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D'Aniello A, Del Bene A, Mottola S, Mazzarella V, Cutolo R, Campagna E, Di Maro S, Messere A. The bright side of chemistry: Exploring synthetic peptide-based anticancer vaccines. J Pept Sci 2024; 30:e3596. [PMID: 38571326 DOI: 10.1002/psc.3596] [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: 12/15/2023] [Revised: 02/27/2024] [Accepted: 02/28/2024] [Indexed: 04/05/2024]
Abstract
The present review focuses on synthetic peptide-based vaccine strategies in the context of anticancer intervention, paying attention to critical aspects such as peptide epitope selection, adjuvant integration, and nuanced classification of synthetic peptide cancer vaccines. Within this discussion, we delve into the diverse array of synthetic peptide-based anticancer vaccines, each derived from tumor-associated antigens (TAAs), including melanoma antigen recognized by T cells 1 (Melan-A or MART-1), mucin 1 (MUC1), human epidermal growth factor receptor 2 (HER-2), tumor protein 53 (p53), human telomerase reverse transcriptase (hTERT), survivin, folate receptor (FR), cancer-testis antigen 1 (NY-ESO-1), and prostate-specific antigen (PSA). We also describe the synthetic peptide-based vaccines developed for cancers triggered by oncovirus, such as human papillomavirus (HPV), and hepatitis C virus (HCV). Additionally, the potential synergy of peptide-based vaccines with common therapeutics in cancer was considered. The last part of our discussion deals with the realm of the peptide-based vaccines delivery, highlighting its role in translating the most promising candidates into effective clinical strategies. Although this discussion does not cover all the ongoing peptide vaccine investigations, it aims at offering valuable insights into the chemical modifications and the structural complexities of anticancer peptide-based vaccines.
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Affiliation(s)
- Antonia D'Aniello
- Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Alessandra Del Bene
- Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Salvatore Mottola
- Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Vincenzo Mazzarella
- Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Roberto Cutolo
- Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Erica Campagna
- Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Salvatore Di Maro
- Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", Caserta, Italy
- Interuniversity Research Centre on Bioactive Peptides (CIRPEB), Naples, Italy
| | - Anna Messere
- Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania "Luigi Vanvitelli", Caserta, Italy
- Interuniversity Research Centre on Bioactive Peptides (CIRPEB), Naples, Italy
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Mei Zhang S, Xue Dong J, Li Wu X, Sen Zhao Y, Lei Li Y, Lin Wang S, Yang Y, An M, Su M, Ya Shi R, Feng Gao Z. A Highly Sensitive and Selective Fluorescent Sensor for Folic Acid Detection Based on D-penicillamine Stabilized Ag/Cu Alloy Nanoclusters. Chembiochem 2024; 25:e202400254. [PMID: 38757240 DOI: 10.1002/cbic.202400254] [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: 03/20/2024] [Revised: 05/07/2024] [Accepted: 05/16/2024] [Indexed: 05/18/2024]
Abstract
In this work, a highly sensitive and selective method for detecting folic acid (FA) was developed using D-penicillamine (DPA) stabilized Ag/Cu alloy nanoclusters (DPA@Ag/Cu NCs). The yellow emission of DPA@Ag/Cu NCs was found to be quenched upon the addition of FA to the system. The fluorescence intensity quenching value demonstrated a linear relationship with FA concentrations ranging from 0.01 to 1200 μM, with a limit of detection (LOD) of 5.3 nM. Furthermore, the detection mechanism was investigated through various characterization analyses, including high resolution transmission electron microscopy, fluorescence spectra, ultraviolet-visible absorption spectra, and fluorescence lifetime. The results indicated that the fluorescence quenching induced by FA was a result of electron transfer from FA to the ligands of DPA@Ag/Cu NCs. The selectivity of the FA sensor was also evaluated, showing that common amino acids and inorganic ions had minimal impact on the detection of FA. Moreover, the standard addition method was successfully applied to detect FA in human serum, chewable tablets and FA tablets with promising results. The use of DPA@Ag/Cu NCs demonstrates significant potential for detecting FA in complex biological samples.
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Affiliation(s)
- Sai Mei Zhang
- College of Chemistry and Materials Science, Hebei University, Key Laboratory of Analytical Science and Technology of Hebei Province, Baoding, 071002, People's Republic of China
| | - Jiang Xue Dong
- College of Chemistry and Materials Science, Hebei University, Key Laboratory of Analytical Science and Technology of Hebei Province, Baoding, 071002, People's Republic of China
| | - Xiao Li Wu
- College of Chemistry and Materials Science, Hebei University, Key Laboratory of Analytical Science and Technology of Hebei Province, Baoding, 071002, People's Republic of China
| | - Yong Sen Zhao
- Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan, 250022, People's Republic of China
| | - Yan Lei Li
- Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan, 250022, People's Republic of China
| | - Shou Lin Wang
- College of Chemistry and Materials Science, Hebei University, Key Laboratory of Analytical Science and Technology of Hebei Province, Baoding, 071002, People's Republic of China
| | - Yang Yang
- College of Chemistry and Materials Science, Hebei University, Key Laboratory of Analytical Science and Technology of Hebei Province, Baoding, 071002, People's Republic of China
| | - Miao An
- College of Chemistry and Materials Science, Hebei University, Key Laboratory of Analytical Science and Technology of Hebei Province, Baoding, 071002, People's Republic of China
| | - Ming Su
- College of Chemistry and Materials Science, Hebei University, Key Laboratory of Analytical Science and Technology of Hebei Province, Baoding, 071002, People's Republic of China
| | - Rong Ya Shi
- Difficult and Severe Liver Disease Center, Baoding People's Hospital, Baoding, 071030, People's Republic of China
| | - Zhong Feng Gao
- Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan, 250022, People's Republic of China
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Sámano R, Martínez-Rojano H, Chico-Barba G, Gamboa R, Tolentino M, Toledo-Barrera AX, Ramírez-González C, Mendoza-Flores ME, Hernández-Trejo M, Godínez-Martínez E. Serum Folate, Red Blood Cell Folate, and Zinc Serum Levels Are Related with Gestational Weight Gain and Offspring's Birth-Weight of Adolescent Mothers. Nutrients 2024; 16:1632. [PMID: 38892565 PMCID: PMC11174574 DOI: 10.3390/nu16111632] [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: 04/29/2024] [Revised: 05/18/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Gestational weight gain below or above the Institute of Medicine recommendations has been associated with adverse perinatal and neonatal outcomes. Very few studies have evaluated the association between serum and red blood cell folate concentrations and gestational weight gain in adolescents. Additionally, zinc deficiency during pregnancy has been associated with impaired immunity, prolonged labor, preterm and post-term birth, intrauterine growth restriction, low birth weight, and pregnancy-induced hypertension. OBJECTIVE The purpose of our study is to evaluate the association between serum concentrations of zinc, serum folate, and red blood cell folate, with the increase in gestational weight and the weight and length of the newborn in a group of adolescent mothers from Mexico City. RESULTS In our study, 406 adolescent-neonate dyads participated. The adolescents' median age was 15.8 years old. The predominant socioeconomic level was middle-low (57.8%), single (57%), 89.9% were engaged in home activities, and 41.3% completed secondary education. Excessive gestational weight gain was observed in 36.7% of cases, while insufficient gestational weight gain was noted in 38.4%. Small for gestational age infants were observed in 20.9% of the sample. Low serum folate (OR 2.1, 95% CI 1.3-3.3), decreased red blood cell folate (OR 1.6, 95% CI 1.0-2.6), and reduced serum zinc concentrations (OR 3.3, 95% CI 2.1-5.2) were associated with insufficient gestational weight gain. Decreased serum zinc levels (OR 1.2, 95% CI 1.2-3.4) were linked to an increased probability of delivering a baby who is small for their gestational age. CONCLUSIONS Low serum folate, red blood cell folate, and serum zinc concentrations were associated with gestational weight gain and having a small gestational age baby. Both excessive and insufficient gestational weight gain, as well as having a small gestational age baby, are frequent among adolescent mothers.
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Affiliation(s)
- Reyna Sámano
- Coordinación de Nutrición y Bioprogramación, Instituto Nacional de Perinatología, Secretaría de Salud, México City 11000, Mexico; (G.C.-B.); (M.T.); (C.R.-G.); (M.E.M.-F.); (E.G.-M.)
| | - Hugo Martínez-Rojano
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, México City 11340, Mexico
- Coordinación de Medicina Laboral, Instituto de Diagnóstico y Referencia Epidemiológicos (InDRE) “Dr. Manuel Martínez Báez”, Secretaría de Salud, México City 01480, Mexico
| | - Gabriela Chico-Barba
- Coordinación de Nutrición y Bioprogramación, Instituto Nacional de Perinatología, Secretaría de Salud, México City 11000, Mexico; (G.C.-B.); (M.T.); (C.R.-G.); (M.E.M.-F.); (E.G.-M.)
| | - Ricardo Gamboa
- Departamento de Fisiología, Instituto Nacional de Cardiología, México City 14080, Mexico;
| | - Maricruz Tolentino
- Coordinación de Nutrición y Bioprogramación, Instituto Nacional de Perinatología, Secretaría de Salud, México City 11000, Mexico; (G.C.-B.); (M.T.); (C.R.-G.); (M.E.M.-F.); (E.G.-M.)
| | | | - Cristina Ramírez-González
- Coordinación de Nutrición y Bioprogramación, Instituto Nacional de Perinatología, Secretaría de Salud, México City 11000, Mexico; (G.C.-B.); (M.T.); (C.R.-G.); (M.E.M.-F.); (E.G.-M.)
| | - María Eugenia Mendoza-Flores
- Coordinación de Nutrición y Bioprogramación, Instituto Nacional de Perinatología, Secretaría de Salud, México City 11000, Mexico; (G.C.-B.); (M.T.); (C.R.-G.); (M.E.M.-F.); (E.G.-M.)
| | - María Hernández-Trejo
- Departamento de Neurobiología del Desarrollo, Instituto Nacional de Perinatología, Secretaría de Salud, México City 11000, Mexico;
| | - Estela Godínez-Martínez
- Coordinación de Nutrición y Bioprogramación, Instituto Nacional de Perinatología, Secretaría de Salud, México City 11000, Mexico; (G.C.-B.); (M.T.); (C.R.-G.); (M.E.M.-F.); (E.G.-M.)
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Yin Y, Shan C, Han Q, Chen C, Wang Z, Huang Z, Chen H, Sun L, Fei S, Tao J, Han Z, Tan R, Gu M, Ju X. Causal effects of human serum metabolites on occurrence and progress indicators of chronic kidney disease: a two-sample Mendelian randomization study. Front Nutr 2024; 10:1274078. [PMID: 38260086 PMCID: PMC10800733 DOI: 10.3389/fnut.2023.1274078] [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: 08/07/2023] [Accepted: 12/18/2023] [Indexed: 01/24/2024] Open
Abstract
Background Chronic kidney disease (CKD) is often accompanied by alterations in the metabolic profile of the body, yet the causative role of these metabolic changes in the onset of CKD remains a subject of ongoing debate. This study investigates the causative links between metabolites and CKD by leveraging the results of genomewide association study (GWAS) from 486 blood metabolites, employing bulk two-sample Mendelian randomization (MR) analyses. Building on the metabolites that exhibit a causal relationship with CKD, we delve deeper using enrichment analysis to identify the metabolic pathways that may contribute to the development and progression of CKD. Methods In conducting the Mendelian randomization analysis, we treated the GWAS data for 486 metabolic traits as exposure variables while using GWAS data for estimated glomerular filtration rate based on serum creatinine (eGFRcrea), microalbuminuria, and the urinary albumin-to-creatinine ratio (UACR) sourced from the CKDGen consortium as the outcome variables. Inverse-variance weighting (IVW) analysis was used to identify metabolites with a causal relationship to outcome. Using Bonferroni correction, metabolites with more robust causal relationships are screened. Additionally, the IVW-positive results were supplemented with the weighted median, MR-Egger, weighted mode, and simple mode. Furthermore, we performed sensitivity analyses using the Cochran Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out (LOO) test. Pathway enrichment analysis was conducted using two databases, KEGG and SMPDB, for eligible metabolites. Results During the batch Mendelian randomization (MR) analyses, upon completion of the inverse-variance weighted (IVW) approach, sensitivity analysis, and directional consistency checks, 78 metabolites were found to meet the criteria. The following four metabolites satisfy Bonferroni correction: mannose, N-acetylornithine, glycine, and bilirubin (Z, Z), and mannose is causally related to all outcomes of CKD. By pathway enrichment analysis, we identified eight metabolic pathways that contribute to CKD occurrence and progression. Conclusion Based on the present analysis, mannose met Bonferroni correction and had causal associations with CKD, eGFRcrea, microalbuminuria, and UACR. As a potential target for CKD diagnosis and treatment, mannose is believed to play an important role in the occurrence and development of CKD.
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Affiliation(s)
- Yu Yin
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Conghui Shan
- Department of Clinical Laboratory, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qianguang Han
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Congcong Chen
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zijie Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhengkai Huang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Chen
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Li Sun
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shuang Fei
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jun Tao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhijian Han
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ruoyun Tan
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Gu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaobing Ju
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Li Y, Jiang Y, Zhang Q, Zhao Y, Zhang L, Song G, Huang K, Yao Z. Rapid and visual detection of folic acid via supramolecular recognition with a perylene bisimide probe in aqueous media. Talanta 2020; 219:121222. [PMID: 32887123 DOI: 10.1016/j.talanta.2020.121222] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 05/21/2020] [Accepted: 05/24/2020] [Indexed: 11/30/2022]
Abstract
In this report, we have established a novel approach for the rapid detection of folic acid (FA) with a water soluble perylene bisimide-based probe in 100% aqueous media. The sensing performance and mechanism of this probe were investigated systematically using spectroscopic techniques. After optimizing conditions, the limit of detection in this assay is as low as 29.2 nmol/L and linear operation range is from 0.1 to 1.2 μmol/L. It relies on the supramolecular recognition between the probe and FA under the synergistic effects of non-covalent interactions such as electrostatic, hydrophobic and π-stacking interactions. Monitoring the FA concentrations in real-world samples is also confirmed.
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Affiliation(s)
- Yining Li
- College of Food Science and Nutritional Engineering, China Agricultural University and Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, 100083, China
| | - Yanping Jiang
- College of Food Science and Nutritional Engineering, China Agricultural University and Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, 100083, China
| | - Qiaojuan Zhang
- College of Food Science and Nutritional Engineering, China Agricultural University and Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, 100083, China
| | - Yiwen Zhao
- College of Food Science and Nutritional Engineering, China Agricultural University and Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, 100083, China
| | - Li Zhang
- College of Food Science and Nutritional Engineering, China Agricultural University and Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, 100083, China
| | - Gang Song
- Guangdong Provincial Key Laboratory of Radionuclides Pollution Control and Resources, Guangzhou University, Guangzhou, 510006, China
| | - Kunlun Huang
- College of Food Science and Nutritional Engineering, China Agricultural University and Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, 100083, China
| | - Zhiyi Yao
- College of Food Science and Nutritional Engineering, China Agricultural University and Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, 100083, China.
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Abstract
Vaccines have had a profound impact on the management and prevention of infectious disease. In addition, the development of vaccines against chronic diseases has attracted considerable interest as an approach to prevent, rather than treat, conditions such as cancer, Alzheimer's disease, and others. Subunit vaccines consist of nongenetic components of the infectious agent or disease-related epitope. In this Review, we discuss peptide-based vaccines and their potential in three therapeutic areas: infectious disease, Alzheimer's disease, and cancer. We discuss factors that contribute to vaccine efficacy and how these parameters may potentially be modulated by design. We examine both clinically tested vaccines as well as nascent approaches and explore current challenges and potential remedies. While peptide vaccines hold substantial promise in the prevention of human disease, many obstacles remain that have hampered their clinical use; thus, continued research efforts to address these challenges are warranted.
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Affiliation(s)
- Ryan J. Malonis
- Department of Biochemistry, Albert Einstein College of Medicine, Michael F. Price Center for Translational Research, 1301 Morris Park Avenue, Bronx, NY 10461
| | - Jonathan R. Lai
- Department of Biochemistry, Albert Einstein College of Medicine, Michael F. Price Center for Translational Research, 1301 Morris Park Avenue, Bronx, NY 10461
| | - Olivia Vergnolle
- Department of Biochemistry, Albert Einstein College of Medicine, Michael F. Price Center for Translational Research, 1301 Morris Park Avenue, Bronx, NY 10461
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Dietary Composition and Effects in Inflammatory Bowel Disease. Nutrients 2019; 11:nu11061398. [PMID: 31234325 PMCID: PMC6628370 DOI: 10.3390/nu11061398] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 06/14/2019] [Accepted: 06/19/2019] [Indexed: 02/07/2023] Open
Abstract
Dramatic changes in the environment and human lifestyle have been associated with the rise of various chronic complex diseases, such as inflammatory bowel disease (IBD). A dysbiotic gut microbiota has been proposed as a crucial pathogenic element, contributing to immune imbalances and fostering a proinflammatory milieu, which may be associated with disease relapses or even the initiation of IBD. In addition to representing important regulators of the mucosal immunity and the composition of the gut microbiota, food components have been shown to be potential environmental triggers of epigenetic modifications. In the context of chronic intestinal inflammation, dietary habits and specific food components have been implicated as important modulators of epigenetic mechanisms, including DNA methylation, which may predispose a person to the increased risk of the initiation and evolution of IBD. This review provides novel insights about how dietary factors may interact with the intestinal mucosa and modulate immune homeostasis by shaping the intestinal ecosystem, as well as the potential influence of diet in the etiopathogenesis and management of IBD.
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Motta C, Delgado I, Matos AS, Gonzales GB, Torres D, Santos M, Chandra-Hioe MV, Arcot J, Castanheira I. Folates in quinoa ( Chenopodium quinoa ), amaranth ( Amaranthus sp.) and buckwheat ( Fagopyrum esculentum ): Influence of cooking and malting. J Food Compost Anal 2017. [DOI: 10.1016/j.jfca.2017.09.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Abstract
Abstract
Clinical practice and experimental studies have shown the necessity of sufficient quantities of folic acid intake for normal embryogenesis and fetal development in the prevention of neural tube defects (NTDs) and neurological malformations. So, women of childbearing age must be sure to have an adequate folate intake periconceptionally, prior to and during pregnancy. Folic acid fortification of all enriched cereal grain product flour has been implemented in many countries. Thus, hundreds of thousands of people have been exposed to an increased intake of folic acid. Folate plays an essential role in the biosynthesis of methionine. Methionine is the principal aminopropyl donor required for polyamine biosynthesis, which is up-regulated in actively growing cells, including cancer cells. Folates are important in RNA and DNA synthesis, DNA stability and integrity. Clinical and epidemiological evidence links folate deficiency to DNA damage and cancer. On the other hand, long-term folate oversupplementation leads to adverse toxic effects, resulting in the appearance of malignancy. Considering the relationship of polyamines and rapidly proliferating tissues (especially cancers), there is a need for better investigation of the relationship between the ingestion of high amounts of folic acid in food supplementation and polyamine metabolism, related to malignant processes in the human body.
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Paniz C, Bertinato JF, Lucena MR, De Carli E, Amorim PMDS, Gomes GW, Palchetti CZ, Figueiredo MS, Pfeiffer CM, Fazili Z, Green R, Guerra-Shinohara EM. A Daily Dose of 5 mg Folic Acid for 90 Days Is Associated with Increased Serum Unmetabolized Folic Acid and Reduced Natural Killer Cell Cytotoxicity in Healthy Brazilian Adults. J Nutr 2017; 147:1677-1685. [PMID: 28724658 PMCID: PMC5712455 DOI: 10.3945/jn.117.247445] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 04/25/2017] [Accepted: 06/15/2017] [Indexed: 01/01/2023] Open
Abstract
Background: The effects of high-dose folic acid (FA) supplementation in healthy individuals on blood folate concentrations and immune response are unknown.Objective: The aim of the study was to evaluate the effects of daily consumption of a tablet containing 5 mg FA on serum folate; number and cytotoxicity of natural killer (NK) cells; mRNA expression of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR), interferon γ (IFNG), tumor necrosis factor α (TNFA), and interleukin 8 (IL8) genes; and concentrations of serum inflammatory markers.Methods: This prospective clinical trial was conducted in 30 healthy Brazilian adults (15 women), aged 27.7 y (95% CI: 26.4, 29.1 y), with a body mass index (in kg/m2) of 23.1 (95% CI: 22.0, 24.3). Blood was collected at baseline and after 45 and 90 d of the intervention. Serum folate concentrations were measured by microbiological assay and HPLC-tandem mass spectrometry [folate forms, including unmetabolized folic acid (UMFA)]. We used real-time polymerase chain reaction to assess mononuclear leukocyte mRNA expression and flow cytometry to measure the number and cytotoxicity of NK cells.Results: Serum folate concentrations increased by ∼5-fold after the intervention (P < 0.001), and UMFA concentrations increased by 11.9- and 5.9-fold at 45 and 90 d, respectively, when compared with baseline (P < 0.001). UMFA concentrations increased (>1.12 nmol/L) in 29 (96.6%) participants at day 45 and in 26 (86.7%) participants at day 90. We observed significant reductions in the number (P < 0.001) and cytotoxicity (P = 0.003) of NK cells after 45 and 90 d. Compared with baseline, DHFR mRNA expression was higher at 90 d (P = 0.006) and IL8 and TNFA mRNA expressions were higher at 45 and 90 d (P = 0.001 for both).Conclusion: This noncontrolled intervention showed that healthy adults responded to a high-dose FA supplement with increased UMFA concentrations, changes in cytokine mRNA expression, and reduced number and cytotoxicity of NK cells. This trial was registered at www.ensaiosclinicos.gov.br as RBR-2pr7zp.
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Affiliation(s)
- Clovis Paniz
- Departments of Clinical and Toxicological Analysis and
| | | | - Maylla Rodrigues Lucena
- Hematology and Blood Transfusion Division, Federal University of Sao Paulo, Sao Paulo, Brazil
| | - Eduardo De Carli
- Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | | | | | | | - Maria Stella Figueiredo
- Hematology and Blood Transfusion Division, Federal University of Sao Paulo, Sao Paulo, Brazil
| | | | - Zia Fazili
- National Center for Environmental Health, CDC, Atlanta, GA; and
| | - Ralph Green
- Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, CA
| | - Elvira Maria Guerra-Shinohara
- Departments of Clinical and Toxicological Analysis and
- Hematology and Blood Transfusion Division, Federal University of Sao Paulo, Sao Paulo, Brazil
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Rapozo DCM, Bernardazzi C, de Souza HSP. Diet and microbiota in inflammatory bowel disease: The gut in disharmony. World J Gastroenterol 2017; 23:2124-2140. [PMID: 28405140 PMCID: PMC5374124 DOI: 10.3748/wjg.v23.i12.2124] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 02/03/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
Bacterial colonization of the gut shapes both the local and the systemic immune response and is implicated in the modulation of immunity in both healthy and disease states. Recently, quantitative and qualitative changes in the composition of the gut microbiota have been detected in Crohn's disease and ulcerative colitis, reinforcing the hypothesis of dysbiosis as a relevant mechanism underlying inflammatory bowel disease (IBD) pathogenesis. Humans and microbes have co-existed and co-evolved for a long time in a mutually beneficial symbiotic association essential for maintaining homeostasis. However, the microbiome is dynamic, changing with age and in response to environmental modifications. Among such environmental factors, food and alimentary habits, progressively altered in modern societies, appear to be critical modulators of the microbiota, contributing to or co-participating in dysbiosis. In addition, food constituents such as micronutrients are important regulators of mucosal immunity, with direct or indirect effects on the gut microbiota. Moreover, food constituents have recently been shown to modulate epigenetic mechanisms, which can result in increased risk for the development and progression of IBD. Therefore, it is likely that a better understanding of the role of different food components in intestinal homeostasis and the resident microbiota will be essential for unravelling the complex molecular basis of the epigenetic, genetic and environment interactions underlying IBD pathogenesis as well as for offering dietary interventions with minimal side effects.
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Ahmad Najar R, Rahat B, Hussain A, Thakur S, Kaur J, Kaur J, Hamid A. Gene specific epigenetic regulation of hepatic folate transport system is responsible for perturbed cellular folate status during aging and exogenous modulation. Mol Nutr Food Res 2016; 60:1501-13. [PMID: 26990146 DOI: 10.1002/mnfr.201500991] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 03/05/2016] [Accepted: 03/09/2016] [Indexed: 01/11/2023]
Abstract
SCOPE The present study was designed to identify the molecular mechanism of folate modulation and aging on aberrant liver folate transporter system. METHODS AND RESULTS An in vivo rat model was used, in which weanling, young and adult rats were given folate deficient diet for 3 and 5 months and after 3 months of folate deficiency, one group received physiological folate repletion (2 mg/kg diet) and another group received over supplemented folate diet (8 mg/kg diet) for another 2 months. In adult group, 3 and 5 months of folate deficiency decreased serum and tissue folate levels with decreased uptake of folate, further associated with decreased expression levels of reduced folate carrier (RFC) and increased expression levels of folate exporter (ABCG2) at both mRNA and protein levels, which in turn regulated by promoter hypermethylation of RFC and promoter hypomethylation of ABCG2 gene. CONCLUSION Promoter hypermethylation of RFC and promoter hypomethylation of ABCG2 may be attributed to the down regulation of RFC and up regulation of ABCG2 at mRNA and protein levels in conditions of 3 and 5 months of folate deficiency in the adult group.
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Affiliation(s)
- Rauf Ahmad Najar
- Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.,Department of Biochemistry, Panjab University, Chandigarh, India
| | - Beenish Rahat
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Aashiq Hussain
- Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India
| | - Shilpa Thakur
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jaspreet Kaur
- University Institute of Engineering and Technology, Panjab University, Chandigarh, India
| | - Jyotdeep Kaur
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Abid Hamid
- Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.,CSIR-Academy of Scientific & Innovative Research, New Delhi, India
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Huang X, He Z, Jiang X, Hou M, Tang Z, Zhen X, Liang Y, Ma J. Folic Acid Represses Hypoxia-Induced Inflammation in THP-1 Cells through Inhibition of the PI3K/Akt/HIF-1α Pathway. PLoS One 2016; 11:e0151553. [PMID: 26974319 PMCID: PMC4790958 DOI: 10.1371/journal.pone.0151553] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 03/01/2016] [Indexed: 11/21/2022] Open
Abstract
Though hypoxia has been implicated as a cause of inflammation, the underlying mechanism is not well understood. Folic acid has been shown to provide protection against oxidative stress and inflammation in patients with cardiovascular disease and various models approximating insult to tissue via inflammation. It has been reported that hypoxia-induced inflammation is associated with oxidative stress, upregulation of hypoxia-inducible factor 1-alpha (HIF-1α), and production of pro-inflammatory molecules. Whether folic acid protects human monocytic cells (THP-1 cells) against hypoxia-induced damage, however, remains unknown. We used THP-1 cells to establish a hypoxia-induced cellular injury model. Pretreating THP-1 cells with folic acid attenuated hypoxia-induced inflammatory responses, including a decrease in protein and mRNA levels of interleukin (IL)-1β and tumor necrosis factor-alpha (TNF-α), coupled with increased levels of IL-10. Folic acid also reduced hypoxia-induced Akt phosphorylation and decreased nuclear accumulation of HIF-1α protein. Both LY294002 (a selective inhibitor of phosphatidyl inositol-3 kinase, PI3K) and KC7F2 (a HIF-1α inhibitor) reduced levels of hypoxia-induced inflammatory cytokines. We also found that insulin (an Akt activator) and dimethyloxallyl glycine (DMOG, a HIF-1α activator) induced over-expression of inflammatory cytokines, which could be blocked by folic acid. Taken together, these findings demonstrate how folic acid attenuates the hypoxia-induced inflammatory responses of THP-1 cells through inhibition of the PI3K/Akt/HIF-1α pathway.
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Affiliation(s)
- Xiaoyan Huang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Zhiying He
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Xinwei Jiang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Mengjun Hou
- Experimental and Teaching Center for public health, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Zhihong Tang
- Experimental and Teaching Center for public health, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Xiaozhou Zhen
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Yuming Liang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Jing Ma
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China
- * E-mail:
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Vergote IB, Marth C, Coleman RL. Role of the folate receptor in ovarian cancer treatment: evidence, mechanism, and clinical implications. Cancer Metastasis Rev 2016; 34:41-52. [PMID: 25564455 DOI: 10.1007/s10555-014-9539-8] [Citation(s) in RCA: 114] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Folate can be transported into the cell by the reduced folate carrier (RFC), the proton-coupled folate transporter (PCFT), or the folate receptor (FR), of which various isoforms exist. While the RFC and PCFT are expressed by many normal cells, the FR is present only in a small proportion of normal tissues. In these tissues, the FR expression level is often low and restricted to the apical surface of polarized epithelial cells. In contrast, FR is expressed on the blood-accessible basal and lateral membranes of many types of epithelial cancer. Considering that FR is expressed in few nonmalignant cell types on luminal membranes generally not accessible for molecules transported in the blood, FR is considered a promising antitumor target. As FR expression seems associated with tumor progression and prognosis, anticancer therapies targeting FR are currently being developed, such as farletuzumab (Morphotek, Exton, PA, USA), IMGN853 (ImmunoGen, Waltham, MA, USA), vintafolide, and EC1456 (both Endocyte Inc., West Lafayette, IN, USA). FR expression could be used as a response-predictive biomarker for these treatments. The ability to identify patients and treat them with an effective therapy based on the known expression of the tumor marker would, indeed, be the next step in predictive medicine for these patients. This review summarizes the role of FR in ovarian cancer and the value of FR as a prognostic biomarker for ovarian cancer and a response-predictive biomarker for folate-targeted therapeutics.
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Affiliation(s)
- Ignace B Vergote
- Department of Obstetrics and Gynaecolog, Leuven Cancer Institute, University Hospital Leuven, Herestraat 49, 3000, Leuven, Belgium,
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Increased synthesis of folate transporters regulates folate transport in conditions of ethanol exposure and folate deficiency. Mol Cell Biochem 2015; 411:151-60. [PMID: 26433955 DOI: 10.1007/s11010-015-2577-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 09/26/2015] [Indexed: 01/31/2023]
Abstract
Excessive alcohol consumption and dietary folate inadequacy are the main contributors leading to folate deficiency (FD). The present study was planned to study regulation of folate transport in conditions of FD and ethanol exposure in human embryonic kidney cell line. Also, the reversible nature of effects mediated by ethanol exposure and FD was determined by folate repletion and ethanol removal. For ethanol treatment, HEK293 cells were grown in medium containing 100 mM ethanol, and after treatment, one group of cells was shifted on medium that was free from ethanol. For FD treatment, cells were grown in folate-deficient medium followed by shifting of one group of cells on folate containing medium. FD as well as ethanol exposure resulted in an increase in folate uptake which was due to an increase in expression of folate transporters, i.e., reduced folate carrier, proton-coupled folate transporter, and folate receptor, both at the mRNA and protein level. The effects mediated by ethanol exposure and FD were reversible on removal of treatment. Promoter region methylation of folate transporters remained unaffected after FD and ethanol exposure. As far as transcription rate of folate transporters is concerned, an increase in rate of synthesis was observed in both ethanol exposure and FD conditions. Additionally, mRNA life of folate transporters was observed to be reduced by FD. An increased expression of folate transporters under ethanol exposure and FD conditions can be attributed to enhanced rate of synthesis of folate transporters.
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16
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Hirako A, Furukawa S, Takeuchi T, Sugiyama A. Effect of methotrexate exposure at late gestation on development of telencephalon in rat fetal brain. J Vet Med Sci 2015; 78:213-20. [PMID: 26369365 PMCID: PMC4785109 DOI: 10.1292/jvms.15-0389] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Pregnant rats were treated with 30 mg/kg of methotrexate (MTX) on gestation day (GD) 16, and fetal brains
were examined time-dependently. On GD 20, the appearance of the telencephalon in the MTX group was different
from that in the control group, and the major axis of the telencephalon of the MTX group was shortened,
compared to that of the control group. In the sagittal section of the telencephalon in the MTX group on GD 20,
histopathological findings of deformation and narrowing of the cerebral ventricle, the disturbance of the
arrangement of the marginal cell layer of subventricular zone (SVZ) and thickening of telencephalic wall,
cortical plate and ventricular zone (VZ)/SVZ were possibly attributable to neuronal migration disorders by
MTX. Through all the experimental period, few pyknotic cells or TUNEL-positive cells were observed in the
VZ/SVZ of the telencephalic wall and striatum in the control group. On the other hand, in the VZ/SVZ of the
telencephalic wall and striatum in the MTX group, pyknotic cells or TUNEL-positive cells were observed on GD
17, and they increased significantly on GD18 and then decreased to the control levels from GD 19 onward. The
phospho-Histone H3-positive rate decreased remarkedly in the VZ/SVZ of the telencephalic wall and striatum of
the MTX group on GDs 17 and 18, compared to the control group, but they recovered on and after GD 19. These
results suggested that there was a high possibility that development of the telencephalon in this period
required strong folic acid.
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Affiliation(s)
- Ayano Hirako
- Courses of Veterinary Laboratory Medicine, School of Veterinary Medicine, Faculty of Agriculture, Tottori University, Minami 4-101 Koyama-cho, Tottori, Tottori 680-8553, Japan
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Thakur S, Kaur J. Regulation at multiple levels control the expression of folate transporters in liver cells in conditions of ethanol exposure and folate deficiency. Biofactors 2015; 41:232-41. [PMID: 26154406 DOI: 10.1002/biof.1217] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2015] [Accepted: 05/27/2015] [Indexed: 01/01/2023]
Abstract
Complex regulatory mechanisms control the expression of folate transporters within cells. Liver is the primary reserve of the folate stores within the body. As excessive alcohol consumption or inefficient dietary folate intake are known to create folate deficiency, so therefore the current study was designed to explore various regulatory mechanisms controlling the expression of folate transport in liver cells in conditions of ethanol exposure and folate deficiency. In order to see whether the effects mediated by the treatments are reversible or not, ethanol removal, and folate repletion was done after ethanol exposure and folate deficiency treatment respectively. Folate deficiency resulted an increase, whereas ethanol treatment decreased the folic acid uptake within the cells. The alterations in folic acid uptake were in agreement with the observed changes in the expression of folate transporters. Ethanol exposure resulted an increase in promoter methylation of reduced folate carrier; however, folate deficiency had no effect. The effects produced by ethanol exposure and folate deficiency were found to be reversible in nature as depicted in case of ethanol removal and folate repletion group. Rate of synthesis of folate transporters was found to be increased whereas half lives of mRNA of folate transporters was found to be decreased on folate deficiency treatment and reverse was the case on ethanol treatment. Overall, alteration in the expression of folate transporters under ethanol exposure and folate deficient conditions can be attributed to those regulatory mechanisms which work at the mRNA level.
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Affiliation(s)
- Shilpa Thakur
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jyotdeep Kaur
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Thakur S, Rahat B, Hamid A, Najar RA, Kaur J. Identification of regulatory mechanisms of intestinal folate transport in condition of folate deficiency. J Nutr Biochem 2015; 26:1084-94. [PMID: 26168702 DOI: 10.1016/j.jnutbio.2015.05.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Revised: 04/03/2015] [Accepted: 05/05/2015] [Indexed: 10/23/2022]
Abstract
Folic acid is an essential micronutrient, deficiency of which can lead to disturbance in various metabolic processes of cell. Folate transport across intestine occurs via the involvement of specialized folate transporters viz. proton coupled folate transporter (PCFT) and reduced folate carrier (RFC), which express at the membrane surfaces. The current study was designed to identify the regulatory mechanisms underlying the effects of folate deficiency (FD) on folate transport in human intestinal cell line as well as in rats and to check the reversibility of such effects. Caco-2 cells were grown for five generations in control and FD medium. Following treatment, one subgroup of cells was shifted on folate sufficient medium and grown for three more generations. Similarly, rats were fed an FD diet for 3 and 5 months, and after 3 months of FD treatment, one group of rats were shifted on normal folate-containing diet. Increase in folate transport and expression of folate transporters were observed on FD treatment. However, when cells and rats were shifted to control conditions after treatment, transport and expression of these genes restored to the control level. FD was found to have no impact on promoter methylation of PCFT and RFC; however, messenger RNA stability of transporters was found to be decreased, suggesting some adaptive response. Overall, increased expression of transporters under FD conditions can be attributed to enhanced rate of transcription of folate transporters and also to the increased binding of specificity protein 1 transcription factor to the RFC promoter only.
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Affiliation(s)
- Shilpa Thakur
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Beenish Rahat
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Abid Hamid
- Cancer Pharmacology Division, Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Rauf Ahmad Najar
- Cancer Pharmacology Division, Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Jyotdeep Kaur
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
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The effect of S-adenosylmethionine on cognitive performance in mice: an animal model meta-analysis. PLoS One 2014; 9:e107756. [PMID: 25347725 PMCID: PMC4210123 DOI: 10.1371/journal.pone.0107756] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 08/15/2014] [Indexed: 11/19/2022] Open
Abstract
Background Alzheimer's disease (AD) is the most frequently diagnosed form of dementia resulting in cognitive impairment. Many AD mouse studies, using the methyl donor S-adenosylmethionine (SAM), report improved cognitive ability, but conflicting results between and within studies currently exist. To address this, we conducted a meta-analysis to evaluate the effect of SAM on cognitive ability as measured by Y maze performance. As supporting evidence, we include further discussion of improvements in cognitive ability, by SAM, as measured by the Morris water maze (MWM). Methods We conducted a comprehensive literature review up to April 2014 based on searches querying MEDLINE, EMBASE, Web of Science, the Cochrane Library and Proquest Theses and Dissertation databases. We identified three studies containing a total of 12 experiments that met our inclusion criteria and one study for qualitative review. The data from these studies were used to evaluate the effect of SAM on cognitive performance according to two scenarios: 1. SAM supplemented folate deficient (SFD) diet compared to a folate deficient (FD) diet and 2. SFD diet compared to a nutrient complete (NC) diet. Hedge's g was used to calculate effect sizes and mixed effects model meta-regression was used to evaluate moderating factors. Results Our findings showed that the SFD diet was associated with improvements in cognitive performance. SFD diet mice also had superior cognitive performance compared to mice on an NC diet. Further to this, meta-regression analyses indicated a significant positive effect of study quality score and treatment duration on the effect size estimate for both the FD vs SFD analysis and the SFD vs NC analysis. Conclusion The findings of this meta-analysis demonstrate efficacy of SAM in acting as a cognitive performance-enhancing agent. As a corollary, SAM may be useful in improving spatial memory in patients suffering from many dementia forms including AD.
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Paayal C, Ganesh U, Shaantanu D. Indian perspective on clinical aspects, usage, and guidelines of folic Acid. J Obstet Gynaecol India 2014; 64:328-31. [PMID: 25368455 DOI: 10.1007/s13224-014-0526-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Accepted: 10/14/2013] [Indexed: 11/30/2022] Open
Abstract
Folic acid (pteroylmonoglutamic acid) is the stable, fully oxidized form of folate which is used in food fortification and supplements. Keen interest has been generated in folic acid due to its suggested role in prevention of various disorders. Strong evidence from clinical trials indicates preventive effect of folic acid on both occurrence and recurrence of neural tube defects. It also plays a significant role in mitigating the risk of cardiovascular disorders through homocysteine regulation. In addition, the beneficial effect of folic acid in various types of cancers, neurological disorders, conditions affecting pregnancy, and other clinical conditions has been reported in literature. Various guidelines reinforce the need for women to obtain adequate amount of folic acid either through food fortification or supplements. In India, national guidelines on the proper dose of folic acid to pregnant women are not available. Given its significant beneficial effects on health, awareness should be spread among communities on the usage and benefits of folic acid.
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Affiliation(s)
- Chobe Paayal
- OBGY, Shree Clinic, Shreya Nagar, Aurangabad, India
| | - Uchit Ganesh
- Pharmacology, Flat no. 603 B-wing, Om Jai Balaji Heights, Ramdev Park, Mira Road (East), Thane, 401107 Maharashtra India
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Juzeniene A, Thu Tam TT, Iani V, Moan J. The action spectrum for folic acid photodegradation in aqueous solutions. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2013; 126:11-6. [DOI: 10.1016/j.jphotobiol.2013.05.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Revised: 05/08/2013] [Accepted: 05/29/2013] [Indexed: 12/14/2022]
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Wani NA, Thakur S, Najar RA, Nada R, Khanduja KL, Kaur J. Mechanistic insights of intestinal absorption and renal conservation of folate in chronic alcoholism. Alcohol 2013; 47:121-30. [PMID: 23267781 DOI: 10.1016/j.alcohol.2012.11.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2011] [Revised: 10/18/2012] [Accepted: 11/27/2012] [Indexed: 01/01/2023]
Abstract
Folate mediated one-carbon metabolism is of fundamental importance for various cellular processes, including DNA synthesis and methylation of biological molecules. Due to the exogenous requirement of folate in mammals, there exists a well developed epithelial folate transport system for regulation of normal folate homeostasis. The intestinal and renal folate uptake is tightly and diversely regulated and disturbances in folate homeostasis like in alcoholism have pathological consequences. The study was sought to delineate the regulatory mechanism of folate uptake in intestine and reabsorption in renal tubular cells that could evaluate insights of malabsorption during alcoholism. The folate transporters PCFT and RFC were found to be associated with lipid rafts of membrane surfaces in intestine and kidney. Importantly, the observed lower intestinal and renal folate uptake was associated with decreased levels of folate transporter viz. PCFT and RFC in lipid rafts of intestinal and renal membrane surfaces. The decreased association of folate transporters in lipid rafts was associated with decreased protein and mRNA levels. In addition, immunohistochemical studies showed that alcoholic conditions deranged that localization of PCFT and RFC. These findings could explain the possible mechanistic insights that may result in folate malabsorption during alcoholism.
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Liu ZB, Wang LP, Shu J, Jin C, Lou ZX. Methylenetetrahydrofolate reductase 677TT genotype might be associated with an increased lung cancer risk in Asians. Gene 2012; 515:214-9. [PMID: 23237779 DOI: 10.1016/j.gene.2012.11.036] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Revised: 10/25/2012] [Accepted: 11/27/2012] [Indexed: 02/01/2023]
Abstract
BACKGROUND The association between methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and lung cancer risk has been studied in various populations with conflicting results. The aim of this study was to assess the association strength by a meta-analysis of published studies. METHODS We searched PubMed and Chinese Biomedical (CBM) databases for relevant literatures published by July 18, 2012. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to assess the strength of the association. RESULTS A total of 20 studies comprising 11,653 cases and 12,032 controls were included in the final meta-analysis. Using the random effect model, we found that MTHFR 677TT variant genotype was associated with an increased lung cancer risk (OR=1.26, 95% CI=1.05-1.50, P=0.011 for TT vs. CC; OR=1.19, 95% CI=1.03-1.37, P<0.001 for TT vs. CC+CT; OR=1.11, 95% CI=1.02-1.22, P=0.017 for T allele vs. C allele). In the further stratified analyses, the increased lung cancer risk was found in Asian subjects (OR=1.31, 95% CI=1.01-1.71, P=0.045 for TT vs. CC; OR=1.17, 95% CI=1.00-1.38, P=0.048 for TT vs. CC+CT). There were no evidences for obvious publication bias in the overall meta-analysis and Asian subjects. CONCLUSIONS MTHFR 677TT genotype might increase the susceptibility of lung cancer, especially in Asians.
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Affiliation(s)
- Zheng-Bing Liu
- Division of Pulmonary and Critical Care Medicine, Department of Medicine and Geriatrics, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Wani NA, Kaur J. Adaptive transport of folic acid across renal epithelia in folate-deficient rats. J Physiol Sci 2012; 62:461-8. [PMID: 22865158 PMCID: PMC10717754 DOI: 10.1007/s12576-012-0223-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2012] [Accepted: 07/16/2012] [Indexed: 01/01/2023]
Abstract
Folate (vitamin B(9)) is an essential vitamin for a wide spectrum of biochemical reactions; however, unlike bacteria and plants, mammals are devoid of folate biosynthesis and thus must obtain this cofactor from exogenous sources. The activities of folate transporters on the kidneys play an important role in conserving folate excretion and reabsorption across the apical membrane of the renal proximal tubules. The different transport system activities may become identifiable in response to external stimuli, such as folate availability and exposure to chemotherapeutic agents. We have explored the effect of folate deficiency on the activity and expression of folate transporters in rat kidneys. Wistar rats were fed a folate-containing diet (2 mg folic acid kg(-1) diet) or a folic acid-free diet over a 3-month period, and mechanisms of folate transport were studied in renal brush border membrane vesicles and basolateral membrane vesicles. The renal folate uptake process is saturable and pH dependent, and it involves the folate receptor and reduced folate carrier (RFC) systems and possibly the proton coupled folate transporter (PCFT) system. We found that folate deficiency increased the renal brush border membrane and basolateral folate uptake by increasing the number of transporter molecules. The observed up-regulation of mRNA expression was also associated with a significant increase in RFC and PCFT expression at the protein level.
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Affiliation(s)
- Nissar Ahmad Wani
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012 India
| | - Jyotdeep Kaur
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012 India
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Wani NA, Nada R, Khanduja KL, Kaur J. Decreased activity of folate transporters in lipid rafts resulted in reduced hepatic folate uptake in chronic alcoholism in rats. GENES AND NUTRITION 2012; 8:209-19. [PMID: 22956120 DOI: 10.1007/s12263-012-0318-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 08/17/2012] [Indexed: 11/29/2022]
Abstract
Folic acid is an essential nutrient that is required for one-carbon biosynthetic processes and for methylation of biomolecules. Deficiency of this micronutrient leads to disturbances in normal physiology of cell. Chronic alcoholism is well known to be associated with folate deficiency, which is due in part to folate malabsorption. The present study deals with the regulatory mechanisms of folate uptake in liver during chronic alcoholism. Male Wistar rats were fed 1 g/kg body weight/day ethanol (20 % solution) orally for 3 months, and the molecular mechanisms of folate uptake were studied in liver. The characterization of the folate transport system in liver basolateral membrane (BLM) suggested it to be a carrier mediated and acidic pH dependent, with the major involvement of proton coupled folate transporter and folate binding protein in the uptake. The folate transporters were found to be associated with lipid raft microdomain of liver BLM. Moreover, ethanol ingestion decreased the folate transport by altering the Vmax of folate transport process and downregulated the expression of folate transporters in lipid rafts. The decreased transporter levels were associated with reduced protein and mRNA levels of these transporters in liver. The deranged folate uptake together with reduced folate transporter levels in lipid rafts resulted in reduced folate levels in liver and thereby to its reduced levels in serum of ethanol-fed rats. The chronic ethanol ingestion led to decreased folate uptake in liver, which was associated with the decreased number of transporter molecules in the lipid rafts that can be ascribed to the reduced synthesis of these transporters.
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Affiliation(s)
- Nissar Ahmad Wani
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
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Hamid A. Folate malabsorption and its influence on DNA methylation during cancer development. DNA Cell Biol 2012. [PMID: 22468673 DOI: 10.1089/dna.2011.1576] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The folate transport across the epithelial of the intestine, colon, kidney, and liver is essential for folate homeostasis. The relative localization of transporters in membranes is an important determinant for the vectorial flow of substrates across the epithelia. Folate deficiency is a highly prevalent vitamin deficiency in the world, and alcohol ingestion has been the major contributor. It can develop because of folate malabsorption in tissues, increased renal excretion dietary inadequacy, and altered hepatobiliary metabolism. Additionally, folate-mediated one-carbon metabolism is important for various cellular processes, including DNA synthesis and methylation. In this regard, the contribution of alcohol-associated and dietary folate deficiency to methylation patterns is under intense investigation, especially in cancer. The epigenetic events have increasing relevance in the development of strategies for early diagnosis, prevention, and treatment of cancer.
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Affiliation(s)
- Abid Hamid
- Cancer Pharmacology Division, Indian Institute of Integrative Medicine, CSIR, Jammu, India
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Abstract
AbstractAccumulating evidence from the field of neuroscience indicates a crucial role for epigenetic regulation of gene expression in development and aging of nervous system and suggests that aberrations in the epigenetic machinery are involved in the etiology of psychiatric disorders. Epidemiologic evidence on epigenetics in psychiatry, however, is currently very sparsely available, but is consistent with a mediating role for epigenetic mechanisms in bringing together inherited and acquired risk factors into a neurodevelopmental etiological model of psychiatric disorders. Here, we review evidence from the epidemiological and neuroscience literature, and aim to converge the evidence into an etiological model of psychiatric disorders that encompasses environmental, genetic and epigenetic contributions. Given the dynamic nature of the epigenetic machinery and the potential reversibility of epigenetic modifications, future well-designed interdisciplinary and translational studies will be of key importance in order to identify new targets for prevention and therapeutic strategies.
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Wani NA, Hamid A, Kaur J. Alcohol-associated folate disturbances result in altered methylation of folate-regulating genes. Mol Cell Biochem 2011; 363:157-66. [PMID: 22147198 DOI: 10.1007/s11010-011-1168-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2011] [Accepted: 11/23/2011] [Indexed: 12/17/2022]
Abstract
Folate plays a critical role in maintaining normal metabolic, energy, differentiation and growth status of all mammalian cells. The steady-state accumulation of folate seems to depend on the activity of two enzymes: folylpolyglutamate synthetase (FPGS), which adds glutamate residues, and gamma-glutamyl hydrolase (GGH), which removes them, enabling it to be transported across the biological membranes. Overexpression of GGH and downregulation of FPGS would be expected to decrease intracellular folate in its polyglutamylated form, thereby increasing efflux of folate and its related molecules, which might lead to resistance to drugs or folate deficiency. The study was sought to delineate the activity of GGH and expression FPGS in tissues involved in folate homeostasis during alcoholism and the epigenetic regulation of these enzymes and transporters regulating intracellular folate levels. We determined the activity of GGH and expression of FPGS in tissues after 3 months of ethanol feeding to rats at 1 g/kg body weight/day. The results showed that there was not any significant change in the activity of folate hydrolyzing enzyme GGH in ethanol-fed rats while there was significant down regulation in the expression of FPGS. Ethanol feeding decreased the total as well as polyglutamated folate levels. There was tissue-specific hyper/hypo methylation of folate transporter genes viz. PCFT and RFC by chronic ethanol feeding. Moreover, hypermethylation of FPGS gene was observed in intestine and kidney without any change in methylation levels of GGH in the ethanol-fed rats. In conclusion, the initial deconjugation of polyglutamylated folate by GGH was not impaired in ethanol-fed rats while the conversion of monoglutamylated folate to polyglutamylated form might be impaired. There was tissue-specific altered methylation of folate transporter genes by chronic ethanol feeding.
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Affiliation(s)
- Nissar Ahmad Wani
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India
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Wani NA, Nada R, Kaur J. Biochemical and molecular mechanisms of folate transport in rat pancreas; interference with ethanol ingestion. PLoS One 2011; 6:e28599. [PMID: 22163044 PMCID: PMC3232245 DOI: 10.1371/journal.pone.0028599] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2011] [Accepted: 11/11/2011] [Indexed: 02/07/2023] Open
Abstract
Folic acid is an essential nutrient that is required for one-carbon biosynthetic processes and for methylation of biomolecules. Deficiency of this micronutrient leads to disturbances in normal physiology of cell. Chronic alcoholism is well known to be associated with folate deficiency which is due, in part to folate malabsorption. The present study deals with the mechanistic insights of reduced folate absorption in pancreas during chronic alcoholism. Male Wistar rats were fed 1 g/kg body weight/day ethanol (20% solution) orally for 3 months and the mechanisms of alcohol associated reduced folate uptake was studied in pancreas. The folate transport system in the pancreatic plasma membrane (PPM) was found to be acidic pH dependent one. The transporters proton coupled folate transporter (PCFT) and reduced folate carrier (RFC) are involved in folate uptake across PPM. The folate transporters were found to be associated with lipid raft microdomain of the PPM. Ethanol ingestion decreased the folate transport by reducing the levels of folate transporter molecules in lipid rafts at the PPM. The decreased transport efficiency of the PPM was reflected as reduced folate levels in pancreas. The chronic ethanol ingestion led to decreased pancreatic folate uptake. The decreased levels of PCFT and RFC expression in rat PPM were due to decreased association of these proteins with lipid rafts (LR) at the PPM.
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Affiliation(s)
- Nissar Ahmad Wani
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, Chandigarh, India
| | - Ritambhara Nada
- Department of Histopathology, Postgraduate Institute of Medical Education and Research Chandigarh, Chandigarh, India
| | - Jyotdeep Kaur
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, Chandigarh, India
- * E-mail:
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Peerbooms OLJ, van Os J, Drukker M, Kenis G, Hoogveld L, de Hert M, Delespaul P, van Winkel R, Rutten BPF. Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability? Brain Behav Immun 2011; 25:1530-43. [PMID: 21185933 DOI: 10.1016/j.bbi.2010.12.006] [Citation(s) in RCA: 112] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2010] [Revised: 11/23/2010] [Accepted: 12/10/2010] [Indexed: 01/17/2023] Open
Abstract
Past analyses examining the relationship between genetic variation in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and psychiatric disorders have provided mixed and largely inconclusive findings. MTHFR is involved in the one-carbon metabolic pathway which is essential for DNA biosynthesis and the epigenetic process of DNA methylation. We conducted a meta-analysis of all published case-control studies investigating associations between two common MTHFR single nucleotide polymorphisms (SNPs), MTHFR C677T (sample size 29,502) and A1298C (sample size 7934), and the major psychiatric disorders (i) schizophrenia (SZ), (ii) bipolar disorder (BPD), and (iii) unipolar depressive disorder (UDD). In order to examine possible shared genetic vulnerability, we also tested for associations between MTHFR and all of these major psychiatric disorders (SZ, BPD and UDD) combined. MTHFR C677T was significantly associated with all of the combined psychiatric disorders (SZ, BPD and UDD); random effects odds ratio (OR)=1.26 for TT versus CC genotype carriers; confidence interval (CI) 1.09-1.46); meta-regression did not suggest moderating effects of psychiatric diagnosis, sex, ethnic group or year of publication. Although MTHFR A1298C was not significantly associated with the combination of major psychiatric disorders, nor with SZ, there was evidence for diagnostic moderation indicating a significant association with BPD (random effects OR=2.03 for AA versus CC genotype carriers, CI: 1.07-3.86). Meta-analysis on UDD was not possible due to the small number of studies available. This study provides evidence for shared genetic vulnerability for SZ, BPD and UDD mediated by MTHFR 677TT genotype, which is in line with epigenetic involvement in the pathophysiology of these psychiatric disorders.
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Affiliation(s)
- Odette L J Peerbooms
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, European Graduate School of Neuroscience, South Limburg Mental Health Research and Teaching Network, Maastricht University, Maastricht, The Netherlands
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Folate malabsorption is associated with down-regulation of folate transporter expression and function at colon basolateral membrane in rats. Br J Nutr 2011; 107:800-8. [PMID: 21861943 DOI: 10.1017/s0007114511003710] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Folates, an essential component (important B vitamin) in the human diet, are involved in many metabolic pathways, mainly in carbon transfer reactions such as purine and pyrimidine biosynthesis and amino acid interconversions. Deficiency of this micronutrient leads to the disruption of folate-dependent metabolic pathways that lead to the development of clinical abnormalities ranging from anaemia to growth retardation. Folate deficiency due to alcohol ingestion is quite common, primarily due to malabsorption. The present study dealt with the mechanistic insights of folate malabsorption in colonic basolateral membrane (BLM). Wistar rats (n 12) were fed 1 g/kg body weight per d ethanol (20 %) solution orally for 3 months and folate transport was studied in the isolated colonic BLM. The folate exit across colon BLM shows characteristics of carrier-mediated process with the major involvement of reduced folate carrier (RFC). The chronic ethanol ingestion decreased the uptake by decreasing the affinity by 46 % (P < 0·01) and the number of transport molecules by 43 % (P < 0·001) at the colon BLM. The decreased uptake was associated with down-regulation of proton-coupled folate transporter (PCFT) and RFC expression at mRNA and protein levels. The extent of decrease was 44 % (P < 0·01) and 24 % (P < 0·05) for PCFT and 23 % (P < 0·01) and 57 % (P < 0·01) for RFC at mRNA and protein levels, respectively. Moreover, folate transporters were associated with lipid rafts (LR) of colon BLM, and chronic alcoholism decreased the association of these transporters with LR.
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Jacobsen K, Ramlau-Hansen CH, Thulstrup AM, Olsen J, Bonde JP. Maternal folic acid supplement intake and semen quality in Danish sons: a follow-up study. Fertil Steril 2011; 96:295-8. [PMID: 21664612 DOI: 10.1016/j.fertnstert.2011.05.037] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2011] [Revised: 05/06/2011] [Accepted: 05/11/2011] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To examine whether maternal folic acid supplement intake during pregnancy is related to better semen quality in male offspring. DESIGN A follow-up study. SETTING Two major Danish municipalities, Aalborg and Odense. PATIENT(S) The study population included 347 singleton sons of mothers enrolled into the Healthy Habits for Two cohort when pregnant in 1984-87. INTERVENTION(S) Information on maternal folic acid supplement intake during pregnancy was provided by self-administered questionnaire in the 36th week of gestation. MAIN OUTCOME MEASURE(S) Semen characteristics and serum concentrations of sex hormones. RESULT(S) The distribution of semen characteristics among sons whose mothers took folic acid supplement during pregnancy (n = 88, 25%) did not differ from the distributions among those without (n = 75, 22%) or with unknown folic acid supplement intake (n = 84, 53%). On the contrary, serum levels of FSH and LH were significantly higher in the folic acid supplement group. CONCLUSION(S) The hypothesis that folic acid supplement intake during pregnancy will improve semen quality in male offspring was not corroborated by a follow-up study in young Danish men.
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Affiliation(s)
- Kristoffer Jacobsen
- Department of Occupational and Environmental Medicine, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
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Ex vivo study for the assessment of behavioral factor and gene polymorphisms in individual susceptibility to oxidative DNA damage metals-induced. Int J Hyg Environ Health 2011; 214:210-8. [DOI: 10.1016/j.ijheh.2011.01.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2010] [Revised: 01/18/2011] [Accepted: 01/22/2011] [Indexed: 12/22/2022]
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Feng D, Zhou Y, Xia M, Ma J. Folic acid inhibits lipopolysaccharide-induced inflammatory response in RAW264.7 macrophages by suppressing MAPKs and NF-κB activation. Inflamm Res 2011; 60:817-22. [PMID: 21528358 DOI: 10.1007/s00011-011-0337-2] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Revised: 04/04/2011] [Accepted: 04/08/2011] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE The aim of the present study was to investigate the effects of folic acid on the inflammatory responses to lipopolysaccharide (LPS) in RAW264.7 cells and the signal transduction pathways involved. METHODS RAW264.7 macrophages were used. The production of nitric oxide (NO) was determined by the Griess test. The protein levels and mRNA expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) were determined by ELISA and RT-PCR, respectively. The phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear nuclear factor-kappa B (NF-κB) p65 protein were analyzed by Western blotting. RESULTS Folic acid inhibited LPS-induced production of NO, TNF-α and IL-1β with decreased mRNAs of inducible nitric oxide synthase (iNOS), TNF-α and IL-1β. Further study showed that folic acid inhibited the LPS-induced phosphorylation of MAPKs and the nuclear translocation of NF-κB. CONCLUSION Folic acid inhibits the inflammatory response of RAW 264.7 cells to LPS through inhibiting the MAPKs and NF-κB pathways.
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Affiliation(s)
- Dan Feng
- Department of Preventive Medicine, School of Public Health, Sun Yat-sen University, 74 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China
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Wani NA, Kaur J. Reduced levels of folate transporters (PCFT and RFC) in membrane lipid rafts result in colonic folate malabsorption in chronic alcoholism. J Cell Physiol 2011; 226:579-87. [PMID: 21069807 DOI: 10.1002/jcp.22525] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
We studied the effect of chronic ethanol ingestion on folate transport across the colonic apical membranes (CAM) in rats. Male Wistar rats were fed 1 g/kg body weight/day ethanol (20%) solution orally for 3 months and folate transport was studied in the isolated colon apical membrane vesicles. The folate transport was found to be carrier mediated, saturable, with pH optima at 5.0. Chronic ethanol ingestion reduced the folate transport across the CAM by decreasing the affinity of transporters (high Km) for the substrate and by decreasing the number of transporter molecules (low Vmax) on the colon luminal surface. The decreased transport activity at the CAM was associated with down-regulation of the proton-coupled folate transporter (PCFT) and the reduced folate carrier (RFC) which resulted in decreased PCFT and RFC protein levels in the colon of rats fed alcohol chronically. Moreover, the PCFT and the RFC were found to be distributed in detergent insoluble fraction of the CAM in rats. Floatation experiments on Optiprep density gradients demonstrated the association of the PCFT and the RFC protein with lipid rafts (LR). Chronic alcoholism decreased the PCFT and the RFC protein levels in the CAM LR in accordance with the decreased synthesis. Hence, we propose that downregulation in the expression of the PCFT and the RFC in colon results in reduced levels of these transporters in colon apical membrane LR as a mechanism of folate malabsorption during chronic alcoholism.
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Affiliation(s)
- Nissar Ahmad Wani
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Regulatory mechanisms of intestinal folate uptake in a rat model of folate oversupplementation. Br J Nutr 2010; 105:827-35. [PMID: 21092376 DOI: 10.1017/s0007114510004538] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Folic acid is essential for numerous biological functions, ranging from nucleotide biosynthesis to the remethylation of homocysteine. Folic acid is unable to cross the biological membranes by simple diffusion, so there exists a well-developed epithelial folate transport system for the regulation of normal folate homeostasis in the intestine. Any perturbances in the folate uptake system might lead to a state of folate deficiency, which in turn is strongly associated with the risk of various cancers, birth defects and CVD. Countries with obligatory folate fortification of food (USA and Canada) have documented a significant decrease in neural tube defects in newborns. However, the effect of folate oversupplementation on the intestinal absorption of folic acid has not been studied. We studied the process of folate transport and the expression of folate transporters in the rat intestine after folate oversupplementation. Rats were oversupplemented with tenfold the normal requirement of folic acid for periods of 10 and 60 d. Folate uptake in intestinal brush-border membrane vesicles followed saturable kinetics with pH optimum at 5·5. Acute, but not chronic, folate oversupplementation led to a significant down-regulation in intestinal folate uptake at acidic pH optima and was associated with a decrease in Vmax without any significant change in the Km of the folate uptake process. The decrease in folate uptake was also associated with the down-regulation in the protein levels of major folate transporters, proton-coupled folate transporter (PCFT) and reduced folate carrier (RFC), without altering their mRNA levels. Hence, it was concluded that acute folate oversupplementation results in a significant decrease in intestinal folate uptake by down-regulating the expressions of RFC and PCFT, via some post-transcriptional or translational mechanisms.
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Barnett M, Bermingham E, McNabb W, Bassett S, Armstrong K, Rounce J, Roy N. Investigating micronutrients and epigenetic mechanisms in relation to inflammatory bowel disease. Mutat Res 2010; 690:71-80. [PMID: 20188748 DOI: 10.1016/j.mrfmmm.2010.02.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2009] [Revised: 01/26/2010] [Accepted: 02/19/2010] [Indexed: 05/28/2023]
Abstract
Epigenomic regulation, via DNA methylation, histone modification and non-coding RNA, is increasingly recognised as having a key role in normal development and function of an organism, acting to control cellular and tissue growth and differentiation. It is also thought to be involved in many complex diseases now common in the Western world, including cardiovascular disease, type 2 diabetes, obesity and inflammatory bowel disease (IBD). There is a range of evidence to suggest that nutrition plays a vital role in the protection from such diseases. However, there is little information about the role of nutrition on the epigenetic regulation of IBD. This review aims to elucidate the interactions of nutrients and the epigenome in IBD. More specifically, the plasticity of epigenetic modifications that occur due to low selenium and folate levels in the diet during gestation and lactation will be discussed. A better understanding of this plasticity, and of nutrient-epigenome interactions, will have important implications for enhancing human health through foods.
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Affiliation(s)
- Matthew Barnett
- Food, Metabolism & Microbiology Section, AgResearch Grasslands, Tennent Drive, Palmerston North 4474, New Zealand.
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Jones RL, Cederberg HMS, Wheeler SJ, Poston L, Hutchinson CJ, Seed PT, Oliver RL, Baker PN. Relationship between maternal growth, infant birthweight and nutrient partitioning in teenage pregnancies. BJOG 2010; 117:200-11. [PMID: 19832832 DOI: 10.1111/j.1471-0528.2009.02371.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVE Teenagers are susceptible to delivering small-for-gestational-age (SGA) infants. Previous studies suggest that maternal growth may contribute, as a result of preferential nutrient partitioning to the mother. We investigated the impact of maternal growth on birthweight in pregnant teenagers in the UK, and examined endocrine mediators of nutrient partitioning. DESIGN A prospective observational multicentre study, About Teenage Eating, conducted between 2004 and 2007. SETTING Four hospitals in socially-deprived areas of Manchester and London. POPULATION A total of 500 pregnant adolescents (14-18 years of age) with a singleton pregnancy were recruited at 10-21 weeks of gestation, with follow-up studies on 368 subjects. A cohort of 80 pregnant adults (25-40 years of age) provided a control group for determining growth. METHODS Skeletal growth, weight gain and skinfold thickness were measured from first to third trimester, together with maternal levels of micronutrients and metabolic hormones: insulin-like growth factor (IGF) system and leptin. Dietary analyses were performed. MAIN OUTCOME MEASURE SGA birth. RESULTS Maternal growth was not associated with SGA birth: growing mothers delivered more large-for-gestational-age infants (OR 2.51; P < 0.05). Growers had greater weight gain (P < 0.001), fat accrual (P < 0.001) and red cell folate concentrations (P < 0.01) than non-growers. Maternal IGF-I (P < 0.01) and leptin (P < 0.001) were positively associated with maternal and fetal growth, whereas IGF-I (P < 0.001) was negatively associated. Teenagers that were underweight at booking or with low weight gain were at greater risk of SGA birth. CONCLUSIONS Maternal growth was not detrimental to fetal growth in this UK population of teenagers. Greater weight gain and higher concentrations of IGF-I in growing teenagers may provide anabolic drive for maternal and fetal growth.
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Affiliation(s)
- R L Jones
- Maternal & Fetal Health Research Group, School of Clinical and Laboratory Sciences, University of Manchester, Manchester Academic Health Science Centre, St Mary's Hospital, Manchester, UK.
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Juzeniene A, Thu Tam TT, Iani V, Moan J. 5-Methyltetrahydrofolate can be photodegraded by endogenous photosensitizers. Free Radic Biol Med 2009; 47:1199-204. [PMID: 19647791 DOI: 10.1016/j.freeradbiomed.2009.07.030] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2009] [Revised: 06/29/2009] [Accepted: 07/27/2009] [Indexed: 10/20/2022]
Abstract
Folate deficiency is linked to serious birth defects, pregnancy complications, male infertility, cardiovascular diseases, and even the evolution of human skin color. Conflicting data exist on whether exposure to sun or artificial UV sources may deplete the levels of blood folate in humans. Blood contains several photosensitizers and proteins, as well as antioxidants, which when exposed to UV radiation and visible light may be involved in the degradation of folate. In this study the photodegradation of 5-methyltetrahydrofolate (5MTHF) in aqueous and deuterious solutions exposed to UVB, UVA, or visible light in the absence or presence of riboflavin, uroporphyrin, and conjugated bilirubin was investigated by absorption spectroscopy. 5MTHF is stable under exposure to visible light and UVA radiation, whereas it is slowly photooxidized under UVB exposure. However, it is rapidly oxidized by UVA or visible radiation in the presence of riboflavin or uroporphyrin, but not in the presence of conjugated bilirubin, which acts in a protective manner. Reactive oxygen species produced in type I and/or type II reactions were involved. This study suggests that 5MTHF in blood can be photodegraded in the presence of the flavins and porphyrins, but protected by bilirubins. This may have health and evolutionary implications.
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Affiliation(s)
- Asta Juzeniene
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0310 Oslo, Norway.
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Schlinzig T, Johansson S, Gunnar A, Ekström TJ, Norman M. Epigenetic modulation at birth - altered DNA-methylation in white blood cells after Caesarean section. Acta Paediatr 2009; 98:1096-9. [PMID: 19638013 DOI: 10.1111/j.1651-2227.2009.01371.x] [Citation(s) in RCA: 135] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
AIM Delivery by C-section (CS) has been associated with increased risk for allergy, diabetes and leukaemia. Whereas the underlying cause is unknown, epigenetic change of the genome has been suggested as a candidate molecular mechanism for perinatal contributions to later disease risk. We hypothesized that mode of delivery affects epigenetic activity in newborn infants. METHODS A total of 37 newborn infants were included. Spontaneous vaginal delivery (VD) occurred in 21, and 16 infants were delivered by elective CS. Blood was sampled from the umbilical cord and 3-5 days after birth. DNA-methylation was analyzed in leucocytes. RESULTS Infants born by CS exhibited higher DNA-methylation in leucocytes compared with that of those born by VD (p < 0.001). After VD, newborn infants exhibited stable levels of DNA-methylation, as evidenced by comparing cord blood values with those 3-5 days after birth (p = 0.55). On postnatal days 3-5, DNA-methylation had decreased in the CS group (p = 0.01) and was no longer significantly different from that of VD (p = 0.10). CONCLUSION DNA-methylation is higher in infants delivered by CS than in infants vaginally born. Although currently unknown how gene expression is affected, or whether epigenetic differences related to mode of delivery are long-lasting, our findings open a new area of clinical research with potentially important public health implications.
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Affiliation(s)
- T Schlinzig
- Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden
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