Search Results (1,118)

Background: Cadmium (Cd) exposure impairs the autophagic response, a core mechanism for cell preservation and organismal homeostasis, eventually resulting in metabolic disturbances, mitochondrial dysfunction, and oxidative stress. L-theanine (LT) exhibits multiple health benefits with a high safety profile. However, the effects of LT on Cd exposure-induced impairments in autophagy and autophagy-related physiological functions remain unclear. Methods: This study investigated the effects of LT on the survival time of mice acutely exposed to Cd and the regulating effect of LT on autophagy and subsequent metabolic dysfunction in mice subjected to subchronic Cd exposure. Results: The results showed that acute Cd exposure resulted in 100% mortality within 8 h. However, LT treatment significantly prolonged the median survival time of mice from 4 h to 16 h and reduced the mortality to 60%. In the context of subchronic Cd exposure, autophagy was inhibited, as evidenced by the downregulation of the AMPK/mTOR signaling pathway mediated by DPP-4 and SIRT1. This exposure also promoted lipid peroxidation and ferroptosis, indicated by the inactivation of the AMPK/p-ACC axis and marked alterations in ferroptosis markers. Furthermore, mitochondrial dysfunction was suggested by the downregulation of the SIRT1/PGC-1α/Nrfs/TFAM signaling pathway and reductions in COX and SDH activities. Additionally, glucolipid metabolism was impaired, as indicated by the downregulation of the AMPK and PI3K/AKT signaling pathways and elevated lipid and glycogen accumulation in the liver of mice. LT significantly decreased the level of DPP-4 and upregulated SIRT1, leading to the activation of AMPK. This activation restored autophagy response by downregulating mTOR, promoted energy homeostasis by reducing lipid biosynthesis and enhancing fatty acid oxidation, blocked lipid peroxidation and ferroptosis through the phosphorylation of ACC at the serine 79 site and reducing the ubiquitination-mediated degradation of GPX4, and maintained mitochondrial function by upregulating the PGC-1α/Nrfs/TFAM signaling pathway. Conclusions: Collectively, LT effectively ameliorates mitochondrial dysfunction, ferroptosis and glucolipid dysmetabolism in Cd-exposed mice, and these effects are accompanied by findings consistent with modulation of autophagy-related signaling in the liver. Full article

Aging and glycative stress are major, interrelated drivers of skeletal fragility, yet the extent to which they act through shared versus distinct biological pathways remains poorly defined, limiting integrated therapeutic strategies. This review compares the convergent and divergent mechanisms by which aging and glycative stress affect osteocytes, osteoblasts, and osteoclasts, extracellular matrix properties, and bone mechanotransduction. Both conditions converge on oxidative stress, mitochondrial dysfunction, chronic low-grade inflammation, cellular senescence, impaired autophagy, NLRP3 inflammasome activation, and ferroptosis, ultimately reducing osteocyte viability and disrupting RANKL/OPG-mediated remodeling. They diverge in their primary drivers: Aging is characterized by hormonal decline, stem-cell exhaustion, and progressive loss of bone mass and microarchitecture, whereas glycative stress acts through AGE–RAGE signaling and collagen cross-linking, compromising bone quality and mechanosensitivity while often preserving bone mineral density, explaining the disproportionate fracture risk seen in diabetes. Since current anabolic and anti-resorptive therapies do not specifically target AGE-related pathways, combined strategies incorporating senolytic, antiglycative, and mechanoprotective approaches—alongside lifestyle interventions—may be needed to more effectively reduce fracture risk in aged and diabetic populations. Full article

GLP-1RAs improve glycemia and body weight, but their effects extend beyond insulin secretion and appetite suppression. Experimental evidence indicates that GLP-1 receptor signaling can relieve lipotoxic stress by reducing lipid influx, restoring lipid trafficking, promoting cholesterol efflux, improving mitochondrial and endoplasmic reticulum homeostasis, and suppressing inflammatory and apoptotic signaling. In pancreatic beta cells, saturated fatty acids, oxidized low-density lipoprotein and excess free cholesterol disrupt membrane microdomains, insulin-granule trafficking, calcium signaling, autophagic flux and beta-cell identity. Preclinical studies with individual GLP-1RAs, principally exendin-4 and liraglutide, implicate cAMP/PKA, PI3K/Akt, ERK1/2, AMPK, Nrf2 and autophagy-related pathways in these protective responses. A relevant mechanism is induction of ATP-binding cassette transporter A1 (ABCA1): exendin-4 stimulates ABCA1 transcription through the CaMKK/CaMKIV/PREB axis, linking incretin signaling to cholesterol export and preservation of glucose-stimulated insulin secretion. Recent work indicates spatially organized GLP-1R signaling at endoplasmic reticulum–mitochondria contact sites. Preclinical genetic evidence in mouse metabolic dysfunction-associated steatohepatitis (MASH) models indicates that pericentral liver sinusoidal endothelial GLP-1 receptors contribute to weight-loss-independent semaglutide-mediated improvements in steatosis, fibrosis and immune remodeling; whether an analogous causal mechanism operates in human MASH remains unknown. This review integrates systemic nutrient unloading, beta-cell cholesterol homeostasis and intrahepatic endothelial signaling as complementary mechanisms of metabolic protection. Full article

Organismal aging is not inevitable in multicellular animals, as early-branching metazoan lineages, such as cnidarians, display negligible senescence under defined conditions, despite conserved cellular pathways. Contrasting longevity phenotypes in Hydra species reveal distinct regulatory mechanisms underlying aging. A comparison between Hydra vulgaris and Hydra oligactis suggests that sustained telomerase activity, autophagy regulation, and microbiome stability in H. vulgaris are associated with stem cell renewal and long-term tissue homeostasis, whereas cold-induced stress in H. oligactis is accompanied by a disruption of these pathways, leading to rapid somatic decline, where autophagy dysfunction and microbiome dysbiosis may act as contributing or amplifying factors. Environmental sensing via conserved pathways may integrate these regulatory mechanisms. These observations suggest that aging in early-branching metazoans is a regulated, context-dependent process characterized by substantial lineage-specific variation rather than an inevitable, universal consequence of cellular senescence. Further mechanistic studies may provide evolutionary insights into longevity mechanisms and identify potential targets for modulating aging, although direct experimental validation remains necessary. Full article

Mitophagy is a selective form of autophagy, essential to maintain cellular homeostasis by removing damaged and dysfunctional mitochondria. Several lines of evidence suggest that defective mitophagy is associated with various diseases, including breast cancer. Disruption of mitochondrial quality control contributes to the production of reactive oxygen species, causing DNA damage and consequently tumorigenesis. Moreover, mitophagy contributes to the regulation of other mechanisms implicated in tumor progression, such as metabolic adaptability, maintenance of stem-like properties, and metabolic remodeling of immune cells. In breast cancer, the role of mitophagy is context-dependent, with evidence suggesting it can both suppress or promote breast cancer depending on tumor stage, tumor microenvironment, or molecular profile. For this reason, while targeting mitophagy represents a promising therapeutic strategy in breast cancer, additional investigation is required to clarify its complex role and how mitophagy modulation can be effectively translated into treatment strategies. This review aims to report on the main evidence on the role of mitophagy in breast cancer, exploring mitophagy-targeted approaches in order to potentially overcome drug resistance in breast cancer. Full article

Tumour hypoxia significantly influences disease advancement and treatment resistance in oral squamous cell carcinoma (OSCC). Hypoxia-inducible factor-1α (HIF-1α) is preserved when oxygen is lacking and triggers the expression of hypoxia-responsive genes that have roles in angiogenesis, metabolic adaptability, tumour cell viability, invasion, and metastasis. The elevated levels of vascular endothelial growth factor (VEGF) induced by HIF-1α result in atypical angiogenesis. The dysfunction of cell junction proteins and heightened activity of matrix metalloproteinases caused by hypoxia facilitate cancer invasion and metastasis. Hypoxic stress prompts cellular modifications, including autophagy and the preservation of cancer cell populations with enhanced survival capabilities, hence facilitating tumour recurrence and heterogeneity. Hypoxia diminishes the effectiveness of standard chemotherapy and radiotherapy due to decreased drug transport, hindered cell growth, and diminished oxygen-dependent radiation-induced DNA damage. Thus, treatment strategies for the hypoxic tumour microenvironment encompass the suppression of HIF and VEGF, tumour reoxygenation, hypoxia radiosensitizers, and hypoxia-activated lethal compounds. Nonetheless, the diverse and fluctuating characteristics of tumour hypoxia, along with the initiation of compensatory survival mechanisms, continue to pose significant obstacles. Enhanced comprehension of hypoxia-induced molecular networks and the advancement of multimodal, biomarker-directed treatment strategies could improve outcomes in OSCC. Full article

Prolonged exposure to 1,2-dichloroethane (1,2-DCE) can lead to cognitive dysfunction, and neuronal loss is a proven key driver. In mice, 1,2-DCE exposure reduced hippocampal ATP levels, triggering AMPK phosphorylation, mTOR suppression, and ULK1 activation, along with increased Beclin 1 and LC3-II/I levels, collectively indicating enhanced autophagy initiation. Meanwhile, p62 accumulation and decreased LAMP1 and CTSD expression indicated impaired autophagic degradation, accompanied by increased neuronal apoptosis. Consistent with these in vivo findings, PC12 cells, a neuron-like cell line, exhibited mitochondrial dysfunction after exposure to 2-chloroethanol (2-CE, a metabolite of 1,2-DCE in vivo), as evidenced by ATP depletion, mitochondrial membrane potential loss, and elevated ROS production. Furthermore, 2-CE activated the AMPK-mTOR-ULK1 signaling pathway to initiate autophagy, while also disrupting lysosomal structure and function, leading to impaired autophagic flux and enhanced apoptosis. In conclusion, prolonged 1,2-DCE exposure induces mitochondrial dysfunction and ATP depletion, activating AMPK-mTOR-ULK1-mediated autophagy initiation. Meanwhile, concomitant lysosomal damage impairs autophagic degradation, and the combined effect promotes neuronal apoptosis. These findings suggest a potential strategy for preventing and treating 1,2-DCE-induced cognitive impairment. Full article

Pseudomonas aeruginosa (PA) is a formidable environmental pathogen. It causes severe and refractory bovine mastitis. The escalating threat of antimicrobial resistance requires new non-antibiotic therapies. These alternative therapies should focus on targeting host-directed responses. Sodium butyrate (SB) is a prominent short-chain fatty acid. It possesses potent immunomodulatory properties. However, its protective mechanisms against PA-induced mammary injury remain elusive. This study investigated the efficacy and underlying molecular mechanisms of SB. bMECs were pretreated with 0.5 mmol/L SB for 18 h prior to challenge with P. aeruginosa (1 × 10⁷ CFU/mL, 6 h). We evaluated its ability to alleviate PA-induced cytotoxicity in bovine mammary epithelial cells (bMECs). Flow cytometry and ELISA demonstrated the strong protective effects of SB. SB pretreatment significantly reduced PA-induced cellular apoptosis. It also suppressed the hypersecretion of pro-inflammatory cytokines, including IL-6 and TNF-α. Next, transcriptomic sequencing (RNA-seq) was performed. We identified 589 differentially expressed genes (DEGs) between the PA-challenged and SB-treated groups. These DEGs were significantly enriched in the Toll-like receptor (Tlr), Mapk, and autophagy signaling pathways. We subsequently conducted molecular validations via RT-qPCR, Western blotting, and immunofluorescence. The results revealed that SB significantly suppressed the overactivation of the TLR4/MAPK cascade. Specifically, SB significantly downregulated the expression of TLR4. It also decreased the downstream phosphorylation levels of p38, ERK, and JNK. Furthermore, PA infection induced a severe blockade of autophagic flux. This dysfunction was evidenced by the concurrent cellular accumulation of LC3-II and the autophagic substrate p62. Remarkably, SB intervention was associated with the reduction in autophagic marker accumulation, evidenced by facilitated lysosomal clearance of p62. Collectively, sodium butyrate protects bMECs against PA-induced inflammation and apoptosis. These protective effects are closely associated with the suppression of the TLR4/MAPK signaling cascade and the alleviation of autophagic marker accumulation. This highlights the potential of SB as a promising preventive strategy for the clinical management of bovine mastitis. Full article

Fabry disease is a rare X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, resulting in deficient α-galactosidase A activity and progressive accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3). Although lysosomal substrate storage represents the primary molecular defect, accumulating evidence indicates that disease progression is driven by interconnected mechanisms, including chronic inflammation, oxidative stress, endothelial dysfunction, and impaired autophagy, leading to progressive multisystem involvement. The marked clinical heterogeneity of Fabry disease, together with nonspecific early manifestations, frequently delays diagnosis and complicates patient stratification and therapeutic decision-making. While advances in biomarkers, genetic testing, and imaging have improved disease recognition, current diagnostic approaches remain insufficient to fully capture disease complexity. Precision medicine is therefore emerging as a promising strategy through the integration of clinical, molecular, imaging, and multi-omics data. In this context, artificial intelligence (AI) offers novel opportunities for early diagnosis, biomarker discovery, risk stratification, and prediction of therapeutic response. This review provides an integrated overview of the molecular mechanisms, inflammatory pathways, clinical manifestations, and precision diagnostic strategies underlying Fabry disease, highlighting how AI-driven approaches may accelerate the transition toward more accurate, personalized, and predictive disease management. Full article

Although the prevalence of acute kidney injury and chronic kidney disease remains high and effective therapeutic targets remain scarce, significant progress has been made in recent years across the following major directions: G2/M phase cell cycle arrest, DNA damage, mitochondrial dysfunction, hypoxia-inducible factor signaling, dysregulated autophagy, and epigenetic alterations. RGC-32 is abundantly expressed in all tubular segments of normal renal tissues and is primarily localized to the cytoplasm and perinuclear region of renal tubular epithelial cells. Moreover, RGC-32 is involved in cell cycle regulation as well as cell proliferation and differentiation. To explore the functional role of RGC-32 in renal repair after acute ischemia–reperfusion injury, we utilized CRISPR-Cas9 technology combined with Cre/loxP recombination to generate a novel, renal tubule-specific RGC-32 knockout mouse model and systematically characterized its phenotype. Our findings demonstrate that renal tubule-specific RGC-32 deficiency does not impair normal growth or baseline renal function but alters the distribution of peripheral blood T lymphocyte subsets; whether this alteration contributes to renal immune regulation remains to be determined by future functional studies. More importantly, upon IRI, RGC-32 knockout in renal tubules leads to significantly aggravated renal dysfunction, elevated injury markers, and a possible association with enhanced chronic fibrosis. Full article

Ovum pick-up (OPU) enables high-frequency oocyte retrieval from selected dairy cow donors, facilitating favorable genetic progression. However, oocytes obtained via OPU and subjected to in vitro maturation frequently suffer from severe oxidative stress, mitochondrial dysfunction, and DNA damage, resulting in lower pregnancy rates compared to those of in vivo-derived embryos. Melatonin (MT), as a potent antioxidant, may exert beneficial effects on these OPU-retrieved oocytes. In the current study, by combining in vitro and in vivo experiments, the protective effects and potential molecular mechanisms of MT on disrupted oocyte quality and development caused by OPU were systemically investigated. By integrating oocyte quality assessment, follicular fluid metabolomics, and blastocyst transcriptomics, the results showed that subcutaneous administration of MT to cows prior to OPU significantly increased the number of high-quality Grade A oocytes and reduced the number of low-quality Grade D oocytes compared to the control. These improvements were accompanied by reduced local and systemic oxidative stress, enhanced glutathione metabolism, and lower serum progesterone concentrations at the measured time points, coinciding with a more favorable endocrine environment for follicular development. The results from untargeted metabolomics of the follicular fluid revealed that MT supplementation was associated with an altered follicular fluid microenvironment characterized by the upregulation of estrogen derivatives and glutathione-related pathways. Transcriptomic analysis of blastocysts showed significant upregulation of the rate-limiting genes steroidogenic acute regulatory protein (STAR) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), suggesting a potential role in promoting the synthesis of reproductive hormones and maintaining the progress of embryo development. The in vitro study showed that MT supplementation at a concentration of 10⁻⁷ mol/L in oocyte maturation media significantly improved cleavage rates, blastocyst rates, and total blastocyst cell numbers compared to the control. In vitro evaluations demonstrated that MT scavenged intracellular reactive oxygen species (ROS), while transcriptomic analysis indicated a reprogramming of the embryonic transcriptome. These transcriptomic changes were associated with the AMPK, FoxO, and autophagy pathways, as well as the modulation of endoplasmic reticulum stress and cellular senescence. The results from both the in vivo and in vitro studies suggested that MT supplementation was associated with a follicular microenvironment favorable for oocyte growth and protected embryos from oxidative damage. Therefore, MT supplementation effectively reduced the disrupted oocyte development caused by OPU and improved oocyte recovery and quality in general. These findings provide promising experimental evidence for the potential application of MT in dairy breeding and offer insights into the associated molecular pathways. However, further functional validation is required to fully elucidate the underlying mechanisms and establish its large-scale applicability. Full article

Osteoarthritis (OA) is a leading cause of disability worldwide, characterized by progressive joint degeneration driven by extracellular matrix (ECM) breakdown, chondrocyte apoptosis, and chronic low-grade inflammation. Despite the availability of several pharmacological and non-pharmacological interventions, no current therapy effectively halts or reverses disease progression. Physical activity is traditionally recognized as a cornerstone in OA management, improving pain and functional outcomes; however, the molecular mechanisms underlying its beneficial effects remain partially understood. Irisin, a myokine generated by proteolytic cleavage of fibronectin type III domain-containing protein 5 in response to muscle contraction, has recently emerged as a potential regulator of cartilage homeostasis. Experimental evidence indicates that irisin exerts pleiotropic effects by modulating inflammatory and catabolic signaling pathways, promoting anabolic and reparative processes, restoring autophagic and mitophagic flux, and preserving mitochondrial function. These actions collectively contribute to the maintenance of ECM integrity and chondrocyte viability. In vitro and in vivo studies consistently support the protective role of irisin in cartilage biology, highlighting its involvement in the muscle–cartilage axis and its potential as both a biomarker and therapeutic target for OA. This narrative review critically evaluates the chondrocyte-specific mechanisms, receptor uncertainties, experimental-model limitations, analytical challenges, and delivery strategies that currently define the biological and translational relevance of irisin in OA. Particular attention is given to the identification of irisin-mediated signaling pathways in chondrocytes, optimization of delivery strategies, and the definition of exercise regimens capable of maximizing its chondroprotective effects. Full article

Background: Nutritional support in critically ill patients remains one of the most debated aspects of intensive care medicine. Although international guidelines have long recommended early nutritional support with progressive protein delivery, recent clinical evidence has questioned the benefit of aggressive early calorie and protein provision during the acute phase of critical illness, highlighting the need for phase-adapted nutritional strategies. Methods: This narrative review summarizes current evidence on individualized, phase-adapted nutritional therapy in critically ill adults and post-ICU survivors, focusing on protein dose and timing, anabolic resistance, muscle wasting, and nutritional management during recovery. Relevant studies published between January 2011 and June 2026 were identified through structured searches of PubMed/MEDLINE, supplemented by reference screening and forward citation tracking. A total of 59 publications were included in the final narrative synthesis. Results: Recent clinical trials indicate that early high-dose protein administration does not consistently improve survival or functional outcomes and may be associated with harm in selected patient subgroups, particularly those with acute kidney injury, severe organ dysfunction, or shock. More conservative early calorie and protein delivery during the early acute phase has been associated with improved gastrointestinal tolerance and faster clinical stabilization without increasing mortality. Complementary mechanistic evidence supports these findings, highlighting persistent endogenous energy production, anabolic resistance, impaired protein utilization, and reduced autophagy during early critical illness. In contrast, the post-ICU recovery phase is characterized by ongoing muscle wasting, weakness, reduced oral intake, and persistent nutritional deficits, while structured nutritional support after ICU discharge remains inconsistently implemented. Conclusions: Current evidence increasingly supports an individualized, phase-adapted approach to nutritional therapy rather than uniform early aggressive calorie and protein targets. Nutritional strategies should consider illness severity, metabolic phase, organ dysfunction, gastrointestinal tolerance, and recovery trajectory. Further studies are needed to define optimal nutritional targets during post-ICU recovery. An evidence-informed practical framework for phase-adapted nutritional therapy is proposed. Full article

Background: Oxidative stress, neuroinflammation, impaired autophagy, and mitochondrial dysfunction are major contributors to ageing and neurodegenerative diseases. This study investigated whether AgeViva could counteract these processes by modulating redox balance, inflammation, autophagy, and mitochondrial function. Methods: The effects of AgeViva were evaluated using two complementary experimental models: lipopolysaccharide (LPS)-stimulated BV2 microglial cells and Caenorhabditis elegans (C. elegans) nematodes. In BV2 cells, the expression of inflammatory, autophagy-related, and antioxidant response genes, including NRF2, SOD, and GPX, was evaluated by RT-qPCR, while cell viability was assessed by Trypan Blue exclusion assay. In C. elegans, lifespan, healthspan parameters, ROS accumulation, mitochondrial integrity, membrane potential, and the expression of stress-response, longevity, and autophagy-related genes were analyzed following AgeViva supplementation. Results: In LPS-stimulated BV2 cells, AgeViva significantly reduced the expression of mRNA the pro-inflammatory cytokines Interleukin-1 beta (IL-1β) and Tumor Necrosis Factor alpha (TNF-α) while increasing Interleukin-10 (IL-10) levels, AgeViva also induced changes in autophagy-related transcripts, such as modulation of microtubule-associated protein 1a/1b-Light Chain (LC3) and Sequestosome 1 (p62) expression, activated antioxidant-related gene expression, increasing the expression of Superoxide Dismutase 1(SOD1) and Glutathione Peroxidase (GPX). In C. elegans, AgeViva supplementation extended lifespan and improved healthspan parameters, including locomotor activity and pharyngeal pumping. Treated nematodes showed reduced cytosolic and mitochondrial ROS accumulation, preservation of mitochondrial network integrity, and maintenance of mitochondrial-associated fluorescence, reflecting mitochondrial content and/or membrane potential during ageing. Molecular analyses revealed modulation of key pathways involved in stress resistance and longevity, including Insulin-like Growth Factor 1 (Insulin/IGF-1) signaling Dauer Formation-2 and 16 (DAF-2/DAF-16), Skinhead-1 (SKN-1/Nrf2) signaling, and autophagy-related genes, like Ligating (lgg-1), Autophagy-Related-7 (atg-7), Autophagy Related-18 (atg-18), uncoordinated-51 (unc-51), and ectopic p-granules autophagy protein 5 (epg-5). Conclusions: AgeViva promotes healthy ageing by modulating oxidative stress, inflammation, autophagy, and mitochondrial homeostasis. Full article

Heat stress compromises male reproductive function in livestock and other mammals. Arginine is a conditionally essential amino acid involved in metabolic regulation; however, its protective effects on the male reproductive system under heat stress remain unclear. Using a heat-stressed Rongchang boar model, this study aimed to explore the possible mechanism of dietary arginine supplementation on sperm quality and testicular function. Twenty-four Rongchang boars were assigned to three treatments: thermoneutral control (CON), heat-stressed control (HS), or heat-stressed treatment supplemented with 0.8% dietary arginine (HA). Results showed that heat stress reduced feed intake, body weight, sperm viability, sperm concentration, and sperm motion parameters (p < 0.05), accompanied by testicular histological damage. However, arginine supplementation improved sperm viability and straight-line velocity (p < 0.05), with partial preservation of testicular morphology. Furthermore, single-cell RNA sequencing revealed heat stress-associated changes in germ-cell composition and enrichment of autophagy-related pathways. Transmission electron microscopy and qRT-PCR showed endoplasmic reticulum swelling, autophagic vesicle accumulation, and increased expression of GABARAPL1, ULK1, BECN1, and CALM3 in heat-stressed testes (p < 0.05); these alterations were attenuated by arginine supplementation, as indicated by reduced ULK1 and BECN1 expression (p < 0.05). Metabolomic and targeted analyses indicated improved circulating arginine availability and reshaped testicular arginine-related amino acid/polyamine metabolism after arginine supplementation (p < 0.05). Overall, dietary arginine supplementation alleviated heat stress-induced testicular dysfunction, which was accompanied by alterations in arginine-related metabolic regulation and autophagy-associated cellular stress responses. Full article