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Molecular Biology Reports Mar 2024The formation of advanced glycation end products (AGEs) is the central process contributing to diabetic complications in diabetic individuals with sustained and...
BACKGROUND
The formation of advanced glycation end products (AGEs) is the central process contributing to diabetic complications in diabetic individuals with sustained and inconsistent hyperglycemia. Methylglyoxal, a reactive carbonyl species, is found to be a major precursor of AGEs, and its levels are elevated in diabetic conditions. Dysfunction of pancreatic beta cells and impairment in insulin secretion are the hallmarks of diabetic progression. Exposure to methylglyoxal-induced AGEs alters the function and maintenance of pancreatic beta cells. Hence, trapping methylglyoxal could be an ideal approach to alleviate AGE formation and its influence on beta cell proliferation and insulin secretion, thereby curbing the progression of diabetes to its complications.
METHODS AND RESULTS
In the present study, we have explored the mechanism of action of (+)-Catechin against methylglyoxal-induced disruption in pancreatic beta cells via molecular biology techniques, mainly western blot. Methylglyoxal treatment decreased insulin synthesis (41.5%) via downregulating the glucose-stimulated insulin secretion pathway (GSIS). This was restored upon co-treatment with (+)-Catechin (29.9%) in methylglyoxal-induced Beta-TC-6 cells. Also, methylglyoxal treatment affected the autocrine function of insulin by disrupting the IRS1/PI3k/Akt pathway. Methylglyoxal treatment suppresses Pdx-1 and Maf A levels, which are responsible for beta cell maintenance and cell proliferation. (+)-Catechin could significantly augment the levels of these transcription factors.
CONCLUSION
This is the first study to examine the impact of a natural compound on methylglyoxal with the insulin-mediated autocrine and paracrine activities of pancreatic beta cells. The results indicate that (+)-Catechin exerts a protective effect against methylglyoxal exposure in pancreatic beta cells and can be considered a potential anti-glycation agent in further investigations on ameliorating diabetic complications.
Topics: Humans; Insulin Secretion; Insulin-Secreting Cells; Pyruvaldehyde; Catechin; Phosphatidylinositol 3-Kinases; Insulin; Diabetes Mellitus; Diabetes Complications; Glycation End Products, Advanced
PubMed: 38520585
DOI: 10.1007/s11033-024-09338-3 -
Cell Reports Mar 2024U1 small nuclear RNA (snRNA) is an abundant and evolutionarily conserved 164-nucleotide RNA species that functions in pre-mRNA splicing, and it is considered to be a...
U1 small nuclear RNA (snRNA) is an abundant and evolutionarily conserved 164-nucleotide RNA species that functions in pre-mRNA splicing, and it is considered to be a housekeeping non-coding RNA. However, the role of U1 snRNA in regulating host antiviral immunity remains largely unexplored. Here, we find that RNVU1-18, a U1 pseudogene, is significantly upregulated in the host infected with RNA viruses, including influenza and respiratory syncytial virus. Overexpression of U1 snRNA protects cells against RNA viruses, while knockdown of U1 snRNA leads to more viral burden in vitro and in vivo. Knockout of RNVU1-18 is sufficient to impair the type I interferon-dependent antiviral innate immunity. U1 snRNA is required to fully activate the retinoic acid-inducible gene I (RIG-I)-dependent antiviral signaling, since it interacts with tripartite motif 25 (TRIM25) and enhances the RIG-I-TRIM25 interaction to trigger K63-linked ubiquitination of RIG-I. Our study reveals the important role of housekeeping U1 snRNA in regulating host antiviral innate immunity and restricting RNA virus infection.
Topics: Transcription Factors; Ubiquitin-Protein Ligases; DEAD Box Protein 58; Immunity, Innate; RNA, Small Nuclear; Ubiquitination; Tripartite Motif Proteins
PubMed: 38483900
DOI: 10.1016/j.celrep.2024.113945 -
Pediatric Rheumatology Online Journal Mar 2024Multicentric carpotarsal osteolysis (MCTO) is a rare genetic disorder characterized by the progressive loss of bone in the hands, feet, and other skeletal structures. It... (Review)
Review
BACKGROUND
Multicentric carpotarsal osteolysis (MCTO) is a rare genetic disorder characterized by the progressive loss of bone in the hands, feet, and other skeletal structures. It presents with symptoms that may resemble those of juvenile idiopathic arthritis, making diagnosis challenging for clinicians. The identification of MAF BZIP Transcription Factor B (MAFB) mutations as significant contributors to MCTO represents a major breakthrough in our understanding of the pathogenesis of this rare skeletal disorder.
CASE PRESENTATION
Our objective was to present the phenotype, treatment, and outcome of a patient with a variant of MAFB-induced MCTO to broaden the range of clinical features associated with MCTO and share our clinical experience for improved diagnosis and treatment. In our case, early MRI examination of the bones and whole exome sequencing enabled an early and accurate MCTO diagnosis, and timely Denosumab administration resulted in no deterioration.
CONCLUSION
This suggests that MRI examination and whole exome sequencing should be considered when MCTO is suspected, and Denosumab might be an option in the treatment of MCTO.
Topics: Humans; Osteolysis; Denosumab; Mutation; Phenotype; MafB Transcription Factor
PubMed: 38481224
DOI: 10.1186/s12969-024-00964-6 -
Nature Apr 2024AIRE is an unconventional transcription factor that enhances the expression of thousands of genes in medullary thymic epithelial cells and promotes clonal deletion or...
AIRE is an unconventional transcription factor that enhances the expression of thousands of genes in medullary thymic epithelial cells and promotes clonal deletion or phenotypic diversion of self-reactive T cells. The biological logic of AIRE's target specificity remains largely unclear as, in contrast to many transcription factors, it does not bind to a particular DNA sequence motif. Here we implemented two orthogonal approaches to investigate AIRE's cis-regulatory mechanisms: construction of a convolutional neural network and leveraging natural genetic variation through analysis of F1 hybrid mice. Both approaches nominated Z-DNA and NFE2-MAF as putative positive influences on AIRE's target choices. Genome-wide mapping studies revealed that Z-DNA-forming and NFE2L2-binding motifs were positively associated with the inherent ability of a gene's promoter to generate DNA double-stranded breaks, and promoters showing strong double-stranded break generation were more likely to enter a poised state with accessible chromatin and already-assembled transcriptional machinery. Consequently, AIRE preferentially targets genes with poised promoters. We propose a model in which Z-DNA anchors the AIRE-mediated transcriptional program by enhancing double-stranded break generation and promoter poising. Beyond resolving a long-standing mechanistic conundrum, these findings suggest routes for manipulating T cell tolerance.
Topics: Animals; Mice; AIRE Protein; Chromatin; DNA Breaks, Double-Stranded; DNA, Z-Form; Epithelial Cells; Genetic Variation; Immune Tolerance; Neural Networks, Computer; NF-E2-Related Factor 2; Promoter Regions, Genetic; T-Lymphocytes; Thymus Gland; Transcription, Genetic; Female
PubMed: 38480882
DOI: 10.1038/s41586-024-07169-7 -
Food Science & Nutrition Mar 2024Studies suggest that mangiferin (MAF) has good therapeutic effects on chronic bronchitis and hepatitis. Also, it is one of the antiviral ingredients in Bunge. However,...
Studies suggest that mangiferin (MAF) has good therapeutic effects on chronic bronchitis and hepatitis. Also, it is one of the antiviral ingredients in Bunge. However, its effect on the LPS-induced inflammation and intestinal flora during sepsis remains unclear yet. In the present study, LPS-stimulated inflammation RAW264.7 cells and LPS-induced sepsis mice were used to evaluate the efficacy of MAF in vitro and in vivo. 16S rDNA sequencing was performed to analyze the characteristics of intestinal flora of the sepsis mice. It has been demonstrated that MAF (12.5 and 25 μg/mL) significantly inhibited protein expressions of TLR4, MyD88, NF-κB, and TNF-α in the LPS-treated cells and reduced the supernatant TNF-α and IL-6 levels. In vivo, MAF (20 mg/kg) markedly protected the sepsis mice and reduced the serum TNF-α and IL-6 levels. Also, MAF significantly downregulated the protein expressions of TLR4, NF-κB, and MyD88 in the livers. Importantly, MAF significantly attenuated the pathological injuries of the livers and small intestines. Further, MAF significantly increased proportion of and decreased the proportions of , , , and at phylum level, and it markedly reduced the proportions of , , at genus level. Moreover, MAF affects some metabolism-related pathways such as citrate cycle (TCA cycle), lipoic acid metabolism, oxidative phosphorylation, bacterial chemotaxis, fatty acid biosynthesis, and peptidoglycan biosynthesis of the intestinal flora. Thus, it can be concluded that MAF as a treatment reduces the inflammatory responses in vitro and in vivo by inhibiting the TLR4/ MyD88/NF-κB pathway, and corrects intestinal flora imbalance during sepsis to some degree.
PubMed: 38455195
DOI: 10.1002/fsn3.3907 -
Science Immunology Mar 2024T follicular helper (T) cells are essential for effective antibody responses, but deciphering the intrinsic wiring of mouse T cells has long been hampered by the lack of...
T follicular helper (T) cells are essential for effective antibody responses, but deciphering the intrinsic wiring of mouse T cells has long been hampered by the lack of a reliable protocol for their generation in vitro. We report that transforming growth factor-β (TGF-β) induces robust expression of T hallmark molecules CXCR5 and Bcl6 in activated mouse CD4 T cells in vitro. TGF-β-induced mouse CXCR5 T cells are phenotypically, transcriptionally, and functionally similar to in vivo-generated T cells and provide critical help to B cells. The study further reveals that TGF-β-induced CXCR5 expression is independent of Bcl6 but requires the transcription factor c-Maf. Classical TGF-β-containing T helper 17 (T17)-inducing conditions also yield separate CXCR5 and IL-17A-producing cells, highlighting shared and distinct cell fate trajectories of T and T17 cells. We demonstrate that excess IL-2 in high-density T cell cultures interferes with the TGF-β-induced T cell program, that T and T17 cells share a common developmental stage, and that c-Maf acts as a switch factor for T versus T17 cell fates in TGF-β-rich environments in vitro and in vivo.
Topics: Animals; Mice; T-Lymphocytes, Helper-Inducer; Transforming Growth Factor beta; B-Lymphocytes; CD4-Positive T-Lymphocytes; Cell Differentiation; Proto-Oncogene Proteins c-maf
PubMed: 38427718
DOI: 10.1126/sciimmunol.add4818 -
Journal of Autoimmunity Apr 2024Chronic nonbacterial osteomyelitis (CNO), an autoinflammatory bone disease primarily affecting children, can cause pain, hyperostosis and fractures, affecting...
Chronic nonbacterial osteomyelitis (CNO), an autoinflammatory bone disease primarily affecting children, can cause pain, hyperostosis and fractures, affecting quality-of-life and psychomotor development. This study investigated CNO-associated variants in P2RX7, encoding for the ATP-dependent trans-membrane K channel P2X7, and their effects on NLRP3 inflammasome assembly. Whole exome sequencing in two related transgenerational CNO patients, and target sequencing of P2RX7 in a large CNO cohort (N = 190) were conducted. Results were compared with publicly available datasets and regional controls (N = 1873). Findings were integrated with demographic and clinical data. Patient-derived monocytes and genetically modified THP-1 cells were used to investigate potassium flux, inflammasome assembly, pyroptosis, and cytokine release. Rare presumably damaging P2RX7 variants were identified in two related CNO patients. Targeted P2RX7 sequencing identified 62 CNO patients with rare variants (32.4%), 11 of which (5.8%) carried presumably damaging variants (MAF <1%, SIFT "deleterious", Polyphen "probably damaging", CADD >20). This compared to 83 of 1873 controls (4.4%), 36 with rare and presumably damaging variants (1.9%). Across the CNO cohort, rare variants unique to one (Median: 42 versus 3.7) or more (≤11 patients) participants were over-represented when compared to 190 randomly selected controls. Patients with rare damaging variants more frequently experienced gastrointestinal symptoms and lymphadenopathy while having less spinal, joint and skin involvement (psoriasis). Monocyte-derived macrophages from patients, and genetically modified THP-1-derived macrophages reconstituted with CNO-associated P2RX7 variants exhibited altered potassium flux, inflammasome assembly, IL-1β and IL-18 release, and pyroptosis. Damaging P2RX7 variants occur in a small subset of CNO patients, and rare P2RX7 variants may represent a CNO risk factor. Observations argue for inflammasome inhibition and/or cytokine blockade and may allow future patient stratification and individualized care.
Topics: Humans; Cytokines; Inflammasomes; Osteomyelitis; Potassium; Pyroptosis; Receptors, Purinergic P2X7
PubMed: 38401466
DOI: 10.1016/j.jaut.2024.103183 -
Gene May 2024The identification of rare genetic variants associated to Systemic Lupus Erythematosus (SLE) could also help to understand the pathogenic mechanisms at the basis of the...
The identification of rare genetic variants associated to Systemic Lupus Erythematosus (SLE) could also help to understand the pathogenic mechanisms at the basis of the disease. In this study we have analyzed a cohort of 200 Italian SLE patients in order to explore the rare protein-coding variants in five genes (TNFAIP3, STAT4, IL10, TRAF3IP2, and HCP5) already investigated for commons variants found associated in our previous studies. Genomic DNA of 200 SLE patients was sequenced by whole exome sequencing. The identified variants were filtered by frequency and evaluated by in silico predictions. Allelic association analysis was performed with standard Fisher's exact test. Introducing a cutoff at MAF < 0.01, a total of 19 rare variants were identified. Seven of these variants were ultra-rare (MAF < 0.001) and six were absent in the GnomAD database. For TNFAIP3 gene, the variant c.A1939C was observed in 4 SLE patients and it is located in a region enriched in phosphorylation sites and affects the predict affinity of specific kinases. In TRAF3IP2 gene, we observed 5 different rare variants, including the novel variant c.G410A, located in the region that mediates interaction with TRAF6, and therefore a possible risk factor for SLE development. In STAT4 gene, we identified 6 different rare variants. Among these, three missense variants decrease the stability of this protein. Moreover, 3 novel rare variants were detected in 3 SLE patients. In particular, c.A767T variant was predicted as damaging by six prediction tools. Concluding, we have observed that even in genes whose common variability is associated with SLE susceptibility, it is possible to identify rare variants that could have a strong effect in the disease development and could therefore allow a better understanding of the functional domain involved.
Topics: Humans; Genetic Predisposition to Disease; Lupus Erythematosus, Systemic; Alleles; DNA; Sequence Analysis, DNA; Polymorphism, Single Nucleotide
PubMed: 38360126
DOI: 10.1016/j.gene.2024.148279 -
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