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Rajesh V, Karthi S, Kumudhavalli MV. Protective Effect of myo-Inositol Against Decitabine-Induced Neural Tube Defects in Embryonic Zebrafish. Neurotox Res 2025; 43:14. [PMID: 40100479 DOI: 10.1007/s12640-025-00735-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 03/05/2025] [Accepted: 03/08/2025] [Indexed: 03/20/2025]
Abstract
Neural tube defects (NTDs) are severe congenital anomalies affecting 1-2 infants per 1000 births, and are influenced by genetic and environmental factors, with DNA hypomethylation and methylation cycle suppression being key causes. In our earlier investigation, decitabine (DCT) caused multiple NTDs in embryonic zebrafish, supporting this hypothesis. Recent research has emphasized the importance of myo-inositol (MI) in embryonic development and its efficacy in reducing the risk of neural tube defects, even in cases resistant to folate. We aimed to examine the effect of MI on DCT-induced NTDs in an embryonic zebrafish model. The embryos were exposed to 1 mM DCT alone, 50 µM MI with 1 mM DCT, 100 µM MI with 1 mM DCT, and a control group for comparison. The development, hatching, mortality rates, neural tube malformations, and neural tube patterning of developing embryos were monitored and recorded. Exposure to MI significantly reduced the incidence of NTDs in developing embryos. At concentrations of 50 µM and 100 µM, MI provided 35% and 30% protection against DCT-induced neural tube malformation, respectively. Multiple NTDs were significantly reduced in the MI groups, with 1 mM DCT causing 95% defects, 50 µM MI with 1 mM DCT causing 50%, and 100 µM MI with 1 mM DCT causing 55% defects. The DCT-induced hatching delay was also reversed by MI treatment. Alizarin red staining and histopathological observations supported these observations. In the context of neural tube development, the protective effects of MI against DCT-induced NTDs could be attributed to its potential role in epigenetic regulation, which may influence genetic expression.
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Affiliation(s)
- Venugopalan Rajesh
- Department of Pharmacology, The Erode College of Pharmacy and Research Institute Affiliated with The Tamil Nadu Dr. M.G.R. Medical University, Veppampalayam, Vallipurathanpalayam (Po), Erode, Tamilnadu, 638112, India.
| | - Subramani Karthi
- Department of Pharmacology, The Erode College of Pharmacy and Research Institute Affiliated with The Tamil Nadu Dr. M.G.R. Medical University, Veppampalayam, Vallipurathanpalayam (Po), Erode, Tamilnadu, 638112, India
| | - Manni Venkatachari Kumudhavalli
- Department of Pharmaceutical Chemistry, Vinayaka Mission's College of Pharmacy Affiliated with Vinayaka Mission Research Foundation (Deemed University, Salem), Kondappanaickenpatti, Yercaud Main Road, Salem, Tamilnadu, 636008, India
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Shi B, Li K, Xu R, Zhang F, Yu Z, Ding Z, Tian H. Methionine-mediated trade-off between plant growth and salt tolerance. PLANT PHYSIOLOGY 2025; 197:kiaf074. [PMID: 40048622 DOI: 10.1093/plphys/kiaf074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 01/18/2025] [Indexed: 03/12/2025]
Abstract
Salt stress is an important environmental factor that limits plant growth and development. A better understanding of the molecular mechanisms underlying plant salt tolerance will help improve plant performance and crop production under saline conditions. Here, we found that the amino acid methionine significantly improves plant salt tolerance. The salinity-induced activation of key genes governing methionine biosynthesis, namely Hcy-S-methyltransferases (HMTs) and methionine synthases (MSs), is controlled by the concerted interplay of abscisic acid (ABA) and reactive oxygen species signaling. This orchestrated gene activation subsequently leads to methionine accumulation, activating ABA signaling and improving plant salt tolerance. Beyond its role in modulating ABA signaling, methionine affects root growth dynamics by suppressing auxin and cytokinin signaling and impeding cell cycle progression. These multiple effects on growth-related signaling pathways lead to an effective redistribution of energy resources to improve the plant's ability to combat salt-induced stress. Our findings underscore methionine's pivotal involvement in enhancing plant adaptation to salinity stress by establishing a delicate balance between growth and salt tolerance. This mechanistic understanding sheds light on a compelling way to increase crop yields in saline soils and provides a strategic framework for sustainable agricultural practices in challenging environments.
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Affiliation(s)
- Benhui Shi
- School of Life Sciences, Shandong University, Qingdao 266237, PR China
- The Key Laboratory of Plant Development and Environmental Adaptation Biology, Ministry of Education, Shandong University, Qingdao 266237, PR China
- Shandong Key Laboratory of Precision Molecular Crop Design and Breeding, School of Life Sciences, Shandong University, Qingdao 266237, China
| | - Ke Li
- Shandong Academy of Grape, Shandong Academy of Agricultural Sciences, Jinan 250100, PR China
| | - Rui Xu
- Shandong Academy of Grape, Shandong Academy of Agricultural Sciences, Jinan 250100, PR China
- College of Life Science, State Key Laboratory of Crop Biology, Shandong Agricultural University, Taian 271018, Shandong, PR China
| | - Feng Zhang
- School of Life Sciences, Shandong University, Qingdao 266237, PR China
- The Key Laboratory of Plant Development and Environmental Adaptation Biology, Ministry of Education, Shandong University, Qingdao 266237, PR China
- Shandong Key Laboratory of Precision Molecular Crop Design and Breeding, School of Life Sciences, Shandong University, Qingdao 266237, China
| | - Zipeng Yu
- School of Life Sciences, Shandong University, Qingdao 266237, PR China
- The Key Laboratory of Plant Development and Environmental Adaptation Biology, Ministry of Education, Shandong University, Qingdao 266237, PR China
- Shandong Key Laboratory of Precision Molecular Crop Design and Breeding, School of Life Sciences, Shandong University, Qingdao 266237, China
| | - Zhaojun Ding
- School of Life Sciences, Shandong University, Qingdao 266237, PR China
- The Key Laboratory of Plant Development and Environmental Adaptation Biology, Ministry of Education, Shandong University, Qingdao 266237, PR China
- Shandong Key Laboratory of Precision Molecular Crop Design and Breeding, School of Life Sciences, Shandong University, Qingdao 266237, China
| | - Huiyu Tian
- School of Life Sciences, Shandong University, Qingdao 266237, PR China
- The Key Laboratory of Plant Development and Environmental Adaptation Biology, Ministry of Education, Shandong University, Qingdao 266237, PR China
- Shandong Key Laboratory of Precision Molecular Crop Design and Breeding, School of Life Sciences, Shandong University, Qingdao 266237, China
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Fryar-Williams S, Tucker G, Clements P, Strobel J. Gene Variant Related Neurological and Molecular Biomarkers Predict Psychosis Progression, with Potential for Monitoring and Prevention. Int J Mol Sci 2024; 25:13348. [PMID: 39769114 PMCID: PMC11677369 DOI: 10.3390/ijms252413348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/14/2024] [Accepted: 11/17/2024] [Indexed: 01/11/2025] Open
Abstract
The (MTHFR) C677T gene polymorphism is associated with neurological disorders and schizophrenia. Patients diagnosed with schizophrenia and schizoaffective disorder and controls (n 134) had data collected for risk factors, molecular and neuro-sensory variables, symptoms, and functional outcomes. Promising gene variant-related predictive biomarkers were identified for diagnosis by Receiver Operating Characteristics and for illness duration by linear regression. These were then analyzed using Spearman's correlation in relation to the duration of illness. Significant correlations were ranked by strength and plotted on graphs for each MTHFR C677T variant. Homozygous MTHFR 677 TT carriers displayed a mid-illness switch to depression, with suicidality and a late-phase shift from lower to higher methylation, with activated psychosis symptoms. MTHFR 677 CC variant carriers displayed significant premorbid correlates for family history, developmental disorder, learning disorder, and head injury. These findings align with those of low methylation, oxidative stress, multiple neuro-sensory processing deficits, and disability outcomes. Heterozygous MTHFR 677 CT carriers displayed multiple shifts in mood and methylation with multiple adverse outcomes. The graphically presented ranked biomarker correlates for illness duration allow a perspective of psychosis development across gene variants, with the potential for phase of illness monitoring and new therapeutic insights to prevent or delay psychosis and its adverse outcomes.
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Affiliation(s)
- Stephanie Fryar-Williams
- Youth in Mind Research Institute, Unley, SA 5061, Australia
- Department of Medical Specialities, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia
| | - Graeme Tucker
- Department of Public Health, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia
| | - Peter Clements
- Department of Paediatrics, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia
| | - Jörg Strobel
- Department of Psychiatry, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia
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Dević Pavlić S, Šverko R, Barišić A, Mladenić T, Vraneković J, Stanković A, Peterlin A, Peterlin B, Ostojić S, Pereza N. MTHFR Gene Polymorphisms and DNA Methylation in Idiopathic Spontaneous Preterm Birth. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:2028. [PMID: 39768908 PMCID: PMC11728409 DOI: 10.3390/medicina60122028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/26/2024] [Accepted: 12/06/2024] [Indexed: 01/16/2025]
Abstract
Background and Objectives: Preterm birth (PTB) is a complex condition with various contributing factors, including genetic and epigenetic influences such as DNA methylation. Methylenetetrahydrofolate reductase (MTHFR) plays a critical role in DNA methylation and the remethylation of homocysteine. This study aimed to investigate the association between maternal MTHFR C677T and A1298C polymorphisms, LINE-1 DNA methylation levels, and the risk of idiopathic spontaneous preterm birth (SPTB) in Caucasian women from Croatia and Slovenia. Materials and Methods: A total of 50 women with SPTB (<34 weeks of gestation) and 50 control women were included in the study. MTHFR polymorphisms were analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), and LINE-1 DNA methylation levels were quantified using the MethyLight method. Results: The study found no significant differences in MTHFR C677T and A1298C polymorphisms' genotype or allele frequencies between women with SPTB and controls. Additionally, no statistical significance of LINE-1 DNA methylation was found between the genotypes of the MTHFR polymorphisms analyzed. Conclusions: The study suggests no conclusive association between MTHFR C677T and A1298C polymorphisms, LINE-1 DNA methylation, and SPTB in Croatian and Slovenian women. Considering prior evidence connecting MTHFR polymorphisms, hyperhomocysteinemia, and PTB, the lack of homocysteine measurements and unassessed impact of folate or vitamin B supplementation limit the conclusions.
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Affiliation(s)
- Sanja Dević Pavlić
- Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia; (T.M.); (J.V.); (S.O.); (N.P.)
| | - Roberta Šverko
- Department of Internal medicine, University Hospital Rijeka, 51000 Rijeka, Croatia;
| | - Anita Barišić
- Department of Gynecology and Obstetrics, University Hospital Rijeka, 51000 Rijeka, Croatia;
| | - Tea Mladenić
- Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia; (T.M.); (J.V.); (S.O.); (N.P.)
| | - Jadranka Vraneković
- Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia; (T.M.); (J.V.); (S.O.); (N.P.)
| | - Aleksandra Stanković
- Department for Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11351 Belgrade, Serbia;
| | - Ana Peterlin
- Institute of Histology and Embryology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia;
| | - Borut Peterlin
- Clinical Institute of Medical Genetics, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia;
| | - Saša Ostojić
- Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia; (T.M.); (J.V.); (S.O.); (N.P.)
| | - Nina Pereza
- Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia; (T.M.); (J.V.); (S.O.); (N.P.)
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He W, Zhang Y, Chen X, Dou Y, He Y, Yan W. Dietary folic acid intake, 13 genetic variants and other factors with red blood cell folate concentration in pregnancy-preparing population. Eur J Nutr 2024; 63:2921-2931. [PMID: 39153125 PMCID: PMC11519176 DOI: 10.1007/s00394-024-03474-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 07/22/2024] [Indexed: 08/19/2024]
Abstract
PURPOSE This study aims to evaluate a combined effect of dietary folic acid intake, multiple genetic polymorphisms in folate metabolism, and other environmental factors on red blood cell (RBC) folate concentration in pregnancy-preparing population. METHODS 519 pregnancy-preparing subjects (260 couples) were investigated. Dietary intake was measured by 3-day dietary recalls. 13 Single Nucleotide polymorphisms (SNPs) reported in association with one-carbon metabolism including the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C were genotyped. RBC folate concentration was measured using chemiluminescence assay. Hierarchical regression was applied for covariate selection. Factors showed significance(p < 0.0125) on RBC folate level was included for prediction model construction and R2 estimation. Validation cohort analysis was performed as post-hoc analysis if applicable. RESULTS The median RBC folate was 212.8 ng/ml. Only 10% took folic acid supplementation within three months. Based on hierarchical selection, folic acid supplementation, genetic polymorphism (especially TT genotype of MTHFR C677T), serum folate level were determinants of the variance of RBC folate concentrations, with adjusted R2 of 0.178-0.242. MTHFR A1298C polymorphism, sex difference with other socio-demographic and lifestyle factors (age, BMI, alcohol drinking, smoking, education, occupation) explained little to change in RBC folate level. Validation in another sub-cohort(n = 8105) had adjusted R2 of 0.273. CONCLUSION In pregnancy-preparing subjects, folic acid supplementation, serum folate level and TT allele of MTHFR C677T polymorphism were determinants of the total variance of RBC folate level, which explained 19.8% variance in our subjects and 27.3% in the validation cohort. Food folate intake, sex and other environmental factors explained little to RBC folate level.
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Affiliation(s)
- Wennan He
- Department of Clinical Epidemiology & Clinical Trial Unit (CTU), Children's Hospital of Fudan University, National Children's Medical Center, 399 Wanyuan Road, Shanghai, 201102, P.R. China
- Research Unit of Early Intervention of Genetically Related Childhood Cardiovascular Diseases (2018RU002), Chinese Academy of Medical Sciences, Shanghai, P.R. China
| | - Yi Zhang
- Department of Clinical Epidemiology & Clinical Trial Unit (CTU), Children's Hospital of Fudan University, National Children's Medical Center, 399 Wanyuan Road, Shanghai, 201102, P.R. China
- Research Unit of Early Intervention of Genetically Related Childhood Cardiovascular Diseases (2018RU002), Chinese Academy of Medical Sciences, Shanghai, P.R. China
| | - Xiaotian Chen
- Department of Clinical Epidemiology & Clinical Trial Unit (CTU), Children's Hospital of Fudan University, National Children's Medical Center, 399 Wanyuan Road, Shanghai, 201102, P.R. China
- Research Unit of Early Intervention of Genetically Related Childhood Cardiovascular Diseases (2018RU002), Chinese Academy of Medical Sciences, Shanghai, P.R. China
| | - Yalan Dou
- Department of Clinical Epidemiology & Clinical Trial Unit (CTU), Children's Hospital of Fudan University, National Children's Medical Center, 399 Wanyuan Road, Shanghai, 201102, P.R. China
- Research Unit of Early Intervention of Genetically Related Childhood Cardiovascular Diseases (2018RU002), Chinese Academy of Medical Sciences, Shanghai, P.R. China
| | - Yuanchen He
- Department of Clinical Epidemiology & Clinical Trial Unit (CTU), Children's Hospital of Fudan University, National Children's Medical Center, 399 Wanyuan Road, Shanghai, 201102, P.R. China
- Research Unit of Early Intervention of Genetically Related Childhood Cardiovascular Diseases (2018RU002), Chinese Academy of Medical Sciences, Shanghai, P.R. China
| | - Weili Yan
- Department of Clinical Epidemiology & Clinical Trial Unit (CTU), Children's Hospital of Fudan University, National Children's Medical Center, 399 Wanyuan Road, Shanghai, 201102, P.R. China.
- Research Unit of Early Intervention of Genetically Related Childhood Cardiovascular Diseases (2018RU002), Chinese Academy of Medical Sciences, Shanghai, P.R. China.
- Shanghai Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai, P.R. China.
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Stoccoro A, Lari M, Migliore L, Coppedè F. Associations between Circulating Biomarkers of One-Carbon Metabolism and Mitochondrial D-Loop Region Methylation Levels. EPIGENOMES 2024; 8:38. [PMID: 39449362 PMCID: PMC11503383 DOI: 10.3390/epigenomes8040038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/30/2024] [Accepted: 10/07/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND/OBJECTIVES One-carbon metabolism is a critical pathway for epigenetic mechanisms. Circulating biomarkers of one-carbon metabolism have been associated with changes in nuclear DNA methylation levels in individuals affected by age-related diseases. More and more studies are showing that even mitochondrial DNA (mtDNA) could be methylated. In particular, methylation of the mitochondrial displacement (D-loop) region modulates the gene expression and replication of mtDNA and, when altered, can contribute to the development of human illnesses. However, no study until now has demonstrated an association between circulating biomarkers of one-carbon metabolism and D-loop methylation levels. METHODS In the study presented herein, we searched for associations between circulating one-carbon metabolism biomarkers, including folate, homocysteine, and vitamin B12, and the methylation levels of the D-loop region in DNA obtained from the peripheral blood of 94 elderly voluntary subjects. RESULTS We observed a positive correlation between D-loop methylation and vitamin B12 (r = 0.21; p = 0.03), while no significant correlation was observed with folate (r = 0.02; p = 0.80) or homocysteine levels (r = 0.02; p = 0.82). Moreover, D-loop methylation was increased in individuals with high vitamin B12 levels compared to those with normal vitamin B12 levels (p = 0.04). CONCLUSIONS This is the first study suggesting an association between vitamin B12 circulating levels and mtDNA methylation in human subjects. Given the potential implications of altered one-carbon metabolism and mitochondrial epigenetics in human diseases, a deeper understanding of their interaction could inspire novel interventions with beneficial effects for human health.
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Affiliation(s)
- Andrea Stoccoro
- Department of Translational Research and of New Surgical & Medical Technologies, Medical School, University of Pisa, 56126 Pisa, Italy; (A.S.); (M.L.); (L.M.)
| | - Martina Lari
- Department of Translational Research and of New Surgical & Medical Technologies, Medical School, University of Pisa, 56126 Pisa, Italy; (A.S.); (M.L.); (L.M.)
| | - Lucia Migliore
- Department of Translational Research and of New Surgical & Medical Technologies, Medical School, University of Pisa, 56126 Pisa, Italy; (A.S.); (M.L.); (L.M.)
| | - Fabio Coppedè
- Department of Translational Research and of New Surgical & Medical Technologies, Medical School, University of Pisa, 56126 Pisa, Italy; (A.S.); (M.L.); (L.M.)
- Interdepartmental Research Center of Biology and Pathology of Aging, University of Pisa, 56126 Pisa, Italy
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Huang F, He Y. Epigenetic control of gene expression by cellular metabolisms in plants. CURRENT OPINION IN PLANT BIOLOGY 2024; 81:102572. [PMID: 38875845 DOI: 10.1016/j.pbi.2024.102572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 05/09/2024] [Accepted: 05/22/2024] [Indexed: 06/16/2024]
Abstract
Covalent modifications on DNA and histones can regulate eukaryotic gene expression and are often referred to as epigenetic modifications. These chemical reactions require various metabolites as donors or co-substrates, such as acetyl coenzyme A, S-adenosyl-l-methionine, and α-ketoglutarate. Metabolic processes that take place in the cytoplasm, nucleus, or other cellular compartments may impact epigenetic modifications in the nucleus. Here, we review recent advances on metabolic control of chromatin modifications and thus gene expression in plants, with a focus on the functions of nuclear compartmentalization of metabolic processes and enzymes in DNA and histone modifications. Furthermore, we discuss the functions of cellular metabolisms in fine-tuning gene expression to facilitate the responses or adaptation to environmental changes in plants.
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Affiliation(s)
- Fei Huang
- Peking-Tsinghua Center for Life Sciences & National Key Laboratory of Wheat Improvement, School of Advanced Agricultural Sciences, Peking University, Beijing 100871, China
| | - Yuehui He
- Peking-Tsinghua Center for Life Sciences & National Key Laboratory of Wheat Improvement, School of Advanced Agricultural Sciences, Peking University, Beijing 100871, China; Peking University Institute of Advanced Agricultural Sciences, Shandong Laboratory of Advanced Agricultural Sciences in Weifang, Shandong 261325, China.
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Guimarães JR, de Souza BF, Filho JMCV, Damascena LCL, Valença AMG, Persuhn DC, de Oliveira NFP. Epigenetic mechanisms and oral mucositis in children with acute lymphoblastic leukaemia. Eur J Oral Sci 2024; 132:e13009. [PMID: 39075736 DOI: 10.1111/eos.13009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 07/12/2024] [Indexed: 07/31/2024]
Abstract
This study aimed to investigate the relationship between epigenetic mechanisms and oral mucositis (OM) in paediatric patients with acute lymphoblastic leukaemia. Oral cells were collected from 76 participants, including 15 healthy individuals, 10 patients with acute lymphoblastic leukaemia but without a history of OM and 51 acute lymphoblastic leukaemia patients with a history of OM (35 with active OM and 16 who had recovered from OM). Global DNA methylation in the miR-9-1 and miR-9-3 genes was performed. Seven polymorphisms rs1801131, rs1801133 (MTHFR), rs2228611 (DNMT1), rs7590760, rs1550117 (DNMT3A), rs6087990, rs2424913 (DNMT3B) were genotyped and an analysis of association with global DNA methylation was performed. The global methylation levels were lower in cancer patients recovered from OM than in the other groups. A higher frequency of unmethylated profile for miR-9-1 and partially methylated profile for miR-9-3 was observed in cancer patients regardless of OM history compared to healthy patients. The GG genotype of the rs2228611 (DNMT1) polymorphism was associated with higher levels of global methylation in cancer patients irrespective of OM. It was concluded that global methylation is associated with mucosal recovery. The effect of DNMT1 genotype on the global DNA methylation profile, as well as the methylation profile of miR-9-1 and miR-9-3 in cancer patients is independent of OM.
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Affiliation(s)
- Juliana Ramalho Guimarães
- Postgraduate Program in Dentistry, Health Sciences Center, Federal University of Paraíba, - UFPB, João Pessoa, Paraíba, Brazil
| | - Beatriz Fernandes de Souza
- Postgraduate Program in Dentistry, Health Sciences Center, Federal University of Paraíba, - UFPB, João Pessoa, Paraíba, Brazil
| | | | - Lecidamia Cristina Leite Damascena
- Postgraduate Program in Decision Models and Health, Center for Exact and Natural Sciences, Federal University of Paraíba, João Pessoa, Paraíba, Brazil
| | - Ana Maria Gondim Valença
- Postgraduate Program in Decision Models and Health, Center for Exact and Natural Sciences, Federal University of Paraíba, João Pessoa, Paraíba, Brazil
| | - Darlene Camati Persuhn
- Department of Molecular Biology, Center for Exact and Natural Sciences, Federal University of Paraíba, - UFPB, João Pessoa, Paraíba, Brazil
| | - Naila Francis Paulo de Oliveira
- Postgraduate Program in Dentistry, Health Sciences Center, Federal University of Paraíba, - UFPB, João Pessoa, Paraíba, Brazil
- Department of Molecular Biology, Center for Exact and Natural Sciences, Federal University of Paraíba, - UFPB, João Pessoa, Paraíba, Brazil
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Sobral AF, Cunha A, Silva V, Gil-Martins E, Silva R, Barbosa DJ. Unveiling the Therapeutic Potential of Folate-Dependent One-Carbon Metabolism in Cancer and Neurodegeneration. Int J Mol Sci 2024; 25:9339. [PMID: 39273288 PMCID: PMC11395277 DOI: 10.3390/ijms25179339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/21/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024] Open
Abstract
Cellular metabolism is crucial for various physiological processes, with folate-dependent one-carbon (1C) metabolism playing a pivotal role. Folate, a B vitamin, is a key cofactor in this pathway, supporting DNA synthesis, methylation processes, and antioxidant defenses. In dividing cells, folate facilitates nucleotide biosynthesis, ensuring genomic stability and preventing carcinogenesis. Additionally, in neurodevelopment, folate is essential for neural tube closure and central nervous system formation. Thus, dysregulation of folate metabolism can contribute to pathologies such as cancer, severe birth defects, and neurodegenerative diseases. Epidemiological evidence highlights folate's impact on disease risk and its potential as a therapeutic target. In cancer, antifolate drugs that inhibit key enzymes of folate-dependent 1C metabolism and strategies targeting folate receptors are current therapeutic options. However, folate's impact on cancer risk is complex, varying among cancer types and dietary contexts. In neurodegenerative conditions, including Alzheimer's and Parkinson's diseases, folate deficiency exacerbates cognitive decline through elevated homocysteine levels, contributing to neuronal damage. Clinical trials of folic acid supplementation show mixed outcomes, underscoring the complexities of its neuroprotective effects. This review integrates current knowledge on folate metabolism in cancer and neurodegeneration, exploring molecular mechanisms, clinical implications, and therapeutic strategies, which can provide crucial information for advancing treatments.
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Affiliation(s)
- Ana Filipa Sobral
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, University Institute of Health Sciences-CESPU, 4585-116 Gandra, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Toxicologic Pathology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal
| | - Andrea Cunha
- UNIPRO-Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences-CESPU, 4585-116 Gandra, Portugal
| | - Vera Silva
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Eva Gil-Martins
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Renata Silva
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Daniel José Barbosa
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, University Institute of Health Sciences-CESPU, 4585-116 Gandra, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal
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Wang G, Wu Y, Jing Z, Wen R, Song Y, Feng Y, Li G, Zou X, Huang G, Jia Z, Guo Y, Yang Z. Association of MTHFR gene polymorphisms with non-Hodgkin lymphoma risk: Evidence from 31 articles. J Cancer 2024; 15:5277-5287. [PMID: 39247589 PMCID: PMC11375544 DOI: 10.7150/jca.99351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 08/02/2024] [Indexed: 09/10/2024] Open
Abstract
Background: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms, particularly C677T and A1298C, have been implicated in various cancers, including non-Hodgkin lymphoma (NHL); however, their association with NHL risk remains inconclusive. Methods: We conducted an updated meta-analysis to assess the relationship between MTHFR gene polymorphisms (C677T and A1298C) and NHL risk. Relevant studies were identified through systematic literature searches in multiple databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Results: The meta-analysis included 32 studies (8222 cases vs. 12956 controls) for MTHFR C677T and 26 studies (6930 cases vs. 11611 controls) for the A1298C polymorphism. Our meta-analysis revealed no significant associations between MTHFR gene polymorphisms (C677T and A1298C) and NHL risk. However, subgroup analysis stratified by ethnicity and NHL subtype yielded interesting findings for the C677T polymorphism. Specifically, in the subgroup analysis of Caucasians, the C677T polymorphism was significantly associated with NHL risk (heterozygous: OR=1.16, 95% CI=1.02-1.32; allele comparison: OR=1.07, 95% CI=1.01-1.13). Furthermore, in the analysis stratified by NHL subtype, the C677T polymorphism was significantly associated with increased follicular lymphoma (FL) risk (homozygous: OR=1.25, 95% CI=1.02-1.53; recessive: OR=1.28, 95% CI=1.06-1.56). False-positive result possibility (FPRP) analysis verified that the association of the MTHFR C677T polymorphism with NHL risk for Caucasians and FL subtypes was a true positive and deserves attention. We also determined that the C677T polymorphism is an expression quantitative trait locus (eQTL) since it is associated with MTHFR gene expression. Conclusion: There was no overall association between MTHFR gene polymorphisms (C677T and A1298C) and NHL risk, but stratified analyses revealed significant associations in specific subgroups. While meta-analyses inherently build upon existing studies, our work distinguishes itself by incorporating recent data, applying rigorous analytical techniques, and providing more evidence of the MTHFR C677T polymorphism as an eQTL.
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Affiliation(s)
- Gang Wang
- Clinical Research Institute of Zhanjiang, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
| | - Yuluo Wu
- Department of Oncology, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
| | - Zuolei Jing
- Clinical Research Institute of Zhanjiang, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
| | - Ruiting Wen
- Department of Hematology, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
- Zhanjiang Key Laboratory of Leukemia Pathogenesis and Targeted Therapy Research, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
| | - Yuanrui Song
- Department of Oncology, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
| | - Yin Feng
- Department of Oncology, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
| | - Guangru Li
- Clinical Research Institute of Zhanjiang, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
| | - Xiaopeng Zou
- Clinical Research Institute of Zhanjiang, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
| | - Gaoxiang Huang
- Clinical Research Institute of Zhanjiang, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
| | - Zhirong Jia
- Clinical Research Institute of Zhanjiang, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
| | - Yunmiao Guo
- Clinical Research Institute of Zhanjiang, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
| | - Zhigang Yang
- Clinical Research Institute of Zhanjiang, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
- Department of Hematology, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
- Zhanjiang Key Laboratory of Leukemia Pathogenesis and Targeted Therapy Research, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, P. R. China
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Baliou S, Ioannou P, Apetroaei MM, Vakonaki E, Fragkiadaki P, Kirithras E, Tzatzarakis MN, Arsene AL, Docea AO, Tsatsakis A. The Impact of the Mediterranean Diet on Telomere Biology: Implications for Disease Management-A Narrative Review. Nutrients 2024; 16:2525. [PMID: 39125404 PMCID: PMC11313773 DOI: 10.3390/nu16152525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/26/2024] [Accepted: 07/29/2024] [Indexed: 08/12/2024] Open
Abstract
INTRODUCTION Telomeres are nucleoprotein complexes at the ends of chromosomes that are under the control of genetic and environmental triggers. Accelerated telomere shortening is causally implicated in the increasing incidence of diseases. The Mediterranean diet has recently been identified as one that confers protection against diseases. This review aimed to identify the effect of each component of the Mediterranean diet on telomere length dynamics, highlighting the underlying molecular mechanisms. METHODS PubMed was searched to identify relevant studies to extract data for conducting a narrative review. RESULTS The Mediterranean diet alleviates clinical manifestations in many diseases. Focusing on autoimmune diseases, the Mediterranean diet can be protective by preventing inflammation, mitochondrial malfunction, and abnormal telomerase activity. Also, each Mediterranean diet constituent seems to attenuate aging through the sustenance or elongation of telomere length, providing insights into the underlying molecular mechanisms. Polyphenols, vitamins, minerals, and fatty acids seem to be essential in telomere homeostasis, since they inhibit inflammatory responses, DNA damage, oxidative stress, mitochondrial malfunction, and cell death and induce telomerase activation. CONCLUSIONS The Mediterranean diet is beneficial for maintaining telomere dynamics and alleviating age-related illnesses. This review provides a comprehensive overview of cross-sectional, observational, and randomized controlled trials regarding the beneficial impact of every constituent in the Mediterranean diet on telomere length and chronic disease management.
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Affiliation(s)
- Stella Baliou
- Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece; (S.B.); (E.V.); (P.F.); (E.K.); (M.N.T.); (A.T.)
- Lifeplus S.A., Science & Technological Park of Crete, C Building, Vassilika Vouton, 70013 Heraklion, Greece
| | - Petros Ioannou
- School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Miruna-Maria Apetroaei
- Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, 6, Traian Vuia Street, 020956 Bucharest, Romania; (M.-M.A.); (A.L.A.)
| | - Elena Vakonaki
- Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece; (S.B.); (E.V.); (P.F.); (E.K.); (M.N.T.); (A.T.)
- Lifeplus S.A., Science & Technological Park of Crete, C Building, Vassilika Vouton, 70013 Heraklion, Greece
| | - Persefoni Fragkiadaki
- Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece; (S.B.); (E.V.); (P.F.); (E.K.); (M.N.T.); (A.T.)
- Lifeplus S.A., Science & Technological Park of Crete, C Building, Vassilika Vouton, 70013 Heraklion, Greece
| | - Evangelos Kirithras
- Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece; (S.B.); (E.V.); (P.F.); (E.K.); (M.N.T.); (A.T.)
- Lifeplus S.A., Science & Technological Park of Crete, C Building, Vassilika Vouton, 70013 Heraklion, Greece
| | - Manolis N. Tzatzarakis
- Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece; (S.B.); (E.V.); (P.F.); (E.K.); (M.N.T.); (A.T.)
| | - Andreea Letitia Arsene
- Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, 6, Traian Vuia Street, 020956 Bucharest, Romania; (M.-M.A.); (A.L.A.)
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
- Department of Toxicology, Faculty of Pharmacy, University of Medicine and Pharmacy, Petru Rares, 200349 Craiova, Romania
| | - Aristides Tsatsakis
- Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece; (S.B.); (E.V.); (P.F.); (E.K.); (M.N.T.); (A.T.)
- Lifeplus S.A., Science & Technological Park of Crete, C Building, Vassilika Vouton, 70013 Heraklion, Greece
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Singh J, Wilkins G, Goodman-Vincent E, Chishti S, Bonilla Guerrero R, McFadden L, Zahavi Z, Santosh P. Co-Occurring Methylenetetrahydrofolate Reductase ( MTHFR) rs1801133 and rs1801131 Genotypes as Associative Genetic Modifiers of Clinical Severity in Rett Syndrome. Brain Sci 2024; 14:624. [PMID: 39061365 PMCID: PMC11275218 DOI: 10.3390/brainsci14070624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 06/18/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
AIM Remethylation disorders such as 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency reduce the remethylation of homocysteine to methionine. The resulting hyperhomocysteinemia can lead to serious neurological consequences and multisystem toxicity. The role of MTHFR genotypes has not been investigated in patients with Rett Syndrome (RTT). In this study, we sought to assess the impact of co-occurring MTHFR genotypes on symptom profiles in RTT. METHOD Using pharmacogenomic (PGx) testing, the MTHFR genetic polymorphisms rs1801133 (c.665C>T mutation) and rs1801131 (c.1286A>C mutation) were determined in 65 patients (18.7 years ± 12.1 [mean ± standard deviation]) with RTT as part of routine clinical care within the Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, a National and Specialist Child and Adolescent Mental Health Service (CAMHS) in the UK. The clinical severity of patients was assessed using the RTT-anchored Clinical Global Impression Scale (RTT-CGI). RESULTS The clinical severity symptom distribution varied between the homozygous and heterozygous MTHFR rs1801133 and rs1801131 genotypes. Those with the homozygous genotype had a narrower spread of severity scores across several domains (language and communication, ambulation, hand-use and eye contact clinical domains). Patients with the homozygous genotype had statistically significantly greater CGI-Severity scores than individuals with a non-homozygous MTHFR genotype (Z = -2.44, p = 0.015). When comparing the ratings of moderately impaired (4), markedly impaired (5), severely impaired (6) and extremely impaired (7), individuals with the homozygous MTHFR genotype were more impaired than those with the non-homozygous MTHFR genotype (Z = -2.06, p = 0.039). There was no statistically significant difference in the number of prescribed anti-epileptic drugs between the genotypes. CONCLUSIONS Our findings show that in those with a pathogenic RTT genetic variant, co-occurring homozygotic MTHFR rs1801133 and rs1801131 polymorphisms may act as associative genetic modifiers of clinical severity in a subset of patients. Profiling of rs1801133 and rs1801131 in RTT may therefore be useful, especially for high-risk patients who may be at the most risk from symptom deterioration.
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Affiliation(s)
- Jatinder Singh
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK; (J.S.); (G.W.); (E.G.-V.); (S.C.); (L.M.)
- Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK
- Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
| | - Georgina Wilkins
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK; (J.S.); (G.W.); (E.G.-V.); (S.C.); (L.M.)
- Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK
- Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
| | - Ella Goodman-Vincent
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK; (J.S.); (G.W.); (E.G.-V.); (S.C.); (L.M.)
- Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK
- Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
| | - Samiya Chishti
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK; (J.S.); (G.W.); (E.G.-V.); (S.C.); (L.M.)
- Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK
- Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
| | | | - Leighton McFadden
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK; (J.S.); (G.W.); (E.G.-V.); (S.C.); (L.M.)
- Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK
- Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
| | - Zvi Zahavi
- Myogenes Limited, Borehamwood WD6 4PJ, UK;
| | - Paramala Santosh
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK; (J.S.); (G.W.); (E.G.-V.); (S.C.); (L.M.)
- Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK
- Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
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Huang Y, Su T, Duan Q, Wei X, Fan X, Wan J, Liu L, Dian Z, Zhang G, Sun Y, Zhou T, Xu Y. Association of Methylenetetrahydrofolate Reductase rs1801133 Gene Polymorphism with Cancer Risk and Septin 9 Methylation in Patients with Colorectal Cancer. J Gastrointest Cancer 2024; 55:778-786. [PMID: 38252186 PMCID: PMC11186932 DOI: 10.1007/s12029-024-01020-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2024] [Indexed: 01/23/2024]
Abstract
PURPOSE Colorectal cancer (CRC) is one of the most common malignancies, with a high incidence and mortality worldwide. Methylated Septin 9 (mSEPT9) has been used clinically as an auxiliary tool for CRC screening. The aim of the present study was to investigate the association of the methylenetetrahydrofolate reductase (MTHFR) rs1801133 polymorphism with the risk of CRC and the methylation status of Septin 9 in CRC. METHODS Information of 540 patients with a confirmed diagnosis of CRC and with a physical examination were utilized to assess the association of the MTHFR rs1801133 polymorphism with CRC and the methylation of SEPT9. MTHFR rs1801133 polymorphism was genotyped using polymerase chain reaction (PCR). The commercial Septin 9 Gene Methylation(mSEPT9) Detection Kit was used for plasma SEPT9 methylation analysis. RESULTS Among 540 patients, 61.48% were men and the median age was 54.47 ± 13.14. 65.37% of all colorectal tumors developed in the rectum. 195 patients had negative mSEPT9 methylation, while 345 had positive results. 87 individuals with stage I, 90 with stage II, 287 with stage III, and 76 with stage IV colorectal cancer were included in the sample. The results demonstrated that the positivity rate and degree of methylation of mSEPT9 were remarkably higher in patients with more advanced TNM stages than in those with less advanced stages. The frequencies of the MTHFR rs1801133 CC genotype and allele C carriers in patients with CRC were significantly higher than those in healthy individuals (P = 0.006 and P = 0.001, respectively). The positivity rate of the mSEPT9 assay was significantly higher among the MTHFR rs1801133 TT genotype and allele T carriers than among the CC and allele C carriers respectively. The MTHFR rs1801133 TT genotype and allele T carriers were positively associated with the methylation of SEPT9 (OR = 3.320, 95% CI 1.485-7.424, P = 0.003 and OR = 1.783, 95% CI 1.056-3.010, P = 0.030, respectively). CONCLUSION In conclusion, individuals harboring the MTHFR rs1801133 CC genotype had a higher risk of CRC and the MTHFR rs1801133 TT carriers were more susceptible to Septin 9 gene methylation.
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Affiliation(s)
- Yafei Huang
- Department of Clinical Laboratory, the First People's Hospital of Yunnan Province, 157 Jinbi Road, Xishan District, Kunming, Yunnan, 650500, P.R. China
- The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Ting Su
- Department of Clinical Laboratory, the First People's Hospital of Yunnan Province, 157 Jinbi Road, Xishan District, Kunming, Yunnan, 650500, P.R. China
- The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Qiuting Duan
- Department of Clinical Laboratory, the First People's Hospital of Yunnan Province, 157 Jinbi Road, Xishan District, Kunming, Yunnan, 650500, P.R. China
- The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Xiangcong Wei
- Medical School, Kunming University of Science and Technology, Kunming, China
| | - Xin Fan
- Department of Clinical Laboratory, the First People's Hospital of Yunnan Province, 157 Jinbi Road, Xishan District, Kunming, Yunnan, 650500, P.R. China
- The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Jinxiu Wan
- Department of Clinical Laboratory, the First People's Hospital of Yunnan Province, 157 Jinbi Road, Xishan District, Kunming, Yunnan, 650500, P.R. China
- The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Luping Liu
- Department of Clinical Laboratory, the First People's Hospital of Yunnan Province, 157 Jinbi Road, Xishan District, Kunming, Yunnan, 650500, P.R. China
- The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Ziqin Dian
- Department of Clinical Laboratory, the First People's Hospital of Yunnan Province, 157 Jinbi Road, Xishan District, Kunming, Yunnan, 650500, P.R. China
- The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Guiqian Zhang
- Department of Clinical Laboratory, the First People's Hospital of Yunnan Province, 157 Jinbi Road, Xishan District, Kunming, Yunnan, 650500, P.R. China
- The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Yi Sun
- Department of Clinical Laboratory, the First People's Hospital of Yunnan Province, 157 Jinbi Road, Xishan District, Kunming, Yunnan, 650500, P.R. China
- The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Tao Zhou
- Department of Clinical Laboratory, The Second Affiliated Hospital of Kunming Medical University, 374 Dianmian Avenue, Kunming, Yunnan, 650500, P.R. China.
| | - Ya Xu
- Department of Clinical Laboratory, the First People's Hospital of Yunnan Province, 157 Jinbi Road, Xishan District, Kunming, Yunnan, 650500, P.R. China.
- The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, China.
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Dash M, Mahajan B, Dar GM, Sahu P, Saluja SS. An update on the cell-free DNA-derived methylome as a non-invasive biomarker for coronary artery disease. Int J Biochem Cell Biol 2024; 169:106555. [PMID: 38428633 DOI: 10.1016/j.biocel.2024.106555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 12/22/2023] [Accepted: 02/25/2024] [Indexed: 03/03/2024]
Abstract
Cardiovascular diseases are the foremost contributor to global mortality, presenting a complex etiology and an expanding array of risk factors. Coronary artery disease characterized by atherosclerotic plaque build-up in the coronary arteries, imposes significant mortality and financial burdens, especially in low- and middle-income nations. The pathogenesis of coronary artery disease involves a multifaceted interplay of genetic, environmental, and epigenetic factors. Epigenetic regulation contributes to the dynamic control of gene expression without altering the underlying DNA sequence. The mounting evidence that highlights the pivotal role of epigenetic regulation in coronary artery disease development and progression, offering potential avenues for the development of novel diagnostic biomarkers and therapeutic targets. Abnormal DNA methylation patterns are linked to the modulation of gene expression involved in crucial processes like lipid metabolism, inflammation, and vascular function in the context of coronary artery disease. Cell-free DNA has become invaluable in tumor biology as a liquid biopsy, while its applications in coronary artery disease are limited, but intriguing. Atherosclerotic plaque rupture causes myocardial infarction, by depriving heart muscles of oxygen, releasing cell-free DNA from dead cardiac cells, and providing a minimally invasive source to explore tissue-specific epigenetic alterations. We discussed the methodologies for studying the global methylome and hydroxy-methylome landscape, their advantages, and limitations. It explores methylome alterations in coronary artery disease, considering risk factors and their relevance in coronary artery disease genesis. The review also details the implications of MI-derived cell-free DNA for developing minimally invasive biomarkers and associated challenges.
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Affiliation(s)
- Manoswini Dash
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; School of Medicine, Center for Aging, Tulane University, LA, United States
| | - Bhawna Mahajan
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of Biochemistry, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India.
| | - Ghulam Mehdi Dar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Parameswar Sahu
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Sundeep Singh Saluja
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of GI Surgery, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
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Martínez Duncker Rebolledo E, Chan D, Christensen KE, Reagan AM, Howell GR, Rozen R, Trasler J. Sperm DNA methylation defects in a new mouse model of the 5,10-methylenetetrahydrofolate reductase 677C>T variant and correction with moderate dose folic acid supplementation. Mol Hum Reprod 2024; 30:gaae008. [PMID: 38366926 PMCID: PMC10980591 DOI: 10.1093/molehr/gaae008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 01/30/2024] [Indexed: 02/19/2024] Open
Abstract
5,10-Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that plays a key role in providing methyl groups for DNA methylation, including during spermatogenesis. A common genetic variant in humans (MTHFR 677C>T) results in reduced enzyme activity and has been linked to various disorders, including male infertility. A new animal model has been created by reproducing the human equivalent of the polymorphism in mice using CRISPR/Cas9. Biochemical parameters in the Mthfr 677TT mice recapitulate alterations found in MTHFR 677TT men. Our aims were to characterize the sperm DNA methylome of the Mthfr 677CC and TT mice on a control diet (2 mg folic acid/kg diet) and assess the effects of folic acid supplementation (10 mg/kg diet) on the sperm DNA methylome. Body and reproductive organ weights, testicular sperm counts, and histology were examined. DNA methylation in sperm was assessed using bisulfite pyrosequencing and whole-genome bisulfite sequencing (WGBS). Reproductive parameters and locus-specific imprinted gene methylation were unaffected by genotype or diet. Using WGBS, sperm from 677TT mice had 360 differentially methylated tiles as compared to 677CC mice, predominantly hypomethylation (60% of tiles). Folic acid supplementation mostly caused hypermethylation in sperm of males of both genotypes and was found to partially correct the DNA methylation alterations in sperm associated with the TT genotype. The new mouse model will be useful in understanding the role of MTHFR deficiency in male fertility and in designing folate supplementation regimens for the clinic.
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Affiliation(s)
- Edgar Martínez Duncker Rebolledo
- Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Donovan Chan
- Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Karen E Christensen
- Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | | | - Gareth R Howell
- The Jackson Laboratory, Bar Harbor, ME, USA
- Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, USA
| | - Rima Rozen
- Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Department of Pediatrics, McGill University, Montreal, QC, Canada
| | - Jacquetta Trasler
- Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Department of Pediatrics, McGill University, Montreal, QC, Canada
- Department of Pharmacology & Therapeutics, Montreal, QC, Canada
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Socha MW, Flis W, Wartęga M. Epigenetic Genome Modifications during Pregnancy: The Impact of Essential Nutritional Supplements on DNA Methylation. Nutrients 2024; 16:678. [PMID: 38474806 PMCID: PMC10934520 DOI: 10.3390/nu16050678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
Pregnancy is an extremely stressful period in a pregnant woman's life. Currently, women's awareness of the proper course of pregnancy and its possible complications is constantly growing. Therefore, a significant percentage of women increasingly reach for various dietary supplements during gestation. Some of the most popular substances included in multi-ingredient supplements are folic acid and choline. Those substances are associated with positive effects on fetal intrauterine development and fewer possible pregnancy-associated complications. Recently, more and more attention has been paid to the impacts of specific environmental factors, such as diet, stress, physical activity, etc., on epigenetic modifications, understood as changes occurring in gene expression without the direct alteration of DNA sequences. Substances such as folic acid and choline may participate in epigenetic modifications by acting via a one-carbon cycle, leading to the methyl-group donor formation. Those nutrients may indirectly impact genome phenotype by influencing the process of DNA methylation. This review article presents the current state of knowledge on the use of folic acid and choline supplementation during pregnancy, taking into account their impacts on the maternal-fetal unit and possible pregnancy outcomes, and determining possible mechanisms of action, with particular emphasis on their possible impacts on epigenetic modifications.
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Affiliation(s)
- Maciej W. Socha
- Department of Perinatology, Gynecology and Gynecologic Oncology, Faculty of Health Sciences, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Łukasiewicza 1, 85-821 Bydgoszcz, Poland;
- Department of Obstetrics and Gynecology, St. Adalbert’s Hospital in Gdańsk, Copernicus Healthcare Entity, Jana Pawła II 50, 80-462 Gdańsk, Poland
| | - Wojciech Flis
- Department of Perinatology, Gynecology and Gynecologic Oncology, Faculty of Health Sciences, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Łukasiewicza 1, 85-821 Bydgoszcz, Poland;
- Department of Obstetrics and Gynecology, St. Adalbert’s Hospital in Gdańsk, Copernicus Healthcare Entity, Jana Pawła II 50, 80-462 Gdańsk, Poland
| | - Mateusz Wartęga
- Department of Pathophysiology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie-Skłodowskiej 9, 85-094 Bydgoszcz, Poland;
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17
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Raghubeer S. The influence of epigenetics and inflammation on cardiometabolic risks. Semin Cell Dev Biol 2024; 154:175-184. [PMID: 36804178 DOI: 10.1016/j.semcdb.2023.02.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 02/18/2023]
Abstract
Cardiometabolic diseases include metabolic syndrome, obesity, type 2 diabetes mellitus, and hypertension. Epigenetic modifications participate in cardiometabolic diseases through several pathways, including inflammation, vascular dysfunction, and insulin resistance. Epigenetic modifications, which encompass alterations to gene expression without mutating the DNA sequence, have gained much attention in recent years, since they have been correlated with cardiometabolic diseases and may be targeted for therapeutic interventions. Epigenetic modifications are greatly influenced by environmental factors, such as diet, physical activity, cigarette smoking, and pollution. Some modifications are heritable, indicating that the biological expression of epigenetic alterations may be observed across generations. Moreover, many patients with cardiometabolic diseases present with chronic inflammation, which can be influenced by environmental and genetic factors. The inflammatory environment worsens the prognosis of cardiometabolic diseases and further induces epigenetic modifications, predisposing patients to the development of other metabolism-associated diseases and complications. A deeper understanding of inflammatory processes and epigenetic modifications in cardiometabolic diseases is necessary to improve our diagnostic capabilities, personalized medicine approaches, and the development of targeted therapeutic interventions. Further understanding may also assist in predicting disease outcomes, especially in children and young adults. This review describes epigenetic modifications and inflammatory processes underlying cardiometabolic diseases, and further discusses advances in the research field with a focus on specific points for interventional therapy.
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Affiliation(s)
- Shanel Raghubeer
- SAMRC/CPUT/Cardiometabolic Health Research Unit, Department of Biomedical Sciences, Faculty of Health & Wellness Sciences, Cape Peninsula University of Technology, South Africa.
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18
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Rajesh V, Divya PK. Embryonic exposure to decitabine induces multiple neural tube defects in developing zebrafish. FISH PHYSIOLOGY AND BIOCHEMISTRY 2023; 49:1357-1379. [PMID: 37982970 DOI: 10.1007/s10695-023-01261-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Accepted: 11/01/2023] [Indexed: 11/21/2023]
Abstract
Neural tube defects are severe congenital disorders of the central nervous system that originate during embryonic development when the neural tube fails to close completely. It affects one to two infants per 1000 births. The aetiology is multifactorial with contributions from both genetic and environmental factors. Dysregulated epigenetic mechanisms, in particular the abnormal genome-wide methylation during embryogenesis, have been linked to developmental abnormalities including neural tube defects. The current study investigated the influence of decitabine (DCT), a DNA methylation inhibitor, on embryonic development in zebrafish, with a focus on neural tube formation. The developing zebrafish embryos were exposed to graded concentrations of decitabine (from 13.69 μM to 1 mM) before the onset of neurulation. The developmental process was monitored at regular time intervals post fertilization. At 120 h post fertilization, the developing embryos were inspected individually to determine the incidence and severity of neural tube defects. Using alizarin red staining, the cranial and caudal neural tube morphology was examined in formaldehyde fixed larvae. Anomalies in neural tube and somite development, as well as a delay in hatching, were discovered at an early stage of development. As development continued, neural tube defects became increasingly evident, and there was a concentration-dependent rise in the prevalence and severity of various neural tube defects. 90% of growing embryos in the group exposed to decitabine 1 mM had multiple neural tube malformations, and 10% had isolated neural tube defects. With several abnormalities, the caudal region of the neural tube was seriously compromised. The histopathological studies supported the malformations in neural tube. Our study revealed the harmful impact of decitabine on the development of the neural tube in growing zebrafish. Moreover, these findings support the hypothesis that the hypomethylation during embryonic development causes neural tube defects.
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Affiliation(s)
- Venugopalan Rajesh
- Department of Pharmacology, The Erode College of Pharmacy and Research Institute affiliated to The Tamil Nadu Dr. M.G.R. Medical University, Veppampalayam, Vallipurathampalayam (Po), Erode, Chennai, Tamil Nadu, 638112, India.
| | - Pachangattupalayam Karuppusamy Divya
- Department of Pharmacology, The Erode College of Pharmacy and Research Institute affiliated to The Tamil Nadu Dr. M.G.R. Medical University, Veppampalayam, Vallipurathampalayam (Po), Erode, Chennai, Tamil Nadu, 638112, India
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19
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Abstract
Unlike genetic changes, epigenetics modulates gene expression without stable modification of the genome. Even though all cells, including sperm and egg, have an epigenome pattern, most of these modifications occur during lifetime and interestingly, some of them, are reversible. Lifestyle and especially nutrients as well as diet regimens are presently gaining importance due to their ability to affect the epigenome. On the other hand, since the epigenome profoundly affects gene expression profile it can be speculated that the epigenome could modulate individual response to nutrients. Recent years have thus seen growing interest on nutrients, macronutrients ratio and diet regimens capable to affect the epigenetic pattern. In fact, while genetic alterations are mostly detrimental at the individual level, reshaping the epigenome may be a feasible strategy to positively counteract the detrimental effect of aging. Here, I review nutrient consumption and diet regimens as a possible strategy to counteract aging-driven epigenome derangement.
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Affiliation(s)
- Mario G Mirisola
- STeBiCeF Department, Università di Palermo, Building 16, Viale delle Scienze, 90128 Palermo, Italy
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20
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Xu X, Zhu J, Fang L, Zou Z, Yuan J, Peng M, Yu G, Wu D, Liu Y, Tang J. Exome sequencing identified novel variants in three Chinese patients with 5,10-methenyltetrahydrofolate synthetase deficiency. Front Genet 2023; 14:1236849. [PMID: 37795244 PMCID: PMC10545881 DOI: 10.3389/fgene.2023.1236849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 08/25/2023] [Indexed: 10/06/2023] Open
Abstract
5,10-methenyltetrahydrofolate synthetase (MTHFS) deficiency is a folate metabolism disorder known as a rare autosomal recessive neurodevelopmental disorder (MIM: #618367). With central nervous system involvements, it is mainly characterized by developmental delay, epilepsy, microcephaly, hypertonia, and cranial nerves involvement. Here, we report three new cases with MTHFS deficiency from two non-consanguineous Chinese families. All patients showed white matter dysplasia and global developmental delay, of which only patient 1 and 2 manifested tonic-clonic seizures. Moreover, patient 2 had severe eczema and patient 3 had recurrent diarrhea. Both phenotypic features are firstly found in MTHFS deficiency. Trio whole-exome sequencing and sanger sequencing were used to identify four novel variants, p.Y169Tfs*17, p.S53F, c.117+1delG, and p.E61G in the MTHFS gene. The identification of four novel pathogenic variants and varied clinical features in three affected patients expands the genotype and phenotype spectrum of MTHFS deficiency. We also reviewed all cases of MTHFS deficiency that had previously been reported. The experience of diagnosis and treatment from these cases provides us a more comprehensive understanding of this rare disease.
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Affiliation(s)
- Xiaoyan Xu
- Pediatric Neurorehabilitation Center, Pediatric Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jing Zhu
- Pediatric Neurorehabilitation Center, Pediatric Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Liwei Fang
- Pediatric Neurorehabilitation Center, Pediatric Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhuo Zou
- Department of Rehabilitation, Kunming Children’s Hospital, Kunming Medical University, Kunming, Yunnan, China
| | - Jingjing Yuan
- Pediatric Neurorehabilitation Center, Pediatric Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Min Peng
- Chigene (Beijing) Translational Medical Research Center Co, Ltd, Beijing, China
| | - Guoliang Yu
- Chigene (Beijing) Translational Medical Research Center Co, Ltd, Beijing, China
| | - De Wu
- Pediatric Neurorehabilitation Center, Pediatric Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yun Liu
- Department of Rehabilitation, Kunming Children’s Hospital, Kunming Medical University, Kunming, Yunnan, China
| | - Jiulai Tang
- Pediatric Neurorehabilitation Center, Pediatric Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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21
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Keuls RA, Finnell RH, Parchem RJ. Maternal metabolism influences neural tube closure. Trends Endocrinol Metab 2023; 34:539-553. [PMID: 37468429 PMCID: PMC10529122 DOI: 10.1016/j.tem.2023.06.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 06/14/2023] [Accepted: 06/19/2023] [Indexed: 07/21/2023]
Abstract
Changes in maternal nutrient availability due to diet or disease significantly increase the risk of neural tube defects (NTDs). Because the incidence of metabolic disease continues to rise, it is urgent that we better understand how altered maternal nutrient levels can influence embryonic neural tube development. Furthermore, primary neurulation occurs before placental function during a period of histiotrophic nutrient exchange. In this review we detail how maternal metabolites are transported by the yolk sac to the developing embryo. We discuss recent advances in understanding how altered maternal levels of essential nutrients disrupt development of the neuroepithelium, and identify points of intersection between metabolic pathways that are crucial for NTD prevention.
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Affiliation(s)
- Rachel A Keuls
- Development, Disease Models, and Therapeutics Graduate Program, Baylor College of Medicine. Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
| | - Richard H Finnell
- Departments of Molecular and Human Genetics and Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Precision Environmental Health, Department of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ronald J Parchem
- Development, Disease Models, and Therapeutics Graduate Program, Baylor College of Medicine. Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
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22
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Choi SW, Friso S. Modulation of DNA methylation by one-carbon metabolism: a milestone for healthy aging. Nutr Res Pract 2023; 17:597-615. [PMID: 37529262 PMCID: PMC10375321 DOI: 10.4162/nrp.2023.17.4.597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/19/2023] [Accepted: 05/01/2023] [Indexed: 08/03/2023] Open
Abstract
Healthy aging can be defined as an extended lifespan and health span. Nutrition has been regarded as an important factor in healthy aging, because nutrients, bioactive food components, and diets have demonstrated beneficial effects on aging hallmarks such as oxidative stress, mitochondrial function, apoptosis and autophagy, genomic stability, and immune function. Nutrition also plays a role in epigenetic regulation of gene expression, and DNA methylation is the most extensively investigated epigenetic phenomenon in aging. Interestingly, age-associated DNA methylation can be modulated by one-carbon metabolism or inhibition of DNA methyltransferases. One-carbon metabolism ultimately controls the balance between the universal methyl donor S-adenosylmethionine and the methyltransferase inhibitor S-adenosylhomocysteine. Water-soluble B-vitamins such as folate, vitamin B6, and vitamin B12 serve as coenzymes for multiple steps in one-carbon metabolism, whereas methionine, choline, betaine, and serine act as methyl donors. Thus, these one-carbon nutrients can modify age-associated DNA methylation and subsequently alter the age-associated physiologic and pathologic processes. We cannot elude aging per se but we may at least change age-associated DNA methylation, which could mitigate age-associated diseases and disorders.
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Affiliation(s)
- Sang-Woon Choi
- Chaum Life Center, CHA University School of Medicine, Seoul 06062, Korea
- Department of Nutrition, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 01003, USA
| | - Simonetta Friso
- Unit of Internal Medicine B and ‘Epigenomics and Gene-Nutrient Interactions’ Laboratory, Department of Medicine, University of Verona School of Medicine, Policlinico “G.B. Rossi,” 37134 Verona, Italy
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23
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Lai TY, Ko YC, Chen YL, Lin SF. The Way to Malignant Transformation: Can Epigenetic Alterations Be Used to Diagnose Early-Stage Head and Neck Cancer? Biomedicines 2023; 11:1717. [PMID: 37371812 PMCID: PMC10296077 DOI: 10.3390/biomedicines11061717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/05/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Identifying and treating tumors early is the key to secondary prevention in cancer control. At present, prevention of oral cancer is still challenging because the molecular drivers responsible for malignant transformation of the 11 clinically defined oral potentially malignant disorders are still unknown. In this review, we focused on studies that elucidate the epigenetic alterations demarcating malignant and nonmalignant epigenomes and prioritized findings from clinical samples. Head and neck included, the genomes of many cancer types are largely hypomethylated and accompanied by focal hypermethylation on certain specific regions. We revisited prior studies that demonstrated that sufficient uptake of folate, the primary dietary methyl donor, is associated with oral cancer reduction. As epigenetically driven phenotypic plasticity, a newly recognized hallmark of cancer, has been linked to tumor initiation, cell fate determination, and drug resistance, we discussed prior findings that might be associated with this hallmark, including gene clusters (11q13.3, 19q13.43, 20q11.2, 22q11-13) with great potential for oral cancer biomarkers, and successful examples in screening early-stage nasopharyngeal carcinoma. Although one-size-fits-all approaches have been shown to be ineffective in most cancer therapies, the rapid development of epigenome sequencing methods raises the possibility that this nonmutagenic approach may be an exception. Only time will tell.
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Affiliation(s)
- Ting-Yu Lai
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan;
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan; (Y.-C.K.); (Y.-L.C.)
| | - Ying-Chieh Ko
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan; (Y.-C.K.); (Y.-L.C.)
| | - Yu-Lian Chen
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan; (Y.-C.K.); (Y.-L.C.)
| | - Su-Fang Lin
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan; (Y.-C.K.); (Y.-L.C.)
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24
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Ledowsky CJ, Schloss J, Steel A. Variations in folate prescriptions for patients with the MTHFR genetic polymorphisms: A case series study. EXPLORATORY RESEARCH IN CLINICAL AND SOCIAL PHARMACY 2023; 10:100277. [PMID: 37228355 PMCID: PMC10205484 DOI: 10.1016/j.rcsop.2023.100277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 03/16/2023] [Accepted: 04/30/2023] [Indexed: 05/27/2023] Open
Abstract
Background Over 48.5 million couples are reported with infertility worldwide. Health policy recommends folic acid in women of childbearing age, particularly in preconception and pregnancy which results in women purchasing over-the-counter prenatal multivitamins containing folic acid through pharmacies and other retail outlets. Emerging studies are investigating whether other forms of supplemental folate are more suitable, particularly for those with methylenetetrahydrofolate reductase (MTHFR) polymorphisms. This case series aimed to document variations in forms and dosage of folate prescribed by Australian practitioners to patients with diagnosed infertility and MTHFR polymorphisms. Methods Australian practitioners were invited to complete a retrospective case report form for patients that presented with unexplained infertility. This case report form documented the form and dose of folate that practitioners were prescribing to their infertility patient with MTHFR polymorphisms, together with their fertility history. Results Six practitioners submitted case information for 12 patients with diagnosed infertility and MTHFR polymorphisms. All patients had been advised by their practitioner to remove folic acid in supplemental form and were prescribed 5-methyltetrahydrofolate (5-MTHF) or a combination of 5-MTHF and folinic acid, at higher doses than the Australian recommended dose (mean daily maximum prescribed dose: 2325μg). Eleven patients conceived within the treatment period (average treatment of one year) and ten were reported as having a live birth. Conclusion This case series has highlighted clinical practices that vary from the recommendations by Australian policy. Further research is required to verify the clinical importance of variations in folate prescriptions for women with MTHFR polymorphisms and how folate recommendations may need to change depending on these polymorphisms. This has direct relevance to those prescribing at the pharmacy and retail level, specifically pharmacists and pharmacy assistants.
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Affiliation(s)
- Carolyn Jane Ledowsky
- Endeavour College of Natural Health, now at University of Technology Sydney, Faculty of Health, Australia
| | - Janet Schloss
- Southern Cross University, Natural Centre for Naturopathic Medicine, Lismore, NSW, Australia
| | - Amie Steel
- University of Technology Sydney, Faculty of Health, Australia
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25
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Simonian R, Pannia E, Hammoud R, Noche RR, Cui X, Kranenburg E, Kubant R, Ashcraft P, Wasek B, Bottiglieri T, Dowling JJ, Anderson GH. Methylenetetrahydrofolate reductase deficiency and high-dose FA supplementation disrupt embryonic development of energy balance and metabolic homeostasis in zebrafish. Hum Mol Genet 2023; 32:1575-1588. [PMID: 36637428 PMCID: PMC10117162 DOI: 10.1093/hmg/ddac308] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 12/03/2022] [Accepted: 12/22/2022] [Indexed: 01/14/2023] Open
Abstract
Folic acid (synthetic folate, FA) is consumed in excess in North America and may interact with common pathogenic variants in methylenetetrahydrofolate reductase (MTHFR); the most prevalent inborn error of folate metabolism with wide-ranging obesity-related comorbidities. While preclinical murine models have been valuable to inform on diet-gene interactions, a recent Folate Expert panel has encouraged validation of new animal models. In this study, we characterized a novel zebrafish model of mthfr deficiency and evaluated the effects of genetic loss of mthfr function and FA supplementation during embryonic development on energy homeostasis and metabolism. mthfr-deficient zebrafish were generated using CRISPR mutagenesis and supplemented with no FA (control, 0FA) or 100 μm FA (100FA) throughout embryonic development (0-5 days postfertilization). We show that the genetic loss of mthfr function in zebrafish recapitulates key biochemical hallmarks reported in MTHFR deficiency in humans and leads to greater lipid accumulation and aberrant cholesterol metabolism as reported in the Mthfr murine model. In mthfr-deficient zebrafish, energy homeostasis was also impaired as indicated by altered food intake, reduced metabolic rate and lower expression of central energy-regulatory genes. Microglia abundance, involved in healthy neuronal development, was also reduced. FA supplementation to control zebrafish mimicked many of the adverse effects of mthfr deficiency, some of which were also exacerbated in mthfr-deficient zebrafish. Together, these findings support the translatability of the mthfr-deficient zebrafish as a preclinical model in folate research.
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Affiliation(s)
- Rebecca Simonian
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Emanuela Pannia
- Department of Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Rola Hammoud
- Department of Laboratory Medicine and Pathobiology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto ON, M5G 1X5, Canada
| | - Ramil R Noche
- Department of Comparative Medicine, Yale Zebrafish Research Core, Yale School of Medicine, New Haven, CT 06511, USA
| | - Xiucheng Cui
- Department of Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Eva Kranenburg
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Ruslan Kubant
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Paula Ashcraft
- Baylor Scott & White Research Institute, Institute of Metabolic Disease, Dallas, TX 75204, USA
| | - Brandi Wasek
- Baylor Scott & White Research Institute, Institute of Metabolic Disease, Dallas, TX 75204, USA
| | - Teodoro Bottiglieri
- Baylor Scott & White Research Institute, Institute of Metabolic Disease, Dallas, TX 75204, USA
| | - James J Dowling
- Department of Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - G Harvey Anderson
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
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26
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Korczowska-Łącka I, Hurła M, Banaszek N, Kobylarek D, Szymanowicz O, Kozubski W, Dorszewska J. Selected Biomarkers of Oxidative Stress and Energy Metabolism Disorders in Neurological Diseases. Mol Neurobiol 2023; 60:4132-4149. [PMID: 37039942 DOI: 10.1007/s12035-023-03329-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 03/22/2023] [Indexed: 04/12/2023]
Abstract
Neurological diseases can be broadly divided according to causal factors into circulatory system disorders leading to ischemic stroke; degeneration of the nerve cells leading to neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's (PD) diseases, and immune system disorders; bioelectric activity (epileptic) problems; and genetically determined conditions as well as viral and bacterial infections developing inflammation. Regardless of the cause of neurological diseases, they are usually accompanied by disturbances of the central energy in a completely unexplained mechanism. The brain makes up only 2% of the human body's weight; however, while working, it uses as much as 20% of the energy obtained by the body. The energy requirements of the brain are very high, and regulatory mechanisms in the brain operate to ensure adequate neuronal activity. Therefore, an understanding of neuroenergetics is rapidly evolving from a "neurocentric" view to a more integrated picture involving cooperativity between structural and molecular factors in the central nervous system. This article reviewed selected molecular biomarkers of oxidative stress and energy metabolism disorders such as homocysteine, DNA damage such as 8-oxo2dG, genetic variants, and antioxidants such as glutathione in selected neurological diseases including ischemic stroke, AD, PD, and epilepsy. This review summarizes our and others' recent research on oxidative stress in neurological disorders. In the future, the diagnosis and treatment of neurological diseases may be substantially improved by identifying specific early markers of metabolic and energy disorders.
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Affiliation(s)
- Izabela Korczowska-Łącka
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 49, Przybyszewskiego St, 60-355, Poznan, Poland
| | - Mikołaj Hurła
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 49, Przybyszewskiego St, 60-355, Poznan, Poland
| | - Natalia Banaszek
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 49, Przybyszewskiego St, 60-355, Poznan, Poland
| | - Dominik Kobylarek
- Chair and Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland
| | - Oliwia Szymanowicz
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 49, Przybyszewskiego St, 60-355, Poznan, Poland
| | - Wojciech Kozubski
- Chair and Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland
| | - Jolanta Dorszewska
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 49, Przybyszewskiego St, 60-355, Poznan, Poland.
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27
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van Otterdijk SD, Klett H, Boerries M, Michels KB. The impact of pre-pregnancy folic acid intake on placental DNA methylation in a fortified cohort. FASEB J 2023; 37:e22698. [PMID: 36520012 DOI: 10.1096/fj.202200476rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 10/28/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022]
Abstract
Folate plays an important role in the modulation of one-carbon metabolism and DNA methylation through a complex biosynthesis pathway. Folate deficiency during pregnancy has been associated with an increased risk for birth defects. This study investigates the extent to which the availability of folate and S-Adenosylmethionine (SAM) affects placental DNA methylation. We hypothesized that maintaining sufficient levels of folate and SAM is particularly important in individuals carrying the MTHFR C677T polymorphism. Maternal- and cord blood was analyzed to genotype the MTHFR rs1801133 SNP. Red blood cell (RBC) folate, vitamin B12, SAM, and S-Adenosylhomocysteine (SAH) were analyzed in cord blood. Epigenome-wide methylation analyses were performed on 90 placenta tissue samples isolated from the fetal side of the placenta; 45 originating from mother-infant dyads homozygous for the MTHFR C677T variant and 45 originating from mother-infant dyads with the homozygous wild type MTHFR677 genotype. Verification of the results was performed using pyrosequencing assays. Genome-wide placental DNA methylation patterns were relatively stable and not significantly affected by levels of one-carbon metabolites. MTHFR genotype was associated with DNA methylation of several loci, including a locus in the MTHFR region. RBC folate and particularly the SAM:SAH ratio did affect overall CpG DNA methylation in some CpG regions when the loci were split according to their CpG island relation. This was most evident in participants carrying the MTHFR C677T variant suggesting a stronger influence of the biosynthesis pathway on the overall placental DNA methylation in MTHFR TT individuals than in MTHFR CC individuals.
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Affiliation(s)
- Sanne D van Otterdijk
- Institute for Prevention and Cancer Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.,German Cancer Consortium (DKTK), Freiburg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Hagen Klett
- Institute of Medical Bioinformatics and Systems Medicine (IBSM), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Melanie Boerries
- German Cancer Consortium (DKTK), Freiburg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Institute of Medical Bioinformatics and Systems Medicine (IBSM), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Karin B Michels
- Institute for Prevention and Cancer Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.,Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California, USA
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28
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Clement K, McGill MR, Miousse IR, Young SG, Melnyk S, Koturbash I. Methylsulfonylmethane Serves as a Donor of Methyl Groups for Methylation of DNA in Human Liver HepaRG Cells. J Diet Suppl 2022; 20:950-962. [PMID: 36469606 PMCID: PMC10239780 DOI: 10.1080/19390211.2022.2153957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Methylsulfonylmethane (MSM), a natural organosulfur compound, is a popular dietary supplement sold both as a single product and as a constituent of multi-ingredient products. It has been postulated that MSM may serve as a donor for methyl groups for various cellular processes; however, studies have yet to demonstrate this. Therefore, the goal of this study was to determine whether or not MSM, supplemented to fully differentiated human HepaRG cells at physiologically-relevant concentrations, can serve as a donor for methyl groups for DNA methylation. For this purpose, methyl groups in the MSM molecule were labeled with deuterium (deuterated) and incorporation of the labeled 5-methylcytosine into the HepaRG cell DNA was evaluated using liquid chromatography/mass spectrometry (LC-MS/MS). We report that MSM supplementation resulted in significant incorporation of deuterated product into DNA in a time- and dose-dependent fashion. These changes were not associated with increased 5-methylcytosine content, did not result in changes of DNA methylation or re-distribution of DNA methylation patterns between the retrotransposons LINE-1 and HERV18, and were not associated with cytotoxicity. In conclusion, short-term supplementation with MSM in vitro demonstrates that MSM can serve as a donor of methyl groups for methylation of DNA, but does not affect the levels of DNA methylation globally and does not lead to redistribution of the DNA methylation patterns within the most abundant repetitive elements. Future studies will be needed to validate these findings in vivo and to investigate whether or not MSM can restore normal DNA methylation patterns within the hypomethylated phenotype.
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Affiliation(s)
- Kirsten Clement
- Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
- Center for Dietary Supplements Research, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
| | - Mitchell R. McGill
- Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
- Center for Dietary Supplements Research, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
| | - Isabelle R. Miousse
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205 USA
| | - Sean G. Young
- Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
| | - Stepan Melnyk
- Arkansas Children’s Research Institute, Little Rock, AR, 72205, USA
| | - Igor Koturbash
- Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
- Center for Dietary Supplements Research, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
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29
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Congenital Heart Diseases: Genetic Risk Variants and Their Methylation Status. Genes (Basel) 2022; 13:genes13112115. [DOI: 10.3390/genes13112115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/01/2022] [Accepted: 11/05/2022] [Indexed: 11/16/2022] Open
Abstract
(1) Background: The interaction between single nucleotide variants (SNVs) associated with congenital heart diseases (CHDs) and their gene methylation status has not been well researched. The aim of the present study was to determine if there is a relationship between the methy lation status (MS) of genes and the allelic variants associated with CHDs. (2) Methods: Seven SNVs of the genes AXIN1, TBX1, TBX20, and MTHFR were selected from the literature. DNA extraction, genotyping, and a methylation analysis were performed on healthy subjects and subjects with CHDs. (3) Results: Twenty-two subjects with CHDs were selected as the case group (15 with ventricular septal defects (VSDs) and 7 with atrial septal defects (ASDs)), and 44 healthy subjects comprised the control group. The MTHFR and AXIN1 genes were hypermethylated in the control group when compared to the case group. When analyzed separately, those with atrial septum defects exhibited greater methylation, except for the gene MTHFR where there were no differences. Only the alternate alleles of MTHFR showed a significantly different methylation status in those without cardiopathy. (4) Conclusions: The MTHFR and AXIN genes were hypermethylated in the control group; however, only the alternate alleles of MTHFR (rs1801133 and rs1801131) showed a significantly different methylation status.
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Ramos-Lopez O, Martinez JA, Milagro FI. Holistic Integration of Omics Tools for Precision Nutrition in Health and Disease. Nutrients 2022; 14:4074. [PMID: 36235725 PMCID: PMC9572439 DOI: 10.3390/nu14194074] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 09/23/2022] [Accepted: 09/29/2022] [Indexed: 11/16/2022] Open
Abstract
The combination of multiple omics approaches has emerged as an innovative holistic scope to provide a more comprehensive view of the molecular and physiological events underlying human diseases (including obesity, dyslipidemias, fatty liver, insulin resistance, and inflammation), as well as for elucidating unique and specific metabolic phenotypes. These omics technologies include genomics (polymorphisms and other structural genetic variants), epigenomics (DNA methylation, histone modifications, long non-coding RNA, telomere length), metagenomics (gut microbiota composition, enterotypes), transcriptomics (RNA expression patterns), proteomics (protein quantities), and metabolomics (metabolite profiles), as well as interactions with dietary/nutritional factors. Although more evidence is still necessary, it is expected that the incorporation of integrative omics could be useful not only for risk prediction and early diagnosis but also for guiding tailored dietary treatments and prognosis schemes. Some challenges include ethical and regulatory issues, the lack of robust and reproducible results due to methodological aspects, the high cost of omics methodologies, and high-dimensional data analyses and interpretation. In this review, we provide examples of system biology studies using multi-omics methodologies to unravel novel insights into the mechanisms and pathways connecting the genotype to clinically relevant traits and therapy outcomes for precision nutrition applications in health and disease.
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Affiliation(s)
- Omar Ramos-Lopez
- Medicine and Psychology School, Autonomous University of Baja California, Tijuana 22390, Mexico
| | - J. Alfredo Martinez
- Precision Nutrition and Cardiometabolic Health, IMDEA Food Institute, CEI UAM+CSIC, 28049 Madrid, Spain
| | - Fermin I. Milagro
- Department of Nutrition, Food Sciences and Physiology, University of Navarra, 31008 Pamplona, Spain
- Center for Nutrition Research, University of Navarra, 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Institute of Health Carlos III, 28029 Madrid, Spain
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
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Almekkawi AK, AlJardali MW, Daadaa HM, Lane AL, Worner AR, Karim MA, Scheck AC, Frye RE. Folate Pathway Gene Single Nucleotide Polymorphisms and Neural Tube Defects: A Systematic Review and Meta-Analysis. J Pers Med 2022; 12:1609. [PMID: 36294748 PMCID: PMC9605131 DOI: 10.3390/jpm12101609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/05/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
Neural tube defects (NTDs) are congenital abnormalities in the central nervous system. The exact etiology of NTDs is still not determined, but several genetic and epigenetic factors have been studied. Folate supplementation during gestation is recommended to reduce the risk of NTDs. In this review we examine single nucleotide polymorphisms (SNPs) of the genes in the folate pathway associated with NTD. We reviewed the literature for all papers discussing both NTDs and SNPs in the folate pathway. Data were represented through five different genetic models. Quality assessment was performed using the Newcastle-Ottawa Scale (NOS) and Cohen's Kappa inter-rater coefficient assessed author agreement. Fifty-nine papers were included. SNPs in MTHFR, MTRR, RFC genes were found to be highly associated with NTD risk. NOS showed that high quality papers were selected, and Kappa Q-test was 0.86. Our combined results support the notion that SNPs significantly influence NTDs across the population, particularly in Asian ethnicity. Additional high-quality research from diverse ethnicities is needed and meta-regression analysis based on a range of criteria may provide a more complete understanding of the role of folate metabolism in NTDs.
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Affiliation(s)
- Ahmad K. Almekkawi
- Phoenix Children’s Hospital, 1919 E. Thomas Rd, Ambulatory Building, Phoenix, AZ 85016, USA
- College of Medicine, Department of Child Health, University of Arizona, 475 N. 5th Street, Phoenix, AZ 85004, USA
| | - Marwa W. AlJardali
- Rose-Marie Chagoury School of Medicine, Lebanese American University Gilbert, Byblos 1102 2801, Lebanon
| | - Hicham M. Daadaa
- Department of Oncology, St James University Hospital, Beckett St., Harehills, Leeds LS9 7TF, UK
| | - Alison L. Lane
- Phoenix Children’s Hospital, 1919 E. Thomas Rd, Ambulatory Building, Phoenix, AZ 85016, USA
- College of Medicine, Department of Child Health, University of Arizona, 475 N. 5th Street, Phoenix, AZ 85004, USA
| | - Ashley R. Worner
- Phoenix Children’s Hospital, 1919 E. Thomas Rd, Ambulatory Building, Phoenix, AZ 85016, USA
- College of Medicine, Department of Child Health, University of Arizona, 475 N. 5th Street, Phoenix, AZ 85004, USA
| | - Mohammad A. Karim
- Phoenix Children’s Hospital, 1919 E. Thomas Rd, Ambulatory Building, Phoenix, AZ 85016, USA
- College of Medicine, Department of Child Health, University of Arizona, 475 N. 5th Street, Phoenix, AZ 85004, USA
| | - Adrienne C. Scheck
- Phoenix Children’s Hospital, 1919 E. Thomas Rd, Ambulatory Building, Phoenix, AZ 85016, USA
- College of Medicine, Department of Child Health, University of Arizona, 475 N. 5th Street, Phoenix, AZ 85004, USA
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Engelhardt DM, Martyr CA, Niswander L. Pathogenesis of neural tube defects: The regulation and disruption of cellular processes underlying neural tube closure. WIREs Mech Dis 2022; 14:e1559. [PMID: 35504597 PMCID: PMC9605354 DOI: 10.1002/wsbm.1559] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 04/04/2022] [Accepted: 04/06/2022] [Indexed: 11/08/2022]
Abstract
Neural tube closure (NTC) is crucial for proper development of the brain and spinal cord and requires precise morphogenesis from a sheet of cells to an intact three-dimensional structure. NTC is dependent on successful regulation of hundreds of genes, a myriad of signaling pathways, concentration gradients, and is influenced by epigenetic and environmental cues. Failure of NTC is termed a neural tube defect (NTD) and is a leading class of congenital defects in the United States and worldwide. Though NTDs are all defined as incomplete closure of the neural tube, the pathogenesis of an NTD determines the type, severity, positioning, and accompanying phenotypes. In this review, we survey pathogenesis of NTDs relating to disruption of cellular processes arising from genetic mutations, altered epigenetic regulation, and environmental influences by micronutrients and maternal condition. This article is categorized under: Congenital Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Stem Cells and Development.
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Affiliation(s)
- David M Engelhardt
- Molecular Cellular Developmental Biology, University of Colorado, Boulder, Colorado, USA
| | - Cara A Martyr
- Molecular Cellular Developmental Biology, University of Colorado, Boulder, Colorado, USA
| | - Lee Niswander
- Molecular Cellular Developmental Biology, University of Colorado, Boulder, Colorado, USA
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33
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Dvoran M, Nemcova L, Kalous J. An Interplay between Epigenetics and Translation in Oocyte Maturation and Embryo Development: Assisted Reproduction Perspective. Biomedicines 2022; 10:biomedicines10071689. [PMID: 35884994 PMCID: PMC9313063 DOI: 10.3390/biomedicines10071689] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/25/2022] [Accepted: 06/28/2022] [Indexed: 12/11/2022] Open
Abstract
Germ cell quality is a key prerequisite for successful fertilization and early embryo development. The quality is determined by the fine regulation of transcriptomic and proteomic profiles, which are prone to alteration by assisted reproduction technology (ART)-introduced in vitro methods. Gaining evidence shows the ART can influence preset epigenetic modifications within cultured oocytes or early embryos and affect their developmental competency. The aim of this review is to describe ART-determined epigenetic changes related to the oogenesis, early embryogenesis, and further in utero development. We confront the latest epigenetic, related epitranscriptomic, and translational regulation findings with the processes of meiotic maturation, fertilization, and early embryogenesis that impact the developmental competency and embryo quality. Post-ART embryo transfer, in utero implantation, and development (placentation, fetal development) are influenced by environmental and lifestyle factors. The review is emphasizing their epigenetic and ART contribution to fetal development. An epigenetic parallel among mouse, porcine, and bovine animal models and human ART is drawn to illustrate possible future mechanisms of infertility management as well as increase the awareness of the underlying mechanisms governing oocyte and embryo developmental complexity under ART conditions.
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Huang W, Yuan Z, Gu H. Exploring epigenomic mechanisms of neural tube defects using multi-omics methods and data. Ann N Y Acad Sci 2022; 1515:50-60. [PMID: 35666948 DOI: 10.1111/nyas.14802] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Neural tube defects (NTDs) are a heterogeneous set of malformations attributed to disruption in normal neural tube closure during early embryogenesis. An in-depth understanding of NTD etiology and mechanisms remains elusive, however. Among the proposed mechanisms, epigenetic changes are thought to play an important role in the formation of NTDs. Epigenomics covers a wide spectrum of genomic DNA sequence modifications that can be investigated via high-throughput techniques. Recent advances in epigenomic technologies have enabled epigenetic studies of congenital malformations and facilitated the integration of big data into the understanding of NTDs. Herein, we review clinical epigenomic data that focuses on DNA methylation, histone modification, and miRNA alterations in human neural tissues, placental tissues, and leukocytes to explore potential mechanisms by which candidate genes affect human NTD pathogenesis. We discuss the links between epigenomics and gene regulatory mechanisms, and the effects of epigenetic alterations in human tissues on neural tube closure.
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Affiliation(s)
- Wanqi Huang
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital, China Medical University, Shenyang, China
| | - Zhengwei Yuan
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital, China Medical University, Shenyang, China
| | - Hui Gu
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital, China Medical University, Shenyang, China
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35
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Abdel Allah HMM, Zahran WE, El-Masry SA, El-Bendary M, Soliman AF. Association of MTHFR and TYMS gene polymorphisms with the susceptibility to HCC in Egyptian HCV cirrhotic patients. Clin Exp Med 2022; 22:257-267. [PMID: 34297238 DOI: 10.1007/s10238-021-00747-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 07/12/2021] [Indexed: 12/24/2022]
Abstract
Identification of host genetic factors influencing the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection may help to refine patients' selection to benefit from specific preventative measures and/or adapted screening policies. Thus, this study aimed to investigate the association of MTHFR c.677C > T and c.1298A > C in addition to TYMS 3'-UTR 6-bp ins/del polymorphisms with the susceptibility to HCV-related HCC in an Egyptian population. Polymerase chain reaction-restriction fragment length polymorphism was performed to genotype the polymorphisms in 194 HCV-infected patients subdivided into liver cirrhotic (LC, n = 104) and HCC (n = 90) patients as well as 100 healthy subjects. In healthy controls, the MTHFR c.677C > T polymorphism under the homozygous and recessive models (p = 0.005) and the c.1298A > C polymorphism under all the tested genetic models (p-values range from < 0.001 to 0.007) were associated with an increased risk of HCC. In LC patients, the MTHFR c.677C > T polymorphism under the homozygous, dominant, and recessive models (p-values range from 0.001 to 0.007), as well as MTHFR c.1298A > C under the homozygous model only (p = 0.014), increased the susceptibility to HCC. The C/C and T/C haplotypes of MTHFR c.677C > T and MTHFR c.1298A > C polymorphisms were contributed to an increased risk of healthy subjects to develop HCC (p-values range from < 0.001 to 0.015), while only the T/C haplotype was associated with the progression of HCC in LC patients (p = 0.001). In conclusion, MTHFR c.677C > T and c.1298A > C in addition to their haplotypes may contribute to the development of HCV-related HCC in an Egyptian population. These findings may aid in the early diagnosis and management of HCC.
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Affiliation(s)
| | - Walid E Zahran
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Samir A El-Masry
- Molecular Biology Department, Genetic Engineering and Biotechnology Institute, University of Sadat City, Menoufia, Egypt
| | - Mahmoud El-Bendary
- Tropical Medicine and Hepatology Department, Faculty of Medicine, Mansoura University, Dakahlia, Egypt
| | - Ahmed F Soliman
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt.
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36
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Fernandez C, Tennyson J, Priscilla AS. Osteoporosis and its Association with Vitamin D Receptor, Oestrogen α Receptor, Parathyroid Receptor and Collagen Type I alpha Receptor Gene Polymorphisms with Bone Mineral Density: A Pilot Study from South Indian Postmenopausal Women of Tamil Nadu. Biochem Genet 2022; 60:2015-2036. [PMID: 35195794 DOI: 10.1007/s10528-022-10197-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 02/02/2022] [Indexed: 11/29/2022]
Abstract
The involvement of many putative genetic factors makes osteoporosis a complex disease. With increasing longevity of the Indian population, it's now being realized that, as within the West, osteoporotic fractures are also a significant explanation for morbidity and mortality in postmenopausal women. Studies have suggested that the genetic component liable for bone mass could be linked to single nucleotide polymorphisms. Therefore, this study is aimed to research the role of seven gene polymorphisms previously associated with bone phenotype in a cohort of postmenopausal South Indian women from Tamil Nadu. The subjects for the study (n = 300) included 100 osteoporotic women (age 59.3 ± 9.26), 100 osteopenic women (age 55.6 ± 8.17) and 100 non-osteoporotic women as controls (age 55.4 ± 8.85).Genetic polymorphisms were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Case-control genetic association analysis of BsmI of the VDR and BstBI of the PTH gene showed a significant allelic association with low bone mineral density amongst the osteoporotic postmenopausal women. The association of BMD with the VDR gene polymorphisms revealed that the average BMD in the BsmI polymorphism with the recessive genotype GG in osteoporotic women was significantly reduced compared with the average BMD in osteoporotic women with AA and AG genotypes. In the BstBI polymorphism, the BMD in the osteoporotic subjects were significantly lower in the AA group than in the GA and GG groups. These results provide evidence for an independent association between BMD and rs1544410 in VDR and rs6254 in PTH and may contribute in being a possible genetic marker for predicting the disease susceptibility in the population tested.
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Affiliation(s)
- Chrisanne Fernandez
- Department of Zoology and Research Centre, Lady Doak College, Madurai, Tamil Nadu, 625002, India
| | - Jebasingh Tennyson
- Department of Plant Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India
| | - A S Priscilla
- Department of Zoology and Research Centre, Lady Doak College, Madurai, Tamil Nadu, 625002, India.
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Mohd Y, Kumar P, Kuchi Bhotla H, Meyyazhagan A, Balasubramanian B, Ramesh Kumar MK, Pappusamy M, Alagamuthu KK, Orlacchio A, Keshavarao S, Sampathkumar P, Arumugam VA. Transmission Jeopardy of Adenomatosis Polyposis Coli and Methylenetetrahydrofolate Reductase in Colorectal Cancer. J Renin Angiotensin Aldosterone Syst 2021; 2021:7010706. [PMID: 34956401 PMCID: PMC8683247 DOI: 10.1155/2021/7010706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 10/14/2021] [Accepted: 11/18/2021] [Indexed: 11/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the globally prevalent and virulent types of cancer with a distinct alteration in chromosomes. Often, any alterations in the adenomatosis polyposis coli (APC), a tumor suppressor gene, and methylenetetrahydrofolate reductase (MTHFR) gene are related to surmise colorectal cancer significantly. In this study, we have investigated chromosomal and gene variants to discern a new-fangled gene and its expression in the southern populations of India by primarily spotting the screened APC and MTHFR variants in CRC patients. An equal number of CRC patients and healthy control subjects (n = 65) were evaluated to observe a chromosomal alteration in the concerted and singular manner for APC and MTHFR genotypes using standard protocols. The increasing prognosis was observed in persons with higher alcoholism and smoking (P < 0.05) with frequent alterations in chromosomes 1, 5, 12, 13, 15, 17, 18, 21, and 22. The APC Asp 1822Val and MTHFR C677T genotypes provided significant results, while the variant alleles of this polymorphism were linked with an elevated risk of CRC. Chromosomal alterations can be the major cause in inducing carcinogenic outcomes in CRCs and can drive to extreme pathological states.
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Affiliation(s)
- Younis Mohd
- Medical Genetics and Epigenetics Laboratory, Department of Human Genetics and Molecular Biology, School of Life Sciences, Bharathiar University, 641046 Tamil Nadu, India
| | - Parvinder Kumar
- Department of Zoology, Jammu University, Jammu, 180006 Jammu and Kashmir, India
- Institution of Human Genetics, Jammu University, Jammu, 180006 Jammu and Kashmir, India
| | - Haripriya Kuchi Bhotla
- Human Genetics Laboratory, Department of Zoology, School of Life Sciences, Bharathiar University, Coimbatore, 461046 Tamil Nadu, India
| | - Arun Meyyazhagan
- Department of Life Sciences, CHRIST (Deemed to be University), Bangalore 560029, India
| | | | - Mithun Kumar Ramesh Kumar
- Department of General Surgery, Mahatma Gandhi Medical College and Research Institute, Pillaiyarkuppam, 607403 Pondicherry, India
| | - Manikantan Pappusamy
- Department of Life Sciences, CHRIST (Deemed to be University), Bangalore 560029, India
| | - Karthick Kumar Alagamuthu
- Department of Biotechnology, Selvamm Arts and Science College (Autonomous), Namakkal, Tamil Nadu 637003, India
| | - Antonio Orlacchio
- Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Sasikala Keshavarao
- Human Genetics Laboratory, Department of Zoology, School of Life Sciences, Bharathiar University, Coimbatore, 461046 Tamil Nadu, India
| | - Palanisamy Sampathkumar
- Department of Chemistry and Biosciences, SASTRA Deemed to be University, Kumbakonam Tamil Nadu 612001, India
| | - Vijaya Anand Arumugam
- Medical Genetics and Epigenetics Laboratory, Department of Human Genetics and Molecular Biology, School of Life Sciences, Bharathiar University, 641046 Tamil Nadu, India
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Li H, Fernández-Guasti A, Xu Y, Swaab D. Retracted: Sexual orientation, neuropsychiatric disorders and the neurotransmitters involved. Neurosci Biobehav Rev 2021; 131:479-488. [PMID: 34597715 DOI: 10.1016/j.neubiorev.2021.09.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 08/17/2021] [Accepted: 09/26/2021] [Indexed: 11/26/2022]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor in Chief of Neuroscience and Biobehavioral Reviews after concerns were raised with respect to the phrasing of comparisons drawn between humans and animal models. These comparisons were deemed unsupportable, and thus in the best interests of publication standards the Editor has concluded it is necessary to retract the paper. The authors disagree with the reason for the retraction.
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Affiliation(s)
- Haimei Li
- Department of Psychiatry, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, PR China; Department of Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, Amsterdam, 1105 BA, the Netherlands
| | | | - Yi Xu
- Department of Psychiatry, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, PR China; The Key Laboratory of Mental Disorder Management in Zhejiang Province, Hangzhou, 310003, PR China; Zhejiang Engineering Center for Mathematical Mental Health, Hangzhou, 310003, PR China; Brain Research Institute of Zhejiang University, Hangzhou, 31003, PR China.
| | - Dick Swaab
- Department of Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, Amsterdam, 1105 BA, the Netherlands.
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Chen CH, Chen PY, Chen CYA, Chiu CC, Lu ML, Huang MC, Lin YK, Chen YH. Associations of Genetic Variants of Methylenetetrahydrofolate Reductase and Serum Folate Levels with Metabolic Parameters in Patients with Schizophrenia. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph182111333. [PMID: 34769853 PMCID: PMC8583146 DOI: 10.3390/ijerph182111333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 10/18/2021] [Accepted: 10/26/2021] [Indexed: 11/16/2022]
Abstract
The one-carbon metabolism pathway is a suitable candidate for studying the genetic and epigenetic factors contributing to metabolic abnormalities in patients with schizophrenia. We recruited 232 patients with schizophrenia and analyzed their serum folate, vitamin B12, and homocysteine levels and metabolic parameters to investigate the associations of genetic variants of methylenetetrahydrofolate reductase (MTHFR) and folate levels with metabolic parameters. MTHFR C677T and MTHFR A1298C were genotyped. Results showed that MTHFR 677T allele carriers had lower levels of total cholesterol and low-density lipoprotein cholesterol than those with the 677CC genotype. Metabolic parameters did not differ between MTHFR 1298C and 1298AA carriers. Patients with a low folate level had a lower high-density lipoprotein cholesterol level than those with a normal folate level, but the effect disappeared after adjustment for age, sex, and types of antipsychotics used. We found significant interactions between MTHFR A1298C and the folate level status (low vs. normal) in terms of body mass index and waist circumference. In conclusion, genetic variants in one-carbon metabolism might play a role in antipsychotic-induced metabolic abnormalities. Prospective studies on drug-naïve, first-episode patients with schizophrenia are warranted to identify key regions of DNA methylation changes accounting for antipsychotic-induced metabolic abnormalities.
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Affiliation(s)
- Chun-Hsin Chen
- Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (C.-C.C.); (M.-L.L.); (M.-C.H.)
- Department of Psychiatry, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan;
- Correspondence: (C.-H.C.); (Y.-H.C.); Tel.: +886-2-2930-7930 (ext. 53961) (C.-H.C.); Fax: +886-2-2933-5221 (C.-H.C.)
| | - Po-Yu Chen
- Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei 110, Taiwan;
- Graduate Institute of Medical Science, School of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Cynthia Yi-An Chen
- Department of Psychiatry, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan;
| | - Chih-Chiang Chiu
- Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (C.-C.C.); (M.-L.L.); (M.-C.H.)
- Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei 110, Taiwan;
| | - Mong-Liang Lu
- Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (C.-C.C.); (M.-L.L.); (M.-C.H.)
- Department of Psychiatry, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan;
| | - Ming-Chyi Huang
- Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (C.-C.C.); (M.-L.L.); (M.-C.H.)
- Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei 110, Taiwan;
| | - Yen-Kuang Lin
- Biostatistics Center, Taipei Medical University, Taipei 110, Taiwan;
| | - Yi-Hua Chen
- School of Public Health, College of Public Health, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: (C.-H.C.); (Y.-H.C.); Tel.: +886-2-2930-7930 (ext. 53961) (C.-H.C.); Fax: +886-2-2933-5221 (C.-H.C.)
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Ghorbani M, Azghandi M, Khayami R, Baharara J, Kerachian MA. Association of MTHFR C677T variant genotype with serum folate and Vit B12 in Iranian patients with colorectal cancer or adenomatous polyps. BMC Med Genomics 2021; 14:246. [PMID: 34645434 PMCID: PMC8513199 DOI: 10.1186/s12920-021-01097-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 10/08/2021] [Indexed: 12/24/2022] Open
Abstract
Background The incidence of colorectal cancer (CRC) has increased during recent years in Iran and other developing countries. Clinical studies suggest that essential folate dietary intake and moderate deficiency of methylenetetrahydrofolate reductase (MTHFR) may protect and reduce the risk of CRC. The present study aimed to investigate the clinical significance of C677T polymorphism within the MTHFR gene and its correlation with the serum folate and Vit B12 in the Iranian population suffering from CRC. Methods Blood samples were taken from 1017 Iranian individuals (517 cases and 500 controls) who were referred for colonoscopy. TaqMan probe assay was performed for C677T MTHFR polymorphism. Sera were fractionated from the blood samples of 43 patients and controls and folate and Vit B12 concentrations were measured by a monobind kit. The correlation of MTHFR polymorphisms and folate/vitamin-B12 with CRC risk was analyzed. Results In the current study, we found the frequency of three different genotypes of MTHFR polymorphism in the Iranian population i.e., CC, CT, and TT, to be 51.31, 26.73, 21.96 and 61, 32.2, 6.8 in case and control groups, respectively. The homozygote genotype of MTHFR rs1801133 polymorphism is associated with an increased risk of CRC by 3.68, 1.42, and 3.74-fold in codominant, dominant, and recessive models respectively (p value < 0.01). Our study revealed that there was no significant difference between the amount of folate and Vit B12 in the case and control groups (p value > 0.05). Conclusions This study revealed that there was no significant difference between the amount of folate and Vit B12 in the case and control groups. Furthermore, our results demonstrated a higher risk association for 677TT and 677TT + C677T genotypes of MTHFR compared with 677CC carriers among CRC patients.
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Affiliation(s)
- Mahla Ghorbani
- Department of Biology, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Marjan Azghandi
- Cancer Genetics Research Unit, Reza Radiotherapy and Oncology Center, Mashhad, Iran.,Department of Animal Science, Faculty of Agriculture, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Reza Khayami
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Javad Baharara
- Research Center for Animal Development Applied Biology and Biology Department, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Mohammad Amin Kerachian
- Cancer Genetics Research Unit, Reza Radiotherapy and Oncology Center, Mashhad, Iran. .,Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. .,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Xiang M, Wang Z, Zou P, Ling X, Zhang G, Zhou Z, Cao J, Ao L. Folate metabolism modifies chromosomal damage induced by 1,3-butadiene: results from a match-up study in China and in vitro experiments. Genes Environ 2021; 43:44. [PMID: 34627392 PMCID: PMC8501532 DOI: 10.1186/s41021-021-00217-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/16/2021] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVES To explore the role of folate metabolism in 1,3-Butadiene (BD)'s genotoxicity, we conducted a match-up study in BD-exposed workers in China to analyze the associations between the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and the chromosomal damage induced by BD exposure, and culture-based experiments in TK-6 cells to examine the global DNA methylation levels and chromosomal damage when exposed both to BD's genotoxic metabolite, 1,2:3,4-diepoxybutane (DEB), and MTHFR's direct catalytic product, 5-methyltetrahydrofolate (5-MTHF). METHODS Cytokinesis block micronucleus assay (CBMN) was used to examine the chromosomal damage induced by BD or DEB. Poisson regression models were produced to quantify the relationship of chromosomal damage and genetic polymorphisms in the BD-exposed workers. Global DNA methylation levels in TK6 cells were examined using DNA Methylation Quantification Kit. RESULTS We found that BD-exposed workers carrying MTHFR C677T CC (2.00 ± 2.00‰) (FR = 0.36, 95%CI: 0.20-0.67, P < 0.01) or MTHFR C677T CT (2.87 ± 1.98‰) (FR = 0.49, 95%CI: 0.32-0.77, P < 0.01) genotypes had significantly lower nuclear bud (NBUD) frequencies than those carrying genotype MTHFR 677 TT (5.33 ± 2.60‰), respectively. The results in TK6 cells showed that there was a significant increment in frequencies of micronucleus (MN), nucleoplasmic bridge (NPB) and nuclear bud (NBUD) with exposure to DEB at each 5-MTHF dose (ANOVA, P < 0.01). Additionally, there was a significant decrease in frequencies of MN, NPB and NBUD in DEB-exposed cultures with increasing concentration of 5-MTHF (ANOVA, P < 0.05). The levels of global DNA methylation were significantly decreased by DEB treatment in a dose-dependent manner within each 5-MTHF concentration in TK-6 cells (ANOVA, P < 0.01), and were significantly increased by 5-MTHF supplementation within each DEB concentration (ANOVA, P < 0.01). CONCLUSION We reported that folate metabolism could modify the association between BD exposure and chromosomal damage, and such effect may be partially mediated by DNA hypomethylation, and 5-MTHF supplementation could rescue it.
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Affiliation(s)
- Menglong Xiang
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China
| | - Zhi Wang
- Center for Disease Control and Prevention of Northern Theater Command, Shenyang, Liaoning Province, China
| | - Peng Zou
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China, 400038
| | - Xi Ling
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China, 400038
| | - Guowei Zhang
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China
| | - Ziyuan Zhou
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China
| | - Jia Cao
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China, 400038
| | - Lin Ao
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China, 400038.
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Alhumaydhi FA, Mackawy AMH, Morgan EN, Al Abdulmonem W, Alsagaby SA, Alwashmi ASS, Aljohani ASM, Aljasir MA, Almatroodi SA, Alruwetei AM, Mousa AM. Potential role of folic acid in preventing male infertility associated with MTHFR gene C677T (rs1801133) polymorphism. ALL LIFE 2021. [DOI: 10.1080/26895293.2021.1963846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Affiliation(s)
- Fahad A. Alhumaydhi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Amal M. H. Mackawy
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
- Department of Medical Biochemistry, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Enas N. Morgan
- Department of Physical Therapy, College of Medical Rehabilitation, Qassim University, Buraydah, Saudi Arabia
- Department of Physiology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Suliman A. Alsagaby
- Department of Medical Laboratories Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, Saudi Arabia
| | - Ameen S. S. Alwashmi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Abdullah S. M. Aljohani
- Department of Veterinary Medicine, College of Agricultural and Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Mohammad A. Aljasir
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Saleh A. Almatroodi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Abdulmohsen M. Alruwetei
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Ayman M. Mousa
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
- Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Benha, Egypt
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Insights into the role of epigenetic mechanisms in migraine: the future perspective of disease management. THE NUCLEUS 2021. [DOI: 10.1007/s13237-021-00366-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
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Li Z, Zhang J, Zou W, Xu Q, Li S, Wu J, Zhu L, Zhang Y, Xu L, Zhang Y, Luo Q, Nie J, Li X, Zou T, Chen C. The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism is associated with breast cancer subtype susceptibility in southwestern China. PLoS One 2021; 16:e0254267. [PMID: 34242313 PMCID: PMC8270429 DOI: 10.1371/journal.pone.0254267] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 06/24/2021] [Indexed: 12/04/2022] Open
Abstract
Methylenetetrahydrofolate reductase (MTHFR), a folate-dependent enzyme, is reportedly involved in several cancer types. The MTHFR C677T polymorphism influences many biological processes, including tumorigenesis. However, the association between the MTHFR C677T polymorphism and breast cancer (BC) subtypes is not fully understood. In this study, the MTHFR C677T polymorphism was genotyped in 490 individuals with or without BC from southwestern China. Analysis of the association between the MTHFR C677T polymorphism and BC revealed that there was a significant association between the MTHFR C677T polymorphism and triple-negative breast cancer (TNBC) (OR = 2.83, 95% CI: 1.12-9.51, P = 0.0401). Furthermore, the MTHFR C677T polymorphism can also serve as a protective factor in luminal A breast cancer (OR = 0.57, 95% CI: 0.34-0.94, P = 0.0258). Evaluation of the association between the MTHFR C677T polymorphism and clinical characteristics indicated that people who suffered from hypertension had an increased risk for BC (OR = 2.27; 95% CI: 1.08-4.6; P = 0.0264), especially TNBC (OR = 215.38; 95% CI: 2.45-84430.3; P = 0.0317). Our results suggest that the MTHFR C677T polymorphism is significantly associated with susceptibility to luminal B breast cancer and TNBC.
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Affiliation(s)
- Zhen Li
- Department of Breast Surgery, Yunnan Tumor Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Ji Zhang
- Department of Breast Surgery, Yunnan Tumor Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Wei Zou
- Queen Mary Institute, Nanchang University, Nanchang, China
| | - Qi Xu
- Department of Molecular Biosciences, Institute of Cellular and Molecular Biology, The University of Texas, Austin, Texas, United States of America
| | - Siyuan Li
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China
| | - Jie Wu
- Yunnan Economy & Society Bigdata Research Institute, Yunnan University of Finance and Economics, Kunming, Yunan, China
| | - Li Zhu
- Yunnan Economy & Society Bigdata Research Institute, Yunnan University of Finance and Economics, Kunming, Yunan, China
| | - Yunjiao Zhang
- Kunming Medical University Haiyuan College, Kunming, Yunnan, China
| | - Lei Xu
- Yunnan Economy & Society Bigdata Research Institute, Yunnan University of Finance and Economics, Kunming, Yunan, China
| | - Ying Zhang
- Department of Breast Surgery, Yunnan Tumor Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Qingsong Luo
- Department of Breast Surgery, Yunnan Tumor Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Jianyun Nie
- Department of Breast Surgery, Yunnan Tumor Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Xingxu Li
- Yunnan Economy & Society Bigdata Research Institute, Yunnan University of Finance and Economics, Kunming, Yunan, China
| | - Tianning Zou
- Department of Breast Surgery, Yunnan Tumor Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China
- China Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
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Hitchler MJ, Domann FE. The epigenetic and morphogenetic effects of molecular oxygen and its derived reactive species in development. Free Radic Biol Med 2021; 170:70-84. [PMID: 33450377 PMCID: PMC8217084 DOI: 10.1016/j.freeradbiomed.2021.01.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 12/11/2022]
Abstract
The development of multicellular organisms involves the unpacking of a complex genetic program. Extensive characterization of discrete developmental steps has revealed the genetic program is controlled by an epigenetic state. Shifting the epigenome is a group of epigenetic enzymes that modify DNA and proteins to regulate cell type specific gene expression. While the role of these modifications in development has been established, the input(s) responsible for electing changes in the epigenetic state remains unknown. Development is also associated with dynamic changes in cellular metabolism, redox, free radical production, and oxygen availability. It has previously been postulated that these changes are causal in development by affecting gene expression. This suggests that oxygen is a morphogenic compound that impacts the removal of epigenetic marks. Likewise, metabolism and reactive oxygen species influence redox signaling through iron and glutathione to limit the availability of key epigenetic cofactors such as α-ketoglutarate, ascorbate, NAD+ and S-adenosylmethionine. Given the close relationship between these cofactors and epigenetic marks it seems likely that the two are linked. Here we describe how changing these inputs might affect the epigenetic state during development to drive gene expression. Combined, these cofactors and reactive oxygen species constitute the epigenetic landscape guiding cells along differing developmental paths.
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Affiliation(s)
- Michael J Hitchler
- Department of Radiation Oncology, Kaiser Permanente Los Angeles Medical Center, 4950 Sunset Blvd, Los Angeles, CA, 90027, USA.
| | - Frederick E Domann
- Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa, Iowa City, IA, 52242, USA.
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Sun M, Wang T, Huang P, Diao J, Zhang S, Li J, Luo L, Li Y, Chen L, Liu Y, Wei J, Song X, Sheng X, Qin J. Association analysis of maternal MTHFR gene polymorphisms and the occurrence of congenital heart disease in offspring. BMC Cardiovasc Disord 2021; 21:298. [PMID: 34126931 PMCID: PMC8204503 DOI: 10.1186/s12872-021-02117-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 06/10/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Although many studies showed that the risk of congenital heart disease (CHD) was closely related to genetic factors, the exact pathogenesis is still unknown. Our study aimed to comprehensively assess the association of single nucleotide polymorphisms (SNPs) of maternal MTHFR gene with risk of CHD and its three subtypes in offspring. METHODS A case-control study involving 569 mothers of CHD cases and 652 health controls was conducted. Thirteen SNPs were detected and analyzed. RESULTS Our study showed that genetic polymorphisms of maternal MTHFR gene at rs4846052 and rs1801131 were significantly associated with risk of CHD in the homozygote comparisons (TT vs. CC at rs4846052: OR = 7.62 [95%CI 2.95-19.65]; GG vs. TT at rs1801131: OR = 5.18 [95%CI 2.77-9.71]). And six haplotypes of G-C (involving rs4846048 and rs2274976), A-C (involving rs1801133 and rs4846052), G-T (involving rs1801133 and rs4846052), G-T-G (involving rs2066470, rs3737964 and rs535107), A-C-G (involving rs2066470, rs3737964 and rs535107) and G-C-G (involving rs2066470, rs3737964 and rs535107) were identified to be significantly associated with risk of CHD. Additionally, we observed that a two-locus model involving rs2066470 and rs1801131 as well as a three-locus model involving rs227497, rs1801133 and rs1801131 were significantly associated with risk of CHD in the gene-gene interaction analyses. For three subtypes including atrial septal defect, ventricular septal defect and patent ductus arteriosus, similar results were observed. CONCLUSIONS Our study indicated genetic polymorphisms of maternal MTHFR gene were significantly associated with risk of fetal CHD in the Chinese population. Additionally, there were significantly interactions among different SNPs on risk of CHD. However, how these SNPs affect the development of fetal heart remains unknown, and more studies in different ethnic populations and with a larger sample are required to confirm these findings.
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Affiliation(s)
- Mengting Sun
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China
| | - Tingting Wang
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China. .,NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, 78 Xiangchun Road, Changsha, 410008, Hunan, China.
| | - Peng Huang
- Department of Cardiothoracic Surgery, Hunan Children's Hospital, Changsha, Hunan, China
| | - Jingyi Diao
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China
| | - Senmao Zhang
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China
| | - Jinqi Li
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China
| | - Liu Luo
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China
| | - Yihuan Li
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China
| | - Letao Chen
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China
| | - Yiping Liu
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China
| | - Jianhui Wei
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China
| | - Xinli Song
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China
| | - Xiaoqi Sheng
- NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, 78 Xiangchun Road, Changsha, 410008, Hunan, China.
| | - Jiabi Qin
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China. .,NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, 78 Xiangchun Road, Changsha, 410008, Hunan, China. .,Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China. .,Hunan Provincial Key Laboratory of Clinical Epidemiology, Hunan, China.
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The role of DNA methylation in syndromic and non-syndromic congenital heart disease. Clin Epigenetics 2021; 13:93. [PMID: 33902696 PMCID: PMC8077695 DOI: 10.1186/s13148-021-01077-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 04/13/2021] [Indexed: 02/07/2023] Open
Abstract
Congenital heart disease (CHD) is a common structural birth defect worldwide, and defects typically occur in the walls and valves of the heart or enlarged blood vessels. Chromosomal abnormalities and genetic mutations only account for a small portion of the pathogenic mechanisms of CHD, and the etiology of most cases remains unknown. The role of epigenetics in various diseases, including CHD, has attracted increased attention. The contributions of DNA methylation, one of the most important epigenetic modifications, to CHD have not been illuminated. Increasing evidence suggests that aberrant DNA methylation is related to CHD. Here, we briefly introduce DNA methylation and CHD and then review the DNA methylation profiles during cardiac development and in CHD, abnormalities in maternal genome-wide DNA methylation patterns are also described. Whole genome methylation profile and important differentially methylated genes identified in recent years are summarized and clustered according to the sample type and methodologies. Finally, we discuss the novel technology for and prospects of CHD-related DNA methylation.
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Petrone I, Bernardo PS, dos Santos EC, Abdelhay E. MTHFR C677T and A1298C Polymorphisms in Breast Cancer, Gliomas and Gastric Cancer: A Review. Genes (Basel) 2021; 12:587. [PMID: 33920562 PMCID: PMC8073588 DOI: 10.3390/genes12040587] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/08/2021] [Accepted: 04/15/2021] [Indexed: 02/07/2023] Open
Abstract
Folate (vitamin B9) is found in some water-soluble foods or as a synthetic form of folic acid and is involved in many essential biochemical processes. Dietary folate is converted into tetrahydrofolate, a vital methyl donor for most methylation reactions, including DNA methylation. 5,10-methylene tetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate metabolism pathway that converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which produces a methyl donor for the remethylation of homocysteine to methionine. MTHFR polymorphisms result in reduced enzyme activity and altered levels of DNA methylation and synthesis. MTHFR polymorphisms have been linked to increased risks of several pathologies, including cancer. Breast cancer, gliomas and gastric cancer are highly heterogeneous and aggressive diseases associated with high mortality rates. The impact of MTHFR polymorphisms on these tumors remains controversial in the literature. This review discusses the relationship between the MTHFR C677T and A1298C polymorphisms and the increased risk of breast cancer, gliomas, and gastric cancer. Additionally, we highlight the relevance of ethnic and dietary aspects of population-based studies and histological stratification of highly heterogeneous tumors. Finally, this review discusses these aspects as potential factors responsible for the controversial literature concerning MTHFR polymorphisms.
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Affiliation(s)
- Igor Petrone
- Stem Cell Laboratory, Center for Bone Marrow Transplants, Brazilian National Cancer Institute—INCA, Rio de Janeiro 20230-240, Brazil; (E.C.d.S.); (E.A.)
- Stricto Sensu Graduate Program in Oncology, INCA, Rio de Janeiro 20230-240, Brazil;
| | - Paula Sabbo Bernardo
- Stricto Sensu Graduate Program in Oncology, INCA, Rio de Janeiro 20230-240, Brazil;
- Laboratory of Cellular and Molecular Hemato-Oncology, Molecular Hemato-Oncology Program, Brazilian National Cancer Institute—INCA, Rio de Janeiro 20230-240, Brazil
| | - Everton Cruz dos Santos
- Stem Cell Laboratory, Center for Bone Marrow Transplants, Brazilian National Cancer Institute—INCA, Rio de Janeiro 20230-240, Brazil; (E.C.d.S.); (E.A.)
- Stricto Sensu Graduate Program in Oncology, INCA, Rio de Janeiro 20230-240, Brazil;
| | - Eliana Abdelhay
- Stem Cell Laboratory, Center for Bone Marrow Transplants, Brazilian National Cancer Institute—INCA, Rio de Janeiro 20230-240, Brazil; (E.C.d.S.); (E.A.)
- Stricto Sensu Graduate Program in Oncology, INCA, Rio de Janeiro 20230-240, Brazil;
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Kim JH, Khan IU, Lee CW, Kim DY, Jang CS, Lim SD, Park YC, Kim JH, Seo YW. Identification and analysis of a differentially expressed wheat RING-type E3 ligase in spike primordia development during post-vernalization. PLANT CELL REPORTS 2021; 40:543-558. [PMID: 33423075 DOI: 10.1007/s00299-020-02651-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 12/06/2020] [Indexed: 06/12/2023]
Abstract
We identified a RING-type E3 ligase (TaBAH1) protein in winter wheat that targets TaSAHH1 for degradation and might be involved in primordia development by regulating targeted protein degradation. Grain yield per spike in wheat (Triticum aestivum), is mainly determined prior to flowering during mature primordia development; however, the genes involved in primordia development have yet to be characterized. In this study, we demonstrated that, after vernalization for 50 days at 4 °C, there was a rapid acceleration in primordia development to the mature stages in the winter wheat cultivars Keumgang and Yeongkwang compared with the Chinese Spring cultivar. Although Yeongkwang flowers later than Keumgang under normal condition, it has the same heading time and reaches the WS9 stage of floral development after vernalization for 50 days. Using RNA sequencing, we identified candidate genes associated with primordia development in cvs. Keumgang and Yeongkwang, that are differentially expressed during wheat reproductive stages. Among these, the RING-type E3 ligase TaBAH1 (TraesCS5B01G373000) was transcriptionally upregulated between the double-ridge (WS2.5) stage and later stages of floret primordia development (WS10) after vernalization. Transient expression analysis indicated that TaBAH1 was localized to the plasma membrane and nucleus and was characterized by self-ubiquitination activity. Furthermore, we found that TaBAH1 interacts with TaSAHH1 to mediate its polyubiquitination and degradation through a 26S proteasomal pathway. Collectively, the findings of this study indicate that TaBAH1 might play a prominent role in post-vernalization floret primordia development.
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Affiliation(s)
- Jae Ho Kim
- Department of Plant Biotechnology, Korea University, Seongbuk-Gu, Seoul, 02841, Republic of Korea
| | - Irfan Ullah Khan
- Department of Plant Biotechnology, Korea University, Seongbuk-Gu, Seoul, 02841, Republic of Korea
| | - Cheol Won Lee
- Department of Plant Biotechnology, Korea University, Seongbuk-Gu, Seoul, 02841, Republic of Korea
| | - Dae Yeon Kim
- Department of Plant Biotechnology, Korea University, Seongbuk-Gu, Seoul, 02841, Republic of Korea
| | - Cheol Seong Jang
- Plant Genomics Laboratory, Department of Applied Plant Sciences, Kangwon National University, Chuncheon, 200-713, Republic of Korea
| | - Sung Don Lim
- Plant Genomics Laboratory, Department of Applied Plant Sciences, Kangwon National University, Chuncheon, 200-713, Republic of Korea
| | - Yong Chan Park
- Plant Genomics Laboratory, Department of Applied Plant Sciences, Kangwon National University, Chuncheon, 200-713, Republic of Korea
| | - Ju Hee Kim
- Plant Genomics Laboratory, Department of Applied Plant Sciences, Kangwon National University, Chuncheon, 200-713, Republic of Korea
| | - Yong Weon Seo
- Department of Plant Biotechnology, Korea University, Seongbuk-Gu, Seoul, 02841, Republic of Korea.
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Wan L, Wei J. Early-Onset Schizophrenia: A Special Phenotype of the Disease Characterized by Increased MTHFR Polymorphisms and Aggravating Symptoms. Neuropsychiatr Dis Treat 2021; 17:2511-2525. [PMID: 34376980 PMCID: PMC8349230 DOI: 10.2147/ndt.s320680] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 07/12/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Patients with early-onset schizophrenia usually exhibit more severe symptoms, revealing a potentially distinctive disease phenotype. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate conversion and methylation modification associated with the disease. We aimed to investigate the potential effects of MTHFR polymorphisms and related methylation patterns in patients with early-onset schizophrenia, which implies special phenotypes of schizophrenia. METHODS In 177 patients with schizophrenia, MTHFR polymorphism at three sites (C677T, A1298C, and G1793A) and the Positive and Negative Syndrome Scale (PANSS) were tested. Differential methylation positions (DMPs) and enrichment of genes and related pathways were analyzed by testing the genomic methylation level. Catechol-O-methyltransferase (COMT), solute carrier family 6 member 4 (SLC6A4), neuregulin1 (NRG1), and brain-derived neurotrophic factor (BDNF) were selected to evaluate the methylation levels of specific CpG regions by pyrosequencing. RESULTS Higher levels of symptom severity and MTHFR polymorphisms and lower levels of global DNA methylation in patients with early-onset schizophrenia were observed in this study. SLC6A4 was hypermethylated, and BDNF was hypomethylated in specific regions of patients with early-onset schizophrenia. CONCLUSION Aggravating symptoms, increased MTHFR polymorphisms, and reduced genomic methylation levels may be characteristics and underlying mechanisms of early-onset schizophrenia, which implies a special disease phenotype. Beyond that, specific genes and biological pathways may imply the potential phenotype of schizophrenia.
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Affiliation(s)
- Lin Wan
- Department of Psychological Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
| | - Jing Wei
- Department of Psychological Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
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