Search Results (4,245)

Schizophrenia is a highly polygenic and clinically heterogeneous disorder. We first review layer-specific evidence across genetics, epigenetics, transcriptomics, proteomics, and patient-derived induced pluripotent stem cell (iPSC) models, then integrate cross-layer findings. Genetics research identifies widespread risk architecture. Hundreds of loci from common, rare, and CNV analyses. Epigenetics reveals disease-associated DNA methylation and histone-mark changes. These occur at neuronally active enhancers and promoters, together with chromatin contacts that link non-coding risk to target genes. Transcriptomics show broad differential expression, isoform-level dysregulation, and disrupted co-expression modules. These alterations span synaptic signaling, mitochondrial bioenergetics, and immune programs. Proteomics demonstrates coordinated decreases in postsynaptic scaffold and mitochondrial respiratory-chain proteins in cortex, with complementary inflammatory signatures in serum/plasma. iPSC models recapitulate disease-relevant phenotypes: including fewer synaptic puncta and excitatory postsynaptic currents, electrophysiological immaturity, oxidative stress, and progenitor vulnerability. These same models show partial rescue under targeted perturbations. Integration across layers highlights convergent pathways repeatedly supported by ≥3 independent data types: synaptic signaling, immune/complement regulation, mitochondrial/energetic function, neurodevelopmental programs and cell-adhesion complexes. Within these axes, several cross-layer convergence genes/proteins (e.g., DLG4/PSD-95, C4A, RELN, NRXN1/NLGN1, OXPHOS subunits, POU3F2/BRN2, PTN) recur across cohorts and modalities. Framing results through cross-layer and shared-pathway convergence organizes heterogeneous evidence and prioritizes targets for mechanistic dissection, biomarker development, and translational follow-up. Full article

Heart failure (HF) has become an emerging problem, especially in regions where life expectancy is increasing. Despite its prevalence, the mechanisms behind HF development are not well understood, which is reflected in the lack of curative therapies. Mitochondria, autophagy, and sirtuins form a crucial triad involved in HF pathogenesis, interconnected by oxidative stress. Identifying a common pathway involving these three components could be valuable in developing new treatment strategies. Since HF is the end result of several cardiovascular diseases, this review highlights the main HF precursors and explores the roles of mitochondrial quality control (mtQC), autophagy, and sirtuins in HF development. Dysfunctional mitochondria may play a key role by enhancing oxidative stress and influencing autophagy and sirtuins, both of which possess antioxidant properties. The dual nature of autophagy—its pro-life and pro-death roles—may contribute to different outcomes in HF related to oxidative stress. As mtQC, autophagy, and sirtuins may interact, we present data on their mutual dependencies in HF. However, the specificity of these interactions remains unclear and needs further investigation, which could help identify new therapeutic targets. In conclusion, the interplay between mtQC, autophagy, and sirtuins may be crucial in HF pathogenesis and could be leveraged in developing HF treatments. Full article

The Marburg virus (MARV) is a zoonotic pathogen that causes a high case fatality rate of up to 100% in humans. In response to Marburg virus disease (MVD) outbreaks in the Kagera region, an ecological investigation was initiated to map the population and ecological threat to the reservoir host of MARV: Egyptian fruit bats. The investigation conducted from October 2023 to December 2024 included interviews with local authorities to locate all known autochthonous bat colonies in the region. Bat species confirmation was performed using high-resolution melting analysis (HRMA) and DNA barcoding, targeting two mitochondrial genes: cytochrome oxidase 1 (COI) and 16S rRNA. We found five considerably large cave-dwelling Egyptian fruit bat colonies (with approximately 100,000 individuals) at the geolocations between 1°06′04.2″ and 2°26′35.8″ S latitude and 30°40′49.7″ and 31°51′19.8″ E longitude. The study also provides the first confirmed identification of Egyptian fruit bats (Rousettus aegyptiacus) (accession numbers: PV700530-PV700534) in major bat colonies in the Kagera River Basin ecosystem. Cave-dwelling Egyptian fruit bats in mines face higher risks, and thus, attention is needed to prevent this species from becoming more vulnerable to extinction. The loss of bat roosting sites and subsequent population declines are primarily driven by the destructive practice of burning car tyres and logs, a method used to eliminate colonies through toxic smoke and heat. The collection of guano and partially eaten fruits in mining caves, as well as daily contact with Egyptian fruit bats in mines, homes, and churches, have become major potential risk factors for MARV transmission to humans. Increased threats to bats in the Kagera region warrant the implementation of conservation strategies that ensure the survival of the bat populations and inform policies on MVD risk reduction in Tanzania and the broader East African region. Full article

Background/Objectives: Acetaminophen (APAP) is used during 50–60% of pregnancies in the U.S. and has been associated with childhood respiratory morbidity, though the underlying mechanism remains unclear. APAP-induced injury is dependent on cell-specific expression of CYP2E1, the enzyme that metabolizes APAP into the mitochondrial toxin NAPQI. In mice, pulmonary Cyp2e1 expression peaks during the saccular stage of lung development on embryonic day 18 (E18). We investigated whether this developmental surge in Cyp2e1 triggers a pulmonary transcriptional response to maternal APAP exposure in embryonic lungs. Methods: Pregnant dams were exposed to APAP on E17 or E18 (150 or 250 mg/kg, IP) using doses derived from prior studies. We assessed the induction of NRF2 target genes and genes associated with inflammation, apoptosis and cellular stress due to their roles in APAP-induced oxidative and cellular stress. Results: At E17, maternal treatment with APAP induced pulmonary Cyp2e1 but resulted in inconsistent transcriptional changes. In contrast, maternal APAP at E18 triggered a robust transcriptional induction of Cyp2e1, NRF2 targets and markers of apoptosis, inflammation and cellular stress. Histopathology at birth after E18 APAP exposure revealed no acute pulmonary injury. Conclusions: We demonstrate a developmentally regulated, dose-dependent transcriptional response to maternal APAP in the embryonic murine lung. Importantly, transcriptional responses do not directly indicate lung injury; thus, future studies should assess protein-level changes following APAP exposure. This study underscores the need for further investigation into the role of developmentally regulated Cyp2e1 expression in APAP-induced toxicity and long-term respiratory morbidity. Full article

Leaf senescence is the final, programmed stage of leaf development, marked by nutrient remobilization and tightly regulated molecular events. Although alternative splicing has emerged as a major regulator of plant development, its role in isoform switching during leaf aging remains poorly understood. To address this, we conducted a genome-wide analysis of isoform switching in Arabidopsis, leveraging publicly available RNA-seq data from mature (16-day-old) and senescent (30-day-old) leaves, analyzed with the IsoformSwitchAnalyzeR package. Between these two developmental stages, we identified 269 genes exhibiting 377 significant isoform switches collectively predicted to alter protein localization, coding potential, and transcript stability. Experimental validation confirmed predicted switching at the PUS3 (Pseudouridine Synthase 3) locus, with sequence analysis revealing an age-dependent shift from mitochondrial-targeted to cytoplasmic isoforms. Gene Ontology enrichment analysis of switching genes revealed 82 significant terms, prominently associated with metabolism, gene expression, developmental regulation, and stress responses. Interestingly, we found nearly one-third of switching genes to overlap with known targets of the splicing factor SR45, with enrichment in pathways related to nucleotide and amino acid metabolism, energy production, and developmental processes. Correspondingly, dark-induced senescence assays revealed accelerated senescence in the sr45 mutant, confirming SR45′s role in regulating leaf aging. Specific complementation of SR45′s two isoforms revealed contrasting functions, with SR45.1 restoring normal senescence timing while SR45.2 failed to complement. Taken together, our findings demonstrate that differential isoform usage, orchestrated by specific splicing regulators, plays a critical role in leaf aging. This insight opens new avenues for manipulating senescence and engineering stay-green traits in crops. Full article

The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function (“OXPHOS-high” cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling, suggestive of increased mitochondrial fusion. A genome-wide CRISPR editing screen in doxorubicin-persistent OXPHOS-high TNBC cells revealed the BCL-XL gene as the top survival dependency in these quiescent tumor cells, but not in their untreated proliferating counterparts. Quiescent OXPHOS-high TNBC cells were highly sensitive to BCL-XL inhibitors, but not to inhibitors of BCL2 and MCL1. Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis-targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy. Full article

Autophagy is a conserved process that involves the degradation of damaged proteins and organelles to restore cellular homeostasis. Autophagy plays a critical role in cell differentiation, immune responses, and protection against pathogens, as well as the development and progression of allergic inflammation. Crosstalk between autophagy and signaling pathways modulates immune responses to inflammatory signals. Here, we discuss the regulatory roles of autophagy in allergic inflammation. Autophagy can promote allergic inflammation by enhancing the secretion of inflammatory mediators. Impaired autophagy resulting from the accumulation of autophagosomes can exacerbate allergic inflammation. Mast cell degranulation and activation require energy provided by mitochondrial respiration. Mast cell activation is accompanied by morphological changes and mitochondrial fragmentation. Mitochondrial fragmentation (mitophagy) induced by oxidative stress involves the degradation of defective mitochondria. Therefore, we discuss the relationship between mitophagy and allergic inflammation. Targeting autophagy and oxidative stress can be a strategy for developing anti-allergy therapeutics. In this review, we also discuss future research directions to better understand allergic diseases with respect to autophagy and develop effective anti-allergy drugs. Full article

Fibromyalgia is a chronic syndrome characterized by widespread musculoskeletal pain, fatigue, non-restorative sleep, and cognitive impairment. Its pathogenesis reflects a complex interplay between central and peripheral mechanisms, including altered pain modulation, neuroinflammation, mitochondrial dysfunction, autonomic imbalance, and genetic and epigenetic factors. Evidence from neuroimaging, omics studies, and neurophysiology supports this multifactorial model. Epidemiological updates confirm a global prevalence of 2–8%, with a strong female predominance and a significant impact on quality of life and healthcare costs. Diagnostic criteria have evolved from the 1990 American College of Rheumatology tender points to the 2010/2011 revisions and the 2016 update, improving case ascertainment but still lacking objective biomarkers. Recent omics and systems biology approaches have revealed transcriptional, proteomic, and metabolic signatures that may enable molecularly informed stratification. Therapeutic management remains multidisciplinary, combining pharmacological interventions (e.g., duloxetine, pregabalin, milnacipran) with non-pharmacological strategies such as graded aerobic exercise and cognitive behavioral therapy. Emerging approaches include drug repurposing to target neuroinflammation, mitochondrial dysfunction, and nociceptive pathways. Despite promising advances, progress is limited by small sample sizes, heterogeneous cohorts, and lack of standardization across studies. Future priorities include large-scale validation of biomarkers, integration of multi-omics with clinical phenotyping, and the design of precision-guided trials. By synthesizing mechanistic insights with clinical evidence, this review provides an updated framework for the diagnosis and management of fibromyalgia, highlighting pathways toward biomarker-guided, personalized medicine. Full article

Pufferfish are an economically important food in Asia despite the potential risk of tetrodotoxin (TTX) poisoning. To promote food safety by ensuring the correct identification of pufferfish species, we developed common and species-specific primer sets for four Lagocephalus species (Lagocephalus spadiceus, Lagocephalus cheesemanii, Lagocephalus wheeleri, and Lagocephalus inermis) based on analysis of mitochondrial DNA cytochrome c oxidase subunit I (COI) in various pufferfish species commonly distributed and/or legally sold in Korea. The common primers were developed based on complete sequence data acquired from GenBank. The total length of fragments amplified by the common primer set was 1280 bp. Then, species-specific multiplex polymerase chain reaction (PCR) amplification was conducted for the four target species, obtaining 980 bp for L. spadiceus, 859 bp for L. cheesemanii, 672 bp for L. wheeleri, and 563 bp for L. inermis. Multiplex PCR is an important tool for the simple, rapid, accurate, and simultaneous identification of target species. The newly developed primer sets will contribute to reducing the occurrence of TTX poisoning and protect consumer rights by eradicating the mislabeling or fraudulent use of pufferfish products. Full article

Hearing loss is a major health burden, often caused by ototoxic drugs such as cisplatin and gentamicin. Effective therapy is limited by the poor penetrability of drugs into inner ear compartments. This study aimed to develop and test magnetic cationic liposomes as nanocarriers for targeted corticosteroid delivery to auditory hair cells. Carboxymethyl chitosan–coated liposomes were prepared by the lipid film hydration method, incorporating magnetic nanoparticles and dexamethasone phosphate in their aqueous core. The optimal liposomal formulation, in terms of size, zeta potential, and drug leakage over time, was selected and tested in an in vitro model of drug-induced ototoxicity. HEI-OC1 cells exposed to cisplatin or gentamicin were co-treated with the liposomal formulations, and viability, mitochondrial membrane potential, and β-galactosidase activity were assessed. The results demonstrated that magnetic, polymer-coated liposomes protected against cytotoxicity by preserving mitochondrial function and significantly reducing senescence. These findings provide a proof of concept for magnetically responsive liposomal systems as potential therapeutic platforms for preventing or treating drug-associated hearing loss. Full article

Obesity contributes to the development of metabolic disorders such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) through sustained low-grade inflammation and mitochondrial dysfunction. In obesity, hypertrophied adipose tissue release high levels of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, and elevates circulating free fatty acids. These changes promote systemic insulin resistance and ectopic lipid deposition. Mitochondrial dysfunction, including reduced oxidative phosphorylation, excess reactive oxygen species (ROS) production, and mitochondrial DNA damage, further stimulate inflammatory pathways such as the NLRP3 inflammasome, creating a feedback loop that worsens metabolic stress. Ultimately, this interaction disrupts energy balance, weakens insulin signaling, and accelerates β-cell dysfunction and hepatic steatosis. In both T2DM and MASLD, oxidative stress, defective mitochondrial quality control, and dysregulated immunometabolic responses are consistently observed pathophysiological features. Interventions aimed at reducing inflammation and restoring mitochondrial function—including lifestyle modification, mitochondria-targeted therapies, inflammasome regulation, and enhancement of mitochondrial biogenesis or mitophagy—may retard disease progression. Full article

Oxidative stress and inflammation are deeply interconnected processes implicated in the onset and progression of numerous chronic diseases. Despite promising mechanistic insights, conventional antioxidant and anti-inflammatory therapies such as NSAIDs, corticosteroids, and dietary antioxidants have shown limited and inconsistent success in long-term clinical applications due to challenges with efficacy, safety, and bioavailability. This review explores the molecular interplay between redox imbalance and inflammatory signaling and highlights why conventional therapeutic translation has often been inconsistent. It further examines emerging strategies that aim to overcome these limitations, including mitochondrial-targeted antioxidants, Nrf2 activators, immunometabolic modulators, redox enzyme mimetics, and advanced delivery platforms such as nanoparticle-enabled delivery. Natural polyphenols, nutraceuticals, and regenerative approaches, including stem cell-derived exosomes, are also considered for their dual anti-inflammatory and antioxidant potential. By integrating recent preclinical and clinical evidence, this review underscores the need for multimodal, personalized interventions that target the redox-inflammatory axis more precisely. These advances offer renewed promise for addressing complex diseases rooted in chronic inflammation and oxidative stress. Full article

Diabetic retinopathy (DR) is a leading cause of vision loss globally and represents one of the most common microvascular complications of diabetes. In addition to metabolic disturbances associated with hyperglycemia, oxidative stress has emerged as a critical contributor to the onset and progression of DR. Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and antioxidant defense mechanisms, leads to cellular injury, inflammation, and increased vascular permeability. In the diabetic retina, excessive ROS production promotes endothelial cell apoptosis, breakdown of the blood-retinal barrier (BRB), and induction of angiogenic factors such as vascular endothelial growth factor (VEGF). This review provides a comprehensive overview of the pathophysiology of DR, focusing on the molecular mechanisms of oxidative stress. Relevant studies were identified through a structured search of PubMed, Web of Science, and Scopus (2000–2025) using terms such as ‘diabetic retinopathy’, ‘oxidative stress’, and ‘antioxidants’. We explore current knowledge on oxidative stress-related biomarkers and therapeutic strategies targeting oxidative damage, including antioxidant compounds and mitochondrial protective agents. Recent findings from both experimental and clinical studies are summarized, highlighting the translational potential of oxidative stress modulation in DR management. Finally, future research directions are discussed, including biomarker standardization, personalized medicine approaches, and long-term clinical validation of antioxidant-based therapies. A deeper understanding of oxidative stress may offer valuable insights into novel diagnostic and therapeutic strategies for DR. Full article

Breast cancer, a leading global malignancy, exhibits extensive metabolic reprogramming that drives tumorigenesis, therapy resistance, and survival. Ferroptosis, an iron-dependent regulated cell death mechanism characterized by lipid peroxidation, emerges as a promising therapeutic vulnerability, particularly in aggressive subtypes like triple-negative breast cancer (TNBC). This literature review comprehensively explores the metabolic regulation of ferroptosis in breast cancer cells, focusing on how dysregulated pathways modulate sensitivity or resistance. The review will discuss iron homeostasis, including upregulated transferrin receptor 1 (TFR1), diminished ferroportin, mitochondrial dynamics, and ferritinophagy, which catalyze ROS via Fenton reactions. It will examine glutathione (GSH) metabolism through the GPX4-GSH axis, with subtype-specific reliance on cystine import via xCT or de novo cysteine synthesis. Lipid metabolism will be analyzed as the core battleground, highlighting polyunsaturated fatty acid (PUFA) incorporation by ACSL4 promoting peroxidation, contrasted with monounsaturated fatty acid (MUFA) protection via SCD1, alongside subtype adaptations. Further, the review will address tumor microenvironment influences, such as cysteine supply from cancer-associated fibroblasts and oleic acid from adipocytes. Oncogenic signaling (e.g., RAS, mTOR) and tumor suppressors (e.g., p53) will be evaluated for their roles in resistance or sensitivity. Intersections with glucose metabolism (Warburg effect) and selenium-dependent antioxidants will be explored. Therapeutically, the review will consider targeting these nodes with GPX4 inhibitors or iron overload, synergized with immunotherapy for immunogenic cell death. Future directions will emphasize multi-omics integration and patient-derived organoids to uncover subtype-specific strategies for precision medicine in breast cancer. Full article

Leprosy is a chronic infectious disease that targets the peripheral nervous system, leading to peripheral neuropathy. Mycobacterium leprae primarily infects Schwann cells, adipocytes, and macrophages, altering their metabolism and gene expression. This study investigates the metabolic interaction between M. leprae and Schwann cells, with a focus on indoleamine 2,3-dioxygenase (IDO), a key enzyme in tryptophan catabolism via the kynurenine pathway. We found that M. leprae induces IDO expression in Schwann cells, suggesting a role in immune modulation and neuropathy. Inhibition of IDO with 1-methyl-L-tryptophan (1-MT) reduced Schwann cell viability and metabolic activity in response to M. leprae. After 24 h of infection, M. leprae impaired mitochondrial membrane potential, although no significant changes in autophagy or mitochondrial ultrastructure were observed by electron microscopy. Interestingly, IDO1 inhibition upregulated the expression of antioxidant genes, including GPX4, NFE2L2, and HMOX1. In conclusion, these findings highlight a central role for IDO in shaping the metabolic and immunological response of Schwann cells to M. leprae infection. IDO induction contributes to immune regulation and cellular stress, while its inhibition disrupts cell viability and promotes antioxidant gene expression. These results position IDO as a potential therapeutic target for modulating host–pathogen interactions and mitigating nerve damage in leprosy. Full article