Search Results (180)

Metastatic pancreatic ductal adenocarcinoma (PDAC) is typically treated with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel (GnP), but the choice between regimens remains largely empirical. This narrative review summarizes biomarkers with potential to inform first-line selection in metastatic PDAC, emphasizing genomic and transcriptomic correlates of differential benefit. Recent head-to-head trials, particularly Pancreatic Adenocarcinoma Signature Stratification for Treatment (PASS-01) and GENERATE (Japan Clinical Oncology Group [JCOG] 1611), indicate that modified FOLFIRINOX (mFOLFIRINOX) is not uniformly superior to GnP, strengthening the rationale for biomarker-guided selection. The strongest evidence favoring platinum-based/FOLFIRINOX strategies involves homologous recombination repair deficiency (HRD), especially alterations in germline breast cancer gene 1/2 (BRCA1/2) or partner and localizer of BRCA2 (PALB2), as well as broader genomic scar signatures. Transcriptomic subtype and GATA-binding protein 6 (GATA6) expression are promising but remain unsettled because retrospective data favor classical/GATA6-high disease for FOLFIRINOX, whereas PASS-01 suggested better outcomes with GnP in classical tumors. Candidate biomarkers favoring GnP include high human equilibrative nucleoside transporter 1 (hENT1), low class III β-tubulin (TUBB3) expression, and exploratory phosphatidylinositol 3-kinase (PI3K)/KIT/NOTCH pathway mutation signals. Comprehensive molecular profiling also identifies actionable alterations that may redirect patients to targeted therapy or clinical trials rather than standard chemotherapy alone. Importantly, no biomarker has yet been prospectively validated in a biomarker-stratified randomized trial with regimen selection as the primary endpoint; all biomarker-regimen associations described in this review should therefore be considered hypothesis-generating rather than practice-defining. Nevertheless, the convergence of genomic, transcriptomic, and organoid-based approaches makes biologically informed first-line selection increasingly feasible in metastatic PDAC. Full article

Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer and a major cause of cancer death. Zinc finger proteins (ZNFs) have been implicated in LUAD progression, functioning either as oncogenes or tumor suppressors. Therefore, an in-depth investigation of ZNFs may contribute to the development of novel diagnostic and therapeutic strategies for LUAD. Methods: Transcriptomic and clinical data were obtained from the TCGA and GEO databases. Prognosis-related ZNF genes were identified using univariate Cox, LASSO, and multivariate Cox regression analyses. An eight-gene ZNF-based prognostic signature was constructed and validated in two independent external cohorts (GSE50081 and GSE26939). A nomogram integrating independent prognostic factors was developed. Immune infiltration, somatic mutation profiles, and drug sensitivity were systematically analyzed. We further focused on FGD3, a key gene from the signature, examining its expression in LUAD cells and tissues, including lorlatinib-resistant models. Results: The prognostic signature comprising TRIM6, TRIM29, CTCFL, FGD3, GATA4, CASZ1, TRAF2, and ZNF322 effectively stratified patients into distinct risk groups with significantly different overall survival (p < 0.05). The risk score, together with T and N stage, served as independent prognostic predictors (n = 500, p < 0.05). High-risk patients exhibited an immune-desert phenotype, increased tumor mutational burden, and distinct drug sensitivity patterns. Notably, FGD3 expression was downregulated in LUAD tissues (n = 14, p < 0.0001) and lorlatinib-resistant cells, and its restoration suppressed resistant cell proliferation and partially reversed drug resistance. Conclusions: This study establishes a promising ZNF-based prognostic model for LUAD, providing a potential tool for risk stratification and individualized therapeutic decision-making. The identification of FGD3 as a potential mediator of drug resistance highlights its promise as a candidate biomarker and therapeutic target in LUAD. Full article

Histone deacetylase 6 (HDAC6), a member of the class IIb HDAC family, plays a crucial role in epigenetic regulation and cytoskeletal dynamics, while participating in host anti-infective immune responses. However, its precise functions and mechanisms during Chlamydia muridarum (C. muridarum) infection remain incompletely defined. Our study demonstrated that C. muridarum respiratory infection upregulates HDAC6 expression at the infection site and in immune organs. Comparative analysis of wild-type (WT) and HDAC6-deficient (HDAC6^−/−) mice in this infection model revealed that HDAC6 deficiency exacerbates disease progression, including significant weight loss, severe pulmonary inflammation, and impaired C. muridarum clearance. Relative to WT mice, HDAC6^−/− mice exhibited elevated Signal Transducer and Activator of Transcription 6 (Stat6) and GATA Binding Protein 3 (Gata3) mRNA expression, enhanced pathological Th2 responses with increased IL-4 secretion, and no significant differences in protective Th1 or Th17 responses following C. muridarum infection. Concurrently, these mice displayed enhanced M2 macrophage polarization, as evidenced by upregulated CD206 and Arg-1 expression, whereas M1 marker expression remained unchanged. The vitro studies confirmed that HDAC6^−/− bone marrow-derived macrophages (BMDMs) promote M2 polarization, characterized by increased Arg-1, IL-10, and TGF-β production, and further co-culture experiments showed that C. muridarum -stimulated HDAC6^−/− BMDMs drive Th2 differentiation. These findings elucidate the critical role of HDAC6 in regulating Th2-M2 immune responses during C. muridarum respiratory infection and suggest targeted modulation of HDAC6 as a novel therapeutic strategy for chlamydial respiratory infection. Full article

Boron (B) toxicity is one of the major abiotic stresses limiting wheat productivity in arid and semi-arid regions of the world. Thus, it is important to understand the molecular basis of tolerance in boron-tolerant wheat genetic resources for effective breeding. Wild emmer wheat is a valuable genetic resource for tolerance to multiple abiotic stresses; however, the molecular mechanisms behind boron toxicity tolerance in this species has not been sufficiently characterized. Here, we present the first RNA sequencing-based transcriptomic analysis of B toxicity response in a boron-tolerant Triticum dicoccoides genotype, PI362036. Shoot tissues exposed to high boron (10 mM B) for 7 days showed extensive transcriptional reprogramming with 2783 differentially expressed genes. Functional enrichment analyses showed that B toxicity significantly altered the genes associated with biosynthesis of secondary metabolites, metabolic pathways, ribosomal activity, carbon metabolism, RNA transport, photosynthesis–antenna proteins, and citrate cycle pathway. Several transcription factor families, including TIG, MYB, MYB-related families, NAC, C2H2-GATA, ARF, and AP2-EREBP families, showed significant differential regulation, emphasizing their regulatory roles in B stress adaptation. Collectively, this study provides the first comprehensive transcriptomic framework of boron toxicity tolerance in T. dicoccoides under short-term high boron exposure, identifying candidate genes and pathways that may be exploited for improving boron tolerance in cultivated wheat through targeted breeding strategies. Given that boron toxicity in agricultural systems primarily arises from excessive boron accumulation in soils and irrigation water, the identified pathways offer insight into early adaptive responses of shoot tissues to elevated boron availability. Full article

Chinese tongue sole (Cynoglossus semilaevis) is an important aquaculture species in China. Under high-temperature conditions, genetically female fish can undergo sex reversal and develop into phenotypic males (pseudomale fish). Previous studies have demonstrated that apoptosis might function in sex differentiation. Based on this, we identified and characterized the functions of six caspase genes (caspase1-like, caspase3a, caspase6, caspase8, caspase8-like, caspase9) in Chinese tongue sole. These six caspase genes were expressed in all analyzed tissues of both males and females. They were detected to be expressed in the gonads at various developmental stages, with expression levels peaking between 7 months and 2 years of age. In situ hybridization (ISH) analysis showed that the caspase genes were mainly localized in spermatocytes and oocytes. Promoter activity analysis indicated that with the exception of caspase3a, the remaining five caspase genes exhibited promoter activity and were regulated by transcription factors, including sp1 and gata4. High-temperature stimulation can significantly affect the expression of caspases in the gonads of both male and female fish, with female fish showing a more pronounced response. An siRNA-mediated knockdown experiment revealed that following caspase knockdown, the expression of sex differentiation-related genes, heat shock transcription factors (hsf), and heat shock proteins (hsp) in Chinese tongue sole was significantly altered. Based on these findings, we speculate that caspases play an important role in the sex differentiation process by responding to temperature stimuli. Full article

Transcription factors (TFs) are ubiquitously distributed in plants and play pivotal roles in regulating plant growth and development. The present study aims to elucidate the function of transcription factors (TFs) in highland barley’s response to selenium stress. The results show that 89, 218, 141, 92, 23, and 34 genes were identified from the bHLH, MYB, NAC, WRKY, GATA, and HSF families, respectively. We analyzed the physicochemical properties of the transcription factor family, including amino acid number and molecular weight, theoretical PI, instability index, hydrophilicity index, and subcellular location. The majority of proteins encoded by these gene families are hydrophilic and predominantly localized in the nucleus. Structural analysis demonstrates that each family contains conserved motifs and domains. Most bHLH genes, such as KAE8811666.1 and KAE8789390.1, contain bHLH_SF superfamily domains. 45 MYB genes possess the myb_SHAQKYF domain. Most NAC genes possess typical NAM domains. Most WRKY proteins showed the WRKY superfamily domain. The 22 members of GATA possess the ZnF_GATA domain. HSF gene family showed that 24 gene family members contained HSF domains. Systematic evolutionary analysis indicates that the bHLH and NAC families can each be divided into nine subfamilies, while the remaining four families are categorized into five to eight subfamilies, respectively. Based on transcriptome data, under low selenium treatment, 56.25%, 76%, 67.39%, 47.37%, 50%, and 56.25% of the genes belonging to the bHLH, MYB, NAC, WRKY, GATA, and HSF transcription factor families were significantly upregulated, respectively. In contrast, under high selenium treatment, the proportions of upregulated genes in these families were 81.25%, 80%, 65.22%, 63.16%, 75%, and 75%, respectively. Additionally, qRT-PCR results were consistent with the trends of the transcriptome expression data, corroborating the reliability and accuracy of the transcriptomic findings. These results elucidate the molecular characteristics and response patterns of six transcription factor families to selenium stress in highland barley, laying a foundation for further in-depth research on the functions of transcription factors in highland barley plants. Full article

Lung adenocarcinoma is the most common form of lung cancer with a 5-year survival rate of 15%, largely due to asymptomatic metastasis and late diagnosis. Overexpression of Polycomb group (PcG) proteins, particularly EZH2, the catalytic component of Polycomb Repressive Complex 2 (PRC2), has been associated with the pathogenesis of lung cancer, frequently showing correlation with cancer progression and poor prognosis. In this study, EZH2 levels were modulated by CRISPR/Cas9 gene editing and PRC2 activity was inhibited with EZH2 inhibitor EPZ6438 or EED inhibitor MAK683. EZH2 gene editing reduced cell proliferation, migration, invasion, and colony formation and reduced NFκ-B signaling activation, indicating an antitumoral effect in vitro. Moreover, EZH2 inhibition also increased the expression of differentiation-related genes, such as GATA5, FOXA2, and lung surfactants, indicating a pro-differentiation effect. However, EZH2-edited cells injected into an immunocompromised mouse model generated larger tumors compared to unedited cells. This was accompanied by increased expression of other PcG genes, including EZH1, CBX2, RING1, EED, and SUZ12, suggesting a compensatory interaction between PRC2 and PRC1 complexes. These findings provide significant clinical relevance, both in elucidating the mechanisms of novel molecular targets and in guiding treatment strategies for lung cancer when using epigenetic inhibitors. Full article

Background: Myocardial fibrosis, a central pathological process leading to heart failure, lacks specific mechanism-based therapies. Although the anti-inflammatory activity of the natural compound protocatechuic acid is recognized, its direct anti-fibrotic mechanism, particularly concerning the critical role of endothelial–mesenchymal transition (EndMT), remains unexplored. This study aimed to investigate the protective effects and underlying mechanisms of protocatechuic acid. Methods: The study employed both in vivo and in vitro models. For in vivo evaluation, a rat model of myocardial fibrosis was induced by isoproterenol hydrochloride (ISO). For in vitro analysis, human umbilical vein endothelial cells (HUVECs) were stimulated with angiotensin II (Ang II) and subjected to siRNA-mediated histone deacetylase 1 (HDAC1) knockdown, alongside a co-culture model involving HUVECs and the AC16 human cardiomyocyte cells. Additionally, molecular docking and dynamics simulations were performed to evaluate the binding affinity and stability of protocatechuic acid with the target protein, HDAC1. Results: In vivo, protocatechuic acid significantly improved cardiac function, attenuated pathological injury, and reduced collagen deposition in ISO-induced fibrotic rats. It also potently suppressed inflammatory responses and inhibited the EndMT process. These beneficial effects were associated with decreased HDAC1 and increased GATA binding protein 4 (GATA4) expression in perivascular regions, which suggests the modulation of the HDAC1/GATA4 pathway. In vitro, protocatechuic acid suppressed Ang II-induced endothelial inflammation in HUVECs. This effect was replicated by HDAC1 knockdown, thus confirming that the HDAC1/GATA4 pathway mediates its anti-inflammatory action at the cellular level. Furthermore, molecular docking and dynamics simulations indicated that protocatechuic acid stably binds to a key target, HDAC1. Conclusions: Protocatechuic acid alleviates inflammation and EndMT by inhibiting the HDAC1/GATA4 signaling pathway, thereby preserving cardiac function and retarding the progression of myocardial fibrosis. These findings provide a theoretical and experimental foundation for the potential application of protocatechuic acid in treating cardiovascular diseases. Full article

Background/Objectives: Identifying candidate genes underlying quantitative trait loci (QTL) in poultry has traditionally required labor-intensive positional cloning. Previous studies using an F₂ population derived from native Japanese Nagoya (NAG) and White Plymouth Rock (WPR) breeds revealed a major QTL on chromosome 2 affecting 3-week body weight and 4-week pectoralis muscle weight. This study aimed to identify candidate genes for this QTL using a hypothesis-free integrative genetic approach. Methods: We employed a multi-step analytical framework combining QTL remapping, transcriptome analysis, gene enrichment analysis, haplotype frequency comparison, and correlation analysis. QTL remapping was performed using individual traits and their first principal component (PC1) in 239 F₂ chickens. RNA-sequencing (RNA-seq) of liver tissue was conducted for F₂ individuals with extreme PC1 scores, followed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) validation. Results: QTL remapping refined the 95% confidence interval to a chromosome 2 region containing 329 genes. RNA-seq analysis identified 23 differentially expressed genes (DEGs) within this interval. Although gene enrichment analysis initially highlighted GATA binding protein 6 (GATA6) as a potential candidate, RT-qPCR in NAG, WPR, and F₁ chickens showed no significant expression differences, excluding GATA6. Haplotype frequency and correlation analyses prioritized cadherin-17 (CDH17) as the strongest candidate gene and ring finger protein 151 (RNF151) as a secondary candidate. Conclusions: Our hypothesis-free integrative approach effectively refined candidate genes for a chromosome 2 QTL influencing early growth and pectoralis muscle weight. CDH17 and RNF151 represent promising targets for functional validation and may support marker-assisted selection to improve muscle-related traits in chickens. Full article

Obesity plays a crucial role in the progression of insulin resistance and type 2 diabetes which are related to inflammation and liver disease. GATA-3 is a transcription factor that is involved in adipogenesis and inflammation. Therefore, it could be a potential therapeutic target for obesity-associated metabolic disorders. This study aimed to examine the effects of GATA-3 suppression on body weight, fat depot redistribution, liver histopathology, and inflammatory markers in transgenic db/db obese mice. Male db/db mice received subcutaneous injections of GATA-3-specific DNAzyme (hgd40; 10 or 100 µg/mL), pioglitazone (as a positive control), or vehicle only (as a negative control), twice weekly for two weeks. Body weight, organ weights, liver histopathology, mRNA expression of selected genes and serum cytokine levels were assessed. GATA-3 expression was not region specific, and its suppression did not significantly affect fat depot distribution or organ weights. However, the low dose of hgd40 accelerated body weight gain transiently. It also increased Il10 mRNA expression in the liver and significantly increased IL-10 protein concentration in the serum. In addition, a high dose of hgd40 resulted in a marked decrease in hepatocyte ballooning degeneration. These findings suggest that GATA-3 suppression may modulate inflammation and liver injury in obesity, warranting further investigation into its therapeutic potential for obesity-related metabolic disorders. Full article

Mutations in the POU1F1 gene cause defects in the expression of the genes encoding thyroid-stimulating hormone (TSH)-β subunit, growth hormone (GH), and prolactin (PRL). Here, we characterized 15 missense and nonsense mutations. Protein stability was reduced in the P14L, P24L, F135C, K145X, F233S and E250X mutants. Transactivation by 15 mutants in the TSHβ promoter was moderately correlated with that of the PRL promoter. Based on their transcriptional activity, we classified them into three groups: group I, equivalent to the wild type; group II, partial; and group III, substantially lost. A review of case reports on four patients with group II mutations revealed that TSH deficiency manifested after recombinant GH therapy. A transcription factor, GATA2, is the main activator in the TSHβ gene, while POU1F1 protects its function from inhibition by the suppressor region (SR). We found that the SR is critical for the pathogenesis of TSH deficiency. The transactivation of the TSHβ promoter by the K216E mutant was equivalent to that of wild-type POU1F1; however, that of the PRL promoter was low, while the opposite was found in the R271W mutant. The functional property of K216E suggests that the interaction of POU1F1 with GATA2 may not always be necessary for the activation of the TSHβ promoter. Full article

Background: Individual differences in immune responses to African swine fever virus (ASFV), whether induced by vaccination or natural infection, may be linked to genetic variation in the genes involved in antigen presentation. Methods: A total of nine pigs from the 112-population were selected for RNA-seq analysis. To pinpoint key transcription factors (TFs) regulating gene expression in the lymph nodes, weighted Kendall’s Tau rank correlation analysis was performed to link the TF binding potential with the extent of differential expression of target genes. Results: CD8⁺ T cells expressing a specific epitope of the ASFV p72 protein (ACD8⁺) accounted for 41% of the total CD8⁺ T cells in peripheral blood. A total of 2062 transcripts were identified as differentially expressed across the nine pigs (q-value < 1 × 10⁻⁸). Differential expression levels of the target genes for MECP2, ETS1, ZBTB33, ELK4, and E2F4 were significantly correlated with their TF binding potential (p < 0.05). Six SNPs were identified in the promoter region of ELK4. Analysis of the 112-pig population revealed that SNPs at S.-404A>G and S.-668C>T loci were significantly associated with ACD8⁺ levels (q-value < 0.01). Individuals with the AA genotype at S.-404A>G had significantly higher ACD8⁺ counts compared to those with AG and GG genotypes (q-value < 0.05). At the S.-668C>T locus, ACD8⁺ levels were highest in the CC genotype, followed by CT and TT genotypes, with CC showing notably higher ACD8⁺ counts (q-value < 0.05). Notably, the S.-404A>G site overlaps with potential binding sites for TFs FOXA2, GATAs, and TRPS1, while the S.-668C>T site lies within the binding regions for NR1H3, RARA, VDR, and NR1I3. Conclusion: These mutations may disrupt TFs binding to the ELK4 promoter, potentially reducing ELK4 expression and impairing antigen processing and presentation. Full article

Background: Adhesion G protein-coupled receptor G6 (ADGRG6), also known as GPR126, has been implicated in several malignancies. However, its expression pattern, clinical significance, and mechanistic role in pancreatic adenocarcinoma (PAAD) remain unclear. Methods: We combined multi-omics analyses, tissue microarray immunohistochemistry, and a series of functional experiments, including 2D and 3D spheroid cultures, zebrafish xenografts, and murine tumor models—to investigate the expression, clinical significance, and mechanism of ADGRG6 in PAAD. The association between ADGRG6 expression and immune infiltration was assessed using TIMER and GEPIA databases, followed by mechanistic validation through ADGRG6 modulation in PAAD cell lines. Results: ADGRG6 was significantly overexpressed in PAAD and correlated with larger tumor size, higher grade, advanced TNM stage, and poor overall survival. Multivariate logistic regression confirmed that high ADGRG6 expression was independently associated with higher pathological grade. Functionally, ADGRG6 silencing markedly inhibited PAAD cell proliferation, migration, and invasion in both 2D and 3D cultures, as well as in zebrafish and nude mouse xenograft models. Integrated transcriptomic and immune analyses revealed that ADGRG6 expression positively correlated with mast cells, macrophages (M1/M2), Th2/Th17 subsets, and interferon–responsive neutrophils. Mechanistically, ADGRG6 silencing reduced STAT6 phosphorylation and GATA3 expression, consistent with the suppression of the NF-κB→STAT6→GATA3 axis. Conclusions: ADGRG6 functions as an oncogenic driver in PAAD, promoting tumor progression and fostering an immunosuppressive microenvironment via NF-κB/STAT6 signaling. These findings not only broaden the mechanistic understanding of ADGRG6 function but also suggest it as a promising target for therapeutic intervention in PAAD. 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

Background: Ulcerative colitis (UC), a chronic and relapsing form of inflammatory bowel disease (IBD), arises from a multifactorial interplay of genetic predisposition, immune dysregulation, and environmental triggers. Despite advances in understanding UC pathogenesis, the identification of reliable biomarkers and key regulatory genes remains essential for unraveling disease mechanisms. Such insights are crucial for improving diagnostic precision and developing personalized therapeutic strategies. Methods: In this study, gene expression profiles from publicly available microarray and RNA-sequencing datasets were systematically analyzed using advanced bioinformatics tools. Differentially expressed genes (DEGs) were identified through statistical comparisons, and functional enrichment analyses were performed to explore their biological relevance. A total of 141 overlapping DEGs were extracted from three GEO datasets, and 20 key DEGs were further prioritized via protein–protein interaction (PPI) network construction. Hub genes, relevant signaling pathways, associated transcription factors (TFs), and microRNAs (miRNAs) linked to disease progression were identified. Potential therapeutic compounds were also predicted through computational drug–gene interaction analysis. Results: The analysis revealed a panel of novel biomarkers-TLR2, IFNG, CD163, CXCL9, CCL4, PRF1, TLR8, ARG1, LILRB2, FPR2, and PPARG-that function as key hub genes implicated in ulcerative colitis (UC) pathogenesis. These genes were associated with critical biological processes including signal transduction, inflammatory and immune responses, proteolysis, lipid transport, and cholesterol/triglyceride homeostasis. Furthermore, transcription factors (FOXC1, GABPA, GATA2, SUPT5H) and microRNAs (hsa-miR-34a-5p, hsa-miR-335-5p, hsa-miR-24-3p, hsa-miR-23a-5p, hsa-miR-26a-5p) revealed key regulatory networks influencing post-transcriptional gene regulation. Molecular docking analysis predicted Apremilast and Golotimod as promising therapeutic candidates for UC intervention. Conclusions: In conclusion, this study enhances our understanding of ulcerative colitis pathogenesis by identifying key biomarkers and therapeutic targets, paving the way for future advancements in personalized diagnosis and treatment strategies. Full article