Search Results (944)

Background and Objectives: Cancer cachexia is a debilitating metabolic syndrome highly prevalent in colorectal cancer (CRC), characterized by progressive skeletal muscle wasting. The myostatin–FOXO signaling pathway contributes to this process by activating the E3 ubiquitin ligases MuRF-1 and Atrogin-1. Exercise is a promising non-pharmacological strategy, but its effects on this pathway in CRC cachexia remain unclear. This review aimed to synthesize preclinical evidence on the impact of exercise on the myostatin–FOXO axis. Materials and Methods: A comprehensive search was performed in PubMed/MEDLINE, Scopus, Web of Science, and Science Direct from inception through August 2025. Eligible studies included murine CRC models (C26 or Apc^Min/+) exposed to aerobic, resistance, or combined exercise interventions, with outcomes assessing myostatin, FOXO, MuRF-1, or Atrogin-1. Study quality was appraised using the CAMARADES 10-item checklist. Results: eleven studies met the criteria, with quality scores ranging from 6 to 8. Aerobic exercise, particularly voluntary wheel running, most consistently reduced MuRF-1 expression and systemic inflammation, whereas resistance and eccentric training exerted stronger inhibitory effects on FOXO and Atrogin-1. Myostatin was directly measured in two studies, yielding inconsistent results. Resistance and eccentric training promoted anabolic signaling (e.g., mTORC1), whereas aerobic protocols improved oxidative capacity. Variability in exercise type, intensity, and duration contributed to heterogeneity across findings. Conclusions: Exercise attenuates skeletal muscle catabolism in CRC-induced cachexia, mainly through modulation of the myostatin–FOXO pathway and downstream ligases. However, limited direct data on myostatin and methodological heterogeneity underscore the need for standardized protocols and translational studies. This review provides the first focused synthesis of exercise-mediated regulation of this pathway in CRC cachexia. Full article

Cadmium (Cd), an environmental toxin, may cause neurological disorders. We studied the role and activation mechanism of FoxO3a in Cd-induced oxidative stress. In addition to oxidative stress, Cd activated the antioxidant defense system in neuronal cells. Furthermore, by using Western blot and confocal microscopy, we found that Cd induced nuclear expression of FoxO3a. Importantly, knockdown of FoxO3a significantly suppressed its target SOD2 protein expression and elevated the level of intracellular ROS, ultimately reducing cell viability in Cd-exposed neuronal cells. These results suggest the protective effect of FoxO3a is associated with oxidative stress resistance. Then, we investigated the activation mechanism of FoxO3a. Our results indicate that the nuclear expression of FoxO3a by Cd may be independent of Akt, which is generally regarded as an important negative regulator of FoxO3a. Furthermore, we found that p38 regulated the nuclear expression of FoxO3a in Cd-exposed cells. Finally, we demonstrate that the p38-FoxO3a pathway inhibits Cd-induced oxidative stress. These signaling molecules may be used as a novel biological marker of Cd-induced oxidative stress and provide potential therapeutic approaches for it. Full article

Cancer progression is primarily driven by disruptions in critical biological pathways, including ErbB signaling, p53-mediated apoptosis, and GSK3 signaling. However, experimental and clinical studies typically identify only limited disease-associated genes, challenging traditional pathway analysis methods that require larger gene sets. To overcome this limitation, reliably expanded gene sets are required to align with cancer-related pathways. Although various propagation methods are available, the key challenge is to select techniques that can effectively propagate signals from limited seed gene sets through protein interaction networks, thereby generating robust, expanded sets capable of revealing pathway disruptions in cancer. In this study, the number of seed genes was systematically varied to evaluate the alignment of pathways obtained from different propagation methods with known pathways using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations. Among the evaluated propagation methods, normalized Laplacian diffusion (NLD) demonstrated the strongest alignment with reference pathways, with an average area under the ROC curve (AUC) of 95.11% and an area under precision–recall (AUPR) of 71.20%. Focusing specifically on well-established cancer pathways, we summarized the enriched pathways and discussed their biological relevance with limited gene input. Results from multiple runs were aggregated to identify genes consistently prioritized but absent from core pathway annotations, representing potential pathway extensions. Notable examples include RAC2 (ErbB pathway), FOXO3 and ESR1 (GSK3 signaling), and XIAP and BRD4 (p53 pathway), which were significantly associated with patient survival. Literature validation confirmed their biological relevance, underscoring their potential as prognostic markers and therapeutic targets. In summary, NLD-based diffusion proves effective for pathway discovery from limited input, extending beyond annotated members to reveal clinically relevant genes with therapeutic and biomarker potential. 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

Background/Objectives: Semen Ziziphi Spinosae (SZS), a medicinal and edible traditional Chinese herb, has been widely used to treat insomnia. As critical regulators of the central nervous system, astrocytes play a pivotal role in maintaining sleep homeostasis. However, the mechanisms by which SZS modulates astrocytic function to improve sleep remain unclear. Methods: In this study, we employed an integrated transcriptomics and metabolomics approach to investigate the protective effects of SZS extract against lipopolysaccharide (LPS)-induced inflammatory injury and metabolic dysfunction in astrocytes. Results: Transcriptomic analysis revealed that SZS ameliorates cellular damage (including apoptosis, autophagy, and cell cycle dysregulation) through a FOXO3-centric signaling network. Concurrently, SZS restored cellular energy metabolism by increasing ATP production and reducing Ca²⁺ overload, thereby activating the AMPK signaling pathway to support normal astrocytic function. Metabolomic profiling further demonstrated that SZS-mediated restoration of energy homeostasis sustains ABC transporter activity, which in turn modulates neurotransmitter (serotonin, L-glutamic acid, adenosine), metabolic mediators (leukotrienes, palmitoylethanolamide, succinic acid), and nucleotide (uridine 5′-diphosphate). These coordinated changes normalized GABAergic synapse activity and neuroactive ligand receptor interactions, ultimately resolving neural metabolic network disturbances. Conclusions: Our findings elucidate a novel FOXO3-energy metabolism-ABC transporter axis through which SZS extract attenuates neuroinflammation and metabolic dysfunction in astrocytes and exerts sleep-promoting and neuroprotective effects. This study provides a scientific foundation for understanding the modern pharmacological mechanisms of traditional Chinese medicine in insomnia treatment, highlighting astrocytic regulation as a potential therapeutic target. Full article

Background: FDA-approved artificial sweeteners (ASs) are widely used in food products due to their low-calorie content and high sweetness. However, growing evidence links them to adverse metabolic effects, including stroke and coronary heart disease. The musculoskeletal system, as a key metabolic target organ, has gradually gained attention, but the potential impact of ASs on its health remains unclear. Objective: This systematic review aims to assess the effects of ASs on bone and muscle, explore the underlying biological mechanisms and provide guidance for future research. Methods: A comprehensive literature search was conducted in PubMed, Embase, and Web of Science using relevant keywords from inception to 25 June 2025. Studies written in English, available in full text, and investigating FDA-approved ASs in relation to the musculoskeletal system were included. Two independent reviewers screened and selected the eligible studies. The findings were summarized using a narrative synthesis approach. Results: A total of 15 studies (12 preclinical, 3 clinical), covering aspartame, acesulfame potassium, sucralose, and saccharin were included from an initial pool of 662 articles identified across PubMed (168), Embase (368), and Web of Science (126). Among them, twelve studies focused on skeletal effects, four on muscles, and two on joints; three studies reported multiple outcomes. No studies investigated ligaments or tendons. Conclusions: Based on our search, this review provides a narrative synthesis of the available evidence on ASs influencing skeletal structure, development, biomechanical strength, and skeletal muscle metabolism. Potential mechanisms involve gut microbiota, oxidative stress, and signaling pathways such as SIRT1/FOXO3a and PGC-1α/UCP3. Further research is warranted to clarify these mechanisms and to assess the chronic health effects of long-term AS exposure on the musculoskeletal system in human populations. Full article

Glucocorticoid therapy, using agents like dexamethasone (Dexa), often leads to muscle atrophy by increasing protein degradation via the ubiquitin–proteasome system while suppressing protein synthesis. Stigmasterol, a phytosterol with known bioactivities, has an unexplored role in muscle atrophy. This study investigated stigmasterol’s protective effects against Dexa-induced muscle atrophy and its impact on the FoxO3 and mTORC1 signaling pathways. Differentiated C2C12 myotubes were treated with Dexa (50 µM) ± stigmasterol (10 µM), and the morphology, viability, and protein levels in the FoxO3/MuRF1/MAFbx catabolic and mTOR/p70S6K/4E-BP1 anabolic signaling pathways were assessed. C57BL/6 mice received Dexa (20 mg/kg/day i.p.) ± stigmasterol (3 mg/kg/day oral) for 21 days, and the body/muscle mass, bone mineral density (BMD), fiber cross-sectional area (CSA), and muscle protein expression were measured. Stigmasterol (10 µM) was non-toxic and attenuated Dexa-induced reductions in myotube diameter and fusion in vitro, concurrent with suppressing Dexa-induced upregulation of FoxO3/MuRF1/MAFbx proteins and preventing the Dexa-induced dephosphorylation of mTOR/p70S6K/4E-BP1 proteins. In vivo, stigmasterol mitigated Dexa-induced losses in body weight, muscle mass, BMD, and fiber CSA. This protection was associated with attenuated upregulation of FoxO3 and MAFbx proteins in muscle tissue. Stigmasterol protected against Dexa-induced muscle atrophy in vitro and in vivo via modulation of the FoxO3–MAFbx catabolic pathway. These findings suggest stigmasterol inhibits excessive glucocorticoid-induced muscle protein breakdown. It therefore warrants further investigation as a potential therapeutic agent for glucocorticoid myopathy. Full article

Breast cancer is the most common malignancy in women, with the Luminal A subtype generally associated with favorable survival. However, age and menopausal status may influence tumor biology and prognosis. To improve prediction beyond conventional models, we analyzed transcriptomic and clinical data from the METABRIC cohort. Patients with Luminal A breast cancer were stratified into premenopausal, postmenopausal–nongeriatric, and geriatric (≥70 years) groups. Differentially expressed genes (DEGs) were identified, and Boruta feature selection revealed 27 clinical and genomic variables. Random Forest, Logistic Regression, Multilayer Perceptron, and ensemble XGBoost models were trained with stratified 5-fold cross-validation, using SMOTE to correct class imbalance. Principal component analysis showed distinct clustering across age groups, while DEG analysis revealed 41 genes associated with age and survival. Key predictors included clinical variables (age, tumor size, NPI, radiotherapy) and molecular markers (ATM, HERC2, AKT2, FOXO3, CYP3A43). Among ML models, XGBoost demonstrated the highest performance (accuracy 98%, sensitivity 98%, specificity 97%, F1-score 0.99, AUC 0.86), outperforming other algorithms. These findings indicate that age-related transcriptomic changes impact survival in Luminal A breast cancer and that an ML-based integrative approach combining clinical and molecular variables provides superior prognostic accuracy, supporting its potential for clinical application. Full article

Human infertility represents a multifaceted condition, with oxidative stress (OS) and microRNAs (miRNAs) emerging as key contributors to its pathophysiology. This comprehensive review explores the complex interplay between reactive oxygen species (ROS) and miRNAs in male and female reproductive dysfunctions. ROS overproduction damages DNA, lipids, and proteins, impairing sperm quality and oocyte maturation. In males, OS is a leading cause of infertility, especially in conditions like varicocele, where key miRNAs such as miR-21, miR-34a, and miR-155 are dysregulated. In females, oxidative imbalance affects granulosa cells and follicular environments in disorders such as PCOS, premature ovarian insufficiency (POI), and endometriosis. Several miRNAs (e.g., miR-132-3p, let-7, miR-642a-5p) regulate mitochondrial function, steroidogenesis, and apoptosis through redox-sensitive signaling pathways (PI3K/Akt, NF-κB, FOXO1). Their altered expression in ovarian and seminal environments correlates with poor reproductive outcomes. Emerging evidence supports their potential role as diagnostic biomarkers and therapeutic targets, although most findings are based on animal models or in vitro studies. This review highlights the therapeutic potential of miRNA modulation and calls for further clinical research to validate miRNA-based interventions. Ultimately, understanding the miRNA–OS nexus offers promising avenues for improving diagnosis, prognosis, and treatment of infertility across both sexes. Full article

Galectin-3 (Gal-3) is a histologic marker of pancreatic cancer and a potential therapeutic target. This study aimed to characterize a novel sulfated agarose-derived oligosaccharide (DP9) from marine algae, Gracilaria lemaneiformis, evaluate its Gal-3 inhibitory activity, and investigate its anti-pancreatic cancer mechanisms. Through controlled acid hydrolysis, a series of odd-numbered oligosaccharides (DP3-11) were obtained, in which DP9 showed the strongest Gal-3 inhibition in hemagglutination assays. Structural analysis confirmed DP9’s unique composition including an alternating β (1→4)-D-galactose and α (1→3)-3,6-anhydro-L-galactose backbone, featuring partial 6-O-methylation on β-D-galactose and 6-O-sulfation on 3,6-anhydro-α-L-galactose residues. Molecular docking revealed DP9’s binding to Gal-3’s carbohydrate recognition domain through key hydrogen bonds (His158, Arg162, Lys176, Asn179 and Arg186) and hydrophobic interactions (Pro117, Asn119, Trp181 and Gly235), with the sulfate group enhancing binding affinity. In vitro studies demonstrated DP9’s selective anti-pancreatic cancer activity against BxPC-3 cells, including inhibition of cell proliferation; S-phase cell cycle arrest; induction of apoptosis; and suppression of migration and invasion. Mechanistically, DP9 attenuated the Gal-3/EGFR/AKT/FOXO3 signaling pathway while showing minimal cytotoxicity to normal cells. This study first demonstrated that agarose-derived odd-numbered oligosaccharides (DP9) can serve as effective Gal-3 inhibitors, which proved its potential as a marine oligosaccharide-based therapeutic agent for pancreatic cancer. Full article

Follicular atresia is mainly driven by the oxidative stress-induced apoptosis of granulosa cells (GCs). Oxidative stress mediated by H₂O₂ is the predominant form of stress in cells and plays a key role in the death of porcine GCs. In the present study, using integrated transcriptomic and untargeted metabolomic approaches, we explored the mechanisms underlying the regulation of oxidative stress in porcine follicular GCs. Per the transcriptomic analysis, compared with the control group, we identified 328 differentially expressed mRNAs (260 upregulated, 68 downregulated) in the H₂O₂-treatment group; these mRNAs were significantly enriched in apoptosis-related pathways, including the tumour necrosis factor (TNF) and p53 signalling pathways. Furthermore, via untargeted metabolomic analysis, we identified 150 differentially expressed metabolites (101 positive, 49 negative). The pathways associated with protein digestion and absorption, glycine, serine, and threonine metabolism, amino acid biosynthesis, and carbon metabolism were enriched with these metabolites. The integrated transcriptomic and metabolomic analyses revealed taurine, creatine, L-serine, and hypoxanthine as the key metabolites under H₂O₂-induced oxidative stress. Both the differential genes and metabolites were notably enriched in the FOXO and mineral absorption pathways. In the present study, we elucidated the regulatory mechanism underlying H₂O₂-induced oxidative stress in porcine follicular GCs via transcriptomic and metabolomic analyses. Our findings offer novel insights into the alleviation of oxidative stress in GCs. Full article

Sirtuin 1 (SIRT1), an NAD⁺-dependent histone deacetylase, exerts complex and context-dependent effects in breast and gynecological cancers. By deacetylating histone and non-histone proteins such as p53, FOXO, and NF-κB, SIRT1 regulates essential processes including DNA repair, apoptosis, metabolism, and stress response. In breast cancer, SIRT1 may act as a tumor suppressor in early stages by maintaining genomic stability but promotes epithelial–mesenchymal transition, metastasis, and chemoresistance in aggressive subtypes such as triple-negative breast cancer. Similarly, in gynecological cancers, SIRT1 displays dual roles: promoting proliferation via estrogen signaling and p53/FOXO1 inhibition in Type I endometrial cancer yet potentially supporting DNA repair in high-grade Type II tumors. Its overexpression in ovarian and cervical cancers is linked to enhanced survival and drug resistance. Preclinical studies show that pharmacological inhibition of SIRT1 (e.g., with EX-527 or cambinol) restores chemosensitivity and reduces tumor cell viability, suggesting potential for SIRT1 inhibitors as adjuncts in cancer therapy. However, clinical trials specifically targeting SIRT1 in these cancers remain limited. Further investigation is needed to define therapeutic windows, molecular contexts, and combination strategies that could optimize SIRT1-targeted therapies. This review summarizes the current understanding of SIRT1’s roles in breast and gynecologic malignancies. Full article

Sarcopenia, characterized by progressive skeletal muscle mass, strength, and functional loss, imposes a substantial global health burden. Irisin, a myokine derived from fibronectin type III domain-containing protein 5 (FNDC5), is critical for muscle health. Here, we investigate its role in mitigating glucocorticoid-induced sarcopenia using a mouse and C2C12 myotubes model. We quantified FNDC5/irisin levels in skeletal muscle and plasma and assessed muscle function (body weight, grip strength, wire-hanging, and locomotor activity), histology, and mitochondrial features following irisin administration to dexamethasone-treated mice. Western blot analyzed synthesis/hydrolysis regulators, apoptosis markers, and mitochondrial regulators in mouse muscle tissues and C2C12 myotubes. The results show that FNDC5/irisin was significantly downregulated in sarcopenic mice and atrophic C2C12 myotubes; exogenous irisin rescued muscle mass loss and functional impairment, improving body weight, muscle mass, grip strength, and mobility. Mechanistically, irisin bound SIRT1 with −12.7 kcal/mol affinity, activating a deacetylation cascade that suppressed FoxO3a transcriptional activity (attenuating proteasomal degradation) and enhanced mTORC1-mediated protein synthesis in C2C12 myotubes. Additionally, irisin potentiated PGC-1α signaling in mouse myocytes, promoting mitochondrial biogenesis and restoring contractile function in dystrophic fibers. Collectively, these findings demonstrate irisin alleviates glucocorticoid-induced muscle atrophy via SIRT1-dependent pathways, rebalancing muscle physiology and systemic energy homeostasis. This highlights irisin-based therapeutics as a promising exercise surrogate for sarcopenia management, offering novel clinical avenues. Full article

The novel hybrid fish BTB, derived from crossing blunt snout bream (Megalobrama amblycephala, BSB) and topmouth culter (Culter alburnus, TC), exhibits markedly hypoxia tolerance in aquaculture. In this study, hypoxic treatment experiments confirmed that, comparing to its original parent BSB, the tolerance to low oxygen of BTB increased by 20.0%. Furthermore, a comparative analysis of the transcriptome and metabolome was performed using gill tissues from BTB exposed to normoxic and hypoxic conditions. Under hypoxic conditions, BTB displayed adaptive modifications in gill lamellae and hemocytes. Transcriptomic profiling identified 789 differentially expressed genes (DEGs), with 298 upregulated and 491 downregulated, enriched in pathways including apoptosis, NK cell-mediated cytotoxicity, MAPK/TNF/Toll-like receptor signaling, and HIF-1/FoXO signaling pathways. Twelve hypoxia-related candidate genes (egln3, im_7150988, znf395a, hif-1an, mknk2b, pck2, ero1a, igfbp-1a, vhl, bpifcl, egln1a, and ccna1) were screened and validated as potential contributors to hypoxia tolerance. Metabolomics analysis revealed a total of 108 differential metabolites (78 upregulated and 30 downregulated), predominantly linked to Arginine and proline metabolism, Ether lipid metabolism, Arachidonic acid metabolism, and Glycerophospholipid metabolism. Association analysis of transcriptomics and metabolomics revealed that the DEGs and DMs were enriched in the pathways of glycerophospholipid metabolism, ether lipid metabolism, arachidonic acid metabolism, and arginine and proline metabolism. In summary, BTB exhibited relatively high hypoxia tolerance, and 12 candidate genes related to hypoxia tolerance were identified. These findings laid a foundation for further investigation into the mechanisms of hypoxia tolerance improvement in hybrid fish. Full article

Glucagonoma, a rare neuroendocrine tumor, lacks targeted treatment drugs. Excessive secretion of glucagon is the main cause of its clinical syndrome. To explore targeted therapeutic drugs that can inhibit glucagon secretion and tumor proliferation, we investigated the effect of Trametenolic Acid (TA) on mouse pancreatic alpha TC1 clone 6 (αTC1-6) cells and its regulatory role in the PI3K/AKT signaling pathway. Cell viability of αTC1-6 cells was assessed via the MTT assay. Glucagon content in cell culture supernatants was measured using an Enzyme-Linked Immunosorbent Assay (ELISA). Autophagic vacuoles were visualized through Monodansylcadaverine (MDC) staining. The expression of autophagy-related proteins including Atg7, LC3 Ⅱ and PI3K/AKT signaling pathway-related proteins mTOR and FoxO1 were determined by Western blot. The results showed that the proliferation of αTC1-6 cells was significantly inhibited by TA in a dose- and time-dependent manner, and the IC₅₀ was 140.71, 26.77 and 1.99 μM after treatment of 12, 24, and 48 h, respectively. The secretion of glucagon was significantly inhibited by TA. The MDC staining results showed that the fluorescent labeled autophagic vesicles in the TA group were increased. The Western blot results showed that the expression of Atg7 and LC3 Ⅱ was promoted by TA in a dose-dependent manner, the phosphorylation of PI3K, AKT, mTOR and FoxO1 was significantly inhibited, and the expression of FoxO1 protein was increased. These results demonstrated that TA can inhibit glucagon secretion, induce autophagy, and suppress cell proliferation in αTC1-6 cells. The mechanism may be associated with the PI3K/AKT signaling pathway. Full article