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Antoniadou C, Gavriilidis E, Ritis K, Tsilingiris D. Anemia in diabetes mellitus: Pathogenetic aspects and the value of early erythropoietin therapy. Metabol Open 2025; 25:100344. [PMID: 39886103 PMCID: PMC11780985 DOI: 10.1016/j.metop.2024.100344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Accepted: 12/30/2024] [Indexed: 02/01/2025] Open
Abstract
Anemia is a frequent, yet increasingly recognized, comorbidity in diabetes mellitus (DM), with prevalence often driven by multifactorial mechanisms. Hematinic deficiencies, common in this population, may arise from associated comorbidities or medications, such as metformin, as well as other drugs commonly employed for DM-related conditions. Among contributing factors, diabetic kidney disease (DKD) plays a pivotal role, with anemia developing more frequently and being more pronounced in earlier stages, than in CKD of other causes. This enhanced susceptibility stems primarily from the combined impact of impaired renal oxygen sensing and deficient erythropoietin (EPO) production linked to tubulointerstitial fibrosis. Additional mechanisms comprise glomerular dysfunction, shortened erythrocyte lifespan, uremia-induced bone marrow suppression, and increased bleeding risk. DM is also recognized as a chronic low-grade inflammatory condition, with its inflammatory burden driving iron maldistribution, suppression of erythropoiesis, and resistance to EPO. The diagnostic approach of anemia in DM mirrors that in the general population. Addressing modifiable causes such as hematinic deficiencies, and other chronic conditions, such as DKD and bone marrow disorders, is paramount. In total, the underlying pathophysiology of anemia in DM primarily reflects a state of absolute or relative EPO deficiency and/or diminished bone marrow responsiveness, effectively corresponding to 'anemia of chronic disease. Early initiation of EPO therapy, even in DM patients without overt DKD, may mitigate disease progression and improve outcomes. Future research should focus on diabetes-specific strategies integrating optimal EPO use, potentially implementing targeted management of renal and inflammatory contributors to anemia.
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Affiliation(s)
- Christina Antoniadou
- First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
- Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Efstratios Gavriilidis
- First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
- Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Konstantinos Ritis
- First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
- Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Dimitrios Tsilingiris
- First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
- Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
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Wu L, Xin Y, Zhang J, Yang X, Chen T, Niu P. Associations between Metals, Serum Folate, and Cognitive Function in the Elderly: Mixture and Mediation Analyses. ENVIRONMENT & HEALTH (WASHINGTON, D.C.) 2024; 2:865-874. [PMID: 39722838 PMCID: PMC11667285 DOI: 10.1021/envhealth.4c00071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 06/18/2024] [Accepted: 06/19/2024] [Indexed: 12/28/2024]
Abstract
Exposure to metals may potentially impact cognitive health in the elderly; however, the evidence remains ambiguous. The specific role of serum folate in this relationship is also unclear. We aimed to evaluate the individual and joint impact of metals on cognition in the elderly from the United States and explore the potential mediating effect of serum folate. Data from the NHANES 2011-2014 were used, with inductively coupled plasma mass spectrometry (ICP-MS) employed to measure blood metal concentrations. Cognitive function was assessed using tests for immediate, delayed, and working memory: Immediate Recall test (IRT), the Delayed Recall test (DRT), the Animal Fluency test (AFT), and the Digit Symbol Substitution test (DSST). Generalized linear regression models (GLMs), Bayesian kernel machine regression model (BKMR), and quantile g-computation (QG-C) models were used to assess associations between metals (lead, cadmium, mercury, selenium, manganese) and cognition, with mediation analyses examining serum folate's involvement in metal effects. This study included 2002 participants aged ≥60. GLMs revealed the negative association between cadmium and the z-scores of IRT (β: -0.17,95% CI: -0.30, -0.04) and DSST (β: -0.15,95% CI: -0.27, -0.04), with negative effects also observed in the BKMR and QG-C models. Selenium displayed significantly positive association with cognition across various statistical models, including GLMs, QG-C, and BKMR. Serum folate played a mediating role in the effects of cadmium and selenium exposure on DSST z-scores, with a proportion of mediation of 17% and 10%, respectively. Our study assessed the impact of metal mixtures on cognition in the elderly population, finding that high selenium level was strongly associated with better cognitive performance, while cadmium was associated with lower cognitive function scores. Serum folate might partially mediate the association between cadmium, selenium, and DSST z-scores.
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Affiliation(s)
- Luli Wu
- Department
of Occupational Health and Environmental Health, School of Public
Health, Capital Medical University, 100069 Beijing, China
- Beijing
Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, 100069 Beijing, China
| | - Ye Xin
- Department
of Occupational Health and Environmental Health, School of Public
Health, Capital Medical University, 100069 Beijing, China
- Beijing
Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, 100069 Beijing, China
| | - Junrou Zhang
- Department
of Occupational Health and Environmental Health, School of Public
Health, Capital Medical University, 100069 Beijing, China
- Beijing
Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, 100069 Beijing, China
| | - Xin Yang
- Department
of Occupational Health and Environmental Health, School of Public
Health, Capital Medical University, 100069 Beijing, China
- Beijing
Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, 100069 Beijing, China
| | - Tian Chen
- Department
of Occupational Health and Environmental Health, School of Public
Health, Capital Medical University, 100069 Beijing, China
- Beijing
Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, 100069 Beijing, China
| | - Piye Niu
- Department
of Occupational Health and Environmental Health, School of Public
Health, Capital Medical University, 100069 Beijing, China
- Beijing
Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, 100069 Beijing, China
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Aydoğdu GS, Akyakar B, Kalaycı Z, Uçar A, Gezmen-Karadağ M. Folic Acid as a Potential Vitamin in Glycemic Control: A Systematic Review. Curr Nutr Rep 2024; 13:729-750. [PMID: 39251542 DOI: 10.1007/s13668-024-00565-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/05/2024] [Indexed: 09/11/2024]
Abstract
PURPOSE This systematic review aims to examine the relationship between serum folate level and folic acid supplements with glycemic control parameters (fasting blood glucose (FBG), insulin level, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and Hemoglobin A1C (HbA1c)) in adult individuals with current studies. METHODS In this study, which was designed as a systematic review, the searches were performed on Web of Science, Science Direct, Medline, Wiley, and Cochrane Library databases between April 10, 2023, and May 10, 2023, and the searches were updated between October 16, 2023, and November 14, 2023. Of the 1855 studies obtained from the screening, 17 met the criteria and were included in the systematic review. The PROSPERO system registered the study protocol (ID: CRD42023472434). RECENT FINDINGS Although no significant correlation was found between serum folate levels and glycemic control parameters in most of the cross-sectional studies included in this systematic review, most of the randomized controlled trials showed that glycemic control parameters (FBG, insulin, HOMA-IR) decreased significantly in the intervention group receiving folic acid supplementation compared to the control group. However, study durations were short, and HbA1c needed to be evaluated in most studies. This makes it difficult to get information about the long-term effects of folic acid supplementation. More comprehensive studies should be conducted to draw more precise conclusions about the relationship between folic acid levels and folic acid supplementation with glycemic control parameters.
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Affiliation(s)
- Gökçe Sueda Aydoğdu
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Anadolu University, Eskişehir, Turkey.
| | - Buket Akyakar
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gazi University, Ankara, Turkey
| | - Zeynep Kalaycı
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Antalya Bilim University, Antalya, Turkey
| | - Ayda Uçar
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gazi University, Ankara, Turkey
| | - Makbule Gezmen-Karadağ
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gazi University, Ankara, Turkey
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Younes S. The role of micronutrients on the treatment of diabetes. HUMAN NUTRITION & METABOLISM 2024; 35:200238. [DOI: 10.1016/j.hnm.2023.200238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/05/2024]
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Liu Y, Liu JE, He H, Qin M, Lei H, Meng J, Liu C, Chen X, Luo W, Zhong S. Characterizing the metabolic divide: distinctive metabolites differentiating CAD-T2DM from CAD patients. Cardiovasc Diabetol 2024; 23:14. [PMID: 38184583 PMCID: PMC10771670 DOI: 10.1186/s12933-023-02102-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 12/25/2023] [Indexed: 01/08/2024] Open
Abstract
OBJECTIVE To delineate the metabolomic differences in plasma samples between patients with coronary artery disease (CAD) and those with concomitant CAD and type 2 diabetes mellitus (T2DM), and to pinpoint distinctive metabolites indicative of T2DM risk. METHOD Plasma samples from CAD and CAD-T2DM patients across three centers underwent comprehensive metabolomic and lipidomic analyses. Multivariate logistic regression was employed to discern the relationship between the identified metabolites and T2DM risk. Characteristic metabolites' metabolic impacts were further probed through hepatocyte cellular experiments. Subsequent transcriptomic analyses elucidated the potential target sites explaining the metabolic actions of these metabolites. RESULTS Metabolomic analysis revealed 192 and 95 significantly altered profiles in the discovery (FDR < 0.05) and validation (P < 0.05) cohorts, respectively, that were associated with T2DM risk in univariate logistic regression. Further multivariate regression analyses identified 22 characteristic metabolites consistently associated with T2DM risk in both cohorts. Notably, pipecolinic acid and L-pipecolic acid, lysine derivatives, exhibited negative association with CAD-T2DM and influenced cellular glucose metabolism in hepatocytes. Transcriptomic insights shed light on potential metabolic action sites of these metabolites. CONCLUSIONS This research underscores the metabolic disparities between CAD and CAD-T2DM patients, spotlighting the protective attributes of pipecolinic acid and L-pipecolic acid. The comprehensive metabolomic and transcriptomic findings provide novel insights into the mechanism research, prophylaxis and treatment of comorbidity of CAD and T2DM.
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Affiliation(s)
- Yingjian Liu
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
- Department of Pharmacy, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Road, Guangzhou, 510080, China
- Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China
| | - Ju-E Liu
- Department of Pharmacy, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Huafeng He
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
- Department of Pharmacy, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Road, Guangzhou, 510080, China
- Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China
| | - Min Qin
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
- Department of Pharmacy, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Road, Guangzhou, 510080, China
- Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China
| | - Heping Lei
- Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China
| | - Jinxiu Meng
- Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China
| | - Chen Liu
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
| | - Wenwei Luo
- Department of Pharmacy, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Road, Guangzhou, 510080, China.
| | - Shilong Zhong
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China.
- Department of Pharmacy, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Road, Guangzhou, 510080, China.
- Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.
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Chan CW, Lin BF. Folate Deficiency Enhanced Inflammation and Exacerbated Renal Fibrosis in High-Fat High-Fructose Diet-Fed Mice. Nutrients 2023; 15:3616. [PMID: 37630806 PMCID: PMC10458828 DOI: 10.3390/nu15163616] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 08/15/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
The prevalence of obesity and chronic kidney disease (CKD) is increasing simultaneously and rapidly worldwide. Our previous study showed that folate deficiency increased lipid accumulation and leptin production of adipocytes. Whether folate plays a role in CKD, particularly obesity-related nephropathy remains unclear. To investigate the effects of folate deficiency on CKD in diet-induced obese mice, four groups of male C57BL/6 mice were fed either a normal-fat diet (NF) with folate (NF+f); NF without folate (NF-f); high-fat high-fructose diet (HFF) with folate (HFF+f); or HFF without folate (HFF-f) for 12 months during the study. The results showed that HFF increased not only body weight, fasting blood glucose, total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol, and blood pressure, but also cytokines levels, such as interleukin (IL)-2, interferon (IFN)-γ, IL-17A/F, IL-6, monocyte chemoattractant protein (MCP)-1, and transforming growth factor (TGF)-β1. The indicators of kidney failure including urinary protein, neutrophil gelatinase-associated lipocalin (NGAL), renal type I and IV collagen deposits and leptin content, and serum creatinine were also increased by HFF. Folate-deficient diets further elevated serum TC, LDL-cholesterol, IL-6, tumor necrosis factor (TNF)-α, MCP-1, TGF-β1, and leptin, but decreased IL-10 level, and thus exacerbated renal fibrosis. To investigate the possible mechanisms of folate deficiency on renal injury, phosphorylation of pro-fibrosis signaling molecules, including signal transducer and activator of transcription (STAT)3 and small mothers against decapentaplegic (Smad)2/3, were assayed. Both HFF and folate deficiency significantly increased the phosphorylation of STAT3 and Smad2/3, suggesting synergistic effects of HFF-f on chronic renal inflammation and fibrosis. In conclusion, the results demonstrated that folate deficiency might aggravate inflammatory status and enhance renal fibrosis.
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Affiliation(s)
| | - Bi-Fong Lin
- Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei 10617, Taiwan;
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Zhang L, Li D, Yi P, Shi J, Guo M, Yin Q, Liu D, Zhuang P, Zhang Y. Peripheral origin exosomal microRNAs aggravate glymphatic system dysfunction in diabetic cognitive impairment. Acta Pharm Sin B 2023; 13:2817-2825. [PMID: 37521866 PMCID: PMC10372831 DOI: 10.1016/j.apsb.2023.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 02/09/2023] [Accepted: 03/02/2023] [Indexed: 08/01/2023] Open
Abstract
Cognitive dysfunction is one of the common central nervous systems (CNS) complications of diabetes mellitus, which seriously affects the quality of life of patients and results in a huge economic burden. The glymphatic system dysfunction mediated by aquaporin-4 (AQP4) loss or redistribution in perivascular astrocyte endfeet plays a crucial role in diabetes-induced cognitive impairment (DCI). However, the mechanism of AQP4 loss or redistribution in the diabetic states remains unclear. Accumulating evidence suggests that peripheral insulin resistance target tissues and CNS communication affect brain homeostasis and that exosomal miRNAs are key mediators. Glucose and lipid metabolism disorder is an important pathological feature of diabetes mellitus, and skeletal muscle, liver and adipose tissue are the key target insulin resistance organs. In this review, the changes in exosomal miRNAs induced by peripheral metabolism disorders in diabetes mellitus were systematically reviewed. We focused on exosomal miRNAs that could induce low AQP4 expression and redistribution in perivascular astrocyte endfeet, which could provide an interorgan communication pathway to illustrate the pathogenesis of DCI. Furthermore, the mechanisms of exosome secretion from peripheral insulin resistance target tissue and absorption to the CNS were summarized, which will be beneficial for proposing novel and feasible strategies to optimize DCI prevention and/or treatment in diabetic patients.
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Affiliation(s)
- Lin Zhang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Dongna Li
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Pengrong Yi
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jiangwei Shi
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300193, China
| | - Mengqing Guo
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Qingsheng Yin
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
| | - Dingbin Liu
- State Key Laboratory of Medicinal Chemical Biology, Research Center for Analytical Sciences, and Tianjin Key Laboratory of Molecular Recognition and Biosensing, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Pengwei Zhuang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
| | - Yanjun Zhang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300193, China
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Wu HHL, McDonnell T, Chinnadurai R. Physiological Associations between Vitamin B Deficiency and Diabetic Kidney Disease. Biomedicines 2023; 11:biomedicines11041153. [PMID: 37189771 DOI: 10.3390/biomedicines11041153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 03/24/2023] [Accepted: 04/10/2023] [Indexed: 05/17/2023] Open
Abstract
The number of people living with chronic kidney disease (CKD) is growing as our global population continues to expand. With aging, diabetes, and cardiovascular disease being major harbingers of kidney disease, the number of people diagnosed with diabetic kidney disease (DKD) has grown concurrently. Poor clinical outcomes in DKD could be influenced by an array of factors-inadequate glycemic control, obesity, metabolic acidosis, anemia, cellular senescence, infection and inflammation, cognitive impairment, reduced physical exercise threshold, and, importantly, malnutrition contributing to protein-energy wasting, sarcopenia, and frailty. Amongst the various causes of malnutrition in DKD, the metabolic mechanisms of vitamin B (B1 (Thiamine), B2 (Riboflavin), B3 (Niacin/Nicotinamide), B5 (Pantothenic Acid), B6 (Pyridoxine), B8 (Biotin), B9 (Folate), and B12 (Cobalamin)) deficiency and its clinical impact has garnered greater scientific interest over the past decade. There remains extensive debate on the biochemical intricacies of vitamin B metabolic pathways and how their deficiencies may affect the development of CKD, diabetes, and subsequently DKD, and vice-versa. Our article provides a review of updated evidence on the biochemical and physiological properties of the vitamin B sub-forms in normal states, and how vitamin B deficiency and defects in their metabolic pathways may influence CKD/DKD pathophysiology, and in reverse how CKD/DKD progression may affect vitamin B metabolism. We hope our article increases awareness of vitamin B deficiency in DKD and the complex physiological associations that exist between vitamin B deficiency, diabetes, and CKD. Further research efforts are needed going forward to address the knowledge gaps on this topic.
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Affiliation(s)
- Henry H L Wu
- Renal Research Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, The University of Sydney, Sydney, NSW 2065, Australia
| | - Thomas McDonnell
- Department of Renal Medicine, Northern Care Alliance NHS Foundation Trust, Salford M6 8HD, UK
| | - Rajkumar Chinnadurai
- Department of Renal Medicine, Northern Care Alliance NHS Foundation Trust, Salford M6 8HD, UK
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M1 7HR, UK
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Machine Learning Model Based on Insulin Resistance Metagenes Underpins Genetic Basis of Type 2 Diabetes. Biomolecules 2023; 13:biom13030432. [PMID: 36979367 PMCID: PMC10046262 DOI: 10.3390/biom13030432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/12/2023] [Accepted: 02/14/2023] [Indexed: 03/03/2023] Open
Abstract
Insulin resistance (IR) is considered the precursor and the key pathophysiological mechanism of type 2 diabetes (T2D) and metabolic syndrome (MetS). However, the pathways that IR shares with T2D are not clearly understood. Meta-analysis of multiple DNA microarray datasets could provide a robust set of metagenes identified across multiple studies. These metagenes would likely include a subset of genes (key metagenes) shared by both IR and T2D, and possibly responsible for the transition between them. In this study, we attempted to find these key metagenes using a feature selection method, LASSO, and then used the expression profiles of these genes to train five machine learning models: LASSO, SVM, XGBoost, Random Forest, and ANN. Among them, ANN performed well, with an area under the curve (AUC) > 95%. It also demonstrated fairly good performance in differentiating diabetics from normal glucose tolerant (NGT) persons in the test dataset, with 73% accuracy across 64 human adipose tissue samples. Furthermore, these core metagenes were also enriched in diabetes-associated terms and were found in previous genome-wide association studies of T2D and its associated glycemic traits HOMA-IR and HOMA-B. Therefore, this metagenome deserves further investigation with regard to the cardinal molecular pathological defects/pathways underlying both IR and T2D.
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Cano A, Vazquez-Chantada M, Conde-Vancells J, Gonzalez-Lahera A, Mosen-Ansorena D, Blanco FJ, Clément K, Aron-Wisnewsky J, Tran A, Gual P, García-Monzón C, Caballería J, Castro A, Martínez-Chantar ML, Mato JM, Zhu H, Finnell RH, Aransay AM. Impaired Function of Solute Carrier Family 19 Leads to Low Folate Levels and Lipid Droplet Accumulation in Hepatocytes. Biomedicines 2023; 11:biomedicines11020337. [PMID: 36830876 PMCID: PMC9953281 DOI: 10.3390/biomedicines11020337] [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: 11/30/2022] [Revised: 01/17/2023] [Accepted: 01/18/2023] [Indexed: 01/27/2023] Open
Abstract
Low serum folate levels are inversely related to metabolic associated fatty liver disease (MAFLD). The role of the folate transporter gene (SLC19A1) was assessed to clarify its involvement in lipid accumulation during the onset of MAFLD in humans and in liver cells by genomic, transcriptomic, and metabolomic techniques. Genotypes of 3 SNPs in a case-control cohort were initially correlated to clinical and serum MAFLD markers. Subsequently, the expression of 84 key genes in response to the loss of SLC19A1 was evaluated with the aid of an RT2 profiler-array. After shRNA-silencing of SLC19A1 in THLE2 cells, folate and lipid levels were measured by ELISA and staining techniques, respectively. In addition, up to 482 amino acids and lipid metabolites were semi-quantified in SLC19A1-knockdown (KD) cells through ultra-high-performance liquid chromatography coupled with mass spectrometry. SNPs, rs1051266 and rs3788200, were significantly associated with the development of fatty liver for the single-marker allelic test. The minor alleles of these SNPs were associated with a 0.6/-1.67-fold decreased risk of developing MAFLD. When SLC19A1 was KD in THLE2 cells, intracellular folate content was four times lower than in wild-type cells. The lack of functional SLC19A1 provoked significant changes in the regulation of genes associated with lipid droplet accumulation within the cell and the onset of NAFLD. Metabolomic analyses showed a highly altered profile, where most of the species that accumulated in SLC19A1-KD-cells belong to the chemical groups of triacylglycerols, diacylglycerols, polyunsaturated fatty acids, and long chain, highly unsaturated cholesterol esters. In conclusion, the lack of SLC19A1 gene expression in hepatocytes affects the regulation of key genes for normal liver function, reduces intracellular folate levels, and impairs lipid metabolism, which entails lipid droplet accumulation in hepatocytes.
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Affiliation(s)
- Ainara Cano
- Food Research, AZTI, Basque Research and Technology Alliance (BRTA), Parque Tecnologico de Bizkaia, Astondo Bidea, Building 609, 48160 Derio, Spain
- OWL Metabolomics, Parque Tecnologico de Bizkaia, Building 502, 48160 Derio, Spain
| | - Mercedes Vazquez-Chantada
- OWL Metabolomics, Parque Tecnologico de Bizkaia, Building 502, 48160 Derio, Spain
- Department of Nutritional Sciences, Dell Paediatric Research Institute, The University of Texas at Austin, Austin, TX 78712, USA
| | - Javier Conde-Vancells
- Department of Nutritional Sciences, Dell Paediatric Research Institute, The University of Texas at Austin, Austin, TX 78712, USA
| | - Aintzane Gonzalez-Lahera
- CIC bioGUNE, Parque Tecnologico de Bizkaia, Building 801-A, 48160 Derio, Spain
- CIBERehd, ISCIII, 28029 Madrid, Spain
| | | | - Francisco J. Blanco
- CIC bioGUNE, Parque Tecnologico de Bizkaia, Building 801-A, 48160 Derio, Spain
- Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain
| | - Karine Clément
- Nutriomics Research Group, Nutrition Department, Pitié-Salpétrière Hospital, INSERM, Sorbonne Université, F-75013 Paris, France
- INSERM, UMR_S 1166, NutriOmics Team 6, F-75013 Paris, France
- Assistance Publique Hôpitaux de Paris, Nutrition department ICAN and CRNH-Ile de France, Pitié-Salpêtrière Hospital, F-75013 Paris, France
| | - Judith Aron-Wisnewsky
- Nutriomics Research Group, Nutrition Department, Pitié-Salpétrière Hospital, INSERM, Sorbonne Université, F-75013 Paris, France
- INSERM, UMR_S 1166, NutriOmics Team 6, F-75013 Paris, France
- Assistance Publique Hôpitaux de Paris, Nutrition department ICAN and CRNH-Ile de France, Pitié-Salpêtrière Hospital, F-75013 Paris, France
| | - Albert Tran
- Team 8 “Chronic Liver Diseases Associated with Obesity and Alcohol”, INSERM, U1065, Centre Hospitalier Universitaire de Nice, C3M, Université Côte d’Azur, 06000 Nice, France
| | - Philippe Gual
- Team 8 “Chronic Liver Diseases Associated with Obesity and Alcohol”, INSERM, U1065, Centre Hospitalier Universitaire de Nice, C3M, Université Côte d’Azur, 06000 Nice, France
| | - Carmelo García-Monzón
- CIBERehd, ISCIII, 28029 Madrid, Spain
- Liver Research Unit, Santa Cristina University Hospital, Instituto de Investigación Sanitaria Princesa, 28009 Madrid, Spain
| | - Joan Caballería
- CIBERehd, ISCIII, 28029 Madrid, Spain
- Liver Unit, Hospital Clinic, 08036 Barcelona, Spain
| | - Azucena Castro
- OWL Metabolomics, Parque Tecnologico de Bizkaia, Building 502, 48160 Derio, Spain
| | - María Luz Martínez-Chantar
- CIC bioGUNE, Parque Tecnologico de Bizkaia, Building 801-A, 48160 Derio, Spain
- CIBERehd, ISCIII, 28029 Madrid, Spain
| | - José M. Mato
- CIC bioGUNE, Parque Tecnologico de Bizkaia, Building 801-A, 48160 Derio, Spain
- CIBERehd, ISCIII, 28029 Madrid, Spain
| | - Huiping Zhu
- Department of Nutritional Sciences, Dell Paediatric Research Institute, The University of Texas at Austin, Austin, TX 78712, USA
| | - Richard H. Finnell
- Department of Nutritional Sciences, Dell Paediatric Research Institute, The University of Texas at Austin, Austin, TX 78712, USA
| | - Ana M. Aransay
- CIC bioGUNE, Parque Tecnologico de Bizkaia, Building 801-A, 48160 Derio, Spain
- CIBERehd, ISCIII, 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-944-061-325 or +34-946-572-524; Fax: +34-946-572-530
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11
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Gill VJS, Soni S, Shringarpure M, . A, Bhardwaj S, Yadav NK, Patel A, Patel A. Gut Microbiota Interventions for the Management of Obesity: A Literature Review. Cureus 2022; 14:e29317. [PMID: 36161997 PMCID: PMC9484223 DOI: 10.7759/cureus.29317] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/19/2022] [Indexed: 11/16/2022] Open
Abstract
The gut microbiota (GM) has been recognized as an important factor in the development of metabolic diseases such as obesity; it has been reported that the composition of the GM differs in obese and lean subjects, suggesting that microbiota dysbiosis can contribute to changes in body weight. Dysbiosis occurs due to an imbalance in the composition of gut bacteria, changes in the metabolic process, or changes in the distribution of microbiota within the gut. Dysbiosis can change the functioning of the intestinal barrier and the gut-associated lymphoid tissues (GALT). Microbial manipulation may help with preventing or treating weight gain and associated comorbidities. Approaches to this may range from dietary manipulation, which is suitable to treat the individual’s microflora, to probiotics, prebiotics, synbiotics, and fecal microbiota transplant (FMT).
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12
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Chan CW, Chan PH, Lin BF. Folate Deficiency Increased Lipid Accumulation and Leptin Production of Adipocytes. Front Nutr 2022; 9:852451. [PMID: 35548560 PMCID: PMC9083361 DOI: 10.3389/fnut.2022.852451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/18/2022] [Indexed: 12/13/2022] Open
Abstract
Imbalanced dietary habits are closely associated with poor micronutrients status and the development of obesity. Previous studies have shown that serum folate level is decreased in obese individuals. However, whether folate deficiency could result in adiposity is still unclear. The aim of this study was to investigate the effects of dietary folate on lipid accumulation and leptin production using both in vivo and in vitro studies. Male C57BL/6 mice were fed with a diet with (f1) or without (f0) folate in a high-fat (HF) diet containing high-sucrose (HFS-f1, HFS-f0) for 4.5-5 months in Experiment 1, or an HF diet (HF-f1, HF-f0) for 12 months in Experiment 2, or an HF diet containing high-fructose (HFF-f1, HFF-f0) for 12 months in Experiment 3, compared with the normal-fat (NF-f1, NF-f0) diet, respectively. The serum levels of folate and leptin, white adipose tissue (WAT), size of adipocytes, hepatic contents of triglyceride (TG), and cholesterol were measured. In vitro study, TG contents, proinflammatory cytokines, leptin, and expressions of hypoxia-inducible factor (HIF)-1α and lipogenesis-related genes of 3T3-L1 adipocytes cultured with (f1) or without (f0) folate were assayed. The results showed that folate deficiency together with a high-fat diet (HFS-f0, HF-f0, HFF-f0) had higher WAT mass, adipocyte size, serum leptin level, and hepatic TG compared to those of the folate-sufficient groups (HFS-f1, HF-f1, and HFF-f1). Folate deficiency with a high-fat high -sucrose or -fructose diet (HFS-f0, HFF-f0) significantly increased the body weight of the mice. Increased intracellular TG, leptin, monocyte chemotactic protein (MCP)-1 and interleukin (IL)-6 levels, and the expression of Hif1α and lipogenesis-related genes Cebpα, Cebpβ, Acc1, Fasn, and Fabp4 were also detected in folate-deficient 3T3-L1 adipocytes. Our results suggested that folate deficiency increased lipid accumulation and leptin production of adipocytes, and thus, inadequate folate status might be one of the risk factors for adiposity.
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Affiliation(s)
| | | | - Bi-Fong Lin
- Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, Taiwan
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13
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Almeida JI, Tenreiro MF, Martinez-Santamaria L, Guerrero-Aspizua S, Gisbert JP, Alves PM, Serra M, Baptista PM. Hallmarks of the human intestinal microbiome on liver maturation and function. J Hepatol 2022; 76:694-725. [PMID: 34715263 DOI: 10.1016/j.jhep.2021.10.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/05/2021] [Accepted: 10/17/2021] [Indexed: 12/18/2022]
Abstract
As one of the most metabolically complex systems in the body, the liver ensures multi-organ homeostasis and ultimately sustains life. Nevertheless, during early postnatal development, the liver is highly immature and takes about 2 years to acquire and develop almost all of its functions. Different events occurring at the environmental and cellular levels are thought to mediate hepatic maturation and function postnatally. The crosstalk between the liver, the gut and its microbiome has been well appreciated in the context of liver disease, but recent evidence suggests that the latter could also be critical for hepatic function under physiological conditions. The gut-liver crosstalk is thought to be mediated by a rich repertoire of microbial metabolites that can participate in a myriad of biological processes in hepatic sinusoids, from energy metabolism to tissue regeneration. Studies on germ-free animals have revealed the gut microbiome as a critical contributor in early hepatic programming, and this influence extends throughout life, mediating liver function and body homeostasis. In this seminar, we describe the microbial molecules that have a known effect on the liver and discuss how the gut microbiome and the liver evolve throughout life. We also provide insights on current and future strategies to target the gut microbiome in the context of hepatology research.
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Affiliation(s)
- Joana I Almeida
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain; Instituto de Biologia Experimental e Tecnológica (iBET), Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Oeiras, Portugal
| | - Miguel F Tenreiro
- Instituto de Biologia Experimental e Tecnológica (iBET), Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Oeiras, Portugal
| | - Lucía Martinez-Santamaria
- Carlos III University of Madrid. Bioengineering and Aerospace Engineering, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, ISCIII), Madrid, Spain; Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain
| | - Sara Guerrero-Aspizua
- Carlos III University of Madrid. Bioengineering and Aerospace Engineering, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, ISCIII), Madrid, Spain
| | - Javier P Gisbert
- Gastroenterology Department. Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Paula M Alves
- Instituto de Biologia Experimental e Tecnológica (iBET), Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Oeiras, Portugal
| | - Margarida Serra
- Instituto de Biologia Experimental e Tecnológica (iBET), Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Oeiras, Portugal
| | - Pedro M Baptista
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain; Carlos III University of Madrid. Bioengineering and Aerospace Engineering, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Fundación ARAID, Zaragoza, Spain.
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14
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Su X, Yu W, Liu A, Wang C, Li X, Gao J, Liu X, Jiang W, Yang Y, Lv S. San-Huang-Yi-Shen Capsule Ameliorates Diabetic Nephropathy in Rats Through Modulating the Gut Microbiota and Overall Metabolism. Front Pharmacol 2022; 12:808867. [PMID: 35058786 PMCID: PMC8764181 DOI: 10.3389/fphar.2021.808867] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
San-Huang-Yi-Shen capsule (SHYS) has been used in the treatment of diabetic nephropathy (DN) in clinic. However, the mechanisms of SHYS on DN remain unknown. In this study, we used a high-fat diet (HFD) combined with streptozotocin (STZ) injection to establish a DN rat model. Next, we used 16S rRNA sequencing and untargeted metabolomics to study the potential mechanisms of SHYS on DN. Our results showed that SHYS treatment alleviated the body weight loss, hyperglycemia, proteinuria, pathological changes in kidney in DN rats. SHYS could also inhibite the oxidative stress and inflammatory response in kidney. 16S rRNA sequencing analysis showed that SHYS affected the beta diversity of gut microbiota community in DN model rats. SHYX could also decrease the Firmicutes to Bacteroidetes (F to B) ratio in phylum level. In genus level, SHYX treatment affected the relative abundances of Lactobacillus, Ruminococcaceae UCG-005, Allobaculum, Anaerovibrio, Bacteroides and Candidatus_Saccharimonas. Untargeted metabolomics analysis showed that SHYX treatment altered the serum metabolic profile in DN model rats through affecting the levels of guanidineacetic acid, L-kynurenine, prostaglandin F1α, threonine, creatine, acetylcholine and other 21 kind of metabolites. These metabolites are mainly involved in glycerophospholipid metabolism, tryptophan metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, tricarboxylic acid (TCA) cycle, tyrosine metabolism, arginine and proline metabolism, arginine and proline metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, and D-glutamine and D-glutamate metabolism pathways. Spearman correlation analysis showed that Lactobacillus, Candidatus_Saccharimonas, Ruminococcaceae UCG-005, Anaerovibrio, Bacteroides, and Christensenellaceae_R-7_group were closely correlated with most of physiological data and the differential metabolites following SHYS treatment. In conclusion, our study revealed multiple ameliorative effects of SHYS on DN including the alleviation of hyperglycemia and the improvement of renal function, pathological changes in kidney, oxidative stress, and the inflammatory response. The mechanism of SHYS on DN may be related to the improvement of gut microbiota which regulates arginine biosynthesis, TCA cycle, tyrosine metabolism, and arginine and proline metabolism.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Shuquan Lv
- Cangzhou Hospital of Integrated TCM and Western Medicine of Hebei Province, Cangzhou, China
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15
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Hayden MR, Tyagi SC. Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer's Disease and Long COVID. MEDICINA (KAUNAS, LITHUANIA) 2021; 58:16. [PMID: 35056324 PMCID: PMC8779539 DOI: 10.3390/medicina58010016] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 12/25/2022]
Abstract
Impaired folate-mediated one-carbon metabolism (FOCM) is associated with many pathologies and developmental abnormalities. FOCM is a metabolic network of interdependent biosynthetic pathways that is known to be compartmentalized in the cytoplasm, mitochondria and nucleus. Currently, the biochemical mechanisms and causal metabolic pathways responsible for the initiation and/or progression of folate-associated pathologies have yet to be fully established. This review specifically examines the role of impaired FOCM in type 2 diabetes mellitus, Alzheimer's disease and the emerging Long COVID/post-acute sequelae of SARS-CoV-2 (PASC). Importantly, elevated homocysteine may be considered a biomarker for impaired FOCM, which is known to result in increased oxidative-redox stress. Therefore, the incorporation of hyperhomocysteinemia will be discussed in relation to impaired FOCM in each of the previously listed clinical diseases. This review is intended to fill gaps in knowledge associated with these clinical diseases and impaired FOCM. Additionally, some of the therapeutics will be discussed at this early time point in studying impaired FOCM in each of the above clinical disease states. It is hoped that this review will allow the reader to better understand the role of FOCM in the development and treatment of clinical disease states that may be associated with impaired FOCM and how to restore a more normal functional role for FOCM through improved nutrition and/or restoring the essential water-soluble B vitamins through oral supplementation.
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Affiliation(s)
- Melvin R. Hayden
- Departments of Internal Medicine, Endocrinology Diabetes and Metabolism Diabetes and Cardiovascular Disease Center, University of Missouri School of Medicine, Columbia, MO 65212, USA
| | - Suresh C. Tyagi
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
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16
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Eszlari N, Bruncsics B, Millinghoffer A, Hullam G, Petschner P, Gonda X, Breen G, Antal P, Bagdy G, Deakin JFW, Juhasz G. Biology of Perseverative Negative Thinking: The Role of Timing and Folate Intake. Nutrients 2021; 13:4396. [PMID: 34959947 PMCID: PMC8703428 DOI: 10.3390/nu13124396] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 12/02/2021] [Accepted: 12/06/2021] [Indexed: 11/20/2022] Open
Abstract
Past-oriented rumination and future-oriented worry are two aspects of perseverative negative thinking related to the neuroticism endophenotype and associated with depression and anxiety. Our present aim was to investigate the genomic background of these two aspects of perseverative negative thinking within separate groups of individuals with suboptimal versus optimal folate intake. We conducted a genome-wide association study in the UK Biobank database (n = 72,621) on the "rumination" and "worry" items of the Eysenck Personality Inventory Neuroticism scale in these separate groups. Optimal folate intake was related to lower worry, but unrelated to rumination. In contrast, genetic associations for worry did not implicate specific biological processes, while past-oriented rumination had a more specific genetic background, emphasizing its endophenotypic nature. Furthermore, biological pathways leading to rumination appeared to differ according to folate intake: purinergic signaling and circadian regulator gene ARNTL emerged in the whole sample, blastocyst development, DNA replication, and C-C chemokines in the suboptimal folate group, and prostaglandin response and K+ channel subunit gene KCNH3 in the optimal folate group. Our results point to possible benefits of folate in anxiety disorders, and to the importance of simultaneously taking into account genetic and environmental factors to determine personalized intervention in polygenic and multifactorial disorders.
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Affiliation(s)
- Nora Eszlari
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary; (P.P.); (G.B.); (G.J.)
- NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary; (A.M.); (X.G.)
| | - Bence Bruncsics
- Department of Measurement and Information Systems, Budapest University of Technology and Economics, Magyar Tudósok krt. 2, H-1521 Budapest, Hungary; (B.B.); (G.H.); (P.A.)
| | - Andras Millinghoffer
- NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary; (A.M.); (X.G.)
- Department of Measurement and Information Systems, Budapest University of Technology and Economics, Magyar Tudósok krt. 2, H-1521 Budapest, Hungary; (B.B.); (G.H.); (P.A.)
| | - Gabor Hullam
- Department of Measurement and Information Systems, Budapest University of Technology and Economics, Magyar Tudósok krt. 2, H-1521 Budapest, Hungary; (B.B.); (G.H.); (P.A.)
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
| | - Peter Petschner
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary; (P.P.); (G.B.); (G.J.)
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
- Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan
| | - Xenia Gonda
- NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary; (A.M.); (X.G.)
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
- Department of Psychiatry and Psychotherapy, Semmelweis University, Gyulai Pál utca 2, H-1085 Budapest, Hungary
| | - Gerome Breen
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Memory Lane, London SE5 8AF, UK;
- UK National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre (BRC), London SE5 8AF, UK
| | - Peter Antal
- Department of Measurement and Information Systems, Budapest University of Technology and Economics, Magyar Tudósok krt. 2, H-1521 Budapest, Hungary; (B.B.); (G.H.); (P.A.)
| | - Gyorgy Bagdy
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary; (P.P.); (G.B.); (G.J.)
- NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary; (A.M.); (X.G.)
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
| | - John Francis William Deakin
- Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Oxford Road, Manchester M13 9PL, UK;
| | - Gabriella Juhasz
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary; (P.P.); (G.B.); (G.J.)
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
- SE-NAP 2 Genetic Brain Imaging Migraine Research Group, Hungarian Brain Research Program, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
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17
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Nieraad H, Pannwitz N, de Bruin N, Geisslinger G, Till U. Hyperhomocysteinemia: Metabolic Role and Animal Studies with a Focus on Cognitive Performance and Decline-A Review. Biomolecules 2021; 11:1546. [PMID: 34680179 PMCID: PMC8533891 DOI: 10.3390/biom11101546] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 10/05/2021] [Accepted: 10/09/2021] [Indexed: 12/18/2022] Open
Abstract
Disturbances in the one-carbon metabolism are often indicated by altered levels of the endogenous amino acid homocysteine (HCys), which is additionally discussed to causally contribute to diverse pathologies. In the first part of the present review, we profoundly and critically discuss the metabolic role and pathomechanisms of HCys, as well as its potential impact on different human disorders. The use of adequate animal models can aid in unravelling the complex pathological processes underlying the role of hyperhomocysteinemia (HHCys). Therefore, in the second part, we systematically searched PubMed/Medline for animal studies regarding HHCys and focused on the potential impact on cognitive performance and decline. The majority of reviewed studies reported a significant effect of HHCys on the investigated behavioral outcomes. Despite of persistent controversial discussions about equivocal findings, especially in clinical studies, the present evaluation of preclinical evidence indicates a causal link between HHCys and cognition-related- especially dementia-like disorders, and points out the further urge for large-scale, well-designed clinical studies in order to elucidate the normalization of HCys levels as a potential preventative or therapeutic approach in human pathologies.
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Affiliation(s)
- Hendrik Nieraad
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany; (N.P.); (N.d.B.); (G.G.)
| | - Nina Pannwitz
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany; (N.P.); (N.d.B.); (G.G.)
| | - Natasja de Bruin
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany; (N.P.); (N.d.B.); (G.G.)
| | - Gerd Geisslinger
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany; (N.P.); (N.d.B.); (G.G.)
- Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Uwe Till
- Former Institute of Pathobiochemistry, Friedrich-Schiller-University Jena, Nonnenplan 2, 07743 Jena, Germany;
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18
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Zhao R, An Z, Sun Y, Xia L, Qiu L, Yao A, Liu Y, Liu L. Metabolic profiling in early pregnancy and associated factors of folate supplementation: A cross-sectional study. Clin Nutr 2021; 40:5053-5061. [PMID: 34455263 DOI: 10.1016/j.clnu.2021.01.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/10/2020] [Accepted: 01/12/2021] [Indexed: 01/05/2023]
Abstract
BACKGROUND Pregnancy generally alters the balance of maternal metabolism, but the molecular profiles in early pregnancy and associated factors of folate supplementation in pregnant women remains incompletely understood. METHODS Untargeted metabonomics based on high-performance liquid chromatography-high-resolution mass spectrometry integrated with multivariate metabolic pathway analysis were applied to characterize metabolite profiles and associated factors of folate supplements in early pregnancy. The metabolic baseline of early pregnancy was determined by metabolic analysis of 510 serum samples from 131 non-pregnant and 379 pregnant healthy Chinese women. The pathophysiology of adaptive reactions and metabolic challenges induced by folate supplementation in early pregnancy was further compared between pregnant women with (n = 168) and without (n = 184) folate supplements. RESULTS Compared with non-pregnant participants, 106 metabolites, majority of which are related to amino acids and lysophosphatidylcholine/phosphatidylcholine, and 13 metabolic pathways were significantly changed in early pregnancy. The supplementation of folate in early pregnancy induced marked changes in N-acyl ethanolamine 22:0, N-acyl taurine 18:2, glycerophosphoserine 44:1 and 8,11,14-eicosatrienoate, proline, and aminoimidazole ribotide levels. CONCLUSIONS During early pregnancy, the metabolism of amino acids significantly changes to meet the physiological requirements of pregnant women. Folate intake may change glucose and lipid metabolism. These findings provide a comprehensive landscape for understanding the basic characteristics and gestational metabolic networks of early pregnancy and folate supplementation. This study provides a basis for further research into the relationship between metabolic markers and pregnancy diseases. TRIAL REGISTRATION This study protocol was registered on www.ClinicalTrials.gov, NCT03651934, on August 29, 2018 (prior to recruitment).
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Affiliation(s)
- Rui Zhao
- Pharmacy Department of Beijing Chao-Yang Hospital Affiliated with Beijing Capital Medical University, Beijing, 100020, PR China
| | - Zhuoling An
- Pharmacy Department of Beijing Chao-Yang Hospital Affiliated with Beijing Capital Medical University, Beijing, 100020, PR China
| | - Yuan Sun
- Pharmacy Department of Beijing Chao-Yang Hospital Affiliated with Beijing Capital Medical University, Beijing, 100020, PR China
| | - Liangyu Xia
- Department of Clinical Laboratory, Peking Union Medical College Hospital, China Academic Medical Science and Peking Union Medical College, Beijing, 100730, PR China
| | - Ling Qiu
- Department of Clinical Laboratory, Peking Union Medical College Hospital, China Academic Medical Science and Peking Union Medical College, Beijing, 100730, PR China
| | - Aimin Yao
- Department of Gynaecology and Obstetrics, Shunyi District Maternal and Child Health Hospital, Beijing, China
| | - Yanping Liu
- Department of Clinical Nutrition, Peking Union Medical College Hospital, China Academic Medical Science and Peking Union Medical College, Beijing, 100730, PR China.
| | - Lihong Liu
- Pharmacy Department of Beijing Chao-Yang Hospital Affiliated with Beijing Capital Medical University, Beijing, 100020, PR China.
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19
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Beydoun S, Fardous AM, Saruna MM, Beydoun AG, Sorge JA, Ma H, Aoun G, Unnikrishnan A, Cabelof DC, Heydari AR. Succinylsulfathiazole modulates the mTOR signaling pathway in the liver of c57BL/6 mice via a folate independent mechanism. Exp Gerontol 2021; 150:111387. [PMID: 33957263 PMCID: PMC8165018 DOI: 10.1016/j.exger.2021.111387] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/25/2021] [Accepted: 04/28/2021] [Indexed: 01/27/2023]
Abstract
Researchers studying the effect of folate restriction on rodents have resorted to the use of the antibiotic succinylsulfathiazole (SST) in the folate depleted diet to induce a folate deficient status. SST has been used extensively in rodent studies since the 1940s. Its localized effect on the gut bacteria as well as its effectiveness in reducing folate producing species is well documented. The possible overlap between the pathways affected by folate depletion and SST could potentially produce a confounding variable in such studies. In our novel study, we analyzed the effect of SST on folate levels in c57Bl/6 male mice fed folate supplemented and deficient diets. We did not observe any significant difference on growth and weight gain at 21 weeks. SST did not significantly affect folate levels in the plasma, liver and colon tissues; however, it did alter energy metabolism and expression of key genes in the mTOR signaling pathway in the liver. This research sheds light on a possible confounding element when using SST to study folate depletion due to the potential overlap with multiple critical pathways such as mTOR. SUMMARY: The antibiotic succinylsulfathiazole (SST) is used to reduce folate producing bacteria in rodent folate depletion studies. SST can modulate critical energy and nutrient sensing pathways converging onto mTOR signaling, and potentially confounding cancer studies.
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Affiliation(s)
- Safa Beydoun
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ali M Fardous
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA
| | - Michael M Saruna
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA
| | - Ali G Beydoun
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA
| | - Johnathan A Sorge
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA
| | - Hongzhi Ma
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA
| | - Ghada Aoun
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA
| | - Archana Unnikrishnan
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health and Science Center, OK 73104, USA
| | - Diane C Cabelof
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48202, USA
| | - Ahmad R Heydari
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48202, USA.
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20
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Yahaya TO, Yusuf AB, Danjuma JK, Usman BM, Ishiaku YM. Mechanistic links between vitamin deficiencies and diabetes mellitus: a review. EGYPTIAN JOURNAL OF BASIC AND APPLIED SCIENCES 2021. [DOI: 10.1080/2314808x.2021.1945395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Tajudeen O. Yahaya
- Department of Biology, Federal University Birnin Kebbi, Birnin Kebbi, Nigeria
| | - AbdulRahman B. Yusuf
- Department of Biochemistry and Molecular Biology, Federal University Birnin Kebbi, Birnin Kebbi, Nigeria
| | - Jamilu K. Danjuma
- Department of Biology, Federal University Birnin Kebbi, Birnin Kebbi Nigeria
| | - Bello M. Usman
- Department of Biology, Federal University Birnin Kebbi, Birnin Kebbi Nigeria
| | - Yahaya M. Ishiaku
- Department of Biochemistry and Molecular Biology, Federal University Dutsinma, Katsina, Nigeria
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21
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Maude H, Sanchez-Cabanillas C, Cebola I. Epigenetics of Hepatic Insulin Resistance. Front Endocrinol (Lausanne) 2021; 12:681356. [PMID: 34046015 PMCID: PMC8147868 DOI: 10.3389/fendo.2021.681356] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 04/20/2021] [Indexed: 01/14/2023] Open
Abstract
Insulin resistance (IR) is largely recognized as a unifying feature that underlies metabolic dysfunction. Both lifestyle and genetic factors contribute to IR. Work from recent years has demonstrated that the epigenome may constitute an interface where different signals may converge to promote IR gene expression programs. Here, we review the current knowledge of the role of epigenetics in hepatic IR, focusing on the roles of DNA methylation and histone post-translational modifications. We discuss the broad epigenetic changes observed in the insulin resistant liver and its associated pathophysiological states and leverage on the wealth of 'omics' studies performed to discuss efforts in pinpointing specific loci that are disrupted by these changes. We envision that future studies, with increased genomic resolution and larger cohorts, will further the identification of biomarkers of early onset hepatic IR and assist the development of targeted interventions. Furthermore, there is growing evidence to suggest that persistent epigenetic marks may be acquired over prolonged exposure to disease or deleterious exposures, highlighting the need for preventative medicine and long-term lifestyle adjustments to avoid irreversible or long-term alterations in gene expression.
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Affiliation(s)
| | | | - Inês Cebola
- *Correspondence: Hannah Maude, ; Inês Cebola,
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22
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Gu X, Al Dubayee M, Alshahrani A, Masood A, Benabdelkamel H, Zahra M, Li L, Abdel Rahman AM, Aljada A. Distinctive Metabolomics Patterns Associated With Insulin Resistance and Type 2 Diabetes Mellitus. Front Mol Biosci 2020; 7:609806. [PMID: 33381523 PMCID: PMC7768025 DOI: 10.3389/fmolb.2020.609806] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 11/23/2020] [Indexed: 01/17/2023] Open
Abstract
Obesity is associated with an increased risk of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) which is a multi-factorial disease associated with a dysregulated metabolism and can be prevented in pre-diabetic individuals with impaired glucose tolerance. A metabolomic approach emphasizing metabolic pathways is critical to our understanding of this heterogeneous disease. This study aimed to characterize the serum metabolomic fingerprint and multi-metabolite signatures associated with IR and T2DM. Here, we have used untargeted high-performance chemical isotope labeling (CIL) liquid chromatography-mass spectrometry (LC-MS) to identify candidate biomarkers of IR and T2DM in sera from 30 adults of normal weight, 26 obese adults, and 16 adults newly diagnosed with T2DM. Among the 3633 peak pairs detected, 62% were either identified or matched. A group of 78 metabolites were up-regulated and 111 metabolites were down-regulated comparing obese to lean group while 459 metabolites were up-regulated and 166 metabolites were down-regulated comparing T2DM to obese groups. Several metabolites were identified as IR potential biomarkers, including amino acids (Asn, Gln, and His), methionine (Met) sulfoxide, 2-methyl-3-hydroxy-5-formylpyridine-4-carboxylate, serotonin, L-2-amino-3-oxobutanoic acid, and 4,6-dihydroxyquinoline. T2DM was associated with dysregulation of 42 metabolites, including amino acids, amino acids metabolites, and dipeptides. In conclusion, these pilot data have identified IR and T2DM metabolomics panels as potential novel biomarkers of IR and identified metabolites associated with T2DM, with possible diagnostic and therapeutic applications. Further studies to confirm these associations in prospective cohorts are warranted.
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Affiliation(s)
- Xinyun Gu
- Department of Chemistry, University of Alberta, Edmonton, AB, Canada
| | - Mohammed Al Dubayee
- Department of Medicine, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Awad Alshahrani
- Department of Medicine, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Afshan Masood
- Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Hicham Benabdelkamel
- Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mahmoud Zahra
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Liang Li
- Department of Chemistry, University of Alberta, Edmonton, AB, Canada
| | - Anas M Abdel Rahman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Department of Chemistry, Memorial University of Newfoundland, St. John's, NL, Canada
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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23
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da Silva MT, Mujica-Coopman MF, Figueiredo ACC, Hampel D, Vieira LS, Farias DR, Shahab-Ferdows S, Allen LH, Brito A, Lamers Y, Kac G, S Vaz J. Maternal plasma folate concentration is positively associated with serum total cholesterol and low-density lipoprotein across the three trimesters of pregnancy. Sci Rep 2020; 10:20141. [PMID: 33214613 PMCID: PMC7677547 DOI: 10.1038/s41598-020-77231-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 11/09/2020] [Indexed: 12/17/2022] Open
Abstract
Increased first-trimester low-density lipoprotein (LDL-C) concentration has been associated with adverse pregnancy outcomes, such as gestational diabetes. The B vitamins folate, B-6, and total B-12 are key for the methyl group-dependent endogenous synthesis of phosphatidylcholine, which is needed for lipoprotein synthesis, e.g., very low-density lipoprotein (VLDL), the precursor of circulating LDL-C. Maternal B-vitamin concentration usually declines across trimesters. Whether changes in maternal B-vitamin concentrations are associated with total cholesterol (TC), triglycerides (TG), and lipoprotein concentrations is unknown. Therefore, we explored the association between plasma folate, vitamin B-6 in the form of pyridoxal 5′-phosphate (PLP), and total B-12 with serum TC, LDL-C, HDL-C, and TG concentrations across trimesters. This secondary analysis used data of a prospective pregnancy cohort study included apparently healthy adult women (n = 179) from Rio de Janeiro, Brazil. The biomarkers were measured in fasting blood samples collected at 5–13, 20–26, and 30–36 weeks of gestation. The associations between B vitamins and lipid concentrations across trimesters were explored using linear mixed-effect models. Among B vitamins, only plasma folate was positively associated with TC (β = 0.244, 95% CI 0.034–0.454) and LDL-C (β = 0.193, 95% CI 0.028–0.357) concentrations. The positive relationship of maternal folate and TC and LDL-C concentrations may indicate the importance of folate as a methyl donor for lipoprotein synthesis during pregnancy.
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Affiliation(s)
- Manoela T da Silva
- Graduate Program in Food and Nutrition, Faculty of Nutrition, Universidade Federal de Pelotas, Rua Gomes Carneiro, 1, Pelotas, RS, 96010-610, Brazil
| | - Maria F Mujica-Coopman
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, The University of British Columbia, Vancouver, BC, Canada
| | - Amanda C C Figueiredo
- Nutritional Epidemiology Observatory, Josué de Castro Nutrition Institute, Department of Social and Applied Nutrition, Rio de Janeiro Federal University, Rio de Janeiro, Brazil
| | - Daniela Hampel
- USDA-ARS Western Human Nutrition Research Center, Department of Nutrition, University of California, Davis, CA, USA
| | - Luna S Vieira
- Graduate Program in Epidemiology, Department of Social Medicine, Federal University of Pelotas, Pelotas, Brazil
| | - Dayana R Farias
- Nutritional Epidemiology Observatory, Josué de Castro Nutrition Institute, Department of Social and Applied Nutrition, Rio de Janeiro Federal University, Rio de Janeiro, Brazil
| | - Setareh Shahab-Ferdows
- USDA-ARS Western Human Nutrition Research Center, Department of Nutrition, University of California, Davis, CA, USA
| | - Lindsay H Allen
- USDA-ARS Western Human Nutrition Research Center, Department of Nutrition, University of California, Davis, CA, USA
| | - Alex Brito
- Laboratory of Pharmacokinetics and Metabolomic Analysis, Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.,Department of Population Health, Nutrition and Health Research Group, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Yvonne Lamers
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, The University of British Columbia, Vancouver, BC, Canada
| | - Gilberto Kac
- Nutritional Epidemiology Observatory, Josué de Castro Nutrition Institute, Department of Social and Applied Nutrition, Rio de Janeiro Federal University, Rio de Janeiro, Brazil
| | - Juliana S Vaz
- Graduate Program in Food and Nutrition, Faculty of Nutrition, Universidade Federal de Pelotas, Rua Gomes Carneiro, 1, Pelotas, RS, 96010-610, Brazil. .,Nutritional Epidemiology Observatory, Josué de Castro Nutrition Institute, Department of Social and Applied Nutrition, Rio de Janeiro Federal University, Rio de Janeiro, Brazil. .,Graduate Program in Epidemiology, Department of Social Medicine, Federal University of Pelotas, Pelotas, Brazil.
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24
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Skuratovskaia D, Komar A, Vulf M, Litvinova L. Mitochondrial destiny in type 2 diabetes: the effects of oxidative stress on the dynamics and biogenesis of mitochondria. PeerJ 2020; 8:e9741. [PMID: 32904391 PMCID: PMC7453922 DOI: 10.7717/peerj.9741] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 07/26/2020] [Indexed: 12/28/2022] Open
Abstract
Background One reason for the development of insulin resistance is the chronic inflammation in obesity. Materials & Methods Scientific articles in the field of knowledge on the involvement of mitochondria and mitochondrial DNA (mtDNA) in obesity and type 2 diabetes were analyzed. Results Oxidative stress developed during obesity contributes to the formation of peroxynitrite, which causes cytochrome C-related damage in the mitochondrial electron transfer chain and increases the production of reactive oxygen species (ROS), which is associated with the development of type 2 diabetes. Oxidative stress contributes to the nuclease activity of the mitochondrial matrix, which leads to the accumulation of cleaved fragments and an increase in heteroplasmy. Mitochondrial dysfunction and mtDNA variations during insulin resistance may be connected with a change in ATP levels, generation of ROS, mitochondrial division/fusion and mitophagy. This review discusses the main role of mitochondria in the development of insulin resistance, which leads to pathological processes in insulin-dependent tissues, and considers potential therapeutic directions based on the modulation of mitochondrial biogenesis. In this regard, the development of drugs aimed at the regulation of these processes is gaining attention. Conclusion Changes in the mtDNA copy number can help to protect mitochondria from severe damage during conditions of increased oxidative stress. Mitochondrial proteome studies are conducted to search for potential therapeutic targets. The use of mitochondrial peptides encoded by mtDNA also represents a promising new approach to therapy.
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Affiliation(s)
| | - Alexandra Komar
- Immanuel Kant Baltic Federal University, Kaliningrad, Russian Federation
| | - Maria Vulf
- Immanuel Kant Baltic Federal University, Kaliningrad, Russian Federation
| | - Larisa Litvinova
- Immanuel Kant Baltic Federal University, Kaliningrad, Russian Federation
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25
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Xin FZ, Zhao ZH, Zhang RN, Pan Q, Gong ZZ, Sun C, Fan JG. Folic acid attenuates high-fat diet-induced steatohepatitis via deacetylase SIRT1-dependent restoration of PPARα. World J Gastroenterol 2020; 26:2203-2220. [PMID: 32476787 PMCID: PMC7235203 DOI: 10.3748/wjg.v26.i18.2203] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 03/27/2020] [Accepted: 04/16/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Folic acid has been shown to improve non-alcoholic steatohepatitis (NASH), but its roles in hepatic lipid metabolism, hepatic one-carbon metabolism, and gut microbiota are still unknown.
AIM To demonstrate the role of folic acid in lipid metabolism and gut microbiota in NASH.
METHODS Twenty-four Sprague-Dawley rats were assigned into three groups: Chow diet, high-fat diet (HFD), and HFD with folic acid administration. At the end of 16 wk, the liver histology, the expression of hepatic genes related to lipid metabolism, one-carbon metabolism, and gut microbiota structure analysis of fecal samples based on 16S rRNA sequencing were measured to evaluate the effect of folic acid. Palmitic acid-exposed Huh7 cell line was used to evaluate the role of folic acid in hepatic lipid metabolism.
RESULTS Folic acid treatment attenuated steatosis, lobular inflammation, and hepatocellular ballooning in rats with HFD-induced steatohepatitis. Genes related to lipid de novo lipogenesis, β-oxidation, and lipid uptake were improved in HFD-fed folic acid-treated rats. Furthermore, peroxisome proliferator-activated receptor alpha (PPARα) and silence information regulation factor 1 (SIRT1) were restored by folic acid in HFD-fed rats and palmitic acid-exposed Huh7 cell line. The restoration of PPARα by folic acid was blocked after transfection with SIRT1 siRNA in the Huh7 cell line. Additionally, folic acid administration ameliorated depleted hepatic one-carbon metabolism and restored the diversity of the gut microbiota in rats with HFD-induced steatohepatitis.
CONCLUSION Folic acid improves hepatic lipid metabolism by upregulating PPARα levels via a SIRT1-dependent mechanism and restores hepatic one-carbon metabolism and diversity of gut microbiota, thereby attenuating HFD-induced NASH in rats.
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Affiliation(s)
- Feng-Zhi Xin
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Ze-Hua Zhao
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Rui-Nan Zhang
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Qin Pan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Zi-Zhen Gong
- Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
- Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Chao Sun
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
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26
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The mechanism of lipopolysaccharide administration-induced cognitive function impairment caused by glucose metabolism disorder in adult rats. Saudi J Biol Sci 2019; 26:1268-1277. [PMID: 31516357 PMCID: PMC6734155 DOI: 10.1016/j.sjbs.2019.06.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 06/26/2019] [Accepted: 06/30/2019] [Indexed: 11/22/2022] Open
Abstract
This essay aims to make investigation on the mechanism of glucose metabolism disorder and Lipopolysaccharide administration-induced cognitive function impairment in adult rats with surgery. Methods: Divide the objects, 40 male Sprague-Dawley rats at the age of 9 months, into 4 groups. Provide unilateral nephrectomy surgery and/or lipopolysaccharide intraperitoneal injection. Postoperative cognitive function evaluation would be tested by the Morris water maze. Rats with Postoperative Cognitive Dysfunction (POCD) were scanned to analyze the brain glucose metabolism by means of 18F-FDG PET/CT. Phosphatidylinositol 3-Kinase (PI3K), Protein Kinase β (AKT), Insulin Substrates Receptor-2 (IRS-2) and Glucose Transporter 4 (GLUT4) were detected as well. Data will be captured through gene expression in POCD rats via Quantitative Real-Time PCR (QRT-PCR). On the other side, Western Blot was used to measure the expression levels of IRS-2, p-IRS-2, p-PI3K, PI3K, p-AKT, AKT, GLUT4, and p-GLUT4. Results: During the Morris water maze test, the staging time (latency) of rats in each group was becoming short gradually as the training progressed. The incubation time of Day 5 of each group was shorter than that of Day 1 (P < 0.05). On the Day 3 after the surgery, the average target quadrant residence time of Group S+L (100 μg/Kg) was shorter, compared with Group C, L and S. Of which, the average number of perforation was reduced greater than that of Group C (P < 0.05). The average swimming speed of the groups is of no distinct difference (P > 0.05). After the operation, there was no great difference shown among the subjects (P > 0.05) in the average residence time of the target quadrant, the mean number of passages, and the mean swimming speed. On Day 3, the average latency of Group S+L (100 μg/Kg) was longer than Group C (P < 0.05) in the working memory test after the operation. The average latency of rats in Group L and S was showed longer than that in Group C, with tiny difference (P > 0.05). In the 7-Day working memory test, the average latency of the rats in Group L, S and S+L (100 μg/Kg) was obviously longer than that in Group C. Comparing to preoperative rats, POCD rats of Group S+L (100 μg/Kg) were scanned by 18F-FDG PET/CT three days later after the operation. Its SUVmax of the frontal and temporal lobe areas were decreased significantly (P < 0.05). However, difference degree was not significantly shown in the SUVmax between Group C and the preoperative rats (P > 0.05). In comparison with the gene expression of of Group C, the PI3K, IRS-2, AKT and GLUT4 mRNA genes are the key genes in the insulin signaling pathways of the hippocampus of the POCD rats. The expression level was reduced. The expression level of all protein of PI3K, IRS-2, GLUT4 and AKT in the POCD rats was of no great contrast with that in Group C. But for IRS-2 protein, the phosphorylation level has increased, and meanwhile decreased for AKT, PI3K and GLUT4 proteins (P < 0.05). Conclusions: Adult SD rats cognitive dysfunction model treated with unilateral nephrectomy combined and 100 μg/kg LPS intraperitoneal injection were led to abnormal both brain glucose metabolism and insulin expression. The proved phenomenal results signal pathway-related proteins PI3K, IRS-2, AKT and GLUT4. It reached the conclusion that surgical trauma, rather than anesthesia, leads to impaired cognitive function. PI3K, IRS-2, AKT, and GLUT4pathway of brain can be partial explanations of the pathogenesis of POCD.
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Key Words
- 18F-FDG PET/CT
- AGE, Advanced Glycation End products
- FDG, Fluorodeoxyglucose
- GLUT4, Glucose Transporter 4
- Glucose metabolism
- IRS-2, Insulin Substrate Receptor-2
- LPS, Lipopolysaccharide
- MAPK, Mitogen-Activated Protein Kinase
- OSEM, Ordered Subsets Expectation Maximization
- PI3K, IRS-2, AKT, and GLUT4 pathway
- PI3K, Phosphatidylinositol 3-Kinase
- POCD, Postoperative Cognitive Dysfunction
- Postoperative cognitive dysfunction
- QRT-PCR, Quantitative Real-Time PCR
- ROS, Reactive Oxygen Species
- SUV, Standard Uptake Value
- Surgical trauma
- TLR4, Toll-like Receptor 4
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27
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Guo X, Dai X, Ni J, Cao N, Yang G, Xue J, Wang X. High concentration of sugars is genotoxic to folate-deficient cells. Mutat Res 2019; 814:15-22. [DOI: 10.1016/j.mrfmmm.2019.01.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/29/2018] [Accepted: 01/08/2019] [Indexed: 04/08/2023]
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