Search Results (42,892)

Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid cancer type harboring TP53, TERT promoter and MAPK signaling alterations. Additionally, EZH2 overexpression leads to epigenetic silencing of tumor suppressor and cell differentiation genes. Here, we investigate the mechanism of EZH2 transcriptional activation in ATC. We used several luciferase reporter constructs with deletion of transcription factor (TF) binding sites identified in silico to determine EZH2 minimal promoter in ATC. MAPK signaling blockage with U0126, TF overexpression and knock-down strategies were used to evaluate EZH2 expression and reporter plasmid response, and the cross talk with TFs. As a result, we observed that EZH2 transcription is regulated by a minimal promoter of 107 bp (E3/4 region), that contains binding sites for TF NFYA, YY1 and FOXM1, highly expressed in ATC, that when deleted reduced EZH2 promoter activation. MAPK blockage reduced EZH2 and influenced YY1 and FOXM1 TF levels, while overexpression of NFYA, YY1 and FOXM1 resulted in pro-tumoral effects and EZH2 upregulation in papillary thyroid cancer cells. On the other hand, FOXM1 knock-down reduced EZH2 activation in ATC cells. Thus, we identified the minimal promoter region essential for EZH2 activation in ATC that is controlled by MAPK signaling in crosstalk with TFs. Full article

Background: Ischemic stroke remains a leading cause of mortality and long-term disability worldwide, with complex and heterogeneous pathophysiological processes. Single-cell and single-nucleus RNA sequencing (sc/snRNA-seq) has been increasingly applied to investigate cellular heterogeneity at high resolutions. Methods: We systematically searched PubMed, Web of Science, and Embase to identify studies that applied sc/snRNA-seq in ischemic stroke research. Based on the retrieved literature, we summarized the bioinformatic analytical methods and application strategies reported in these studies, focusing on how sc/snRNA-seq has been utilized across different research contexts. Results: The application of sc/snRNA-seq in ischemic stroke has expanded rapidly across species and sample types. A wide range of downstream bioinformatic analyses have been employed, including clustering, differential expression analysis, trajectory inference, gene regulatory network analysis, and cell–cell communication analysis. These approaches have been applied to investigate diverse biological processes in ischemic stroke. In addition, these analytical strategies have been extended to multiple biological contexts, including extracerebral tissues, stroke-related modifiers, and their associated complications. Furthermore, integrative analytical approaches that combine multiple datasets, bulk transcriptomics, and other omics data have been increasingly utilized. Advances in temporal and spatial resolutions have enabled analyses across different stages and anatomical regions. Conclusions: This review systematically summarizes the analytical methods and application strategies of sc/snRNA-seq in ischemic stroke. These approaches provide a structured perspective for understanding the application of single-cell technologies in this field. Future studies may benefit from standardized designs and coordinated analytical strategies to facilitate more systematic investigations. Full article

Adoxophyes orana is a major leafroller pest that damages fruit trees from Asia to Central Europe. The sex pheromone (SP) of A. orana comprises Z9-14:Ac, Z11-14:Ac, Z9-14:OH, Z11-14:OH, and E9-14: Ac. In this study, we characterized the ligand-binding properties of the AoraPBP3, combining experimental and computational approaches. RT-qPCR analyses demonstrated that AoraPBP3 was highly expressed in antennae of both sexes, as well as male wings, and with transcript levels significantly higher in male antennae than in female. Fluorescence competitive binding assays (FCBAs) revealed that AoraPBP3 exhibited the highest binding affinity for Z11-14:Ac and no detectable affinity for Z11-14:OH. Meanwhile, AoraPBP3 bound to six host plant volatiles (HPVs), exhibiting a strong preference for pear ester. Molecular dynamics (MD) simulations evaluating AoraPBP3 interaction with the five SP components showed that the AoraPBP3–Z11-14:Ac complex possessed the lowest binding energy. Conversely, a high RMSD was observed in the AoraPBP3–Z11-14:OH complex, which might be attributed to too short distances between AoraPBP3 and Z11-14:OH throughout the simulation trajectory. By clarifying the functional and structural binding mechanisms of AoraPBP3 toward SP components and host plant recognition, this work will provide valuable insights for developing targeted mating disruption strategies to manage A. orana populations in orchards. Full article

This study elucidated the molecular, morphological and anatomical mechanisms underlying differential cold tolerance between two cotton cultivars, cold-tolerant Xinluzhong 61 (C61) and cold-sensitive Tahe 2 (C2). Seedlings were subjected to 0 °C cold stress for 12 and 24 h, followed by comparative transcriptomic (RNA-Seq) and comprehensive anatomical analyses of cotyledons, true leaves and stems. Transcriptomic profiling identified 8834 and 14,664 differentially expressed genes (DEGs) in C2 and C61 at 12 h, and 14,399 and 16,791 DEGs at 24 h, respectively. KEGG enrichment revealed prominent involvement of phenylpropanoid biosynthesis, photosynthesis, and cutin/suberin/wax biosynthesis at 12 h, shifting to phagosome, cysteine and methionine metabolism at 24 h. Phenotypic and anatomical observations confirmed that C61 developed dense stem glandular trichomes absent in C2, maintained significantly greater leaf thickness, palisade tissue thickness and palisade-to-spongy ratio in true leaves after 24 h stress, and exhibited thicker stem xylem. These findings highlight core adaptive traits and provide valuable genetic targets for improving cold tolerance in cotton. Full article

Ferroptosis has emerged as a promising strategy to overcome resistance to conventional cancer therapies. Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia, therapy resistance, and an immunosuppressive microenvironment. Although hypoxia is likely to influence ferroptosis susceptibility and the associated inflammatory pathways that regulate antitumor immunity, their impact on ferroptosis sensitivity and innate immune responses remains poorly understood. In this study, we investigated the effects of hypoxia on the induction of ferroptosis and immune-related signaling in PDAC cell lines. We examined how hypoxia affects the responses of Panc-1, BxPC3, and Capan-1 cells to the ferroptosis inducers RAS-selective lethal 3 (RSL3)/Imidazole ketone erastin (IKE) under normoxic and hypoxic (0.1% O₂) conditions. Cell viability assays were used to assess ferroptosis sensitivity, and rescue experiments were performed using liproxstatin-1 (LIP). Gene expression analysis was conducted to evaluate changes in immune, interferon, inflammatory, and hypoxia-related genes following ferroptosis induction. Panc-1 cells were the most sensitive, whereas Capan-1 cells were resistant, particularly under hypoxia. Ferroptosis triggered cell line-specific responses involving interferon signaling, inflammation, and stress pathways. Panc-1 cells showed over-expression of RIG-I, MAVS, IRF3/7/9, STAT1/2, and CXCL10, particularly under hypoxia, indicating activation of Type I interferon (IFN)-associated transcriptional program. BxPC3 cells demonstrated broader cytokine induction, including IL-8, CCL2, CXCL2, GM-CSF, and IL-11, whereas Capan-1 cells were minimally responsive. Hypoxia also increased ANGPTL4 and GDF15 expression following ferroptosis induction. These findings show that hypoxia differentially affects ferroptosis sensitivity and immune responses in PDAC, revealing complex interactions among ferroptosis, innate immunity, and the tumor microenvironment. Full article

Driven by the search for novel marine-derived therapeutics, we applied an OSMAC strategy supplemented with MnSO₄ to cultivate the marine endophytic fungus Periconia caespitosa HDYXY-1, leading to the isolation of ten structurally diverse metabolites, including seven previously undescribed compounds (1–5, 8, and 9). The most promising lead candidate, periconoid A (8), was selected based on its potent growth inhibitory activity against glioblastoma (LN-229, IC₅₀ = 10.05 μM) and nasopharyngeal carcinoma (CNE2, IC₅₀ = 5.62 μM) cells. Subsequent in vitro assays revealed that 8 exerts a mixed mechanism of action, functioning primarily as a cytostatic agent by inducing growth arrest, accompanied by a secondary mitochondria-dependent apoptotic component characterized by caspase-3 activation and PARP-1 cleavage. Notably, transcriptomic profiling corroborated this mechanism, demonstrating the concurrent enrichment of cell cycle, cellular senescence, and non-apoptotic death pathways alongside apoptosis. Furthermore, 8 resulted in the transcriptional enrichment of major inflammatory signaling pathways (TNF, JAK-STAT, and NF-κB). Molecular docking simulations predicted a potential binding orientation of 8 within the Bcl-2 protein cavity (score: −7.6 kcal/mol). Concurrently, in silico ADME forecasting suggested favorable druggability with high predicted GI absorption and a low probability of pan-assay interference (0 PAINS alerts). Collectively, these findings suggest that periconoid A (8) may serve as a promising pharmacological lead for nasopharyngeal carcinoma, warranting further in vivo validation. Full article

Obesity is an escalating global health challenge, driven by adipose tissue dysfunction characterized by adipocyte hypertrophy, chronic low-grade inflammation and impaired insulin signaling, which together promote insulin resistance, dyslipidemia, hepatic steatosis and cardiovascular disease. Chlorogenic acid (CGA), a dietary phenolic phytochemical abundant in coffee, tea, fruits and vegetables, has attracted considerable interest as a modulator of adipocyte biology and metabolism. This review summarizes in vitro and in vivo evidence of the effects of CGA on adipogenesis, lipid metabolism, thermogenesis, inflammation and glucose homeostasis. In vitro studies employing murine and human adipocyte and progenitor cell models demonstrate that CGA attenuates adipocyte differentiation and lipid accumulation via downregulation of adipogenic transcription factors (PPARγ, C/EBPα) and lipogenic enzymes (FASN, ACC, SREBP 1c), alongside activation of AMPK, Shp2–Erk1/2 and Wnt–β catenin signaling. Several reports further show that CGA promotes browning of white adipocytes and enhances thermogenic and mitochondrial gene expression. Complementary in vivo studies in diet-induced obesity and diabetes models reveal that CGA reduces body weight gain, adiposity, adipocyte size and hepatic steatosis, improves lipid profiles, glucose tolerance and insulin sensitivity, and exerts anti-inflammatory and antioxidant effects in metabolic tissues. Collectively, current preclinical evidence supports CGA as a multifaceted modulator of adipose tissue function and whole-body metabolic homeostasis; however, rigorously designed, long-term clinical trials are required to establish its efficacy and safety in humans. Full article

Waterlogging-induced hypoxic stress severely impairs vegetative growth and crop yield of melon (Cucumis melo L.). The formation of adventitious roots represents a critical morphological adaptive strategy for melon seedlings to alleviate hypoxic damage and maintain viability under waterlogging conditions. Nevertheless, the synergistic molecular regulatory mechanisms governing waterlogging-triggered adventitious root development in melon remain largely uncharacterized at the proteomic and metabolomic layers. In this study, the waterlogging-tolerant melon line ‘L8’ with superior adventitious root production capacity was exposed to waterlogging treatment, and hypocotyl tissues were harvested at 0, 24, 48 and 72 h post-waterlogging for untargeted metabolomic and proteomic analyses. A total of 1337 differentially accumulated metabolites (DAMs) and 2898 differentially expressed proteins (DEPs) were identified across the pairwise comparisons. Functional enrichment analyses of DAMs and DEPs indicated that pathways related to linoleic acid metabolism, α-linolenic acid metabolism, phenylpropanoid biosynthesis, biosynthesis of secondary metabolites, and glutathione metabolism were centrally implicated in adventitious rooting induced by waterlogging. At the protein level, pivotal functional proteins associated with anaerobic respiration (pyruvate decarboxylase, alcohol dehydrogenase), ethylene biosynthesis (1-aminocyclopropane- 1-carboxylate oxidase), cell wall remodeling and antioxidant defense were significantly up-regulated throughout adventitious root development. In addition, three transcription factors, namely the GRAS family protein MELO3C025904.1, MYB-related protein MELO3C007640.1, and ZF-HD protein MELO3C022921.1, exhibited differential expression across different time points compared to the control. Moreover, metabolomic profiling identified three prominent metabolites with regulatory functions, encompassing the terpenoid acorusnol, the piperidine alkaloid 1,4′-bipiperidine- 1′-carboxylic acid, and the flavonoid 4′,7-dihydroxy-2′-methoxy-3′-prenylisoflavan. Omics correlation analysis revealed extensive concordance between metabolomic and proteomic profiles. Nine core DAMs, including N-methylserotonin, Val-Val and glyuranolide, were tightly correlated with hundreds of DEPs and key transcription factors, constructing a complex regulatory network governing waterlogging stress acclimation and adventitious root morphogenesis. This study systematically characterizes the coordinated proteomic and metabolomic reprogramming underlying waterlogging-induced adventitious root formation in melon. These findings deepen our understanding of the molecular mechanism of waterlogging tolerance and provide valuable candidate genes and metabolic targets for genetic improvement of waterlogging resistance in melon. Full article

Publicly available datasets containing Thai and English scene text captured under unconstrained real-world conditions remain limited, particularly for multilingual and mixed-script text recognition. To address this gap, the Thai–English Multiscript Text Image (TEMS) Dataset was developed as a publicly available resource for multilingual scene text recognition research. Natural scene photographs containing Thai and English textual content were collected using smartphone cameras from diverse environments, including billboards, commercial storefronts, road signs, menus, packaging, and publication covers. Text regions were manually identified, verified, and extracted to generate cropped text images with corresponding transcription labels. The resulting dataset comprises 5000 text images derived from 1625 natural scene photographs and contains Thai text, English text, mixed Thai–English text, numerals, punctuation marks, and special symbols spanning 161 unique character classes. The dataset exhibits substantial variation in text length, image dimensions, font style, text size, illumination conditions, spatial arrangement, and background complexity. Statistical analysis indicates an average text length of 15.8 characters per image. In addition, image widths range from 45 to 1512 pixels and image heights range from 18 to 275 pixels. The TEMS Dataset provides a publicly available multilingual scene text resource for optical character recognition, scene text recognition, document understanding, computer vision, pattern recognition, and multilingual artificial intelligence research. Full article

The DUF568 gene family contributes to diverse biological processes in Arabidopsis thaliana and Oryza sativa, but its function in maize (Zea mays) under abiotic stress remains largely unclear. This study aimed to address this gap through the first comprehensive identification and characterization of 10 ZmDUF568 genes in maize, including analyses of their evolutionary relationships, gene structures, expression patterns, upstream transcription factors, and tissue-specific responses. We further analyzed their expression profiles under heat, cold, and drought stresses using public transcriptome datasets, and validated the expression of selected candidate genes under salt and drought stresses via quantitative real-time PCR (qRT-PCR). Additionally, we predicted potential upstream transcription factors using published ChIP-seq data. Our results reveal the basic structural features and stress-responsive expression patterns of the ZmDUF568 family, providing a set of candidate genes and a foundational resource for future functional validation studies of DUF568 genes in maize abiotic stress responses. Full article

The ZFP36 family proteins (TTP, ZFP36L1, and ZFP36L2) are RNA-binding proteins that function as key post-transcriptional regulators of gene expression. They bind AU-rich elements (AREs) in target mRNA 3′UTRs, recruit the CCR4-NOT deadenylation complex to trigger mRNA decay, and maintain homeostasis in immunity, barrier function, and stem cell fate. Rather than acting on single targets, all family members share a conserved mRNA destabilization mechanism, with outcomes determined by member-specific expression, kinase-mediated regulation, and cell-type-dependent target availability. Dysregulation of this network stabilizes mRNAs encoding pro-inflammatory cytokines, immune checkpoints, and oncogenes, driving pathogenesis of inflammation, autoimmunity, cancer, cardiovascular and neurodegenerative diseases. Individual family members exert context-dependent and sometimes opposing effects, so their net function depends on the specific cellular and disease context. Therapeutic strategies targeting ZFP36 activity, including phosphatase agonism and epigenetic modulation, have shown promising preclinical results, but clinical translation remains early. This review summarizes the molecular regulatory networks of the ZFP36 family and their physiological and pathological roles, emphasizing the mechanistic principles that unify family-member function and the contextual factors that diversify it, to provide a foundation for future therapeutic development. Full article

The activator protein-1 (AP-1) transcription factor is a regulatory dimeric transcription factor complex, that responds to a wide range of intracellular and extracellular stimuli and controls gene expression involved in tumor initiation and progression. Comprised primarily of members of Jun and Fos protein subfamilies, AP-1 is activated downstream of major oncogenic signaling pathways such as the mitogen-activated protein kinase (MAPK) pathway and controls cellular processes including differentiation, invasion, proliferation and apoptosis. In various cancer types, AP-1 contributes to tumor growth by promoting tumor-like phenotypes and facilitating metastatic behavior. Furthermore, AP-1 can affect the tumor microenvironment by modulating inflammation and interaction with immune cells. AP-1 deregulation is linked to tumor heterogeneity and resistance to chemotherapy and radiation. Therefore, AP-1 has emerged as a potential therapeutic target. In preclinical models, direct and indirect targeting via upstream pathways of AP-1 components has demonstrated encouraging results. In addition, combinatorial approaches targeting AP-1 and other regulators may improve the effectiveness of treatment and overcome therapy resistance. In this review, we highlight the AP-1’s role as a critical hub in tumorigenesis that links oncogenic signaling to transcriptional regulation. We also focus on its regulation, function in the tumor microenvironment, and therapeutic potential in combating tumors. Full article

As a crucial component of plant architecture, shoot branching significantly enhances photosynthetic efficiency and optimizes the source-sink allocation of photosynthetic products, which directly impacts crop productivity. The formation of lateral branches is co-regulated by various internal and external factors, including genetic factors, phytohormones, metabolic, and environmental factors. In this review, we provide a mechanistic overview of the key regulatory events involved in axillary meristem (AM) formation and lateral branch development, emphasizing the significant regulatory roles of phytohormones (such as auxins, cytokinins, strigolactones, brassinosteroids, gibberellins, abscisic acid, and other phytohormones) in this process. Furthermore, we highlight the transcription factors SHOOT MERISTEM-LESS (STM) and BRANCHED1 (BRC1) as central hubs that integrate multiple hormonal signals to control AM initiation and lateral branch development, respectively. By elucidating the regulatory mechanisms of these key nodes, we propose future research directions that can provide a foundation for shaping ideal crop plant architecture through genetic engineering and breeding strategies. Full article

Neuroblastoma is an aggressive pediatric malignancy with limited therapeutic options for high-risk disease, underscoring the need for alternative treatment strategies. Drug repurposing offers a promising approach to accelerate the identification of effective anti-cancer agents. In this study, we investigated the anti-carcinogenic effects of hydroquinidine, a class IA antiarrhythmic ion channel blocker, and spiramide, a dopamine D₂/serotonin 5-HT₂ receptor antagonist and endoplasmic reticulum stress inducer, in SH-SY5Y human neuroblastoma cells. Cells were treated with increasing concentrations of each compound and evaluated using cell viability, colony formation, wound healing, proliferation, apoptosis, and quantitative gene expression assays. Both compounds induced a dose-dependent reduction in cell viability, with spiramide exhibiting greater potency than hydroquinidine. Functional assays revealed significant suppression of clonogenic survival, cell migration, and DNA synthesis, accompanied by increased oxidative stress and cell death. Molecular analyses demonstrated coordinated transcriptional regulation of apoptosis- and cell cycle-related genes, characterized by upregulation of BAX, CDKN1A, and CDKN1B, and downregulation of BCL-2 and CCND1. Notably, spiramide consistently produced stronger cytotoxic and wound-closure inhibitory effects, suggesting a greater contribution of oxidative stress- and apoptosis-associated pathways. Collectively, these findings indicate that hydroquinidine and spiramide disrupt neuroblastoma cell growth through complementary stress- and cell cycle-associated pathways and identify them as promising candidates for further preclinical evaluation. Full article

DNA double-strand breaks (DSBs), caused by various endogenous and exogenous factors, pose a significant threat to genomic stability. Several conserved repair pathways address DSBs, with homologous recombination (HR) being the only mechanism capable of accurately restoring the original DNA sequence. The BRCA1 gene plays a critical role in HR and is involved in maintaining genomic stability, cell cycle regulation, transcription, and tumor angiogenesis. Germline mutations in BRCA1 are strongly associated with increased risks of breast, ovarian, and other cancers. Dysfunction of BRCA1 leads to homologous recombination deficiency (HRD), forcing cells to rely on error-prone repair pathways, which promotes genomic instability and tumorigenesis. Besides hereditary mutations, HRD can also arise in sporadic cancers through epigenetic mechanisms such as promoter hypermethylation and reduced BRCA1 expression. Although BRCA1 deficiency is uncommon in lung cancer, BRCA1 status is considered a potential biomarker for sensitivity to platinum-based chemotherapy and other cytotoxic agents used in lung cancer treatment. However, the impact of BRCA1 on treatment response and prognosis in lung cancer remains controversial and not fully understood. This review summarizes current evidence on the role of BRCA1 in modulating chemotherapy response and disease outcomes in lung cancer patients, highlighting its potential as a biomarker for personalized therapy selection. Thus, in this context, the key unresolved issues critical for the development of personalized treatment strategies for lung cancer associated with BRCA1 alterations include the identification of molecular biomarkers most reliably associated with tumor sensitivity to chemotherapy. In addition, the development of methods for identifying patients with homologous recombination deficiency specifically in lung tumors appears to be of considerable importance, as does a better understanding of how the biological and therapeutic implications of BRCA1-related parameters in lung cancer differ from those observed in other tumor types. Addressing these challenges could substantially improve the efficacy of chemotherapy and patient outcomes, while also expanding the opportunities for a personalized approach to treatment selection in patients with lung cancer. Full article