Search Results (2,218)

Prostate cancer remains a leading cause of cancer-related mortality and castration-resistant prostate cancer (CRPC) is a critical therapeutic challenge. This review establishes a conceptual framework analyzing ferroptosis vulnerability through two principles: “robustness through redundancy” in defense systems and the “evolutionary arms race” between androgen receptor (AR) signaling and oxidative resistance. We traced the evolutionary trajectory of hormone-sensitive diseases, where the AR coordinates ferroptosis defenses via SLC7A11, MBOAT2, and PEX10 regulation through progressive adaptations: AR-V7 splice variants that maintain defense independently of androgens, AR amplification conferring hypersensitivity, and AR-independent JMJD6-ATF4 bypass in SPOP-mutated tumors. This transforms ferroptosis from a static vulnerability to a stage-specific strategy. Novel approaches include menadione-based VPS34 targeting, which induces triaptosis through an oxidative endosomal catastrophe. We categorized the rational combinations mechanistically as vertical inhibition (multi-step targeting of single pathways), horizontal inhibition (synthetic lethality across parallel defenses), and vulnerability induction (creating exploitable dependencies). Ferroptosis-induced immunogenic cell death enables synergy with checkpoint inhibitors, potentially transforming immunologically “cold” prostate tumors. This review establishes ferroptosis targeting as a precision medicine paradigm exploiting the tension between the oxidative requirements of cancer cells and their evolved, yet architecturally vulnerable, defense systems, providing a framework for stage-specific, biomarker-guided interventions. Full article

Prolonged periods of sailing may contribute to the development of functional constipation, which can significantly impair an individual’s work efficiency. Currently, the efficacy of Bifidobacteria in treating functional constipation is gaining recognition. However, since the therapeutic effects of Bifidobacteria are strain-specific, further research is required on strains isolated from pre-voyage fecal samples. This study examines the role of gut microbiota in post-stroke constipation, aiming to identify specific microbial biomarkers for the development of targeted therapeutic strategies. B. adolescentis was identified through metagenomic analysis and subsequently isolated for validation. In the experimental group (EG), C57BL/6J mice received fecal suspension treatment following a 12-day navigation period, which was subsequently followed by a 12-day oral administration of B. adolescentis. After treatment, EG significantly improved fecal volume, intestinal motility, and goblet cells; reversed microbial ecological imbalance; reduced pathogens (E. coli and Klebsiella) by restoring arginine/bile acid metabolism, decreasing Tauro-ursodeoxycholic acid (TUDCA) content, 5-Hydroxytryptamine 4 Receptor (5-HT4R)/Slc8a1 signaling, and Ca²⁺ signaling pathway; and restoring beneficial species (B. adolescentis, Pseudomonas aeruginosa). This study provides new insights into probiotics in improving human intestinal health. Full article

Background/Objectives: AXL, a receptor tyrosine kinase of the TAM family, has emerged as a key target in cancer therapy due to its role in tumour growth, metastasis, immune evasion, and therapy resistance. SLC-391, a novel, orally bioavailable and selective AXL inhibitor, has demonstrated potent anti-tumour effects in preclinical studies. This first-in-human, open-label, multi-centre Phase I clinical trial (NCT03990454) was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of SLC-391 in patients with advanced solid tumours. Methods: Using a 3 + 3 design, SLC-391 was administered orally, either once daily (from 25 mg up to 175 mg QD) or twice daily (from 75 mg to 200 mg BID) in 21-day cycles. Results: Following single and repeated dosing, SLC-391 was generally well tolerated by subjects. The maximum tolerated dose (MTD) was not reached in this study. A total of 34/35 subjects experienced at least one TEAE. Three (8.6%) subjects experienced Grade 3 TRAEs that were considered related to SLC-391. Eight SAEs were reported in five (14.3%) subjects (seven Grade 3 SAEs and one Grade 2 SAE), in 150 mg QD (3/6, 50%), 175 mg QD (1/2, 50%), and 110 mg BID (1/3, 33.3%) cohorts. Four SAEs in three (8.6%) subjects led to dose interruption, drug withdrawal, or study discontinuation. Three DLTs were reported in two subjects: one subject experienced Grade 3 hematochezia (SUSAR/DLT) at 175 mg QD, and another subject experienced Grade 3 thrombocytopenia associated with Grade 1 hematuria at 200 mg BID. The median T_max was 2.0 h. Plasma concentrations following multiple doses generally increased with higher doses and appeared to reach steady state by Day 21 and were generally dose-proportional. Twelve (12) out of 35 subjects with solid tumours achieved stable disease according to RECIST or mRECIST (mesothelioma), with durations of stable disease lasting up to 318 days on SLC-391 monotherapy. The clinical benefit rate was 34.3%. Conclusions: This first study of SLC-391 in adult subjects with advanced solid tumours demonstrated that a total daily dose of 300 mg (150 mg BID) of SLC-391 monotherapy was generally well tolerated, with no DLTs or SAEs observed at this dose. The drug’s promising safety profile, along with stable disease reported for several subjects with advanced solid tumours, provides a strong rationale for the phase 1b/2a clinical investigation of SLC-391 in combination with pembrolizumab in subjects with advanced or metastatic non-small cell lung cancer (NSCLC) (NCT05860296). Full article

Colorectal cancer (CRC) remains the third leading cause of mortality among cancer patients in developed countries. Each new study in this field can contribute to better detection, diagnosis, and treatment of this disease. Our study aimed to assess transcriptional activity of genes associated with the biotransformation of xenobiotics and endobiotics in all three phases in the CRC adenocarcinoma, including correlations between them, as well as the aromatic hydrocarbon receptor (AhR) pathways. Based on transcriptome analysis (1252 mRNAs) of the CRC tissue and healthy colon, the upregulation or downregulation of 46 significant mRNAs was presented. The study also revealed the downregulation of AKR7A2 and upregulation of SLC5A6 and SLC29A2, previously undistinguished and potentially therapeutically valuable in CRC. The diagnostic potential of ADH1C, GGT5, NQO2, and SLC25A5 was demonstrated. It was stated that the AHR, EPHX1, GSTP1, and SLC25A32 did not correlate in healthy intestinal tissue whereas AHCY, ALDH1A1, NNMT, GSTM4, UGT2B17, and SLCO1B3 did not correlate in CRC. The disturbed transcriptional activity of genes related to the biotransformation process at all stages of CRC suggests that this may be the cause of its occurrence; the genes ought to be taken into account in preventive strategies and the treatment of patients. Full article

Water alkalinization is a critical global stressor for freshwater fish, yet the systemic patterns of multi-organ responses and injury remain insufficiently understood. This study integrates histopathology, biochemistry, and multi-organ transcriptomics to provide an integrated, time-resolved assessment of stress responses in European perch (Perca fluviatilis) exposed to acute alkaline stress (20 mmol/L). The analysis indicated that alkaline stress initially causes structural disturbance of gill tissue (lamellar fusion, necrosis) within 96 h, associated with impaired osmoregulatory functions. This primary dysfunction was followed by progressive hepatic impairment, characterized by uncontrolled oxidative stress (elevated levels in Malondialdehyde, MDA) and widespread hepatocyte necrosis. Transcriptomic analysis identified extensive transcriptional shifts associated with these alterations: large-scale differential expression in the liver (3629 Differentially Expressed Genes, DEGs) and kidney (478 DEGs). Notably, the liver exhibited a stress-responsive transcriptional profile involving activation of the HIF-1 signaling pathway and mobilizing protein quality control systems (e.g., ‘Proteasome,’ ‘Lysosome’) consistent with mitigation of proteotoxic stress. This compensatory response appeared insufficient to prevent severe metabolic disruption and cellular injury. This study presents a time-associated sequence of organ-specific stress responses under acute alkalinity, identifying candidate stress-associated genes (slc7a11, egln3, klhl38b) as potential targets for future functional studies and breeding alkali-tolerant strains. Full article

Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer is an aggressive malignancy with limited treatment options. The herbal composition SLC contains Salvia miltiorrhiza Bunge (Dan shen), Ligusticum wallichii Franch. (Chuan xiong), and Carthamus tinctorius L. (Hong hua), three herbs that have demonstrated antitumor properties. This study aims to investigate the inhibitory effects and mechanisms of SLC against HER2-positive breast cancer. UPLC-Q/TOF-MS identified 113 compounds in SLC. SLC inhibited the proliferation, migration, and mitochondrial function of HER2-positive cells by reducing glucose uptake, ATP production, and oxygen consumption rate (OCR). Furthermore, SLC downregulated the levels of p-HER2/HER2, p-AKT/AKT, and p-ERK/ERK by Western blot, thereby inhibiting the HER2 signaling pathway. Mechanistically, SLC decreased the protein expression of PDK1 and inhibited the phosphorylation of PDHA1 (Ser293), and also inhibited mitochondrial-related proteins in SIRT1/PGC-1α/NRF1/TFAM signaling axes. Additionally, through the overexpression of PDK1, SLC repressed PDK1, downregulated PDHA1, and induced apoptosis. In vivo xenograft model studies demonstrated that SLC inhibited tumor growth. Molecular docking highlighted Monomethyl lithospermate as a key active component. Overall, SLC influences oxidative phosphorylation via the PDK1/PDHA1 and SIRT1/PGC-1α/NRF1/TFAM signaling pathways and downregulates the HER2 pathway, thereby ultimately inhibiting HER2-positive breast cancer progression. Full article

This study aimed to examine the role of maternal BPS gestational and lactational exposure to BPS in neurotoxicity in offspring mice and to uncover the regulatory mechanisms driven by microglial ferroptosis. In this study, C57BL/6J mice were treated with BPS during pregnancy and lactation. The results revealed that BPS induced memory impairment and anxiety in offspring mice, accompanied by abnormal expression levels of brain neurotrophic factor and synaptic plasticity factor (PSD95, SYP). Additionally, exposure to BPS activated microglia by upregulating the expression of IBA1 and concurrently promoting the release of inflammatory factors in the hippocampus and cortex. BPS exposure also contributed to iron overload, aberrant mitochondrial morphology, oxidative stress, and abnormal expression of ferroptosis-associated genes (GPX4, SCL7A11, TFR1, ACSL4) in the brains of offspring mice. Importantly, immunofluorescence analysis demonstrated concomitant microglial activation and ferroptosis in the brain tissue of offspring mice following BPS exposure. Moreover, experiments in BV2 microglial cells showed that the ferroptosis inhibitor Fer-1 reversed BPS-induced microglial ferroptosis and the release of inflammatory cytokines. These findings collectively elucidate the regulatory role mechanism of microglial ferroptosis in BPS-induced neurotoxicity in offspring mice, and we propose potential therapeutic targets for attenuating BPS-mediated neurotoxic effects. Full article

During oocyte maturation, granulosa cells (GCs) respond to fluctuating hormone levels in the ovary. The study aims to reveal metabolism and activity patterns of isolated and cultured GCs, reflecting in vivo processes. A downregulation of GARNL3 and ARRDC4 across all time points (48 h, 96 h, and 144 h) suggests reduced cell signaling and response to external stimuli, which may be related to the isolation and in vitro culturing of GCs from the complex ovarian microenvironment. The consistent elevation of LOX underscores its role in extracellular matrix (ECM) cross-linking, crucial for oocyte quality, whereas FN1 and ITGB3 highlight cellular adhesion and ECM interaction during adaptation to in vitro conditions. The study further demonstrates that ANKRD1 and SLC1A1 are upregulated over time in vitro, indicating cellular differentiation and metabolic alterations. Furthermore, proteoglycan and MAPK signaling pathways are identified as key players in cell-to-cell and cell-to-ECM interactions. GSEA revealed heightened activity in vasculature development, the TGF-β signaling pathway, cell development, and lipid response. The findings suggest that while GCs in vitro mimic in vivo processes related to ECM remodeling and oocyte development, they also exhibit a tendency towards aging. The research emphasizes that isolated GCs in vitro exhibit time-dependent activity shifts related to cellular differentiation, ECM remodeling, and lipid metabolism, which also have implications for the understanding of reproductive physiology and pathologies. Full article

The ketogenic diet (KD) is a metabolic intervention characterized by high fat and very low carbohydrate intake, showing significant metabolic, neuroprotective, and therapeutic effects. However, its efficacy varies widely due to individual genetic and epigenetic factors. This review synthesizes current knowledge of genes most strongly associated with KD response, including polymorphisms in FTO, APOA2, PPAR, SCN1A, KCNQ2, STXBP1, CDKL5, the MODY gene group, and SLC2A1, which shape outcomes across lipid metabolism, energy expenditure, inflammation, and neurotransmission. Epigenomic modifications induced by a KD, such as changes in DNA methylation and histone acetylation involving BDNF, SLC12A5, KLF14, and others, modulate functional metabolic and neurological effects. Sex and age further modulate KD effects through distinct patterns of gene activation and hormonal interactions. These variables together impact metabolic and neurological outcomes and are critical for developing personalized nutrition and disease management strategies. Based on the reviewed evidence, genetic and epigenetic profiling can help identify patients who are likely to benefit from a KD (e.g., GLUT1DS, PDH deficiency) and those in whom a KD may be ineffective or harmful (e.g., SCOT or SLC2A1-independent defects). The review concludes that genetic and epigenetic profiling is recommended for personalized dietary interventions. Full article

Psychosomatic disorders are conditions in which physical (somatic) symptoms are triggered or aggravated by psychological distress. These disorders result from complex interactions among the endocrine, central nervous, and immune systems. Emerging evidence indicates that gut microbiota (GM) dysbiosis, epigenetic alterations, and immune system dysregulation play pivotal roles in the pathogenesis of psychosomatic disorders and may serve as potential biomarkers for disease states and therapeutic outcomes. This review first outlines how epigenetic dysregulation contributes to psychosomatic disorders through altered expression of genes such as GRM2, TRPA1, SLC6A4, NR3C1, leptin, BDNF, NAT15, HDAC4, PRKCA, RTN1, PRKG1, and HDAC7. We then examine current evidence linking psychosomatic disorders with changes in GM composition and GM-derived epigenetic metabolites, which influence immune function and neurobiological pathways. The core focus of this review is on therapeutic interventions—including probiotics, prebiotics, postbiotics, fecal microbiota transplantation, and targeted dietary approaches—that modulate the gut–brain axis through epigenetic mechanisms for the management of psychosomatic disorders. Finally, we highlight the current challenges and future directions in elucidating the interplay between epigenetics, the GM, and psychosomatic disease mechanisms. In this context, human iPSC-derived multicellular organoids may serve as powerful platforms to unravel mechanistic pathways underlying inter-organ interactions. Full article

Background and Objectives: ADAM17, a sheddase that regulates cytokine and receptor ectodomains, amplifies inflammatory signaling. Acute liver injury (ALI) is driven by dysregulated inflammation, accompanied by both oxidative and endoplasmic reticulum (ER) stress responses. We investigated whether pharmacological inhibition of ADAM17 with GW280264X mitigates lipopolysaccharide (LPS)-induced acute liver injury by targeting these pathways. Methods: Male C57BL/6J mice received intraperitoneal LPS (10 mg/kg). GW280264X (500 µg/kg, i.p.) was administered at one and three hours post-LPS treatment. At the fifth hour, serum and liver samples were collected to determine serum ALT/AST levels and to perform hematoxylin and eosin (H&E) staining. Inflammatory (TNF-α), oxidative (MDA, 4-HNE, Fe²⁺, GSH; NRF2/KEAP1), endoplasmic reticulum (ER) stress (GRP78, ATF6, CHOP), and ferroptosis-related (GPX4, SLC7A11) markers, along with ADAM17 protein levels, were analyzed using ELISA, colorimetric assays, and Western blotting. Results: LPS triggered hepatic injury. This was accompanied by marked elevations in TNF-α, oxidative indices (MDA, 4-HNE, Fe²⁺) and ER stress proteins (GRP78, ATF6, CHOP), together with depletion of hepatic GSH. GW280264X significantly reduced AST levels, attenuated inflammatory, oxidative, and ER stress responses, and improved hepatic histopathology. GPX4 and SLC7A11 tended to increase following treatment, but the changes did not reach statistical significance and should be interpreted cautiously due to the limited sample size (n = 5). Similarly, ADAM17 protein levels tended to decrease, although the change was not statistically significant. Conclusions: Pharmacological inhibition of ADAM17 with GW280264X may confer early hepatoprotection in LPS-induced ALI by attenuating inflammatory, oxidative and ER stress pathways. ADAM17 inhibition yielded partial and statistically non-significant protective effects at this early stage; therefore, these findings should be considered exploratory. Future studies with larger sample sizes and longer observation periods are warranted to confirm the durability and mechanistic basis of this response. Full article

Major depressive disorder (MDD) is a complex and heterogeneous psychiatric condition with high global prevalence and significant personal and societal burdens. While traditionally focused on neuronal dysfunction, emerging research highlights a critical role for astrocytes—glial cells essential for maintaining brain homeostasis in the pathogenesis of depression. This review explores how chronic stress, a major risk factor for MDD, disrupts astrocyte function through multiple converging mechanisms. We detail the normal physiological roles of astrocytes in synaptic regulation, neurotransmitter cycling, metabolic support, and neurovascular integrity, and examine how these functions are compromised under chronic stress. Key molecular pathways implicated include glucocorticoid receptor (GR) signaling dysregulation, neuroinflammatory responses, glutamate excitotoxicity, oxidative stress, and epigenetic alterations. Evidence from histological and transcriptomic studies in both human postmortem tissue and rodent models reveals consistent changes in astrocyte-specific genes, such as GFAP, SLC1A2, SLC1A3, BDNF, and AQP4, supporting their involvement in depressive pathology. Finally, we discuss therapeutic strategies targeting astrocyte dysfunction—including EAAT2 upregulation, neuromodulation, anti-inflammatory approaches, GR modulation, and glial-focused epigenetic therapies. Understanding astrocyte pathology in the context of chronic stress not only refines our understanding of MDD but also opens novel avenues for treatment development. Full article

Sheep are an economically important livestock species, and reproductive performance is a key trait affecting productivity. The Dorper × Hu hybrid sheep (DHS), widely bred in China, provides a valuable model for studying the genetic basis of prolificacy. This study aimed to investigate the genomic architecture and identify candidate genes associated with high litter size in DHS using whole-genome selective sweep analysis and genome-wide association study (GWAS). A total of 31 DHS individuals with complete reproductive records were sequenced and compared with publicly available genomic data from 20 Hu sheep (HUS) and 10 Dorper sheep (DPS). Population genetic structure and diversity were assessed using phylogenetic trees, principal component analysis (PCA), and ADMIXTURE analysis. To identify key genomic regions associated with litter size, we performed selective sweep analysis between the polytocous and monotocous subpopulations of DHS using multiple methods within a 50 kb sliding window framework, including $F_{ST}$, ${\theta }_{\pi }$ ratio, XP-CLR, and XP-EHH; we also conducted GWAS. DHS exhibited a distinct genetic structure with admixed ancestry and elevated genetic diversity. Genetic diversity analysis showed that DHS retained moderate levels of heterozygosity and polymorphism, comparable to or exceeding those of its parental breeds. Comparative analysis between polytocous and monotocous DHS identified reproduction-associated genes, including MUC1, PLCB4, SIN3A, and ELAVL2, enriched in pathways such as ovarian steroidogenesis, insulin secretion, and circadian entrainment. Furthermore, genome-wide association study (GWAS) identified 140 significant loci (p < 10⁻⁵) associated with reproductive traits. From these, 10 candidate SNPs were selected for validation through single-marker association analysis in 200 DHS individuals, among which two loci—g.88680390 C>A (SLC24A2/MLLT3) and g.18197516 T>C (ABCA1)—showed significant correlations with litter size. These findings enhance our understanding of the genetic basis of prolificacy in DHS and provide valuable molecular markers for genomic selection in sheep-breeding programs. Full article

With the increasing global burden of major depressive disorder (MDD), identifying modifiable environmental risk factors has become a critical priority. Per- and polyfluoroalkyl substances (PFASs), characterized by environmental persistence and bioaccumulation, have been linked to elevated mental health risks. However, the potential neurotoxicity of GenX—a novel PFAS developed to replace perfluorooctanoic acid (PFOA)—and its molecular association with MDD remain unclear. In this study, peripheral blood serum transcriptomic data from the Gene Expression Omnibus (GEO) were integrated with multidimensional bioinformatics analyses to elucidate molecular mechanisms connecting GenX exposure with MDD. Four hub genes (UCP2, AKR1B1, TP53, and F5) were identified, showing strong combined diagnostic performance (AUC = 0.925). Functional enrichment and immune infiltration analyses revealed their involvement in energy metabolism, oxidative stress, and immune-coagulation regulation. Molecular docking and dynamics simulations further confirmed stable interactions between GenX and these proteins, providing structural support for their mechanistic roles. Although classical dopaminergic markers (TH, SLC6A3, DRD1–5) were not detected in the serum-derived transcriptomes, the identified hub genes may still affect dopaminergic function indirectly by modulating metabolic, oxidative stress, and inflammatory/coagulation pathways, thereby influencing MDD susceptibility. This study provides the first integrated transcriptomic and structural evidence linking GenX to psychiatric risk, proposing a novel “GenX-dopamine-MDD” framework for understanding pollutant-mediated neuropsychiatric mechanisms. Full article

Ground settlement is a multifaceted geological phenomenon driven by natural and man-made forces, posing a significant impediment to sustainable urban development. Thus, ground settlement susceptibility (GSS) mapping has emerged as a critical tool for understanding and mitigating cascading hazards in seismically active and anthropogenically modified sedimentary basins. Here, we develop an integrated framework for assessing GSS in the Pohang region, South Korea, by integrating Persistent Scatterer Interferometric Synthetic Aperture Radar (PSInSAR)-derived vertical land motion (VLM) data with seismological, geotechnical, and topographic parameters (i.e., peak ground acceleration (PGA), effective shear-wave velocity (V_s³⁰), site period (T_s), general amplification factor (A_F), seismic vulnerability index (K_g), soil depth, topographic slope, and landform classes) through ensemble machine learning models such as Random Forest (RF), XGBoost, and Decision Tree (DT). Analysis of 56 Sentinel-1 SLC images (2017–2023) revealed persistent subsidence concentrated in Quaternary alluvium, reclaimed coastal plains, and basin-fill deposits. Among the tested models, RF achieved the best performance and strongly agreed with field evidence of sand boils, liquefaction, and structural damage from the 2017 Pohang earthquake. The very-high-susceptibility zones exhibited mean subsidence rates of −3.21 mm/year, primarily within soft sediments (V_s³⁰ < 360 m/s) and areas of thick alluvium deposits. Integration of the optimal RF-based GSS index with regional building inventories revealed that nearly 65% of existing buildings fell within high- to very-high-susceptibility zones. The proposed framework demonstrates that integrating PSInSAR and ensemble learning provides a robust and transferable approach for quantifying ground settlement hazards and supporting risk-informed urban planning in seismically active and complex geological coastal environments. Full article