins was detected, with notable enrichment in lipid digestion and absorption, cholesterol metabolism, and several key immune-related signaling pathways. These findings provide a theoretical basis for understanding the molecular mechanisms of carotenoid-mediated pigmentation in L. erythropterus. Full article

Di(2-ethylhexyl) phthalate (DEHP), a widely employed exogenous plasticizer, has become pervasive in the environment and living organisms due to its extensive use in food packaging, medical devices, and daily consumer products, and is established as a typical endocrine-disrupting chemical. Growing evidence indicates a strong association between DEHP exposure and the incidence of chronic bone disorders, including osteoporosis (OP), osteoarthritis (OA), and osteonecrosis of the femoral head (ONFH). However, the molecular mechanisms underlying its pathogenic effects across these diseases remain poorly defined. In this study, we applied an environmental network toxicology approach to integrate predicted protein targets of DEHP with known disease-associated targets of the three bone disorders using multiple databases. Through Venn analysis, protein–protein interaction (PPI) network construction, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, we identified core targets and key signaling pathways. Molecular docking and molecular dynamics (MD) simulations were further employed to validate the binding modes and stability between DEHP and the core targets, thereby elucidating common and distinct mechanisms of DEHP across these bone diseases. A total of 109 overlapping targets of DEHP and the three bone diseases were identified, among which 7 core targets—AKT1, SRC, ESR1, CASP3, MMP9, BCL2, and BCL2L1—were common to all three disorders. These are implicated in critical biological processes such as apoptosis regulation, inflammation, extracellular matrix degradation, and estrogen signaling. KEGG enrichment analysis revealed significant involvement of the PI3K-Akt, MAPK, Ras, TNF, and estrogen signaling pathways across all three diseases. Molecular docking and MD simulations confirmed stable binding of DEHP to key targets including AKT1, ESR1, and MMP9, supporting its potential to disrupt bone metabolic homeostasis via multi-target and multi-pathway mechanisms. Further analysis indicated that DEHP exerts both shared and disease-specific effects: it disrupts osteoblast/osteoclast balance in OP, amplifies inflammatory responses and matrix degradation in OA, and contributes to impaired angiogenesis and osteocyte necrosis in ONFH. This study systematically reveals how DEHP disrupts bone homeostasis through a multi-target and multi-pathway network, constructing a cross-disease osteotoxicity framework. It is the first to delineate the common and distinct molecular mechanisms of DEHP in OP, OA, and ONFH. Although these insights are derived from computational models and require further experimental validation, they provide a novel theoretical basis for combined intervention strategies targeting multiple bone diseases and for environmental health risk assessment. Full article

Vitamin homeostasis plays a critical role in inflammatory bowel disease management, yet the protective mechanisms and clinical utility of specific vitamins remain incompletely characterized. Within this context, a two-sample Mendelian randomization analysis leveraging genetic instruments for measuring circulating vitamin levels identified folate as a protective factor against ulcerative colitis (UC). To validate these findings, a DSS-induced colitis model was established with serial serum folate measurements. Therapeutic folate supplements were subsequently administered, followed by a comprehensive evaluation of epithelial barrier modulation through in vivo and recombinant TNF-α/IFN-γ-induced in vitro models. This included assessment of junctional proteins, ultrastructural analysis by transmission electron microscopy, and functional quantification of barrier integrity using transepithelial electrical resistance with paracellular permeability assays in epithelial monolayers. Molecular mechanisms were investigated through RNA sequencing complemented by immunoblot validation of key pathway components. The results demonstrated decreased serum folate levels in DSS-induced colitis mice, whereas folate supplementation ameliorated disease severity and attenuated intestinal inflammation and histopathological damage. Crucially, folate restored epithelial barrier structural integrity and function both in vivo and in vitro. Mechanistically, folate mediated barrier restoration through suppression of the PI3K/AKT/NF-κB/MLCK/MLC2 signaling axis. Collectively, the results of this study provide mechanistic insights that support the use of folate as an active therapeutic molecule in patients with UC. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed to treat type 2 diabetes mellitus, are now being investigated as agents in oncology. Recent preclinical studies have demonstrated their antitumor activity in several solid malignancies, including pancreatic, colorectal, breast, and prostate. Importantly, GLP-1 RAs modulate key signalling pathways such as PI3K/Akt, PKA, and AMPK, and exert anti-inflammatory effects by reducing cytokine production and macrophage infiltration. Preclinical data support their antineoplastic activity in vitro and in vivo, particularly by inhibiting tumour growth and metastasis. Nevertheless, there are ongoing concerns about tumorigenic effects in certain cancer types. This review critically examines the molecular mechanisms by which GLP-1 RAs influence cancer cell proliferation, apoptosis, angiogenesis, and inflammation, and emphasizes the need for further clinical studies to determine their therapeutic relevance. It also proposes assessing GLP-1 RAs as adjuncts in the management of solid tumours. Full article

Disuse-induced muscle atrophy (DMA), commonly resulting from immobilization, is driven by chronic inflammation and oxidative stress, which disrupts the balance between protein synthesis and degradation. Quinic acid (QA), a natural compound with known antioxidant and anti-inflammatory properties, was investigated for its potential to counteract muscle atrophy. Using a DMA-induced immobilization model in male C57BL/6N (8 weeks) mice, we found that oral QA administration significantly restored the weight and cross-sectional area of atrophic muscles and improved muscle function, as measured by grip strength and treadmill performance. QA also reduced the expression of pro-inflammatory cytokines (Tnf, Il6, and Myostatin) and E3 ubiquitin ligases (Trim63 and Fbxo32), while increasing antioxidant enzyme levels and serum IL-15 in DMA. In tumor necrosis factor-α-stimulated L6 myotubes, QA reversed inflammation- and oxidative stress-induced gene changes, suppressed NF-ĸB activation, and downregulated protein degradation pathways mediated by FoxO3α. Furthermore, QA restored the expression of myogenesis-related genes and reactivated PI3K/Akt and mTOR/p70S6K/4EBP1 signaling pathways, enhancing protein synthesis. Collectively, our findings demonstrate that QA mitigates immobilization-induced muscle atrophy by modulating inflammation, oxidative stress, and key anabolic and catabolic signaling pathways. These results suggest that QA is a promising functional compound for preserving skeletal muscle health under conditions of disuse. Full article

Insulin is a key anabolic hormone traditionally considered to be exclusively produced by pancreatic β-cells. Insulin exerts several systemic effects involved in glucose uptake and metabolism. In the retina, insulin signaling acts as a regulator of photoreceptor- retinal pigment epithelium (RPE) metabolic coupling as well as of neuronal survival via the PI3K/Akt and MAPK/ERK pathways. Impaired insulin signaling contributes to diabetic retinopathy, retinitis pigmentosa, and age-related degeneration by disrupting energy homeostasis and trophic support. However, growing evidence suggests that the retina, particularly RPE, locally synthesizes and secretes insulin. Although the role of local insulin production in the retina remains to be clarified, this discovery introduces a paradigm shift in retinal physiology, suggesting a self-sustaining insulin signaling system that supports glucose uptake, lipid metabolism, and neurovascular integrity. Emerging data indicate that RPE-derived insulin is stimulated by photoreceptor outer segment (POS) phagocytosis and may act through autocrine and paracrine mechanisms to maintain retinal function, even under conditions of systemic insulin deficiency. Understanding this extra-pancreatic insulin source opens new therapeutic perspectives aimed at enhancing local insulin signaling to preserve vision and prevent retinal degeneration. Thus, the objective of this review is to summarize current evidence on RPE-derived insulin and to discuss its potential implications for retinal homeostasis and disease. Full article

The complex bidirectional relationship between diabetes mellitus (DM) and oral cancer (OC) denotes that metabolic dysfunction and malignancy intersect at molecular, cellular, and systemic levels. This state-of-the-art review analyzes the most recent literature data on the multiple interconnected pathways linking DM and OC, including hyperinsulinemia/IGF-1 signaling, chronic hyperglycemia-induced cellular damage, persistent inflammation, immune dysfunction, and oral microbiota dysbiosis. These mechanisms create a permissive environment for oral carcinogenesis while simultaneously impairing the body’s natural tumor surveillance systems. Key molecular networks explored include the PI3K/AKT/mTOR pathway, AGE-RAGE interactions, NF-κB signaling, the p53 tumor suppressor pathway, and HIF-mediated responses. Clinical evidence demonstrates that patients with diabetes have higher OC prevalence (250 per 100,000 patients) and significantly increased mortality (HR of 2.09) compared to non-diabetics. The review highlights metformin as the most promising anti-diabetic agent for OC management, showing anti-tumor effects through mTOR inhibition. Novel therapeutics, such as GLP-1 agonists, particularly semaglutide, may be helpful but require further clinical validation. Understanding the shared molecular pathways enables the development of integrated therapeutic strategies that target both conditions simultaneously, and it supports effective screening programs, personalized prevention strategies, and optimized multidisciplinary management approaches for this high-risk patient population. Full article

Phytochemicals are plant-derived bioactive compounds with antioxidant, anti-inflammatory, and epigenetic modulatory effects that may contribute to the prevention and management of chronic diseases. This review synthesizes recent evidence on the molecular mechanisms through which phytochemicals influence oxidative stress, inflammatory signaling, and epigenetic regulation. A targeted literature search of the PubMed and Web of Science databases (2015–2025) identified over 400 experimental and review studies investigating phytochemicals with documented antioxidant and epigenetic activities. Eligible articles were selected based on relevance to oxidative stress, inflammation, and DNA or histone modification pathways in chronic diseases. Data were qualitatively analyzed to highlight mechanistic links between redox balance, transcriptional regulation, and disease modulation. The results indicate that several phytochemicals, including hesperidin, phloretin, lycopene, and silybin, modulate signaling cascades—NF-κB, Nrf2, and PI3K/Akt—while also influencing DNA methylation and histone acetylation to restore gene expression homeostasis. Despite strong in vitro and in vivo evidence, translation to clinical practice remains limited by low bioavailability, lack of standardized formulations, and insufficient human trials. Future research should prioritize integrative study designs linking molecular mechanisms to clinical endpoints. Understanding the epigenetic actions of phytochemicals may guide the development of nutraceutical strategies for chronic disease prevention. Full article

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumour with limited treatment options and a poor prognosis. Hypoxia, a hallmark of solid tumours, contributes to therapeutic resistance and tumour progression. Gastrin-releasing peptide receptor (GRPR) is known to be overexpressed in SCLC; however, its regulation under hypoxic conditions is not well described. In this study, we demonstrate that hypoxia significantly enhances GRPR expression in SCLC cell lines, COR-L24 and DMS79, as confirmed by Western blot, immunofluorescence, and flow cytometric analysis of binding with fluorescein isothiocyanate–labelled bombesin (BBN-FITC), a known GRPR ligand. To exploit this upregulation, we synthesised a previously discovered butylated neuropeptide antagonist (BU peptide) using a new method of solid-phase peptide synthesis (SPPS) by Boc chemistry and evaluated its therapeutic potential. BU peptide exhibited potent, dose-dependent cytotoxicity in both cell lines, with significantly greater efficacy under hypoxic conditions compared to normoxia. Mechanistic studies revealed that BU peptide inhibits GRP–GRPR-mediated activation of the PI3K/Akt and MAPK/ERK signalling pathways, known to be key regulators of tumour cell survival and proliferation. Moreover, BU peptide induced robust caspase 3/7-mediated apoptosis, especially under hypoxic conditions. These findings suggest that GRPR is a hypoxia-inducible target in SCLC and demonstrate that a synthetically optimised BU peptide antagonist exerts selective efficacy against hypoxic tumour cells, outperforming conventional chemotherapy agents. These findings provide new mechanistic insights into SCLC and suggest translational potential to inform the development of future treatment strategies for this and other hypoxia-driven malignancies. Full article