Search Results (3,833)

Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy—the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes—Kearns–Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies—as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which circadian rhythm disruption (CRD) emerges as both a prodromal feature and a potential pathogenic driver. Elucidating the bidirectional interplay between PD and CRD is essential for identifying early biomarkers and developing chronotherapeutic strategies. We narratively synthesized literature published over the past two decades in PubMed, Web of Science, and CNKI, focusing on molecular mechanisms, clinical manifestations, biomarker development, and interventional studies addressing the PD–CRD interface. In the CRD-PD direction, circadian disruption accelerates dopaminergic neurodegeneration through four convergent mechanisms: (i) REV-ERBα–mediated dysregulation of dopamine biosynthesis and NF-κB/NLRP3-driven neuroinflammation; (ii) impaired sleep-dependent glymphatic clearance of α-synuclein (α-syn); (iii) NAD⁺–SIRT1–BMAL1–PGC-1α axis dysfunction leading to mitochondrial bioenergetic failure; and (iv) C/EBPβ-dependent autophagic rhythm disruption coupled with pro-inflammatory microglial activation, collectively establishing a dual pro-inflammatory–autophagy-suppressive milieu permissive for α-syn aggregation. In the reverse PD-CRD direction, PD pathology destabilizes the circadian system via Braak-stage degeneration of rhythm-regulatory nuclei, retinal dopaminergic denervation attenuating SCN photic entrainment, pineal–melatonin axis suppression, iatrogenic effects of dopaminergic pharmacotherapy, and gut microbiota dysbiosis propagated through the microbiota–gut–brain axis. Emerging multi-modal chronobiomarkers—including peripheral clock gene expression profiles, melatonin secretion patterns, tryptophan–kynurenine metabolites, and gut microbial oscillation signatures—show promise for prodromal diagnosis and disease subtyping. Circadian-targeted precision interventions—encompassing timed bright light therapy, exogenous melatonin, and chronopharmacological interventions—represent a promising translational paradigm for the early identification and management of PD. Full article

Skeletal muscle, as the largest metabolic organ, maintains its homeostasis highly dependent on the precise regulation of mitochondrial quality control. Mitochondrial quality control (MQC) encompasses three core aspects: mitochondrial biogenesis, dynamic balance, and autophagy. All of these jointly ensure mitochondrial network functional integrity. MQC imbalance is mainly manifested as decreased mitochondrial biosynthesis capacity, disordered fusion and division dynamics, and reduced autophagy clearance efficiency. MQC imbalance can lead to atrophy of skeletal muscles, metabolic dysfunction, and decline in motor function. As a physiological stress stimulus, exercise can precisely regulate MQC through multiple targets and pathways and restore the homeostasis of skeletal muscles. Exercise activates AMPK-PGC-1α to promote mitochondrial biogenesis, regulates MFN1/2, OPA1, and DRP1 to optimize mitochondrial dynamics, and activates the PINK1/Parkin pathway and receptor-mediated autophagy pathway to enhance mitochondrial autophagy. The regulatory effects of different exercise modes on MQC vary significantly. Aerobic exercise focuses on promoting mitochondrial biogenesis and fusion, while high-intensity interval training can more efficiently activate the autophagy pathway. Resistance exercise, on the other hand, requires a longer period to manifest its regulation of dynamic proteins. This article systematically reviews the molecular regulatory mechanism of MQC and its impact on skeletal muscle imbalance and elaborates on the mechanisms by which exercise regulates the remodeling of skeletal muscle through MQC. This article also further compares the differential effects of different exercise modes on the regulation of mitochondrial quality control to maintain skeletal muscle homeostasis. Future research needs to further explore the dose and effect relationship of exercise on regulating MQC and the optimal combination of exercise modes to provide a scientific basis for formulating precise and safe exercise intervention strategies. Full article

Exopolysaccharides (EPS) from microalgae have emerged as promising natural anticancer agents owing to their selective cytotoxicity toward tumor cells and low toxicity to healthy tissues. However, the molecular mechanisms and targets underlying their anticancer activity remain poorly understood. In the present study, EPS isolated from Coelastrella sp. BGV was evaluated for cytotoxicity and antiproliferative activity against a panel of human cancer cell lines (HepG2, HCT116, A549, and MDA-MB-231). The effects of EPS on mitochondrial function, cell cycle progression, apoptosis, and autophagy were investigated using flow cytometry and fluorescence microscopy. To gain mechanistic insight, molecular docking of a representative EPS disaccharide, α-L-Fucp-(1→6)-β-D-Galp, was performed against DC-SIGN and galectin-3 using the CB-Dock2 platform with the AutoDock Vina engine. The EPS exhibited minimal cytotoxicity toward non-tumor cells, and induced significant concentration-dependent antiproliferative activity in all tested cancer cell lines. MDA-MB-231 breast cancer cells were the most sensitive, with an IC₅₀ value of 57.5 ± 10 µg/mL and a selectivity index of 5.2 relative to non-tumor cells. Mechanistically, EPS treatment induced mitochondrial membrane depolarization, S-phase cell cycle arrest, autophagy, and apoptosis, as demonstrated by nuclear fragmentation, chromatin condensation, and increased Annexin V positivity. Molecular docking identified DC-SIGN and galectin-3 as plausible molecular targets, suggesting potential anticancer activity of Coelastrella sp. BGV EPS that may involve both direct pro-apoptotic effects and modulation of carbohydrate-mediated signaling pathways. Collectively, these findings provide new mechanistic insight into the anticancer activity of Coelastrella sp. BGV EPS and support its further investigation as a promising natural candidate for adjunctive cancer therapy. Full article

The high-pathogenicity island (HPI) is a major virulence determinant in pathogenic Escherichia coli (E. coli), contributing to severe inflammation and tissue damage. Autophagy plays a critical role in clearing intracellular pathogens and modulating inflammation, but whether HPI manipulates this process remains unknown. Here, using a swine-pathogenic E. coli strain and its HPI-deficient mutant (Δirp2) generated by CRISPR/Cas9, we investigated the interplay between HPI and autophagy in RAW264.7 macrophages and a mouse intestinal infection model. We found that HPI⁺ infection induced autophagic activation, as evidenced by increased LC3 puncta (immunofluorescence), upregulated Beclin-1 and autophagy-related gene mRNA levels (qPCR), and downregulated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) expression at both mRNA (qPCR) and protein (immunohistochemistry) levels. In a mouse model, HPI⁺ infection upregulated intestinal Microfold (M) cell markers and secretory Immunoglobulin A (IgA), triggered robust production of pro-inflammatory cytokines, and induced more severe tissue pathology than the HPI-deficient mutant. Pharmacological activation of autophagy with rapamycin alleviated HPI-induced inflammation and injury, whereas inhibition of autophagy by 3-methyladenine (3-MA) or Beclin-1 silencing exacerbated damage. These findings suggest that HPI induces autophagy, but the endogenous autophagic response is insufficient to counteract HPI-induced pathology; pharmacological enhancement of autophagy partially alleviated this insufficiency and reduced tissue damage. Notably, Beclin-1 knockdown blunted HPI-induced upregulation of PI3K and autophagy-related genes, suggesting a role for Beclin-1 in the transcriptional regulation of these responses. In conclusion, HPI simultaneously exerts direct pro-inflammatory effects and induces Beclin-1-dependent autophagy. Enhancing this autophagic response pharmacologically, rather than relying on the endogenous level triggered by HPI alone, limits excessive tissue damage. Thus, boosting autophagy may represent a promising therapeutic strategy against HPI-bearing pathogenic E. coli infections. Full article

Background: 2,3,3,3-Tetrafluoro-2-(heptafluoropropoxy)propanoic acid (GenX) is a perfluoroether carboxylic acid that has been detected in drinking water sources. Its potential hepatotoxicity has raised concern, although the associated molecular alterations remain incompletely understood. Chlorogenic acid (CGA), a naturally occurring polyphenol, has been reported to affect oxidative stress and metabolic homeostasis. Methods: Adult male C57BL/6J mice were exposed to GenX (2 mg/kg/day) with or without CGA (30 mg/kg/day) by gavage for 12 weeks. AML12 cells were treated with GenX (10–800 μM) for 24 or 48 h to assess cell viability, and intracellular lipid accumulation was evaluated after exposure to 200 μM GenX for 24 h. Results: GenX exposure induced hepatomegaly, microvesicular steatosis, inflammatory cell infiltration, and a reduction in hepatic glycogen stores. It also decreased hepatic glutathione concentrations and increased hepatic malondialdehyde concentrations. Serum alanine aminotransferase, aspartate aminotransferase, total cholesterol, and triglyceride levels were elevated. In AML12 cells, GenX increased intracellular lipid accumulation, as assessed by Oil Red O staining. Transcriptomic analysis identified significant enrichment of the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Consistently, GenX altered the expression of genes and proteins involved in lipogenesis, fatty acid uptake, lipid storage, and fatty acid oxidation, suggesting disturbed PPAR-related lipid metabolic regulation. Moreover, the decreased p-mTOR/mTOR ratio, increased LC3-II/I, and overexpression of Beclin1, p62, and inflammatory mediators in the GenX group might suggest changes in autophagy-related proteins and inflammatory response. CGA coadministration partially attenuated several GenX-induced hepatic alterations, including liver enlargement, hepatic lipid accumulation, lipid peroxidation, and changes in selected autophagy- and inflammation-related proteins. Conclusions: Subchronic GenX exposure-induced adverse hepatic effects might be associated with disrupted PPAR-related lipid metabolic regulation, oxidative stress, inflammatory responses, and changes in autophagy-related proteins. CGA might exert potential modulatory effects. Full article

Salinity fluctuations pose a severe threat to the survival and physiological homeostasis of freshwater crustaceans. Here, an integrated transcriptomic and metabolomic approach was utilised to characterise the dynamic regulatory responses in the hepatopancreas of adult Macrobrachium rosenbergii subjected to acute high-salinity stress (20‰). The number of differentially expressed genes (DEGs) and metabolites (DMs) increased from 24 to 48 h, signalling a transition from an initial acute stress reaction to systemic homeostatic remodelling. At the molecular level, M. rosenbergii activated autophagy (Atg8a) and p53 (TP53INP) signalling, alongside the reprogramming of lipid and nucleotide metabolism. Pathway analysis identified “alanine, aspartate, and glutamate metabolism” as a central regulatory node. Notably, the downregulation of the glutamate dehydrogenase gene (Gdh) alongside the accumulation of L-glutamate suggests a potential transcriptional-metabolic decoupling phenomenon, wherein the organism appears to prioritise the conservation of critical osmoregulatory effectors over their oxidative degradation. These findings detail the systemic adaptive responses of M. rosenbergii to salinity fluctuations, providing candidate targets for the selective breeding of stress-resilient crustacean strains. Full article

Cancer cells are able to survive under conditions of high endoplasmic reticulum (ER) stress by activating the adaptive unfolded protein response (UPR), which is closely linked with autophagy. On the other hand, excessive and prolonged ER stress leads to apoptosis. However, the relationships between different UPR branches and apoptosis or autophagy vary in cancer cells of different origins and depend on the extent and nature of the stress signal. This study was designed to establish the role of ER stress sensors protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1 (IRE1α) in apoptosis or autophagy signaling in T-lymphoblastic leukemia MOLT-3 cells via the RNA interference method. The cells were transfected with small interfering RNAs (si-PERK, si-IRE1α, or si-Cont) for 6 h and further cultured under normal conditions for 72 h to provide an insight into chronic effects of the gene silencing. The expression of apoptosis and autophagy effectors at the mRNA and protein levels was compared using RT-PCR and Western blot assays, respectively. Transfection of the cells with PERK siRNA led to a significant decrease in PERK protein and gene expression, and decreased phosphorylation of its downstream effector eukaryotic initiation factor 2α (eIF2α). PERK silencing was accompanied by activation of apoptosis-related genes and proteins—BCL2-associated X (Bax), caspase-3, C/EBP homologous protein (CHOP), while the levels of autophagy markers (Unc-51 like autophagy activating kinase 1 (ULK1), Beclin-1, and microtubule-associated proteins 1A/1B light chain 3 (LC3A/B)) remained stable. In contrast, treatment of the cells with si-IRE1α reduced the content of IRE1α, X-box-binding protein 1 (sXBP1), and glucose-regulated protein 78 (GRP78) proteins, but increased ERN1 gene expression. IRE1α RNA interference did not affect the levels of the pro-apoptotic marker Bax, but suppressed caspase-3, CHOP, c-Jun N-terminal kinase (JNK), and autophagy signaling molecules (ULK1, Beclin-1, LC3A/B) at both the transcriptional and translational levels. These results indicate that the PERK pathway is an important contributor to the survival of MOLT-3 cells under basal ER stress, while PERK depletion compromises the resistance of cells to UPR-mediated apoptosis. The IRE1α UPR branch is directly linked with autophagy-dependent signaling, although IRE1α knockdown exerted a more complicated influence on the cells, probably via activation of multiple pro-death and compensatory pro-survival regulatory mechanisms. Full article

Brassinosteroids (BRs) are essential steroid hormones that coordinate plant growth, development and adaptation to changing environments. Although BR signaling has long been viewed primarily as a phosphorylation-dependent pathway, increasing evidence shows that ubiquitination provides an additional regulatory layer that shapes the abundance, activity, subcellular distribution and turnover of key signaling components. Ubiquitin-mediated regulation operates at multiple points in the BR pathway, including receptor homeostasis at the plasma membrane, turnover of GSK3-like kinases, and stability control of the transcription factors BES1/BZR1. These processes determine not only the strength and duration of BR signaling but also its coordination with other hormonal and stress-response pathways. In this review, we discuss recent advances in ubiquitin-mediated regulation of BR signaling, focusing on receptor-level control, proteolytic regulation of core signaling components, and modulation of transcriptional outputs. We also highlight emerging links between ubiquitination, selective autophagy, deubiquitination and BR-associated stress responses and outline key questions concerning ubiquitin chain specificity, substrate recognition and conservation of these regulatory modules in crops. Defining how ubiquitination fine-tunes BR signaling will deepen our understanding of plant steroid hormone regulation and may provide new strategies for optimizing crop architecture, productivity, and stress resilience. Full article

Cyclin-dependent kinase 4/6 inhibitors have fundamentally changed the management of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. However, these drugs are not interchangeable and the field is moving away from the notion of a uniform “class effect.” In early breast cancer, adjuvant abemaciclib and ribociclib improve invasive disease-free survival in patients at a high risk of recurrence, whereas palbociclib does not. This difference likely stems from agent-specific pharmacological profiles, differences in trial design, and patient selection, rather than simply dosing nuances. In metastatic breast cancer, all three agents prolong progression-free survival when combined with endocrine therapy, but only ribociclib and potentially abemaciclib have shown an overall survival advantage. In addition, resistance remains a major obstacle in clinical practice. We propose that resistance mechanisms can be meaningfully grouped into two categories: target-driven (e.g., RB1 loss, CDK6 amplification) and bypass-driven (e.g., ESR1 mutations, PI3K/AKT pathway activation, APOBEC3-mediated mutagenesis). Distinguishing between these classes helps in the design of rational sequencing algorithms and combinatorial regimens. Emerging strategies, such as next-generation protein degraders, oral selective estrogen receptor degraders, antibody–drug conjugates, and inhibition of autophagy, are promising methods for overcoming resistance. Moving forward, the greatest need in breast cancer treatment will be not simply developing additional agents but using current therapies more intelligently by refining biomarker-guided patient selection, tailoring treatment duration, and ensuring broad global access. Full article

Decoy receptor 3 (DcR3) is a pleiotropic soluble factor that modulates cellular functions through both decoy and non-decoy mechanisms. DcR3 has been reported to exert anti-apoptotic and anti-inflammatory effects in humans, particularly in cancers and inflammatory diseases. In the present study, we investigated the role of DcR3 in TLR4-mediated innate immune responses in macrophages. Because the DcR3 gene is absent in the mouse genome, we generated myeloid-specific DcR3 knock-in mice and isolated bone marrow-derived macrophages (BMDMs) for functional analyses. Our results showed that DcR3 did not significantly affect LPS-induced expression of COX-2, iNOS, NLRP3, or pro-IL-1β. Aggresome-like induced structures (ALIS), which consist of aggregates of ubiquitinated proteins, are stress-induced cytoplasmic compartments implicated in MHC class I antigen presentation. We found that DcR3 suppressed LPS-induced ALIS formation by attenuating cellular reactive oxygen species production and p38 MAPK activation. In addition to LPS stimulation, DcR3 also reduced the accumulation of ubiquitinated proteins induced by HO-1 inhibitor ZnPP, lysosomal inhibitor bafilomycin A1, and proteasomal inhibitor MG132. Consistent with a role for autophagy in ALIS regulation, rapamycin reduced LPS-induced ALIS formation, whereas bafilomycin A1 induced comparable LC3-II accumulation in both wild-type and DcR3-expressing macrophages. Furthermore, DcR3 expression did not significantly alter LPS-induced p62 or HO-1 expression. Collectively, although DcR3 does not markedly influence LPS-induced inflammatory responses in BMDMs, our findings reveal a previously unrecognized role for DcR3 in suppressing ALIS formation and the accumulation of ubiquitinated proteins in macrophages, thereby suggesting a novel function for DcR3 in maintaining intracellular protein homeostasis under stress conditions. Full article

Lifespan is increasing throughout the world leading to a rise in non-communicable diseases in the global population that impacts over 800 million individuals with metabolic disorders, such as diabetes mellitus. Metabolic disease presents a significant challenge for clinical care since multi-organ disease progression ensues despite a broad array of treatment protocols. The pursuit of innovative strategies with mammalian forkhead transcription factors of the “O” class (FoxOs) and intimately related pathways of aging, cellular senescence, telomere integrity, oxidative stress, programmed cell death with apoptosis, autophagy, ferroptosis, pyroptosis, and cuproptosis, Wnt/β-catenin signaling, Wnt1 inducible signaling pathway protein 1, and the gut microbiome becomes vital to address the clinical hurdles of metabolic disorders. Platforms incorporating novel diagnostics with artificial intelligence and machine learning can further address the underlying mechanisms tied to FoxOs that include the mechanistic target of rapamycin, AMP activated protein kinase, silent mating type information regulation 2 homolog 1 (S. cerevisiae), and glucagon-like peptide-1 receptor agonists that can markedly influence biological outcomes. Given the premise that it is essential to comprehend the intimate relationship that FoxO signaling pathways hold, FoxOs offer an exciting and promising approach to address the clinical aspects of disease onset, progression, and treatment with metabolic disorders. Full article

Intravenous immunoglobulin (IVIG) resistance occurs in 10–20% of children with Kawasaki disease (KD) and is associated with a 3- to 5-fold higher risk of coronary artery lesions (CALs). Yet the mechanistic basis for why some patients progress from reversible inflammation to irreversible vascular damage after IVIG remains poorly understood. Most existing reviews have focused on risk prediction rather than the mechanistic chain linking resistance to CALs. Here, we synthesize current evidence across three interconnected pathways. First, autophagy dysfunction—particularly impaired mitophagy—sustains inflammation through cGAS-STING activation. Second, neutrophil extracellular traps (NETs) play a controversial role in KD vasculitis, with PAD2 and PAD4 possibly acting redundantly via the NLRP3 inflammasome. Third, endothelial-to-mesenchymal transition (EndMT), driven by the IL-1β/TNF axis and the USP7-TGFβ2/SMAD pathway, emerges as a core event in vascular remodeling. Building on these findings, we propose the “autophagy–inflammasome axis” as a candidate molecular switch that dictates whether inflammation resolves or persists. This hypothesis is actionable: it generates three explicit, testable predictions linking autophagic integrity to inflammatory outcomes and therapeutic response. Direct experimental validation in IVIG-resistant KD models and patient samples is now urgently needed. This review provides a systematic framework for understanding how IVIG resistance transitions to irreversible CALs. It also identifies candidate biomarkers (e.g., S100A12, mtDNA, and MCM8) and therapeutic targets (autophagy inducers, NLRP3 inhibitors, USP7 inhibitors, and anakinra) that could enable earlier intervention. Full article

Cancer continues to be a primary cause of death globally, necessitating the constant development of effective and less toxic therapeutics. Cucurbitacins belong to the tetracyclic triterpenoids found mainly in the Cucurbitaceae family. Cucurbitaceae plants exert various biological activities such as anti-diabetic, anti-cancer and anti-inflammatory properties, which make them beneficial in addressing metabolic disorders. This review focuses on cucurbitacins namely A, B, C, D, E, I, IIa, which have been explored in cancer research. Cucurbitacins suppress tumor progression by activating cell death pathways, including apoptosis, autophagy, pyroptosis and ferroptosis. They are known to target multiple crucial biomolecular key players, such as STAT3, AKT, mTOR, ERK, EGFR and TLR4. Additionally, they disrupt cytoskeletal proteins and inhibit cell proliferation, invasion, migration, angiogenesis, and cell-cycle arrest. Cucurbitacins have been demonstrated to modulate tumor microenvironment, leading to enhanced host immune surveillance that reverses traditional therapy resistance from cisplatin, doxorubicin, and paclitaxel. In this review, we highlight the strong potential of cucurbitacins as anti-cancer agents, either as monotherapy or in combination, for the development of safer, cost-effective drugs with improved patient treatment outcomes. Full article

Eucommia ulmoides leaf extract (ELE) boasts a high concentration of bioactive components including flavonoids, chlorogenic acid, and polysaccharides. It exhibits multiple biological functions, including antioxidant, anti-inflammatory, and gut microbiota-modulating properties, showing great potential in enhancing immunity, maintaining intestinal health, and delaying cellular senescence. This study investigated the protective effects and underlying mechanisms of ELE against D-galactose-induced senescence in chick embryo primary intestinal epithelial cells (IECs). Using an in vitro model (200 mmol/L D-galactose), we found that 100 µg/mL ELE pretreatment significantly preserved cell viability, mitigated apoptosis, and delayed cellular senescence, as evidenced by cytological and biochemical assays. Furthermore, RNA-seq transcriptomic analysis identified seven key differentially expressed genes (DEGs) mediating these anti-aging effects. Mechanistic investigations revealed that ELE modulates ATP6V0D2 and NCF2 to activate autophagy signaling pathways. This ELE-induced promotion of autophagy effectively suppresses inflammatory responses in IECs, thereby delaying senescence progression. These findings elucidate the molecular mechanisms by which ELE antagonizes intestinal cellular senescence, providing a solid theoretical foundation for its development as a functional anti-aging additive in the food industry. Full article