Search Results (1,460)

Maternal metabolic dysfunction adversely influences embryonic muscle oxidative capacity and mitochondrial biogenesis, increasing the child’s long-term risks of developing obesity and metabolic syndrome in later life. This pilot study explored the mechanistic basis of embryonic muscle metabolic programming, employing non-invasive magnetic field exposures. Brief (10 min) exposure to low-energy (1.5 milliTesla at 50 Hertz) pulsing electromagnetic fields (PEMFs) has been shown in mammals to promote oxidative muscle development, associated with enhanced muscular mitochondriogenesis, augmented lipid metabolism, and attenuated inflammatory status. In this study, quail eggs were used as a model system to investigate the potential of analogous PEMF therapy to modulate embryonic muscle oxidative capacity independently of maternal influence. Quail eggs were administered five 10-min PEMF exposures to either upward-directed or downward-directed magnetic fields over 13 days. Embryos receiving magnetic treatment exhibited increased embryo weight, size, and survival compared to non-exposed controls. Upward exposure was associated with larger embryos, redder breast musculature, and upregulated levels of PPAR-α and PGC-1α, transcriptional regulators promoting oxidative muscle development, mitochondriogenesis, and angiogenesis, whereas downward exposure augmented collagen levels and reduced angiogenesis. Exposure to upward PEMFs may hence serve as a method to promote embryonic growth and oxidative muscle development and improve embryonic mortality. Full article

Retinoic acid (RA) exerts biological effects through RA receptors (RARs) to regulate transcription. RA also elicits rapid, RAR-independent (noncanonical) activities mediated by Cellular RA Binding Protein 1 (CRABP1) to modulate cytosolic signaling. CRABP1 functions by forming protein complexes, named CRABP1 signalosomes, to modulate signal propagation in a cell type-specific manner. This review summarizes multiple CRABP1 signalosomes and their physiological functions. CRABP1 knockout (CKO) mice develop multiple phenotypes progressively throughout the lifespan. These include altered brain function, obesity, and insulin resistance starting at young adult stages, increased vulnerability to heart failure and altered serum exosome profiles in midlife, and motor deterioration and thyroid dysfunction (hypothyroidism) in later life. The mouse Crabp1 gene is tightly regulated by multiple epigenetic mechanisms, whereas human CRABP1 gene dysregulation is associated with multiple human diseases in which age is an important factor. Further, CRABP1 expression in human and mouse thyroid glands gradually increases with aging. This underscores the clinical relevance of CRABP1 signalosomes in maintaining health and the functions of certain cells/organ systems, especially in the thyroid and during the aging process. The CRABP1 sequence is highly conserved, likely due to its functional constraint in forming various signalosomes; its tight regulation ensures proper expression of CRABP1 required for the forming of various signalosomes critical to the health and functions of multiple cell types/organ systems. Finally, CRABP1-specific (without activating RARs) signaling pathway-selective compounds have been designed. It may be an attractive therapeutic strategy to exploit these CRABP1-specific compounds to modulate selective signaling pathways in certain disease conditions, such as thyroid dysfunction, to maximize efficacy while minimizing retinoid toxicity. Full article

The Nuclear factor erythroid 2-related factor 2 (NRF2) Neurogenic locus NOTCH homolog protein (NOTCH) crosstalk has emerged as a critical regulatory axis in the progression of solid cancers, especially lung, affecting tumor growth and resistance to therapy. NRF2 is a master transcription factor that orchestrates the cellular antioxidant response, while NOTCH signaling is involved in the cell–cell communication processes by influencing the patterns of gene expression and differentiation. Although frequently altered independently, genetic and epigenetic dysregulation of both NRF2 and NOTCH pathways often converge to deregulate oxidative stress responses and promote tumor cell survival. Recent findings reveal that the NRF2/NOTCH interplay extends beyond canonical signaling, contributing to metabolic reprogramming and reshaping the tumor microenvironment (TME) to promote cancer malignancy. Emerging scientific evidences highlight the key role of biochemical and metabolomic changes within NRF2–NOTCH crosstalk, in contributing to cancer progression and metabolic reprogramming, beyond facilitating the adaptation of cancer cells to the TME. Actually, the effects of the NRF2–NOTCH bidirectional interaction in either supporting or suppressing lung tumor phenotypes are still unclear. This review explores the molecular mechanisms underlying NRF2–NOTCH crosstalk in lung cancer, highlighting the impact of genetic and epigenetic deregulation mechanisms on neoplastic processes, modulating the TME and driving the metabolic reprogramming. Furthermore, we discuss therapeutic opportunities for targeting this regulatory network, which may open new avenues for overcoming drug resistance and improving clinical outcomes in lung cancer. Full article

The R2R3-MYB transcription factor GAMYB plays crucial roles in plant growth and development, but the biological functions of SlGAMYB1 in tomato remain poorly understood. Here, we investigated the roles of SlGAMYB1 by overexpressing a miR159-resistant version (35S:SlGAMYB1^m) in tomato. Transgenic plants exhibited a dwarf phenotype with reduced internode elongation, which was associated with decreased bioactive gibberellin (GA) levels due to transcriptional repression of SlGA3ox1 and activation of SlGA2ox1/2/4/5. Additionally, 35S:SlGAMYB1^m altered leaf morphology by inhibiting cell proliferation through downregulation of cell cycle genes, resulting in larger but fewer epidermal cells. Intriguingly, 35S:SlGAMYB1^m plants displayed increased floral organ number, a process likely mediated by the upregulation of SlWUS rather than GA signaling. These findings demonstrate that SlGAMYB1 regulates diverse aspects of tomato development through both GA-dependent and independent pathways, providing new insights into the functional diversification of GAMYB genes and potential strategies for genetic improvement of tomato architecture and yield. Full article

Aberrant ubiquitination drives hepatocellular carcinoma (HCC) progression, yet the role of FBXO10—a key F-box E3 ubiquitin ligase component—remains uncharacterized. Through bioinformatics analyses and functional validation, we establish FBXO10 as a critical oncogenic driver in HCC. Transcriptomic data from public databases (TIMER, UALCAN, GEO) revealed significant FBXO10 upregulation in HCC tissues, with elevated expression predicting advanced tumor stage, metastasis, and reduced survival. Functionally, FBXO10 silencing suppressed HCC cell proliferation while its overexpression promoted tumor growth. Mechanistic studies revealed that FBXO10 directly interacts with FRMPD1 to mediate its K63-linked polyubiquitination and stabilization, independent of transcriptional regulation. FRMPD1 restoration rescued FBXO10-mediated proliferation, confirming its role as the key downstream effector. Clinically, FBXO10 expression correlated with TP53 mutations and adverse clinicopathological features. Our findings reveal a novel FBXO10–FRMPD1 axis promoting hepatocarcinogenesis through post-translational stabilization, positioning FBXO10 as both a prognostic biomarker and therapeutic target in HCC. Full article

We profiled the gene expressions in the hypothalamic paraventricular nuclei of 12 male and 12 female pups from a standard rat model of infantile spasms to determine the sex dichotomy of the neurotransmission genomic fabrics. Infantile spasms were triggered in rat pups prenatally primed with two doses of betamethasone followed by the postnatal repeated administration of N-methyl-D-aspartic acid to induce spasms. Publicly available microarray data were used to characterize each gene in each condition for both sexes by the independent transcriptomic features: average expression level, control of the transcript abundance, and expression correlation with every other gene. This study revealed substantial sex differences in the expression level, control, and inter-coordination of the investigated genes among the studied groups. The transcriptomic differences assist in providing a molecular explanation of the behavioral differences and development of infantile epilepsy spasm syndrome in the two sexes. Full article

Background: Chemoresistance and tumor recurrence remain major obstacles in colorectal cancer (CRC) therapy. Elucidating the molecular mechanisms underlying treatment resistance is critical for improving therapeutic outcomes. Methods: We analyzed transcriptomic profiles from public datasets (TCGA and GSE39582) to identify differentially expressed genes associated with a poor response to neoadjuvant chemotherapy in CRC patients. Among 298 candidate genes, ANXA9 emerged as significantly overexpressed in chemoresistant tumors and associated with a poor prognosis. These findings were further validated in an independent cohort of 146 Stage III CRC patients using immunohistochemistry and survival analysis. The expression of ANXA9 was evaluated in oxaliplatin acquired-resistant CRC cell lines via qPCR and Western blot. Functional studies, including RNA interference, colony formation, apoptosis assays, and drug sensitivity testing, were performed in vitro and in vivo to assess the role of ANXA9. A high-throughput drug screen identified G749, a FLT3 inhibitor, as a potential therapeutic agent. Results: ANXA9 expression was significantly elevated in non-responders to chemotherapy and oxaliplatin-resistant CRC cell lines. The knockdown of ANXA9 reduced proliferation and enhanced oxaliplatin sensitivity. G749 was found to suppress ANXA9 expression in a dose-dependent manner and inhibit CRC cell growth in vitro and in patient-derived organoids. In a CRC xenograft mouse model, G749 reduced the tumor burden without observable toxicity. Mechanistically, we identified ZMYM2 as a transcriptional regulator of ANXA9. ChIP-qPCR confirmed ZMYM2 binding to the ANXA9 promoter, especially in resistant cells. Silencing ZMYM2 suppressed tumor cell growth and restored chemosensitivity. Conclusions: The ZMYM2-ANXA9 signaling axis drives chemoresistance and tumor progression in CRC. FLT3 inhibition by G749 effectively downregulates ANXA9 and sensitizes tumors to chemotherapy, highlighting a novel therapeutic approach for chemoresistant CRC. Full article

Transposable elements (TEs) are major drivers of plant genome plasticity, but the immediate molecular consequences of new TE insertions remain poorly understood. In this study, we generated a wild-type Arabidopsis thaliana population with novel insertions of ONSEN retrotransposon to investigate early epigenomic and transcriptomic changes using whole-genome and cDNA nanopore sequencing. We found that novel ONSEN insertions were distributed non-randomly, with a strong preference for genic regions, particularly in chromatin enriched for H2A.Z, H3K27me3, and H3K4me2. Most full-length ONSEN insertions within genes were rapidly recognized and spliced out as new introns (intronization), thereby mitigating potential deleterious effects on transcript isoforms. In some cases, ONSEN insertions provided alternative transcription start or termination sites, generating novel transcript isoforms. Genome-wide methylation analysis revealed that new ONSEN copies were efficiently and precisely targeted by DNA methylation. Independently on the location of the original ONSEN element, the euchromatic and heterochromatic insertions display distinct methylation signatures, reflecting the action of different epigenetic pathways. In conclusion, our results demonstrate that DNA methylation and alternative splicing are effective control mechanisms safeguarding the plant genome and transcriptome integrity after retrotransposition burst. Full article

Background: Ammonia (NH₃), a harmful gas, reduces livestock productivity, threatens their health, and causes economic losses. Luteolin (Lut), an anti-inflammatory flavonoid, may counteract these effects. Methods: Our study explored luteolin’s protective mechanisms on chicken splenic lymphocytes under ammonia stress using a simulation model and four-dimensional fast data-independent acquisition (4D-FastDIA) proteomics. We identified 316 proteins, with 69 related to ammonia’s negative effects and 247 to Lut’s protection. Thirty differentially expressed proteins (DEPs) were common to both groups, with 27 showing counter-regulation with Lut. Results: Gene Ontology (GO) analysis showed DEPs enriched in molecular responses to interferons and the negative regulation of immune responses, mainly located extracellularly. Molecular function analysis revealed DEPs in antigen binding and synthase activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis linked DEPs to pathways like estrogen signaling, NOD-like receptor signaling, cytokine–cytokine receptor interaction, and JAK-STAT signaling. The quantitative real-time polymerase chain reaction (qRT-PCR) results indicated that the mRNA levels of Interferon Alpha and Beta Receptor subunit 2 (IFNAR2) and Signal Transducer and Activator of Transcription 1 (STAT1) were trending downward. This observation was in strong agreement with the downregulation noted in the proteomics analysis. Conclusions: Lut’s protective role against ammonia’s adverse effects on chicken splenic lymphocytes is linked to the modulation of key signaling pathways, offering insights for further research on treating ammonia exposure with Lut. Full article

Wounding triggers complex secondary metabolic pathways in plants, including benzylisoquinoline alkaloid (BIA) biosynthesis in opium poppy (Papaver somniferum L.). This study explores transcriptional and metabolic responses to wounding and methyl jasmonate (MeJA) treatment, focusing on BIA biosynthesis and regulatory mechanisms. Real-time expression analysis revealed significant up-regulation of transcripts in the (S)-reticuline and papaverine biosynthetic pathway, while the noscapine pathway was suppressed. The morphinan pathway also showed transcriptional activation, except in the case of codeinone reductase (COR), which remained unresponsive to both wounding and MeJA, suggesting a partially uncoupled mechanism. Metabolite profiling using HPLC-MS demonstrated a rapid accumulation of morphine post wounding, further supporting the hypothesis of independent regulatory control over COR. The role of phospholipase C (PLC) in modulating wound-induced BIA accumulation was investigated, revealing that PLC inhibition reduced morphine production and suppressed COR expression. These findings highlight the importance of phospholipid-dependent signalling in activating morphine biosynthesis, potentially at the expense of other BIAs. This study provides insights into plant stress responses and suggests strategies for enhancing BIA production through targeted interventions, offering potential applications in improving alkaloid yield. Full article

In this study, we examined the activation of the ATG8, HSP12, KGD1, and POT1 genes in response to decreased glucose levels in the culture medium. Our results show that in top1Δ strains, gene activation is further enhanced compared to WT strains under low glucose conditions, indicating that Top1p represses these genes. This repression occurs independently of its catalytic function. We investigated Rpd3p as an interacting factor of Top1p and found that in rpd3Δ mutants, gene expression under low glucose conditions is even higher than in top1Δ strains, suggesting that Rpd3p also acts as a negative regulator. ChIP analysis revealed that while Top1p levels in regulatory regions remain constant, Rpd3 recruitment increases on promoters after glucose reduction in WT strains but significantly decreases in top1Δ strains. Overall, our findings suggest that Rpd3p is recruited by Top1p to regulate gene expression at controlled physiological levels, highlighting the role of Top1p in transcriptional regulation, controlling helical stress, and interacting with key regulatory factors in response to environmental changes. Full article

Background/Objectives: Gelsolin (GSN) is an actin-binding protein that helps maintain neuronal structure and shape, regulates neuronal growth, and apoptosis. Our previous work demonstrated that GSN associated with estrogen receptor beta (ERβ1) in the brains of female rats, but this association was lost in advanced age. GSN was also required for ERβ1-mediated transcriptional repression at activator protein-1 (AP-1) motifs upstream of a minimal gene promoter. However, the consequences of the loss of GSN:ERβ1 protein interaction on ERβ1 nuclear translocation and transcriptional repression at AP-1 sites located within complex endogenous gene promoters remained unclear. Methods: We used immunofluorescent super resolution microscopy and luciferase reporter assays to test the hypothesis that GSN facilitates ERβ1 nuclear translocation and transcriptional repression of two genes relevant for Alzheimer Disease: APP (amyloid-beta precursor protein) and ITPKB (inositol-1,4,5-trisphosphate 3-kinase B). Results: Our results revealed the novel finding that GSN is required for ERβ1 ligand-independent nuclear translocation in neuronal cells. Moreover, we show that GSN increased APP and ITPKB promoter activity, which was repressed by ERβ1. Conclusions: Together, these data revealed the importance of the cytoskeletal protein, GSN, in regulating intracellular trafficking of nuclear receptors and demonstrate the first evidence of ERβ1 directly regulating two genes that are implicated in the progression of AD. Full article

Background: The formin family proteins play an important role in guiding the assembly and nucleation of linear actin and can promote the formation of actin filaments independently of the Arp2/3 complex. As a key protein that regulates the cytoskeleton and cell morphological structure, the formin gene family has been widely studied in plants such as Arabidopsis thaliana and rice. Methods: In this study, we conducted comprehensive analyses, including phylogenetic tree construction, conserved motif identification, co-expression network analysis, and transcriptome data mining. Results: A total of 18 MtFH gene family members were identified, and the distribution of these genes on chromosomes was not uniform. The phylogenetic tree divided the FH proteins of the four species into two major subgroups (Clade I and Clade II). Notably, Medicago truncatula and soybean exhibited closer phylogenetic relationships. The analysis of cis-acting elements revealed the potential regulatory role of the MtFH gene in light response, hormone response, and stress response. GO enrichment analysis again demonstrated the importance of FH for reactions such as actin nucleation. Expression profiling revealed that MtFH genes displayed significant transcriptional responsiveness to cold, drought, and salt stress conditions. And there was a temporal complementary relationship between the expression of some genes under stress. The protein interaction network indicated an interaction relationship between MtFH protein and profilin, etc. In addition, 22 miRNAs were screened as potential regulators of the MtFH gene at the post-transcriptional level. Conclusions: In general, this study provides a basis for deepening the understanding of the physiological function of the MtFH gene and provides a reference gene for stress resistance breeding in agricultural production. Full article

Background/Objectives: Lumbosacral spinal stenosis (LSS) is a degenerative condition characterized by narrowing of the spinal canal and associated neuropathic pain. While mechanical compression is well-characterized, the molecular mechanisms contributing to symptom severity remain poorly understood. Neurturin (NRTN), a member of the glial cell line-derived neurotrophic factor family, has emerged as a potential mediator of neural plasticity and nociception, but its role in spinal stenosis is largely unexplored. Methods: We analyzed NRTN mRNA and protein expression in ligamentum flavum samples from 96 patients undergoing surgery for LSS and 85 non-degenerative postmortem controls. Quantification was performed using real-time quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), Western blotting, and immunohistochemistry. Pain severity Visual Analog Scale (VAS), body mass index (BMI), diabetes, smoking, and alcohol use were assessed as modulators of NRTN expression. Results: NRTN expression was significantly elevated in LSS patients versus controls at both transcript and protein levels (p < 0.05). NRTN levels positively correlated with pain intensity (VAS; ANOVA p = 0.032 for mRNA, p = 0.041 for protein). Multivariate regression identified BMI (β = 0.50, p = 0.015) and diabetes (β = 0.39, p = 0.017) as independent predictors of increased NRTN expression. Alcohol use also showed a positive association (p = 0.046), while smoking showed no significant independent effect. Conclusions: Neurturin is upregulated in ligamentum flavum tissue from LSS patients and correlates with pain severity and metabolic risk factors. These findings suggest NRTN as a potential biomarker and therapeutic target in degenerative spine disease. Further longitudinal and mechanistic studies are warranted to elucidate its role in chronic pain and neuroinflammation. Full article

Background/Objectives: In the tumor microenvironment, hypoxia regulates genes that support tumor cell invasion and angiogenesis under the control of the hypoxia-inducible transcription factors (HIFs). Pleiotrophin (PTN) is a secreted protein that activates cell migration in endothelial and cancer cells that express α_νβ₃ integrin but has inhibitory effects in cells that do not express α_νβ₃ integrin. In both cases, the protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) seems to mediate the effects of PTN. In the present work, we studied the effect of hypoxia on PTN and PTPRZ1 expression and the functional consequences of this effect. Methods: Western blot, quantitative real-time PCR, and luciferase assays were used to study the impact of hypoxia at the protein, mRNA, and transcriptional levels, respectively. Decoy oligonucleotides (ODNs), siRNA technology, and plasmid overexpression were used to study the involvement of the transcription factors studied. Functional assays were used to study the effect of hypoxia on cell proliferation and migration. Results: Hypoxia increases PTN expression through the transcriptional activation of the corresponding gene in α_νβ₃ integrin-expressing cells. The transcription factors HIF-1α, HIF-2α, and AP-1 mediate the up-regulation of PTN by hypoxia. Functional assays in endothelial cells from PTN knockout mice or endothelial and cancer cells following the downregulation of PTN expression showed that PTN negatively affects chemical hypoxia-induced cell proliferation and migration. In cancer cells that do not express α_νβ₃ integrin, hypoxia or chemical hypoxia inhibits PTN expression in a HIF-1α-, HIF-2α-, and AP-1-independent manner. The expression of PTPRZ1 is up-regulated by chemical hypoxia, is HIF-1α- and HIF-2α-dependent, and seems to limit the activation of HIF-1α, at least in endothelial cells. Conclusions: Hypoxia or chemical hypoxia regulates PTN and PTPRZ1 expressions to restrict the stimulatory effects of hypoxia on endothelial and cancer cell migration. Full article