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1
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Milić M, Kazensky L, Matovinović M. The Impact of the Metabolic Syndrome Severity on the Appearance of Primary and Permanent DNA Damage. MEDICINA (KAUNAS, LITHUANIA) 2024; 61:21. [PMID: 39859002 PMCID: PMC11767129 DOI: 10.3390/medicina61010021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/29/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025]
Abstract
The prevalence of metabolic syndrome (MetS) worldwide is rapid and significant on a global scale. A 2022 meta-analysis of data from 28 million individuals revealed a global prevalence of 45.1%, with notably higher rates in the Eastern Mediterranean Region and the Americas, particularly in high-income countries. MetS is associated with impaired antioxidant defense mechanisms, resulting in the excessive generation of reactive oxygen and nitrogen species (RONS) and elevated levels of DNA damage. Unrepaired damage can lead to DNA base changes, chromosomal mutations, genomic loss and instability, and disrupted gene and protein expression. Such changes contribute to an increased risk of tumorigenesis, cancer progression, and mortality. The alkaline comet and micronucleus cytome assay are commonly used assays for DNA damage evaluation. The estimation of damage with those two techniques demonstrated the link between the increased risk of cancer and mortality. Incorporating these techniques in a set of biomarkers to assess the MetS severity holds promise; however, comprehensive literature reviews featuring large-scale studies integrating both assays remain scarce. This systematic review aims to integrate and critically evaluate the existing scientific literature regarding this topic.
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Affiliation(s)
- Mirta Milić
- Division of Toxicology, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000 Zagreb, Croatia;
| | - Luka Kazensky
- Division of Toxicology, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000 Zagreb, Croatia;
| | - Martina Matovinović
- Department of Internal Medicine, Division of Endocrinology, University Hospital Centre Zagreb, Croatian Referral Center for Obesity Treatment, Kišpatićeva 12, 10000 Zagreb, Croatia;
- The Faculty of Kinesiology, University of Zagreb, Horvaćanski zavoj 15, 10000 Zagreb, Croatia
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2
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Vernì F. Vitamin B6 and diabetes and its role in counteracting advanced glycation end products. VITAMINS AND HORMONES 2024; 125:401-438. [PMID: 38997171 DOI: 10.1016/bs.vh.2024.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/14/2024]
Abstract
Naturally occurring forms of vitamin B6 include six interconvertible water-soluble compounds: pyridoxine (PN), pyridoxal (PL), pyridoxamine (PM), and their respective monophosphorylated derivatives (PNP, PLP, and PMP). PLP is the catalytically active form which works as a cofactor in approximately 200 reactions that regulate the metabolism of glucose, lipids, amino acids, DNA, and neurotransmitters. Most of vitamers can counteract the formation of reactive oxygen species and the advanced glycation end-products (AGEs) which are toxic compounds that accumulate in diabetic patients due to prolonged hyperglycemia. Vitamin B6 levels have been inversely associate with diabetes, while vitamin B6 supplementation reduces diabetes onset and its vascular complications. The mechanisms at the basis of the relation between vitamin B6 and diabetes onset are still not completely clarified. In contrast more evidence indicates that vitamin B6 can protect from diabetes complications through its role as scavenger of AGEs. It has been demonstrated that in diabetes AGEs can destroy the functionality of macromolecules such as protein, lipids, and DNA, thus producing tissue damage that result in vascular diseases. AGEs can be in part also responsible for the increased cancer risk associated with diabetes. In this chapter the relationship between vitamin B6, diabetes and AGEs will be discussed by showing the acquired knowledge and questions that are still open.
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Affiliation(s)
- F Vernì
- Department of Biology and Biotechnology "Charles Darwin" Sapienza University of Rome, Rome, Italy.
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3
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Thongsroy J, Mutirangura A. The inverse association between DNA gaps and HbA1c levels in type 2 diabetes mellitus. Sci Rep 2023; 13:18987. [PMID: 37923892 PMCID: PMC10624909 DOI: 10.1038/s41598-023-46431-2] [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: 06/10/2023] [Accepted: 10/31/2023] [Indexed: 11/06/2023] Open
Abstract
Naturally occurring DNA gaps have been observed in eukaryotic DNA, including DNA in nondividing cells. These DNA gaps are found less frequently in chronologically aging yeast, chemically induced senescence cells, naturally aged rats, D-galactose-induced aging model rats, and older people. These gaps function to protect DNA from damage, so we named them youth-associated genomic stabilization DNA gaps (youth-DNA-gaps). Type 2 diabetes mellitus (type 2 DM) is characterized by an early aging phenotype. Here, we explored the correlation between youth-DNA-gaps and the severity of type 2 DM. Here, we investigated youth-DNA-gaps in white blood cells from normal controls, pre-DM, and type 2 DM patients. We found significantly decreased youth-DNA-gap numbers in the type 2 DM patients compared to normal controls (P = 0.0377, P = 0.0018 adjusted age). In the type 2 DM group, youth-DNA-gaps correlate directly with HbA1c levels. (r = - 0.3027, P = 0.0023). Decreased youth-DNA-gap numbers were observed in patients with type 2 DM and associated with increased HbA1c levels. Therefore, the decrease in youth-DNA-gaps is associated with the molecular pathogenesis of high blood glucose levels. Furthermore, youth-DNA-gap number is another marker that could be used to determine the severity of type 2 DM.
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Affiliation(s)
- Jirapan Thongsroy
- School of Medicine, Walailak University, Nakhon Si Thammarat, 80160, Thailand.
- Research Center in Tropical Pathobiology, Walailak University, Nakhon Si Thammarat, 80160, Thailand.
| | - Apiwat Mutirangura
- Center for Excellence in Molecular Genetics of Cancer and Human Diseases, Chulalongkorn University, Bangkok, Thailand
- Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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4
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Hong X, Hu Y, Yuan Z, Fang Z, Zhang X, Yuan Y, Guo C. Oxidatively Damaged Nucleic Acid: Linking Diabetes and Cancer. Antioxid Redox Signal 2022; 37:1153-1167. [PMID: 35946074 DOI: 10.1089/ars.2022.0096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Significance: Our current knowledge of the mechanism between diabetes and cancer is limited. Oxidatively damaged nucleic acid is considered a critical factor to explore the connections between these two diseases. Recent Advances: The link between diabetes mellitus and cancer has attracted increasing attention in recent years. Emerging evidence supports that oxidatively damaged nucleic acid caused by an imbalance between reactive oxygen species generation and elimination is a bridge connecting diabetes and cancer. 8-Oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydroguanosine assume important roles as biomarkers in assessing the relationship between oxidatively damaged nucleic acid and cancer. Critical Issues: The consequences of diabetes are extensive and may lead to the occurrence of cancer by influencing a combination of factors. At present, there is no direct evidence that diabetes causes cancer by affecting a single factor. Furthermore, the difficulty in controlling variables and differences in detection methods lead to poor reliability and repeatability of results, and there are no clear cutoff values for biomarkers to indicate cancer risk. Future Directions: A better understanding of connections as well as mechanisms between diabetes and cancer is still needed. Both diabetes and cancer are currently intractable diseases. Further exploration of the specific mechanism of oxidatively damaged nucleic acid in the connection between diabetes and cancer is urgently needed. In the future, it is necessary to further take oxidatively damaged nucleic acid as an entry point to provide new ideas for the diagnosis and treatment of diabetes and cancer. Experimental drugs targeting the repair process of oxidatively generated damage require an extensive preclinical evaluation and could ultimately provide new treatment strategies for these diseases. Antioxid. Redox Signal. 37, 1153-1167.
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Affiliation(s)
- Xiujuan Hong
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yiqiu Hu
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhijun Yuan
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhihao Fang
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoxiao Zhang
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ying Yuan
- Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Center, Zhejiang University, Hangzhou, China
| | - Cheng Guo
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Center, Zhejiang University, Hangzhou, China
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5
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Flemming N, Pernoud L, Forbes J, Gallo L. Mitochondrial Dysfunction in Individuals with Diabetic Kidney Disease: A Systematic Review. Cells 2022; 11:cells11162481. [PMID: 36010558 PMCID: PMC9406893 DOI: 10.3390/cells11162481] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/06/2022] [Accepted: 08/07/2022] [Indexed: 11/25/2022] Open
Abstract
Mitochondrial dysfunction is implicated in the pathogenesis of diabetic kidney disease (DKD). Compared to the vast body of evidence from preclinical in vitro and in vivo studies, evidence from human studies is limited. In a comprehensive search of the published literature, findings from studies that reported evidence of mitochondrial dysfunction in individuals with DKD were examined. Three electronic databases (PubMed, Embase, and Scopus) were searched in March 2022. A total of 1339 articles were identified, and 22 articles met the inclusion criteria. Compared to non-diabetic controls (NDC) and/or individuals with diabetes but without kidney disease (DC), individuals with DKD (age ~55 years; diabetes duration ~15 years) had evidence of mitochondrial dysfunction. Individuals with DKD had evidence of disrupted mitochondrial dynamics (11 of 11 articles), uncoupling (2 of 2 articles), oxidative damage (8 of 8 articles), decreased mitochondrial respiratory capacity (1 of 1 article), decreased mtDNA content (5 of 6 articles), and decreased antioxidant capacity (3 of 4 articles) compared to ND and/or DC. Neither diabetes nor glycemic control explained these findings, but rather presence and severity of DKD may better reflect degree of mitochondrial dysfunction in this population. Future clinical studies should include individuals closer to diagnosis of diabetes to ascertain whether mitochondrial dysfunction is implicated in the development of, or is a consequence of, DKD.
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Affiliation(s)
- Nicole Flemming
- School of Medicine and Dentistry, Griffith University, Birtinya 4556, Australia
- Faculty of Medicine, University of Queensland, Brisbane 4072, Australia
- Mater Research Institute, The University of Queensland (MRI-UQ), Brisbane 4072, Australia
- Correspondence:
| | - Laura Pernoud
- School of Health and Behavioural Sciences, University of the Sunshine Coast, Maroochydore 4558, Australia
| | - Josephine Forbes
- Mater Research Institute, The University of Queensland (MRI-UQ), Brisbane 4072, Australia
| | - Linda Gallo
- School of Health and Behavioural Sciences, University of the Sunshine Coast, Maroochydore 4558, Australia
- School of Biomedical Sciences, University of Queensland, Brisbane 4072, Australia
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6
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Borisovs V, Bodrenko J, Kalnina J, Sjakste N. Nitrosative stress parameters and the level of oxidized DNA bases in patients with multiple sclerosis. Metab Brain Dis 2021; 36:1935-1941. [PMID: 34417942 DOI: 10.1007/s11011-021-00786-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 07/01/2021] [Indexed: 10/20/2022]
Abstract
Multiple sclerosis (MS) is a neurodegenerative disease with various factors affecting its etiology. Overproduction of nitric oxide and subsequent lesions of biopolymers are some of the possible causes of the disease. This study aimed to measure the most relevant nitrosative and oxidative stress biomarkers and the level of modified DNA bases in patients with MS. Each parameter was assayed in 25 patients with MS and 25 healthy controls. This study involved detecting blood plasma and serum nitric oxide metabolites by chemiluminescence detector Sievers NOA-280i, malondialdehyde (MDA) measurements with thiobarbituric acid reactive substance (TBARS) assay, detection of oxidized purines and pyrimidines with the enzyme-modified comet assay. Statistical analysis of the results was performed by one-way analysis of variance (ANOVA) and unpaired t test for the comparison of less than three data sets. DNA single-strand breaks, levels of modified purines and pyrimidines, as well as nitrite and nitrate levels in plasma and serum samples, were significantly higher in patients with MS than in healthy controls. On the contrary, MDA levels appeared to be lower in patients with MS.
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Affiliation(s)
- Vitalijs Borisovs
- Faculty of Medicine, Academic Centre for Natural Sciences, University of Latvia, Jelgavas Str. 1, Riga, LV1004, Latvia.
| | - Jevgenijs Bodrenko
- Faculty of Medicine, Academic Centre for Natural Sciences, University of Latvia, Jelgavas Str. 1, Riga, LV1004, Latvia
| | - Jolanta Kalnina
- Genomics and Bioinformatics, Institute of Biology of the University of Latvia, Riga, Latvia
| | - Nikolajs Sjakste
- Faculty of Medicine, Academic Centre for Natural Sciences, University of Latvia, Jelgavas Str. 1, Riga, LV1004, Latvia
- Genomics and Bioinformatics, Institute of Biology of the University of Latvia, Riga, Latvia
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Yang GH, Fontaine DA, Lodh S, Blumer JT, Roopra A, Davis DB. TCF19 Impacts a Network of Inflammatory and DNA Damage Response Genes in the Pancreatic β-Cell. Metabolites 2021; 11:metabo11080513. [PMID: 34436454 PMCID: PMC8400192 DOI: 10.3390/metabo11080513] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/31/2021] [Accepted: 08/02/2021] [Indexed: 12/13/2022] Open
Abstract
Transcription factor 19 (TCF19) is a gene associated with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in genome-wide association studies. Prior studies have demonstrated that Tcf19 knockdown impairs β-cell proliferation and increases apoptosis. However, little is known about its role in diabetes pathogenesis or the effects of TCF19 gain-of-function. The aim of this study was to examine the impact of TCF19 overexpression in INS-1 β-cells and human islets on proliferation and gene expression. With TCF19 overexpression, there was an increase in nucleotide incorporation without any change in cell cycle gene expression, alluding to an alternate process of nucleotide incorporation. Analysis of RNA-seq of TCF19 overexpressing cells revealed increased expression of several DNA damage response (DDR) genes, as well as a tightly linked set of genes involved in viral responses, immune system processes, and inflammation. This connectivity between DNA damage and inflammatory gene expression has not been well studied in the β-cell and suggests a novel role for TCF19 in regulating these pathways. Future studies determining how TCF19 may modulate these pathways can provide potential targets for improving β-cell survival.
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Affiliation(s)
- Grace H. Yang
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; (G.H.Y.); (D.A.F.); (S.L.); (J.T.B.)
| | - Danielle A. Fontaine
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; (G.H.Y.); (D.A.F.); (S.L.); (J.T.B.)
| | - Sukanya Lodh
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; (G.H.Y.); (D.A.F.); (S.L.); (J.T.B.)
- Department of Biological Sciences, Marquette University, Milwaukee, WI 53233, USA
| | - Joseph T. Blumer
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; (G.H.Y.); (D.A.F.); (S.L.); (J.T.B.)
| | - Avtar Roopra
- Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA;
| | - Dawn Belt Davis
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; (G.H.Y.); (D.A.F.); (S.L.); (J.T.B.)
- William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA
- Correspondence:
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8
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Wang Y, Qian YX, Liu JH, Miao YM, Ma QH, Pan CW. Longitudinal association between sleep and 5-year incident metabolic syndrome in older Chinese adults: a community-based cohort study. Sleep Med 2021; 81:1-7. [PMID: 33621789 DOI: 10.1016/j.sleep.2021.02.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/31/2021] [Accepted: 02/01/2021] [Indexed: 01/02/2023]
Abstract
PURPOSE Our aim was to investigate the association between sleep and the development of metabolic syndrome (MetS) in Chinese older adults and to accumulate evidence for the prevention of MetS through sleep management. METHODS This prospective study followed 3005 participants aged over 60 derived from the Weitang Geriatric Diseases Study who were without MetS at baseline. MetS was defined according to the Adult Treatment Panel III (ATP III) criteria. Logistic regression models were fit to assess the association between sleep and MetS incident and a linear regression model was used to examine the impact of sleep duration on every component of MetS. Data on sleep-related parameters were obtained based on a self-reported questionnaire. RESULTS After five-year follow-up, 13.51% participants developed MetS, of which 46.86% were women. The incidence of MetS was highest among adults who slept 6 h or less and lowest among those who slept 7 h after adjusted for multiple variables. Subgroup analyses showed no gender specificity. The variation of fasting plasma glucose (FBG) for ≥9 h per night was significantly lower than that for 7.01-7.99 h per night (β = -0.18, P < 0.05). Sleeping for 8-8.99 h also decreased the variation of diastolic blood pressure (DBP) compared to 7.01-7.99 h (β = -0.84, P < 0.05). CONCLUSION We conclude that both short and long sleep duration are risk factors for MetS incident in older adults.
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Affiliation(s)
- Ying Wang
- School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Yu-Xi Qian
- School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Jing-Hong Liu
- School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Yi-Ming Miao
- Department of Mathematics, Statistics, and Computer Science, Macalester College, St. Paul, MN, USA
| | - Qing-Hua Ma
- The 3rd People's Hospital of Xiangcheng District, Suzhou, China
| | - Chen-Wei Pan
- School of Public Health, Medical College of Soochow University, Suzhou, China.
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9
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Osonoi S, Mizukami H, Itabashi C, Wada K, Kudoh K, Igawa A, Ogasawara S, Ishibashi Y, Daimon M, Yagihashi S, Nakaji S. Increased Oxidative Stress Underlies Abnormal Pain Threshold in a Normoglycemic Japanese Population. Int J Mol Sci 2020; 21:E8306. [PMID: 33167536 PMCID: PMC7663937 DOI: 10.3390/ijms21218306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 01/13/2023] Open
Abstract
Normal-high HbA1c levels are a risk factor for attenuated pain sensation in normoglycemic subjects. It is unclear, however, what mechanisms underlie the pathogenesis of attenuated pain sensation in such a population. We, therefore, explored the relationship between oxidative stress (OS) and pain sensation in a rural Japanese population. A population-based study of 894 individuals (average age 53.8 ± 0.5 years) and 55 subjects with impaired fasting glucose (IFG) were enrolled in this study. Individuals with diabetes were excluded. Relationships between pain threshold induced by intraepidermal electrical stimulation (PINT) and clinico-hematological parameters associated with OS were evaluated. Univariate linear regression analyses revealed age, BMI, HbA1c, the OS biomarker urine 8-hydroxy-2'-deoxyguanosine (8-OHdG), systolic blood pressure, and decreased Achilles tendon reflex on the PINT scores. Adjustments for age, gender, and multiple clinical measures confirmed a positive correlation between PINT scores and urine 8-OHdG (β = 0.09, p < 0.01). Urine 8-OHdG correlated positively with higher HbA1c levels and age in the normoglycemic population. Unlike in the normoglycemic population, both inflammation and OS were correlated with elevated PINT scores in IFG subjects. OS may be a major contributing factor to elevated PINT scores in a healthy Japanese population.
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Affiliation(s)
- Sho Osonoi
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (S.O.); (C.I.); (K.K.); (S.O.); (S.Y.)
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan;
| | - Hiroki Mizukami
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (S.O.); (C.I.); (K.K.); (S.O.); (S.Y.)
| | - Chieko Itabashi
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (S.O.); (C.I.); (K.K.); (S.O.); (S.Y.)
| | - Kanichiro Wada
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (K.W.); (Y.I.)
| | - Kazuhiro Kudoh
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (S.O.); (C.I.); (K.K.); (S.O.); (S.Y.)
| | - Akiko Igawa
- Department of Gastroenterological Surgery and Pediatric Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan;
| | - Saori Ogasawara
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (S.O.); (C.I.); (K.K.); (S.O.); (S.Y.)
| | - Yasuyuki Ishibashi
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (K.W.); (Y.I.)
| | - Makoto Daimon
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan;
| | - Soroku Yagihashi
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (S.O.); (C.I.); (K.K.); (S.O.); (S.Y.)
| | - Shigeyuki Nakaji
- Department of Social Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan;
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10
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Fan B, Chopp M, Zhang ZG, Liu XS. Emerging Roles of microRNAs as Biomarkers and Therapeutic Targets for Diabetic Neuropathy. Front Neurol 2020; 11:558758. [PMID: 33192992 PMCID: PMC7642849 DOI: 10.3389/fneur.2020.558758] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 09/16/2020] [Indexed: 12/12/2022] Open
Abstract
Diabetic neuropathy (DN) is the most prevalent chronic complication of diabetes mellitus. The exact pathophysiological mechanisms of DN are unclear; however, communication network dysfunction among axons, Schwann cells, and the microvascular endothelium likely play an important role in the development of DN. Mounting evidence suggests that microRNAs (miRNAs) act as messengers that facilitate intercellular communication and may contribute to the pathogenesis of DN. Deregulation of miRNAs is among the initial molecular alterations observed in diabetics. As such, miRNAs hold promise as biomarkers and therapeutic targets. In preclinical studies, miRNA-based treatment of DN has shown evidence of therapeutic potential. But this therapy has been hampered by miRNA instability, targeting specificity, and potential toxicities. Recent findings reveal that when packaged within extracellular vesicles, miRNAs are resistant to degradation, and their delivery efficiency and therapeutic potential is markedly enhanced. Here, we review the latest research progress on the roles of miRNAs as biomarkers and as potential clinical therapeutic targets in DN. We also discuss the promise of exosomal miRNAs as therapeutics and provide recommendations for future research on miRNA-based medicine.
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Affiliation(s)
- Baoyan Fan
- Department of Neurology, Henry Ford Health System, Detroit, MI, United States
| | - Michael Chopp
- Department of Neurology, Henry Ford Health System, Detroit, MI, United States.,Department of Physics, Oakland University, Rochester, MI, United States
| | - Zheng Gang Zhang
- Department of Neurology, Henry Ford Health System, Detroit, MI, United States
| | - Xian Shuang Liu
- Department of Neurology, Henry Ford Health System, Detroit, MI, United States
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11
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Ma M, Liu H, Yu J, He S, Li P, Ma C, Zhang H, Xu L, Ping F, Li W, Sun Q, Li Y. Triglyceride is independently correlated with insulin resistance and islet beta cell function: a study in population with different glucose and lipid metabolism states. Lipids Health Dis 2020; 19:121. [PMID: 32487177 PMCID: PMC7268278 DOI: 10.1186/s12944-020-01303-w] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 05/28/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Previous studies on the effects of lipotoxicity and oxidative stress on islet beta cell function mainly focused on patients with diabetes, whereas studies on normal glucose tolerance (NGT) are few. The aim of this study was to explore the relationships among triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), oxidative stress indicators, insulin resistance, and beta cell function in populations with different glucose and lipid metabolism states. METHODS A total of 517 individuals were recruited from a rural community in Beijing, China. Glucose metabolism status was defined according to the results of a 75-g oral glucose tolerance test (OGTT). Dyslipidemia was defined as abnormal TG, HDL-c, or LDL-c levels. The population was divided into four groups: individuals with normal glucose and lipid levels (group A, n = 62); those with dyslipidemia alone (group B, n = 82); those with dysglycemia alone (group C, n = 121); and those with dysglycemia and dyslipidemia (group D, n = 247). Oxidative stress indicators, including superoxide dismutase (SOD), glutathione reductase (GR) and 8-hydroxydeoxyguanosine (8-OHdG), were measured. Homeostasis model assessment of insulin resistance (HOMA-IR) and glucose disposition index (DI30, DI120) were calculated to assess insulin resistance and islet beta cell function, respectively. Stratified multiple linear regression analysis was used to explore relationships between TG, HDL-c, LDL-c, oxidative stress indicators, and insulin resistance (natural log transformation of HOMA-IR, LnHOMA-IR) and beta cell function (natural log transformation of DI30, Ln DI30). RESULTS Compared with the control group, populations with dyslipidemia and/or dysglycemia showed significantly increased insulin resistance. Dyslipidemia aggravated insulin resistance and beta cell dysfunction in individuals with dysglycemia. Stratified regression analysis showed that TG positively correlated with LnHOMA-IR in individuals with normal glucose levels (beta = 0.321, 0.327, P = 0.011, 0.003 in groups A and B, respectively) and negatively correlated with LnDI30 in participants with dyslipidemia (beta = - 0.225, - 0.122, P = 0.035, 0.048 in groups B and D, respectively). Reduced serum SOD levels in individuals with dysglycemia plus dyslipidemia were observed, and a negative association between TG and SOD levels was found (r = - 0.461, P < 0.001). CONCLUSION TG correlated with both insulin resistance and beta cell function in individuals with dyslipidemia alone. SOD negatively correlated with TG, indicating a close relationship between oxidative stress and glucose-lipid metabolism. Due to the adverse effect of hypertriglyceridemia on insulin sensitivity and islet beta cell function, more attention should be paid to the detection and management of hypertriglyceridemia.
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Affiliation(s)
- Minglei Ma
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Haibin Liu
- Department of Basic Physiology, The Health School affiliated with Capital Medical University, Beijing, China
| | - Jie Yu
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Shuli He
- Department of Nutrition, Peking Union Medical College Hospital, Beijing, China
| | - Pingping Li
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.,Diabetes Research Center of the Chinese Academy of Medical Sciences, Beijing, 100050, China
| | - Chunxiao Ma
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.,Diabetes Research Center of the Chinese Academy of Medical Sciences, Beijing, 100050, China
| | - Huabing Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Lingling Xu
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Fan Ping
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Wei Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Qi Sun
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Yuxiu Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, 100730, China.
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12
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Vitamin B6 and Diabetes: Relationship and Molecular Mechanisms. Int J Mol Sci 2020; 21:ijms21103669. [PMID: 32456137 PMCID: PMC7279184 DOI: 10.3390/ijms21103669] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 05/21/2020] [Accepted: 05/21/2020] [Indexed: 12/14/2022] Open
Abstract
Vitamin B6 is a cofactor for approximately 150 reactions that regulate the metabolism of glucose, lipids, amino acids, DNA, and neurotransmitters. In addition, it plays the role of antioxidant by counteracting the formation of reactive oxygen species (ROS) and advanced glycation end-products (AGEs). Epidemiological and experimental studies indicated an evident inverse association between vitamin B6 levels and diabetes, as well as a clear protective effect of vitamin B6 on diabetic complications. Interestingly, by exploring the mechanisms that govern the relationship between this vitamin and diabetes, vitamin B6 can be considered both a cause and effect of diabetes. This review aims to report the main evidence concerning the role of vitamin B6 in diabetes and to examine the underlying molecular and cellular mechanisms. In addition, the relationship between vitamin B6, genome integrity, and diabetes is examined. The protective role of this vitamin against diabetes and cancer is discussed.
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13
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Sanchez M, Hoang S, Kannengiesser C, Potier L, Hadjadj S, Marre M, Roussel R, Velho G, Mohammedi K. Leukocyte Telomere Length, DNA Oxidation, and Risk of Lower-Extremity Amputation in Patients With Long-standing Type 1 Diabetes. Diabetes Care 2020; 43:828-834. [PMID: 31988064 DOI: 10.2337/dc19-0973] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 01/01/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Telomere shortening and DNA oxidation are associated with premature vascular aging, which may be involved in lower-extremity amputation (LEA). We sought to investigate whether leukocyte telomere length (LTL) and plasma 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of DNA oxidation, were associated with LEA in subjects with type 1 diabetes at high vascular risk. RESEARCH DESIGN AND METHODS LTL (quantitative PCR) and plasma 8-OHdG concentrations (immunoassay method) were assessed at baseline in the GENEDIAB (Génétique de la Néphropathie Diabétique) type 1 diabetes cohort. Logistic and Cox proportional hazards regression models were fitted to estimate odds ratio (OR) (at baseline) and hazard ratio (HR) (during follow-up), with related 95% CI, by increasing biomarker tertiles (T1, T2, T3). RESULTS Among 478 participants (56% male, mean ± SD age 45 ± 12 years and diabetes duration 29 ± 10 years), 84 patients had LEA at baseline. Baseline history of LEA was associated with shorter LTL (OR for T2 vs. T1 0.62 [95% CI 0.32-1.22] and for T3 vs. T1 0.41 [0.20-0.84]) but not with plasma 8-OHdG (1.16 [0.56-2.39] and 1.24 [0.61-2.55], respectively). New cases of LEA occurred in 34 (12.3%) participants during the 10-year follow-up. LTL were shorter (HR T2 vs. T1 0.25 [95% CI 0.08-0.67] and T3 vs. T1 0.29 [0.10-0.77]) and plasma 8-OHdG higher (2.20 [0.76-7.35] and 3.11 [1.07-10.32]) in participants who developed LEA during follow-up compared with others. No significant interaction was observed between biomarkers on their association with LEA. CONCLUSIONS We report the first independent association between LTL shortening and excess risk of LEA in type 1 diabetes. High plasma 8-OHdG was also associated with incident LEA but partly dependent on cofounding variables.
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Affiliation(s)
- Manuel Sanchez
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France .,UFR de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.,Department of Geriatric Medicine, Assistance Publique - Hôpitaux de Paris, Bichat Hospital, Paris, France
| | - Sophie Hoang
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France
| | - Caroline Kannengiesser
- UFR de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.,Department of Genetics, Assistance Publique - Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Paris, France
| | - Louis Potier
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.,UFR de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.,Department of Diabetology, Endocrinology and Nutrition, Assistance Publique - Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Paris, France
| | - Samy Hadjadj
- L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France
| | - Michel Marre
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.,UFR de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.,Department of Diabetology, Endocrinology and Nutrition, Assistance Publique - Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Paris, France
| | - Ronan Roussel
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.,UFR de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.,Department of Diabetology, Endocrinology and Nutrition, Assistance Publique - Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Paris, France
| | - Gilberto Velho
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France
| | - Kamel Mohammedi
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.,Department of Endocrinology, Diabetes and Nutrition, Hôpital Haut-Lévêque, Pessac, France.,UFR de médecine, Université de Bordeaux, Bordeaux, France
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14
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Pereira CA, Carlos D, Ferreira NS, Silva JF, Zanotto CZ, Zamboni DS, Garcia VD, Ventura DF, Silva JS, Tostes RC. Mitochondrial DNA Promotes NLRP3 Inflammasome Activation and Contributes to Endothelial Dysfunction and Inflammation in Type 1 Diabetes. Front Physiol 2020; 10:1557. [PMID: 32009974 PMCID: PMC6978691 DOI: 10.3389/fphys.2019.01557] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 12/11/2019] [Indexed: 12/20/2022] Open
Abstract
Background: NLRP3 inflammasome activation in response to several signals, including mitochondrial DNA (mDNA), regulates inflammatory responses by caspase-1 activation and interleukin-1β (IL-1β) release. Circulating mDNA is linked to micro and macrovascular complications in diabetes. However, a role for mDNA in endothelial dysfunction is not clear. We tested the hypothesis that mDNA contributes to diabetes-associated endothelial dysfunction and vascular inflammation via NLRP3 activation. Methods: Vascular reactivity, reactive oxygen species (ROS) generation, calcium (Ca2+) influx and caspase-1 and IL-1β activation were determined in mesenteric resistance arteries from normoglicemic and streptozotocin-induced diabetic C57BL/6 and NLRP3 knockout (Nlrp3-/- ) mice. Endothelial cells and mesenteric arteries were stimulated with mDNA from control (cmDNA) and diabetic (dmDNA) mice. Results: Diabetes reduced endothelium-dependent vasodilation and increased vascular ROS generation and caspase-1 and IL-1β activation in C57BL/6, but not in Nlrp3-/- mice. Diabetes increased pancreatic cytosolic mDNA. dmDNA decreased endothelium-dependent vasodilation. In endothelial cells, dmDNA activated NLRP3 via mitochondrial ROS and Ca2+ influx. Patients with type 1 diabetes exhibited increased circulating mDNA as well as caspase-1 and IL-1β activation. Conclusion: dmDNA activates endothelial NLRP3 inflammasome by mechanisms that involve Ca2+ influx and mitochondrial ROS generation. NLRP3 deficiency prevents diabetes-associated vascular inflammatory damage and endothelial dysfunction. Our study highlights the importance of NLRP3 inflammasome in diabetes-associated vascular dysfunction, which is key to diabetic complications.
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Affiliation(s)
- Camila A Pereira
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Daniela Carlos
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Nathanne S Ferreira
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Josiane F Silva
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Camila Z Zanotto
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Dario S Zamboni
- Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Valéria D Garcia
- Department of Experimental Psychology, Institute of Psychology, University of São Paulo, São Paulo, Brazil
| | - Dora Fix Ventura
- Department of Experimental Psychology, Institute of Psychology, University of São Paulo, São Paulo, Brazil
| | - João S Silva
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Rita C Tostes
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
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15
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Selig JI, Ouwens DM, Raschke S, Thoresen GH, Fischer JW, Lichtenberg A, Akhyari P, Barth M. Impact of hyperinsulinemia and hyperglycemia on valvular interstitial cells - A link between aortic heart valve degeneration and type 2 diabetes. Biochim Biophys Acta Mol Basis Dis 2019; 1865:2526-2537. [PMID: 31152868 DOI: 10.1016/j.bbadis.2019.05.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 04/27/2019] [Accepted: 05/28/2019] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes is a known risk factor for cardiovascular diseases and is associated with an increased risk to develop aortic heart valve degeneration. Nevertheless, molecular mechanisms leading to the pathogenesis of valve degeneration in the context of diabetes are still not clear. Hence, we hypothesized that classical key factors of type 2 diabetes, hyperinsulinemia and hyperglycemia, may affect signaling, metabolism and degenerative processes of valvular interstitial cells (VIC), the main cell type of heart valves. Therefore, VIC were derived from sheep and were treated with hyperinsulinemia, hyperglycemia and the combination of both. The presence of insulin receptors was shown and insulin led to increased proliferation of the cells, whereas hyperglycemia alone showed no effect. Disturbed insulin response was shown by impaired insulin signaling, i.e. by decreased phosphorylation of Akt/GSK-3α/β pathway. Analysis of glucose transporter expression revealed absence of glucose transporter 4 with glucose transporter 1 being the predominantly expressed transporter. Glucose uptake was not impaired by disturbed insulin response, but was increased by hyperinsulinemia and was decreased by hyperglycemia. Analyses of glycolysis and mitochondrial respiration revealed that VIC react with increased activity to hyperinsulinemia or hyperglycemia, but not to the combination of both. VIC do not show morphological changes and do not acquire an osteogenic phenotype by hyperinsulinemia or hyperglycemia. However, the treatment leads to increased collagen type 1 and decreased α-smooth muscle actin expression. This work implicates a possible role of diabetes in early phases of the degeneration of aortic heart valves.
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Affiliation(s)
- Jessica I Selig
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
| | - D Margriet Ouwens
- Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany; Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.
| | - Silja Raschke
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - G Hege Thoresen
- Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Jens W Fischer
- Department of Pharmacology and Clinical Pharmacology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
| | - Artur Lichtenberg
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
| | - Payam Akhyari
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
| | - Mareike Barth
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
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16
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Castilla-Peon MF, Medina Bravo PG, Sánchez-Urbina R, Gallardo-Montoya JM, Soriano-López LC, Coronel Cruz FM. Diabetes and obesity during pregnancy are associated with oxidative stress genotoxicity in newborns. J Perinat Med 2019; 47:347-353. [PMID: 30676004 DOI: 10.1515/jpm-2018-0201] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 11/23/2018] [Indexed: 01/22/2023]
Abstract
Objective To compare the level of oxidative deoxyribonucleic acid (DNA) damage (genotoxicity) between the offspring of mothers with and without diabetes diagnosed during pregnancy and its association with maternal body mass index (BMI). Methods We measured 8-hydroxy-deoxyguanosine (8-OH-dG), a marker of DNA oxidative damage, in venous umbilical cord plasma from newborns of mothers with (n=34) and without (n=56) diabetes diagnoses obtained during pregnancy. Two markers of oxidative stress - namely, nitric oxide degradation products (NOx) and total glutathione (GSH) - were quantified in both mothers and newborns. The effects of BMI, glycated hemoglobin (HbA1c), age and delivery mode were also analyzed. Results Newborns of mothers with diabetes during pregnancy exhibited higher levels of 8-OH-dG than those of mothers without diabetes (P<0.001). The other markers of oxidative stress were also higher in both mothers with diabetes and their newborns, with the exception of NOx in the mothers. The association of diabetes with 8-OH-dG was independent of other analyzed factors. Conclusion The offspring of mothers with diabetes during pregnancy are born with increased genotoxicity than the offspring of mothers without diabetes. BMI and HbA1c display an independent association with 8-OH-dG, particularly in the offspring of mothers not diagnosed with diabetes.
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Affiliation(s)
| | | | - Rocío Sánchez-Urbina
- Research Unit in Congenital Heart Diseases, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
| | - Juan Manuel Gallardo-Montoya
- Research Unit in Renal Diseases, Centro Médico Nacional "Siglo XXI", Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Luis César Soriano-López
- Research Unit in Congenital Heart Diseases, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
| | - Fausto Moisés Coronel Cruz
- Materno-Fetal Medicine Unit, Obstetrics and Gynecology Department, Hospital General de México Eduardo Liceaga O.D., Mexico City, Mexico
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17
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Mahat RK, Singh N, Rathore V, Arora M, Yadav T. Cross-sectional correlates of oxidative stress and inflammation with glucose intolerance in prediabetes. Diabetes Metab Syndr 2019; 13:616-621. [PMID: 30641776 DOI: 10.1016/j.dsx.2018.11.045] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 11/13/2018] [Indexed: 01/22/2023]
Abstract
BACKGROUND Prediabetes is a condition in which blood glucose level is above the normal but below the diagnostic value of diabetes mellitus. Besides progression to diabetes mellitus, prediabetic subjects are at risk for cardiovascular disease (CVD). It is associated with oxidative stress and inflammation and therefore this research was conducted with the aim to evaluate the risk of cardiovascular disease in prediabetic subjects by measuring the markers of oxidative stress and inflammation and their possible correlation with glucose intolerance. MATERIALS AND METHODS A total of 400 human subjects were recruited for the present cross-sectional study. Of them, 200 were prediabetic subjects and 200 were age and gender-matched control subjects. Blood samples were collected from all participants and analyzed for 8-hydroxy-2'-deoxy-guanosine (8-OHdG), malondialdehyde (MDA), reduced glutathione (GSH) and high sensitivity C-reactive protein (hs-CRP). RESULTS The markers of oxidative stress i.e. 8-OHdG and MDA were found to be significantly increased in prediabetic subjects as compared to control subjects except GSH, which was significantly reduced in prediabetic subjects. Similarly, hs-CRP (a marker of inflammation) was significantly increased in prediabetic subjects compared to controls. On correlation analysis, 8-OHdG, MDA and hs-CRP were significantly and positively correlated with glucose intolerance in prediabetes whereas GSH showed significant negative correlation with glucose intolerance. CONCLUSION In conclusion, markers of oxidative stress and inflammation should be taken into consideration while evaluating the risk for CVD in prediabetes since these markers were well correlated with glucose intolerance in prediabetic subjects.
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Affiliation(s)
- Roshan Kumar Mahat
- Department of Biochemistry, Gajra Raja Medical College, Jiwaji University, Gwalior, Madhya Pradesh, 474009, India.
| | | | - Vedika Rathore
- Department of Biochemistry, Shyam Shah Medical College, Rewa, Madhya Pradesh, 486001, India
| | - Manisha Arora
- Department of Biochemistry, Muzaffarnagar Medical College, Muzaffarnagar, Uttar Pradesh, 251203, India
| | - Tapeshwar Yadav
- Department of Laboratory Medicine, Green Tara College of Health Sciences, Bhaisepati, Lalitpur, Nepal
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18
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Daniel OO, Adeoye AO, Ojowu J, Olorunsogo OO. Inhibition of liver mitochondrial membrane permeability transition pore opening by quercetin and vitamin E in streptozotocin-induced diabetic rats. Biochem Biophys Res Commun 2018; 504:460-469. [DOI: 10.1016/j.bbrc.2018.08.114] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 08/17/2018] [Indexed: 11/29/2022]
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19
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Al-Kharashi AS. Role of oxidative stress, inflammation, hypoxia and angiogenesis in the development of diabetic retinopathy. Saudi J Ophthalmol 2018; 32:318-323. [PMID: 30581303 PMCID: PMC6300752 DOI: 10.1016/j.sjopt.2018.05.002] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Revised: 04/29/2018] [Accepted: 05/18/2018] [Indexed: 12/15/2022] Open
Abstract
Diabetic retinopathy (DR) is a retinal disease which is one of the most severe complications occuring due to diabetes mellitus and is a major cause of blindness. Patients who have diabetes mellitus for number of years develop characteristic group of lesions in the retina which leads to Diabetic retinopathy. It is a multifactorial condition occuring due to complex cellular interactions between biochemical and metabolic abnormalities taking place in all retinal cells. Considerable research efforts in the past 20 years have suggested that the microvasculature of the retina responds to hyperglycemia through a number of biochemical changes, which includes polyol pathway, protein kinase C activation, upregulation of advanced glycation end products formation and renin angiotensin system activation. Various previous studies had suggest that interaction of these biochemical changes may cause a cascade of events, such as apoptosis, oxidative stress, inflammation and angiogenesis which can lead to the damage of a diabetic retina, causing DR. This highlights that oxidative stress, inflammation, angiogenesis-related factors triggers the occurrence of retinal complication in diabetes are highlighted.
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Affiliation(s)
- Abdullah S. Al-Kharashi
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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20
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Protective role of vitamin B6 (PLP) against DNA damage in Drosophila models of type 2 diabetes. Sci Rep 2018; 8:11432. [PMID: 30061626 PMCID: PMC6065437 DOI: 10.1038/s41598-018-29801-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 07/19/2018] [Indexed: 12/24/2022] Open
Abstract
Growing evidence shows that improper intake of vitamin B6 increases cancer risk and several studies indicate that diabetic patients have a higher risk of developing tumors. We previously demonstrated that in Drosophila the deficiency of Pyridoxal 5′ phosphate (PLP), the active form of vitamin B6, causes chromosome aberrations (CABs), one of cancer prerequisites, and increases hemolymph glucose content. Starting from these data we asked if it was possible to provide a link between the aforementioned studies. Thus, we tested the effect of low PLP levels on DNA integrity in diabetic cells. To this aim we generated two Drosophila models of type 2 diabetes, the first by impairing insulin signaling and the second by rearing flies in high sugar diet. We showed that glucose treatment induced CABs in diabetic individuals but not in controls. More interestingly, PLP deficiency caused high frequencies of CABs in both diabetic models demonstrating that hyperglycemia, combined to reduced PLP level, impairs DNA integrity. PLP-depleted diabetic cells accumulated Advanced Glycation End products (AGEs) that largely contribute to CABs as α-lipoic acid, an AGE inhibitor, rescued not only AGEs but also CABs. These data, extrapolated to humans, indicate that low PLP levels, impacting on DNA integrity, may be considered one of the possible links between diabetes and cancer.
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Decreased Chromosomal Damage in Lymphocytes of Obese Patients After Bariatric Surgery. Sci Rep 2018; 8:11195. [PMID: 30046046 PMCID: PMC6060147 DOI: 10.1038/s41598-018-29581-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 07/16/2018] [Indexed: 01/10/2023] Open
Abstract
The number of bariatric surgeries being performed worldwide has markedly risen. While the improvement in obesity-associated comorbidities after bariatric surgery is well-established, very little is known about its impact on cancer risk. The peripheral lymphocyte micronucleus test is a widely used method for the monitoring of chromosomal damage levels in vivo, and micronucleus frequency positively correlates with cancer risk. Therefore, the aim of this study was to compare the micronucleus frequency before and after bariatric surgery in obese subjects. Peripheral blood mononuclear cells were collected from 45 obese subjects before and at two time-points after bariatric surgery (6 and 12 months) to assess spontaneous micronucleus frequency. Consistent with the increased cancer risk previously shown, bariatric surgery-induced weight loss led to a significant reduction in lymphocyte micronucleus frequency after 12 months. Interestingly, comorbidities such as type 2 diabetes mellitus and metabolic syndrome further seemed to have an impact on the lymphocyte micronucleus frequency. Our findings may indicate a successful reduction of cancer risk in patients following weight loss caused by bariatric surgery.
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Almási A, Pinto ÉDILN, Kovács NP, Fischer T, Markovics Z, Fischer E, Perjési P. Changes in hepatic metabolic enzyme activities and biliary excretion of 4-nitrophenol in streptozotocin induced diabetic rats. BRAZ J PHARM SCI 2018. [DOI: 10.1590/s2175-97902018000117347] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
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Zhang J, Liu J, Qin X. Advances in early biomarkers of diabetic nephropathy. ACTA ACUST UNITED AC 2018; 64:85-92. [PMID: 29561946 DOI: 10.1590/1806-9282.64.01.85] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 09/09/2017] [Indexed: 01/06/2023]
Abstract
Diabetic nephropathy is the main cause of chronic kidney disease, and represents the most common and serious complication of diabetes. The exact pathogenesis is complex and not elucidated. Several factors and mechanisms contribute to the development and outcome of diabetic nephropathy. An early diagnosis and intervention may slow down disease progression. A variety of biological markers associated with diabetic nephropathy were found in recent years, which was important for predicting the occurrence and development of the disease. Therefore, this article provides an overview of early biomarkers that are associated with diabetic nephropathy.
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Affiliation(s)
- Jin Zhang
- Masters Student, Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jianhua Liu
- MD, PhD. Associate Professor of Laboratory Medicine, Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaosong Qin
- MD, PhD. Professor of Laboratory Medicine, Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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24
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Sanchez M, Roussel R, Hadjadj S, Moutairou A, Marre M, Velho G, Mohammedi K. Plasma concentrations of 8-hydroxy-2'-deoxyguanosine and risk of kidney disease and death in individuals with type 1 diabetes. Diabetologia 2018; 61:977-984. [PMID: 29185011 DOI: 10.1007/s00125-017-4510-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 11/01/2017] [Indexed: 12/19/2022]
Abstract
AIMS/HYPOTHESIS Oxidative stress is involved in the pathogenesis of diabetic kidney disease. We evaluated the association between 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA oxidative damage, and end-stage renal disease (ESRD) or death in individuals with type 1 diabetes. METHODS Plasma 8-OHdG concentrations were measured at baseline in participants with type 1 diabetes from GENEDIAB (n = 348) and GENESIS (n = 571) cohorts. A follow-up was conducted in 205 and 499 participants for a mean ± SD duration of 8.9 ± 2.3 years and 5.2 ± 1.9 years, respectively. We tested associations between 8-OHdG concentrations and urinary albumin concentration (UAC) or eGFR at baseline, and the risk of ESRD or all-cause mortality during follow-up. Analyses were performed in pooled cohorts. RESULTS The highest UAC (geometric mean [95% CI]) was observed in the third 8-OHdG tertile (tertile 1, 9 [6, 13] mg/l; tertile 2, 10 [7, 16] mg/l; tertile 3, 16 [10, 25] mg/l; p = 0.36 for tertile 1 vs tertile 2 and p = 0.003 for tertile 3 vs tertile 1) after adjustment for potential confounding covariates. The lowest eGFR (mean [95% CI]) was observed in the third tertile (tertile 1, 87 [82, 93] ml min-1 1.73 m-2; tertile 2, 88 [82, 94] ml min-1 1.73 m-2; tertile 3, 74 [68, 80] ml min-1 1.73 m-2; p = 0.61 for tertile 1 vs tertile 2; p < 0.001 for tertile 3 vs tertile 1). ESRD and death occurred in 48 and 64 individuals, respectively. The HR for ESRD, but not death, was higher in the third tertile than in the first (tertile 2 vs tertile 1, 1.45 [0.45, 5.04], p = 0.54; tertile 3 vs tertile 1, 3.05 [1.16, 9.60], p = 0.02) after multiple adjustments. CONCLUSIONS/INTERPRETATION Higher plasma concentrations of 8-OHdG were independently associated with increased risk of kidney disease in individuals with type 1 diabetes, suggesting that this marker can be used to evaluate the progression of diabetic kidney disease.
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Affiliation(s)
- Manuel Sanchez
- Inserm, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France
- Department of Geriatric Medicine, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Paris, France
- UFR de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Ronan Roussel
- Inserm, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France
- UFR de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Department of Diabetology, Endocrinology and Nutrition, Assistance Publique Hôpitaux de Paris, Bichat Hospital, DHU FIRE, 46 rue Henri Huchard, 75877, Paris Cedex 18, France
| | - Samy Hadjadj
- Department of Endocrinology and Diabetology, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
- Inserm, Research Unit 1082, Poitiers, France
- Université de Poitiers, UFR de Médecine et Pharmacie, Poitiers, France
| | - Abdul Moutairou
- Inserm, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France
| | - Michel Marre
- Inserm, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France
- UFR de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Department of Diabetology, Endocrinology and Nutrition, Assistance Publique Hôpitaux de Paris, Bichat Hospital, DHU FIRE, 46 rue Henri Huchard, 75877, Paris Cedex 18, France
| | - Gilberto Velho
- Inserm, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France
| | - Kamel Mohammedi
- Inserm, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.
- Department of Diabetology, Endocrinology and Nutrition, Assistance Publique Hôpitaux de Paris, Bichat Hospital, DHU FIRE, 46 rue Henri Huchard, 75877, Paris Cedex 18, France.
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Oxidative DNA Damage and Carotid Intima Media Thickness as Predictors of Cardiovascular Disease in Prediabetic Subjects. J Cardiovasc Dev Dis 2018. [PMID: 29518984 PMCID: PMC5872363 DOI: 10.3390/jcdd5010015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Prediabetes is considered as a risk factor for the development of diabetes mellitus and cardiovascular disease. The present study was conducted with the aim of finding out the relationship between oxidative DNA damage and carotid intima media thickness for the prediction of cardiovascular disease in prediabetic subjects. The study included 100 prediabetic subjects and 100 normal individuals as controls. In both cases and controls, 8-OHdG was measured by ELISA, and CIMT was measured by B mode ultrasonography. Both 8-OHdG and CIMT were significantly higher in subjects with prediabetes as compared to controls (185.80 ± 10.72 pg/mL vs. 126.13 ± 16.01 pg/mL, p < 0.001 and 0.70 ± 0.04 mm vs. 0.57 ± 0.03 mm, p < 0.001, respectively). There was significant and positive correlation of IGT with 8-OHdG (r = 0.783; p < 0.001) and CIMT (r = 0.787; p < 0.001) in prediabetic subjects. Moreover, 8-OHdG showed significant positive correlation with CIMT (r = 0.704; p < 0.001) in prediabetic subjects. In conclusion, increased 8-OHdG and CIMT in prediabetic subjects indicate that biochemical changes of atherosclerosis start even before the onset of diabetes mellitus. Hence, 8-OHdG and CIMT could be used as indicators of cardiovascular disease risk in these subjects.
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Lim YJ, Kim JH, Pan JH, Kim JK, Park TS, Kim YJ, Lee JH, Kim JH. Naringin Protects Pancreatic β-Cells Against Oxidative Stress-Induced Apoptosis by Inhibiting Both Intrinsic and Extrinsic Pathways in Insulin-Deficient Diabetic Mice. Mol Nutr Food Res 2018; 62. [PMID: 29314619 DOI: 10.1002/mnfr.201700810] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 11/16/2017] [Indexed: 12/12/2022]
Abstract
SCOPE Oxidative stress has been suggested to play a central role in the pathogenesis of diabetes, as well as other metabolic disorders. Naringin, a major flavanone glycoside in citrus species, has been shown to display strong antioxidant potential in in vitro and in vivo models of oxidative stress; however, the underlying protective mechanisms in diabetes are unclear. METHODS AND RESULTS To study the protective effects and molecular mechanisms of naringin in preventing islet dysfunction and diabetes, we examined glucose homeostasis, β-cell apoptosis, and inflammatory response in insulin-deficient diabetic mice exposed to acute oxidative stress with streptozotocin (STZ). Naringin dose-dependently ameliorated hyperglycemia and islet dysfunction in insulin-deficient diabetic mice. Naringin counteracted STZ-induced β-cell apoptosis by inhibiting both the intrinsic (mitochondria-mediated) and extrinsic (death receptor-mediated) pathways. Furthermore, these protective effects were associated with suppression of DNA damage response and nuclear factor-kappa B- and mitogen-activated protein kinase-mediated signaling pathways, as well as reduction of reactive oxygen species accumulation and pro-inflammatory cytokine production in the pancreas. CONCLUSION Taken together, our study provides insights into the underlying mechanisms through which naringin protects the pancreatic β-cells against oxidative stress-induced apoptosis.
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Affiliation(s)
- Ye Jin Lim
- Department of Food and Biotechnology, Korea University, Sejong, South Korea
| | - Jung Ho Kim
- Department of Food and Biotechnology, Korea University, Sejong, South Korea
| | - Jeong Hoon Pan
- School of Human Environmental Sciences, University of Arkansas, Fayetteville, AR, USA
| | - Jae Kyeom Kim
- School of Human Environmental Sciences, University of Arkansas, Fayetteville, AR, USA
| | - Tae-Sik Park
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Inchon, South Korea
| | - Young Jun Kim
- Department of Food and Biotechnology, Korea University, Sejong, South Korea
| | - Jin Hyup Lee
- Department of Food and Biotechnology, Korea University, Sejong, South Korea
| | - Jun Ho Kim
- Department of Food and Biotechnology, Korea University, Sejong, South Korea
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Pan CW, Wang S, Xu CL, Song E. Combined effect of glycemic and blood pressure control on diabetic retinopathy among Chinese with type-2 diabetes mellitus. Diabetol Metab Syndr 2018; 10:73. [PMID: 30302129 PMCID: PMC6167778 DOI: 10.1186/s13098-018-0377-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Accepted: 09/27/2018] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND To explore the associations of glycemic and blood pressure (BP) control with diabetic retinopathy (DR), with special focus on whether different combinations of categories of these two interventions are additive. METHODS A community-based survey including 913 patients with known type-2 diabetes mellitus (T2DM) was conducted in Suzhou, China. Retinal photographs were graded for the presence of DR using the Airlie House classification system. BP and blood hemoglobin A1c (HbA1C) levels were measured by standardized protocols. Binary logistic regression models were established to examine the associations of risk factors with DR. RESULTS The overall prevalence of any DR was 18.0% [95% confidence interval (95% CI) 15.5-20.6%] in this population. Stratified by conventional control thresholds, lower levels of either systolic blood pressure (SBP, < 140 mmHg) or HbA1C (< 7.0%) were not significantly associated with decreased susceptibility to DR, while patients simultaneously with lower HbA1C and SBP levels demonstrated 43% reduced likelihood of developing DR [adjusted odds ratio (OR) = 0.57, 95% CI 0.33-0.99, P = 0.045)], comparing with those with both higher levels of HbA1C (≥ 7.0%) and SBP (≥ 140 mmHg). Meanwhile, the group achieved intensive HbA1C (< 6.5%) and SBP (< 120 mmHg) control goals were found to have the smallest OR, but failed in yielding statistical significance (P = 0.10). CONCLUSIONS In this community-based DR screening study of Chinese adults with T2DM, combination but not individual of lower SBP (< 140 mmHg) and HbA1C (< 7.0%) levels, were suggested to be associated with a significantly reduced likelihood of having DR.
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Affiliation(s)
- Chen-Wei Pan
- School of Public Health, Medical College of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| | - Shan Wang
- School of Public Health, Medical College of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| | - Cai-Lian Xu
- Lixiang Eye Hospital of Soochow University, 200 East Gan Jiang Road, Suzhou, 215123 China
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun, China
| | - E. Song
- Lixiang Eye Hospital of Soochow University, 200 East Gan Jiang Road, Suzhou, 215123 China
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun, China
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Jouni H, Chareonthaitawee P. Unraveling Inflammation and Oxidative Stress in Cardiac Sarcoidosis. Circ Cardiovasc Imaging 2017; 10:CIRCIMAGING.117.007287. [DOI: 10.1161/circimaging.117.007287] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Hayan Jouni
- From the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN
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Increased Oxidative Damage of RNA in Early-Stage Nephropathy in db/db Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:2353729. [PMID: 29201270 PMCID: PMC5671745 DOI: 10.1155/2017/2353729] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 09/03/2017] [Accepted: 09/12/2017] [Indexed: 11/18/2022]
Abstract
To evaluate RNA oxidation in the early stage of diabetic nephropathy, we applied an accurate method based on isotope dilution high-performance liquid chromatography-triple quadruple mass spectrometry to analyze the oxidatively generated guanine nucleosides in renal tissue and urine from db/db mice of different ages. We further investigated the relationship between these oxidative stress markers, microalbumin excretion, and histological changes. We found that the levels of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) were increased in the urine and renal tissue of db/db mice and db/db mice with early symptoms of diabetic nephropathy suffered from more extensive oxidative damage than lean littermate control db/m mice. Importantly, in contrast to the findings in db/m mice, the 8-oxoGuo levels in the urine and renal tissue of db/db mice were higher than those of 8-oxodGuo at four weeks. These results indicate that RNA oxidation is more apparent than DNA oxidation in the early stage of diabetic nephropathy. RNA oxidation may provide new insight into the pathogenesis of diabetic nephropathy, and urinary 8-oxoGuo may represent a novel, noninvasive, and easily detected biomarker of diabetic kidney diseases if further study could clarify its source and confirm these results in a large population study.
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30
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Usta A, Dede S. The Effect of Thymoquinone on Nuclear Factor Kappa B Levels and Oxidative DNA Damage on Experimental Diabetic Rats. Pharmacogn Mag 2017; 13:S458-S461. [PMID: 29142399 PMCID: PMC5669082 DOI: 10.4103/pm.pm_134_17] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 05/17/2017] [Indexed: 12/19/2022] Open
Abstract
Background: Thymoquinone (TQ), the basic bioactive phytochemical constituent of seed oil of Nigella sativa, is one of these herbal drugs known for antidiabetic effects. This study was carried out to assess the effects of the possible role of TQ on nuclear factor kappa B (NF-κB) and oxidative DNA damage levels in experimental diabetic rats. Materials and Methods: Twenty-eight male Wistar Albino rats (200–250 g) were used as experimental subjects. The rats were divided into four groups, including the control, control supplemented with TQ (CT), diabetic (D), and diabetic supplemented with TQ (DT), each containing seven rats. The D and the DT groups were treated with 45 mg/kg streptozotocin (STZ) (intraperitoneal). TQ was administered 30 mg/kg/day for 21 days by oral gavage in the DT and the T groups. Results: It was determined that glucose, glycosylated hemoglobin (HbA1c) levels and alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase activities were decreased significantly and approached the control group in the DT group after TQ supplement (P < 0.05). Urea levels were the lowest in CT (P < 0.05). Oxidative DNA damage (8 hydroxy-2-deoxyguanosine) was increased in both of the diabetic groups (D and DT). The NF-κB levels were the highest in Group D (P < 0.05). Conclusion: It was observed that increased glucose and HbA1c levels and the indicators of liver and kidney damages were decreased significantly after TQ supplementation. Oxidative DNA damage and NF-κB levels were increased in the diabetic group, and TQ administration caused a statistically insignificant reduction. SUMMARY
In this study, the effects of thymoquinone (TQ), the basic bioactive phytochemical constituent of seed oil of Nigella sativa, on nuclear factor kappa B (NF-κB), oxidative DNA damage levels, and, some biochemical parameters was invesigated. It was observed that some biochemical parameters (glucose, glycosylated hemoglobin (HbA1c), ALT, AST, GGT) were close to the control group after TQ treatment in diabetic group. Oxidative DNA damage (8 hydroxy 2 deoxyguanosine) and NF-κB were highest levels and TQ implementation caused statistically insignificant decrease, in the diabetic group.
Abbreviations used: 8-OHdG: 8 hydroxi-2-deoxiguanosin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transpeptidase; HbA1c: Glycosylated hemoglobin; NF-κB: Nuclear factor kappa protein; STZ: Streptozotocin; TQ: Thymoquinone.
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Affiliation(s)
- Ayşe Usta
- Department of Chemistry, Faculty of Science, Yuzuncu Yil University, Van, Turkey
| | - Semiha Dede
- Department of Biochemistry, Yuzuncu Yil University, Faculty of Veterinary Medicine, Van, Turkey
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Nawab A, Nichols A, Klug R, Shapiro JI, Sodhi K. Spin Trapping: A Review for the Study of Obesity Related Oxidative Stress and Na +/K +-ATPase. ACTA ACUST UNITED AC 2017; 8. [PMID: 28815154 PMCID: PMC5555609 DOI: 10.4172/2155-9899.1000505] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Reactive oxygen species (ROS) have gained attention with mounting evidence of their importance in cell signaling and various disease states. ROS is produced continuously as a natural by-product of normal oxygen metabolism. However, high levels ROS causes oxidative stress and damage to biomolecules. This results in loss of protein function, DNA cleavage, lipid peroxidation, or ultimately cell injury or death. Obesity has become a worldwide epidemic; studies show fat accumulation is associated with increased ROS and oxidative stress. Evidence exists supporting oxidative stress as a factor driving forward insulin resistance (IR), potentially resulting in diabetes. Na+/K+-ATPase signaling is also a potential source of ROS promoting oxidative stress. The best way to observe radical species in biological systems is electron paramagnetic resonance spectroscopy with spin trapping. EPR spin trapping is an important technique to study the mechanisms driving disease states attributed to ROS.
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Affiliation(s)
- Athar Nawab
- Department of Medicine, Joan C. Edwards School of Medicine, Marshall University, USA
| | - Alexandra Nichols
- Department of Medicine, Joan C. Edwards School of Medicine, Marshall University, USA
| | - Rebecca Klug
- Department of Surgery and Biomedical Sciences, Marshall University, USA
| | - Joseph I Shapiro
- Department of Medicine, Joan C. Edwards School of Medicine, Marshall University, USA
| | - Komal Sodhi
- Department of Surgery and Biomedical Sciences, Marshall University, USA
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Ma ZG, Yuan YP, Xu SC, Wei WY, Xu CR, Zhang X, Wu QQ, Liao HH, Ni J, Tang QZ. CTRP3 attenuates cardiac dysfunction, inflammation, oxidative stress and cell death in diabetic cardiomyopathy in rats. Diabetologia 2017; 60:1126-1137. [PMID: 28258411 DOI: 10.1007/s00125-017-4232-4] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 02/03/2017] [Indexed: 01/03/2023]
Abstract
AIMS/HYPOTHESIS Oxidative stress, inflammation and cell death are closely involved in the development of diabetic cardiomyopathy (DCM). C1q/tumour necrosis factor-related protein-3 (CTRP3) has anti-inflammatory properties but its role in DCM remains largely unknown. The aims of this study were to determine whether CTRP3 could attenuate DCM and to clarify the underlying mechanisms. METHODS Streptozotocin (STZ) was injected intraperitoneally to induce diabetes in Sprague-Dawley rats. Cardiomyocyte-specific CTRP3 overexpression was achieved using an adeno-associated virus system 12 weeks after STZ injection. RESULTS CTRP3 expression was significantly decreased in diabetic rat hearts. Knockdown of CTRP3 in cardiomyocytes at baseline resulted in increased oxidative injury, inflammation and apoptosis in vitro. Cardiomyocyte-specific overexpression of CTRP3 decreased oxidative stress and inflammation, attenuated myocyte death and improved cardiac function in rats treated with STZ. CTRP3 significantly activated AMP-activated protein kinase α (AMPKα) and Akt (protein kinase B) in H9c2 cells. CTRP3 protected against high-glucose-induced oxidative stress, inflammation and apoptosis in vitro. AMPKα deficiency abolished the protective effects of CTRP3 in vitro and in vivo. Furthermore, we found that CTRP3 activated AMPKα via the cAMP-exchange protein directly activated by cAMP (EPAC)-mitogen-activated protein kinase kinase (MEK) pathway. CONCLUSIONS/INTERPRETATION CTRP3 protected against DCM via activation of the AMPKα pathway. CTRP3 has therapeutic potential for the treatment of DCM.
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Affiliation(s)
- Zhen-Guo Ma
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Cardiovascular Research Institute of Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Yu-Pei Yuan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Cardiovascular Research Institute of Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Si-Chi Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Cardiovascular Research Institute of Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Wen-Ying Wei
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Cardiovascular Research Institute of Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Chun-Ru Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Cardiovascular Research Institute of Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Xin Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Cardiovascular Research Institute of Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Qing-Qing Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Cardiovascular Research Institute of Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Hai-Han Liao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Cardiovascular Research Institute of Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Jian Ni
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Cardiovascular Research Institute of Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Qi-Zhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China.
- Cardiovascular Research Institute of Wuhan University, Wuhan, People's Republic of China.
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China.
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Hubei Key Laboratory of Cardiology, Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China.
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DNA damage-dependent mechanisms of ageing and disease in the macro- and microvasculature. Eur J Pharmacol 2017; 816:116-128. [PMID: 28347738 DOI: 10.1016/j.ejphar.2017.03.050] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 03/07/2017] [Accepted: 03/23/2017] [Indexed: 12/15/2022]
Abstract
A decline in the function of the macro- and micro-vasculature occurs with ageing. DNA damage also accumulates with ageing, and thus DNA damage and repair have important roles in physiological ageing. Considerable evidence also supports a crucial role for DNA damage in the development and progression of macrovascular disease such as atherosclerosis. These findings support the concept that prolonged exposure to risk factors is a major stimulus for DNA damage within the vasculature, in part via the generation of reactive oxygen species. Genomic instability can directly affect vascular cellular function, leading to cell cycle arrest, apoptosis and premature vascular cell senescence. In contrast, the study of age-related impaired function and DNA damage mechanisms in the microvasculature is limited, although ageing is associated with microvessel endothelial dysfunction. This review examines current knowledge on the role of DNA damage and DNA repair systems in macrovascular disease such as atherosclerosis and microvascular disease. We also discuss the cellular responses to DNA damage to identify possible strategies for prevention and treatment.
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Carlos D, Costa FRC, Pereira CA, Rocha FA, Yaochite JNU, Oliveira GG, Carneiro FS, Tostes RC, Ramos SG, Zamboni DS, Camara NOS, Ryffel B, Silva JS. Mitochondrial DNA Activates the NLRP3 Inflammasome and Predisposes to Type 1 Diabetes in Murine Model. Front Immunol 2017; 8:164. [PMID: 28289409 PMCID: PMC5326761 DOI: 10.3389/fimmu.2017.00164] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Accepted: 02/01/2017] [Indexed: 01/14/2023] Open
Abstract
Although a correlation between polymorphisms of NOD-like receptor family-pyrin domain containing 3 (NLRP3) and predisposition to type 1 diabetes (T1D) has been identified, the potential function and activation of the NLRP3 inflammasome in T1D have not been clarified. The present study shows that non-obese diabetic mice exhibited increased NLRP3, and pro-IL-1β gene expression in pancreatic lymph nodes (PLNs). Similar increases in gene expression of NLRP3, apoptosis associated speck like protein (ASC) and pro-IL-1β were induced by multiple low doses of streptozotocin (STZ) in C57BL/6 mice. In addition, diabetic C57BL/6 mice also exhibited increased IL-1β protein expression in the pancreatic tissue at day 7, which remained elevated until day 15. Diabetic mice also showed increased positive caspase-1 macrophages in the PLNs, which were decreased in NLRP3-/- mice, but not in ASC-/- mice, after STZ treatment. NLRP3- and IL-1R-deficient mice, but not ASC-deficient mice, showed reduced incidence of diabetes, less insulitis, lower hyperglycemia, and normal insulin levels compared to wild-type (WT) diabetic mice. Notably, these mice also displayed a decrease in IL-17-producing CD4 and CD8 T cells (Th17 and Tc17) and IFN-γ-producing CD4 and CD8 T cells (Th1 and Tc1) in the PLNs. Following STZ treatment to induce T1D, NLRP3-deficient mice also exhibited an increase in myeloid-derived suppressor cell and mast cell numbers in the PLNs along with a significant increase in IL-6, IL-10, and IL-4 expression in the pancreatic tissue. Interestingly, diabetic mice revealed increased circulating expression of genes related to mitochondrial DNA, such as cytochrome b and cytochrome c, but not NADH dehydrogenase subunit 6 (NADH). Mitochondrial DNA (mDNA) from diabetic mice, but not from non-diabetic mice, induced significant IL-1β production and caspase-1 activation by WT macrophages, which was reduced in NLRP3-/- macrophages. Finally, mDNA administration in vivo increased Th17/Tc17/Th1/Tc1 cells in the PLNs and precipitated T1D onset, which was abolished in NLRP3-/- mice. Overall, our results demonstrate that mDNA-mediated NLRP3 activation triggers caspase-1-dependent IL-1β production and contributes to pathogenic cellular responses during the development of STZ-induced T1D.
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Affiliation(s)
- Daniela Carlos
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo , Ribeirao Preto , Brazil
| | - Frederico R C Costa
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo , Ribeirao Preto , Brazil
| | - Camila A Pereira
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo , Ribeirao Preto , Brazil
| | - Fernanda A Rocha
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo , Ribeirao Preto , Brazil
| | - Juliana N U Yaochite
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo , Ribeirao Preto , Brazil
| | - Gabriela G Oliveira
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo , Ribeirao Preto , Brazil
| | - Fernando S Carneiro
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo , Ribeirao Preto , Brazil
| | - Rita C Tostes
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo , Ribeirao Preto , Brazil
| | - Simone G Ramos
- Department of Pathology and Legal Medicine, Ribeirão Preto Medical School, University of São Paulo , Ribeirao Preto , Brazil
| | - Dario S Zamboni
- Department of Molecular and Cell Biology, Ribeirão Preto Medical School, University of São Paulo , Ribeirao Preto , Brazil
| | - Niels O S Camara
- Department of Immunology, Institute of Biomedical Sciences (ICB), University of São Paulo , São Paulo , Brazil
| | - Bernhard Ryffel
- University of Orleans and CNRS, INEM, Molecular Immunology, UMR6218, Orleans, France; IDM, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - João S Silva
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo , Ribeirao Preto , Brazil
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Muthuraj MSA, Janakiram S, Chithresan K, Maradi AP, Maddur PK, Rangaraju R. Effect of scaling and root planing on levels of 8-hydroxydeoxyguanosine in gingival crevicular fluid of chronic periodontitis patients with and without Type II diabetes mellitus. J Indian Soc Periodontol 2017; 21:201-206. [PMID: 29440786 PMCID: PMC5803875 DOI: 10.4103/jisp.jisp_184_17] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Context: Chronic periodontitis (CP) and diabetes mellitus are associated with increased oxidative damage to DNA with formation of 8-hydroxydeoxyguanosine (8-OHdG). The aim of this study was to evaluate the change in gingival crevicular fluid (GCF) levels of 8-OHdG and glycosylated hemoglobin (HbA1c) by 3 months after scaling and root planing (SRP), in CP patients with and without Type II diabetes mellitus. Settings and Design: Sixteen patients with CP, 16 patients with CP and Type II diabetes mellitus (CP-D), and 16 systemically healthy individuals with clinically healthy periodontium who served as controls were included in the study. Materials and Methods: The clinical parameters (plaque index [PI], probing depth [PD], clinical attachment level [CAL], and bleeding on probing [BOP%]), HbA1c levels, and GCF 8-OHdG levels were measured at baseline. All the patients except controls were treated with SRP followed by evaluation of the above-mentioned clinical and biochemical parameters after 3 months. Statistical Analysis Used: Statistical analysis was performed using paired t-test, independent t-test, and Mann–Whitney U-test. Results: After SRP, CP-D group showed a greater reduction in PI, PD, BOP%, and greater gain in CAL when compared to CP patients (P < 0.05). Levels of 8-OHdG and HbA1c in CP-D patients also showed a greater reduction, 3 months after SRP when compared to CP patients (P < 0.05). Conclusions: GCF 8-OHdG levels, HbA1c levels, and clinical parameters were reduced significantly in CP and CP-D patients, with maximum reduction achieved in CP-D patients 3 months after SRP.
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Affiliation(s)
| | - Srihari Janakiram
- Department of Periodontics and Implantology, Sri Ramakrishna Dental College, Coimbatore, Tamil Nadu, India
| | - Koshy Chithresan
- Department of Periodontics and Implantology, Sri Ramakrishna Dental College, Coimbatore, Tamil Nadu, India
| | - Arun Parappa Maradi
- Department of Periodontics and Implantology, Sri Ramakrishna Dental College, Coimbatore, Tamil Nadu, India
| | - Praveen Krishna Maddur
- Department of Periodontics and Implantology, Sri Ramakrishna Dental College, Coimbatore, Tamil Nadu, India
| | - Rajesh Rangaraju
- Department of Periodontics and Implantology, Sri Ramakrishna Dental College, Coimbatore, Tamil Nadu, India
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Pan CW, Qian DJ, Sun HP, Ma Q, Xu Y, Song E. Visual Impairment among Older Adults in a Rural Community in Eastern China. J Ophthalmol 2016; 2016:9620542. [PMID: 27777793 PMCID: PMC5061962 DOI: 10.1155/2016/9620542] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 07/20/2016] [Indexed: 02/06/2023] Open
Abstract
Purpose. To determine the prevalence, causes, and associations of visual impairment (VI) among participants aged 60 years or older in a rural community in China. Methods. A community-based survey was undertaken in a rural town located in Eastern China and 4579 people aged 60 years or older participated in the study. Presenting visual acuity was assessed using a Snellen chart with tumbling-E optotypes and anterior segment was examined using a slit-lamp. VI was defined as presenting VA <6/18 and it included moderate VI (<6/18 to 6/60) and blindness (<6/60). Results. The prevalence of VI was 5.4% (95% confidence interval [CI] 4.7-6.0). In multivariate analysis, the presence of VI was positively associated with increasing age (odds ratio [OR] = 1.12, 95% CI 1.10-1.16, per year increase), female gender (OR = 2.33, 95% CI 1.53-3.55), the presence of hypertension (OR = 1.31, 95% CI 1.001-1.85), living alone (OR = 1.52, 95% CI 1.08-2.62), and increased sleeping hours (OR = 1.10, 95% CI 1.001-1.22). Drinking 3 or more glasses of green tea per day was inversely associated with VI (OR = 0.79, 95% CI 0.63-0.98). Conclusion. VI was less prevalent in this community compared with previous report in other areas in China.
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Affiliation(s)
- Chen-Wei Pan
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - Deng-Juan Qian
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - Hong-Peng Sun
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - Qinghua Ma
- The 3rd People's Hospital of Xiangcheng District, Suzhou 215134, China
| | - Yong Xu
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - E. Song
- Lixiang Eye Hospital of Soochow University, Suzhou 215021, China
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun 130021, China
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Lin CH, Chang YC, Chuang LM. Early detection of diabetic kidney disease: Present limitations and future perspectives. World J Diabetes 2016; 7:290-301. [PMID: 27525056 PMCID: PMC4958689 DOI: 10.4239/wjd.v7.i14.290] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/29/2016] [Accepted: 06/29/2016] [Indexed: 02/05/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the most common diabetic complications, as well as the leading cause of chronic kidney disease and end-stage renal disease around the world. To prevent the dreadful consequence, development of new assays for diagnostic of DKD has always been the priority in the research field of diabetic complications. At present, urinary albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR) are the standard methods for assessing glomerular damage and renal function changes in clinical practice. However, due to diverse tissue involvement in different individuals, the so-called “non-albuminuric renal impairment” is not uncommon, especially in patients with type 2 diabetes. On the other hand, the precision of creatinine-based GFR estimates is limited in hyperfiltration status. These facts make albuminuria and eGFR less reliable indicators for early-stage DKD. In recent years, considerable progress has been made in the understanding of the pathogenesis of DKD, along with the elucidation of its genetic profiles and phenotypic expression of different molecules. With the help of ever-evolving technologies, it has gradually become plausible to apply the thriving information in clinical practice. The strength and weakness of several novel biomarkers, genomic, proteomic and metabolomic signatures in assisting the early diagnosis of DKD will be discussed in this article.
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Fujihara R, Chiba Y, Nakagawa T, Nishi N, Murakami R, Matsumoto K, Kawauchi M, Yamamoto T, Ueno M. Albumin microvascular leakage in brains with diabetes mellitus. Microsc Res Tech 2016; 79:833-7. [PMID: 27333535 DOI: 10.1002/jemt.22708] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 05/20/2016] [Accepted: 06/03/2016] [Indexed: 11/09/2022]
Abstract
Their aim was to examine whether microvascular leakage of endogenous albumin, a representative marker for blood-brain barrier (BBB) damage, was induced in the periventricular area of diabetic db/db mice because periventricular white matter hyperintensity formation in magnetic resonance images was accelerating in elderly patients with diabetes mellitus. Using light and electron microscopes, and semi-quantitative analysis techniques, immunoreactivity of endogenous albumin, indicating vascular permeability, was examined in the periventricular area and spinal cord of db/db mice and db/+m control mice. Greater immunoreactivity of albumin was observed in the vessel wall of the periventricular area of db/db mice than in controls. Additionally, weak immunoreactivity was observed in the spinal cord of both db/db mice and controls. The number of gold particles, indicating immunoreactivity of albumin, in the perivascular area of db/db mice was significantly higher than that of control mice, but there was no significant difference in the number of particles in the spinal cord between db/db mice and controls. These findings suggest that albumin microvascular leakage, or BBB breakdown, is induced in the periventricular area of diabetic mice. Microsc. Res. Tech. 79:833-837, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ryuji Fujihara
- Department of Pathology and Host Defense, , Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan.,Department of Orthopaedic Surgery, Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan
| | - Yoichi Chiba
- Department of Pathology and Host Defense, , Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan
| | - Toshitaka Nakagawa
- Life Science Research Center, Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan
| | - Nozomu Nishi
- Life Science Research Center, Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan
| | - Ryuta Murakami
- Department of Pathology and Host Defense, , Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan
| | - Koichi Matsumoto
- Department of Pathology and Host Defense, , Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan
| | - Machi Kawauchi
- Department of Pathology and Host Defense, , Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan
| | - Tetsuji Yamamoto
- Department of Orthopaedic Surgery, Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan
| | - Masaki Ueno
- Department of Pathology and Host Defense, , Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan
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Kloppenborg JT, Fonvig CE, Johannesen J, Bjerrum PJ, Poulsen HE, Holm JC. Urinary markers of nucleic acid oxidation in Danish overweight/obese children and youths. Free Radic Res 2016; 50:691-7. [PMID: 26982114 DOI: 10.3109/10715762.2016.1164310] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Urinary excretion of the RNA and DNA oxidation markers, 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in newly diagnosed adult type 2 diabetics are reported to be long-term predictors of mortality independent of conventional risk factors. In the current study, we investigated the relationships between urinary markers of nucleic acid oxidation concentrations and the degree of obesity and glucose metabolism in overweight compared to lean children. Forty-two (24 girls) overweight and 35 lean (19 girls) children and adolescents were recruited from the Registry of the Danish Childhood Obesity Biobank. Anthropometric measurements were collected at baseline and glucose metabolism was assessed by an oral glucose tolerance test. A urine sample was obtained during the test. Linear regression did not demonstrate any associations between the urinary markers and the degree of obesity or glucose metabolism in lean and obese children. However, sub-analyses adjusted for age, sex, and the degree of obesity showed positive associations between the 2 h glucose and the urinary markers, 8-oxoGuo (p = 0.02, r(2)= 0.63) and 8-oxodG (p = 0.046, r(2)= 0.48), and between the insulinogenic index and 8-oxoGuo (p = 0.03, r(2 )=( )0.60) in the 12 obese children exhibiting impaired glucose tolerance. Excretion of the urinary markers of nucleic acid oxidation and the degree of obesity or the glucose metabolism were not associated in this study. Nevertheless, obese children with impaired glucose tolerance seem to exhibiting an increased oxidative stress level, but due to the small sample size in this study, further investigations are required to elucidate this correlation.
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Affiliation(s)
- Julie Tonsgaard Kloppenborg
- a Department of Pediatrics, The Children's Obesity Clinic , Copenhagen University Hospital Holbæk , Holbæk , Denmark ;,b Department of Pediatrics , Copenhagen University Hospital Herlev , Herlev , Denmark
| | - Cilius Esmann Fonvig
- a Department of Pediatrics, The Children's Obesity Clinic , Copenhagen University Hospital Holbæk , Holbæk , Denmark ;,c The Novo Nordisk Foundation Center for Basic Metabolic Research , University of Copenhagen , Copenhagen , Denmark
| | - Jesper Johannesen
- b Department of Pediatrics , Copenhagen University Hospital Herlev , Herlev , Denmark ;,d Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
| | - Poul Jannik Bjerrum
- e Department of Clinical Biochemistry , Copenhagen University Hospital Holbæk , Holbæk , Denmark
| | - Henrik Enghusen Poulsen
- d Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark ;,f Laboratory of Clinical Pharmacology , Rigshospitalet , Copenhagen , Denmark ;,g Department of Clinical Pharmacology , Bispebjerg Hospital , Copenhagen , Denmark
| | - Jens-Christian Holm
- a Department of Pediatrics, The Children's Obesity Clinic , Copenhagen University Hospital Holbæk , Holbæk , Denmark ;,c The Novo Nordisk Foundation Center for Basic Metabolic Research , University of Copenhagen , Copenhagen , Denmark ;,d Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
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Lee SC, Chan JCN. Evidence for DNA damage as a biological link between diabetes and cancer. Chin Med J (Engl) 2016; 128:1543-8. [PMID: 26021514 PMCID: PMC4733759 DOI: 10.4103/0366-6999.157693] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Objective: This review examines the evidence that: Diabetes is a state of DNA damage; pathophysiological factors in diabetes can cause DNA damage; DNA damage can cause mutations; and DNA mutation is linked to carcinogenesis. Data Sources: We retrieved information from the PubMed database up to January, 2014, using various search terms and their combinations including DNA damage, diabetes, cancer, high glucose, hyperglycemia, free fatty acids, palmitic acid, advanced glycation end products, mutation and carcinogenesis. Study Selection: We included data from peer-reviewed journals and a textbook printed in English on relationships between DNA damage and diabetes as well as pathophysiological factors in diabetes. Publications on relationships among DNA damage, mutagenesis, and carcinogenesis, were also reviewed. We organized this information into a conceptual framework to explain the possible causal relationship between DNA damage and carcinogenesis in diabetes. Results: There are a large amount of data supporting the view that DNA mutation is a typical feature in carcinogenesis. Patients with type 2 diabetes have increased production of reactive oxygen species, reduced levels of antioxidant capacity, and increased levels of DNA damage. The pathophysiological factors and metabolic milieu in diabetes can cause DNA damage such as DNA strand break and base modification (i.e., oxidation). Emerging experimental data suggest that signal pathways (i.e., Akt/tuberin) link diabetes to DNA damage. This collective evidence indicates that diabetes is a pathophysiological state of oxidative stress and DNA damage which can lead to various types of mutation to cause aberration in cells and thereby increased cancer risk. Conclusions: This review highlights the interrelationships amongst diabetes, DNA damage, DNA mutation and carcinogenesis, which suggests that DNA damage can be a biological link between diabetes and cancer.
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Affiliation(s)
- Shao Chin Lee
- Department of Biological Sciences, School of Life Sciences, Shanxi University, Taiyuan, Shanxi 030006, China
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Novel carbocyclic nucleoside analogs suppress glomerular mesangial cells proliferation and matrix protein accumulation through ROS-dependent mechanism in the diabetic milieu. II. Acylhydrazone-functionalized pyrimidines. Bioorg Med Chem Lett 2016; 26:1020-1024. [DOI: 10.1016/j.bmcl.2015.12.042] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 12/06/2015] [Accepted: 12/11/2015] [Indexed: 11/19/2022]
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Ma Q, Chen D, Sun HP, Yan N, Xu Y, Pan CW. Regular Chinese Green Tea Consumption is Protective for Diabetic Retinopathy: A Clinic-Based Case-Control Study. J Diabetes Res 2015; 2015:231570. [PMID: 26539551 PMCID: PMC4619946 DOI: 10.1155/2015/231570] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 01/20/2015] [Accepted: 02/08/2015] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE To determine the association between regular Chinese green tea consumption and the risk of diabetic retinopathy (DR) in diabetic patients in China. METHODS 100 DR patients and 100 age-sex-matched diabetic controls without retinopathy were recruited in a clinic-based, case-control study. DR was defined from retinal photographs and detailed information on Chinese green tea consumption of the participants was collected through a face-to-face interview. RESULTS The crude odds ratio [OR] of Chinese green tea consumption for DR was 0.49 (95% confidence interval: 0.26-0.90). When stratified by sex, the protective effect of Chinese green tea consumption on DR was statistically significant in women (P = 0.01) but not in men (P = 0.63). After adjusting for age, sex, and other confounders, DR was significantly associated with Chinese green tea consumption (OR = 0.48; P = 0.04), higher systolic blood pressure (OR = 1.02; P = 0.05), longer duration of diabetes (OR = 1.07; P = 0.02), and the presence of family history of diabetes (OR = 2.35; P = 0.04). CONCLUSIONS Diabetic patients who had regularly drunk Chinese green tea every week for at least one year in their lives had a DR risk reduction of about 50% compared with those who had not. Regular Chinese green tea consumption may be a novel approach for the prevention of DR.
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Affiliation(s)
- Qinghua Ma
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
- The 3rd People's Hospital of Xiangcheng District, Suzhou 215134, China
| | - Dandan Chen
- School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou 215123, China
- Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, China
| | - Hong-Peng Sun
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - Ning Yan
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - Yong Xu
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - Chen-Wei Pan
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
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Ahmadi A, Behmanesh M, Boroumand MA, Tavallaei M. Up-regulation of MSH2, XRCC1 and ATM genes in patients with type 2 diabetes and coronary artery disease. Diabetes Res Clin Pract 2015; 109:500-6. [PMID: 26088318 DOI: 10.1016/j.diabres.2015.05.049] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2015] [Revised: 05/05/2015] [Accepted: 05/28/2015] [Indexed: 11/23/2022]
Abstract
AIMS Coronary artery disease (CAD) is a major problem in some patients with type 2 diabetes mellitus (T2DM). CAD has been suggested to be the main result of reduced efficacy of DNA repair systems. Analysis of the DNA repair system in patients with diabetes can potentially uncover the molecular basis of their susceptibility to the CAD. The aim of the present study was to compare the expression levels of some important DNA repair genes, including ATM, XRCC1 and MSH2, in CAD+ versus CAD- patients with T2DM. Furthermore, the relevance of putative single nucleotide polymorphisms (SNPs) in the promoter regions of these genes with mRNA expression was evaluated. METHODS Expression analysis was performed by RT-qPCR on 76 patients with T2DM (41 CAD+ and 35 CAD- individuals confirmed by angiography). The genotypes of the patients were examined by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS Significant up-regulation of the MSH2 (2.49-fold, P=0.001), XRCC1 (2.11-fold, P=0.001) and ATM (2.15-fold, P=0.003) genes was observed in patients with T2DM and CAD. We could not detect any function for SNPs by comparing gene expression. In a receiver operating characteristic (ROC) curve analysis, the area under the ROC curve for sum of relative expressions of all genes reached 0.81 (95% CI: 0.690-0.936, P=0.003), which indicates a potential biomarker for identifying patients with T2DM and CAD. CONCLUSION These results suggest that expression levels of DNA repair genes may serve as informative biomarkers for identifying patients with T2DM and CAD.
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Affiliation(s)
- Amirhossein Ahmadi
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, P.O. Box 14115-154, Tehran, Iran
| | - Mehrdad Behmanesh
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, P.O. Box 14115-154, Tehran, Iran.
| | - Mohammad Ali Boroumand
- Department of Pathology, Tehran Heart Center, Tehran University of Medical Sciences, P.O. Box 1411713138, Tehran, Iran
| | - Mahmoud Tavallaei
- Human Genetics Research Center, Baqiyatallah Medical Sciences University, Tehran, Iran
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Gorin Y, Wauquier F. Upstream regulators and downstream effectors of NADPH oxidases as novel therapeutic targets for diabetic kidney disease. Mol Cells 2015; 38:285-96. [PMID: 25824546 PMCID: PMC4400302 DOI: 10.14348/molcells.2015.0010] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 01/12/2015] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress has been linked to the pathogenesis of diabetic nephropathy, the complication of diabetes in the kidney. NADPH oxidases of the Nox family, and in particular the homologue Nox4, are a major source of reactive oxygen species in the diabetic kidney and are critical mediators of redox signaling in glomerular and tubulointerstitial cells exposed to the diabetic milieu. Here, we present an overview of the current knowledge related to the understanding of the role of Nox enzymes in the processes that control mesangial cell, podocyte and tubulointerstitial cell injury induced by hyperglycemia and other predominant factors enhanced in the diabetic milieu, including the renin-angiotensin system and transforming growth factor-β. The nature of the upstream modulators of Nox enzymes as well as the downstream targets of the Nox NADPH oxidases implicated in the propagation of the redox processes that alter renal biology in diabetes will be highlighted.
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Affiliation(s)
- Yves Gorin
- Department of Medicine, University of Texas Health Science Center, San Antonio, Texas,
USA
| | - Fabien Wauquier
- Department of Medicine, University of Texas Health Science Center, San Antonio, Texas,
USA
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Prasad M, Bronson SC, Warrier T, Badarinath A, Rai S, Baid K, Sitaraman S, George A, Moses A, Saraswathy R, Vasuki R, Shanmugam A. Evaluation of DNA damage in Type 2 diabetes mellitus patients with and without peripheral neuropathy: A study in South Indian population. J Nat Sci Biol Med 2015; 6:80-4. [PMID: 25810640 PMCID: PMC4367074 DOI: 10.4103/0976-9668.149096] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background: The increasing incidence of Type 2 diabetes mellitus globally has collaterally increased the incidence of diabetes-associated complications such as neuropathy. Oxidative stress induced DNA damage is one of the mechanisms implicated in the pathogenesis of diabetic complications. Here we aimed to evaluate the extent of DNA damage in diabetes patients with and without clinical neuropathy using the Cytokinesis Block Micronucleus Cytome assay, in a group of South Indian population. Materials and Methods: The Cytokinesis Block Micronucleus Cytome assay was performed in lymphocyte cultures of 42 type 2 diabetes patients (22 with neuropathy and 20 without neuropathy) and 42 age and sex matched controls. Nuclear aberrations like Nuclear Buds, Nucleoplasmic Bridges and Micronuclei were analyzed. Results: The frequency of nuclear aberrations in diabetes patients with neuropathy was higher than compared to diabetes patients without neuropathy. The mean frequencies of nuclear aberrations per cell in diabetes patients with neuropathy and without neuropathy were 0.02 ± 0.02 and 0.01 ± 0.01, respectively. This was significantly higher than in the controls (0.002 ± 0.002) (P < 0.0001). An increasing trend of nuclear aberrations in correlation with the duration of diabetes was observed. Conclusion: This study highlights the use of the Cytokinesis Block Micronucleus Cytome assay as a potent tool for the identification of DNA damage, which may prove to be useful biomarker to assess the severity diabetes-associated complications such as neuropathy. Implementation of this technique at the clinical level would potentially enhance the quality of management of patients with diabetes and its complications like neuropathy.
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Affiliation(s)
- Mukul Prasad
- Biomedical Genetics Research Lab, Division of Biomolecules and Genetics, School of Bio Sciences and Technology, VIT University, Vellore, India
| | - Stephen Charles Bronson
- Institute of Diabetology, Madras Medical College & Rajiv Gandhi Government General Hospital, Chennai, Tamil Nadu, India
| | - Tushar Warrier
- Biomedical Genetics Research Lab, Division of Biomolecules and Genetics, School of Bio Sciences and Technology, VIT University, Vellore, India
| | - Agnihotram Badarinath
- Biomedical Genetics Research Lab, Division of Biomolecules and Genetics, School of Bio Sciences and Technology, VIT University, Vellore, India
| | - Shivam Rai
- Biomedical Genetics Research Lab, Division of Biomolecules and Genetics, School of Bio Sciences and Technology, VIT University, Vellore, India
| | - Kaushal Baid
- Biomedical Genetics Research Lab, Division of Biomolecules and Genetics, School of Bio Sciences and Technology, VIT University, Vellore, India
| | - Sneha Sitaraman
- Biomedical Genetics Research Lab, Division of Biomolecules and Genetics, School of Bio Sciences and Technology, VIT University, Vellore, India
| | - Alex George
- Biomedical Genetics Research Lab, Division of Biomolecules and Genetics, School of Bio Sciences and Technology, VIT University, Vellore, India
| | - Anand Moses
- Institute of Diabetology, Madras Medical College & Rajiv Gandhi Government General Hospital, Chennai, Tamil Nadu, India
| | - Radha Saraswathy
- Biomedical Genetics Research Lab, Division of Biomolecules and Genetics, School of Bio Sciences and Technology, VIT University, Vellore, India
| | - Ranganathan Vasuki
- Institute of Diabetology, Madras Medical College & Rajiv Gandhi Government General Hospital, Chennai, Tamil Nadu, India
| | - Alagianambi Shanmugam
- Institute of Diabetology, Madras Medical College & Rajiv Gandhi Government General Hospital, Chennai, Tamil Nadu, India
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Waris S, Winklhofer-Roob BM, Roob JM, Fuchs S, Sourij H, Rabbani N, Thornalley PJ. Increased DNA dicarbonyl glycation and oxidation markers in patients with type 2 diabetes and link to diabetic nephropathy. J Diabetes Res 2015; 2015:915486. [PMID: 25950009 PMCID: PMC4408631 DOI: 10.1155/2015/915486] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2015] [Revised: 03/14/2015] [Accepted: 03/23/2015] [Indexed: 02/07/2023] Open
Abstract
AIM The aim of this study was to assess the changes of markers of DNA damage by glycation and oxidation in patients with type 2 diabetes and the association with diabetic nephropathy. METHODOLOGY DNA oxidation and glycation adducts were analysed in plasma and urine by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. DNA markers analysed were as follows: the oxidation adduct 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-OxodG) and glycation adducts of glyoxal and methylglyoxal--imidazopurinones GdG, MGdG, and N2-(1,R/S-carboxyethyl)deoxyguanosine (CEdG). RESULTS Plasma 8-OxodG and GdG were increased 2-fold and 6-fold, respectively, in patients with type 2 diabetes, with respect to healthy volunteers. Median urinary excretion rates of 8-OxodG, GdG, MGdG, and CEdG were increased 28-fold, 10-fold, 2-fold, and 2-fold, respectively, in patients with type 2 diabetes with respect to healthy controls. In patients with type 2 diabetes, nephropathy was associated with increased plasma 8-OxodG and increased urinary GdG and CEdG. In a multiple logistic regression model for diabetic nephropathy, diabetic nephropathy was linked to systolic blood pressure and urinary CEdG. CONCLUSION DNA oxidative and glycation damage-derived nucleoside adducts are increased in plasma and urine of patients with type 2 diabetes and further increased in patients with diabetic nephropathy.
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Affiliation(s)
- Sahar Waris
- Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry CV2 2DX, UK
| | - Brigitte M. Winklhofer-Roob
- Human Nutrition & Metabolism Research and Training Center Graz, Institute of Molecular Biosciences, Karl Franzens University, 8010 Graz, Austria
| | - Johannes M. Roob
- Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Sebastian Fuchs
- Human Nutrition & Metabolism Research and Training Center Graz, Institute of Molecular Biosciences, Karl Franzens University, 8010 Graz, Austria
| | - Harald Sourij
- Clinical Division of Endocrinology and Nuclear Medicine, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Naila Rabbani
- Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry CV2 2DX, UK
- Warwick Systems Biology Centre, Senate House, University of Warwick, Coventry CV4 7AL, UK
- *Naila Rabbani:
| | - Paul J. Thornalley
- Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry CV2 2DX, UK
- Warwick Systems Biology Centre, Senate House, University of Warwick, Coventry CV4 7AL, UK
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Currie G, McKay G, Delles C. Biomarkers in diabetic nephropathy: Present and future. World J Diabetes 2014; 5:763-776. [PMID: 25512779 PMCID: PMC4265863 DOI: 10.4239/wjd.v5.i6.763] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 10/03/2014] [Accepted: 10/27/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetic nephropathy (DN) is the leading cause of end stage renal disease in the Western world. Microalbuminuria (MA) is the earliest and most commonly used clinical index of DN and is independently associated with cardiovascular risk in diabetic patients. Although MA remains an essential tool for risk stratification and monitoring disease progression in DN, a number of factors have called into question its predictive power. Originally thought to be predictive of future overt DN in 80% of patients, we now know that only around 30% of microalbuminuric patients progress to overt nephropathy after 10 years of follow up. In addition, advanced structural alterations in the glomerular basement membrane may already have occurred by the time MA is clinically detectable.Evidence in recent years suggests that a significant proportion of patients with MA can revert to normoalbuminuria and the concept of nonalbuminuric DN is well-documented, reflecting the fact that patients with diabetes can demonstrate a reduction in glomerular filtration rate without progressing from normo-to MA. There is an unmet clinical need to identify biomarkers with potential for earlier diagnosis and risk stratification in DN and recent developments in this field will be the focus of this review article.
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Milic M, Frustaci A, Del Bufalo A, Sánchez-Alarcón J, Valencia-Quintana R, Russo P, Bonassi S. DNA damage in non-communicable diseases: A clinical and epidemiological perspective. Mutat Res 2014; 776:118-27. [PMID: 26255943 DOI: 10.1016/j.mrfmmm.2014.11.009] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 11/28/2014] [Accepted: 11/30/2014] [Indexed: 02/02/2023]
Abstract
Non-communicable diseases (NCDs) are a leading cause of death and disability, representing 63% of the total death number worldwide. A characteristic phenotype of these diseases is the accelerated aging, which is the result of phenomena such as accumulated DNA damage, telomere capping loss and subcellular irreversible/nonrepaired oxidative damage. DNA damage, mostly oxidative, plays a key role in the development of most common NCDs. The present review will gather some of the most relevant knowledge concerning the presence of DNA damage in NCDs focusing on cardiovascular diseases, diabetes, chronic obstructive pulmonary disease, and neurodegenerative disorders, and discussing a selection of papers from the most informative literature. The challenge of comorbidity and the potential offered by new systems approaches for introducing these biomarkers into the clinical decision process will be discussed. Systems Medicine platforms represent the most suitable approach to personalized medicine, enabling to identify new patterns in the pathogenesis, diagnosis and prognosis of chronic diseases.
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Affiliation(s)
- Mirta Milic
- IRCCS San Raffaele Pisana, Area of Clinical and Molecular Epidemiology, 00166 Rome, Italy; Institute for Medical Research and Occupational Health, Mutagenesis Unit, 10 000 Zagreb, Croatia
| | - Alessandra Frustaci
- IRCCS San Raffaele Pisana, Area of Clinical and Molecular Epidemiology, 00166 Rome, Italy
| | - Alessandra Del Bufalo
- IRCCS San Raffaele Pisana, Area of Clinical and Molecular Epidemiology, 00166 Rome, Italy
| | - Juana Sánchez-Alarcón
- Universidad Autónoma de Tlaxcala, Facultad de Agrobiología, Evaluación de Riesgos Ambientales, 90062 Tlaxcala, Mexico
| | - Rafael Valencia-Quintana
- Universidad Autónoma de Tlaxcala, Facultad de Agrobiología, Evaluación de Riesgos Ambientales, 90062 Tlaxcala, Mexico
| | - Patrizia Russo
- IRCCS San Raffaele Pisana, Area of Clinical and Molecular Epidemiology, 00166 Rome, Italy
| | - Stefano Bonassi
- IRCCS San Raffaele Pisana, Area of Clinical and Molecular Epidemiology, 00166 Rome, Italy.
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Lin KY, Kwong GA, Warren AD, Wood DK, Bhatia SN. Nanoparticles that sense thrombin activity as synthetic urinary biomarkers of thrombosis. ACS NANO 2013; 7:9001-9. [PMID: 24015809 PMCID: PMC3807694 DOI: 10.1021/nn403550c] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Abstract
Thrombin is a serine protease and regulator of hemostasis that plays a critical role in the formation of obstructive blood clots, or thrombosis, that is a life-threatening condition associated with numerous diseases such as atherosclerosis and stroke. To detect thrombi in living animals, we design and conjugate thrombin-sensitive peptide substrates to the surface of nanoparticles. Following intravenous infusion, these "synthetic biomarkers" survey the host vasculature for coagulation and, in response to substrate cleavage by thrombin, release ligand-encoded reporters into the host urine. To detect the urinary reporters, we develop a companion 96-well immunoassay that utilizes antibodies to bind specifically to the ligands, thus capturing the reporters for quantification. Using a thromboplastin-induced mouse model of pulmonary embolism, we show that urinary biomarker levels differentiate between healthy and thrombotic states and correlate closely with the aggregate burden of clots formed in the lungs. Our results demonstrate that synthetic biomarkers can be engineered to sense vascular diseases remotely from the urine and may allow applications in point-of-care diagnostics.
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Affiliation(s)
- Kevin Y. Lin
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Gabriel A. Kwong
- Harvard−MIT Division of Heath Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Andrew D. Warren
- Harvard−MIT Division of Heath Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - David K. Wood
- Harvard−MIT Division of Heath Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Sangeeta N. Bhatia
- Harvard−MIT Division of Heath Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Electrical Engineering and Computer Science, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02139, United States
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115, United States
- Howard Hughes Medical Institute, Cambridge, Massachusetts 02139, United States
- Address correspondence to
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