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Wang W, Gong J. Identification of Key Nucleotide Metabolism Genes in Diabetic Retinopathy Based on Bioinformatics Analysis and Experimental Verification. BIOLOGY 2025; 14:409. [PMID: 40282274 PMCID: PMC12024606 DOI: 10.3390/biology14040409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/09/2025] [Accepted: 04/10/2025] [Indexed: 04/29/2025]
Abstract
A dysregulated nucleotide metabolism has been implicated in the pathogenesis of diabetic retinopathy (DR). RNA sequencing datasets, GSE102485, GSE60436, and GSE165784, were downloaded from the GEO database. The differentially expressed genes (DEGs) between the DR and controls overlapped with nucleotide metabolism-related genes (NM-RGs), resulting in the differentially expressed NM-RGs (DE-NMRGs). Next, the core genes were identified by the five algorithms of the CytoHubba plugin. Receiver Operating Characteristic (ROC) curves and gene expression analysis were utilized to confirm the biomarkers. Then, the correlations between biomarker expression and the immune-related module were analyzed. The miRNA and transcription factor (TF) predictions, biomarker-targeting drugs, and molecular docking were implemented separately. The interaction between each subcluster of DR was elucidated through single-cell RNA (scRNA) analysis. Moreover, RT-PCR was applied to verify the expression of the biomarkers. In GSE102485, 48 DE-NMRGs were identified via the intersection of 1359 DEGs and 882 NM-RGs. Using the CytoHubba plugin, HMOX1, TLR4, and ACE were selected as core genes. As per the GSVA result, the interferon alpha response, IL6_JAK_STAT3 signaling, and apoptosis were activated in the DR group. The TF prediction identified TLR4 and HMOX1 as potential target genes of USF2. In conclusion, ACE and HMOX1 were possible diagnostic biomarkers related to nucleotide metabolism in DR.
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Affiliation(s)
- Wei Wang
- Department of Ophthalmology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China;
- Anhui Public Health Clinical Center, Hefei 230022, China
| | - Jianyang Gong
- Department of Ophthalmology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China;
- Anhui Public Health Clinical Center, Hefei 230022, China
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2
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Liu Y, Pu G, Yang C, Wang Y, Jin K, Wang S, Liang X, Hu S, Sun S, Lai M. Association analysis of MTHFR (rs1801133 and rs1801131) gene polymorphism towards the development of type 2 diabetes mellitus in Dali area population from Yunnan Province, China. PeerJ 2024; 12:e18334. [PMID: 39465169 PMCID: PMC11512809 DOI: 10.7717/peerj.18334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 09/25/2024] [Indexed: 10/29/2024] Open
Abstract
Background Type 2 diabetes mellitus (T2DM) is a common complex metabolic disorder that exhibits a strong genetic predisposition. 5,10-methylenetetrahydrofolate reductase (MTHFR) regulates folate metabolism, which has been proposed to be associated with T2DM, although the relationship is inconsistent among different geographical areas. This study aimed to investigate the effects of MTHFR C677T (rs1801133) and A1298C (rs1801131) loci polymorphisms on T2DM susceptibility in the population of the Dali area in Yunnan Province, China. Methods This case-control study included 445 patients with T2DM and 272 healthy control individuals from the Dali area of Yunnan Province. Genotyping of the MTHFR gene polymorphisms was performed using the competitive allele-specific PCR (KASP) method. The effects of genetic variations of the MTHFR gene on T2DM risk were evaluated using odds ratios (OR) and 95% confidence intervals. Results The results of the present study revealed that the TT genotype (OR = 1.750, P = 0.030) and the T allele (OR = 1.252, P = 0.047) at the MTHFR C677T locus were considerably associated with the increased odds of developing T2DM. In addition, the CC genotype (OR = 3.132, P = 0.032) at the MTHFR A1298C locus also substantially increased the odds of developing T2DM. The T-A haplotype (OR = 1.305, P = 0.030) of MTHFR C677T and A1298C exhibited the increased odds of developing T2DM. Biochemical index analyses showed that patients with T2DM who carried the CT or TT genotype of MTHFR C677T expressed substantially higher levels of fasting blood glucose (FBG), homocysteine (Hcy), and tumor necrosis factor-alpha (TNF-α) than those of the CC genotype. Moreover, the FBG and Hcy levels were considerably higher in patients with T2DM who carried the CC or AC genotype of MTHFR A1298C than those of the AA genotype. No obvious association was observed between these MTHFR polymorphisms and cardiovascular risk in T2DM. Conclusion Our study suggests that the genetic variations of MTHFR C677T and A1298C are significantly associated with T2DM susceptibility in the population of the Dali area of Yunnan Province, China.
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Affiliation(s)
- Yongxin Liu
- School of Basic Medicine, Dali University, Dali, Yunnan, China, Dali, China
| | - Genyuan Pu
- School of Basic Medicine, Dali University, Dali, Yunnan, China, Dali, China
| | - Caiting Yang
- School of Basic Medicine, Dali University, Dali, Yunnan, China, Dali, China
| | - Yuqing Wang
- School of Basic Medicine, Dali University, Dali, Yunnan, China, Dali, China
| | - Kaitai Jin
- School of Basic Medicine, Dali University, Dali, Yunnan, China, Dali, China
| | - Shengrong Wang
- School of Basic Medicine, Dali University, Dali, Yunnan, China, Dali, China
| | - Xiao Liang
- School of Basic Medicine, Dali University, Dali, Yunnan, China, Dali, China
| | - Shenghe Hu
- The First Affiliated Hospital of Dali University, Dali, Yunnan, China, Dali, China
| | - Shuguang Sun
- The First Affiliated Hospital of Dali University, Dali, Yunnan, China, Dali, China
| | - Mingming Lai
- School of Basic Medicine, Dali University, Dali, Yunnan, China, Dali, China
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Harada M, Han S, Shi M, Ge J, Yu S, Adam J, Adamski J, Scheerer MF, Neschen S, de Angelis MH, Wang-Sattler R. Metabolic effects of SGLT2i and metformin on 3-hydroxybutyric acid and lactate in db/db mice. Int J Biol Macromol 2024; 265:130962. [PMID: 38503370 DOI: 10.1016/j.ijbiomac.2024.130962] [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: 09/06/2023] [Revised: 03/15/2024] [Accepted: 03/15/2024] [Indexed: 03/21/2024]
Abstract
Combining a Sodium-Glucose-Cotransporter-2-inhibitor (SGLT2i) with metformin is recommended for managing hyperglycemia in patients with type 2 diabetes (T2D) who have cardio-renal complications. Our study aimed to investigate the metabolic effects of SGLT2i and metformin, both individually and synergistically. We treated leptin receptor-deficient (db/db) mice with these drugs for two weeks and conducted metabolite profiling, identifying 861 metabolites across kidney, liver, muscle, fat, and plasma. Using linear regression and mixed-effects models, we identified two SGLT2i-specific metabolites, X-12465 and 3-hydroxybutyric acid (3HBA), a ketone body, across all examined tissues. The levels of 3HBA were significantly higher under SGLT2i monotherapy compared to controls and were attenuated when combined with metformin. We observed similar modulatory effects on metabolites involved in protein catabolism (e.g., branched-chain amino acids) and gluconeogenesis. Moreover, combination therapy significantly raised pipecolate levels, which may enhance mTOR1 activity, while modulating GSK3, a common target of SGLT2i and 3HBA inhibition. The combination therapy also led to significant reductions in body weight and lactate levels, contrasted with monotherapies. Our findings advocate for the combined approach to better manage muscle loss, and the risks of DKA and lactic acidosis, presenting a more effective strategy for T2D treatment.
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Affiliation(s)
- Makoto Harada
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Siyu Han
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Mengya Shi
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Jianhong Ge
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Shixiang Yu
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Jonathan Adam
- Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Jerzy Adamski
- Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Markus F Scheerer
- Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Susanne Neschen
- Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Martin Hrabe de Angelis
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Chair of Experimental Genetics, School of Life Sciences, Technical University of Munich (TUM), Freising, Germany
| | - Rui Wang-Sattler
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
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Wang R, Cheng F, Yang X. FTO attenuates the cytotoxicity of cisplatin in KGN granulosa cell-like tumour cells by regulating the Hippo/YAP1 signalling pathway. J Ovarian Res 2024; 17:62. [PMID: 38491479 PMCID: PMC10941382 DOI: 10.1186/s13048-024-01385-5] [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: 09/16/2023] [Accepted: 03/01/2024] [Indexed: 03/18/2024] Open
Abstract
Premature ovarian failure (POF) is a devastating condition for women under 40 years old. Chemotherapy, especially the use of cisplatin, has been demonstrated to promote the apoptosis of granulosa cells in primary and secondary follicles, leading to POF. Our previous studies demonstrated that fat mass- and obesity-associated (FTO) plays an essential role in protecting granulosa cells from cisplatin-induced cytotoxicity. Various studies have suggested that the Hippo/YAP signalling pathway plays a significant role in regulating cell apoptosis and proliferation. Additionally, YAP1 is the main downstream target of the Hippo signalling pathway and is negatively regulated by the Hippo signalling pathway. However, whether the Hippo/YAP signalling pathway is involved in the protective effect of FTO on granulosa cells has not been determined. In this study, we found that after cisplatin treatment, the apoptosis of granulosa cells increased in a concentration-dependent manner, accompanied by the downregulation of FTO and YAP1. Furthermore, overexpression of FTO decreased cisplatin-induced granulosa cell apoptosis, inhibited the Hippo/YAP kinase cascade-induced phosphorylation of YAP1, and promoted the entry of YAP1 into the nucleus. The downstream targets of YAP1 (CTGF, CYR61, and ANKRD1) were also increased. Si-RNA-mediated downregulation of FTO promoted cisplatin-induced granulosa cell apoptosis, activated the Hippo/YAP kinase cascade, and inhibited the YAP1 entry into the nucleus. These effects were completely reversed by the small molecule inhibitor of YAP1-verteporfin (VP). Taken together, these data suggested that FTO-YAP1 plays a positive role in regulating the proliferation of injured granulosa cells induced by cisplatin.
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Affiliation(s)
- Rongli Wang
- Department of Obstetrics and Gynecology, Peking University People's Hospital, No. 11, Xi-Zhi-Men South Street, Xi Cheng District, Beijing, 100044, China.
- Department of Obstetrics and Gynecology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Feiyan Cheng
- Department of Obstetrics and Gynecology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xinyuan Yang
- Department of Obstetrics and Gynecology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China.
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Papadopoulos KI, Hallengren B. Multiple etiologies explain the association between sarcoidosis and diabetes mellitus. Expert Rev Respir Med 2022; 16:367-368. [PMID: 35100074 DOI: 10.1080/17476348.2022.2035220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 01/25/2022] [Indexed: 02/08/2023]
Affiliation(s)
| | - Bengt Hallengren
- Department of Endocrinology, Skåne University Hospital, Malmö, Sweden
- Department of Clinical Sciences, Lund University, Lund, Sweden
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Qi W, Hu C, Zhao D, Li X. SIRT1-SIRT7 in Diabetic Kidney Disease: Biological Functions and Molecular Mechanisms. Front Endocrinol (Lausanne) 2022; 13:801303. [PMID: 35634495 PMCID: PMC9136398 DOI: 10.3389/fendo.2022.801303] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 04/15/2022] [Indexed: 12/14/2022] Open
Abstract
Diabetic kidney disease (DKD) is a severe microvascular complication in patients with diabetes and is one of the main causes of renal failure. The current clinical treatment methods for DKD are not completely effective, and further exploration of the molecular mechanisms underlying the pathology of DKD is necessary to improve and promote the treatment strategy. Sirtuins are class III histone deacetylases, which play an important role in many biological functions, including DNA repair, apoptosis, cell cycle, oxidative stress, mitochondrial function, energy metabolism, lifespan, and aging. In the last decade, research on sirtuins and DKD has gained increasing attention, and it is important to summarize the relationship between DKD and sirtuins to increase the awareness of DKD and improve the cure rates. We have found that miRNAs, lncRNAs, compounds, or drugs that up-regulate the activity and expression of sirtuins play protective roles in renal function. Therefore, in this review, we summarize the biological functions, molecular targets, mechanisms, and signaling pathways of SIRT1-SIRT7 in DKD models. Existing research has shown that sirtuins have the potential as effective targets for the clinical treatment of DKD. This review aims to lay a solid foundation for clinical research and provide a theoretical basis to slow the development of DKD in patients.
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Affiliation(s)
- Wenxiu Qi
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Wenxiu Qi,
| | - Cheng Hu
- College of Laboratory Medicine, Jilin Medical University, Jilin City, China
| | - Daqing Zhao
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Xiangyan Li
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
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Raghubeer S, Matsha TE. Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks. Nutrients 2021; 13:nu13124562. [PMID: 34960114 PMCID: PMC8703276 DOI: 10.3390/nu13124562] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 12/07/2021] [Accepted: 12/15/2021] [Indexed: 02/06/2023] Open
Abstract
The 5-10-methylenetetrahydrofolate reductase (MTHFR) enzyme is vital for cellular homeostasis due to its key functions in the one-carbon cycle, which include methionine and folate metabolism and protein, DNA, and RNA synthesis. The enzyme is responsible for maintaining methionine and homocysteine (Hcy) balance to prevent cellular dysfunction. Polymorphisms in the MTHFR gene, especially C677T, have been associated with various diseases, including cardiovascular diseases (CVDs), cancer, inflammatory conditions, diabetes, and vascular disorders. The C677T MTHFR polymorphism is thought to be the most common cause of elevated Hcy levels, which is considered an independent risk factor for CVD. This polymorphism results in an amino acid change from alanine to valine, which prevents optimal functioning of the enzyme at temperatures above 37 °C. Many studies have been conducted to determine whether there is an association between the C677T polymorphism and increased risk for CVD. There is much evidence in favour of this association, while several studies have concluded that the polymorphism cannot be used to predict CVD development or progression. This review discusses current research regarding the C677T polymorphism and its relationship with CVD, inflammation, diabetes, and epigenetic regulation and compares the evidence provided for and against the association with CVD.
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Senamontree S, Lakthan T, Charoenpanich P, Chanchao C, Charoenpanich A. Betulinic acid decreases lipid accumulation in adipogenesis-induced human mesenchymal stem cells with upregulation of PGC-1α and UCP-1 and post-transcriptional downregulation of adiponectin and leptin secretion. PeerJ 2021; 9:e12321. [PMID: 34721992 PMCID: PMC8520689 DOI: 10.7717/peerj.12321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/25/2021] [Indexed: 12/24/2022] Open
Abstract
Background Controlling cellular functions, including stem cell growth and differentiation, can be the key for the treatment of metabolic disorders, such as type II diabetes mellitus (T2DM). Previously identified as peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, betulinic acid (BA) may have the capability to control stem cell homeostasis, benefiting T2DM treatment. In this study, the effects of BA on osteogenesis and adipogenesis mechanisms of human mesenchymal stem cells (hMSCs) were investigated. Results We observed that BA increased hMSC osteogenesis by enhancing the alkaline phosphatase activity, calcium deposition, and mRNA expressions of osteogenic markers, namely, runt-related transcription factor 2, osteocalcin, and osteopontin. In addition, BA decreased hMSC adipogenesis with the decrease in glycerol-3-phosphate dehydrogenase activity, reduced intracellular lipid accumulations, down-regulated CCAAT-enhancer-binding protein alpha, and suppressed post-transcriptional adiponectin and leptin secretion. BA increased the brown adipocyte characteristics with the increase in the ratio of small lipid droplets and glucose uptake. Furthermore, the mRNA expressions of brown adipocyte markers, namely, PPARγ coactivator one alpha, uncoupling protein 1, and interleukin-6 increased. Conclusions Our results uncovered the mechanisms of how BA improved glucose and lipid metabolisms by decreasing white adipogenesis and increasing brown adipogenesis. Altogether, BA may be used for balancing glucose metabolisms without the potential side effects on bone loss or weight gain.
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Affiliation(s)
- Sasithon Senamontree
- Department of Biology, Faculty of Science, Silpakorn University, Nakhon Pathom, Thailand
| | - Thitiporn Lakthan
- Department of Biology, Faculty of Science, Silpakorn University, Nakhon Pathom, Thailand
| | - Pornsri Charoenpanich
- Department of Food Technology, Faculty of Engineering and Industrial Technology, Silpakorn University, Nakhon Pathom, Thailand
| | - Chanpen Chanchao
- Department of Biology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| | - Adisri Charoenpanich
- Department of Biology, Faculty of Science, Silpakorn University, Nakhon Pathom, Thailand
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Papadopoulos KI, Sutheesophon W, Manipalviratn S, Aw TC. Age and genotype dependent erythropoietin protection in COVID-19. World J Stem Cells 2021; 13:1513-1529. [PMID: 34786155 PMCID: PMC8567454 DOI: 10.4252/wjsc.v13.i10.1513] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/23/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
Erythropoietin (EPO) is the main mediator of erythropoiesis and an important tissue protective hormone that appears to mediate an ancestral neuroprotective innate immune response mechanism at an early age. When the young brain is threatened-prematurity, neonatal hyperbilirubinemia, malaria- EPO is hyper-secreted disproportionately to any concurrent anemic stimuli. Under eons of severe malarial selection pressure, neuroprotective EPO augmenting genetic determinants such as the various hemoglobinopathies, and the angiotensin converting enzyme (ACE) I/D polymorphism, have been positively selected. When malarial and other cerebral threats abate and the young child survives to adulthood, EPO subsides. Sustained high ACE and angiotensin II (Ang II) levels through the ACE D allele in adulthood may then become detrimental as witnessed by epidemiological studies. The ubiquitous renin angiotensin system (RAS) influences the α-klotho/fibroblast growth factor 23 (FGF23) circuitry, and both are interconnected with EPO. Here we propose that at a young age, EPO augmenting genetic determinants through ACE D allele elevated Ang II levels in some or HbE/beta thalassemia in others would increase EPO levels and shield against coronavirus disease 2019, akin to protection from malaria and dengue fever. Human evolution may use ACE2 as a "bait" for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to gain cellular entry in order to trigger an ACE/ACE2 imbalance and stimulate EPO hypersecretion using tissue RAS, uncoupled from hemoglobin levels. In subjects without EPO augmenting genetic determinants at any age, ACE2 binding and internalization upon SARS-CoV-2 entry would trigger an ACE/ACE2 imbalance, and Ang II oversecretion leading to protective EPO stimulation. In children, low nasal ACE2 Levels would beneficially augment this imbalance, especially for those without protective genetic determinants. On the other hand, in predisposed adults with the ACE D allele, ACE/ACE2 imbalance, may lead to uncontrolled RAS overactivity and an Ang II induced proinflammatory state and immune dysregulation, with interleukin 6 (IL-6), plasminogen activator inhibitor, and FGF23 elevations. IL-6 induced EPO suppression, aggravated through co-morbidities such as hypertension, diabetes, obesity, and RAS pharmacological interventions may potentially lead to acute respiratory distress syndrome, cytokine storm and/or autoimmunity. HbE/beta thalassemia carriers would enjoy protection at any age as their EPO stimulation is uncoupled from the RAS system. The timely use of rhEPO, EPO analogs, acetylsalicylic acid, bioactive lipids, or FGF23 antagonists in genetically predisposed individuals may counteract those detrimental effects.
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Affiliation(s)
| | | | - Somjate Manipalviratn
- Department of Reproductive Endocrinology, Jetanin Institute for Assisted Reproduction, Bangkok 10330, Thailand
| | - Tar-Choon Aw
- Department of Laboratory Medicine, Changi General Hospital, Singapore 529889, Singapore
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Hu F, Sha W, Dai H, Yang X, Hu P, Chu Y, Qiu X, Bu S. Lower expression of Hsa_circRNA_102682 in diabetic hyperhomocysteinemia negatively related to creatinemia is associated with TGF-β and CTGF. J Clin Lab Anal 2021; 35:e23860. [PMID: 34296783 PMCID: PMC8373364 DOI: 10.1002/jcla.23860] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 05/11/2021] [Accepted: 05/12/2021] [Indexed: 02/07/2023] Open
Abstract
Background Diabetic nephropathy is a kidney disease caused by long‐term hyperglycemia. Hsa_circRNA_102682 is related to the pathogenesis of preeclampsia. Preeclampsia is related to hypertension and proteinuria, and diabetic nephropathy is mainly manifested by hypertension and proteinuria. The main pathological change in diabetic nephropathy is glomerular fibrosis. Methods This study used serum samples of patients treated at Li Huili Eastern Hospital, Ningbo, China, from July 10, 2018 to February 15, 2019. We included 73 patients with diabetes and divided them into a normal‐homocysteine group and a high‐homocysteine group. We selected used quantitative reverse transcriptase‐polymerase chain reaction to measure Hsa_circRNA_102682 concentration in the serum. Serum transforming growth factor‐beta and connective tissue growth factor levels were tested using ELISA. The Pearson correlation test was used to assess the correlations between Hsa_circRNA_102682, transforming growth factor‐beta, connective tissue growth factor, homocysteine, and creatinine. Result Hsa_circRNA_102682 was significantly lower in diabetic patients with high levels of homocysteine than in those with normal levels of homocysteine, whereas transforming growth factor‐beta and connective tissue growth factor levels were higher in diabetic patients with hyperhomocysteinemia. Hsa_circRNA_102682 was negatively correlated with the levels of transforming growth factor‐beta, connective tissue growth factor, homocysteine, and creatinine. Transforming growth factor‐beta and connective tissue growth factor were both positively correlated with homocysteine and creatinine. Conclusion Low Hsa_circRNA_102682 was associated with high levels of transforming growth factor‐beta and connective tissue growth factor as well as homocysteine and creatinine. These results suggest that Hsa_circRNA_102682 might be related to the pathogenesis of hyperhomocysteinemia in diabetic nephropathy.
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Affiliation(s)
- Fei Hu
- Diabetes Research Center, School of Medicine, Ningbo University, Ningbo, China.,Zhejiang Provincial Key Laboratory of Pathophysiology, Department of Biochemistry and Molecular Biology, School of Medicine, Ningbo University, Ningbo, China.,Cixi Biomedical Research Institute, Wenzhou Medical University, Cixi, China
| | - Wenxin Sha
- Diabetes Research Center, School of Medicine, Ningbo University, Ningbo, China.,Zhejiang Provincial Key Laboratory of Pathophysiology, Department of Biochemistry and Molecular Biology, School of Medicine, Ningbo University, Ningbo, China
| | - Huixue Dai
- Department of endocrinology, Ninghai Chengguan Hospital, Ningbo, China
| | - Xiangwei Yang
- Department of endocrinology, Ninghai Chengguan Hospital, Ningbo, China
| | - Peng Hu
- Department of endocrinology, Ninghai Chengguan Hospital, Ningbo, China
| | - Yudong Chu
- Diabetes Research Center, School of Medicine, Ningbo University, Ningbo, China.,Department of Nephrology, Ningbo Medical Center Lihuili Hospital, Ningbo, China
| | - Xiaohui Qiu
- Department of Nephrology, Ningbo Medical Center Lihuili Hospital, Ningbo, China
| | - Shizhong Bu
- Diabetes Research Center, School of Medicine, Ningbo University, Ningbo, China.,Zhejiang Provincial Key Laboratory of Pathophysiology, Department of Biochemistry and Molecular Biology, School of Medicine, Ningbo University, Ningbo, China
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Svoboda LK, Neier K, Wang K, Cavalcante RG, Rygiel CA, Tsai Z, Jones TR, Liu S, Goodrich JM, Lalancette C, Colacino JA, Sartor MA, Dolinoy DC. Tissue and sex-specific programming of DNA methylation by perinatal lead exposure: implications for environmental epigenetics studies. Epigenetics 2020; 16:1102-1122. [PMID: 33164632 DOI: 10.1080/15592294.2020.1841872] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Early developmental environment can influence long-term health through reprogramming of the epigenome. Human environmental epigenetics studies rely on surrogate tissues, such as blood, to assess the effects of environment on disease-relevant but inaccessible target tissues. However, the extent to which environment-induced epigenetic changes are conserved between these tissues is unclear. A better understanding of this conservation is imperative for effective design and interpretation of human environmental epigenetics studies. The Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET II) consortium was established by the National Institute of Environmental Health Sciences to address the utility of surrogate tissues as proxies for toxicant-induced epigenetic changes in target tissues. We and others have recently reported that perinatal exposure to lead (Pb) is associated with adverse metabolic outcomes. Here, we investigated the sex-specific effects of perinatal exposure to a human environmentally relevant level of Pb on DNA methylation in paired liver and blood samples from adult mice using enhanced reduced-representation bisulphite sequencing. Although Pb exposure ceased at 3 weeks of age, we observed thousands of sex-specific differentially methylated cytosines in the blood and liver of Pb-exposed animals at 5 months of age, including 44 genomically imprinted loci. We observed significant tissue overlap in the genes mapping to differentially methylated cytosines. A small but significant subset of Pb-altered genes exhibit basal sex differences in gene expression in the mouse liver. Collectively, these data identify potential molecular targets for Pb-induced metabolic diseases, and inform the design of more robust human environmental epigenomics studies.
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Affiliation(s)
- Laurie K Svoboda
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Kari Neier
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Kai Wang
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School Palmer Commons, Ann Arbor, MI, USA
| | | | - Christine A Rygiel
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Zing Tsai
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.,Department of Computational Medicine and Bioinformatics, University of Michigan Medical School Palmer Commons, Ann Arbor, MI, USA
| | - Tamara R Jones
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Siyu Liu
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School Palmer Commons, Ann Arbor, MI, USA
| | - Jaclyn M Goodrich
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Claudia Lalancette
- Epigenomics Core, University of Michigan, Medical School, Ann Arbor, MI, USA
| | - Justin A Colacino
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.,Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Maureen A Sartor
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School Palmer Commons, Ann Arbor, MI, USA.,Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, MI, USA
| | - Dana C Dolinoy
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.,Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
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12
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Deng X, Wang P, Yuan H. Epidemiology, risk factors across the spectrum of age-related metabolic diseases. J Trace Elem Med Biol 2020; 61:126497. [PMID: 32247247 DOI: 10.1016/j.jtemb.2020.126497] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 02/13/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Population aging is dynamic process of increasing proportion of older adults in the total population, which is an inescapable result of decline in fertility rate and extension in life expectancy. Inevitably, age-related metabolic diseases, for example obesity, type 2 diabetes, metabolic syndrome, dyslipidemia, and nonalcoholic fatty liver disease, are becoming epidemic globally along with the demographic transition. CONTENT The review examines the literatures related to: 1) the epidemiology of age related metabolic diseases including obesity, type 2 diabetes, metabolic syndrome, dyslipidemia, and nonalcoholic fatty liver disease; and 2) the risk factors of age related metabolic diseases including genetic factors, diet, smoking, Physical activity, intestinal microbiota and environmental factors. CONCLUSION Population aging is becoming epidemic worldwide, resulting in increasing incidence and prevalence of a serious of age-related metabolic diseases. Both genetic and environmental factors contribute to the diseases, thus interventions targeting on these factors may have beneficial effect on the development of age-related metabolic diseases.
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Affiliation(s)
- Xinru Deng
- Department of Endocrinology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China
| | - Pengxu Wang
- Department of Endocrinology, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China
| | - Huijuan Yuan
- Department of Endocrinology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China.
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13
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FTO accelerates ovarian cancer cell growth by promoting proliferation, inhibiting apoptosis, and activating autophagy. Pathol Res Pract 2020; 216:153042. [PMID: 32825930 DOI: 10.1016/j.prp.2020.153042] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 05/15/2020] [Accepted: 05/31/2020] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Fat mass and obesity-associated protein (FTO) is identified as a critical demethylase involved in various physiological processes. Despite efforts have been made to study the biological functions of FTO in certain cancers, the role of FTO in ovarian cancer is largely unknown. In this study, we sought to investigate the function of FTO on proliferation, apoptosis and autophagy of ovarian cancer cells. METHODS Quantitative real-time PCR was performed to detect FTO expression in ovarian tumor tissues and ovarian cancer cell lines OVCAR-3, SKOV-3, COC1, HO-8910 and A2780. SKOV-3 cells were constructed with FTO overexpression and A2780 cells were constructed with FTO knockdown. CCK-8 assay was used to examine cell viability and flow cytometry was used to detect cell apoptosis. Activity assay kits were applied to detect caspase-3 and caspase-9 levels. Western blot was performed to measure the expressions of FTO, PCNA, Bax, Bcl-2, LC3, ATG5, P62, p-AKT and AKT. Stable FTO-overexpression SKOV-3 cells or FTO-depletion A2780 cells were injected subcutaneously into male Balb/c-nu mice. Xenografted tumors were assayed by H&E staining. Immunohistochemistry was subjected to measure FTO and Ki67 expressions. RESULTS FTO was up-regulated in ovarian tumor tissues compared with non-cancerous ovarian tissues. FTO overexpression markedly increased viability and autophagy function, but decreased apoptosis of ovarian cancer cells. In addition, FTO overexpression promoted AKT phosphorylation. In contrast, FTO silence showed the opposite effect. CONCLUSION FTO accelerated ovarian cancer cell growth by promoting proliferation, inhibiting apoptosis, and activating autophagy.
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14
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Sarkar P, Chatterjee D, Bandyopadhyay AR. Association of PPARG (rs1801282) genetic polymorphism and obesity with T2DM: A study on Bengalee Hindu caste population of West Bengal, India. Meta Gene 2020. [DOI: 10.1016/j.mgene.2020.100662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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15
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Coskun ZM, Ersoz M, Adas M, Hancer VS, Boysan SN, Gonen MS, Acar A. Kruppel-Like Transcription Factor-4 Gene Expression and DNA Methylation Status in Type 2 Diabetes and Diabetic Nephropathy Patients. Arch Med Res 2019; 50:91-97. [PMID: 31495395 DOI: 10.1016/j.arcmed.2019.05.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 04/12/2019] [Accepted: 05/24/2019] [Indexed: 01/08/2023]
Abstract
BACKGROUND/AIM Diabetic nephropathy (DN) is one of the most serious microvascular complications in diabetic patients. The kruppel-like transcription factor-4 (KLF-4) affects the expression of genes involved in the pathogenesis of DN. The present study aims to identify the KLF-4 expression and DNA methylation (DNAMe) status in patients with type-2 diabetes (T2D) and DN and to reveal the contribution of the KLF-4 to the development of DN. MATERIAL AND METHODS The cohort study was performed with blood samples from 120 individuals; T2D group (n = 40), DN group (n = 40) and control group (n = 40). The expression level of the KLF-4 gene was analyzed using the real-time polymerase chain reaction (qRT-PCR) and the methylation profile detected using the methylation-specific PCR (MS-PCR) technique. RESULTS According to our findings, KLF-4 mRNA expression in the T2D group was 1.60 fold lower than in the control group (p = 0.001). In the DN group, the expression of KLF-4 mRNA was 2.92-fold less than that of the T2D group (p = 0.001). There was no significant alteration in the DNAMe status among the groups. CONCLUSION Our findings showed that regardless of the DNAMe status, KLF-4 gene expression may play a role in the development of T2D and DN. This suggests that the KLF-4 gene may be the target gene in understanding the mechanism of nephropathy, which is the most important complication of diabetes, and planning nephropathy-related treatments, but the data should be supported with more studies.
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Affiliation(s)
- Zeynep Mine Coskun
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Demiroglu Bilim University, Istanbul, Turkey.
| | - Melike Ersoz
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Demiroglu Bilim University, Istanbul, Turkey
| | - Mine Adas
- Department of Endocrinology, Ministry of Health Okmeydani Research and Training Hospital, Health Sciences University, Istanbul, Turkey
| | - Veysel Sabri Hancer
- Department Medical Genetics, Faculty of Medicine, Istinye University, Istanbul, Turkey
| | - Serife Nur Boysan
- Department of Endocrinology, Faculty of Medicine, Demiroglu Bilim University, Istanbul, Turkey
| | - Mustafa Sait Gonen
- Department of Endocrinology, Faculty of Cerrahpasa Medicine, Istanbul University, Istanbul, Turkey
| | - Aynur Acar
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Demiroglu Bilim University, Istanbul, Turkey
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16
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Corrêa-Giannella ML. (Epi) Genetics and the complexity of diabetes mellitus. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2018; 62:4-5. [PMID: 29694636 PMCID: PMC10118681 DOI: 10.20945/2359-3997000000002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 02/20/2018] [Indexed: 11/23/2022]
Affiliation(s)
- Maria Lúcia Corrêa-Giannella
- Laboratório de Carboidrato e Radioimunoensaio (LIM-18), Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brasil
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17
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Pirozzi FF, Belini E, Okumura JV, Salvarani M, Bonini-Domingos CR, Ruiz MA. The relationship between of ACE I/D and the MTHFR C677T polymorphisms in the pathophysiology of type 2 diabetes mellitus in a population of Brazilian obese patients. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2018; 62:21-26. [PMID: 29694640 PMCID: PMC10118689 DOI: 10.20945/2359-3997000000005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 06/07/2017] [Indexed: 11/23/2022]
Abstract
Objectives This study aimed to evaluate the frequencies of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) and methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphisms in obese patients with and without type 2 diabetes mellitus (T2DM). Subjects and methods These polymorphisms were analyzed by polymerase chain reaction in 125 patients with obesity, 47 (T2DM) and 78 (Control Group). Results No significant difference was found on comparing the T2DM and Control Groups in respect to the genotypic frequencies of the polymorphisms - (II: 13.3% vs. 12.0%; ID: 37.8% vs. 37.3; DD: 48.9% vs. 50.7%; CC: 36.2% vs. 39.0%; CT: 46.8% vs. 49.3%; TT: 17.0% vs. 11.7%), and alleles (I: 32.2% vs. 30.7%; D: 67.8% vs. 69.3%; C: 59.6% vs. 63.6%; T: 40.4% vs. 36.4%) and their synergisms in the pathophysiology of T2DM. On analyzing the T2DM Group, there were no significant differences in the presence of complications. In this population of Brazilian obese patients, no correlation was found between the ACE and MTHFR polymorphisms in the development of T2DM. Conclusion Analyzing only the group with diabetes, there was also no relationship between these polymorphisms and comorbidities.
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Affiliation(s)
- Flavio Fontes Pirozzi
- Universidade Estadual PaulistaUniversidade Estadual Paulista “Júlio de Mesquita Filho”Departamento de BiologiaSão José do Rio PretoSPBrasilDepartamento de Biologia, Universidade Estadual Paulista “Júlio de Mesquita Filho” (Unesp), São José do Rio Preto, SP, Brasil
- Associação Portuguesa de BeneficênciaSão José do Rio PretoSPBrasilAssociação Portuguesa de Beneficência, São José do Rio Preto, SP, Brasil
- União das Faculdades dos Grandes LagosFaculdade de MedicinaSão José do Rio PretoSPBrasilFaculdade de Medicina União das Faculdades dos Grandes Lagos (Unilago), São José do Rio Preto, SP, Brasil
| | - Edis Belini
- Universidade Estadual PaulistaUniversidade Estadual Paulista “Júlio de Mesquita Filho”Departamento de BiologiaSão José do Rio PretoSPBrasilDepartamento de Biologia, Universidade Estadual Paulista “Júlio de Mesquita Filho” (Unesp), São José do Rio Preto, SP, Brasil
| | - Jessika Viviani Okumura
- Universidade Estadual PaulistaUniversidade Estadual Paulista “Júlio de Mesquita Filho”Departamento de BiologiaSão José do Rio PretoSPBrasilDepartamento de Biologia, Universidade Estadual Paulista “Júlio de Mesquita Filho” (Unesp), São José do Rio Preto, SP, Brasil
| | - Mariana Salvarani
- Universidade Estadual PaulistaUniversidade Estadual Paulista “Júlio de Mesquita Filho”Departamento de BiologiaSão José do Rio PretoSPBrasilDepartamento de Biologia, Universidade Estadual Paulista “Júlio de Mesquita Filho” (Unesp), São José do Rio Preto, SP, Brasil
| | - Claudia Regina Bonini-Domingos
- Universidade Estadual PaulistaUniversidade Estadual Paulista “Júlio de Mesquita Filho”Departamento de BiologiaSão José do Rio PretoSPBrasilDepartamento de Biologia, Universidade Estadual Paulista “Júlio de Mesquita Filho” (Unesp), São José do Rio Preto, SP, Brasil
| | - Milton Artur Ruiz
- Universidade Estadual PaulistaUniversidade Estadual Paulista “Júlio de Mesquita Filho”Departamento de BiologiaSão José do Rio PretoSPBrasilDepartamento de Biologia, Universidade Estadual Paulista “Júlio de Mesquita Filho” (Unesp), São José do Rio Preto, SP, Brasil
- Associação Portuguesa de BeneficênciaSão José do Rio PretoSPBrasilAssociação Portuguesa de Beneficência, São José do Rio Preto, SP, Brasil
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18
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Gupta A, Ali A, Tewari P, Agrawal NK, Patel R, Byadgi PS. Association of Kaphaja and Kapha-Pittaja Prakriti and methylenetetrahydrofolate reductase C677T allele with type 2 diabetes. Ayu 2018; 39:146-150. [PMID: 31000991 PMCID: PMC6454916 DOI: 10.4103/ayu.ayu_230_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background and Objectives: Type 2 diabetes is a multifactorial disorder that results from the interaction between genetic predisposition and environmental factors. Different Prakriti (body constitution) individuals have different susceptibility for the diseases, and this Prakriti is determined by both genetic and environmental factor. This study was undertaken to determine the association status of Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C with type 2 diabetes and Prakriti. Materials and Methods: After informed consent, 54 patients with type 2 diabetes and 56 individuals as normal controls were analyzed. Their constitution and pathological data were collected and MTHFR C677T and A1298C genotypes were determined. Results: Kapha/Kapha-Pittaja Prakriti were associated and found to be strong risk factors (Chi-square test = 39.67, P < 0.00001, odds ratio [OR] = 16.133, 95% confidence interval [CI] = 6.32–41.20) for type 2 diabetes. MTHFR C677T was associated (Chi-square test = 7.743, P = 0.02) with type 2 diabetes where the major CC genotype was found to be a risk for type 2 diabetes (OR = 3.78, 95% CI = 1.14–12.45). A1298C was not associated with type 2 diabetes (Chi-square test = 2.264, P = 0.322). None of the Prakriti was associated with C677T and A1298C variants. Interpretation and Conclusion: In the present study, an extremely strong association between Prakriti (Kaphaja/Kapha-Pittaja) and type 2 diabetes (P < 0.00001) was detected. The present study gives a strong clue for the association of Prakriti (body constitutional) and clinical phenotype.
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Affiliation(s)
- Archana Gupta
- Department of Vikriti Vigyan, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Akhtar Ali
- Center for Genetic Disorders, Faculty of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Priyadarshini Tewari
- Department of Vikriti Vigyan, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Neeraj Kumar Agrawal
- Department of Endocrinology and Metabolism, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Rashmi Patel
- Center for Genetic Disorders, Faculty of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Parameswarappa Shivappa Byadgi
- Department of Vikriti Vigyan, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
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19
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Owens DR, Monnier L, Barnett AH. Future challenges and therapeutic opportunities in type 2 diabetes: Changing the paradigm of current therapy. Diabetes Obes Metab 2017; 19:1339-1352. [PMID: 28432748 PMCID: PMC5637910 DOI: 10.1111/dom.12977] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 04/05/2017] [Accepted: 04/13/2017] [Indexed: 02/06/2023]
Abstract
Most algorithms for type 2 diabetes mellitus (T2DM) do not recommend treatment escalation until glycated haemoglobin (HbA1c) fails to reach the recommended target of 7% (53 mmol/mol) within approximately 3 months on any treatment regimen ("treat to failure"). Clinical inertia and/or poor adherence to therapy contribute to patients not reaching glycaemic targets when managed according to this paradigm. Clinical inertia exists across the entire spectrum of anti-diabetes therapies, although it is most pronounced when initiating and optimizing insulin therapy. Possible reasons include needle aversion, fear of hypoglycaemia, excessive weight gain and/or the need for increased self-monitoring of blood glucose. Studies have suggested, however, that early intensive insulin therapy in newly diagnosed, symptomatic patients with T2DM with HbA1c >9% (75 mmol/mol) can preserve beta-cell function, thereby modulating the disease process. Furthermore, postprandial plasma glucose is a key component of residual dysglycaemia, evident especially when HbA1c remains above target despite fasting normoglycaemia. Therefore, to achieve near normoglycaemia, additional treatment with prandial insulin or a glucagon-like peptide-1 receptor agonist (GLP-1 RA) is often required. Long- or short-acting GLP-1 RAs offer effective alternatives to basal or prandial insulin in patients inadequately controlled with other therapies or basal insulin alone, respectively. This review highlights the limitations of current algorithms, and proposes an alternative based on the early introduction of insulin therapy and the rationale for the sequential or fixed combination of GLP-1 RAs with insulin ("treat-to-success" paradigm).
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Affiliation(s)
- David R. Owens
- Diabetes Research Unit, Institute of Life Sciences, College of MedicineSwansea UniversitySwanseaUK
| | - Louis Monnier
- Laboratory of Human Nutrition and Atherosclerosis, Institute of Clinical ResearchUniversity of MontpellierMontpellierFrance
| | - Anthony H. Barnett
- Diabetes and Endocrine CentreHeart of England NHS Foundation Trust, Birmingham Heartlands HospitalBirminghamUK
- University of BirminghamBirminghamUK
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20
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Type 2 Diabetes Susceptibility in the Greek-Cypriot Population: Replication of Associations with TCF7L2, FTO, HHEX, SLC30A8 and IGF2BP2 Polymorphisms. Genes (Basel) 2017; 8:genes8010016. [PMID: 28067832 PMCID: PMC5295011 DOI: 10.3390/genes8010016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 12/13/2016] [Accepted: 12/30/2016] [Indexed: 01/17/2023] Open
Abstract
Type 2 diabetes (T2D) has been the subject of numerous genetic studies in recent years which revealed associations of the disease with a large number of susceptibility loci. We hereby initiate the evaluation of T2D susceptibility loci in the Greek-Cypriot population by performing a replication case-control study. One thousand and eighteen individuals (528 T2D patients, 490 controls) were genotyped at 21 T2D susceptibility loci, using the allelic discrimination method. Statistically significant associations of T2D with five of the tested single nucleotide polymorphisms (SNPs) (TCF7L2 rs7901695, FTO rs8050136, HHEX rs5015480, SLC30A8 rs13266634 and IGF2BP2 rs4402960) were observed in this study population. Furthermore, 14 of the tested SNPs had odds ratios (ORs) in the same direction as the previously published studies, suggesting that these variants can potentially be used in the Greek-Cypriot population for predictive testing of T2D. In conclusion, our findings expand the genetic assessment of T2D susceptibility loci and reconfirm five of the worldwide established loci in a distinct, relatively small, newly investigated population.
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dos Santos Nunes MK, Silva AS, de Queiroga Evangelista IW, Filho JM, Gomes CNAP, do Nascimento RAF, Luna RCP, de Carvalho Costa MJ, de Oliveira NFP, Persuhn DC. Hypermethylation in the promoter of the MTHFR gene is associated with diabetic complications and biochemical indicators. Diabetol Metab Syndr 2017; 9:84. [PMID: 29075332 PMCID: PMC5648437 DOI: 10.1186/s13098-017-0284-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Accepted: 10/10/2017] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND DNA methylation is an epigenetic mechanism for regulating the transcription of many genes and has been linked to the development of various diseases. A promising gene to investigate is methylenetetrahydrofolate reductase (MTHFR), since the enzyme methylenetetrahydrofolate reductase (MTHFR) promotes methyl radical synthesis in the homocysteine cycle and can provide methyl groups for DNA methylation. In addition, several studies have correlated gene polymorphisms of this enzyme with a greater risk of diabetes, but little is known regarding the relationship between epigenetic changes in this gene and diabetes and its complications. The aim of this study was to investigate the relationship between methylation profile in the MTHFR gene promoter and biochemical, inflammatory and oxidative stress markers in individuals with type 2 diabetes (T2DM) who have been diagnosed for 5-10 years with or without diabetic retinopathy (DR) and nephropathy (DN). METHODS Specific PCR for methylation (MSP) was used to analyze MTHFR methylation profile in leucocytes DNA. Biochemical markers (glycemia, glycated hemoglobin, total cholesterol, LDL, HDL, triglycerides, serum creatinine), inflammatory markers (C-reactive protein and alpha-1 acid glycoprotein) and oxidative stress (total antioxidant and malonaldehyde) were determined in peripheric blood samples and microalbuminuria in 24 h urine samples. The X2 and Mann-Whitney statistical tests were performed and p < 0.05 were considered significant. RESULTS The hypermethylated profile was most frequently observed in individuals with retinopathy (p < 0.01) and was associated with higher total cholesterol and LDL levels (p = 0.0046, 0.0267, respectively). Individuals with DN and hypermethylated profiles had higher levels of alpha-1 acid glycoprotein (p = 0.0080) and total antioxidant capacity (p = 0.0169) compared to subjects without complications. CONCLUSIONS Hypermethylation in the promoter of the MTHFR gene is associated with the occurrence of DR and with biochemical, inflammatory and oxidative stress parameters in the context of chronic complications.
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Affiliation(s)
| | | | | | - João Modesto Filho
- Department of Internal Medicine, Federal University of Paraiba, Joao Pessoa, Brazil
| | | | | | | | - Maria José de Carvalho Costa
- Nutrition Science Department and Post-Graduate Program in Nutrition Science, Federal University of Paraiba, Joao Pessoa, Brazil
| | | | - Darlene Camati Persuhn
- Department of Molecular Biology and Post-Graduation Program in Nutrition Science, Federal University of Paraiba, CEP 58051-900 Joao Pessoa, Brazil
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Thrombosis Related ABO, F5, MTHFR, and FGG Gene Polymorphisms in Morbidly Obese Patients. DISEASE MARKERS 2016; 2016:7853424. [PMID: 27999448 PMCID: PMC5141527 DOI: 10.1155/2016/7853424] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 10/23/2016] [Accepted: 11/01/2016] [Indexed: 11/17/2022]
Abstract
Objective. Obesity is a well-known risk factor for thrombotic complications. The aim of the present study was to determine the frequency of thrombosis related ABO, F5, MTHFR, and FGG gene polymorphisms in morbidly obese patients and compare them with the group of nonobese individuals. Methods. Gene polymorphisms were analyzed in 320 morbidly obese patients (BMI > 40 kg/m2) and 303 control individuals (BMI < 30 kg/m2) of European descent. ABO C>T (rs505922), F5 C>G (rs6427196), MTHFR C>T (rs1801133), and FGG C>T (rs6536024) SNPs were genotyped by RT-PCR. Results. We observed a tendency for MTHFR rs1801133 TT genotype to be linked with morbid obesity when compared to CC genotype; however, the difference did not reach the significant P value (OR 1.84, 95% CI 0.83–4.05, P = 0.129). Overall, the genotypes and alleles of rs505922, rs6427196, rs1801133, and rs6536024 SNPs had similar distribution between morbidly obese and nonobese control individuals. Distribution of height and weight means among individuals carrying different rs505922, rs6427196, rs1801133, and rs6536024 genotypes did not differ significantly. Conclusions. Gene polymorphisms ABO C>T (rs505922), F5 C>G (rs6427196), MTHFR C>T (rs1801133), and FGG C>T (rs6536024) were not associated with height, weight, or morbid obesity among European subjects.
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Breimer LH, Mikhailidis DP. Does bilirubin protect against developing diabetes mellitus? J Diabetes Complications 2016; 30:728-37. [PMID: 26922581 DOI: 10.1016/j.jdiacomp.2016.01.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 01/22/2016] [Accepted: 01/24/2016] [Indexed: 01/05/2023]
Abstract
After 25 years of evaluating bilirubin as a possible protective agent in neonatal and cardiovascular disease, interest has moved on to a exploring a possible protective role in diabetes mellitus (DM). This review finds conflicting prospective data for a protective relationship though there are retrospective, case-controlled data, that can only show association, which is not causality. Only prospective studies can show causality. Also, it would appear that the underlying biochemical assumptions do not readily translate from the animal to the human setting. Given that many factors impact on circulating bilirubin levels, it is not surprising that a clear-cut answer is not available; the jury is still out. Any relationship between DM and bilirubin might relate to intermediates in bilirubin metabolism, including relationships involving the genes for the enzymes participating in those steps. Nevertheless, the pursuit of bilirubin in disease causation is opening new avenues for research and if it is established that serum bilirubin can predict risks, much will have been achieved. The answer may have to come from molecular genetic analyses.
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Affiliation(s)
- Lars H Breimer
- Dept of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro University Hospital, SE-701 85, Örebro, Sweden.
| | - Dimitri P Mikhailidis
- Dept. of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free campus, University College London Medical School, University College London (UCL), London, NW3 2QG, UK
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Gesteiro E, Sánchez-Muniz FJ, Ortega-Azorín C, Guillén M, Corella D, Bastida S. Maternal and neonatal FTO rs9939609 polymorphism affect insulin sensitivity markers and lipoprotein profile at birth in appropriate-for-gestational-age term neonates. J Physiol Biochem 2016; 72:169-81. [PMID: 26851950 DOI: 10.1007/s13105-016-0467-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 01/27/2016] [Indexed: 11/30/2022]
Abstract
The influence of maternal fat mass and obesity (FTO) gene polymorphism on neonatal insulin sensitivity/resistance biomarkers and lipoprotein profile has not been tested. The study aimed to assess the association between the FTO rs9939609 polymorphism in mother-neonate couples and neonatal anthropometrical measurements, insulin sensitivity/resistance, and lipid and lipoprotein concentrations at birth. Fifty-three term, appropriate-for-gestational-age, Caucasian newborns together with their respective mothers participated in a cross-sectional study. Sixty-six percent of mothers and neonates carried the A allele (being AA or AT). TT mothers gained less weight during pregnancy, but non-significant maternal gene influence was found for neonatal bodyweight, body mass index, or ponderal index. Neonates from AA + AT mothers showed lower glucose, insulin, and homeostatic model assessment insulin resistance (HOMA-IR) but higher homeostatic model assessment insulin sensitivity (HOMA-IS) and homocysteine than neonates whose mothers were TT. AA + AT neonates had higher insulin and HOMA-IR than TT. The genotype neonatal × maternal association was tested in the following four groups of neonates: TT neonates × TT mothers (nTT × mTT), TT neonates × AA + AT mothers (nTT × mAA + AT), AA + AT neonates × TT mothers (nAA + AT × mTT), and AA + AT neonates × AA + AT mothers (nAA + AT × mAA + AT). Non-significant interactions between neonatal and maternal alleles were found for any parameter tested. However, maternal alleles affected significantly glucose, insulin, HOMA-IR, and homocysteine while neonatal alleles the arylesterase activity. Most significant differences were found between nATT + AA × mTT and nATT + AA × mAA + AT. Glycemia, insulinemia, and HOMA-IR were lower, while the Mediterranean diet adherence (MDA) was higher in the mAA + AT vs. mTT whose children were AA + AT. This dietary fact seems to counterbalance the potential negative effect on glucose homeostasis of the obesogenic A allele in neonates.
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Affiliation(s)
- Eva Gesteiro
- Departamento de Nutrición y Bromatología I (Nutrición), Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain.,Servicio de Análisis Clínicos, Hospital de Mérida, Polígono Nueva Ciudad s/n, 06800, Mérida (Badajoz), Spain
| | - Francisco J Sánchez-Muniz
- Departamento de Nutrición y Bromatología I (Nutrición), Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain.
| | - Carolina Ortega-Azorín
- Departamento de Medicina Preventiva y CIBER Fisiopatología de la Obesidad y Nutrición, ISCIII, Facultad de Medicina, Universidad de Valencia, 46010, Valencia, Spain
| | - Marisa Guillén
- Departamento de Medicina Preventiva y CIBER Fisiopatología de la Obesidad y Nutrición, ISCIII, Facultad de Medicina, Universidad de Valencia, 46010, Valencia, Spain
| | - Dolores Corella
- Departamento de Medicina Preventiva y CIBER Fisiopatología de la Obesidad y Nutrición, ISCIII, Facultad de Medicina, Universidad de Valencia, 46010, Valencia, Spain
| | - Sara Bastida
- Departamento de Nutrición y Bromatología I (Nutrición), Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain
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Melnik BC. Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases. J Transl Med 2015; 13:385. [PMID: 26691922 PMCID: PMC4687119 DOI: 10.1186/s12967-015-0746-z] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 12/04/2015] [Indexed: 12/14/2022] Open
Abstract
Single-nucleotide polymorphisms within intron 1 of the FTO (fat mass and obesity-associated) gene are associated with enhanced FTO expression, increased body weight, obesity and type 2 diabetes mellitus (T2DM). The N6-methyladenosine (m6A) demethylase FTO plays a pivotal regulatory role for postnatal growth and energy expenditure. The purpose of this review is to provide translational evidence that links milk signaling with FTO-activated transcription of the milk recipient. FTO-dependent demethylation of m6A regulates mRNA splicing required for adipogenesis, increases the stability of mRNAs, and affects microRNA (miRNA) expression and miRNA biosynthesis. FTO senses branched-chain amino acids (BCAAs) and activates the nutrient sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), which plays a key role in translation. Milk provides abundant BCAAs and glutamine, critical components increasing FTO expression. CpG hypomethylation in the first intron of FTO has recently been associated with T2DM. CpG methylation is generally associated with gene silencing. In contrast, CpG demethylation generally increases transcription. DNA de novo methylation of CpG sites is facilitated by DNA methyltransferases (DNMT) 3A and 3B, whereas DNA maintenance methylation is controlled by DNMT1. MiRNA-29s target all DNMTs and thus reduce DNA CpG methylation. Cow´s milk provides substantial amounts of exosomal miRNA-29s that reach the systemic circulation and target mRNAs of the milk recipient. Via DNMT suppression, milk exosomal miRNA-29s may reduce the magnitude of FTO methylation, thereby epigenetically increasing FTO expression in the milk consumer. High lactation performance with increased milk yield has recently been associated with excessive miRNA-29 expression of dairy cow mammary epithelial cells (DCMECs). Notably, the galactopoietic hormone prolactin upregulates the transcription factor STAT3, which induces miRNA-29 expression. In a retrovirus-like manner milk exosomes may transfer DCMEC-derived miRNA-29s and bovine FTO mRNA to the milk consumer amplifying FTO expression. There is compelling evidence that obesity, T2DM, prostate and breast cancer, and neurodegenerative diseases are all associated with increased FTO expression. Maximization of lactation performance by veterinary medicine with enhanced miRNA-29s and FTO expression associated with increased exosomal miRNA-29 and FTO mRNA transfer to the milk consumer may represent key epigenetic mechanisms promoting FTO/mTORC1-mediated diseases of civilization.
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Affiliation(s)
- Bodo C Melnik
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Sedanstrasse 115, 49090, Osnabrück, Germany.
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Khodaeian M, Enayati S, Tabatabaei-Malazy O, Amoli MM. Association between Genetic Variants and Diabetes Mellitus in Iranian Populations: A Systematic Review of Observational Studies. J Diabetes Res 2015; 2015:585917. [PMID: 26587547 PMCID: PMC4637497 DOI: 10.1155/2015/585917] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 01/15/2015] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION Diabetes mellitus as the most prevalent metabolic disease is a multifactorial disease which is influenced by environmental and genetic factors. In this systematic review, we assessed the association between genetic variants and diabetes/its complications in studies with Iranian populations. METHODS Google Scholar, PubMed, Scopus, and Persian web databases were systematically searched up to January 2014. The search terms were "gene," "polymorphism," "diabetes," and "diabetic complications"; nephropathy, retinopathy, neuropathy, foot ulcer, and CAD (coronary artery diseases); and Persian equivalents. Animal studies, letters to editor, and in vitro studies were excluded. RESULTS Out of overall 3029 eligible articles, 88 articles were included. We found significant association between CTLA-4, IL-18, VDR, TAP2, IL-12, and CD4 genes and T1DM, HNFα and MODY, haptoglobin, paraoxonase, leptin, TCF7L2, calreticulin, ERα, PPAR-γ2, CXCL5, calpain-10, IRS-1 and 2, GSTM1, KCNJ11, eNOS, VDR, INSR, ACE, apoA-I, apo E, adiponectin, PTPN1, CETP, AT1R, resistin, MMP-3, BChE K, AT2R, SUMO4, IL-10, VEGF, MTHFR, and GSTM1 with T2DM or its complications. DISCUSSION We found some controversial results due to heterogeneity in ethnicity and genetic background. We thought genome wide association studies on large number of samples will be helpful in identifying diabetes susceptible genes as an alternative to studying individual candidate genes in Iranian populations.
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Affiliation(s)
- Mehrnoosh Khodaeian
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Samaneh Enayati
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ozra Tabatabaei-Malazy
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahsa M. Amoli
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Li T, Xi HF, Luo HM, Liu WX, Gao X, Liu DW, Yang L. Association of the NAD(P)H oxidase p22 phox gene C242T polymorphism with type 2 diabetes mellitus, diabetic nephropathy, and carotid atherosclerosis with type 2 diabetes mellitus: A meta-analysis. Meta Gene 2015; 6:1-8. [PMID: 26380814 PMCID: PMC4556815 DOI: 10.1016/j.mgene.2015.07.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Revised: 07/23/2015] [Accepted: 07/29/2015] [Indexed: 11/16/2022] Open
Abstract
Background Several epidemiological studies have evaluated the association between the NAD(P)H oxidase p22 phox gene C242T polymorphism and the risk of type 2 diabetes mellitus (T2DM), diabetic nephropathy (DN), and carotid atherosclerosis with T2DM (CA), but the results are inconclusive. This meta-analysis was therefore designed to clarify these controversies. Methods Systematic searches were performed using electronic databases such as MEDLINE, PubMed, EMBASE, and China National Knowledge Infrastructure, as well as through manual searching of the references of identified articles. A total of 11 publications were eligible for this meta-analysis after running a search on the NAD(P)H oxidase p22 phox gene C242T polymorphism, including 7 with outcomes for T2DM, 7 with outcomes for DN, and 3 with outcomes for CA. The pooled odds ratio (OR) with a 95% confidence interval (CI) was calculated using a fixed effects model (FEM) or a random effects model (REM). Publication bias was tested by Begg's funnel plot analysis. Sensitivity analysis was also performed. Results The results showed a significant association between the NAD(P)H oxidase p22 phox gene C242T polymorphism and T2DM risk in the allelic model (REM: OR = 1.23, 95% CI = 1.06–1.43), additive model (FEM: OR = 1.61, 95% CI = 1.14–2.26), and recessive model (FEM: OR = 1.50, 95% CI = 1.10–2.05). A significant association was also observed for DN in the allelic model (REM: OR = 1.25, 95% CI = 1.06–1.47), additive model (FEM: OR = 1.61, 95% CI = 1.08–2.38), and dominant model (REM: OR = 1.26, 95% CI = 1.03–1.54). However, no association was observed for CA. Similar results were obtained in subgroup analysis based on ethnicity. Conclusions Results of this meta-analysis suggest that the NAD(P)H oxidase p22 phox gene 242T allele might be associated with an increased risk of T2DM and DN, but not CA.
There are significant association between P22 phox gene C242T polymorphism with T2DM DN risk but no significant association with CA.
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Affiliation(s)
- Tao Li
- Department of Epidemiology and Statistic, Hebei Medical University, Shijiazhuang 050017, China
| | - Hai-Feng Xi
- Hebei Provincial Health and Family Planning Commission, Shijiazhuang, China
| | - Hong-Min Luo
- Department of Nephrology Third Hospital, Hebei Medical University, Shijiazhuang, China
| | - Wen-Xuan Liu
- Department of Epidemiology and Statistic, Hebei Medical University, Shijiazhuang 050017, China
| | - Xia Gao
- Department of Epidemiology and Statistic, Hebei Medical University, Shijiazhuang 050017, China
| | - Dian-Wu Liu
- Department of Epidemiology and Statistic, Hebei Medical University, Shijiazhuang 050017, China
| | - Lei Yang
- Department of Epidemiology and Statistic, Hebei Medical University, Shijiazhuang 050017, China
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Nikitin AG, Potapov VA, Brovkin AN, Lavrikova EY, Khodyrev DS, Shamhalova MS, Smetanina SA, Suplotova LN, Shestakova MV, Nosikov VV, Averyanov AV. Association of FTO, KCNJ11, SLC30A8, and CDKN2B polymorphisms with type 2 diabetes mellitus. Mol Biol 2015. [DOI: 10.1134/s0026893315010112] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Chen LL, Han SM, Tang FF, Li Q. MTLRP genetic polymorphism (214C>A) was associated with Type 2 diabetes in Caucasian population: a meta-analysis. Lipids Health Dis 2014; 13:124. [PMID: 25095788 PMCID: PMC4237884 DOI: 10.1186/1476-511x-13-124] [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] [Received: 04/04/2014] [Accepted: 06/18/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Previous studies reported the relation between MTLRP genetic polymorphism and type 2 diabetes, however, the conclusion were conflicting. In the present study, we performed a meta-analysis to reveal this association. METHODS Literature retrieval, selection and assessment, data extraction, and meta-analyses were performed according to the RevMan 5.0 guidelines. In the meta-analysis, we utilized random-effect model or fixed-effect model to pool the Odds ratio (OR) according to the test of heterogeneity. RESULTS A total of nine case-control studies included 4460 type 2 diabetes patients and 4114 healthy control subjects were analyzed. We did not found association between the MTLRP polymorphism and type 2 diabetes risk in the overall population (CC vs CA + AA: OR = 1.02; 95% CI: 0.89-1.17, P = 0.77; A vs C: OR = 1.02; 95% CI: 0.84-0.96, P = 0.62). However, in subgroup analyses stratified by ethnicity, we found significant association of MTLRP polymorphism with type 2 diabetes in Caucasians (CC vs CA + AA: OR = 1.27; 95% CI: 1.02-1.57, P = 0.03; A vs C: OR = 0.74, 95% CI: 0.60-0.91, P = 0.005). CONCLUSION The MTLRP polymorphism was associated with type 2 diabetes in Caucasians.
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Affiliation(s)
| | | | | | - Qiang Li
- Department of Endocrinology, The Second Affiliated Hospital of Harbin Medical University, NO, 246, Xuefu Road, Nangang District, Harbin, Heilongjiang Province 150086, P,R, China.
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Gao XH, Zhang GY, Wang Y, Zhang HY. Correlations of MTHFR 677C>T polymorphism with cardiovascular disease in patients with end-stage renal disease: a meta-analysis. PLoS One 2014; 9:e102323. [PMID: 25050994 PMCID: PMC4106822 DOI: 10.1371/journal.pone.0102323] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 06/17/2014] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE This meta-analysis was conducted to evaluate the correlations of a common polymorphism (677C>T) in the methylenetetrahydrofolate reductase (MTHFR) gene with risk of cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). METHOD The following electronic databases were searched without language restrictions: Web of Science (1945∼2013), the Cochrane Library Database (Issue 12, 2013), MEDLINE (1966∼2013), EMBASE (1980∼2013), CINAHL (1982∼2013) and the Chinese Biomedical Database (CBM) (1982∼2013). Meta-analysis was performed using STATA statistical software. Odds ratios (ORs) with their 95% confidence intervals (95%CIs) were calculated. RESULTS Eight cohort studies met all inclusion criteria and were included in this meta-analysis. A total of 2,292 ESRD patients with CVD were involved in this meta-analysis. Our meta-analysis results revealed that the MTHFR 677C>T polymorphism might increase the risk of CVD in ESRD patients (TT vs. CC: OR = 2.75, 95%CI = 1.35∼5.59, P = 0.005; CT+TT vs. CC: OR = 1.39, 95%CI = 1.09∼1.78, P = 0.008; TT vs. CC+CT: OR = 2.52, 95%CI = 1.25∼5.09, P = 0.010; respectively). Further subgroup analysis by ethnicity suggested that the MTHFR 677C>T polymorphism was associated with an elevated risk for CVD in ESRD patients among Asians (TT vs. CC: OR = 3.38, 95%CI = 1.11∼10.28, P = 0.032; CT+TT vs. CC: OR = 1.44, 95%CI = 1.05∼1.97, P = 0.022; TT vs. CC+CT: OR = 3.15, 95%CI = 1.02∼9.72, P = 0.046; respectively), but not among Africans or Caucasians (all P>0.05). CONCLUSION Our findings indicate that the MTHFR 677C>T polymorphism may be associated with an elevated risk for CVD in ESRD patients, especially among Asians.
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Affiliation(s)
- Xian-Hui Gao
- Laboratory of Preventive Medicine, School of Public Health, Liaoning Medical University, Jinzhou, China
- * E-mail:
| | - Guo-Yi Zhang
- Laboratory of Preventive Medicine, School of Public Health, Liaoning Medical University, Jinzhou, China
| | - Ying Wang
- Department of Toxicology, School of Public Health, Liaoning Medical University, Jinzhou, China
| | - Hui-Ying Zhang
- Sleep Monitoring Center, First Affiliated Hospital of Liaoning Medical University, Jinzhou, China
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Zhu B, Wu X, Zhi X, Liu L, Zheng Q, Sun G. Methylenetetrahydrofolate reductase C677T polymorphism and type 2 diabetes mellitus in Chinese population: a meta-analysis of 29 case-control studies. PLoS One 2014; 9:e102443. [PMID: 25047451 PMCID: PMC4105552 DOI: 10.1371/journal.pone.0102443] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 06/19/2014] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, had significant effects on the homocysteine levels. The common functional MTHFR C677T polymorphism had been extensively researched. Several studies had evaluated the relationship between MTHFR C677T polymorphism and type 2 diabetes mellitus (T2DM), but the results were still controversial in the Chinese Han population. This meta-analysis was conducted to evaluate the relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. METHODS We searched the relevant studies in multiple electronic databases, which published up to December 2013. We reviewed and extracted data from all the included studies on the relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. The odds ratios (ORs) and their 95% confidence intervals (95%CIs) were used to evaluate the relationship. Fixed-effects and random-effects meta-analysis were used to pool ORs by the heterogeneity. Publication bias and sensitivity analysis were also examined. RESULTS 29 studies were finally included in our meta-analysis, which contained 4656 individuals with T2DM and 2127 healthy controls. There was a significant relationship between MTHFR C677T polymorphism and T2DM under dominant (OR: 1.70, 95% CI: 1.42-2.02), recessive (OR: 1.48, 95% CI: 1.21-1.80), homozygous (OR: 1.89, 95% CI: 1.47-2.42), heterozygous (OR: 1.58, 95% CI: 1.33-1.87), and additive (OR: 1.46, 95% CI: 1.28-1.68) genetic model in a random-effects model. Subgroup analysis also reached similar results. Sensitivity analysis indicated that the overall result were dependable. CONCLUSIONS There was a significant relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. The results of our meta-analysis suggested that MTHFR 677T allele might be a risk genetic factor of T2DM in the Chinese Han population.
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Affiliation(s)
- Bo Zhu
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, People's Republic of China
- Liaoning Academy of Safety Science, Shenyang, People's Republic of China
| | - Xiaomei Wu
- Department of Clinical Epidemiology and Evidence Medicine, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Xueyuan Zhi
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, People's Republic of China
| | - Lei Liu
- Key Laboratory of Endocrine diseases in Liaoning Province, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Quanmei Zheng
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, People's Republic of China
| | - Guifan Sun
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, People's Republic of China
- * E-mail:
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Watkins AJ, Sinclair KD. Paternal low protein diet affects adult offspring cardiovascular and metabolic function in mice. Am J Physiol Heart Circ Physiol 2014; 306:H1444-52. [DOI: 10.1152/ajpheart.00981.2013] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Although the association between maternal periconceptional diet and adult offspring health is well characterised, our understanding of the impact of paternal nutrition at the time of conception on offspring phenotype remains poorly defined. Therefore, we determined the effect of a paternal preconception low protein diet (LPD) on adult offspring cardiovascular and metabolic health in mice. Male C57BL/6 mice were fed either normal protein diet (NPD; 18% casein) or LPD (9% casein) for 7 wk before mating. At birth, a reduced male-to-female ratio ( P = 0.03) and increased male offspring weight ( P = 0.009) were observed in litters from LPD compared with NPD stud males with no differences in mean litter size. LPD offspring were heavier than NPD offspring at 2 and 3 wk of age ( P < 0.02). However, no subsequent differences in body weight were observed. Adult male offspring derived from LPD studs developed relative hypotension (decreased by 9.2 mmHg) and elevated heart rate ( P < 0.05), whereas both male and female offspring displayed vascular dysfunction and impaired glucose tolerance relative to NPD offspring. At cull (24 wk), LPD males had elevated adiposity ( P = 0.04), reduced heart-to-body weight ratio ( P = 0.04), and elevated circulating TNF-α levels ( P = 0.015) compared with NPD males. Transcript expression in offspring heart and liver tissue was reduced for genes involved in calcium signaling ( Adcy, Plcb, Prkcb) and metabolism ( Fto) in LPD offspring ( P < 0.03). These novel data reveal the impact of suboptimal paternal nutrition on adult offspring cardiovascular and metabolic homeostasis, and provide some insight into the underlying regulatory mechanisms.
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Affiliation(s)
- Adam J. Watkins
- School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, UK; and
- Aston Research Centre for Healthy Ageing, School of Life and Health Sciences, Aston University, Birmingham, UK
| | - Kevin D. Sinclair
- School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, UK; and
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Eddouks M, Bidi A, El Bouhali B, Hajji L, Zeggwagh NA. Antidiabetic plants improving insulin sensitivity. ACTA ACUST UNITED AC 2014; 66:1197-214. [PMID: 24730446 DOI: 10.1111/jphp.12243] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 02/23/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND Globally, the prevalence of diabetes mellitus is increasing at an alarming rate. This chronic pathology gravely troubled the human health and quality of life. Both insulin deficiency and insulin resistance are involved in the pathophysiology of diabetes mellitus. Moreover, insulin resistance is being diagnosed nowadays in a growing population of diabetic and obese patients, especially in industrialized societies. There are lots of conventional agents available to control and to treat diabetes, but total recovery from this disorder has not been reported up to this date. Plants provided a potential source of hypoglycemic drugs and are widely used in several traditional systems of medicine to prevent diabetes. A few reviews with less attention paid to mechanisms of action have been published on antidiabetic plants. OBJECTIVES The present review focuses on the various plants that have been reported to be effective in improving insulin sensitivity associated with diabetes. KEY FINDINGS In this work, an updated systematic review of the published literature has been conducted to review the antidiabetic plants improving insulin sensitivity and 111 medicinal plants have been reported to have a beneficial effect on insulin sensitivity using several in-vitro and in-vivo animal models of diabetes. CONCLUSION The different metabolic and cellular effects of the antidiabetic plants improving insulin sensitivity are reported indicating the important role of medicinal plants as potential alternative or complementary use in controlling insulin resistance associated with diabetes mellitus.
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Affiliation(s)
- Mohamed Eddouks
- Faculty of Sciences and Techniques Errachidia, Moulay Ismail University, Errachidia, Morocco
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