Search Results (11,754)

Background/Objectives: The breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene whose mutations are associated with increased susceptibility to develop breast or ovarian cancer. BRCA1 mainly exerts its protective effects through DNA double-strand break repair. Although not itself a transcriptional factor, BRCA1, through its multiple protein interaction domains, exerts transcriptional coregulation. In addition, BRCA1 expression alters cellular metabolism including inhibition of de novo fatty acid synthesis, changes in cellular bioenergetics, and activation of antioxidant defenses. Some of these actions may contribute to its global oncosuppressive effects. However, the breadth of metabolic pathways reprogrammed by BRCA1 is not fully elucidated. Methods: Breast cancer cells expressing BRCA1 were investigated by multiplatform metabolomics, metabolism-related transcriptomics, and joint metabolomics/transcriptomics data processing techniques, namely two-way orthogonal partial least squares and pathway analysis. Results: Joint analyses revealed the most important metabolites, genes, and pathways of metabolic reprogramming in BRCA1-expressing breast cancer cells. The breadth of metabolic reprogramming included fatty acid synthesis, bioenergetics, HIF-1 signaling pathway, antioxidation, nucleic acid synthesis, and other pathways. Among them, rewiring of glycerophospholipid (including phosphatidylcholine, -serine and -inositol) metabolism and increased arginine metabolism have not been reported yet. Conclusions: Rewired glycerophospholipid and arginine metabolism were identified as components of BRCA1-induced metabolic reprogramming in breast cancer cells. The study helps to identify metabolites that are candidate biomarkers of the BRCA1 genotype and metabolic pathways that can be exploited in targeted therapies. Full article

Antibiotic misuse accelerates resistance dissemination via plasmid conjugation, but quorum sensing (QS) regulatory mechanisms remain undefined. Using Escherichia coli (E. coli) MG1655 conjugation models (RP4-7/EC600 plasmids), we demonstrate that long-chain acyl-homoserine lactones (C10/C12-HSL) enhance transfer frequency by up to 7.7-fold (200μM C12-HSL; p < 0.001), while quorum-quenching by sub-inhibitory vanillin suppressed this effect by 95% (p < 0.0001). C12-HSL compromised membrane integrity via ompF upregulation (4-fold; p < 0.01) and conjugative pore assembly (trbBp upregulated by 1.38-fold; p < 0.05), coinciding with ROS accumulation (1.5-fold; p < 0.0001) and SOS response activation (recA upregulated by 1.68-fold; p < 0.001). Crucially, rpoS and rmf deletion mutants reduced conjugation by 65.5% and 55.8%, respectively (p < 0.001), exhibiting attenuated membrane permeability (≤65.5% reduced NPN influx; p < 0.0001), suppressed ROS (≤54% downregulated; p < 0.0001), and abolished transcriptional induction of conjugation/stress genes. Reciprocal RpoS–RMF (ribosomal hibernation factor) crosstalk was essential for AHL responsiveness, with deletions mutually suppressing expression (≤65.9% downregulated; p < 0.05). We establish a hierarchical mechanism wherein long-chain AHLs drive resistance dissemination through integrated membrane restructuring, stress adaptation, and RpoS–RMF-mediated genetic plasticity, positioning QS signaling as a viable target for curbing resistance spread. Full article

Sea buckthorn is a vital woody oil species valued for its role in soil conservation and its bioactive seed oil, which is rich in unsaturated fatty acids and other compounds. However, low seed oil content and small seed size are the main bottlenecks restricting the development and utilization of sea buckthorn. In this study, we tested the seed oil content and seed size of 12 sea buckthorn cultivars and identified the key genes and transcription factors involved in seed development and lipid biosynthesis via the integration of UID RNA-seq (Unique Identifiers, UID), WGCNA (weighted gene co-expression network analysis) and qRT-PCR (quantitative real-time PCR) analysis. The results revealed five cultivars (CY02, CY11, CY201309, CY18, CY21) with significantly higher oil contents and five cultivars (CY10, CY201309, CY18, CY21, CY27) with significantly heavier seeds. A total of 10,873 genes were significantly differentially expressed between the S1 and S2 seed developmental stages of the 12 cultivars. WGCNA was used to identify five modules related to seed oil content and seed weight/size, and 417 candidate genes were screened from these modules. Among them, multiple hub genes and transcription factors were identified; for instance, ATP synthase, ATP synthase subunit D and Acyl carrier protein 1 were related to seed development; plastid–lipid-associated protein, acyltransferase-like protein, and glycerol-3-phosphate 2-O-acyltransferase 6 were involved in lipid biosynthesis; and transcription factors DOF1.2, BHLH137 and ERF4 were associated with seed enlargement and development. These findings provide crucial insights into the genetic regulation of seed traits in sea buckthorn, offering targets for future breeding efforts aimed at improving oil yield and quality. Full article

The plant-specific TCP transcription factor family originated before the emergence of land plants. However, the timing of the appearance of their specific transcriptional repressor family, the TCP Interactor containing EAR motif protein (TIE), remains unknown. Here, through phylogenetic analyses, we traced the origin of the TIE family to the early evolution of the embryophyte, while an earlier diversification in algae cannot be ruled out. Strikingly, we found that the number of TIE members is highly constrained compared to the expansion of TCPs in angiosperms. We used co-expression data to identify potential TIE-TCP regulatory targets across Arabidopsis thaliana and rice. Notably, the expression pattern between these species is remarkably similar. TCP Class I and Class II genes formed two distinct clusters, and TIE genes cluster within the TCP Class I group. This study provides a comprehensive evolutionary analysis of the TIE family, shedding light on its conserved role in the regulation of gene transcription in flowering plant development. Full article

Transcription factors play crucial roles in regulating gene expression, and any dysregulation in their levels could be involved in cancer progression. The role of androgen receptors (AR) and zinc finger (ZNF) proteins in tumors, like prostate cancer (PC), remains poorly understood. Moreover, due to the multifaceted transcriptional behavior of ARs and ZNFs, their biological role in cancer progression may also depend on the interplay with micro-RNAs (miRNAs). Based on The Cancer Genome Atlas (TCGA) database, we analyzed the expression levels of zinc finger transcripts and ARs in PC. Specifically, exploring their involvement in cancer progression and regulation by miRNAs. The analysis relied on several tools to create a multivariate combination of the original biomarkers to improve their diagnostic efficacy. Multidimensional Scaling (MDS) identified two new dimensions that were entered into a regression analysis to determine the best predictors of overall survival (OS) and disease-free interval (DFI). A combination of both dimensions predicted almost 50% (R² = 0.46) of the original variance of OS. Kaplan–Meier survival analysis also confirmed the significance of these two dimensions regarding the clinical output. This study showed preliminary evidence that several transcription factor expression levels belonging to the zinc family and related miRNAs can effectively predict patients’ overall PC survivability. Full article

Early blight, caused by the pathogen Alternaria solani, is a major fungal disease impacting potato production globally, with reported yield losses of up to 40% in susceptible varieties. As one of the most common diseases affecting potatoes, its incidence has been steadily increasing year after year. This study aimed to elucidate the molecular mechanisms underlying resistance to early blight by comparing gene expression profiles in resistant (B1) and susceptible (D30) potato seedlings. Transcriptome sequencing was conducted at three time points post-infection (3, 7, and 10 dpi) to identify differentially expressed genes (DEGs). Weighted Gene Co-expression Network Analysis (WGCNA) and pathway enrichment analyses were performed to explore resistance-associated pathways and hub genes. Over 11,537 DEGs were identified, with the highest number observed at 10 dpi. Genes such as LOC102603761 and LOC102573998 were significantly differentially expressed across multiple comparisons. In the resistant B1 variety, upregulated genes were enriched in plant–pathogen interaction, MAPK signaling, hormonal signaling, and secondary metabolite biosynthesis pathways, particularly flavonoid biosynthesis, which likely contributes to biochemical defense against A. solani. WGCNA identified 24 distinct modules, with hub transcription factors (e.g., WRKY33, MYB, and NAC) as key regulators of resistance. These findings highlight critical molecular pathways and candidate genes involved in early blight resistance, providing a foundation for further functional studies and breeding strategies to enhance potato resilience. Full article

Background: Severe damage to one side of the brain often leads to adverse consequences and can also cause widespread changes throughout the brain, especially in the contralateral area. Studying molecular changes in the contralateral cerebral hemisphere, especially with regard to genetic regulation, can help discover potential treatment strategies to promote recovery after severe brain trauma on one side. Methods: In our study, the right motor cortex was surgically removed to simulate severe unilateral brain injury, and changes in glial cells and synaptic structure in the contralateral cortex were subsequently assessed through immunohistological, morphological, and Western blot analyses. We conducted transcriptomic studies to explore changes in gene expression levels associated with the inflammatory response. Results: Seven days after corticotomy, levels of reactive astrocytes and hypertrophic microglia increased significantly in the experimental group, while synapsin-1 and PSD-95 levels in the contralateral motor cortex increased. These molecular changes are associated with structural changes, including destruction of dendritic structures and the encapsulation of astrocytes by synapses. Genome-wide transcriptome analysis showed a significant increase in gene pathways involved in inflammatory responses, synaptic activity, and nerve fiber regeneration in the contralateral cortex after corticorectomy. Key transcription factors such as NF-κB1, Rela, STAT3 and Jun were identified as potential regulators of these contralateral changes. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) confirmed that the mRNA expression levels of Cacna1c, Tgfb1 and Slc2a1 genes related to STAT3, JUN, and NF-κB regulation significantly increased in the contralateral cortex of the experimental group. Conclusions: After unilateral brain damage occurs, changes in the contralateral cerebral hemisphere are closely related to processes involving inflammation and synaptic function. Full article

Botryosphaeria dothidea is the causative agent of Chinese hickory trunk canker, which poses significant threat to the production of Chinese hickory (Carya cathayensis Sarg.). Previous studies reported that endophytic–pathogenic phase transition, also referred to as latent infection, plays an important role in the interaction of Botryosphaeria dothidea with various host plants, including Chinese hickory. However, the mechanism underlying this phase transition is not well understood. Here, we employed RNA-Seq to investigate transcriptional changes in B. dothidea during its phase transition upon interaction with Chinese hickory. A co-expression network was generated based on 6391 differentially expressed genes (DEGs) identified from different infection stages and temperature treatments. One co-expressed module was found that highly correlated with temperature treatments which simulated conditions of B. dothidea latent infection in the field. Subsequently, 53 hub genes were detected, and gene ontology (GO) enrichment analysis revealed three categories of enriched GO terms: transmembrane transport or activity, ion homeostasis or transport, and carbohydrate metabolism. One PacC transcriptional factor (BDLA_00001555, an ambient pH regulator), and one endo-β-1,3-glucanase (BDLA_00010249) were specifically upregulated under temperature treatments that corresponded with the activation stage of B. dothidea’s pathogenic state. The knockout mutant strain of BDLA_00001555 demonstrated defective capability upon the activation of the pathogenic state. This confirmed that BDLA_00001555, the PacC transcriptional factor, plays an important role in the latent infection phase of B. dothidea. Our findings provide insights into the pathogenic mechanism of Chinese hickory trunk canker disease. Full article

Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with disrupted lipid metabolism. This study aimed to uncover novel molecular subtypes and biomarkers by integrating sphingolipid metabolism-related genes (SMGs) with machine learning approaches. Using data from the GEO and GeneCards databases, 29 UC-related SMGs were identified. Consensus clustering was employed to define distinct molecular subtypes of UC, and a diagnostic model was developed through various machine learning algorithms. Further analyses—including functional enrichment, transcription factor prediction, single-cell localization, potential drug screening, molecular docking, and molecular dynamics simulations—were conducted to investigate the underlying mechanisms and therapeutic prospects of the identified genes in UC. The analysis revealed two molecular subtypes of UC: C1 (metabolically dysregulated) and C2 (immune-enriched). A diagnostic model based on three key genes demonstrated high accuracy in both the training and validation cohorts. Moreover, the transcription factor FOXA2 was predicted to regulate the expression of all three genes simultaneously. Notably, mebendazole and NVP-TAE226 emerged as promising therapeutic agents for UC. In conclusion, SMGs are integral to UC molecular subtyping and immune microenvironment modulation, presenting a novel framework for precision diagnosis and targeted treatment of UC. Full article

Background: Congenital diarrhea is persistent diarrhea that manifests during the neonatal period. Mutations in DGAT1, which is crucial for triglyceride synthesis and lipid absorption in the small intestine, are causal factors for congenital diarrhea. In this study, we aimed to determine the value of tissue RNA sequencing (RNA-seq) for assisting with the clinical diagnosis of some genetic variants of uncertain significance. Methods: We clinically evaluated a patient with watery diarrhea, vomiting, severe malnutrition, and total parenteral nutrition dependence. Possible pathogenic variants were detected using whole-exome sequencing (WES). RNA-seq was utilized to explore the transcriptional alterations in DGAT1 variants identified by WES with unknown clinical significance, according to the American College of Medical Genetics guidelines. Systemic examinations, including endoscopic and histopathological examinations of the intestinal mucosa, were conducted to rule out other potential diagnoses. Results: We successfully diagnosed a patient with congenital diarrhea and protein-losing enteropathy caused by a DGAT1 mutation and reviewed the literature of 19 cases of children with DGAT defects. The missense mutation c.620A>G, p.Lys207Arg located in exon 15, and the intronic mutation c.1249-6T>G in DGAT1 were identified by WES. RNA-seq revealed two aberrant splicing events in the DGAT1 gene of the patient’s small intestinal tissue. Both variants lead to loss-of-function consequences and are classified as pathogenic variants of congenital diarrhea. Conclusions: Rare DGAT1 variants were identified as pathogenic evidence of congenital diarrhea, and the detection of tissue-specific mRNA splicing and transcriptional effects can provide auxiliary evidence. Full article

CNOT2, a central component of the CCR4-NOT transcription complex subunit 2, plays a pivotal role in the regulation of gene expression and metabolism. CNOT2 is involved in various cellular processes, including transcriptional regulation, mRNA deadenylation, and the modulation of mRNA stability. CNOT2 specifically contributes to the structural integrity and enzymatic activity of the CCR4-NOT complex with transcription factors and RNA-binding proteins. Recent studies have elucidated its involvement in cellular differentiation, immune response modulation, and the maintenance of genomic stability. Abnormal regulation of CNOT2 has been implicated in a spectrum of pathological conditions, including oncogenesis, neurodegenerative disorders, and metabolic dysfunctions. This review comprehensively examines the interplay between CNOT2 and p53, elucidating their collaborative and antagonistic interactions in various cellular contexts. CNOT2 is primarily involved in transcriptional regulation, mRNA deadenylation, and the modulation of mRNA stability, thereby influencing diverse biological processes such as cell proliferation, apoptosis, and differentiation. Conversely, p53 is renowned for its role in maintaining genomic integrity, inducing cell cycle arrest, apoptosis, and senescence in response to cellular stress and DNA damage. Emerging evidence suggests that CNOT2 can modulate p53 activity through multiple mechanisms, including the regulation of p53 mRNA stability and the modulation of p53 target gene expression. The dysregulation of CNOT2 and p53 interactions has been implicated in the pathogenesis and progression of various cancers, highlighting their potential as therapeutic targets. Additionally, CNOT2 regulates c-Myc, a well-known oncogene, in cancer cells. This review shows the essential roles of CNOT2 in maintaining cancer cellular homeostasis and explores its interactions within the CCR4-NOT complex that influence transcriptional and post-transcriptional regulation. Furthermore, we investigate the potential of CNOT2 as a biomarker and therapeutic target across various disease states, highlighting its significance in disease progression and treatment responsiveness. Full article

A dietary supplement, trans-resveratrol and hesperetin (tRES+HESP)—also known as GlucoRegulate—induces increased expression of glyoxalase 1 (Glo1) by activation of transcription factor Nrf2, countering accumulation of the reactive dicarbonyl glycating agent, methylglyoxal. tRES+HESP corrected insulin resistance and decreased fasting and postprandial plasma glucose and low-grade inflammation in overweight and obese subjects in a clinical trial. The aim of this study was to explore, for the first time, health-beneficial gene expression other than Glo1 induced by tRES+HESP in human endothelial cells and fibroblasts in primary culture and HepG2 hepatoma cell line and activity of cis-resveratrol (cRES) as a Glo1 inducer. We measured antioxidant response element-linked gene expression in these cells in response to 5 µM tRES+HESP by the NanoString method. tRES+HESP increases gene expression linked to the prevention of dicarbonyl stress, lipid peroxidation, oxidative stress, proteotoxicity and hyperglycemia-linked glycolytic overload. Downstream benefits were improved regulation of glucose and lipid metabolism and decreased inflammation, extracellular matrix remodeling and senescence markers. The median effective concentration of tRES was ninefold lower than cRES in the Glo1 inducer luciferase reporter assay. The GlucoRegulate supplement provides a new treatment option for the prevention of type 2 diabetes and metabolic dysfunction–associated steatotic liver disease and supports healthy aging. Full article

Cadmium (Cd) is a toxic environmental heavy metal that exerts harmful effects on multiple tissues, including the kidney, liver, lung, and bone, and is also associated with the development of anemia. However, the precise molecular mechanisms underlying Cd-induced toxicity remain incompletely understood. In this paper, we review the recent molecular mechanisms of Cd-induced toxicity and its modification, with a particular emphasis on our recent findings. Using a combination of DNA microarray analysis, protein–DNA binding assays, and siRNA-mediated gene silencing, we identified several transcription factors, YY1, FOXF1, ARNT, and MEF2A, as novel molecular targets of Cd. The downregulation of their downstream genes, including UBE2D2, UBE2D4, BIRC3, and SLC2A4, was directly associated with the expression of cytotoxicity. In addition, PPARδ plays a pivotal role in modulating cellular susceptibility to Cd-induced renal toxicity, potentially by regulating apoptosis-related signaling pathways. In addition to apoptosis pathways, Cd toxicity through ROS generation, ferroptosis and pyroptosis were summarized. Furthermore, it has been revealed that Cd suppresses the expression of iron transport-related genes in duodenal epithelial cells leading to impaired intestinal iron absorption as well as decreased hepatic iron levels. These findings provide a mechanistic basis for Cd-induced iron deficiency anemia, implicating disrupted iron homeostasis as a contributing factor. Full article

Nosocomial infections caused by ESKAPE pathogens represent a significant burden to global health. These pathogens may exhibit multidrug resistance (MDR) mechanisms, of which mechanisms such as efflux pumps and biofilm formation are gaining significant importance. Multidrug resistance mechanisms in ESKAPE pathogens have led to an increase in the effective costs in health care and a higher risk of mortality in hospitalized patients. These pathogens utilize antimicrobial efflux pump mechanisms and bacterial biofilm-forming capabilities to escape the bactericidal action of antimicrobials. ESKAPE bacteria forming colonies demonstrate increased expression of efflux pump-encoding genes. Efflux pumps not only expel antimicrobial agents but also contribute to biofilm formation by bacteria through (1) transport of molecules and transcription factors involved in biofilm quorum sensing, (2) bacterial fimbriae structure transport for biofilm adhesion to surfaces, and (3) regulation of a transmembrane gradient to survive the difficult conditions of biofilm microenvironments. The synergistic role of these mechanisms complicates treatment outcomes. Given the mechanistic link between biofilms and efflux pumps, therapeutic strategies should focus on targeting anti-biofilm mechanisms alongside efflux pump inactivation with efflux pump inhibitors. This review explores the molecular interplay between efflux pumps and biofilm formation, emphasizing potential therapeutic strategies such as efflux pump inhibitors (EPIs) and biofilm-targeting agents. Full article

Late-spring frost events severely damage low-chill peach blossoms, causing significant yield losses. Although 5-aminolevulinic acid (ALA) enhances cold tolerance through the PpC3H37-PpWRKY18 module, the regulatory mechanism of ALA on PpC3H37 remains to be elucidated. Using yeast one-hybrid screening with the PpC3H37 promoter as bait, we identified PpDof9 as a key interacting transcription factor. A genome-wide analysis revealed 25 PpDof genes in peaches (Prunus persica). These genes exhibited variable physicochemical properties, with most proteins predicted as nuclear-localized. Subcellular localization experiments in tobacco revealed that PpDof9 was localized to the nucleus, consistent with predictions. A synteny analysis indicated nine segmental duplication pairs and tandem duplications on chromosomes 5 and 6, suggesting duplication events drove family expansion. A conserved motif analysis confirmed universal presence of the Dof domain (Motif 1). Promoter cis-element screening identified low-temperature responsive (LTR) elements in 12 PpDofs, including PpDof1, PpDof8, PpDof9, and PpDof25. The quantitative real-time PCR (qRT-PCR) results showed that PpDof1, PpDof8, PpDof9, PpDof15, PpDof16, and PpDof25 were significantly upregulated under low-temperature stress, and this upregulation was further enhanced by ALA pretreatment. Our findings demonstrate ALA-mediated modulation of specific PpDof TFs in cold response and provide candidates (PpDof1, PpDof9, PpDof8, PpDof25) for enhancing floral frost tolerance in peaches. Full article