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Cells Jun 2024Hepatocellular carcinoma (HCC) development is associated with altered modifications in DNA methylation, changing transcriptional regulation. Emerging evidence indicates...
Hepatocellular carcinoma (HCC) development is associated with altered modifications in DNA methylation, changing transcriptional regulation. Emerging evidence indicates that DNA methyltransferase 1 (DNMT1) plays a key role in the carcinogenesis process. This study aimed to investigate how pirfenidone (PFD) modifies this pathway and the effect generated by the association between c-Myc expression and DNMT1 activation. Rats F344 were used for HCC development using 50 mg/kg of diethylnitrosamine (DEN) and 25 mg/kg of 2-Acetylaminofluorene (2-AAF). The HCC/PFD group received simultaneous doses of 300 mg/kg of PFD. All treatments lasted 12 weeks. On the other hand, HepG2 cells were used to evaluate the effects of PFD in restoring DNA methylation in the presence of the inhibitor 5-Aza. Histopathological, biochemical, immunohistochemical, and western blot analysis were carried out and our findings showed that PFD treatment reduced the amount and size of tumors along with decreased Glipican-3, β-catenin, and c-Myc expression in nuclear fractions. Also, this treatment improved lipid metabolism by modulating PPARγ and SREBP1 signaling. Interestingly, PFD augmented DNMT1 and DNMT3a protein expression, which restores global methylation, both in our in vivo and in vitro models. In conclusion, our results suggest that PFD could slow down HCC development by controlling DNA methylation.
Topics: Animals; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Pyridones; Rats; Carcinoma, Hepatocellular; Humans; Hep G2 Cells; Proliferating Cell Nuclear Antigen; Male; Rats, Inbred F344; Liver Neoplasms; Gene Expression Regulation, Neoplastic; Diethylnitrosamine; Liver Neoplasms, Experimental
PubMed: 38920644
DOI: 10.3390/cells13121013 -
Cells Jun 2024Non-coding RNAs (ncRNAs) have emerged as pivotal regulators in cellular biology, dispelling their former perception as 'junk transcripts'. Notably, the DLK1-DIO3 region...
Non-coding RNAs (ncRNAs) have emerged as pivotal regulators in cellular biology, dispelling their former perception as 'junk transcripts'. Notably, the DLK1-DIO3 region harbors numerous ncRNAs, including long non-coding RNAs (lncRNAs) and over 50 microRNA genes. While papillary thyroid cancer showcases a pervasive decrease in DLK1-DIO3-derived ncRNA expression, the precise mechanisms driving this alteration remain elusive. We hypothesized that epigenetic alterations underlie shifts in ncRNA expression during thyroid cancer initiation and progression. This study aimed to elucidate the epigenetic mechanisms governing DLK1-DIO3 region expression in this malignancy. We have combined the analysis of DNA methylation by bisulfite sequencing together with that of histone modifications through ChIP-qPCR to gain insights into the epigenetic contribution to thyroid cancer in cell lines representing malignancies with different genetic backgrounds. Our findings characterize the region's epigenetic signature in thyroid cancer, uncovering distinctive DNA methylation patterns, particularly within CpG islands on the lncRNA MEG3-DMR, which potentially account for its downregulation in tumors. Pharmacological intervention targeting DNA methylation combined with histone deacetylation restored ncRNA expression. These results contribute to the understanding of the epigenetic mechanisms controlling the DLK1-DIO3 region in thyroid cancer, highlighting the combined role of DNA methylation and histone marks in regulating the locus' expression.
Topics: Humans; Epigenesis, Genetic; DNA Methylation; Thyroid Neoplasms; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Calcium-Binding Proteins; Iodide Peroxidase; RNA, Long Noncoding; CpG Islands; Intercellular Signaling Peptides and Proteins; Histones; Membrane Proteins
PubMed: 38920632
DOI: 10.3390/cells13121001 -
Organic & Biomolecular Chemistry Jun 2024Peptide nucleic acid (PNA) is a prominent artificial nucleic acid mimetic and modifications at the γ-position of the peptidic backbone are known to further enhance the...
Peptide nucleic acid (PNA) is a prominent artificial nucleic acid mimetic and modifications at the γ-position of the peptidic backbone are known to further enhance the desirable properties of PNA in terms of duplex stability. Here, we leveraged a propargyl ether modification at this position for late stage functionalization of PNA to obtain positively charged (cationic amino and guanidinium groups), negatively charged (anionic carboxylate and alkyl phosphonate groups) and neutral (PEG) PNAs to assess the impact of these charges on DNA : PNA and PNA : PNA duplex formation. Thermal stability analysis findings concurred with prior studies showing PNA : DNA duplexes are moderately more stable with cationic PNAs than anionic PNAs at physiological salt concentrations. We show that this effect is derived predominantly from differences in the association kinetics. For PNA : PNA duplexes, anionic PNAs were found to form the most stable duplexes, more stable than neutral PNA : PNA duplexes.
PubMed: 38920402
DOI: 10.1039/d4ob00887a -
Neuro-oncology Jun 2024Outcome of children with medulloblastoma (MB) and Fanconi Anemia (FA), an inherited DNA repair deficiency, has not been described systematically. Treatment is...
BACKGROUND
Outcome of children with medulloblastoma (MB) and Fanconi Anemia (FA), an inherited DNA repair deficiency, has not been described systematically. Treatment is complicated by high vulnerability to treatment-associated side effects, yet structured data are lacking. This study aims at giving a comprehensive overview about clinical and molecular characteristics of pediatric FA MB patients.
METHODS
Clinical data including detailed information on treatment and toxicities of six previously unreported FA MB patients were supplemented with data of 16 published cases.
RESULTS
We identified 22 cases of children with FA and MB with clinical data available. All MBs with subgroup reporting were SHH-activated (n=9), confirmed by methylation profiling in five patients. FA MB patients exclusively belonged to complementation groups FA-D1 (n=16) or FA-N (n=3). Patients were treated with postoperative chemotherapy only (50%) or radiotherapy (RT)±chemotherapy (27%). 23% did not receive adjuvant therapy. Excessive treatment-related toxicities were frequent. Severe hematological toxicity occurred in 91% of patients treated with alkylating chemotherapy, while non-alkylating agents and RT were less toxic. Median overall survival (OS) was 1 year (95%CI 0.3-1.8). 1-year-progression-free-survival (PFS) was 26.3±10.1% and 1-year-OS was 42.1±11.3%. Adjuvant therapy prolonged survival (1y-OS/1y-PFS 0%/0% without adjuvant therapy vs. 53.3±12.9%/33.3±12.2% with adjuvant therapy, p=0.006/p=0.086).
CONCLUSIONS
MB in FA patients is strongly associated with SHH activation and FA-D1/FA-N. Despite the dismal prognosis, adjuvant therapy may prolong survival. Non-alkylating chemotherapy and RT are feasible in selected patients with careful monitoring of toxicities and dose adjustments. Curative therapy for FA MB-SHH remains an unmet medical need.
PubMed: 38919026
DOI: 10.1093/neuonc/noae111 -
Scientific Reports Jun 2024The benefits of breastfeeding for the health and wellbeing of both infants and mothers are well documented, yet global breastfeeding rates are low. One factor associated...
The benefits of breastfeeding for the health and wellbeing of both infants and mothers are well documented, yet global breastfeeding rates are low. One factor associated with low breast feeding is maternal body mass index (BMI), which is used as a measure of obesity. The negative relationship between maternal obesity and breastfeeding is likely caused by a variety of social, psychological, and physiological factors. Maternal obesity may also have a direct biological association with breastfeeding through changes in maternal DNA methylation. Here, we investigate this potential biological association using data from a UK-based cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). We find that pre-pregnancy body mass index (BMI) is associated with lower initiation to breastfeed and shorter breastfeeding duration. We conduct epigenome-wide association studies (EWAS) of pre-pregnancy BMI and breastfeeding outcomes, and run candidate-gene analysis of methylation sites associated with BMI identified via previous meta-EWAS. We find that DNA methylation at cg11453712, annotated to PHTP1, is associated with pre-pregnancy BMI. From our results, neither this association nor those at candidate-gene sites are likely to mediate the link between pre-pregnancy BMI and breastfeeding.
Topics: Humans; DNA Methylation; Breast Feeding; Body Mass Index; Female; Pregnancy; Adult; Longitudinal Studies; Genome-Wide Association Study; United Kingdom; Obesity; Epigenesis, Genetic
PubMed: 38918574
DOI: 10.1038/s41598-024-65605-0 -
Scientific Reports Jun 2024PTBP1 is an oncogene that regulates the splicing of precursor mRNA. However, the relationship between PTBP1 expression and gene methylation, cancer prognosis, and tumor...
PTBP1 is an oncogene that regulates the splicing of precursor mRNA. However, the relationship between PTBP1 expression and gene methylation, cancer prognosis, and tumor microenvironment remains unclear. The expression profiles of PTBP1 across various cancers were derived from the TCGA, as well as the GTEx and CGGA databases. The CGGA mRNA_325, CGGA mRNA_301, and CGGA mRNA_693 datasets were utilized as validation cohorts. Immune cell infiltration scores were approximated using the TIMER 2.0 tool. Functional enrichment analysis for groups with high and low PTBP1 expression was conducted using Gene Set Enrichment Analysis (GSEA). Methylation data were predominantly sourced from the SMART and Mexpress databases. Linked-omics analysis was employed to perform functional enrichment analysis of genes related to PTBP1 methylation, as well as to conduct protein functional enrichment analysis. Single-cell transcriptome analysis and spatial transcriptome analysis were carried out using Seurat version 4.10. Compared to normal tissues, PTBP1 is significantly overexpressed and hypomethylated in various cancers. It is implicated in prognosis, immune cell infiltration, immune checkpoint expression, genomic variation, tumor neoantigen load, and tumor mutational burden across a spectrum of cancers, with particularly notable effects in low-grade gliomas. In the context of gliomas, PTBP1 expression correlates with WHO grade and IDH1 mutation status. PTBP1 expression and methylation play an important role in a variety of cancers. PTBP1 can be used as a marker of inflammation, progression and prognosis in gliomas.
Topics: Humans; Polypyrimidine Tract-Binding Protein; Heterogeneous-Nuclear Ribonucleoproteins; Prognosis; Biomarkers, Tumor; Glioma; Gene Expression Regulation, Neoplastic; Tumor Microenvironment; DNA Methylation; Gene Expression Profiling; Inflammation; Transcriptome; Brain Neoplasms; Disease Progression; Multiomics
PubMed: 38918441
DOI: 10.1038/s41598-024-64979-5 -
Scientific Reports Jun 2024Type 2 diabetes (T2D) is the fastest growing non-infectious disease worldwide. Impaired insulin secretion from pancreatic beta-cells is a hallmark of T2D, but the...
Type 2 diabetes (T2D) is the fastest growing non-infectious disease worldwide. Impaired insulin secretion from pancreatic beta-cells is a hallmark of T2D, but the mechanisms behind this defect are insufficiently characterized. Integrating multiple layers of biomedical information, such as different Omics, may allow more accurate understanding of complex diseases such as T2D. Our aim was to explore and use Machine Learning to integrate multiple sources of biological/molecular information (multiOmics), in our case RNA-sequening, DNA methylation, SNP and phenotypic data from islet donors with T2D and non-diabetic controls. We exploited Machine Learning to perform multiOmics integration of DNA methylation, expression, SNPs, and phenotypes from pancreatic islets of 110 individuals, with ~ 30% being T2D cases. DNA methylation was analyzed using Infinium MethylationEPIC array, expression was analyzed using RNA-sequencing, and SNPs were analyzed using HumanOmniExpress arrays. Supervised linear multiOmics integration via DIABLO based on Partial Least Squares (PLS) achieved an accuracy of 91 ± 15% of T2D prediction with an area under the curve of 0.96 ± 0.08 on the test dataset after cross-validation. Biomarkers identified by this multiOmics integration, including SACS and TXNIP DNA methylation, OPRD1 and RHOT1 expression and a SNP annotated to ANO1, provide novel insights into the interplay between different biological mechanisms contributing to T2D. This Machine Learning approach of multiOmics cross-sectional data from human pancreatic islets achieved a promising accuracy of T2D prediction, which may potentially find broad applications in clinical diagnostics. In addition, it delivered novel candidate biomarkers for T2D and links between them across the different Omics.
Topics: Humans; Diabetes Mellitus, Type 2; Machine Learning; DNA Methylation; Islets of Langerhans; Polymorphism, Single Nucleotide; Male; Female; Middle Aged; Biomarkers; Adult; Aged
PubMed: 38918439
DOI: 10.1038/s41598-024-64846-3 -
Database : the Journal of Biological... Jun 2024Major depressive disorder (MDD) is a pressing global health issue. Its pathogenesis remains elusive, but numerous studies have revealed its intricate associations with...
Major depressive disorder (MDD) is a pressing global health issue. Its pathogenesis remains elusive, but numerous studies have revealed its intricate associations with various biological factors. Consequently, there is an urgent need for a comprehensive multi-omics resource to help researchers in conducting multi-omics data analysis for MDD. To address this issue, we constructed the MDDOmics database (Major Depressive Disorder Omics, (https://www.csuligroup.com/MDDOmics/), which integrates an extensive collection of published multi-omics data related to MDD. The database contains 41 222 entries of MDD research results and several original datasets, including Single Nucleotide Polymorphisms, genes, non-coding RNAs, DNA methylations, metabolites and proteins, and offers various interfaces for searching and visualization. We also provide extensive downstream analyses of the collected MDD data, including differential analysis, enrichment analysis and disease-gene prediction. Moreover, the database also incorporates multi-omics data for bipolar disorder, schizophrenia and anxiety disorder, due to the challenge in differentiating MDD from similar psychiatric disorders. In conclusion, by leveraging the rich content and online interfaces from MDDOmics, researchers can conduct more comprehensive analyses of MDD and its similar disorders from various perspectives, thereby gaining a deeper understanding of potential MDD biomarkers and intricate disease pathogenesis. Database URL: https://www.csuligroup.com/MDDOmics/.
Topics: Depressive Disorder, Major; Humans; Databases, Genetic; Polymorphism, Single Nucleotide; Genomics; DNA Methylation; Multiomics
PubMed: 38917209
DOI: 10.1093/database/baae042 -
Journal of Molecular Histology Jun 2024Chemical carcinogen-induced oxidative stress has a key role in cell signaling linked to the development of cancer. Oxidative stress leads to oxidative damage to cellular...
Chemical carcinogen-induced oxidative stress has a key role in cell signaling linked to the development of cancer. Oxidative stress leads to oxidative damage to cellular membranes, proteins, chromosomes and genetic material. It is thought that compounds like hesperidin with high antioxidant and anticancer potential can reduce development of cancer induced by chemical carcinogens via neutralizing their oxidative damages. We investigated protective effect of hesperidin against N-Ethyl-N-Nitrosourea (ENU)-induced neurotoxicity, congenital abnormalities and possible brain cancer after exposure of mice during pregnancy as model of glioma. The mice were divided to four groups; control (normal saline), ENU (40 mg/kg daily for three consecutive days from the 17th to the 19th of pregnancy), hesperidin (pretreated with 25 mg/kg for 30 consecutive days, before mating) + ENU and hesperidin alone. Developmental toxicity parameters (the number of pregnant mice, stillbirths, abortion, live and dead offspring), behavioral tests (novel object recognition, open field and elevated plus maze) were performed. Moreover, the activity of butrylcholinesterase and acetylcholinesterase enzymes, oxidative markers and histopathological abnormalities were detected in brain tissue. Our data showed that conversely, the pretreatment of hesperidin reduces various degrees of developmental toxicity, neurobehavioral dysfunction, neurotoxicity, oxidative stress and histopathological abnormalities induced by ENU as a neurotoxic and carcinogenic agent in the next generation. In conclusion, pre-mating exposure with hesperidin may open new avenues for prevention of primary brain cancer in next generation and could be valuable for enhancing the antioxidant defense and minimizing the developmental and neurotoxicity of DNA alkylating agents.
PubMed: 38916842
DOI: 10.1007/s10735-024-10218-0 -
Frontiers in Immunology 2024The innate immune system of insects can respond more swiftly and efficiently to pathogens based on previous experience of encountering antigens. The understanding of... (Review)
Review
The innate immune system of insects can respond more swiftly and efficiently to pathogens based on previous experience of encountering antigens. The understanding of molecular mechanisms governing immune priming, a form of immune memory in insects, including its transgenerational inheritance, remains elusive. It is still unclear if the enhanced expression of immune genes observed in primed insects can persist and be regulated through changes in chromatin structure via epigenetic modifications of DNA or histones, mirroring observations in mammals. Increasing experimental evidence suggests that epigenetic changes at the level of DNA/RNA methylation and histone acetylation can modulate the activation of insects' immune responses to pathogen exposure. Moreover, transgenerational inheritance of certain epigenetic modifications in model insect hosts can influence the transmission of pre-programmed immune responses to the offspring, leading to the development of evolved resistance. Epigenetic research in model insect hosts is on the brink of significant progress in the mechanistic understanding of chromatin remodeling within innate immunity, particularly the direct relationships between immunological priming and epigenetic alterations. In this review, we discuss the latest discoveries concerning the involvement of DNA methylation and histone acetylation in shaping the development, maintenance, and inheritance of immune memory in insects, culminating in the evolution of resistance against pathogens.
Topics: Animals; Epigenesis, Genetic; Immunologic Memory; Insecta; DNA Methylation; Histones; Immunity, Innate; Chromatin Assembly and Disassembly; Acetylation
PubMed: 38915407
DOI: 10.3389/fimmu.2024.1397521