Search Results (363)

The adrenal medulla and organs of Zuckerkandl consist of chromaffin cells that produce, store, and secrete catecholamines. In humans, the adrenal medulla is known to function throughout postnatal life, while the organs of Zuckerkandl degenerate by 2–3 years of postnatal life. Although the history of investigation of chromaffin cells goes back more than a century, little is known about the reciprocal organogenesis of the adrenal glands and organs of Zuckerkandl during human fetal development. In the current study, we compared these two organs using serial sectioning, routine histological staining, and immunohistochemical reactions in human embryos, prefetuses, and fetuses from 8 to 26 gestational weeks. In our study, we used antibodies for tyrosine hydroxylase, dopamine beta-hydroxylase, and phenylethanolamine N-methyltransferase, which are enzymes of catecholamine synthesis, β-III tubulin, and S100. We found two morphological cell types (large and small) in the developing ganglia, organs of Zuckerkandl, and adrenal medulla, and two migration patterns of large cells and small cells. The immunohistochemical characteristics of these cells were determined. We revealed that the number of small cells increased significantly at the ages from 16 to 21–22 gestational weeks, followed by a decrease at 22.5–26 gestational weeks. The presence of two large cell subpopulations was suggested—those that migrate primarily from organs of the Zuckerkandl region and those that differentiate later from the small cells. We also determined that 12 gestational weeks was the age of the first appearance of phenylethanolamine N-methyltransferase reactivity in developing chromaffin cells, temporally correlating with synaptogenesis events. This is important data in the light of the controversial glucocorticoid theory of phenylethanolamine N-methyltransferase induction in humans. Full article

Patients with Inflammatory Bowel Disease (IBD) exhibit a dysregulated immune response that may be further exacerbated by bioactive compounds, such as histamine. Current dietary guidelines for IBD primarily focus on symptom management and flare-up prevention, yet targeted nutritional strategies addressing histamine metabolism remain largely unexplored. This narrative review aims to summarize the existing literature on the complex interplay between IBD and histamine metabolism and propose a novel dietary framework for managing IBD progression in patients with histamine intolerance (HIT). Relevant studies were identified through a comprehensive literature search of PubMed/MEDLINE, Google Scholar, ScienceDirect, Scopus, and Web of Science. The proposed low-histamine diet (LHD) aims to reduce the overall histamine burden in the body through two primary strategies: (1) minimizing exogenous intake by limiting high-histamine and histamine-releasing foods and (2) reducing endogenous histamine production by modulating gut microbiota composition, specifically targeting histamine-producing bacteria. In parallel, identifying individuals who are histamine-intolerant and understanding the role of histamine-degrading enzymes, such as diamine oxidase (DAO) and histamine-N-methyltransferase (HNMT), are emerging as important areas of focus. Despite growing interest in the role of histamine and mast cell activation in gut inflammation, no clinical trials have investigated the effects of a low-histamine diet in IBD populations. Therefore, future research should prioritize the implementation of LHD interventions in IBD patients to evaluate their generalizability and clinical applicability. Full article

Background: N6-methyladenosine (m6A) is the most prevalent chemical modification of eukaryotic RNA, playing a crucial role in regulating plant growth and development, stress responses, and other essential biological processes. The enzymes involved in m6A modification—methyltransferases (writers), demethylases (erasers), and recognition proteins (readers)—have been identified in various plant species; however, their roles in the economically significant tree species Populus deltoides × P. euramericana (NL895) remain underexplored. Results: In this study, we identified 39 m6A-related genes in the NL895 genome, comprising 8 writers, 13 erasers, and 18 readers. Evolutionary analysis indicated that the expansion of writers and readers primarily resulted from whole-genome duplication events. Purifying selection pressures were observed on all duplicated gene pairs, suggesting their essential roles in functional differentiation. Phylogenetic analysis revealed that writers, erasers, and readers are categorized into six, four, and two groups, respectively, with these genes being more conserved among dicotyledonous plants. Gene structure, protein domains, and motifs exhibited greater conservation within the same group. Promoter analysis of m6A-related genes showed enrichment of cis-acting elements associated with responses to light, phytohormones, and stress, indicating their potential involvement in gene expression regulation. Under cadmium treatment, the expression of all writers was significantly upregulated in both the aboveground and root tissues of NL895. Conclusions: This study systematically identified m6A-related gene families in Populus deltoides × P. euramericana (NL895), elucidating their evolutionary patterns and expression regulation characteristics. These findings provide a theoretical foundation for analyzing the molecular mechanisms of m6A modification in poplar growth, development, and stress adaptation, and offered candidate genes for molecular breeding in forest trees. Full article

N¹-methyladenosine (m¹A) serves as a critical regulatory modification in plant mRNA. In Arabidopsis, the TRM61/TRM6 complex functions as m¹A58 methyltransferase writers essential for organogenesis, reproduction, and hormonal signaling. However, the evolutionary dynamics of the TRM61/TRM6 complex across plant lineages remain poorly understood. In this study, we systematically identified TRM6 and TRM61 homologs across 306 plant species and uncovered the conserved evolutionary trajectories between them. These two methyltransferase subunits retain conserved structural motifs, respectively, and exhibit coordinated expression patterns in plants. In wheat (Triticum aestivum L.) and its progenitors, TRM6 and TRM61 proteins demonstrate polyploidization-associated evolutionary coordination. Their promoters harbor stress-, light-, and hormone-responsive cis-elements. Furthermore, the TRM6 and TRM61 genes in wheat exhibit diverse expression profiles across developmental tissues and under abiotic stress conditions. The differences in allelic frequency among TRM6 and TRM61 variants between wild and domesticated wheat populations suggest that they may have undergone selection during wheat domestication and improvement. This study provides an evolutionary framework for the TRM61/TRM6 complex. Full article

Nipah virus (NiV), a highly lethal zoonotic paramyxovirus, displays strain-specific pathogenicity, yet the molecular basis for this divergence remains elusive. Here, we identify N6-methyladenosine (m6A) modification as a pivotal regulator of NiV replication. Higher m6A methylation levels on viral genomic RNA and mRNAs are associated with the increased virulence observed in the NiV-Malaysia (NiV-M) strain compared to NiV-Bangladesh (NiV-B). Underlying this phenomenon, NiV infection orchestrates a reprogramming of the host m6A machinery by downregulating the methyltransferase METTL3 and the demethylase ALKBH5, while concurrently upregulating m6A reader proteins YTHDF1-3. Both METTL3 and ALKBH5 bind directly to NiV RNA, with METTL3 installing m6A to promote viral replication and ALKBH5 removing them to inhibit it. Strikingly, pharmacological inhibition of m6A modification markedly attenuates NiV replication in vitro and in vivo, underscoring the therapeutic potential of targeting the m6A pathway. Our study establishes m6A as a key determinant of NiV pathogenicity and provides a paradigm for host-directed antiviral strategies against high-risk RNA viruses. Full article

DNA methylation is a conserved and vital epigenetic modification that plays essential roles in plant growth, development, and responses to environmental stress. Cytosine-5 DNA methyltransferases (C5-MTases) and DNA demethylases (dMTases) are key regulators of DNA methylation dynamics. However, a comprehensive characterization of these gene families in sweet potato has remained elusive. In this study, we systematically identified and analyzed eight C5-MTase and five dMTase genes in the genomes of diploid (Ipomoea trifida, 2n = 2x = 30) and autohexaploid (Ipomoea batatas, 2n = 6x = 90) sweet potato. Phylogenetic, structural, and synteny analyses revealed a high degree of conservation among these genes, suggesting their essential roles during evolution. Promoter analysis uncovered multiple cis-acting elements, particularly those responsive to light and hormones. In addition, we examined the expression profiling of IbC5-MTases and IbdMTases genes during storage root development, revealing that several were highly expressed during the early and rapid expansion stages. These findings suggest that C5-MTases and dMTases may contribute to the regulation of storage root formation in sweet potato through epigenetic mechanisms, offering valuable insights for future functional studies and epigenetic breeding efforts. Full article

Prostate cancer cell lines are particularly clinically homogenous, mostly representing metastatic states rather than localized disease. While there has been significant work in the development of additional models, few have been created without oncogenic transformation. We derived a primary prostate cancer cell line from a patient with localized Gleason 7 prostate cancer—designated CaB34—which spontaneously immortalized. We leveraged CaB34 to generate a paired radioresistant subline, CaB34-CF, using a clinically relevant fractionated radiotherapy schedule. These two paired cell lines were investigated extensively to determine their molecular characteristics and therapy responses. Both CaB34 and CaB34-CF express prostate-specific markers, including KRT18, NKX3.1, and AMACR. Multi-omic analyses using RNAseq and shotgun proteomics identified NNMT as the most significantly dysregulated component in CaB34-CF. A bioinformatic analysis determined that NNMT was more abundant within prostate tumors compared to benign prostate, suggesting a role in tumor progression. Knockdown studies of NNMT demonstrated significant radiosensitization of CaB34-CF cells, which was largely a result of increased radiation-induced cellular senescence. Growth as 3D organoids was significantly higher in the CaB34-CF line, and demonstrated a less structured pattern of expression of cytokeratin markers. Radiosensitization with NNMT siRNA was recapitulated in a 3D organoid clonogenic assay in CaB34-CF cells. Our research provides a paired primary model of treatment-naïve and radioresistant disease to address mechanisms of therapy resistance, while expanding the repertoire of localized prostate cancer cell lines for the research community. In addition, our findings present NNMT as a potential therapeutic target for sensitization of radioresistant disease. Full article

Objectives: This study aimed to evaluate the prognostic significance of DNA methyltransferases (DNMTs) expression, including DNMT1, DNMT3A, and DNMT3B, in assessing the risk of locoregional recurrence after radiotherapy in patients with locally advanced laryngeal squamous cell carcinoma (LSCC), in order to optimize treatment decision making. Methods: A retrospective analysis was performed on pre-treatment biopsy tissues and clinical data from 58 patients with locally advanced LSCC (stages T3–T4, M0) treated with primary curative radiotherapy. DNMT expression was assessed through immunohistochemistry, and Cox regression analysis was applied to examine associations between methylation marker expression, demographic and clinical data, and both locoregional recurrence and disease-specific mortality. Results: Low expression of DNMT3A (p = 0.045) and the presence of locoregional lymph node metastases at diagnosis (N+-status) (p = 0.002) were associated with disease-specific mortality. Clinical N-status was also associated with locoregional recurrent disease after primary radiotherapy (p < 0.001). Expression of DNMT1 and DNMT3B, age, sex, and clinical T-status were not associated with locoregional recurrences or disease-specific mortality. Conclusions: Low expression of DNMT3A and the presence of regional lymph node metastases were independently associated with disease-specific mortality in patients with locally advanced LSCC treated primarily with definitive, curatively intended radiotherapy. Full article

Background/Objectives: Glioblastoma (GBM) is a highly aggressive primary central nervous system tumor with a median survival of 14 months. MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation status is a key biomarker as a prognostic indicator and a predictor of chemotherapy response in GBM. Patients with MGMT methylated disease progress later and survive longer (median survival rate 22 vs. 15 months, respectively) as compared to patients with MGMT unmethylated disease. Patients with GBM undergo an MRI of the brain prior to diagnosis and following surgical resection for radiation therapy planning and ongoing follow-up. There is currently no imaging biomarker for GBM. Studies have attempted to connect MGMT methylation status to MRI imaging appearance to determine if brain MRI can be leveraged to provide MGMT status information non-invasively and more expeditiously. Methods: Artificial intelligence (AI) can identify MRI features that are not distinguishable to the human eye and can be linked to MGMT status. We employed the UPenn-GBM dataset patients for whom methylation status was available (n = 146), employing a novel radiomic method grounded in hybrid feature selection and weighting to predict MGMT methylation status. Results: The best MGMT classification and feature selection result obtained resulted in a mean accuracy rate value of 81.6% utilizing 101 selected features and five-fold cross-validation. Conclusions: This compared favorably with similar studies in the literature. Validation with external datasets remains critical to enhance generalizability and propagate robust results while reducing bias. Future directions include multi-channel data integration with radiomic features and deep and ensemble learning methods to improve predictive performance. Full article

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, remains a global health challenge with limited therapeutic options and high mortality rates. Despite advances in understanding its molecular pathogenesis, the role of metabolic reprogramming in HCC progression and therapy resistance demands further exploration. Nicotinamide N-methyltransferase (NNMT), a metabolic enzyme central to NAD⁺ and methionine cycles, has emerged as a critical regulator of tumorigenesis across cancers. However, its tissue-specific mechanisms in HCC—particularly in the context of viral hepatitis and methionine cycle dependency—remain understudied. This review systematically synthesizes current evidence on NNMT’s dual role in HCC: (1) driving NAD⁺ depletion and homocysteine (Hcy) accumulation via metabolic dysregulation, (2) promoting malignant phenotypes (proliferation, invasion, metastasis, and drug resistance), and (3) serving as a prognostic biomarker and therapeutic target. We highlight how NNMT intersects with epigenetic modifications, immune evasion, and metabolic vulnerabilities unique to HCC. Additionally, we critically evaluate NNMT inhibitors, RNA-based therapies, and non-pharmacological strategies (e.g., exercise) as novel interventions. By bridging gaps between NNMT’s molecular mechanisms and clinical relevance, this review provides a roadmap for advancing NNMT-targeted therapies and underscores the urgency of addressing challenges in biomarker validation, inhibitor specificity, and translational efficacy. Our work positions NNMT not only as a metabolic linchpin in HCC but also as a promising candidate for precision oncology. Full article

Background: Basolateral amygdala (BLA) deep brain stimulation (DBS) has been shown to alleviate the symptoms of post-traumatic stress disorder (PTSD), but the specific mechanisms remain incompletely understood. The hippocampus, a brain region closely connected to the amygdala, plays a key role in the pathological processes of PTSD. The N6-methyladenosine (m⁶A) methylation of RNAs in the hippocampus is known to play a significant role in regulating the brain’s response to stress and emotional disorders. Methods: This study aimed to comprehensively analyze the roles of transcriptome-wide m⁶A modifications of the hippocampus in the BLA DBS treatment of a PTSD mouse model using m⁶A sequencing. Results: Significant alterations in functional connectivity between the ventral hippocampus (vHPC) and BLA were observed in foot shock (FS) mice through functional magnetic resonance imaging (fMRI) analysis. Furthermore, we observed that the expression of the key m⁶A methyltransferase enzyme, METTL3, in the FS and BLA DBS groups was higher than that in the control group. At the same time, both FS and BLA DBS induced the widespread m⁶A methylation of RNAs in the vHPC. Gene ontology (GO) enrichment analysis revealed that FS altered methylation in metabolic, developmental, and cytoskeletal pathways, while BLA DBS targeted metabolic, cell cycle, and neuroplasticity-related genes. Additionally, BLA DBS reversed the aberrant methylation of genes associated with multiple functional pathways induced by FS, including those related to cholinergic transmission, sodium and calcium ion homeostasis, and stress hormone responsiveness. We identified a set of RNAs with methylation changes that were reversed by BLA DBS in the FS vs. Ctrl (control) comparison, including those associated with cholinergic transmission, sodium and calcium ion balance, and stress hormone response. Additionally, we detected several specific BLA DBS-related genes through MeRIP-qPCR, indicating that DBS influences crucial genes linked to calcium signaling and synaptic plasticity. Conclusions: We draw two conclusions from these findings: BLA DBS may alleviate PTSD-like symptoms by reversing FS-induced methylation changes and by altering the methylation levels of crucial genes. These findings indicate that epigenetic m⁶A modifications in the vHPC may play an important role in the amelioration of PTSD using BLA DBS. Full article

Background: Although several studies investigated the efficacy of long-term adjuvant temozolomide (TMZ) therapy in glioblastomas (GBs), no univocal data are currently available, and this topic remains controversial. The present study on our ongoing experience aims to assess whether the extended STUPP protocol confers prognostic benefits with acceptable safety. Methods: From 2004 to 2018, 81 patients with a new diagnosis of GB according to the World Health Organization (WHO) 2021 classification, treated with gross total resection (GTR) or subtotal resection (STR), were enrolled. Patients were divided into Group A (long-term TMZ; N = 40) and Group B (standard STUPP protocol; N = 41). Results: In the extended STUPP group, compared with the standard STUPP group, progression-free survival (PFS) and overall survival (OS) were significantly improved (PFS: 27.8 vs. 7.5 months, p = 0.00001; OS: 35.9 vs. 11.3 months, p = 0.0001). To mitigate a potential survival bias, we focused on those in Group B who completed the recommended six cycles. Patients in Group A demonstrated a prolonged OS compared to Group B (27 vs. 10 months, p < 0.001). Similar findings were observed in a focused analysis of patients who had achieved a minimum survival of 12 months (27 vs. 15 months, p < 0.001) or 18 months (34 vs. 24 months, p = 0.044). Conclusions: Our analysis demonstrates a PFS and OS advantage with extended STUPP and suggests that young patients without corpus callosum invasion, with methylguanine-DNA methyltransferase (MGMT) promoter methylation, and treated with GTR are the best candidates. No significant safety difference emerged between extended and standard TMZ treatment. Full article

Recent studies have identified N6-methyladenosine (m6A) RNA methylation as a key regulatory mechanism in tumor progression. This study aimed to elucidate the biological function and clinical relevance of the m6A methyltransferase METTL3 in cutaneous T-cell lymphoma (CTCL). Our findings demonstrated that METTL3 expression is upregulated in CTCL, and its knockdown suppresses CTCL progression. Mechanistically, the downregulation of METTL3-mediated m6A modification on ARHGEF12 mRNA accelerated its degradation, a process that is closely associated with tumor behaviors. These results suggest that METTL3 may serve as a potential therapeutic target in CTCL. Full article

N⁶-methyladenosine (m⁶A) RNA modification plays important regulatory roles in plant development and adaptation to the environment. However, there has been no research regarding m⁶A RNA methyltransferases (MT-A70) in Przewalskia tangutica Maxim. Here, we performed a comprehensive analysis of the MT-A70 family in Przewalskia tangutica (PtMTs), including gene structures, phylogenetic relationships, conserved motifs, gene location, promoter analysis, GO enrichment analysis, and expression profiles. We identified seven PtMT genes. Phylogeny analysis indicated that the seven PtMT genes could be divided into three groups; two MTA genes, three MTB genes, and two MTC genes, and domains and motifs exhibited similar patterns within the same group. These PtMT genes were found to contain a large number of cis-acting elements associated with plant hormones, light response, and stress response, suggesting their widespread regulatory function. Furthermore, the expression profiling of different tissues was investigated using RNA-seq data, and the expression of seven genes was further validated by qPCR analysis. These results provided valuable information to further elucidate the function of m⁶A regulatory genes and their epigenetic regulatory mechanisms in Przewalskia tangutica. Full article

Epigenetics of N6-methyladenine (m6A) modification may play a key role during the regulation of various diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). The m6A modification has been shown to be accomplished via the exploitation of several players such as methyltransferases, demethylases, and/or methylation-binding molecules. Significantly, the m6A methylation can regulate the key eukaryotic transcriptome by affecting the subcellular localization, splicing, export, stability, translation, and decay of those RNAs. An increasing amount of data has designated that the m6A modification of RNAs can also modulate the expression of autophagy-related genes, which could also control the autophagy in hepatocytes. Oxidative stress with reactive oxygen species (ROS) can induce m6A RNA methylation, which might be associated with the regulation of mitochondrial autophagy (mitophagy) and/or the development of MASLD. Therefore, both autophagy and the m6A modification could play important roles in regulating the pathogenesis of MASLD. Comprehending the relationship between m6A and mitophagy may be helpful for the development of future therapeutic strategies against MASLD. This review would advance the understanding of the regulatory mechanisms of m6A RNA modification, focusing on the impact of mitochondrial dysregulation and mitophagy in the liver with MASLD. Full article