Search Results (307)

Ovarian endometriosis (OE) is a chronic, inflammatory gynecological disorder associated with sterility and an elevated risk of ovarian cancer. Despite its high prevalence, the complex molecular mechanisms governing OE pathogenesis remain poorly investigated. We conducted a comprehensive histopathological and molecular investigation of OE in a cohort of 188 Saudi women (88 patients with OE and 100 healthy controls) using histopathological, qRT-PCR, immunostaining, and Western blot techniques. Histopathological analysis confirmed significant stromal fibrosis and chronic inflammation in endometriotic lesions. Gene expression profiling revealed a pro-proliferative, anti-apoptotic signature, marked by the upregulation of PTTG1 and the downregulation of TNFRSF10D, CDK4, and CDKN1A. Interestingly, we identified a post-transcriptional regulatory paradox in the inflammatory response: while IL-6 mRNA was significantly upregulated, its corresponding protein level was downregulated, suggesting a novel, tightly controlled mechanism to limit excessive local inflammation. Besides the increased autophagic activity and decreased Ubiquitin mRNA levels, epigenetic dysregulation was prominent, characterized by the upregulation of DNA methyltransferase DNMT3B and the downregulation of the histone variant H3.1. These findings elucidate novel molecular pathways underlying OE pathogenesis as evidenced by a post-transcriptional paradox in IL-6 expression, and uncover key dysregulations spanning cell proliferation, apoptosis, inflammation, autophagy, and epigenetic regulation. Full article

Objectives: Obesity precipitates excessive lipid accumulation within the kidney, culminating in ectopic lipid deposition that compromises target organ function through lipotoxicity. Given the pivotal role of GDF15 in lipid metabolism, this study aims to determine whether GDF15 can ameliorate ectopic lipid deposition and mitigate the resulting renal injury. Methods: C57BL/6J mice were used to establish a high-fat diet-induced obesity model. Based on Lee’s index, the mice were categorized into a diet-induced obesity group and an obesity-resistant group. Subsequently, the diet-induced obesity group received an injection of AAV-shGFRAL to knock down the GFRAL receptor. Results: In obesity resistant mice, ectopic lipid deposition in the kidneys was markedly reduced, accompanied by decreased expression of the renal injury marker KIM-1 and significantly elevated levels of GDF15. Modulation of the GDF15-GFRAL axis demonstrated that reduced autophagy levels led to increased lipid accumulation and exacerbated renal injury. Conversely, GDF15 activates the AMPK/SIRT1 signaling pathway to promote cellular autophagy, thereby mitigating renal damage induced by ectopic lipid deposition. Consistent with this mechanism, the suppression of autophagy results in the aggravation of renal injury caused by ectopic lipid accumulation. Conclusions: GDF15 ameliorates renal injury induced by ectopic lipid deposition in the kidney primarily through activation of autophagy via the AMPK/SIRT1 signaling pathway. Full article

Females with iron overload suffer from follicular dysplasia, and effective therapeutic strategies for preserving fertility remain lacking. As a natural aliphatic polyamine, spermidine exerts antioxidant activity and plays an anti-ferroptosis role in the pathogenesis of various diseases. However, the role and underlying mechanism of spermidine in iron overload-induced ovarian ferroptosis remain largely elusive. This study aimed to investigate the therapeutic potential of spermidine against iron overload-induced ferroptosis in ovarian granulosa cells and elucidate its molecular mechanism. As a result, iron overload models were established in female mice (in vivo, ferrous sulfate) and porcine ovarian granulosa cells (in vitro, ferric ammonium citrate), with spermidine administered at 3 mM (in vivo) or 150 μM (in vitro). Ferritin heavy chain (FHC) and solute carrier family 7 member 11 (SLC7A11) silencing were performed via siRNA transfection, and relevant controls were set. In vivo studies showed that spermidine elevated serum estradiol and progesterone levels, enhanced ovarian catalase (CAT) and superoxide dismutase (SOD) activities, improved granulosa cell mitochondrial morphology, and increased estrous cycle regularity from 35.6% (high-iron group) to 63.1%. In vitro, spermidine improved ferric ammonium citrate (FAC)-impaired cell viability; attenuated reactive oxygen species (ROS) accumulation; upregulated FHC, Nrf2/p-Nrf2/GPX4, SLC7A11 and anti-müllerian hormone (AMH) expression; and inhibited excessive autophagy (decreased LC3BII/I ratio). Mechanistically, spermidine activated AKT-mediated autophagy, modulated iron homeostasis and glutathione (GSH) synthesis via FHC, alleviated ferroptosis-related Nrf2/p-Nrf2/HO-1 pathway overactivation, reduced lipid peroxidation and DNA damage, and restored mitochondrial function. SLC7A11 silencing disrupted glutathione metabolism, induced mitochondrial ROS accumulation, and inhibited autophagy. Proteomic analysis identified microsomal glutathione S-transferase 3 (MGST3) as a potential key downstream target of spermidine in suppressing SLC7A11-mediated ferroptosis. This study reveals a novel therapeutic strategy wherein spermidine protects against ovarian ferroptosis and preserves ovarian function by regulating iron homeostasis through the FHC/SLC7A11 axis. Full article

Oxidative stress is an important component of cancer biology and is characterized by an imbalance between the production of reactive oxygen species (ROS) and antioxidant defense systems. Excess ROS can cause molecular damage and genomic instability; at the same time, ROS signaling remains necessary for normal cellular function. Redox homeostasis is of particular importance in this balance. The aim of this structured narrative review was to summarize and critically discuss current evidence on how dietary antioxidants influence redox-sensitive pathways involved in cancer prevention, with particular attention to metabolic inflammation, mitochondrial quality control, and gut microbiota-related mechanisms. We performed a structured literature search of Scopus, Web of Science, and PubMed, focusing on articles published between 2021 and 2026. The evidence covered major redox-sensitive pathways, including Nrf2-Keap1-ARE signaling, AMPK-mTOR regulation, NF-κB-mediated inflammation, mitochondrial quality control (autophagy and mitophagy), and inflammasome activation. These pathways, which are involved in tumor initiation and progression, link oxidative stress to metabolic and inflammatory processes. Current evidence suggests that dietary antioxidants act primarily by supporting endogenous defense systems. This may help explain the “antioxidant paradox”, in which antioxidant-rich dietary patterns are associated with a lower risk of cancer. In some studies, high-dose supplementation with isolated antioxidants has produced inconsistent or sometimes adverse results. These effects depend on dose, chemical form, metabolic context, and baseline redox state. The gut microbiota is also an important mediator of antioxidant bioactivity; by converting dietary polyphenols into bioactive metabolites, it can influence systemic redox balance and metabolic signaling. This microbiota-dependent modulation may partially explain inter-individual variability in responses to dietary interventions. In conclusion, dietary antioxidants should be considered as modulators of redox-sensitive signaling networks, not merely as simple radical scavengers. Personalized modulation of redox homeostasis is a future strategy for cancer prevention, with a greater emphasis on whole-diet and biomarker-guided approaches. Full article

Feline infectious peritonitis virus (FIPV) remains one of the most challenging viral diseases in veterinary medicine, largely owing to the absence of a consistently effective and safe vaccine. Despite widespread feline coronavirus infection, only a subset of infected cats progresses to feline infectious peritonitis, indicating that host immune responses are key determinants of disease outcomes. Accumulating evidence indicates that disease severity is driven not only by viral replication but also by macrophage- and monocyte-centered immune signaling, leading to excessive inflammation and systemic immunopathology in the host. Previous vaccine approaches against FIPV have failed to provide consistent protection and, in some cases, have been associated with enhanced disease. These outcomes suggest that vaccine-induced immune responses that recapitulate pathogenic signaling patterns may exacerbate disease rather than confer protection. In this review, we discuss the current knowledge of immune cell signaling pathways implicated in FIPV infection, including innate sensing through Toll-like receptors, downstream mitogen-activated protein kinases and NF-κB signaling, cytokine production profiles, Fc receptor-associated processes, and intracellular pathways such as autophagy, and how these mechanisms shape vaccine-induced immunity. By integrating insights from immune signaling kinetics, antibody functionality, adjuvant-driven pathway engagement, and platform-specific immune signatures, this review emphasizes the need to reframe FIPV vaccine development strategies that actively shape host immune responses. Rather than maximizing immunogenicity, successful vaccine design is likely to depend on limiting sustained macrophage activation and pro-inflammatory cytokine amplification while supporting antiviral immune functions, thereby reducing the risk of antibody-dependent enhancement and immunopathology. Beyond feline diseases, these considerations provide broader lessons for vaccine design in settings where immune-mediated pathology contributes to disease severity. Full article

Zearalenone (ZEA) is a mycotoxin widely present in cereals, feeds, and foods, posing a persistent threat to human and animal health. Hepatic fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition. Chronic liver injury caused by sustained oxidative stress can initiate the development of early hepatic fibrosis. However, whether liver injury induced by ZEA can trigger hepatic stellate cell (HSC) activation and promote early profibrotic responses remains unclear. The aim of this study was to assess whether ZEA-induced liver injury promotes HSC activation and early profibrotic responses. To address this, we established a BALB/c mouse exposure model and used the murine HSC line (JS-1) for in vitro validation. The results showed that ZEA exposure caused structural damage in hepatic tissue and produced an incomplete bridging pattern of collagen thickening suggestive of an early profibrotic tendency. ZEA shaped a proinflammatory microenvironment by activating the IκBα/NF-κB axis and induced the TGF-β1/Smad2/3 pathway, accompanied by Smad7 suppression, thereby promoting HSC activation and the expression of fibrosis-related genes. ZEA also altered autophagy-related markers in liver tissue and JS-1 cells. Pharmacological inhibition with chloroquine partially attenuated ZEA-induced upregulation of α-SMA and collagen I/III, suggesting that autophagy-related processes may be involved in ZEA-associated HSC activation and early ECM deposition. In summary, ZEA promotes HSC activation and early profibrotic changes in the liver and is associated with inflammatory activation, TGF-β1/Smad signaling, and altered autophagy-related activity. These findings provide a basis for further investigation into the mechanisms underlying ZEA-induced early profibrotic remodeling in the liver. Full article

Down syndrome (DS), caused by trisomy 21, is the most prevalent genetic condition associated with accelerated aging and near-universal development of early-onset Alzheimer’s disease (AD). Beyond gene-dosage imbalance, trisomy 21 induces widespread transcriptional, metabolic, and proteomic remodeling that establishes a chronic state of proteotoxic and oxidative stress from early development. Increasing evidence identifies DS as a disorder of proteostasis network failure, in which sustained translational pressure, redox disequilibrium, and degradation pathway insufficiency progressively erode cellular resilience. In the DS brain, persistent endoplasmic reticulum stress with PERK-dominant signaling, mitochondrial dysfunction characterized by oxidative phosphorylation deficits and excessive reactive oxygen species production, and impaired antioxidant responses create a highly vulnerable intracellular environment. Concomitantly, degradation systems become compromised: proteasomal catalytic activity declines, ubiquitin-dependent signaling is remodeled, and chronic mTOR hyperactivation suppresses autophagic and mitophagic flux. The coordinated impairment of the ubiquitin–proteasome system and autophagy establish a feed-forward cycle of proteotoxic accumulation and redox amplification. Within this framework, Alzheimer-like neuropathology in DS emerges not solely from amyloid precursor protein triplication but as the late manifestation of decades-long proteostasis exhaustion. Therapeutic strategies aimed at restoring global proteostasis and redox balance may therefore represent a more effective systems-level approach to mitigating neurodegeneration in DS. Full article

Vascular ageing is a complex process marked by progressive endothelial dysfunction, chronic low-grade inflammation (“inflammageing”), and reduced regenerative capacity, driven in part by an imbalance between protective endothelial autophagy and cellular senescence characterized by a proinflammatory senescence-associated secretory phenotype (SASP). Disruption of this autophagy–senescence axis accelerates vascular inflammation, arterial stiffening, and atherogenesis. High-intensity interval training (HIIT), consisting of repeated bouts of near-maximal anaerobic effort with recovery periods, is widely used by both elite and recreational athletes and is increasingly recognized as an effective nonpharmacological strategy to enhance endothelial function, arterial elasticity, and mitochondrial biogenesis. However, excessively intense or poorly structured HIIT, particularly in the absence of adequate recovery or in individuals with underlying cardiometabolic or vascular vulnerability, may induce endothelial stress and promote maladaptive vascular remodelling, including calcification and plaque instability. These considerations underscore the need for refined individualized exercise prescription strategies that balance performance benefits with endothelial protection. Based on these observations, here, we introduce a novel conceptual framework, “shear dose–calibrated HIIT,” designed to understand and define an optimal shear dose capable of maximizing autophagic flux while minimizing SASP activation. Experimental and clinical evidence of HIIT-induced effects on flow-mediated dilation (FMD), pulse wave velocity (PWV), and redox biomarkers is presented, followed by the proposal of a biomarker panel for assessing autophagic flux and cellular senescence in peripheral samples (peripheral blood mononuclear cells (PBMCs), extracellular vehicles (EVs), and plasma). This integrative approach, which combines vascular mechanotransduction, redox biology, and autophagic signalling, provides a novel translational perspective on how individually calibrated HIIT can promote vascular longevity and reduce cardiometabolic risk associated with aging and metabolic syndrome. Full article

Heat stress (HS) occurs when animals are unable to effectively dissipate excess body heat, leading to increased core temperature and physiological imbalance. In mammals, HS negatively affects female reproduction. Infertility associated with HS is well documented in swine and is increasingly recognized in other mammals, including humans. HS disrupts several systemic processes that are essential for normal reproductive function, including endocrine regulation, nutrient metabolism, immune activity, and intestinal barrier integrity. Reduced feed intake and changes in metabolic hormones such as insulin and prolactin can impair ovarian function. Increased intestinal permeability during HS may allow bacterial endotoxins to enter the bloodstream, triggering inflammation that further compromises reproductive physiology. At the ovarian level, HS alters key cellular pathways involved in cell survival and metabolism, including Janus Kinase/Signal Transducer and Activator of Transcription (JAK–STAT), Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/AKT), oxidative stress responses, autophagy, apoptosis, and heat shock protein expression. These changes disrupt follicular development, hormone production, oocyte quality, and corpus luteum function, resulting in reduced conception rates and increased embryonic loss. This review summarizes current knowledge of systemic and ovarian mechanisms by which HS impairs female reproduction in pigs and identifies areas requiring further investigation to improve fertility under increasing environmental temperatures. Full article

Background: Triptolide (TPL) is an epoxytriptolide diterpenoid lactone isolated from the traditional Chinese medicinal herb Tripterygium wilfordii and exhibits broad pharmacological activities, including anti-inflammatory, immunomodulatory, and antitumor effects. Its water-soluble prodrug, minnelide, is currently undergoing clinical trials for the treatment of pancreatic cancer. Reactive oxygen species (ROS) regulate cellular fate by inducing oxidative damage and activating autophagy, which can promote cell survival under moderate stress but contribute to cell death when excessively or persistently activated. Although TPL has been reported to induce ROS accumulation, its mechanistic role in non-small cell lung cancer (NSCLC) remains incompletely understood. This study aimed to systematically investigate the role of ROS-mediated autophagy in TPL-induced cytotoxicity and to evaluate the therapeutic potential of combining TPL with autophagy inhibition in NSCLC. Methods: A series of in vitro experiments was performed to characterize TPL-mediated changes in NSCLC cell proliferation, migration, and ROS production. Autophagy- and apoptosis-related molecular alterations were analyzed using Western blotting and fluorescence microscopy with fluorescent reporter constructs. An H1299 xenograft mouse model was established to assess the antitumor efficacy of TPL in vivo and its combination effects with an autophagy inhibitor. Results: In this study, we demonstrated that TPL induces NSCLC cell death primarily through increased ROS levels. Mechanistic analyses further revealed that ROS accumulation simultaneously activates a protective autophagic response. Notably, in vivo experiments showed that co-administration of TPL with the autophagy inhibitor chloroquine resulted in significantly stronger tumor growth suppression than either treatment alone. Conclusions: Autophagy acts as a resistance mechanism against TPL-induced cytotoxicity in NSCLC, and pharmacological autophagy inhibition potentiates the antitumor activity of TPL. These findings clarify the ROS–autophagy interplay underlying TPL-mediated cell death and provide a preclinical rationale for combining TPL with autophagy inhibitors as a therapeutic strategy for NSCLC. Full article

Autophagy is an evolutionarily preserved intracellular degradation process pivotal in maintaining proteostasis, mitochondrial homeostasis, and metabolic equilibrium, all of which are dysregulated with aging. Aberrant autophagy has been recognized as a hallmark of human aging and age-related diseases, including neurodegeneration, metabolic dysfunction, cardiovascular diseases, and cancer. Bioactive natural compounds derived from plants, foods, and marine organisms have emerged as potent modulators of autophagy, offering a promising strategy to counteract aging and promote healthy lifespan. Mechanistically, these compounds regulate autophagy by modulating key signaling pathways, such as AMPK, PI3K/AKT/mTOR, SIRT1, and FOXO, while also alleviating oxidative stress, inflammation, and mitochondrial dysfunction. Natural compounds like polyphenols, flavonoids, alkaloids, terpenoids, and carotenoids exhibit dual roles by restoring age-related suppressed autophagic flux and inhibiting excessive autophagy-induced cell death. In this review, we provide a comprehensive overview of the molecular mechanisms through which bioactive natural compounds modulate autophagy and impact human aging and longevity. We discuss both experimental and clinical evidence supporting their geroprotective effects, limitations regarding bioavailability and dose-dependent effects, and prospects for the utilization of autophagy-targeting natural products in aging intervention strategies. Full article

Autophagy is a critical cellular mechanism that regulates the degradation of misfolded and aggregated proteins and non-functional intracellular organelles. Based on the fundamental qualities of the substrates targeted for degradation and the distinct molecular mechanisms involved, autophagy can be classified into three major types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Sequestosome 1 (SQSTM1)/p62, which functions as a signaling hub integrating nuclear factor kappa B (NF-κB), the mechanistic target of rapamycin complex 1 (mTORC1), and Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2–related factor 2 (NRF2) pathways, serves as a selective macroautophagy/autophagy receptor that binds ubiquitinated cargo proteins and recruits them to the autophagosome for subsequent degradation in the autolysosome. Furthermore, the phase separation of p62 is an important regulatory process in the autophagy mechanism, but recent studies have demonstrated that impaired or excessive autophagy mediated by p62 is associated with cancer development. This review summarizes the role of autophagy—including its types, mechanisms, and the pathway related to the ubiquitin-dependent selective autophagy receptor p62—in cancer progression. Full article

Autophagy and paraptosis are two distinct physiological mechanisms involved in regulating cell fate in cancer. Recent studies have demonstrated that autophagy is a crucial process for maintaining cellular homeostasis by facilitating the removal of misfolded proteins and damaged organelles. However, autophagy is found to play a dual role in cancer. Severe ER and mitochondrial dysfunction can trigger different forms of programmed cell death, including autophagic cell death. In cancer cells that evade apoptosis, paraptosis, a caspase-independent alternate death pathway, is triggered by ER and mitochondrial swelling, leading to extensive cytoplasmic vacuolation. It can be induced by natural compounds, metallic complexes, nanoparticles, or chemotherapeutic agents, primarily through excessive ROS production and disruption of protein, thiol, and calcium/ion homeostasis. Autophagy and paraptosis have been found to be connected through crosstalk. While MAPK activation drives paraptosis, ER stress and the unfolded protein response (UPR) can initiate both paraptosis and autophagy. UPR-mediated PERK activation promotes survival autophagy in ER-stressed melanoma, whereas PERK elimination triggers paraptosis via sec61β with unresolved ER stress. Similarly, CHOP and DDIT4 can enhance ER stress and proteotoxicity, thereby favouring paraptosis. This review is unique in exploring the dynamic interplay between autophagy and paraptosis in cancer cells, highlighting promising therapeutic targets for chemotherapy-resistant cancers. Full article

Sensorineural hearing loss (SNHL), the predominant form of global hearing impairment, stems from the irreversible loss of inner ear sensory cells and neurons. Since mammalian cochlea lacks regenerative capacity, cell death represents a final common pathway for diverse insults. Current therapies are merely compensatory, underscoring an urgent need for mechanistic, targeted interventions. Autophagy, a critical homeostatic process, plays complex and dynamic roles in the cochleae. This review synthesizes current evidence on its regulation, highlighting its stage-specific and dual roles in SNHL. We emphasize mitophagy and its context-dependent effects on cell survival. Critically, we discuss an emerging therapeutic paradigm: a dual-phase autophagy modulation strategy. This approach proposes enhancing cytoprotective autophagy in early stages to maintain homeostasis, while inhibiting excessive autophagic flux later to prevent catastrophic cell death. This precision-targeting framework holds significant promise for guiding novel drug development and future clinical translation, moving beyond symptomatic management towards transformative treatment. Full article

Sympathetic nervous system (SNS) imbalance is a common pathological basis for cardiovascular diseases, non-alcoholic fatty liver disease, and diabetes. This review focuses on these diseases, analyzing two core mechanisms: excessive sympathetic excitation induced by endoplasmic reticulum stress (ERS) or autophagy dysfunction in key central nuclei (e.g., hypothalamus, rostral ventrolateral medulla); and ERS/autophagy abnormalities in peripheral target organs caused by chronic SNS overactivation. Existing studies confirm that chronic SNS overactivation promotes peripheral metabolic overload via sustained catecholamine release, inducing persistent ERS and disrupting the protective unfolded protein response (UPR)–autophagy network, ultimately leading to cell apoptosis, inflammation, and fibrosis. Notably, central ERS or autophagy dysfunction further perturbs autonomic homeostasis, exacerbating sympathetic overexcitation. This review systematically elaborates on SNS overactivation as a critical bridge mediating UPR–autophagy network dysregulation in central and peripheral tissues, and explores therapeutic prospects of targeting key nodes (e.g., chemical chaperones, specific UPR modulators, nanomedicine), providing a theoretical basis for basic research and clinical translation. Full article