Search Results (45,494)

Nuclear receptors (NRs) are transcription factors regulated by ligands that direct metabolism, development, and immunity. The NR superfamily constitutes a principal category of pharmacological targets for human ailments. Retinoic acid receptor-related orphan receptors (RORs) α, β, and γ are part of the nuclear receptor superfamily. They are nevertheless classified as “orphan” receptors due to the contentious nature of identifying their endogenous ligands. RORγ nuclear receptor protein further consists of two isoforms, namely RORγ1 and RORγ2 or RORγt. RORγt is largely found in immune cells and has been primarily associated with chronic inflammatory conditions. The expression of STAT3 is a major driver of Th17 differentiation and induces RORγt expression through the JAK-STAT pathway. Type 3 innate lymphoid cells (ILC3s), Th17 cells, and γδT cells express RORγt, the master transcription regulator for the pro-inflammatory cytokine interleukin IL-17. In chronic inflammatory skin disorders, a significant increase in IL-17 has been observed, which plays a key role in both immune cell recruitment to the site of inflammation and the propagation of tissue damage. In this review, we will discuss how RORγt regulates IL-17-driven inflammation and explore potential strategies to target the RORγt-IL-17 axis as a viable therapeutic intervention in chronic inflammatory skin disorders. Full article

Background/Objectives: Bacterial blight (BB) represents one of the most devastating diseases threatening global rice production. Exploring and characterizing disease resistance (R) genes provides an effective strategy for controlling BB and enhancing rice resilience. Common wild rice (Oryza rufipogon) serves as a valuable reservoir of genetic diversity and disease resistance resources. In this study, we identified and functionally characterized a novel NLR gene, YPR1, from common wild rice (Oryza rufipogon), which exhibited significant spatial, temporal, and tissue-specific expression patterns. Methods: Using a combination of conventional PCR, RT-PCR, bioinformatics, transgenic analysis, and CRISPR/Cas9 gene-editing approaches, the full-length YPR1 sequence was successfully cloned. Results: The gene spans 4689 bp with a coding sequence (CDS) of 2979 bp, encoding a 992-amino acid protein. Protein domain prediction revealed that YPR1 is a typical CNL-type NLR protein, comprising RX-CC_like, NB-ARC, and LRR domains. The predicted molecular weight of the protein is 112.43 kDa, and the theoretical isoelectric point (pI) is 8.36. The absence of both signal peptide and transmembrane domains suggests that YPR1 functions intracellularly. Furthermore, the presence of multiple phosphorylation sites across diverse residues implies a potential role for post-translational regulation in its signal transduction function. Sequence alignment showed that YPR1 shared 94.02% similarity with Os09g34160 and up to 96.47% identity with its closest homolog in the NCBI database, confirming that YPR1 is a previously unreported gene. To verify its role in disease resistance, an overexpression vector (Ubi–YPR1) was constructed and introduced into the BB-susceptible rice cultivar JG30 via Agrobacterium tumefaciens-mediated transformation. T₁ transgenic lines were subsequently inoculated with 15 highly virulent Xanthomonas oryzae pv. oryzae (Xoo) strains. The transgenic plants exhibited strong resistance to eight strains (YM1, YM187, C1, C5, C6, T7147, PB, and HZhj19), demonstrating a broad-spectrum resistance pattern. Conversely, CRISPR/Cas9-mediated knockout of YPR1 in common wild rice resulted in increased susceptibility to most Xoo strains. Although the resistance of knockout lines to strains C7 and YM187 was comparable to that of the wild type (YP^WT), the majority of knockout plants exhibited more severe symptoms and significantly lower YPR1 expression levels compared with YP^WT. Conclusions: Collectively, these findings demonstrate that YPR1 plays a crucial role in bacterial blight resistance in common wild rice. As a novel CNL-type NLR gene conferring specific resistance to multiple Xoo strains, YPR1 provides a promising genetic resource for the molecular breeding of BB-resistant rice varieties. Full article

Heavy metal and metalloid stress, particularly from toxic elements like cadmium (Cd), poses a growing threat to plant ecosystems, crop productivity, and global food security. Elevated concentrations of these contaminants can trigger cytotoxic and genotoxic effects in plants, severely impairing growth, development, and reproduction. In recent years, epigenetic mechanisms have emerged as crucial regulators of plant responses to heavy metal stress, offering novel insights and strategies for enhancing plant resilience in contaminated environments. This review synthesises current advances in the field of plant epigenetics, focusing on key modifications such as DNA methylation, histone acetylation and remodelling, chromatin dynamics, and small RNA-mediated regulation. These processes not only influence gene expression under metal-induced stress but also hold promise for long-term adaptation through transgenerational epigenetic memory. Recent developments in high-throughput sequencing and functional genomics have accelerated the identification of epigenetic markers associated with stress tolerance, enabling the integration of these markers into breeding programs and targeted epigenome editing strategies. Special attention is given to cadmium stress responses, where specific epigenetic traits have been linked to enhanced tolerance. As plant epigenomic research progresses, its application in sustainable agriculture becomes increasingly evident offering environmentally friendly solutions to mitigate the impact of heavy metal pollution. This review provides a foundation for future research aimed at leveraging epigenetic tools to engineer crops capable of thriving under metal stress, thereby contributing to resilient agricultural systems and sustainable food production. Full article

The imbalance of the renin–angiotensin system (RAS), characterized by the overactivation of the pro-tumor ACE/AngII/AT1R axis, is closely linked to tumor growth, angiogenesis, metastasis, and poor prognosis. Natural polyphenols, such as EGCG and resveratrol, exert anti-cancer effects by dual-regulating RAS: they inhibit the pro-tumor axis by blocking renin, ACE activity, and AT1R expression, while simultaneously activating the protective ACE2/Ang(1-7)/MasR axis. Furthermore, polyphenols and their autoxidation products (e.g., EAOP) modify thiol-containing transmembrane proteins (such as ADAM17 and integrins) and interact with RAS components, further disrupting oncogenic pathways (including MAPK and PI3K/Akt/mTOR) to induce apoptosis, suppress invasion, and reduce oxidative stress. Notably, EAOP exhibits stronger RAS-modulating efficacy than its parent polyphenols. However, challenges such as low bioavailability, insufficient targeting, and limited clinical evidence impede their application. This review provides a comprehensive overview of the anti-cancer mechanisms of polyphenols through RAS regulation, discusses the associated challenges, and proposes potential solutions (including nanodelivery and structural modification) and strategies to advance natural product-based adjuvant treatments. Full article

Background/Objectives: Breast cancer is a heterogeneous disease, and the role of the transcription factor SPDEF remains controversial. We aimed to clarify the prognostic value of SPDEF, explore demographic and molecular correlates of its expression, and investigate potential regulatory mechanisms underlying its dysregulation. Methods: Genomic and clinical data for 1218 breast cancer tumors were obtained from The Cancer Genome Atlas (TCGA). SPDEF mRNA expression was compared across intrinsic subtypes, age, and race, and prognostic significance was evaluated by Kaplan–Meier analysis. Promoter methylation patterns and DNA methyltransferase (DNMT) expression were examined as potential regulatory drivers. Co-expression analysis was performed using gene panels representing luminal differentiation, basal identity, EMT, proliferation, DNA repair, and immune signaling. Results: Low SPDEF expression was significantly associated with worse overall, relapse-free, and metastasis-free survival across all breast cancers. Expression was lowest in Basal tumors, as well as among younger and Black or African American patients. Promoter methylation at six CpG islands correlated with both reduced SPDEF expression and inferior survival, and DNMT1, DNMT3A, and DNMT3B overexpression also aligned with poor prognosis and Basal enrichment. Co-expression analysis revealed that SPDEF downregulation coincided with loss of luminal markers and increased EMT, proliferation, DNA repair, and immune pathways. Conclusions: SPDEF functions as a tumor suppressor in breast cancer, with reduced expression linked to poor outcomes, aggressive molecular features, and epigenetic regulation. These findings highlight SPDEF and DNMT-driven methylation as potential prognostic biomarkers for enhanced risk stratification and targets for novel therapies, particularly in Basal breast cancers. Full article

Endocrine-disrupting chemicals (EDCs) are widespread contaminants that interfere with hormonal signaling and compromise reproductive success in aquatic organisms. Vitellogenin (VTG) is one of the most widely established biomarkers of estrogenic exposure, especially in males and juveniles. However, evidence from multi-omics studies indicates that VTG induction occurs within broader transcriptional and regulatory networks, involving genes such as cyp19a1 (aromatase), cyp1a (cytochrome P4501A), and other stress-responsive genes, underscoring the complexity of endocrine disruption. This review focuses on nuclear receptor isoforms, including estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and androgen receptor (AR) variants. We examine the diversification of vtg gene repertoires across teleost genomes and epigenetic mechanisms, such as DNA methylation and microRNAs, that modulate sex-dependent sensitivity. In addition, we discuss integrative approaches that combine VTG with transcriptomic, epigenetic, and histological endpoints. Within the Adverse Outcome Pathway (AOP) and weight-of-evidence (WoE) frameworks, these strategies provide mechanistic links between receptor activation and reproductive impairment. Finally, we outline future directions, focusing on the development of sex-specific biomarker panels, the integration of omics-based data with machine learning, and advances in ecogenomics. Embedding molecular responses into ecological and regulatory contexts will help bridge mechanistic insights with environmental relevance and support sustainability goals such as SDG 14 (Life Below Water). Full article

Background: Male infertility is evaluated using standard semen parameters. However, these criteria offer limited insight into sperm functionality and poorly predict natural fertility or assisted reproductive technology (ART) outcomes. Methods: In this study, the expression levels of three genes (AURKA, HDAC4, and CARHSP1) involved in mitosis regulation, epigenetic modulation and early embryonic development, were measured by RT-qPCR in sperm samples (training dataset). For each gene, thresholds of normal and reduced expression were established by biostatistical modeling and combined with the number of motile spermatozoa to develop the Spermatozoa Function Index (SFI). Results: The ROC analysis was used to interpret the SFI values: SFI > 320 (normal), 290–320 (intermediate), and <290 (low). Then, this index was validated using 627 fresh semen samples from 25- to 60-year-old men at our ART center. Based on the World Health Organization criteria, 54.5% of the 627 sperm samples were normospermic, 8.8% showed oligo-astheno-teratospermia, and 36.6% had one or two abnormal parameters. According to the SFI values, 41% of sperm samples displayed normal expression, 55.9% low expression, and 4.1% intermediate expression. Only 57% of the 342 normospermic samples had normal SFI values and 37% had low SFI values. Among the 81 samples with stringent normal criteria (≥50 million/mL, ≥50% total motility, ≥14% normal morphology), 67.9% displayed normal SFI and 22.2% low SFI values. These findings suggest that even sperm with normal parameters may harbor dysfunctions. Conclusions: Our data highlight a gene signature with strong discriminatory power and promising diagnostic value for detecting subclinical sperm defects and improving male infertility assessment. Full article

Background: The E26 transformation-specific (ETS) transcription factor Friend Leukemia Integration 1 (FLI1) has been linked to breast cancer aggressiveness, stromal remodeling, and immune modulation, yet the regulatory mechanisms governing its activity remain poorly defined. Of note, various studies have shown that EWS-FLI1-mediated transcription programs are facilitated via direct recruitment and binding of the NuRD-LSD1 complex, regulating its associated gene targets. Furthermore, LSD1 inhibition exhibited reverse transcriptional profiles driven by ETS-FLI and reduced in vivo tumorigenesis in cancers. Methods: We evaluated FLI1 expression across multiple invasive breast carcinoma (IBC) cohorts to determine its prognostic significance and associations with stromal features. In parallel, we investigated FLI1 regulation in humanized breast cancer mouse models treated with an LSD1 inhibitor. Results: High FLI1 expression was associated with advanced histological grade in IBC, consistent with an oncogenic function. FLI1-high tumors also exhibited elevated stromal and immune scores, indicating a role in remodeling the tumor microenvironment. Additionally, LSD1 inhibition downregulated FLI1 target genes involving angiogenesis and invasion. Conclusions: These findings highlight the dual role of FLI1: tumor-intrinsic FLI1 promotes proliferation and invasion, whereas its transcriptional regulation in tumor and endothelial compartments likely reflects LSD1 dependence. Collectively, our results support a mechanistic model in which LSD1–FLI1 crosstalk is involved in immune and stromal remodeling, positioning FLI1 as both a marker of tumor aggressiveness and a potential predictor of response to epigenetic therapies in breast cancer. Full article

Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, demanding improved biomarkers and therapeutic approaches. This review synthesizes the extensive evidence positioning the miR-200 family as a master regulator of NSCLC progression. We detail the core molecular circuitry centered on the bistable, double-negative feedback loop between miR-200 and the ZEB1/ZEB2 transcription factors, which governs epithelial–mesenchymal transition (EMT). This review connects this central mechanism to critical clinical challenges, including the development of resistance to EGFR-targeted therapies and the regulation of immune evasion through PD-L1 expression and CD8+ T cell infiltration. We evaluate the strong clinical evidence for the miR-200 family’s utility as a diagnostic, prognostic, and predictive biomarker. Finally, we explore emerging therapeutic strategies that target this network, including miRNA replacement, epigenetic reactivation, and rational combinations with immunotherapy and targeted agents. We synthesize evidence positioning the miR-200/ZEB feedback circuit as a central regulatory node in NSCLC that links EMT with therapeutic resistance and immune evasion. Beyond summarizing associations, we interpret how this circuitry could inform biomarker development and rational combinations with targeted and immune therapies. Given heterogeneous study designs and non-standardized assays, translational claims remain provisional; we outline immediate priorities for assay harmonization and biomarker-stratified trials. Full article

There are no disease-modifying treatments available for Huntington’s disease (HD), a neurodegenerative disease caused by a genetic mutation in the Huntingtin gene. Previous research suggests that disruptions in the bioenergetics of the mitochondria and increased oxidative stress are potential inducers of HD. Therapies that enhance antioxidant pathways intend to target and attenuate the overproduction of reactive oxygen species associated with mitochondrial dysfunction. We have investigated the effect of Methylene Blue (MB) as a potential therapy for HD. MB is a small molecule demonstrated to exhibit neuroprotective effects in other neurodegenerative disease models, including Parkinson’s and Alzheimer’s, by attenuating the oxidative stress pathways implicated in their pathophysiology. We used an established striatal cell model of HD expressing wild-type (STHdh^Q7/Q7) or mutant (STHdh^Q111/Q111) HTT and a chemical inducer of HD, 3-Nitropropionic acid (3-NPA), to determine the HD-specific mechanisms regulated by 3 h of MB pre-treatment. Upon 24 h of exposure to 3-NPA, mutant HD cells exhibited a significant concentration-dependent decrease in cell survival and a concomitant increase in cell death compared to wild-type, confirming that 3-NPA exacerbates mutant HTT neurotoxicity. Examination of mitochondrial membrane potential and mitochondrial function in the striatal cells by JC-1 and ATP assays, respectively, revealed MB mediated neuroprotection against 3-NPA-induced reduction in mitochondrial activity. Immunoblotting analysis revealed that MB restores baseline expression of oxidative-stress-related proteins, including HO1 and p62, in both wild-type and mutant cells exposed to 3-NPA. Our findings establish a novel neuroprotective role of MB in both genetic and pharmacological models of HD, suggesting that MB might be a promising therapeutic candidate for altering the underlying pathophysiology of HD by improving mitochondrial function. Full article

Training not only enhances the athletic performance of horses but also improves cardiac structure and function, strengthens cardiovascular adaptability, and reduces the risk of cardiovascular diseases. However, the consequences of training on equine cardiac structure and function remain unclear. This study investigated the morphological, functional, genetic, and metabolic changes in the hearts of Yili horses divided into three groups: high athletic performance (agility group, AG), low athletic performance (ordinary group, OG), and untrained (untrained group, UN). The results showed remodeling of the cardiac structure and physiological adaptations in AG and OG compared to UN groups, with differences between AG and OG primarily in the left ventricle. To explore the molecular mechanisms underlying these phenotypic changes, transcriptomic and metabolomic analyses (particularly GO and KEGG pathway analyses) were performed to assess differences in gene expression and metabolite levels among the three groups. Our results show that miR-1842, miR-671, miR-106b and miR-18a were differentially expressed in the trained groups (AG group and OG group) compared with the control group that did not receive training. These regulatory factors would regulate PFKFB3 to affect the glycolytic activity mediated by HIF-1, there by promoting glycolysis and changing lactate level. This, in turn, would positively feedback to stabilize HIF-1, thus forming a closed loop for the reprogramming of myocardial energy metabolism. In the AG group, positive effects of cAMP signaling were noticeable. In conclusion, our findings offer new insights into physiological cardiac remodeling in Yili horses by highlighting genetic and metabolomic changes resulting from exercise training. Full article

The TIP60/NuA4 complex is a large, multifunctional histone acetyltransferase assembly of ~1.7 megadaltons, composed of 17–20 subunits, which plays a central role in epigenetic regulation. Through recognition of H3K4me3 by the ING3 reader, TIP60/NuA4 is recruited to sites of active transcription, where it remodels chromatin to regulate gene expression. Its activities include histone acetylation, histone variant exchange, transcriptional co-activation, and regulation of the cell cycle and apoptosis. In this review, we examine how altered subunit levels or mutations impact the chromatin structure and transcriptional activity, and how these changes influence differentiation across diverse cell types. We emphasize the molecular mechanisms by which TIP60/NuA4 shapes lineage specification, including histone H2A and H4 acetylation by the KAT5 catalytic subunit, H2A.Z incorporation by EP400, and interactions with transcription factors such as MyoD, PPARγ, and Myc. By integrating mechanistic and functional insights, we highlight how TIP60/NuA4 acts as a central epigenetic hub in differentiation and contributes to proper developmental transitions. Full article

Litchi (Litchi chinensis Sonn.) is a popular subtropical fruit with a red pericarp that is primarily determined by the accumulation of anthocyanins. The peel color and fruit quality are also influenced by proanthocyanins (PAs), which play roles in fruit development and postharvest quality. In this study, we identified LcMYB2 as a key regulator of both anthocyanin and PA biosynthesis in litchi. Phylogenetic analysis revealed that LcMYB2 belongs to the VvMYB5 subclade. Expression analysis showed that LcMYB2 is highly expressed in the early stages of fruit development. Its expression pattern was consistent with that of LcLAR and LcANR, two key genes in the PA biosynthetic pathway. Subcellular localization and protein–protein interaction assays confirmed that LcMYB2 localizes to the nucleus and interacts with LcbHLH3. Dual-luciferase reporter assays demonstrated that the LcMYB2-LcbHLH3 complex activates the promoters of LcLAR and LcANR, supporting its role in regulating PA biosynthesis. Furthermore, overexpression of LcMYB2 in tobacco resulted in the synthesis of anthocyanins and PAs in the flower, indicating that LcMYB2 can regulate anthocyanin and PA biosynthesis. Additionally, transgenic tobacco plants with LcMYB2 overexpression exhibited delayed anther dehiscence, suggesting a broader role in plant development. These findings highlight the multifunctional nature of LcMYB2 in regulating both anthocyanin and PA biosynthesis, as well as its involvement in reproductive development. Full article

The aim of this study was to investigate the prognostic and predictive properties of four specific genes in triple-negative breast cancer (TNBC). We focused on ADIPOQ, GAS5, GATA4, and YAP1, which are known for their roles in key molecular pathways related to tumorigenesis, such as adipokine signaling, lncRNA regulation, transcriptional control, and Hippo signaling, but have not been sufficiently explored in the context of epigenetic regulation in breast cancer. Using the methylospecific PCR (MSP) method, we analyzed the methylation of the four genes in the tumor tissues collected from 57 TNBC patients. We evaluated their association with response to neoadjuvant treatment and clinicopathological characteristics. Additionally, we performed a bioinformatic analysis of methylation and expression data from The Cancer Genome Atlas (TCGA) TNBC cohort to explore their relationships with overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), progression-free interval (PFI), and relapse-free survival (RFS). No significant associations were observed between methylation patterns and clinicopathological characteristics in the patients. However, in silico analysis of the TNBC cohort identified ADIPOQ methylation as having the most significant associations, correlating with all five survival endpoints, including OS, DSS, DFI, PFI, and RFS. GAS5 methylation was significantly associated with OS, DSS, and RFS, and GATA4 methylation showed significant associations with PFI, whereas YAP1 methylation was significantly associated with OS and RFS. In addition, GAS5 expression was linked to DSS, DFI and RFS. This study highlights the potential prognostic significance of the epigenetic regulation of ADIPOQ in TNBC. The in silico findings shed light on the molecular pathways associated with TNBC progression and warrant further investigation to validate their role in clinical outcomes and underlying biological mechanisms. Full article

The transcription factor homeodomain-only protein X (HOPX) is the smallest member of the homeodomain protein family. Lacking a DNA-binding domain, it acts as a co-effector, interacting with other transcription factors such as serum response factor (SRF) and GATA-binding factor 6 (GATA6) to regulate the differentiation and development of the heart and lung. HOPX exerts a tumor-suppressive function in various types of epithelial-derived carcinoma, while it promotes oncogenic effects in mesenchymal-derived sarcoma, indicating a distinct role of HOPX in the two major types of the malignancy. In addition, accumulating evidence shows that HOPX is expressed in the immune system and involved in the differentiation of immune cells. Recently, the emerging role of HOPX in metabolism has gained attention. This review describes the identification of HOPX in various tissues and discusses its role in carcinogenesis, as well as its functions in tissue differentiation, lipid metabolism, immunity, and the tumor microenvironment. The participation of HOPX in carcinogenesis and immunity implies that it may serve as a potential enhancer in tumor immunotherapy. Full article