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Journal of Clinical Medicine Jan 2024: Histamine intolerance manifests when there is an imbalance between the production of histamine and the body's capacity to metabolise it. Within the gastrointestinal...
Exploring the Relationship between Diamine Oxidase and Psychotropic Medications in Fibromyalgia Treatment, Finding No Reduction in Diamine Oxidase Levels and Activity except with Citalopram.
: Histamine intolerance manifests when there is an imbalance between the production of histamine and the body's capacity to metabolise it. Within the gastrointestinal tract, diamine oxidase (DAO) plays a pivotal role in breaking down ingested histamine. Insufficient levels of DAO have been linked to various diseases affecting the respiratory, cardiovascular, nervous, muscular, and digestive systems; some of these symptoms are evidenced in fibromyalgia syndrome. This underscores the crucial role of DAO in maintaining the histamine balance and highlights its association with diverse physiological systems and health conditions. The management of fibromyalgia commonly involves the use of psychotropic medications; however, their potential interactions with DAO remain not fully elucidated. : This study delved into the influence of various psychotropic medications on DAO activity through experiments. Additionally, we explored their impact on the human intestinal cell line Caco-2, examining alterations in DAO expression at both the mRNA and protein levels along with DAO activity. : Notably, the examined drugs-sertraline, pregabalin, paroxetine, alprazolam, and lorazepam-did not exhibit inhibitory effects on DAO activity or lead to reductions in DAO levels. In contrast, citalopram demonstrated a decrease in DAO activity in assays without influencing DAO levels and activity in human enterocytes. : These findings imply that a collaborative approach involving psychotropic medications and DAO enzyme supplementation for individuals with fibromyalgia and a DAO deficiency could offer potential benefits for healthcare professionals in their routine clinical practice.
PubMed: 38337486
DOI: 10.3390/jcm13030792 -
Journal of Human Genetics Apr 2024Non-syndromic orofacial cleft (NSOC) is one of the most common craniofacial malformations with complex etiology. This study aimed to explore the role of specific SNPs in...
BACKGROUND
Non-syndromic orofacial cleft (NSOC) is one of the most common craniofacial malformations with complex etiology. This study aimed to explore the role of specific SNPs in ZFP36L2 and its functional relevance in zebrafish models.
METHODS
We analyzed genetic data of the Chinese Han population from two previous GWAS, comprising of 2512 cases and 2255 controls. Based on the Hardy-Weinberg Equilibrium (HWE) and minor allele frequency (MAF), SNPs in the ZFP36L2 were selected for association analysis. In addition, zebrafish models were used to clarify the in-situ expression pattern of zfp36l2 and the impact of its Morpholino-induced knockdown.
RESULTS
Via association analysis, rs7933 in ZFP36L2 was significantly associated with various non-syndromic cleft lip-only subtypes, potentially conferring a protective effect. Zebrafish embryos showed elevated expression of zfp36l2 in the craniofacial region during critical stages of oral cavity formation. Furthermore, Morpholino-induced knockdown of zfp36l2 led to craniofacial abnormalities, including cleft lip, which was partially rescued by the addition of zfp36l2 mRNA.
CONCLUSION
Our findings highlight the significance of ZFP36L2 in the etiology of NSOC, supported by both human genetic association data and functional studies in zebrafish. These results pave the way for further exploration of targeted interventions for craniofacial malformations.
Topics: Animals; Humans; Cleft Lip; Cleft Palate; Zebrafish; Genetic Predisposition to Disease; Morpholinos; Polymorphism, Single Nucleotide; Craniofacial Abnormalities; Genotype; Transcription Factors
PubMed: 38321215
DOI: 10.1038/s10038-024-01222-z -
Molecular Medicine (Cambridge, Mass.) Feb 2024Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by inflammation of the synovial tissue and joint bone destruction, often leading to... (Review)
Review
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by inflammation of the synovial tissue and joint bone destruction, often leading to significant disability. The main pathological manifestation of joint deformity in RA patients is bone destruction, which occurs due to the differentiation and proliferation of osteoclasts. The transcription factor nuclear factor-activated T cell 1 (NFATc1) plays a crucial role in this process. The regulation of NFATc1 in osteoclast differentiation is influenced by three main factors. Firstly, NFATc1 is activated through the upstream nuclear factor kappa-B ligand (RANKL)/RANK signaling pathway. Secondly, the Ca-related co-stimulatory signaling pathway amplifies NFATc1 activity. Finally, negative regulation of NFATc1 occurs through the action of cytokines such as B-cell Lymphoma 6 (Bcl-6), interferon regulatory factor 8 (IRF8), MAF basic leucine zipper transcription factor B (MafB), and LIM homeobox 2 (Lhx2). These three phases collectively govern NFATc1 transcription and subsequently affect the expression of downstream target genes including TRAF6 and NF-κB. Ultimately, this intricate regulatory network mediates osteoclast differentiation, fusion, and the degradation of both organic and inorganic components of the bone matrix. This review provides a comprehensive summary of recent advances in understanding the mechanism of NFATc1 in the context of RA-related bone destruction and discusses potential therapeutic agents that target NFATc1, with the aim of offering valuable insights for future research in the field of RA. To assess their potential as therapeutic agents for RA, we conducted a drug-like analysis of potential drugs with precise structures.
Topics: Humans; Arthritis, Rheumatoid; Cell Differentiation; NF-kappa B; NFATC Transcription Factors; Osteoclasts; T-Lymphocytes
PubMed: 38310228
DOI: 10.1186/s10020-024-00788-w -
BMC Genomics Feb 2024Pseudogenes have been implicated for their role in regulating cellular differentiation and organismal development. However, their role in promoting cancer-associated...
INTRODUCTION
Pseudogenes have been implicated for their role in regulating cellular differentiation and organismal development. However, their role in promoting cancer-associated differentiation has not been well-studied. This study explores the tumour landscape of oesophageal carcinoma to identify pseudogenes that may regulate events of differentiation to promote oncogenic transformation.
MATERIALS AND METHOD
De-regulated differentiation-associated pseudogenes were identified using DeSeq2 followed by 'InteractiVenn' analysis to identify their expression pattern. Gene expression dependent and independent enrichment analyses were performed with GSEA and ShinyGO, respectively, followed by quantification of cellular reprogramming, extent of differentiation and pleiotropy using three unique metrics. Stage-specific gene regulatory networks using Bayesian Network Splitting Average were generated, followed by network topology analysis. MEME, STREME and Tomtom were employed to identify transcription factors and miRNAs that play a regulatory role downstream of pseudogenes to initiate cellular reprogramming and further promote oncogenic transformation. The patient samples were stratified based on the expression pattern of pseudogenes, followed by GSEA, mutation analysis and survival analysis using GSEA, MAF and 'survminer', respectively.
RESULTS
Pseudogenes display a unique stage-wise expression pattern that characterizes stage II (SII) ESCA with a high rate of cellular reprogramming, degree of differentiation and pleiotropy. Gene regulatory network and associated topology indicate high robustness, thus validating high pleiotropy observed for SII. Pseudogene-regulated expression of SOX2, FEV, PRRX1 and TFAP2A in SII may modulate cellular reprogramming and promote oncogenesis. Additionally, patient stratification-based mutational analysis in SII signifies APOBEC3A (A3A) as a potential hallmark of homeostatic mutational events of reprogrammed cells which in addition to de-regulated APOBEC3G leads to distinct events of hypermutations. Further enrichment analysis for both cohorts revealed the critical role of combinatorial expression of pseudogenes in cellular reprogramming. Finally, survival analysis reveals distinct genes that promote poor prognosis in SII ESCA and patient-stratified cohorts, thus providing valuable prognostic bio-markers along with markers of differentiation and oncogenesis for distinct landscapes of pseudogene expression.
CONCLUSION
Pseudogenes associated with the events of differentiation potentially aid in the initiation of cellular reprogramming to facilitate oncogenic transformation, especially during SII ESCA. Despite a better overall survival of SII, patient stratification reveals combinatorial de-regulation of pseudogenes as a notable marker for a high degree of cellular differentiation with a unique mutational landscape.
Topics: Humans; Pseudogenes; Bayes Theorem; Carcinogenesis; Esophageal Neoplasms; Cellular Reprogramming; Carcinoma; Homeodomain Proteins; Cytidine Deaminase; Proteins
PubMed: 38308202
DOI: 10.1186/s12864-024-10023-9 -
BMC Genomics Jan 2024Single-cell transcriptomics provides means to study cell populations at the level of individual cells. In leukocyte biology this approach could potentially aid the...
BACKGROUND
Single-cell transcriptomics provides means to study cell populations at the level of individual cells. In leukocyte biology this approach could potentially aid the identification of subpopulations and functions without the need to develop species-specific reagents. The present study aimed to evaluate single-cell RNA-seq as a tool for identification of chicken peripheral blood leukocytes. For this purpose, purified and thrombocyte depleted leukocytes from 4 clinically healthy hens were subjected to single-cell 3' RNA-seq. Bioinformatic analysis of data comprised unsupervised clustering of the cells, and annotation of clusters based on expression profiles. Immunofluorescence phenotyping of the cell preparations used was also performed.
RESULTS
Computational analysis identified 31 initial cell clusters and based on expression of defined marker genes 28 cluster were identified as comprising mainly B-cells, T-cells, monocytes, thrombocytes and red blood cells. Of the remaining clusters, two were putatively identified as basophils and eosinophils, and one as proliferating cells of mixed origin. In depth analysis on gene expression profiles within and between the initial cell clusters allowed further identification of cell identity and possible functions for some of them. For example, analysis of the group of monocyte clusters revealed subclusters comprising heterophils, as well as putative monocyte subtypes. Also, novel aspects of TCRγ/δ + T-cell subpopulations could be inferred such as evidence of at least two subtypes based on e.g., different expression of transcription factors MAF, SOX13 and GATA3. Moreover, a novel subpopulation of chicken peripheral B-cells with high SOX5 expression was identified. An overall good correlation between mRNA and cell surface phenotypic cell identification was shown.
CONCLUSIONS
Taken together, we were able to identify and infer functional aspects of both previously well known as well as novel chicken leukocyte populations although some cell types. e.g., T-cell subtypes, proved more challenging to decipher. Although this methodology to some extent is limited by incomplete annotation of the chicken genome, it definitively has benefits in chicken immunology by expanding the options to distinguish identity and functions of immune cells also without access to species specific reagents.
Topics: Animals; Female; Chickens; Single-Cell Gene Expression Analysis; Leukocytes; Monocytes; Gene Expression Profiling; Single-Cell Analysis; Sequence Analysis, RNA
PubMed: 38287279
DOI: 10.1186/s12864-024-10044-4 -
BMC Oral Health Jan 2024The aim of this study was to analyse the differences in the phenotypes of missing teeth between a pair of brothers with hypohidrotic ectodermal dysplasia (HED) and to...
BACKGROUND
The aim of this study was to analyse the differences in the phenotypes of missing teeth between a pair of brothers with hypohidrotic ectodermal dysplasia (HED) and to investigate the underlying mechanism by comparing the mutated gene loci between the brothers with whole-exome sequencing.
METHODS
The clinical data of the patients and their mother were collected, and genomic DNA was extracted from peripheral blood samples. By Whole-exome sequencing filtered for a minor allele frequency (MAF) ≤0.05 non-synonymous single-nucleotide variations and insertions/deletions variations in genes previously associated with tooth agenesis, and variations considered as potentially pathogenic were assessed by SIFT, Polyphen-2, CADD and ACMG. Sanger sequencing was performed to detect gene variations. The secondary and tertiary structures of the mutated proteins were predicted by PsiPred 4.0 and AlphaFold 2.
RESULTS
Both brothers were clinically diagnosed with HED, but the younger brother had more teeth than the elder brother. An EDA variation (c.878 T > G) was identified in both brothers. Additionally, compound heterozygous variations of WNT10A (c.511C > T and c.637G > A) were identified in the elder brother. Digenic variations in EDA (c.878 T > G) and WNT10A (c.511C > T and c.637G > A) in the same patient have not been reported previously. The secondary structure of the variant WNT10A protein showed changes in the number and position of α-helices and β-folds compared to the wild-type protein. The tertiary structure of the WNT10A variant and molecular simulation docking showed that the site and direction where WNT10A binds to FZD5 was changed.
CONCLUSIONS
Compound heterozygous WNT10A missense variations may exacerbate the number of missing teeth in HED caused by EDA variation.
Topics: Male; Humans; Ectodermal Dysplasia 1, Anhidrotic; Ectodermal Dysplasia; Phenotype; Tooth; Anodontia; Mutation; Wnt Proteins
PubMed: 38280992
DOI: 10.1186/s12903-024-03888-5 -
Drug Resistance Updates : Reviews and... Mar 2024Lung cancer is the leading cause of cancer mortality and lung adenocarcinoma (LUAD) accounts for more than half of all lung cancer cases. Tumor elimination is mostly...
AIMS
Lung cancer is the leading cause of cancer mortality and lung adenocarcinoma (LUAD) accounts for more than half of all lung cancer cases. Tumor elimination is mostly hindered by drug resistance and the mechanisms remain to be explored in LUAD.
METHODS
CRISPR screens in cell and murine models and single-cell RNA sequencing were conducted, which identified MAF bZIP transcription factor F (MAFF) as a critical factor regulating tumor growth and treatment resistance in LUAD. RNA and ChIP sequencing analyses were performed for transcriptional target expression and specific binding sites of MAFF. Functions of MAFF in inhibiting tumor growth and promoting cisplatin or irradiation efficacy were investigated using cellular and xenograft models.
RESULTS
Patients with lung adenocarcinoma and reduced MAFF expression had worse clinical outcomes. MAFF inhibited tumor cell proliferation by regulating the expression of SLC7A11, CDK6, and CDKN2C, promoting ferroptosis and preventing cell cycle progression from G1 to S. MAFF also conferred tumor cells vulnerable to cisplatin-based or ionizing radiation treatments. MAFF reduction was a final event in the acquisition of cisplatin resistance of LUAD cells. The intracellular cAMP/PKA/CREB1 pathway upregulated MAFF in response to cisplatin-based or ionizing radiation treatments.
CONCLUSIONS
MAFF suppresses tumor growth, and pharmacological agonists targeting MAFF may improve cisplatin or irradiation therapies for lung adenocarcinoma patients.
Topics: Humans; Animals; Mice; Cisplatin; Ferroptosis; Cell Line, Tumor; Adenocarcinoma of Lung; Lung Neoplasms; Cell Proliferation; Cell Cycle; Nuclear Proteins; MafF Transcription Factor
PubMed: 38266355
DOI: 10.1016/j.drup.2024.101057 -
Genes Jan 2024Stalk rot caused by fungi is one of the most widespread and devastating diseases of maize, and the introduction of resistant genotypes is one of the most effective...
Stalk rot caused by fungi is one of the most widespread and devastating diseases of maize, and the introduction of resistant genotypes is one of the most effective strategies for controlling the disease. Breeding genotypes with genetically determined resistance will also allow less use of crop protection products. The aim of the research was to identify molecular markers and associated candidate genes determining maize plant resistance to Fusarium stalk rot. The plant material for this study consisted of 122 maize hybrids. The experiment was conducted in two localities: Smolice and Kobierzyce. The Fusarium stalk rot values ranged from 1.65% (for genotype G01.10) to 31.18% (for genotype G03.07) in Kobierzyce and from 0.00% (for 58 genotypes) to 6.36% (G05.03) in Smolice. The analyzed genotypes were simultaneously subjected to next-generation sequencing using the Illumina platform. Illumina sequencing identified 60,436 SilicoDArT markers and 32,178 SNP markers (92,614 in total). For association mapping, 32,900 markers (26,234 SilicoDArT and 6666 SNP) meeting the criteria (MAF > 0.25 and the number of missing observations <10%) were used. The results of the observation of the degree of infection and sequencing were used for association mapping, which ultimately resulted in the selection of ten molecular markers important at both places. Among the identified markers, two SNP markers that are located inside candidate genes play an important role. Marker 4772836 is located inside the serine/threonine-protein kinase bsk3 gene, while marker 4765764 is located inside the histidine kinase 1 gene. Both genes can be associated with plant resistance to Fusarium stalk rot, and these genes can also be used in breeding programs to select resistant varieties.
Topics: Fusarium; Plant Breeding; Genotype; High-Throughput Nucleotide Sequencing; Technology; Zea mays
PubMed: 38254995
DOI: 10.3390/genes15010106 -
Molecular Biology Reports Jan 2024Teak (Tectona grandis L.f.), an important source of tropical timber with immense economic value, is a highly outcrossing forest tree species. 150 unrelated accessions of...
BACKGROUND
Teak (Tectona grandis L.f.), an important source of tropical timber with immense economic value, is a highly outcrossing forest tree species. 150 unrelated accessions of teak (Tectona grandis L.f.) plus trees assembled as clones at National Teak Germplasm Bank, Chandrapur, Maharashtra, India was investigated for association mapping of candidate lignin biosynthesis gene (CAD1) and transcription factors (MYB1 and MYB2).
METHODS AND RESULTS
The CAD1, MYB1 and MYB2 were amplified using specifically designed primers. The amplified sequences were then sequenced and genotyped for 112 SNPs/11 indels. We evaluated the association between SNPs and wood density in teak accessions using GLM and MLM statistical models, with Bonferroni correction applied. The teak accessions recorded an average wood density of 416.69 kg.m (CV 4.97%) and comprised of three loosely structured admixed sub-populations (K = 3), containing 72.05% genetic variation within sub-populations with low intragenic LD (0-21% SNP pairs) at P < 0.05 and high LD decay (33-934 bp) at R = 0.1. GLM and MLM models discounting systematic biases (Q and K matrices) to avoid false discovery revealed five loci at rare variants (MAF 0.003) and three loci at common variants (MAF 0.05) to be significantly (P < 0.05) associated with the wood density. However, the stringent Bonferroni correction (4.06-7.04 × 10) yielded only a single associated locus (B1485C/A) from exon of MYB1 transcription factor, contributing to about 10.35% phenotypic variation in wood density trait.
CONCLUSION
Scored SNP locus (B1485C/A) can be developed as a molecular probe for selection of improved planting stock with proven wood density trait for a large-scale teak plantation.
Topics: Transcription Factors; Wood; Genotype; Lignin; Polymorphism, Single Nucleotide; India; Lamiaceae
PubMed: 38252339
DOI: 10.1007/s11033-023-09006-y -
Haematologica May 2024
Topics: Humans; Translocation, Genetic; Prognosis; Chromosome Aberrations; Female; Male; Proto-Oncogene Proteins c-maf; Middle Aged; Aged; Adult; Myelodysplastic Syndromes
PubMed: 38235518
DOI: 10.3324/haematol.2023.284666