Search Results (4,839)

(1) Background: The search for new polymodal antioxidants to correct oxidative stress of various origins and its consequences remains one of the most pressing and rapidly developing areas of biomedical research. (2) Methods: Hydrogen peroxide and hydroxyl radical detection, induced luminescence assay, ELISA for 8-oxoguanine detection, animal survival, blood cell count, micronucleus test, and PCR were used. (3) Results: 2R,3R-trans-dihydroquercetin (DHQ) was shown to reduce the amount of hydrogen peroxide and hydroxyl radicals formed during water radiolysis, leading to reduced damage to biomolecules. DHQ is a radioprotector, most effective at a dose of 300 mg/kg administered 15 min before radiation exposure. The dose reduction factor is 1.22. DHQ administration reduces the severity of radiation-induced leukopenia and thrombopenia by protecting red bone marrow cells. The mechanism of DHQ’s radioprotective action is fundamentally different from that of classical stress response inducers and is based on the normalization of the target cell transcriptional profile, rather than its hyperstimulation. (4) Conclusions: DHQ’s ability to restore the expression of antioxidant defense, DNA repair, and apoptotic genes to physiological levels under radiation exposure allows it to be considered a promising pharmacological agent for the correction of radiation-induced damage to normal tissues. Full article

Introduction: Brain metastases represent a major clinical challenge due to a distinct immunosuppressive microenvironment and limited, heterogeneous efficacy of PD-1/PD-L1 immune checkpoint inhibition. The adenosine pathway, mediated by the ectonucleotidases CD39 and CD73, has emerged as an alternative immune escape mechanism, yet its relevance in brain metastases across tumor entities remains insufficiently characterized. Methods: We conducted targeted panel sequencing of brain metastases from multiple primary tumor entities and evaluated compartment-resolved expression of CD39, CD73, and PD-L1 by immunohistochemistry, distinguishing tumor cell and immune cell expression. Tumor mutational burden (TMB), recurrent gene alterations, and gene fusions were analyzed and integrated with immune marker profiles to define immunogenomic subtypes. Results: Brain metastases displayed a heterogeneous mutational landscape with recurrent alterations including TP53, KRAS, PIK3CA, and APC. CD39 and CD73 expression was frequent and highly variable, occurring on both tumor cells and tumor-infiltrating immune cells, and only partially overlapping with PD-L1 expression. A substantial subset of cases exhibited an adenosine-high phenotype despite low or absent PD-L1. Marker-associated enrichment analyses identified distinct genetic correlates, including enrichment of KRAS alterations in tumors with CD39/CD73 positivity on malignant cells, and APC/PIK3CA-associated patterns linked to immune compartment marker expression. TMB did not significantly differ across major tumor entity groups. Gene fusions were detected in a subset of tumors but were largely independent of immune phenotypes. Conclusions: Adenosine pathway activation is a frequent, genetically associated immune escape feature of brain metastases that complements PD-L1-based stratification. Integrating CD39/CD73 with PD-L1 enables actionable immunogenomic subtyping and supports rational immunotherapy strategies targeting adenosine-mediated immunosuppression. Full article

Codon usage bias is important for regulating protein translation efficiency and accuracy. The HSP90 gene, a pivotal gene in plants, maintains homeostasis in plant protein stress responses and organelle immune defense functions. We systematically examine codon usage preferences in six forage grass species and the regulatory mechanisms of the HSP90 gene in governing codon preference. A set of metrics is evaluated, including effective codon number (ENC), codon adaptation index, and relative synonymous codon usage. Neutral evolutionary trajectories reveal usage preferences for six plant codons, with natural selection serving as the primary driving factor. The correlation between the ENC–GC3 curve (ENC relative to third-position GC content in synonymous codons) and codon bias index reveals these genes to exhibit moderate codon bias. The phenomenon of evolutionary constraints is exemplified by a propensity for C/G-terminating codons, concomitant with a suppression of NUA/NCG codons (NUA is an abbreviation for UA dinucleotide, and NCG is an abbreviation for CG dinucleotide). Phylogenomic reconstruction reveals a conserved diversification pathway, positioning P. giganteum A. Rich. at the basal node of the evolutionary framework. This study identified through systematic assessment that natural selection is the primary evolutionary force driving the biased use of codons in grass HSP90 genes. This finding provides actionable insights for enhancing abiotic stress tolerance in forage germplasm through precise codon engineering. Full article

The vitamin D receptor (VDR) acts as both a nuclear transcription factor and a non-genomic mediator that regulates a broad spectrum of physiological processes beyond calcium and phosphate homeostasis. VDR plays an important role in the modulation of ion channels across multiple tissues, including osteoblasts, renal and intestinal epithelial cells, neurons, and vascular smooth muscle. These regulatory mechanisms encompass genomic actions through vitamin D response elements in target genes—such as TRPV5, TRPV6, KCNK3, and KCNH1—as well as rapid, non-genomic actions at the plasma membrane involving protein disulfide isomerase A3 and associated signaling cascades. VDR-mediated transcriptional control of calcium, potassium, and chloride channels contributes to the fine-tuning of cellular excitability, calcium transport, and mitochondrial function. Evidence also implicates VDR–ion channel crosstalk in various pathological contexts, including renal cell carcinoma, breast and cervical cancers, pulmonary arterial hypertension, and osteoporosis. Understanding the molecular interplay between VDR and ion channels provides new perspectives on the pleiotropic effects of vitamin D and offers promising therapeutic opportunities in oncology, cardiovascular disease, and skeletal disorders. This review synthesizes previous and current evidence on the genomic and non-genomic mechanisms underlying VDR–ion channel regulation and highlights novel frontiers in vitamin D signaling relevant to human health and disease. Full article

Rice sheath blight caused by Rhizoctonia solani is one of the most destructive diseases of rice. Bixafen has been proposed as a promising control agent with moderate resistance risk; however, its cellular mode of action remains unclear. Therefore, this study investigated the antifungal mechanism of bixafen from the perspective of programmed cell death (PCD). Bioassays showed that bixafen strongly inhibited R. solani, with a median effective concentration (EC₅₀) of 1.16 μg/mL. Morphologically, bixafen induced hyphae collapse, vacuolization, chromatin aggregation, and mitochondrial disruption. Transcriptome analysis further revealed that bixafen significantly altered the expression of genes involved in the tricarboxylic acid cycle and PCD pathways. In addition, bixafen, at the concentration of EC₅₀, triggered ROS accumulation accompanied by increased malondialdehyde (MDA) levels. These oxidative effects led to mitochondrial damage, characterized by loss of membrane potential, reduced Tomm20 expression, and decreased Aco-2 activity. Subsequently, bixafen activated apoptosis, as evidenced by induction of the mitochondria-associated inducer of death (AMID), down-regulation of Bcl-2, and DNA fragmentation. Moreover, bixafen also induced autophagy by reducing p62 and increasing Beclin-1 expression, which suggests the clearance of damaged mitochondria. Collectively, these results demonstrated that bixafen induced mitochondrial-dependent apoptosis and autophagy in R. solani, which provided novel insights into its cellular antifungal mechanism and supported its potential as a PCD-targeted fungicide. Full article

Ginkgetin (GK) is a naturally occurring biflavonoid predominantly isolated from Ginkgo biloba and has attracted increasing attention because of its broad pharmacological activities. Structurally, GK belongs to the 3′-8″-linked biflavone subclass, which distinguishes it from other biflavonoids like amentoflavone (the parent compound of this subclass) and its monomeric counterparts such as apigenin. This unique C-C linked dimeric architecture confers distinct molecular planarity and lipophilicity, contributing to its enhanced membrane permeability and multitarget engagement capabilities. GK has been shown to exert pleiotropic biological effects in preclinical studies, including anti-inflammatory, antioxidant, antifibrotic, anticancer, neuroprotective, cardioprotective, metabolic regulatory and antibacterial activities. Mechanistically, preclinical evidence indicates that GK functions as a multitarget modulator of key signaling pathways involved in oxidative stress, inflammation, cell death and tissue remodeling, such as nuclear factor erythroid 2–related factor 2/heme oxygenase-1 (Nrf2/HO-1), nuclear factor kappa-B(NF-κB), Janus kinase/signal transducer and activator of transcription(JAK/STAT), mitogen-activated protein kinases(MAPKs), AMP-activated protein kinase/mechanistic target of rapamycin(AMPK/mTOR), phosphoinositide 3-kinase/protein kinase B(PI3K/Akt) and cyclic GMP-AMP synthase–stimulator of interferon genes(cGAS–STING). Notably, GK has been observed to display context-dependent regulation of cell fate decisions, including apoptosis, autophagy and ferroptosis, thereby enabling the selective elimination of pathological cells while preserving normal tissue function. Preclinical studies further demonstrate that GK exhibits therapeutic potential across diverse disease systems, including cancer, metabolic disorders, cardiovascular diseases, neurological disorders and musculoskeletal diseases. In addition, emerging evidence highlights its antibacterial and antivirulence properties through the inhibition of biofilm formation and quorum sensing. It is crucial to note, however, that this promising profile is predominantly derived from preclinical studies, and clinical evidence in humans remains to be established. Despite these promising findings, the clinical translation of GK remains limited by challenges related to pharmacokinetics, bioavailability and druggability. This review systematically summarizes the chemical characteristics, pharmacological activities and molecular mechanisms of GK, with an emphasis on its multitarget actions and therapeutic potential across disease systems, and discusses current limitations and future perspectives to facilitate the rational development of GK-based interventions. Full article

Lysine propionylation (Kpr) is a metabolically coupled lysine acylation that links propionyl-CoA availability to the molecular regulation of gene expression and protein function. Although lysine acetylation (Kac) is the most extensively characterized, recent proteomic and metabolic studies suggest that Kpr is more frequent than previously appreciated, occurs at defined lysine sites, and displays tissue-resolved and context-dependent patterns. Kpr often co-varies with other short-chain acylations such as Kac and lysine butyrylation (Kbu); however, emerging genomic-scale evidence indicates mark-biased genomic distributions and functional associations, suggesting that Kpr is not simply an extension or alternative to Kac. Notably, propionyl-CoA, the direct acyl donor for Kpr, can be influenced by microbiome-derived short-chain fatty acids (SCFAs), implying that interventions modulating SCFA availability (e.g., dietary manipulation) may provide an actionable route to tune Kpr and related acylations. Here, we summarize recent advances in propionyl-CoA sources and compartmentalization, the enzymatic writers/erasers/readers, the molecular mechanisms underlying Kpr, and the functional consequences of Kpr in physiology and disease. Full article

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare lung malignancy characterized by an aggressive clinical course and an unfavorable prognosis. Next-generation sequencing (NGS) has revealed that LCNECs exhibit molecular features resembling either small-cell lung carcinoma (SCLC-like LCNEC) or non-small cell lung carcinoma (NSCLC-like LCNEC). This study aimed to characterize the incidence of actionable gene variants in a retrospective cohort of LCNEC patients using a targeted NGS approach. Microscopic diagnosis was established according to the 2021 World Health Organization (WHO) classification using a standard immunohistochemical (IHC) panel. In total, 216 LCNEC tumor samples were analyzed for molecular variants in 17 genes using the RNA-based Archer FusionPlex Lung NGS assay (Integrated DNA Technologies, USA) and the MiSeq platform (Illumina, USA)—an algorithm utilized for routine NSCLC diagnosis. Overall, 46 variants were identified in 46/216 (21.3%) tumor samples, with 28/216 (13%) LCNECs harboring at least one actionable molecular variant potentially targetable by registered or investigational agents. KRAS variants (5%; including G12C at 2%) and PIK3CA variants (5%) were the most prevalent, followed by RET single-nucleotide variants (3%), uncommon EGFR variants (1%), and BRAF class II and III variants (<1%). Notably, no classical EGFR exon 18–21 mutations nor ALK, FGFR1/2/3, or ROS1 alterations (mutations or fusions) were detected, despite the technical capability of the assay to identify such variants. A novel in-frame gene fusion (TMEM79::NTRK1) was identified in a single tumor sample (0.5%). Our results confirm that LCNECs harbor potentially targetable alterations in KRAS, PIK3CA, RET, BRAF, and NTRK1, albeit at lower frequencies than those typically observed in NSCLC. Full article

The study analyzed ten reproductive traits in three major commercial breeds—Yorkshire, Landrace, and Duroc—raised under uniform management. Genetic parameters were estimated using a repeatability animal model in ASReml, genome-wide association studies (GWAS) were performed with 46,358 post-QC SNPs using GCTA, and genomic prediction was evaluated with GBLUP. Heritability estimates were low to moderate, with gestation length (GL) highest (0.33–0.41). GWAS identified significant loci across breeds: in Yorkshire, 37 genome-wide significant SNPs across 17 SSCs for seven traits; in Landrace, 16 SNPs for TNB and one for NBW; and in Duroc, 31 SNPs across 12 SSCs (predominantly for TNB). Among these SNPs, CNC10042060, CNC10160995, and CNCB10003799 were consistently associated with TNB in both Yorkshire and Duroc pigs. Additionally, five SNPs, CNC10012965, CNC10042060, CNC10120451, CNCB10003799, and CNCB10007759, showed significant associations with NBW in Yorkshire and Landrace pigs. Candidate genes mapped within ±1 Mb of significant SNPs were enriched for biologically plausible pathways. Genomic prediction accuracies ranged from low to high depending on trait and breed, such as reaching 0.68 for GL in 39 Yorkshire and 0.59 in Landrace. These results delineate shared and breed-specific genetic architectures, provide actionable markers and candidate genes, and can accelerate genetic gains in commercial breeding programs. Full article

Infertility is a prevalent clinical issue which disrupts normal human life and exerts an impact on fertility rates within the population. The increase in environmental pollutants, including acetyl tributyl citrate (ATBC), has given rise to concerns regarding their potential toxicity in infertility-related disorders. Icariin exhibits therapeutic effects on infertility, yet its mechanism of action against plasticiser-induced reproductive disorders remains unclear. This study aims to elucidate the potential toxicological targets and molecular mechanisms of ATBC-induced infertility, as well as the therapeutic targets and mechanisms of icariin in treating ATBC-induced reproductive disorders, through network toxicology, molecular-docking techniques and molecular dynamics simulation. Utilising the component-target database SwissTargetPrediction, the Similarity Ensemble Approach, PharmMapper, the ChEMBL database, and disease databases including the Therapeutic Target Database, OMIM, GeneCards, and DrugBank, 63 targets for ATBC-induced infertility and 33 targets for icariin treatment were identified. Screening via the STRING platform and Cytoscape 3.10.1 software yielded four core targets for ATBC-induced infertility—HSP90AA1, PIK3CA, CASP3, HRAS—and four core targets for icariin treatment—IL6, TNF, STAT3, and INS. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that ATBC-induced infertility correlates with pathways including pathways in cancer, prostate cancer, and PI3K-Akt signalling pathways. Conversely, the core targets of icariin therapy for related reproductive disorders are closely associated with tumour-associated signalling pathways and the AGE-RAGE signalling pathway. Molecular-docking and molecular dynamics simulation further confirmed the strong binding interactions between ATBC and infertility-related targets, as well as between icariin and core targets for treating reproductive disorders. This provides a theoretical foundation for understanding ATBC’s toxicological targets and the complex molecular mechanisms underpinning icariin’s treatment of infertility. It informs the development of strategies for icariin to prevent and treat infertility caused by exposure to ATBC-containing plastics or excessive ATBC contact. Full article

Background/Objectives: Primary dysmenorrhea is a common gynecological disorder characterized by painful uterine contractions. Danggui Buxue Decoction (DBD) is used to treat menstrual irregularities, but its mechanism in primary dysmenorrhea remains unclear. This study investigated the efficacy of DBD against dysmenorrhea and its calcium signaling-related mechanism. Methods: DBD components were analyzed by UPLC–Orbitrap MS. Isolated uterine muscle strips precontracted with oxytocin (OT, 50 ng/mL) or KCl (60 mM) were used to assess the effects of DBD and its active compounds (Quercetin, Formononetin, Ononin, Ferulic acid, Senkyunolide I, Calycosin, Ligustilide, Calycosin-7-O-β-D-glucoside). Ca²⁺-dependent experiments, intracellular calcium release assays, and inhibitor treatments (Nifedipine, 2-APB) were performed to evaluate the involvement of L-type calcium channels and the IP₃R pathway. A primary dysmenorrhea model induced by estradiol benzoate and oxytocin was used to assess the analgesic effects, histopathology, inflammatory factors, and IP₃/Ca²⁺-related proteins and genes following DBD and Quercetin treatment. Results: A total of 161 compounds were identified in DBD. DBD and its eight active constituents relaxed OT (50 ng/mL) or KCl (60 mM)-induced uterine contractions, with Quercetin, Calycosin, and Ligustilide showing particularly prominent relaxant activity. These three compounds suppressed extracellular calcium influx and intracellular calcium release through the blockade of L-type calcium channels and IP₃R. In vivo, DBD and Quercetin alleviated pain, reduced inflammation, and decreased uterine Ca²⁺ and IP₃ levels in dysmenorrhea mice. Conclusions: DBD and its active component Quercetin promote uterine relaxation by lowering Ca²⁺ levels, which is achieved through suppression of L-type calcium channels and the IP₃/Ca²⁺ pathway. This contributes to their therapeutic action against primary dysmenorrhea. Full article

Background: Cardiac amyloidosis (CA) is an increasingly recognized cause of heart failure with preserved ejection fraction, resulting from myocardial deposition of misfolded amyloid fibrils derived predominantly from transthyretin (ATTR wild-type [ATTRwt] or variant [ATTRv]) or immunoglobulin light chains (AL). Despite advances in noninvasive imaging and disease-modifying therapies, delayed diagnosis remains common, and clinically actionable molecular biomarkers for early detection, phenotypic discrimination, and therapeutic monitoring are limited. MicroRNAs (miRNAs), small noncoding regulators of post-transcriptional gene expression, have emerged as key modulators of cardiovascular remodeling and systemic amyloid biology. Methods: We performed a comprehensive review of experimental, translational, and clinical studies to evaluate the role of miRNAs in transthyretin and light-chain cardiac amyloidosis, incorporating data from myocardial tissue analyses, circulating miRNA profiling, and mechanistic studies in cellular and animal models. Results: Dysregulated miRNA networks contribute to amyloid-induced cardiac injury by modulating mitochondrial energetics, oxidative stress, inflammation, fibrosis, proteostasis, and neurocardiac signaling. Specific miRNAs, including members of the miR-21, miR-29, and miR-30 families, as well as miR-150-5p and miR-339, have been associated with amyloid burden, adverse myocardial remodeling, plasma cell biology, and disease severity. Distinct circulating and tissue miRNA signatures differentiate transthyretin from light-chain cardiac amyloidosis and correlate with functional status, heart failure biomarkers, and clinical outcomes. Conclusions: MiRNAs represent promising diagnostic and prognostic biomarkers in cardiac amyloidosis and offer mechanistic insights into disease pathogenesis. Integration of miRNA profiling with multimodality imaging and emerging RNA-based therapeutics may enable earlier diagnosis and support precision management of amyloid-related heart failure. Full article

Background: Urothelial bladder cancer (UBC) is a molecularly heterogeneous disease, and most sequencing studies have relied on bladder-specific or solid tumor-restricted panels. Whether broader pan-cancer assays provide additional clinically relevant information remains unclear. Methods: We performed targeted next-generation sequencing using an extended gene panel on tumor samples from 100 patients with UBC treated at a tertiary center. Somatic single-nucleotide variants, small insertions/deletions, copy-number alterations, and gene co-occurrence patterns were analyzed and correlated with clinicopathological features, disease-free survival (DFS), and overall survival (OS). Results: Recurrent alterations were identified in FGFR3 (≈50%), TP53 (≈35%), STAG2 (≈25%), and PIK3CA (≈20%), consistent with established molecular pathways in UBC. Less frequent but potentially actionable alterations, including mutations in BRCA1 and ALK, were also detected, reflecting the extended coverage of the panel. TP53 mutations were independently associated with worse OS, whereas STAG2 alterations were associated with improved OS, particularly in tumors without concurrent TP53 mutations. FGFR3 mutations showed a favorable but non-independent trend. No gene retained independent prognostic significance for DFS. Co-occurrence analysis revealed an FGFR3/PIK3CA-associated pathway and relative mutual exclusivity between FGFR3 and TP53. Copy-number alterations were modest overall. Comparison with TCGA data demonstrated a higher frequency of FGFR3 alterations in our cohort, likely reflecting the larger proportion of non–muscle-invasive tumors. Conclusions: Pan-cancer targeted sequencing provided a comprehensive genomic landscape of UBC, capturing canonical drivers and additional alterations that may be overlooked by bladder-restricted assays. The identification of TP53 and STAG2 as prognostic markers highlights the potential value of broader genomic profiling for biologically informed risk stratification in urothelial bladder cancer. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of type 2 diabetes and obesity, yet their actions extend beyond glycemic control and weight loss. This narrative review synthesizes current preclinical and clinical evidence examining the bidirectional relationship between glucagon-like peptide-1 (GLP-1) receptor agonists and circadian biology. A structured literature search was conducted in PubMed using combinations of the terms ‘GLP-1,’ ‘circadian,’ ‘chronobiology,’ ‘sleep,’ ‘obesity,’ and ‘type 2 diabetes’ through January 2026. Accumulating evidence indicates that GLP-1 physiology is closely coupled to circadian timing systems and sleep–wake regulation. In this narrative review, we synthesize emerging data that reframe GLP-1RAs as chronometabolic modulators, acting at the intersection of metabolism, circadian biology, and sleep. We review circadian control of GLP-1 secretion by intestinal L-cells, emphasizing the role of core clock genes and the vulnerability of incretin rhythms to circadian misalignment from shift work, nocturnal light exposure, and sleep loss. We then examine GLP-1 receptor signaling within central and peripheral clock networks, including feedback effects on hypothalamic and hepatic circadian regulation. Emerging data suggest that GLP-1 signaling is under circadian regulation and may, in turn, influence central and peripheral clock systems. Comparative discussion of semaglutide, liraglutide, and tirzepatide highlights agent-specific pharmacokinetics and emerging clinical data linking GLP-1RA therapy to sleep outcomes, particularly obstructive sleep apnea. Finally, we outline translational opportunities for chronotherapy and precision medicine, positioning GLP-1RAs as integrative tools for metabolic and sleep-related disease rather than purely weight-centric therapies. We propose that GLP-1 receptor agonists may function as chronometabolic modulators, with potential implications for personalized chronopharmacological strategies in metabolic disease. Full article

The immunosuppressive nature of porcine reproductive and respiratory syndrome virus (PRRSV) remains the central obstacle to its effective control. Conventional microRNA (miRNA)-based antiviral approaches are limited by their modest potency and the high risk of viral escape. Here, we rationally designed an engineered miRNA carrying a 5′-triphosphate (5′-PPP) terminus that integrates RIG-I-driven innate immune activation and sequence-specific gene silencing within a single molecule. In vitro-transcribed 5′-PPP miRNAs are efficiently recognized by the pattern-recognition receptor RIG-I, triggering a robust type I interferon response that counteracts PRRSV-induced immunosuppression. In MARC-145 cells, one such construct, 5′-PPP BZL-sRNA-20, potently inhibited PRRSV replication through the synergistic action of immune activation and gene silencing. However, in porcine alveolar macrophages (PAMs)—the natural host cells for PRRSV—the antiviral effect depended primarily on 5′-PPP-induced interferon responses, with the targeting sequence providing limited or context-dependent benefits. Dual-luciferase assays confirmed that the gene-silencing activity depends on 5′-PPP modification, which enhances the stability of BZL-sRNA-20. This bifunctional strategy establishes an “immune activation plus targeting” paradigm by simultaneously acting as a RIG-I ligand that triggers broad antiviral responses and specifically cleaves viral RNA via direct base-pairing to conserved regions of the PRRSV genome. These findings reveal the potential of engineered 5′-PPP miRNAs as immunomodulatory antiviral agents, while highlighting that the contribution of RNAi targeting varies depending on the cellular context. Full article