Search Results (2,416)

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation, playing a critical role in the pathogenesis of various cardiomyopathies, including hypertrophic, dilated, diabetic, ischemic, doxorubicin-induced, and septic cardiomyopathy, as well as myocardial ischemia–reperfusion injury. This article provides a comprehensive narrative review of the molecular mechanisms of ferroptosis—centered on dysregulation of the GPX4/System Xc⁻ axis, iron metabolism, and lipid metabolism—and its role in cardiovascular diseases, with a specific focus on the cardioprotective effects of Traditional Chinese Medicine (TCM). Through a systematic analysis of recent literature, we highlight active components (e.g., baicalin, ginsenoside Rg3, resveratrol, tanshinone IIA), compound formulations (e.g., Qishen Granule, Zhilong Huoxue Tongyu Capsule), and electroacupuncture therapy, which exert effects via multi-target regulation of ferroptosis-related pathways such as Nrf2/HO-1/GPX4, p53/SLC7A11, and PI3K/AKT. Evidence indicates that TCM interventions effectively alleviate cardiomyocyte ferroptosis by activating the Nrf2 antioxidant pathway to upregulate GPX4/SLC7A11, modulating iron metabolism to reduce labile iron pools, and inhibiting ACSL4/ALOX15-mediated lipid peroxidation, with these effects validated in diverse cardiovascular disease models showing improved cardiac function. Targeting ferroptosis offers a novel therapeutic strategy for cardiovascular diseases, and TCM—with its synergistic multi-component, multi-target, multi-pathway advantages—holds significant potential in this context. Future research should prioritize elucidating complex network mechanisms and advancing clinical translation via high-quality studies to provide new theoretical foundations and drug candidates for cardiovascular disease management. Full article

Probiotic supplements are increasingly being touted to have health benefits for pregnant women consuming such supplements and their unborn offspring. The placenta is in direct communication with maternal blood, and bioactive agents can thus easily be transferred to this organ where they may influence gene expression by the different trophoblast (TB) cell lineages. The underlying hypothesis assessed herein is that maternal probiotic supplementation can influence the placenta and fetal brain. The composition of bacterial short-chain fatty acids (SCFAs) was examined in fecal boli of mouse dams on a maternal probiotic supplement relative to control dams. Further, SCFA and transcriptomic profiles were examined in placenta and fetal brain from conceptuses derived from dams on the probiotic supplement and conceptuses from control dams. While this treatment did not affect bacterial SCFAs, placenta and fetal brain changes were evident in male and female conceptuses carried by dams receiving probiotics relative to controls. For the placenta, females were more sensitive to maternal probiotic supplementation, whereas the opposite was the case for the fetal brain. Slc6a4 showed increased expression in female placenta from probiotic-treated dams, which could enhance uptake of maternal 5-HT. Male placenta from probiotic-treated dams had dramatic reduction in Hsd11b2 that may render them more vulnerable to maternal stress. In the fetal brain, maternal probiotic supplementation was associated with genes linked to forebrain development, suggesting this treatment might impact life-long neurobehavioral responses. Current studies suggest that maternal probiotic supplementation might lead to adverse changes in the placenta and fetal brain of their unborn children. Full article

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness driven by elevated intraocular pressure from compromised aqueous outflow. While genome-wide association studies have identified numerous risk loci, specific candidate proteins and their cellular mechanisms remain elusive. We employed a multi-omics framework integrating UK Biobank plasma proteomics (N = 53,022) and large-scale POAG GWAS summary statistics. We performed a Proteome-Wide Association Study, Mendelian Randomization, and Bayesian colocalization to infer causality. Identified candidates were mapped to human and mouse ocular scRNA-seq atlases to characterize cell-type specificity, followed by druggability assessments. We prioritized five putative causal proteins, with SEL1L and TFPI demonstrating the strongest evidence. Cross-species scRNA-seq revealed that SEL1L and SERPINF1 are robustly expressed in the trabecular meshwork (TM), particularly the juxtacanalicular tissue, implicating them in outflow resistance. Conversely, TFPI and SLC9A3R2 localize to Schlemm’s canal endothelium, suggesting a role in modulating barrier function. Pathway analyses highlighted endoplasmic reticulum protein processing and coagulation cascades. This study maps putative causal POAG proteins to conventional outflow pathway cells, highlighting SEL1L as a novel target for TM homeostasis and TFPI for drug repurposing, thereby providing data-driven hypotheses to facilitate precision glaucoma therapeutics. Full article

Thyroid hormones (THs) are essential regulators of human brain development, and disrupted TH availability during pregnancy or early life is linked to adverse neurodevelopmental outcomes. Concerns that environmental chemicals interfere with TH signalling have increased the need for human-relevant in vitro systems to identify thyroid hormone system-disrupting chemicals (THSDCs) for risk assessment. Here, we compared two human-induced pluripotent stem cell (hiPSC)-derived brain organoid models for THSDC assessment: (i) human cortical organoids (COs) generated by unguided differentiation, offering higher architectural complexity but lower throughput; and (ii) neural stem cell-derived organoids (NSCOs), designed for scalability with reduced cellular diversity. Both models expressed key TH handling components, including the transporter SLC16A2 (MCT8) and the inactivating enzyme DIO3. Using LC–MS/MS, we show that exogenous T3 is depleted from culture media and metabolized to 3,3′-T2 and 3′-T1 in both models, alongside upregulation of T3-responsive genes (HR, KLF9, DIO3, SEMA3C). Pulse and chronic co-exposures to reference disruptors iopanoic acid (IA, deiodinase inhibitor) and silychristin (SC, MCT8 inhibitor) altered T3 metabolism and modulated T3-responsive transcriptional endpoints. In NSCOs, high-content imaging revealed treatment-associated changes in cell composition, with chronic T3 reducing the SOX2-positive progenitor pool and THSDCs blocking this effect. Together, these findings provide a framework for organoid qualification—linking TH handling, transcriptomic responsiveness, and scalable phenotypic readouts—as a necessary step toward model validation and implementation of brain organoids in THSDC risk assessment pipelines. Full article

Context/Objective: Fungi of the genus Tolypocladium are known for their diverse metabolic capabilities and medicinal potential. Indole diterpenoids (IDTs) represent a structurally unique class of fungal metabolites. Beyond their established roles as mycotoxins, these compounds have recently shown promise for neuroprotective effects. The objective of this study was to isolate and characterize novel IDTs from Tolypocladium album DWS131 and evaluate their neuroprotective activities and underlying mechanisms. Methods: IDTs were isolated through comprehensive chromatographic techniques. Their structures were elucidated using HRESIMS data, 1D/2D NMR spectra, and quantum chemical calculations. Neuroprotective effects were evaluated using glutamate (Glu)-induced R28 cells in vitro and N-methyl-D-aspartic acid-induced mouse models in vivo. A total of 48 mice were utilized for in vivo evaluations, divided into two separate experimental cohorts. In each cohort, mice were randomly assigned to four groups (n = 6 per group). Post-intravitreal injection, retinal survival and visual function were assessed via Brn3a-stained flat-mounts, H&E staining, f-VEP, f-ERG, and OptoDrum. Mechanisms involving the SLC7A11/GPX4/ACSL4 axis were investigated by Western blotting and immunofluorescence. Results: Seven previously undescribed paxilline-type IDTs, tolypindoles A–G (1–7), and two known analogues (8–9) were identified. Compounds 8 and 9 exhibited significant neuroprotection closely associated with the attenuation of oxidative stress and the modulation of ferroptosis-related pathways in Glu-induced R28 cells. In vivo, they preserved retinal ganglion cells, maintained retinal structure, and protected visual function, with compound 8 demonstrating superior efficacy. Mechanistic investigations revealed that both compounds modulate the SLC7A11/GPX4/ACSL4 signaling axis. Conclusions: This study expands the chemical diversity of T. album DWS131. Compounds 8 and 9, characterized by isopentenyl moieties, highlight a promising therapeutic potential for retinal neurodegenerative diseases such as glaucoma. Full article

Heat stress (HS) is among the most economically consequential environmental challenges to global dairy production, causing progressive declines in milk yield, compositional quality, and mammary cellular integrity. The temperature–humidity index (THI) is the primary thermal load metric, with performance-impairment thresholds typically beginning at THI 68 in Holstein cattle, with severe impacts manifesting beyond THI 72; breed-specific thresholds for Jersey, Brown Swiss, and Simmental cows differ owing to their lower metabolic heat load and greater inherent thermotolerance. At the molecular level, HS activates heat shock protein networks—notably HSPA1A, HSP90B1, and HSPH1—through HSF1/HSF4 transcriptional activation, while simultaneously suppressing casein genes (CSN1S1, CSN2, CSN3), lipogenic genes (FASN, SCD, CD36), amino acid transporters (SLC7A5, SLC38A2), and mTOR-AKT-STAT5 translational machinery, collectively impairing milk biosynthetic capacity. Pro-apoptotic signaling (BAX, CASP3 upregulation; BCL2 downregulation) and mitochondrial dysfunction further compromise mammary epithelial viability. Post-transcriptional regulation through miRNA, circRNA, and lncRNA competing endogenous RNA networks, alongside epitranscriptomic m6A modifications, adds further regulatory complexity. Genome-wide association studies have identified SNPs in HSP70A1A, HSPA4, TLR4, and PRLR as thermotolerance candidates compatible with sustained milk production. Nutritional supplementation with methionine, arginine, and taurine partially restores cellular synthetic capacity. Integrating multi-trait genomic selection with Bos indicus introgression, precision cooling, and targeted nutrition offers the most viable path toward climate-resilient, high-producing dairy cattle. Full article

Background: Dystonia is a heterogeneous hyperkinetic movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and postures. Although numerous genes associated with dystonia have been identified, the genetic background remains unknown in many patients. Data on genotype–phenotype correlations in Polish populations remain limited. Objective: To analyze the clinical characteristics of patients with generalized dystonia and compare clinical features between individuals with and without genetically confirmed dystonia-causative variants in a Polish cohort. Methods: A retrospective analysis of patients diagnosed with generalized dystonia at a single neurological center was performed. Diagnosis was established according to MDS criteria. Genetic analysis included whole-exome sequencing, targeted NGS genetic panel, MLPA, Sanger sequencing and PCR_RFLP analysis. Clinical and demographic data were extracted from medical records. Clinical characteristics of individuals with and without causative variants were compared. Results: A total of 113 patients with generalized dystonia were included. Genetic variants were identified in 13 patients (11.5%). These included variants within the TOR1A, THAP1, SGCE, GCH1, NKX2-1, SLC2A1, KMT2B, PDHA1, MFN2, and GNAL genes. We found detailed clinical data of 46 patients included in the study. Our comparative analysis of patients with causative (n = 7) and without causative variants (n = 39) revealed no statistically significant differences in age of onset, initial symptom localization, treatment response, family history, or associated neurological features. Conclusions: In this cohort of Polish patients with generalized dystonia, we identified pathogenic variants in approximately 11.5% of cases. No significant clinical differences were observed between patients with genetically confirmed dystonia and those without identified variants. In this study, we report the first two Polish cases with DYT-GNAL variants. Further studies are required to reveal the clinical heterogeneity of dystonia and characterize dystonia subtypes. Full article

In aquaculture, fish physiological information serves as the foundation for behavior recognition, precise feeding, and health monitoring. The acquisition of such information relies on accurate keypoint detection and pose estimation of the fish body. To address the challenges caused by inter-occlusion among fish schools and blurred keypoint boundaries in underwater environments, a novel fish pose estimation method based on the Adaptive-kernel Hybrid-center Structural Constraint Network (AHSC-Net) is proposed. Optimized specifically for the characteristics of fish poses, the proposed method effectively enhances detection accuracy and robustness in complex underwater scenarios. First, a Stochastic Local Centroid Sampling (SLCS) strategy is introduced to improve detection capability. By simulating centroid positions in occluded samples, this approach enhances the model’s ability to detect partially occluded fish. Next, a Spatial-Awareness Enhanced Pose Structural Constraint (SAPSC) is established through coordinate embedding and morphological constraints. It ensures the rationality of the predicted poses. Furthermore, an Adaptive Kernel Modulation Module (AKMM) is designed to dynamically adjust the Gaussian kernel distribution, effectively addressing challenges posed by underwater blurring and variations in fish scales. Experimental results demonstrate that AHSC-Net achieves 92.0% AP and 94.6% AR on a self-constructed largemouth bass dataset, outperforming state-of-the-art methods such as HRNet, HigherHRNet, DEKR, and YOLO-Pose. This study presents a fish pose estimation method that provides effective technical support for automated and precise monitoring in aquaculture. Full article

Chronic intermittent hypoxia (CIH), the cardinal pathophysiological feature of obstructive sleep apnea, is increasingly recognized as an important modifier of metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying mechanisms remain incompletely understood. In this study, male C57BL/6 mice were fed a standard diet or a high-fat diet (HFD) and exposed to normoxia or CIH for 8 weeks. Histological, ultrastructural, biochemical, transcriptomic, proteomic, and metabolomic analyses were integrated to characterize hepatic alterations induced by CIH under metabolic stress. CIH markedly aggravated HFD-induced liver injury, as evidenced by increased body fat, hepatomegaly, serum transaminases, steatosis, mitochondrial ultrastructural alterations, and inflammatory infiltration. Mechanistically, CIH promoted hepatic lipid metabolic reprogramming by suppressing the PPARα/CPT1A fatty acid β-oxidation axis while enhancing the SREBP-1c/FASN/PLIN2 lipogenic pathway, impaired the Nrf2/HO-1/SLC7A11/GPX4 antioxidant defense system, increased lipid peroxidation and iron accumulation, and activated NF-κB/NLRP3 signaling. These findings support a multifactorial model in which CIH functions as an additional hypoxic stressor that exacerbates HFD-induced MASLD-like liver injury through coordinated metabolic, oxidative, and inflammatory dysregulation. Full article

Caffeine (CAF) is a widely consumed psychostimulant known to modulate adenosine receptors and neurotransmitter systems, although its effects in invertebrates remain poorly understood. Environmentally relevant concentrations (5, 30, and 50 µg/L) are associated with altered behavior, including locomotion, exploration, and feeding, in the freshwater gastropod Physella acuta. This study examined molecular responses underlying these effects. Adult snails were exposed to CAF for 24 h and 7 days. Gene expression related to the nervous system and stress pathways was analyzed by RT-PCR, including A1AR, ADORA2B, AChE, GLRA2, DRD2, RYR, HSD11β, HSP70, SLC6A2, and SLC6A1. After 24 h, exposure to 50 µg/L CAF altered A1AR expression and caused downregulation of AChE, GLRA2, and DRD2, associated with observed behavioral changes. A1AR upregulation may indicate compensatory adjustment in adenosine signaling. After 7 days, A1AR remained upregulated, while genes linked to inhibitory neurotransmission showed partial recovery. Increased expression of genes involved in dopamine regulation and steroid metabolism suggested physiological adaptation. Overall, CAF induced dose- and time-dependent molecular responses in P. acuta, linking neurochemical disruption with behavioral changes and highlighting its ecological risk as an emerging freshwater contaminant. Full article

Skeletal muscle satellite cells are indispensable for muscle growth and regeneration, and their myogenic differentiation is precisely controlled by transcription factors. As a core member of the TEAD family, TEAD4 participates in various biological processes, yet its function and regulatory mechanism in porcine skeletal muscle satellite cells (PSCs) remain largely unknown. High-purity PSCs were isolated and identified from 7-day-old Large White piglets. Combined approaches of siRNA-mediated TEAD4 knockdown, RT-qPCR, Western blotting, immunofluorescence, EdU assays, and transcriptome sequencing were applied to explore the role of TEAD4 during myogenic differentiation. TEAD4 expression was gradually upregulated during PSC differentiation and positively correlated with myogenic marker genes. Knockdown of TEAD4 did not affect PSC proliferation but significantly suppressed myogenic differentiation, as indicated by reduced expression of myogenic genes and blocked myotube formation. Transcriptomic analysis demonstrated that DEGs were highly enriched in metabolic pathways, particularly the AMPK signaling pathway. TEAD4 knockdown led to excessive upregulation of PRKAG3 and prominent induction of SLC2A4. Collectively, these results indicate that TEAD4 promotes myogenic differentiation in PSCs, likely by maintaining metabolic homeostasis. This study provides the first characterization of TEAD4 in porcine skeletal muscle satellite cells and demonstrates that it promotes myogenic differentiation. Full article

Endometriosis (EMT) is characterized by a chronic inflammatory disorder in the female reproductive system, posing significant challenges to global women’s health. Necrosis by Sodium Overload (NESCO) is a novel immunogenic programmed cell death (PCD) pattern that may potentially inhibit natural killer (NK) cell activation by increasing cytotoxicity and the inflammatory response in the EMT microenvironment. By integrating three bulk datasets to compare endometrium tissues between endometriosis patients and normal controls and the NESCO gene list from a public database, we identified NK- and NESCO (NN)-associated hub genes via integrative bioinformatic analyses utilizing Limma, WGCNA, CIBERSORT and machine learning frameworks. The diagnostic performance of NN-associated hub genes was evaluated across the three aforementioned datasets and two independent validation sets. Furthermore, their molecular and immune features were estimated at the bulk and single-cell transcriptomic levels. In addition, endometriosis patients were classified into two novel molecular subgroups based on consensus clustering of NN. Finally, the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and molecular docking were used to identify compounds in Chinese traditional medicine (CTM) that can target NN-associated hub genes for endometriosis treatment. FABP4 and SLC2A1 can be considered NN-associated hub genes that are involved in EMT pathogenesis, and natural compounds including the CTM GuiZhiFuLingWan (GZFLW) can be considered therapeutic agents for EMT treatment as they target FABP4 and SLC2A1. Our study is the first to reveal the diagnostic and druggable roles of NESCO and NK cells, the corresponding molecular and immune features of NN-associated hub genes, and the therapeutic potential of GZFLW. Full article

Zinc transport plays a critical role in cellular signaling, but its function in the tumor microenvironment remains poorly understood. We aimed to investigate the role of zinc transporters in cancer-associated fibroblasts in head and neck squamous cell carcinoma. Single-cell RNA sequencing data were analyzed to evaluate zinc transporter expression across tumor cell populations, and bulk RNA sequencing of primary fibroblast cultures was used for validation. Clinical relevance was assessed using transcriptomic and survival data from a large patient cohort. We found that zinc transporter expression, particularly SLC39A13, was enriched in fibroblasts and strongly associated with myofibroblastic activation signatures, including extracellular matrix remodeling and TGFβ signaling. Fibroblasts with high SLC39A13 expression were linked to immunosuppressive tumor environments characterized by reduced cytotoxic T-cell infiltration and increased immunosuppressive cells. Clinically, SLC39A13 expression was associated with poor progression-free survival and remained an independent prognostic factor. These findings suggest that zinc transporter-mediated pathways play a key role in stromal activation and immune regulation, highlighting SLC39A13 as a potential therapeutic target in head and neck squamous cell carcinoma. 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

The buffalo is an important agricultural species due to its many productive characteristics, which encourage its use worldwide. Uncovering the processes of selective sweeps is critical for a comprehensive understanding of genomic mechanisms that influence phenotypic differentiation in buffalo. This study aims to refine signatures of selection in Bulgarian (BUL), Hungarian (HUN), and Romanian (ROM) buffalo breeds using runs of homozygosity (ROHs), the integrated haplotype score (iHS), the standardized log-ratio of the integrated site-specific extended haplotype homozygosity (EHH) between pairs of breeds test (Rsb), and cross-population EHH (XP-EHH) approaches. The SNP dataset of 160 genotypes from BUL, HUN, and ROM buffalo breeds was genotyped using the Axiom^® Buffalo Genotyping Array 90K from Affymetrix. By combining the ROH, iHS, Rsb, and XP-EHH methods, we identified many important genomic regions and candidate genes associated with milk production (SLC24A2, TMEM132C, and ALCAM), reproduction (CSMD1, NTS, PLIN2, GPC5, and FSHR), growth (MYOM2, CLN8, and RRAGA), immune response (METTL25, MLLT3, NAALADL2, and GAB2), and adaptation (ADAMTSL1) in BUL, HUN, and ROM buffalo breeds. Our findings highlighted selection signals and genes related to important economic traits in the BUL, HUN, and ROM buffalo breeds, providing promising candidate genes for further research and inclusion in conservation and selection plans for these breeds. Full article