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Macan TP, Magenis ML, Damiani AP, Monteiro IDO, Silveira GDB, Zaccaron RP, Silveira PCL, Teixeira JPF, Gajski G, Andrade VMD. Brazil nut consumption reduces DNA damage in overweight type 2 diabetes mellitus patients. MUTATION RESEARCH. GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2024; 895:503739. [PMID: 38575248 DOI: 10.1016/j.mrgentox.2024.503739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 02/15/2024] [Accepted: 02/22/2024] [Indexed: 04/06/2024]
Abstract
Type 2 diabetes mellitus (T2D) is a metabolic disease, which occurs largely due to unhealthy lifestyle. As oxidative stress is believed to promote T2D, by inducing damage to lipids, proteins, and DNA, appropriate dietary interventions seem critical to prevent, manage, and even reverse this condition. Brazil nuts (Bertholletia excelsa, H.B.K.) are nature's richest source of selenium, a mineral that has shown several health benefits. Therefore, this study aims to assess the effects of selenium consumption, through Brazil nuts, on biochemical and oxidative stress parameters, and genomic instability in T2D patients. We recruited 133 patients with T2D, registered in the Integrated Clinics of the University of Southern Santa Catarina (Brazil). Participants consumed one Brazil nut a day for six months. Blood samples and exfoliated buccal cells were collected at the beginning and the end of the intervention. The glycemic profile, lipid profile, renal profile and hepatic profile, DNA damage and selenium content were evaluated. A total of 74 participants completed the intervention. Brazil nut consumption increased selenium and GSH levels, GPx, and CAT activity while DCF and nitrites levels decreased. Total thiols increased, and protein carbonyl and MDA levels decreased. Levels of baseline and oxidative DNA damage in T2D patients were significantly decreased, as well as the frequency of micronuclei and nuclear buds. The fasting glucose levels, HDL and LDL cholesterol, and GGT levels that increased significantly in patients with type 2 diabetes were significantly reduced with nut consumption. Our results show an increase in antioxidant activity, along with reductions of protein and lipid oxidation as well as DNA damage, suggesting that Brazil nut consumption could be an ally in reducing oxidative stress and modulating the genomic instability in T2D patients.
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Affiliation(s)
- Tamires Pavei Macan
- Laboratory of Translational Biomedicine, Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Criciúma, SC, Brazil; Environmental Health Department, Portuguese National Institute of Health Dr. Ricardo Jorge, Porto, Portugal
| | - Marina Lummertz Magenis
- Laboratory of Translational Biomedicine, Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Criciúma, SC, Brazil
| | - Adriani Paganini Damiani
- Laboratory of Translational Biomedicine, Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Criciúma, SC, Brazil
| | - Isadora de Oliveira Monteiro
- Laboratory of Translational Biomedicine, Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Criciúma, SC, Brazil
| | - Gustavo De Bem Silveira
- Laboratory of Experimental Physiopathology, Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Criciúma, SC, Brazil
| | - Rubya Pereira Zaccaron
- Laboratory of Experimental Physiopathology, Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Criciúma, SC, Brazil
| | - Paulo Cesar Lock Silveira
- Laboratory of Experimental Physiopathology, Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Criciúma, SC, Brazil
| | | | - Goran Gajski
- Mutagenesis Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | - Vanessa Moraes de Andrade
- Laboratory of Translational Biomedicine, Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Criciúma, SC, Brazil.
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Goriuc A, Cojocaru KA, Luchian I, Ursu RG, Butnaru O, Foia L. Using 8-Hydroxy-2'-Deoxiguanosine (8-OHdG) as a Reliable Biomarker for Assessing Periodontal Disease Associated with Diabetes. Int J Mol Sci 2024; 25:1425. [PMID: 38338704 PMCID: PMC10855048 DOI: 10.3390/ijms25031425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/20/2024] [Accepted: 01/22/2024] [Indexed: 02/12/2024] Open
Abstract
In recent years, research has shown that oxidative stress plays a significant role in chronic inflammatory conditions. The alteration of the oxidant/antioxidant balance leads to the appearance of free radicals, important molecules involved in both diabetes mellitus and periodontal disease. Diabetes is considered to be one of the major risk factors of periodontal disease and the inflammation characterizing this condition is associated with oxidative stress, implicitly resulting in oxidative damage to DNA. 8-Hydroxydeoxyguanosine (8-OHdG) is the most common stable product of oxidative DNA damage caused by reactive oxygen species, and its levels have been reported to increase in body fluids and tissues during inflammatory conditions. 8-OHdG emerges as a pivotal biomarker for assessing oxidative DNA damage, demonstrating its relevance across diverse health conditions, including neurodegenerative disorders, cancers, inflammatory conditions, and periodontal disease. Continued research in this field is crucial for developing more precise treatments and understanding the detailed link between oxidative stress and the progression of periodontitis. The use of the 8-OHdG biomarker in assessing and managing chronic periodontitis is an area of increased interest in dental research, with the potential to provide crucial information for diagnosis and treatment.
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Affiliation(s)
- Ancuta Goriuc
- Department of Biochemistry, Faculty of Dental Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iasi, Romania; (A.G.); (K.-A.C.); (L.F.)
| | - Karina-Alexandra Cojocaru
- Department of Biochemistry, Faculty of Dental Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iasi, Romania; (A.G.); (K.-A.C.); (L.F.)
| | - Ionut Luchian
- Department of Periodontology, Faculty of Dental Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iasi, Romania
| | - Ramona-Garbriela Ursu
- Department of Preventive Medicine and Interdisciplinarity (IX)—Microbiology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Oana Butnaru
- Department of Biophysics, Faculty of Dental Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iasi, Romania;
| | - Liliana Foia
- Department of Biochemistry, Faculty of Dental Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iasi, Romania; (A.G.); (K.-A.C.); (L.F.)
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Krawczyk M, Burzynska-Pedziwiatr I, Wozniak LA, Bukowiecka-Matusiak M. Impact of Polyphenols on Inflammatory and Oxidative Stress Factors in Diabetes Mellitus: Nutritional Antioxidants and Their Application in Improving Antidiabetic Therapy. Biomolecules 2023; 13:1402. [PMID: 37759802 PMCID: PMC10526737 DOI: 10.3390/biom13091402] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/10/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia and oxidative stress. Oxidative stress plays a crucial role in the development and progression of diabetes and its complications. Nutritional antioxidants derived from dietary sources have gained significant attention due to their potential to improve antidiabetic therapy. This review will delve into the world of polyphenols, investigating their origins in plants, metabolism in the human body, and relevance to the antioxidant mechanism in the context of improving antidiabetic therapy by attenuating oxidative stress, improving insulin sensitivity, and preserving β-cell function. The potential mechanisms of, clinical evidence for, and future perspectives on nutritional antioxidants as adjuvant therapy in diabetes management are discussed.
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Rahmoon MA, Elghaish RA, Ibrahim AA, Alaswad Z, Gad MZ, El-Khamisy SF, Elserafy M. High Glucose Increases DNA Damage and Elevates the Expression of Multiple DDR Genes. Genes (Basel) 2023; 14:144. [PMID: 36672885 PMCID: PMC9858638 DOI: 10.3390/genes14010144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 12/19/2022] [Accepted: 12/31/2022] [Indexed: 01/06/2023] Open
Abstract
The DNA Damage Response (DDR) pathways sense DNA damage and coordinate robust DNA repair and bypass mechanisms. A series of repair proteins are recruited depending on the type of breaks and lesions to ensure overall survival. An increase in glucose levels was shown to induce genome instability, yet the links between DDR and glucose are still not well investigated. In this study, we aimed to identify dysregulation in the transcriptome of normal and cancerous breast cell lines upon changing glucose levels. We first performed bioinformatics analysis using a microarray dataset containing the triple-negative breast cancer (TNBC) MDA-MB-231 and the normal human mammary epithelium MCF10A cell lines grown in high glucose (HG) or in the presence of the glycolysis inhibitor 2-deoxyglucose (2DG). Interestingly, multiple DDR genes were significantly upregulated in both cell lines grown in HG. In the wet lab, we remarkably found that HG results in severe DNA damage to TNBC cells as observed using the comet assay. In addition, several DDR genes were confirmed to be upregulated using qPCR analysis in the same cell line. Our results propose a strong need for DDR pathways in the presence of HG to oppose the severe DNA damage induced in cells.
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Affiliation(s)
- Mai A. Rahmoon
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza 12578, Egypt
- Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Reem A. Elghaish
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza 12578, Egypt
- University of Science and Technology, Zewail City of Science and Technology, Giza 12578, Egypt
| | - Aya A. Ibrahim
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza 12578, Egypt
- University of Science and Technology, Zewail City of Science and Technology, Giza 12578, Egypt
| | - Zina Alaswad
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza 12578, Egypt
- University of Science and Technology, Zewail City of Science and Technology, Giza 12578, Egypt
| | - Mohamed Z. Gad
- Department of Biochemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Sherif F. El-Khamisy
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza 12578, Egypt
- The Healthy Lifespan Institute and Institute of Neuroscience, School of Bioscience, University of Sheffield, Sheffield S10 2TN, UK
- The Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1 DP, UK
| | - Menattallah Elserafy
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza 12578, Egypt
- University of Science and Technology, Zewail City of Science and Technology, Giza 12578, Egypt
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Mirahmad M, Mohseni S, Tabatabaei-Malazy O, Esmaeili F, Alatab S, Bahramsoltani R, Ejtahed HS, Qulami H, Bitarafan Z, Arjmand B, Nazeri E. Antioxidative hypoglycemic herbal medicines with in vivo and in vitro activity against C-reactive protein; a systematic review. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 109:154615. [PMID: 36610136 DOI: 10.1016/j.phymed.2022.154615] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 11/16/2022] [Accepted: 12/17/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Inflammation is a double-edged sword in the pathophysiology of chronic diseases, such as type 2 diabetes mellitus (T2DM). The global rise in the prevalence of T2DM in one hand, and poor disease control with currently-available treatments on the other hand, along with an increased tendency towards the use of natural products make scientists seek herbal medicines for the management of diabetes and its complications by reducing C-reactive protein (CRP) as an inflammatory marker. PURPOSE To systematically review the literature to identify the efficacy of various medicinal plants with antioxidative and anti-inflammatory properties considering their effect on CRP in animal models of T2DM. STUDY DESIGN systematic review. METHODS Electronic databases including PubMed, Scopus, Web of Science and Cochran Library were searched using the search terms "herbal medicine", "diabetes", "c-reactive protein", "antioxidants" till August 2021. The quality of evidence was assessed using the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE's) tool. The study protocol was registered in PROSPERO with an ID number CRD42020207190. A manual search to detect any articles not found in the databases was also made. The identified studies were then critically reviewed and relevant data were extracted and summarized. RESULTS Among total of 9904 primarily-retrieved articles, twenty-three experimental studies were finally included. Our data indicated that numerous herbal medicines, compared to placebo or hypoglycemic medications, are effective in treatment of diabetes and its complications through decreasing CRP concentrations and oxidative stresses levels. Medicinal plants including Psidium guajava L., Punica granatum L., Ginkgo biloba L., Punica granatum L., Dianthus superbusn L.. Moreover, Eichhornia crassipes (Mart.) Solms, Curcuma longa L., Azadirachta indica A. Juss., Morus alba L., and Ficus racemosa L. demonstrated potential neuroprotective effects in animal models of diabetes. CONCLUSION Hypoglycemic medicinal plants discussed in this review seem to be promising regulators of CRP, and oxidative stress. Thus, these plants are suitable candidates for management of diabetes' complications. Nevertheless, further high-quality in vivo studies and clinical trials are required to confirm these effects.
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Affiliation(s)
- Maryam Mirahmad
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahrzad Mohseni
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ozra Tabatabaei-Malazy
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Fataneh Esmaeili
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sudabeh Alatab
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Roodabeh Bahramsoltani
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran; PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hanieh-Sadat Ejtahed
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Husseyn Qulami
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Bitarafan
- Division of Biotechnology and Plant Health, Norwegian Institute of Bioeconomy Research, Høgskoleveien 7, As 1433, Norway
| | - Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Elahe Nazeri
- Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
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Effects of Alcohol Consumption on Oxidative Stress in a Sample of Patients Recruited in a Dietary Center in a Southern University Hospital: A Retrospective Study. Medicina (B Aires) 2022; 58:medicina58111670. [DOI: 10.3390/medicina58111670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/11/2022] [Accepted: 11/14/2022] [Indexed: 11/22/2022] Open
Abstract
Background and objectives: The aim of this retrospective study was to evaluate the effects of alcohol consumption on oxidative stress. Materials and Methods: The study was conducted by analyzing the increase in lipid peroxidation, the reduction of antioxidant defenses and the alteration of the oxidation/antioxidant balance after the administration of ethanol in 25% aqueous solution (v/v) at a concentration of 0.76 g/kg of body weight daily in two doses for 3 days. The changes in oxidative stress indices were investigated by standard methods previously described. Results: Ethanol administration has determined a significant increase in plasma levels of lipid hydroperoxide (LOOH), malonilaldehyde (MDA) and oxidized glutathione (GSSH), and a decrease in total antioxidant capacity (TAC), reduced glutathione (GSH) and GSH/GSSH ratio. Conclusions: In the proposed experimental condition, the excessive and repeated consumption of ethanol causes oxidative damage, as shown by the increase in lipid peroxidation, the reduction of antioxidant defenses and the alteration of the oxidation/antioxidant balance, which, at least in part, are responsible for the harmful effects of excess ethanol.
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Syringic Acid Ameliorates Cardiac, Hepatic, Renal and Neuronal Damage Induced by Chronic Hyperglycaemia in Wistar Rats: A Behavioural, Biochemical and Histological Analysis. Molecules 2022; 27:molecules27196722. [PMID: 36235257 PMCID: PMC9573038 DOI: 10.3390/molecules27196722] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/29/2022] [Accepted: 10/04/2022] [Indexed: 11/16/2022] Open
Abstract
This study investigated the effects of syringic acid (SA) on renal, cardiac, hepatic, and neuronal diabetic complications in streptozotocin-induced neonatal (nSTZ) diabetic rats. STZ (110 mg/kg i.p) was injected into Wistar rat neonates as a split dose (second and third postnatal day). Diabetes mellitus was diagnosed in adults by measuring fasting blood glucose levels, urine volume, and food and water intake. The treatment of SA (25 mg/kg, 50 mg/kg p.o) was given from the 8th to 18th postnatal week. To assess the development of diabetic complications and the effect of therapy, biochemical indicators in serum and behavioural parameters were recorded at specific intervals during the study period. SA (25 mg/kg, 50 mg/kg p.o) treatment reduced hyperglycaemia, polydipsia, polyphagia, polyuria, relative organ weight, cardiac hypertrophic indices, inflammatory markers, cell injury markers, glycated haemoglobin, histopathological score, and oxidative stress, and increased Na/K ATPase activity. These findings suggest that SA might significantly alleviate diabetic complications and/or renal, neuronal, cardiac, and hepatic damage in nSTZ diabetic rats.
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Møller P, Stopper H, Collins AR. Measurement of DNA damage with the comet assay in high-prevalence diseases: current status and future directions. Mutagenesis 2021; 35:5-18. [PMID: 31294794 DOI: 10.1093/mutage/gez018] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 06/19/2019] [Indexed: 12/12/2022] Open
Abstract
The comet assay is widely used in studies on genotoxicity testing, human biomonitoring and clinical studies. The simple version of the assay detects a mixture of DNA strand breaks and alkali-labile sites; these lesions are typically described as DNA strand breaks to distinguish them from oxidatively damaged DNA that are measured with the enzyme-modified comet assay. This review assesses the association between high-prevalence diseases in high-income countries and DNA damage measured with the comet assay in humans. The majority of case-control studies have assessed genotoxicity in white blood cells. Patients with coronary artery disease, diabetes, kidney disease, chronic obstructive pulmonary disease and Alzheimer's disease have on average 2-fold higher levels of DNA strand breaks compared with healthy controls. Patients with coronary artery disease, diabetes, kidney disease and chronic obstructive pulmonary disease also have 2- to 3-fold higher levels of oxidatively damaged DNA in white blood cells than controls, although there is not a clear difference in DNA damage levels between the different diseases. Case-control studies have shown elevated levels of DNA strand breaks in patients with breast cancer, whereas there are only few studies on colorectal and lung cancers. At present, it is not possible to assess if these neoplastic diseases are associated with a different level of DNA damage compared with non-neoplastic diseases.
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Affiliation(s)
- Peter Møller
- Department of Public Health, Section of Environmental Health, University of Copenhagen, Copenhagen H, Denmark
| | - Helga Stopper
- Institute of Pharmacology and Toxicology, University of Wuerzburg, Wuerzburg, Germany
| | - Andrew R Collins
- Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway
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Rout D, Chandra Dash U, Kanhar S, Swain SK, Sahoo AK. The modulatory role of prime identified compounds in the bioactive fraction of Homalium zeylanicum in high-fat diet fed-streptozotocin-induced type 2 diabetic rats. JOURNAL OF ETHNOPHARMACOLOGY 2020; 260:113099. [PMID: 32535241 DOI: 10.1016/j.jep.2020.113099] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 06/06/2020] [Accepted: 06/07/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Homalium zeylanicum (Gardner) Benth. is a medicinal plant traditionally used in controlling diabetes which thus far has been assessed by the authors only to a very limited extent. PURPOSE To fill the research gap in the literature review, we investigated the antihyperglycemic effects of hydro alcohol fraction of bark of H. zeylanicum (HAHZB) by modulating oxidative stress and inflammation in high-fat diet fed-streptozotocin (HFD/STZ)-induced type-2 diabetic rats. MATERIALS AND METHODS To understand the antioxidant capacity of HAHZB, oxygen radical absorbance capacity (ORAC) and cell-based antioxidant protection in erythrocytes (CAP-e) were performed. GC-MS/MS analysis was performed to assess the bioactive components in HAHZB. HFD/STZ-induced diabetic rats were treated orally with HAHZB (300 and 400 mg/kg) for 28 days. After the end of the experiment, marker profiling and histopathological observation of blood and pancreas were examined. The study also highlights interaction between diabetes, oxidative stress and inflammation by examining the increased pro-inflammatory cytokines e.g. TNF-α and C-reactive protein (CRP) promotes DNA damage e.g. oxidation of 8-hydroxy-2-deoxyguanosine (8-OHdG) in chronic hyperglycaemia. RESULTS In ex vivo cellular antioxidant capacity of -CAP-e and ORAC assays, HAHZB showed remarkable free radical scavenging ability in a dose dependent manner. GC-MS/MS analysis identified 28 no. of compounds and out of which, oleic acid (1.03%), ethyl tridecanoate (11.77%), phytol (1.29), 9,12-octadecadienoic acid, methyl ester, (E,E)-(5.97%), stigmasterol (1.30%) and β-sitosterol (2.86%) have antioxidant, anti-inflammatory and anti-diabetic activities. HAHZB 400 mg/kg significantly (p < 0.001) improved the lipid profile (TC: 74.66 ± 0.59, HDL-C: 22.08 ± 0.46, LDL-C: 38.06 ± 0.69, and TG: 171.92 ± 1.01 mg/dL) as well as restoring antidiabetic markers (SG: 209.62 ± 1.05 mg/dL, SI: 15.07 ± 0.11 μIU/mL, HOMA-IR: 7.79 ± 0.04 %, and HbA1C: 8.93 ± 0.03 %) and renal functional markers (Tg: 291.26 ± 0.57 pg/mL, BUN: 23.79 ± 0.14 mg/dL, and Cr: 1.34 ± 0.04 mg/dL) in diabetic rats. Oxidative stress markers of pancreas (MDA: 3.65 ± 0.17 nM TBARS /mg protein, SOD: 3.14 ± 0.28 U/mg protein, CAT: 7.88 ± 0.23 U/mg protein, GSH: 12.63 ± 0.28 µM/g of tissue) were restored to normal as evidenced by histological architecture of pancreatic islet cells. The increased level of pro-inflammatory cytokines and oxidative DNA damage were significantly restored (TNF-α: 54.48 ± 3.19 pg/mL, CRP: 440.22 ± 7.86 ng/mL, and 8-OHdG: 63.65 ± 1.84 ng/mL) by HAHZB in diabetic rats. CONCLUSION The present findings confirm that the presence of bioactive compounds in HAHZB exert therapeutic protective effect by decreasing oxidative, inflammation and pancreatic β-cell damage in oxidative stress induced diabetic rats.
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MESH Headings
- 8-Hydroxy-2'-Deoxyguanosine/blood
- Animals
- Anti-Inflammatory Agents/isolation & purification
- Anti-Inflammatory Agents/pharmacology
- Antioxidants/isolation & purification
- Antioxidants/pharmacology
- Biomarkers/blood
- Blood Glucose/drug effects
- Blood Glucose/metabolism
- Cytokines/blood
- DNA Damage
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/chemically induced
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/chemically induced
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/pathology
- Diet, High-Fat
- Female
- Hypoglycemic Agents/isolation & purification
- Hypoglycemic Agents/pharmacology
- Inflammation Mediators/blood
- Insulin-Secreting Cells/drug effects
- Insulin-Secreting Cells/metabolism
- Insulin-Secreting Cells/pathology
- Male
- Oxidative Stress/drug effects
- Plant Bark
- Plant Extracts/isolation & purification
- Plant Extracts/pharmacology
- Rats, Wistar
- Salicaceae/chemistry
- Streptozocin
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Affiliation(s)
- Deeptimayee Rout
- Regional Plant Resource Centre, Medicinal & Aromatic Plant Division, Forest & Environment Department, Govt. of Odisha, Nayapalli, Bhubaneswar, 751015, India
| | - Umesh Chandra Dash
- Regional Plant Resource Centre, Medicinal & Aromatic Plant Division, Forest & Environment Department, Govt. of Odisha, Nayapalli, Bhubaneswar, 751015, India
| | - Satish Kanhar
- Regional Plant Resource Centre, Medicinal & Aromatic Plant Division, Forest & Environment Department, Govt. of Odisha, Nayapalli, Bhubaneswar, 751015, India
| | - Sandeep Kumar Swain
- Regional Plant Resource Centre, Medicinal & Aromatic Plant Division, Forest & Environment Department, Govt. of Odisha, Nayapalli, Bhubaneswar, 751015, India
| | - Atish Kumar Sahoo
- Regional Plant Resource Centre, Medicinal & Aromatic Plant Division, Forest & Environment Department, Govt. of Odisha, Nayapalli, Bhubaneswar, 751015, India.
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Macan TP, de Amorim TA, Damiani AP, Beretta ÂCDL, Magenis ML, Vilela TC, Teixeira JP, Andrade VMD. Brazil nut prevents oxidative DNA damage in type 2 diabetes patients. Drug Chem Toxicol 2020; 45:1066-1072. [PMID: 32811197 DOI: 10.1080/01480545.2020.1808667] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The Brazil nut (Bertholletia excelsa, H.B.K.) originating from the Amazon region is one of the richest known sources of selenium (Se), a micronutrient that is essential and required for optimal physiological functioning. This mineral presents several health benefits, including improvement of the redox cellular status and maintenance of genomic stability. Knowing that type 2 diabetes mellitus (T2D) is strongly linked to oxidative stress and consequently DNA damage, the aim of this study was to assess the ex vivo antioxidative effects of Se through Brazil nut consumption and its potential in preventing oxidative DNA damage induced by H2O2. In order to accomplish this, the Comet assay (single-cell gel electrophoresis) was used to measure DNA damage in peripheral blood cells harvested before and after supplementation with Brazil nut. Comet assay was also applied ex vivo to measure the potential of Se to prevent oxidative damage to DNA induced by H2O2 in blood of type 2 diabetes patients collected before and after six months of supplementation with Brazil nut. We found that supplementation with Brazil nuts significantly increased serum Se levels. Furthermore, we observed a significant increase in fasting blood glucose after six months of consuming Brazil nuts; however, no significant effect was observed on the levels of glycated hemoglobin. Finally, we noticed that the cells were more resistant to H2O2-induced DNA damage after six months of supplementation with Brazil nut. Thus, consumption of Brazil nuts could decrease oxidative DNA damage in T2D patients, probably through the antioxidative effects of Se.
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Affiliation(s)
- Tamires Pavei Macan
- Translational Biomedicine Laboratory, Graduate Program of Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Brazil.,Department of Environmental Health, National Institute of Health Dr. Ricardo Jorge, Porto, Portugal
| | - Thais Aquino de Amorim
- Translational Biomedicine Laboratory, Graduate Program of Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Brazil
| | - Adriani Paganini Damiani
- Translational Biomedicine Laboratory, Graduate Program of Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Brazil
| | - Ângela Caroline da Luz Beretta
- Translational Biomedicine Laboratory, Graduate Program of Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Brazil
| | - Marina Lummertz Magenis
- Translational Biomedicine Laboratory, Graduate Program of Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Brazil
| | - Thais Ceresér Vilela
- Translational Biomedicine Laboratory, Graduate Program of Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Brazil
| | - João Paulo Teixeira
- Department of Environmental Health, National Institute of Health Dr. Ricardo Jorge, Porto, Portugal
| | - Vanessa Moraes de Andrade
- Translational Biomedicine Laboratory, Graduate Program of Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Brazil
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11
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Sreevallabhan S, Mohanan R, Sukumaran S, Sobha AP, Jose SP, Sukumarapillai A, Jagmag T, Tilwani J. Ameliorating effect of glutathione-enriched herbal formulation (glothione) on alloxan-induced experimental diabetic model by modulating oxidative stress and pathogenesis. J Food Biochem 2020; 44:e13153. [PMID: 32026494 DOI: 10.1111/jfbc.13153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 12/08/2019] [Accepted: 01/02/2020] [Indexed: 11/26/2022]
Abstract
Diabetes Mellitus is a common metabolic or endocrine disorder that occurs as a result of insufficient amounts of insulin secretion or defect in the action of insulin produced from pancreatic beta cells. Antioxidant containing food items are very effective in reducing complications that arise due to diabetes, indicating that it may be beneficial for treating metabolic disorders. In this study, we used some essential nutrients enriched with glutathione, named as Glothione (GN), and evaluated the antidiabetic effect of GN in alloxan-induced diabetic rats. The treatment with GN showed significant reduction in the blood glucose level, HbA1c level, and liver markers like SGOT, SGPT, and ALP and shows increased antioxidant status and decreased inflammatory markers. Histopathological analysis of pancreas and liver tissue showed that there were no abnormalities in the rat after the administration of GN. Thus, antioxidant-enriched formulation of GN can be used as a potent hypoglycaemic drug. PRACTICAL APPLICATIONS: Glothione is a glutathione-enriched formulation that contains essential nutrients required for the normal functioning of the body. Recent trends in lifestyle and food habits have been noted to cause health risks and subject the body through physical and physiological stress--hence the importance of antioxidant-rich foods. Antioxidants are capable of boosting metabolism and other physiological processes. Thus, the consumption of GN can enhance the antioxidant status within the body. GN does not contain any chemical ingredients so it will not cause any side effects. It has a strong antidiabetic effect and is also able to control a number of diseases.
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Affiliation(s)
| | | | - Sandya Sukumaran
- Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, India
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12
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Chemistry, Biological, and Pharmacological Properties of Gum Arabic. BIOACTIVE MOLECULES IN FOOD 2019. [DOI: 10.1007/978-3-319-78030-6_11] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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13
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Carrillo-Ibarra S, Miranda-Díaz AG, Sifuentes-Franco S, Cardona-Muñoz EG, Rodríguez-Carrizalez AD, Villegas-Rivera G, Román-Pintos LM. Effect of statins on oxidative DNA damage in diabetic polyneuropathy. J Circ Biomark 2018; 7:1849454418804099. [PMID: 30302131 PMCID: PMC6170961 DOI: 10.1177/1849454418804099] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 09/10/2018] [Indexed: 12/22/2022] Open
Abstract
Oxidative stress induces nerve damage in type 2 diabetes mellitus and leads to diabetic polyneuropathy (DPN) and can affect the DNA and antioxidant status. Statins have pleiotropic, protective effects on the peripheral nerves of patients with diabetes. The aim of this study was to determine the effects of ezetimibe/simvastatin and rosuvastatin on DNA damage in patients with DPN. This randomized, double-blind, placebo-controlled, clinical trial comprised outpatients from Guadalajara, Mexico. The inclusion criteria were either gender, age 35–80 years, type 2 diabetes, glycated hemoglobin ≤10%, diabetic polyneuropathy stage 1/2, and signed informed consent. Patients who were taking antioxidant therapy or statins, had hypersensitivity to drugs, experienced organ failure, were pregnant or breastfeeding, or had other types of neuropathy were excluded. We assigned patients to placebo, ezetimibe/simvastatin 10/20 mg, or rosuvastatin 20 mg, and the primary outcomes were 8-hydroxy-2′-deoxyguanosine (8-OHdG) for DNA damage, 8-oxoguanine-DNA-N-glycosilase (hOGG1) for DNA repair, and superoxide dismutase (SOD). Seventy-four patients were recruited. Nine patients were included as negative controls. There were no differences in 8-OHdG between the healthy subjects (4.68 [3.53–6.38] ng/mL) and the DPN patients (4.51 [1.22–9.84] ng/mL), whereas the hOGG1 level was 0.39 (0.37–0.42) ng/mL in the healthy subjects and 0.41 (0.38–0.54) ng/mL in patients with DPN at baseline (p = 0.01). SOD decreased significantly in patients with DPN (5.35 [0.01–17.90] U/mL) compared with the healthy subjects (9.81 [8.66–12.61] U/mL) at baseline (p < 0.001). No significant changes in DNA biomarkers were observed in any group between baseline and final levels. We noted a rise in hOGG1 in patients with DPN, without modifications after treatment. There was a slight, albeit insignificant, increase in SOD in patients who were on statins.
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Affiliation(s)
- Sandra Carrillo-Ibarra
- Departament of Physiology, Institute of Clinical and Experimental Therapeutics, University Health Sciences Centre, University of Guadalajara, Guadalajara, Jalisco, México
| | - Alejandra Guillermina Miranda-Díaz
- Departament of Physiology, Institute of Clinical and Experimental Therapeutics, University Health Sciences Centre, University of Guadalajara, Guadalajara, Jalisco, México
| | - Sonia Sifuentes-Franco
- Departament of Physiology, Institute of Clinical and Experimental Therapeutics, University Health Sciences Centre, University of Guadalajara, Guadalajara, Jalisco, México
| | - Ernesto Germán Cardona-Muñoz
- Departament of Physiology, Institute of Clinical and Experimental Therapeutics, University Health Sciences Centre, University of Guadalajara, Guadalajara, Jalisco, México
| | - Adolfo Daniel Rodríguez-Carrizalez
- Departament of Physiology, Institute of Clinical and Experimental Therapeutics, University Health Sciences Centre, University of Guadalajara, Guadalajara, Jalisco, México
| | - Geannyne Villegas-Rivera
- Department of Health-Disease Sciences as an Individual Process, Tonala University Centre, University of Guadalajara, Jalisco, México
| | - Luis Miguel Román-Pintos
- Department of Health-Disease Sciences as an Individual Process, Tonala University Centre, University of Guadalajara, Jalisco, México
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14
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Varut RM, Gîrd CE, Rotaru LT, Varut MC, Pisoschi CG. Evaluation of Polyphenol and Flavonoid Profiles and the Antioxidant Effect of Carduus Acanthoides Hydroalcoholic Extract Compared with Vaccinium Myrtillus in an Animal Model of Diabetes Mellitus. Pharm Chem J 2018. [DOI: 10.1007/s11094-018-1746-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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15
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16
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Metro D, Cernaro V, Santoro D, Papa M, Buemi M, Benvenga S, Manasseri L. Beneficial effects of oral pure caffeine on oxidative stress. J Clin Transl Endocrinol 2017; 10:22-27. [PMID: 29204368 PMCID: PMC5691215 DOI: 10.1016/j.jcte.2017.10.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 09/24/2017] [Accepted: 10/03/2017] [Indexed: 12/11/2022] Open
Abstract
Ingestion of coffee (which is a mixture of over 1000 hydrosoluble substances) is known to protect from type-2 diabetes mellitus and its complications, and other chronic disorders associated with increased oxidative damage in blood and tissues. This protection is generally attributed to polyphenols and melanoidins. Very few studies were conducted on the amelioration of classic blood markers of oxidative stress induced after a few days of caffeine administration, but results vary. To assess whether caffeine per se could account for antioxidant properties of coffee in the short-term, we tested the ability of pure caffeine ingestion (5 mg/kg body weight/day in two daily doses for seven consecutive days) to improve plasma levels of six biochemical indices in healthy male volunteers (n = 15). These indices were total antioxidant capacity (TAC), glutathione (GSH), oxidized glutathione (GSSG), GSH to GSSG ratio, lipid hydroperoxides (LOOH) and malondialdehyde (MDA). We found that all indices changed significantly (P < .05 or < .01) in a favourable manner, ranging from -41% for GSSG to -70% for LHP levels, and +106% for GSH levels to +249% for the GSG/GSSG ratio. Changes of any given index were uniform across subjects, with no outliers. We conclude that caffeine has unequivocal, consistent antioxidant properties.
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Affiliation(s)
- Daniela Metro
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, University Hospital Policlinico G. Martino, Padiglione G, Messina, Italy
| | - Valeria Cernaro
- Department of Clinical and Experimental Medicine, University of Messina, University Hospital Policlinico G. Martino Padiglione C, Via Consolare Valeria, 98100 Messina, Italy
| | - Domenico Santoro
- Department of Clinical and Experimental Medicine, University of Messina, University Hospital Policlinico G. Martino Padiglione C, Via Consolare Valeria, 98100 Messina, Italy
| | - Mattia Papa
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, University Hospital Policlinico G. Martino, Padiglione G, Messina, Italy
| | - Michele Buemi
- Department of Clinical and Experimental Medicine, University of Messina, University Hospital Policlinico G. Martino Padiglione C, Via Consolare Valeria, 98100 Messina, Italy
| | - Salvatore Benvenga
- Department of Clinical and Experimental Medicine, University of Messina, Italy
- Master Program on Childhood, Adolescent and Women’s Endocrine Health, University of Messina, Italy
- Interdep Program of Molecular & Clinical Endocrinology and Women’s Endocrine Health, University Hospital Policlinico G. Martino, Padiglione H, Messina, Italy
| | - Luigi Manasseri
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, University Hospital Policlinico G. Martino, Padiglione G, Messina, Italy
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17
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Dimauro I, Sgura A, Pittaluga M, Magi F, Fantini C, Mancinelli R, Sgadari A, Fulle S, Caporossi D. Regular exercise participation improves genomic stability in diabetic patients: an exploratory study to analyse telomere length and DNA damage. Sci Rep 2017. [PMID: 28646223 PMCID: PMC5482873 DOI: 10.1038/s41598-017-04448-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Physical activity has been demonstrated to be effective in the prevention and treatment of different chronic conditions, including type 2 diabetes (T2D). In particular, several studies highlighted how the beneficial effects of physical activity may be related to the stability of the DNA molecule, such as longer telomeric ends. Here we analyze the effect of exercise training on telomere length, spontaneous and H2O2-induced DNA damage, as well as the apoptosis level in leukocytes from untrained or trained T2D patients vs. age-matched control subjects (CS) (57–66 years). Moreover, expression analysis of selected genes belonging to DNA repair systems, cell cycle control, antioxidant and defence systems was performed. Subjects that participated in a regular exercise program showed a longer telomere sequence than untrained counterparts. Moreover, ex vivo treatment of leukocytes with H2O2 highlighted that: (1) oxidative DNA damage induced similar telomere attrition in all groups; (2) in T2D subjects, physical activity seemed to prevent a significant increase of genomic oxidative DNA damage induced by chronic exposure to pro-oxidant stimulus, and (3) decreased the sensitivity of leukocytes to apoptosis. Finally, the gene expression analysis in T2D subjects suggested an adaptive response to prolonged exercise training that improved the response of specific genes.
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Affiliation(s)
- Ivan Dimauro
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | | | - Monica Pittaluga
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Fiorenza Magi
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Cristina Fantini
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Rosa Mancinelli
- Department of Neuroscience, Imaging and Clinical Sciences, Interuniversity Institute of Miology (IIM), University "G d'Annunzio", Chieti, Italy
| | - Antonio Sgadari
- Department of Geriatrics, Gerontology and Physiatry, University Hospital Agostino Gemelli, Catholic University of the Sacred Heart, Rome, Italy
| | - Stefania Fulle
- Department of Neuroscience, Imaging and Clinical Sciences, Interuniversity Institute of Miology (IIM), University "G d'Annunzio", Chieti, Italy
| | - Daniela Caporossi
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy.
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18
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Stocker P, Cassien M, Vidal N, Thétiot-Laurent S, Pietri S. A fluorescent homogeneous assay for myeloperoxidase measurement in biological samples. A positive correlation between myeloperoxidase-generated HOCl level and oxidative status in STZ-diabetic rats. Talanta 2017; 170:119-127. [PMID: 28501147 DOI: 10.1016/j.talanta.2017.03.102] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 03/27/2017] [Accepted: 03/29/2017] [Indexed: 01/23/2023]
Abstract
Myeloperoxidase (MPO) is a key enzyme derived from leukocytes which is associated with the initiation and progression of many inflammatory diseases. Increased levels of MPO may contribute to cellular dysfunction and tissues injury by producing highly reactive oxidants such as hypochlorous acid (HOCl). Myeloperoxidase-generated HOCl is therefore considered as a relevant biomarker of oxidative stress-related damage and its quantitation is of great importance to the study of disease progression. In this context, the current study describes a rapid, sensitive and homogeneous fluorescence-based method for detecting the MPO chlorination activity in biological samples. This assay utilizes 7-hydroxy-2-oxo-2H-chromene-8-carbaldehyde oxime as a selective probe for HOCl detection, and is adapted to 96-well microplates to allow high-throughput quantitation of active MPO. The ability of the method to monitor HOCl release was further investigated in hyperglycemic streptozotocin-treated diabetic rats. The data proved that the present assay has a reliable performance when quantitating the active MPO in the plasma of diabetic animals, a feature of inflammatory disease found concomitant with an elevation of protein carbonyls levels and lipid peroxidation and which was negatively correlated with the ratio of reduced-to-oxidized glutathione.
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Affiliation(s)
- Pierre Stocker
- Aix Marseille Univ, CNRS, ICR, SMBSO, Marseille, France.
| | | | - Nicolas Vidal
- Aix Marseille Univ, CNRS, ICR, SMBSO, Marseille, France
| | | | - Sylvia Pietri
- Aix Marseille Univ, CNRS, ICR, SMBSO, Marseille, France
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19
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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: 22] [Impact Index Per Article: 2.8] [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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20
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Lowe J, Taveira-da-Silva R, Hilário-Souza E. Dissecting copper homeostasis in diabetes mellitus. IUBMB Life 2017; 69:255-262. [DOI: 10.1002/iub.1614] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 02/15/2017] [Indexed: 01/21/2023]
Affiliation(s)
- Jennifer Lowe
- Laboratório de Físico-Química Biológica Aída Hassón-Voloch; Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro; Rio de Janeiro Brazil
| | - Rosilane Taveira-da-Silva
- Laboratório de Físico-Química Biológica Aída Hassón-Voloch; Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro; Rio de Janeiro Brazil
| | - Elaine Hilário-Souza
- Laboratório de Físico-Química Biológica Aída Hassón-Voloch; Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro; Rio de Janeiro Brazil
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Mohammed OJ, Latif ML, Pratten MK. Diabetes-induced effects on cardiomyocytes in chick embryonic heart micromass and mouse embryonic D3 differentiated stem cells. Reprod Toxicol 2017; 69:242-253. [PMID: 28286266 DOI: 10.1016/j.reprotox.2017.03.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 03/03/2017] [Accepted: 03/07/2017] [Indexed: 11/16/2022]
Abstract
Diabetes mellitus during pregnancy is a considerable medical challenge, since it is related to augmented morbidity and mortality concerns for both the fetus and the pregnant woman. Records show that the etiology of diabetic embryopathy is complicated, as many teratological factors might be involved in the mechanisms of diabetes mellitus-induced congenital malformation. In this study, the potential cardiotoxic effect of hyperglycemia with hyperketonemia was investigated by using two in vitro models; primary chick embryonic cardiomyocytes and stem cell derived cardiomyocytes, where adverse effects were recorded in both systems. The cells were evaluated by changes in beating activity, cell activity, protein content, ROS production, DNA damage and differentiating stem cell migration. The diabetic formulae used produced an increase in DNA damage and a decline in cell migration in mouse embryonic stem cells. These results provide an additional insight into adverse effects during gestational diabetes mellitus and a recommendation for expectant mothers and maternity staff to monitor glycaemic levels months ahead of conception. This study also supports the recommendation of using antioxidants during pregnancy to prevent DNA damage by the production of ROS, which might result in heart defects as well as other developmental anomalies.
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Affiliation(s)
- Omar J Mohammed
- School of Life Sciences, Faculty of Medicine and Health Sciences, Medical School, University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Muhammad Liaque Latif
- School of Life Sciences, Faculty of Medicine and Health Sciences, Medical School, University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Margaret K Pratten
- School of Life Sciences, Faculty of Medicine and Health Sciences, Medical School, University of Nottingham, Nottingham NG7 2UH, United Kingdom.
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22
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Grindel A, Guggenberger B, Eichberger L, Pöppelmeyer C, Gschaider M, Tosevska A, Mare G, Briskey D, Brath H, Wagner KH. Oxidative Stress, DNA Damage and DNA Repair in Female Patients with Diabetes Mellitus Type 2. PLoS One 2016; 11:e0162082. [PMID: 27598300 PMCID: PMC5012603 DOI: 10.1371/journal.pone.0162082] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 08/17/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Diabetes mellitus type 2 (T2DM) is associated with oxidative stress which in turn can lead to DNA damage. The aim of the present study was to analyze oxidative stress, DNA damage and DNA repair in regard to hyperglycemic state and diabetes duration. METHODS Female T2DM patients (n = 146) were enrolled in the MIKRODIAB study and allocated in two groups regarding their glycated hemoglobin (HbA1c) level (HbA1c≤7.5%, n = 74; HbA1c>7.5%, n = 72). In addition, tertiles according to diabetes duration (DD) were created (DDI = 6.94±3.1 y, n = 49; DDII = 13.35±1.1 y, n = 48; DDIII = 22.90±7.3 y, n = 49). Oxidative stress parameters, including ferric reducing ability potential, malondialdehyde, oxidized and reduced glutathione, reduced thiols, oxidized LDL and F2-Isoprostane as well as the activity of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase were measured. Damage to DNA was analyzed in peripheral blood mononuclear cells and whole blood with single cell gel electrophoresis. DNA base excision repair capacity was tested with the modified comet repair assay. Additionally, mRNA expressions of nine genes related to base excision repair were analyzed in a subset of 46 matched individuals. RESULTS No significant differences in oxidative stress parameters, antioxidant enzyme activities, damage to DNA and base excision repair capacity, neither between a HbA1c cut off />7.5%, nor between diabetes duration was found. A significant up-regulation in mRNA expression was found for APEX1, LIG3 and XRCC1 in patients with >7.5% HbA1c. Additionally, we observed higher total cholesterol, LDL-cholesterol, LDL/HDL-cholesterol, triglycerides, Framingham risk score, systolic blood pressure, BMI and lower HDL-cholesterol in the hyperglycemic group. CONCLUSION BMI, blood pressure and blood lipid status were worse in hyperglycemic individuals. However, no major disparities regarding oxidative stress, damage to DNA and DNA repair were present which might be due to good medical treatment with regular health checks in T2DM patients in Austria.
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Affiliation(s)
- Annemarie Grindel
- Department of Nutritional Sciences, Emerging Field Oxidative Stress and DNA Stability, University of Vienna, Vienna, Austria
- Research Platform Active Ageing, University of Vienna, Vienna, Austria
| | - Bianca Guggenberger
- Department of Nutritional Sciences, Emerging Field Oxidative Stress and DNA Stability, University of Vienna, Vienna, Austria
| | - Lukas Eichberger
- Department of Nutritional Sciences, Emerging Field Oxidative Stress and DNA Stability, University of Vienna, Vienna, Austria
| | - Christina Pöppelmeyer
- Department of Nutritional Sciences, Emerging Field Oxidative Stress and DNA Stability, University of Vienna, Vienna, Austria
| | - Michaela Gschaider
- Department of Nutritional Sciences, Emerging Field Oxidative Stress and DNA Stability, University of Vienna, Vienna, Austria
| | - Anela Tosevska
- Department of Nutritional Sciences, Emerging Field Oxidative Stress and DNA Stability, University of Vienna, Vienna, Austria
| | - George Mare
- Department of Nutritional Sciences, Emerging Field Oxidative Stress and DNA Stability, University of Vienna, Vienna, Austria
| | - David Briskey
- School of Human Movement and Nutrition Sciences, University of Queensland, St Lucia, QLD, Australia
| | - Helmut Brath
- Diabetes Outpatient Clinic, Health Centre South, Vienna, Austria
| | - Karl-Heinz Wagner
- Department of Nutritional Sciences, Emerging Field Oxidative Stress and DNA Stability, University of Vienna, Vienna, Austria
- Research Platform Active Ageing, University of Vienna, Vienna, Austria
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23
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Dong D, Reece EA, Lin X, Wu Y, AriasVillela N, Yang P. New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link to structural birth defects. Am J Obstet Gynecol 2016; 214:192-202. [PMID: 26432466 PMCID: PMC4744545 DOI: 10.1016/j.ajog.2015.09.082] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 09/18/2015] [Accepted: 09/22/2015] [Indexed: 12/12/2022]
Abstract
Maternal diabetes mellitus is a significant risk factor for structural birth defects, including congenital heart defects and neural tube defects. With the rising prevalence of type 2 diabetes mellitus and obesity in women of childbearing age, diabetes mellitus-induced birth defects have become an increasingly significant public health problem. Maternal diabetes mellitus in vivo and high glucose in vitro induce yolk sac injuries by damaging the morphologic condition of cells and altering the dynamics of organelles. The yolk sac vascular system is the first system to develop during embryogenesis; therefore, it is the most sensitive to hyperglycemia. The consequences of yolk sac injuries include impairment of nutrient transportation because of vasculopathy. Although the functional relationship between yolk sac vasculopathy and structural birth defects has not yet been established, a recent study reveals that the quality of yolk sac vasculature is related inversely to embryonic malformation rates. Studies in animal models have uncovered key molecular intermediates of diabetic yolk sac vasculopathy, which include hypoxia-inducible factor-1α, apoptosis signal-regulating kinase 1, and its inhibitor thioredoxin-1, c-Jun-N-terminal kinases, nitric oxide, and nitric oxide synthase. Yolk sac vasculopathy is also associated with abnormalities in arachidonic acid and myo-inositol. Dietary supplementation with fatty acids that restore lipid levels in the yolk sac lead to a reduction in diabetes mellitus-induced malformations. Although the role of the human yolk in embryogenesis is less extensive than in rodents, nevertheless, human embryonic vasculogenesis is affected negatively by maternal diabetes mellitus. Mechanistic studies have identified potential therapeutic targets for future intervention against yolk sac vasculopathy, birth defects, and other complications associated with diabetic pregnancies.
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Affiliation(s)
- Daoyin Dong
- Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD
| | - E Albert Reece
- Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD
| | - Xue Lin
- Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD
| | - Yanqing Wu
- Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD
| | - Natalia AriasVillela
- Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD
| | - Peixin Yang
- Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD.
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24
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Dong D, Reece EA, Yang P. The Nrf2 Activator Vinylsulfone Reduces High Glucose-Induced Neural Tube Defects by Suppressing Cellular Stress and Apoptosis. Reprod Sci 2016; 23:993-1000. [PMID: 26802109 DOI: 10.1177/1933719115625846] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is one of the primary pathways responsible for the cellular defense system against oxidative stress. Oxidative stress-induced apoptosis is a causal event in diabetic embryopathy. Thus, the Nrf2 pathway may play an important role in the induction of diabetic embryopathy. In the present study, we investigated the potentially protective effect of the Nrf2 activator, vinylsulfone, on high glucose-induced cellular stress, apoptosis, and neural tube defects (NTDs). Embryonic day 8.5 (E8.5) whole mouse embryos were cultured in normal (5 mmol/L) or high (16.7 mmol/L) glucose conditions, with or without vinylsulfone. At a concentration of 10 μmol/L, vinylsulfone had an inhibitory effect on high glucose-induced NTD formation, but it was not significant. At a concentration of 20 μmol/L, vinylsulfone significantly reduced high glucose-induced NTDs. In addition, 20 μmol/L vinylsulfone abrogated the high glucose-induced oxidative stress markers lipid hydroperoxide (LPO), 4-hydroxynonenal (4-HNE), and nitrotyrosine-modified proteins. The high glucose-induced endoplasmic reticulum (ER) stress biomarkers were also suppressed by 20 μmol/L vinylsulfone through the inhibition of phosphorylated protein kinase RNA-like ER kinase (PERK), inositol requiring protein 1α (IRE1a), eukaryotic initiation factor 2α (eIF2a), upregulated C/EBP-homologous protein (CHOP), binding immunoglobulin protein (BiP), and x-box binding protein 1 (XBP1) messenger RNA splicing. Furthermore, 20 μmol/L vinylsulfone abolished caspase 3 and caspase 8 cleavage, markers of apoptosis, in embryos cultured under high glucose conditions. The Nrf2 activator, vinylsulfone, is protective against high glucose-induced cellular stress, caspase activation, and subsequent NTD formation. Our data suggest that vinylsulfone supplementation is a potential therapy for diabetes-associated neurodevelopmental defects.
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Affiliation(s)
- Daoyin Dong
- Department of Obstetrics, Gynecology & Reproductive Sciences, Nashville, TN, USA
| | - E Albert Reece
- Department of Obstetrics, Gynecology & Reproductive Sciences, Nashville, TN, USA Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Peixin Yang
- Department of Obstetrics, Gynecology & Reproductive Sciences, Nashville, TN, USA Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA
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Ahmed AA, Fedail JS, Musa HH, Kamboh AA, Sifaldin AZ, Musa TH. Gum Arabic extracts protect against hepatic oxidative stress in alloxan induced diabetes in rats. PATHOPHYSIOLOGY 2015; 22:189-94. [DOI: 10.1016/j.pathophys.2015.08.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Revised: 08/20/2015] [Accepted: 08/21/2015] [Indexed: 02/08/2023] Open
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Dincer Y, Yüksel S, Batar B, Güven M, Onaran I, Celkan T. DNA Repair Gene Polymorphisms and Their Relation With DNA Damage, DNA Repair, and Total Antioxidant Capacity in Childhood Acute Lymphoblastic Leukemia Survivors. J Pediatr Hematol Oncol 2015; 37:344-50. [PMID: 24577548 DOI: 10.1097/mph.0000000000000133] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Oxidative stress and defective DNA repair are major contributory factors in the initiation and progression of carcinogenesis. Chemotherapy and radiotherapy cause oxidative DNA damage, consume antioxidant capacity, and impair DNA repair activity. These effects of chemotherapy and radiotherapy may be contributory factors in the development of secondary malignancy in cancer survivors. Basal, H2O2-induced, and postrepair DNA damage; urinary 8-hydroxydeoxyguanosine level as a marker of oxidatively damaged DNA; and serum total antioxidant capacity were measured; XPD Lys751Gln, XRCC1 Arg399Gln, and XRCC1 Arg194Trp polymorphisms were analyzed in childhood acute lymphoblastic leukemia (ALL) survivors. Basal and H2O2-induced DNA damage were found to be higher in the ALL survivor group versus the control group, however, there was no significant difference between the other parameters. No association was found between the examined parameters and polymorphisms of XPD 751 and XRCC1 399 and both the groups. XRCC1 194Trp allele was found to be associated with a low level of postrepair DNA damage in the ALL survivors. In conclusion, basal DNA damage and susceptibility to oxidation are high in childhood ALL survivors. This situation which may easily lead to occurrence of a secondary cancer does not seem to be a result of deficient DNA repair.
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Affiliation(s)
- Yildiz Dincer
- Departments of *Biochemistry †Medical Biology ‡Pediatric Hematology-Oncology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
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Xavier DJ, Takahashi P, Evangelista AF, Foss-Freitas MC, Foss MC, Donadi EA, Passos GA, Sakamoto-Hojo ET. Assessment of DNA damage and mRNA/miRNA transcriptional expression profiles in hyperglycemic versus non-hyperglycemic patients with type 2 diabetes mellitus. Mutat Res 2015; 776:98-110. [PMID: 26364207 DOI: 10.1016/j.mrfmmm.2015.01.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 01/28/2015] [Accepted: 01/30/2015] [Indexed: 06/05/2023]
Abstract
The development of type 2 diabetes mellitus (T2D) is associated with a number of genetic and environmental factors. Hyperglycemia, a T2D hallmark, is related to several metabolic complications, comorbidities and increased DNA damage. However, the molecular alterations of a proper glucose control are still unclarified. In this study, we aimed to evaluate DNA damage (comet assay), as well as to compare the transcriptional expression (mRNA and miRNA analyzed by the microarray technique) displayed by peripheral blood mononuclear cells (PBMCs) from three distinct groups: hyperglycemic T2D patients (T2D-H, n=14), non-hyperglycemic T2D patients (T2D-N, n=15), and healthy non-diabetic individuals (n=16). The comet assay revealed significantly (p<0.05) higher levels of DNA damage in T2D-H group compared to both T2D-N and control groups, while a significant difference was not observed between the control and T2D-N groups. After bioinformatics analysis, the differentially expressed mRNAs were subjected to functional enrichment analysis (DAVID) and inflammatory response was among the enriched terms found when comparing T2D-N with controls and T2D-H with T2D-N. Concerning the gene set enrichment and gene set analyses, among the differentially expressed gene sets, three were of interest: regulation of DNA repair (T2D-H versus T2D-N), superoxide response (T2D-H versus control group), and response to endoplasmic reticulum stress (T2D-H versus control group). We also identified miRNAs related with T2D and hyperglycemia not yet associated with these conditions in the literature. Some of the differentially expressed mRNAs were among the predicted targets of the differentially expressed miRNAs. Our results showed the association of hyperglycemia with increased DNA damage and aberrant expression of miRNAs and genes related to several biological processes, such as inflammation, DNA repair, ROS production and antioxidant defense, highlighting the importance of proper glycemic control. Moreover, the transcriptional expression of miRNAs provided novel information for understanding the regulatory mechanisms involved in the T2D progression.
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Affiliation(s)
- Danilo J Xavier
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14049-900 Ribeirão Preto, SP, Brazil
| | - Paula Takahashi
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14049-900 Ribeirão Preto, SP, Brazil
| | - Adriane F Evangelista
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14049-900 Ribeirão Preto, SP, Brazil
| | - Maria C Foss-Freitas
- Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14048-900 Ribeirão Preto, SP, Brazil
| | - Milton C Foss
- Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14048-900 Ribeirão Preto, SP, Brazil
| | - Eduardo A Donadi
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14049-900 Ribeirão Preto, SP, Brazil; Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14048-900 Ribeirão Preto, SP, Brazil
| | - Geraldo A Passos
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14049-900 Ribeirão Preto, SP, Brazil; Disciplines of Genetics and Molecular Biology, Department of Morphology, Faculty of Dentistry of Ribeirão Preto, University of São Paulo - USP, Av. Do Café, s/n, Monte Alegre, 14040-904 Ribeirão Preto, SP, Brazil
| | - Elza T Sakamoto-Hojo
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14049-900 Ribeirão Preto, SP, Brazil; Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14040-901 Ribeirão Preto, SP, Brazil.
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Yang P, Reece EA, Wang F, Gabbay-Benziv R. Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling. Am J Obstet Gynecol 2015; 212:569-79. [PMID: 25434839 PMCID: PMC4417047 DOI: 10.1016/j.ajog.2014.11.036] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 11/14/2014] [Accepted: 11/24/2014] [Indexed: 12/25/2022]
Abstract
Maternal diabetes-induced birth defects occur in 6-10% of babies born to mothers with pregestational diabetes, representing a significant maternal-fetal health problem. Currently, these congenital malformations represent a significant maternal-fetal medicine issue, but are likely to create an even greater public health threat as 3 million women of reproductive age (19-44 years) have diabetes in the United States alone, and this number is expected to double by 2030. Neural tube defects (NTDs) and congenital heart defects are the most common types of birth defects associated with maternal diabetes. Animal studies have revealed that embryos under hyperglycemic conditions exhibit high levels of oxidative stress resulting from enhanced production of reactive oxygen species and impaired antioxidant capability. Oxidative stress activates a set of proapoptotic kinase signaling intermediates leading to abnormal cell death in the embryonic neural tube, which causes NTD formation. Work in animal models also has revealed that maternal diabetes triggers a series of signaling intermediates: protein kinase C (PKC) isoforms, PKCα, βII and δ; apoptosis signal-regulating kinase 1; c-Jun-N-terminal kinase (JNK)1/2; caspase; and apoptosis. Specifically, maternal diabetes in rodent models activates the proapoptotic unfolded protein response and endoplasmic reticulum (ER) stress. A reciprocal causation between JNK1/2 activation and ER stress exists in diabetic embryopathy. Molecular studies further demonstrate that deletion of the genes for Prkc, Ask1, Jnk1, or Jnk2 abolishes maternal diabetes-induced neural progenitor apoptosis and ameliorates NTD formation. Similar preventive effects are also observed when apoptosis signal-regulating kinase 1, JNK1/2, or ER stress is inhibited. Cell membrane stabilizers and antioxidant supplements are also effective in prevention of diabetes-induced birth defects. Mechanistic studies have revealed important insights into our understanding the cause of diabetic embryopathy and have provided a basis for future interventions against birth defects or other pregnancy complications associated with maternal diabetes. The knowledge of a molecular pathway map identified in animal studies has created unique opportunities to identify molecular targets for therapeutic intervention.
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Affiliation(s)
- Peixin Yang
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD.
| | - E Albert Reece
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD
| | - Fang Wang
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD
| | - Rinat Gabbay-Benziv
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD
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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: 45] [Impact Index Per Article: 4.1] [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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Sozen H, Celik OI, Cetin ES, Yilmaz N, Aksozek A, Topal Y, Cigerci IH, Beydilli H. Evaluation of the Protective Effect of Silibinin in Rats with Liver Damage Caused by Itraconazole. Cell Biochem Biophys 2014; 71:1215-23. [DOI: 10.1007/s12013-014-0331-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Xavier DJ, Takahashi P, Manoel-Caetano FS, Foss-Freitas MC, Foss MC, Donadi EA, Passos GA, Sakamoto-Hojo ET. One-week intervention period led to improvements in glycemic control and reduction in DNA damage levels in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2014; 105:356-63. [PMID: 25043705 DOI: 10.1016/j.diabres.2014.06.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 02/01/2014] [Accepted: 06/13/2014] [Indexed: 01/09/2023]
Abstract
AIMS Hyperglycemia leads to increased production of reactive oxygen species (ROS), which reduces cellular antioxidant defenses and induces several DNA lesions. We investigated the effects on DNA damage of a seven-day hospitalization period in patients with type 2 diabetes mellitus (T2DM) to achieve adequate blood glucose levels through dietary intervention and medication treatment, compared with non-diabetic individuals. METHODS DNA damage levels were evaluated by the alkaline comet assay (with modified and without conventional use of hOGG1 enzyme, which detects oxidized DNA bases) for 10 patients and 16 controls. Real time PCR array method was performed to analyze the transcriptional expression of a set of 84 genes implicated in antioxidant defense and response to oxidative stress in blood samples from T2DM patients (n=6) collected before and after the hospitalization period. RESULTS The seven-day period was sufficient to improve glycemic control and to significantly decrease (p<0.05) DNA damage levels in T2DM patients, although those levels were slightly higher than those in control subjects. We also found a tendency towards a decrease in the levels of oxidative DNA damage in T2DM patients after the hospitalization period. However, for all genes analyzed, a statistically significant difference in the transcriptional expression levels was not observed. CONCLUSIONS The study demonstrated that although the transcriptional expression of the genes studied did not show significant alterations, one-week of glycemic control in hospital resulted in a significant reduction in DNA damage levels detected in T2DM patients, highlighting the importance of an adequate glycemic control.
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Affiliation(s)
- Danilo J Xavier
- Department of Genetics, Faculty of Medicine of Ribeirão Preto (FMRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil
| | - Paula Takahashi
- Department of Genetics, Faculty of Medicine of Ribeirão Preto (FMRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil
| | - Fernanda S Manoel-Caetano
- Department of Genetics, Faculty of Medicine of Ribeirão Preto (FMRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil; Department of Biology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto (FFCLRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil
| | - Maria C Foss-Freitas
- Department of Internal Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo-USP, Ribeirão Preto, SP, Brazil
| | - Milton C Foss
- Department of Internal Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo-USP, Ribeirão Preto, SP, Brazil
| | - Eduardo A Donadi
- Department of Genetics, Faculty of Medicine of Ribeirão Preto (FMRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil; Division of Clinical Immunology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo-USP, Ribeirão Preto, SP, Brazil
| | - Geraldo A Passos
- Department of Genetics, Faculty of Medicine of Ribeirão Preto (FMRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil; Disciplines of Genetics and Molecular Biology, Department of Morphology, Faculty of Dentistry of Ribeirão Preto, University of São Paulo-USP, Ribeirão Preto, SP, Brazil
| | - Elza T Sakamoto-Hojo
- Department of Genetics, Faculty of Medicine of Ribeirão Preto (FMRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil; Department of Biology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto (FFCLRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil.
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Kulshrestha A, Jarouliya U, Prasad GBKS, Flora SJS, Bisen PS. Arsenic-induced abnormalities in glucose metabolism: Biochemical basis and potential therapeutic and nutritional interventions. World J Transl Med 2014; 3:96-111. [DOI: 10.5528/wjtm.v3.i2.96] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 06/21/2014] [Accepted: 07/17/2014] [Indexed: 02/05/2023] Open
Abstract
Health hazards due to the consumption of heavy metals such as arsenic have become a worldwide problem. Metabolism of arsenic produces various intermediates which are more toxic and cause toxicity. Arsenic exposure results in impairment of glucose metabolism, insulin secretion in pancreatic β-cells, altered gene expressions and signal transduction, and affects insulin-stimulated glucose uptake in adipocytes or skeletal muscle cells. Arsenic toxicity causes abnormalities in glucose metabolism through an increase in oxidative stress. Arsenic interferes with the sulfhydryl groups and phosphate groups present in various enzymes involved in glucose metabolism including pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and contributes to their impairment. Arsenic inhibits glucose transporters present in the cell membrane, alters expression of genes involved in glucose metabolism, transcription factors and inflammatory cytokines which stimulate oxidative stress. Some theories suggest that arsenic exposure under diabetic conditions inhibits hyperglycemia. However, the exact mechanism behind the behavior of arsenic as an antagonist or synergist on glucose homeostasis and insulin secretion is not yet fully understood. The present review delineates the relationship between arsenic and the biochemical basis of its relationship to glucose metabolism. This review also addresses potential therapeutic and nutritional interventions for attenuating arsenic toxicity. Several other potential nutritional supplements are highlighted in the review that could be used to combat arsenic toxicity.
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The comet assay as a tool for human biomonitoring studies: The ComNet Project. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2014; 759:27-39. [DOI: 10.1016/j.mrrev.2013.10.001] [Citation(s) in RCA: 161] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 10/17/2013] [Accepted: 10/23/2013] [Indexed: 02/07/2023]
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Markers of Oxidative Stress during Diabetes Mellitus. J Biomark 2013; 2013:378790. [PMID: 26317014 PMCID: PMC4437365 DOI: 10.1155/2013/378790] [Citation(s) in RCA: 434] [Impact Index Per Article: 36.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2013] [Accepted: 11/07/2013] [Indexed: 11/17/2022] Open
Abstract
The prevalence of diabetes mellitus is rising all over the world. Uncontrolled state of hyperglycemia due to defects in insulin secretion/action leads to a variety of complications including peripheral vascular diseases, nephropathy, neuropathy, retinopathy, morbidity, and/or mortality. Large body of evidence suggests major role of reactive oxygen species/oxidative stress in development and progression of diabetic complications. In the present paper, we have discussed the recent researches on the biomarkers of oxidative stress during type 2 diabetes mellitus.
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Storr SJ, Woolston CM, Zhang Y, Martin SG. Redox environment, free radical, and oxidative DNA damage. Antioxid Redox Signal 2013; 18:2399-408. [PMID: 23249296 DOI: 10.1089/ars.2012.4920] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
SIGNIFICANCE Effective redox homeostasis is critical, and disruption of this process can have important cellular consequences. An array of systems protect the cell from potentially damaging reactive oxygen species (ROS), however if these systems are overwhelmed, for example, in aberrantly functioning cells, ROS can have a number of detrimental consequences, including DNA damage. Oxidative DNA damage can be repaired by a number of DNA repair pathways, such as base excision repair (BER). RECENT ADVANCES The role of ROS in oxidative DNA damage is well established, however, there is an emerging role for ROS and the redox environment in modulating the efficiency of DNA repair pathways targeting oxidative DNA lesions. CRITICAL ISSUES Oxidative DNA damage and modulation of DNA damage and repair by the redox environment are implicated in a number of diseases. Understanding how the redox environment plays such a critical role in DNA damage and repair will allow us to further understand the far reaching cellular consequence of ROS. FUTURE DIRECTIONS In this review, we discuss the detrimental effects of ROS, oxidative DNA damage repair, and the redox systems that exist to control redox homeostasis. We also describe how DNA pathways can be modulated by the redox environment and how the redox environment and oxidative DNA damage plays a role in disease.
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Affiliation(s)
- Sarah J Storr
- Academic Oncology, University of Nottingham, School of Molecular Medical Sciences, Nottingham University Hospitals Trust, City Hospital Campus, Nottingham, United Kingdom
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Moresco RN, Sangoi MB, De Carvalho JAM, Tatsch E, Bochi GV. Diabetic nephropathy: traditional to proteomic markers. Clin Chim Acta 2013; 421:17-30. [PMID: 23485645 DOI: 10.1016/j.cca.2013.02.019] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 02/06/2013] [Accepted: 02/09/2013] [Indexed: 01/11/2023]
Abstract
Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes and it is defined as a rise in the urinary albumin excretion (UAE) rate and abnormal renal function. Currently, changes in albuminuria are considered a hallmark of onset or progression of DN. However, some patients with diabetes have advanced renal pathological changes and progressive kidney function decline even if urinary albumin levels are in the normal range, indicating that albuminuria is not the perfect marker for the early detection of DN. The present article provides an overview of the literature reporting some relevant biomarkers that have been found to be associated with DN and that potentially may be used to predict the onset and/or monitor the progression of nephropathy. In particular, biomarkers of renal damage, inflammation, and oxidative stress may be useful tools for detection at an early stage or prediction of DN. Proteomic-based biomarker discovery represents a novel strategy to improve diagnosis, prognosis and treatment of DN; however, proteomics-based approaches are not yet available in most of the clinical chemistry laboratories. The use of a panel with a combination of biomarkers instead of urinary albumin alone seems to be an interesting approach for early detection of DN, including markers of glomerular damage (e.g., albumin), tubular damage (e.g., NAG and KIM-1), inflammation (e.g., TNF-α) and oxidative stress (e.g., 8-OHdG) because these mechanisms contribute to the development and outcomes of this disease.
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Affiliation(s)
- Rafael N Moresco
- Laboratório de Pesquisa em Bioquímica Clínica, Departamento de Análises Clínicas e Toxicológicas, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
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Müllner E, Brath H, Pleifer S, Schiermayr C, Baierl A, Wallner M, Fastian T, Millner Y, Paller K, Henriksen T, Poulsen HE, Forster E, Wagner KH. Vegetables and PUFA-rich plant oil reduce DNA strand breaks in individuals with type 2 diabetes. Mol Nutr Food Res 2012; 57:328-38. [PMID: 23148048 DOI: 10.1002/mnfr.201200343] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Revised: 08/23/2012] [Accepted: 09/15/2012] [Indexed: 12/30/2022]
Abstract
SCOPE Type 2 diabetes is a multifactorial disease associated with increased oxidative stress, which may lead to increased DNA damage. The aim of this study was to investigate the effect of a healthy diet on DNA oxidation in diabetics and nondiabetics. METHODS AND RESULTS Seventy-six diabetic and 21 nondiabetic individuals participated in this study. All subjects received information about the benefits of a healthy diet, while subjects randomly assigned to the intervention group received additionally 300 g of vegetables and 25 mL PUFA-rich plant oil per day. DNA damage in mononuclear cells (Comet Assay), urinary excretion of 8-oxo-7-hydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and glycated hemoglobin (HbA1c) were measured at baseline, after 4, 8 (end of intervention), and 16 weeks. The intervention with vegetables and PUFA-rich oil led to a significant increase in plasma antioxidant concentrations. Diabetic individuals of the intervention group showed a significant reduction in HbA1c and DNA strand breaks. Levels of HbA1c were also improved in diabetics of the information group, but oxidative damage to DNA was not altered. Urinary 8-oxodG and 8-oxoGuo excretion remained unchanged in both groups. CONCLUSIONS This study provides evidence that a healthy diet rich in antioxidants reduces levels of DNA strand breaks in diabetic individuals.
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Affiliation(s)
- Elisabeth Müllner
- Department of Nutritional Sciences, Emerging Field Oxidative Stress and DNA Stability, University of Vienna, Vienna, Austria.
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Pang J, Xi C, Dai Y, Gong H, Zhang TM. Altered expression of base excision repair genes in response to high glucose-induced oxidative stress in HepG2 hepatocytes. Med Sci Monit 2012; 18:BR281-5. [PMID: 22739728 PMCID: PMC3560773 DOI: 10.12659/msm.883206] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background It is widely accepted that chronic hyperglycemia induces DNA oxidative damage in type 2 diabetes, but little is known about the effect of hyperglycemia on the DNA repair system which plays a critical role in the maintenance of genomic DNA stability in diabetes. Material/Methods To investigate the alteration of base excision repair (BER) genes under hyperglycemia, the relative expression of the mRNAs of the BER genes – ogg1, polβ, lig3, xrcc1, and parp1 – were quantified using real-time PCR in HepG2 hepatocytes incubated with 5.5 mM or 30 mM glucose. Results High levels of glucose induced ROS accumulation and DNA damage, paralleling the dynamic alterations of BER mRNA expression. Compared to 5.5 mM glucose-treated cells, ogg1 and polβ mRNA expression transiently increased at day 1 and decreased after day 4 in cells exposed to 30 mM glucose. Exposure to 30 mM glucose increased the activity of PARP1, which led to reduced cellular NAD content and insulin receptor phosphorylation. Conclusions Exposure to high concentrations of glucose initially led to the increased expression of BER mRNAs to counteract hyperglycemia-induced DNA damage; however, long-term exposure to high glucose concentrations reduced the expression of mRNA from BER genes, leading to accumulated DNA damage.
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Affiliation(s)
- Jing Pang
- The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, China
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Tatsch E, Bochi GV, Piva SJ, De Carvalho JA, Kober H, Torbitz VD, Duarte T, Signor C, Coelho AC, Duarte MM, Montagner GF, Da Cruz IB, Moresco RN. Association between DNA strand breakage and oxidative, inflammatory and endothelial biomarkers in type 2 diabetes. Mutat Res 2012; 732:16-20. [DOI: 10.1016/j.mrfmmm.2012.01.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2011] [Revised: 01/14/2012] [Accepted: 01/14/2012] [Indexed: 04/09/2023]
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Wrońska-Nofer T, Nofer JR, Jajte J, Dziubałtowska E, Szymczak W, Krajewski W, Wąsowicz W, Rydzyński K. Oxidative DNA damage and oxidative stress in subjects occupationally exposed to nitrous oxide (N(2)O). Mutat Res 2012; 731:58-63. [PMID: 22085808 DOI: 10.1016/j.mrfmmm.2011.10.010] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2011] [Revised: 09/27/2011] [Accepted: 10/25/2011] [Indexed: 05/31/2023]
Abstract
OBJECTIVES Occupational exposure to nitrous oxide (N(2)O) and/or halogenated hydrocarbons has been suggested to induce damage of genetic material, but the underlying mechanisms remain obscure. This study investigated the role of oxidative processes in the genotoxicity associated with exposure to waste anaesthetic gases. METHODS The study was performed in 36 female nurses and in 36 unexposed female health care workers matched for age and employment duration. Genotoxic effects were examined by Comet test modification employing formamidopyrimidine glycosylase (FPG) that allows assessment of oxidative DNA damage. Reactive oxygen species (ROS) in leukocytes were investigated by fluorescence spectroscopy with 2',7'-dichlorofluorescin diacetate. Oxidative stress markers including 8-iso-prostaglandin F(2α) (8-iso-PGF(2α)), thiobarbituric acid-reacive substances (TBARS), α-tocopherol, and glutathione peroxidise (GPX) activity were measured immuno- or colorimetrically. N(2)O, sevoflurane and isoflurane were monitored by gas chromatography and mass spectrometry. RESULTS The study documents for the first time the positive correlation between the oxidative DNA damage and the N(2)O levels in the ambient air. By contrast, no association was observed between genotoxic effects and sevoflurane or isoflurane. In addition, ROS generation and plasma and urine concentrations of TBARS and 8-iso-PGF(2α), respectively, were elevated, while GPX activity was reduced in nurses exposed to waste anaesthetic gases. Path analysis pointed to a causal relationship between N(2)O exposure, oxidative stress and DNA damage. CONCLUSION Occupational exposure to N(2)O is associated with increased oxidative DNA damage and the level of exposure plays a critical role in this regard. Increased oxidative stress may represent a mechanistic link between chronic N(2)O exposure and genotoxicity.
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Affiliation(s)
- Teresa Wrońska-Nofer
- Department of Toxicology and Carcinogeneis, Nofer Institute of Occupational Medicine, Lodz, Poland.
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Su H, Velly AM, Salah MH, Benarroch M, Trifiro M, Schipper HM, Gornitsky M. Altered redox homeostasis in human diabetes saliva. J Oral Pathol Med 2011; 41:235-41. [PMID: 22077396 DOI: 10.1111/j.1600-0714.2011.01092.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Oxidative stress has been implicated in the pathogenesis of diabetes mellitus (DM). Levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-epi-prostaglandin-F(2α) (8-epi-PGF2α), and total protein carbonyls were measured to assess whether DM is associated with altered salivary redox homeostasis. METHODS A total of 215 patients with diabetes and 481 healthy controls were recruited from the Department of Endocrinology at the Jewish General Hospital in Montreal. Levels of oxidative biomarkers were assayed using enzyme-linked immunosorbent assay (ELISA) in whole unstimulated saliva. Associations of the redox data with exposure to insulin, metformin and dietary control were assessed by logistic regression analyses. RESULTS We observed (i) significantly higher mean levels of 8-OHdG and protein carbonyls in whole unstimulated saliva of patients with diabetes compared to controls, (ii) higher mean levels of protein carbonyls in type 1 diabetes as well as higher mean levels of 8-OHdG and protein carbonyls in type 2 diabetes compared to controls, (iii) elevated levels of protein carbonyls in diet-controlled patients and in patients with diabetes on insulin and metformin, (iv) elevated levels of 8-OHdG in patients on metformin, and (v) significant associations between subjects with DM and salivary 8-OHdG and protein carbonyls. CONCLUSION DM is associated with increased oxidative modification of salivary DNA and proteins. Salivary redox homeostasis is perturbed in DM and may inform on the presence of the disease and efficacy of therapeutic interventions.
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Affiliation(s)
- Haixiang Su
- Center for Neurotranslational Research, Lady Davis Institute for Medical Research, Montreal, QC, Canada
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Pácal L, Varvařovská J, Rušavý Z, Lacigová S, Stětina R, Racek J, Pomahačová R, Tanhäuserová V, Kaňková K. Parameters of oxidative stress, DNA damage and DNA repair in type 1 and type 2 diabetes mellitus. Arch Physiol Biochem 2011; 117:222-30. [PMID: 21338322 DOI: 10.3109/13813455.2010.551135] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVES (i) to determine the extent of oxidative stress and DNA damage and repair using a panel of selected markers in patients with type 1 and type 2 diabetes mellitus (T1DM, T2DM), (ii) to find their possible relationships with diabetes compensation and duration, and finally (iii) to test for the effect of functional polymorphisms in the 8-oxoguanin DNA glycosylase (rs1052133), catalase (rs1001179) and superoxide dismutase (rs4880) genes on respective intermediate phenotypes. METHODS A total of 207 subjects (23 children and 44 adults with T1DM, 52 adult patients with T2DM and 88 healthy adult control subjects) were enrolled in the study. The following markers of redox state were determined in participants: erythrocyte superoxide dismutase (Ery-SOD), whole blood glutathione peroxidase (WB-GPx), erythrocyte glutathione (Ery-GSH), plasma total antioxidant capacity (P-tAOC) and plasma malondialdehyde (P-MDA). Furthermore, the extent of DNA damage and repair was ascertained using the following parameters: DNA single strand breaks (DNAssb), DNA repair capacity (DNArc) and DNA repair index (DNRI). RESULTS Comparison of T1DM vs. T2DM patients revealed significantly higher Ery-GSH content (P < 0.0001) and significantly lower Ery-SOD activity (P = 0.0006) and P-tAOC level (P < 0.0001) in T1DM subjects. T2DM diabetics exhibited a significant increase in DNAssb (P < 0.0001) and significant decrease in both DNArc (P < 0.0001) and DNRI (P < .0001) compared with T1DM patients. Patient's age (irrespective of DM type) significantly correlated with DNAssb (r = 0.48, P < 0.0001), DNArc (r = -0.67, P < 0.0001) and DNRI (r = -0.7, P < 0.0001). Allele frequencies of all studied polymorphisms did not exhibit any significant association with the investigated parameters. CONCLUSION We demonstrated significant age- and DM type-related changes of oxidative DNA modification and capacity for its repair in subjects with T1DM and T2DM.
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Affiliation(s)
- Lukáš Pácal
- Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno.
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Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology 2011; 283:65-87. [PMID: 21414382 DOI: 10.1016/j.tox.2011.03.001] [Citation(s) in RCA: 2264] [Impact Index Per Article: 161.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2010] [Revised: 02/28/2011] [Accepted: 03/01/2011] [Indexed: 11/30/2022]
Abstract
Detailed studies in the past two decades have shown that redox active metals like iron (Fe), copper (Cu), chromium (Cr), cobalt (Co) and other metals undergo redox cycling reactions and possess the ability to produce reactive radicals such as superoxide anion radical and nitric oxide in biological systems. Disruption of metal ion homeostasis may lead to oxidative stress, a state where increased formation of reactive oxygen species (ROS) overwhelms body antioxidant protection and subsequently induces DNA damage, lipid peroxidation, protein modification and other effects, all symptomatic for numerous diseases, involving cancer, cardiovascular disease, diabetes, atherosclerosis, neurological disorders (Alzheimer's disease, Parkinson's disease), chronic inflammation and others. The underlying mechanism of action for all these metals involves formation of the superoxide radical, hydroxyl radical (mainly via Fenton reaction) and other ROS, finally producing mutagenic and carcinogenic malondialdehyde (MDA), 4-hydroxynonenal (HNE) and other exocyclic DNA adducts. On the other hand, the redox inactive metals, such as cadmium (Cd), arsenic (As) and lead (Pb) show their toxic effects via bonding to sulphydryl groups of proteins and depletion of glutathione. Interestingly, for arsenic an alternative mechanism of action based on the formation of hydrogen peroxide under physiological conditions has been proposed. A special position among metals is occupied by the redox inert metal zinc (Zn). Zn is an essential component of numerous proteins involved in the defense against oxidative stress. It has been shown, that depletion of Zn may enhance DNA damage via impairments of DNA repair mechanisms. In addition, Zn has an impact on the immune system and possesses neuroprotective properties. The mechanism of metal-induced formation of free radicals is tightly influenced by the action of cellular antioxidants. Many low-molecular weight antioxidants (ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), glutathione (GSH), carotenoids, flavonoids, and other antioxidants) are capable of chelating metal ions reducing thus their catalytic activity to form ROS. A novel therapeutic approach to suppress oxidative stress is based on the development of dual function antioxidants comprising not only chelating, but also scavenging components. Parodoxically, two major antioxidant enzymes, superoxide dismutase (SOD) and catalase contain as an integral part of their active sites metal ions to battle against toxic effects of metal-induced free radicals. The aim of this review is to provide an overview of redox and non-redox metal-induced formation of free radicals and the role of oxidative stress in toxic action of metals.
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Affiliation(s)
- Klaudia Jomova
- Department of Chemistry, Faculty of Natural Sciences, Constantine The Philosopher University, SK-949 74 Nitra, Slovakia.
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Leukocyte DNA damage in children with iron deficiency anemia: effect of iron supplementation. Eur J Pediatr 2010; 169:951-6. [PMID: 20169450 DOI: 10.1007/s00431-010-1147-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2009] [Accepted: 01/18/2010] [Indexed: 10/19/2022]
Abstract
Iron deficiency is frequently associated with anemia. Iron is a transition-metal ion, and it can induce free radical formation, which leads to formation of various lesions in DNA, proteins, and lipids. The aim of this study was to investigate baseline oxidative DNA damage and to clarify the role of the administration of a therapeutic dose of iron on DNA oxidation in children with iron deficiency anemia (IDA). Twenty-seven children with IDA and 20 healthy children were enrolled in the study. Leukocyte DNA damage (strand breaks and Fpg-sensitive sites) was assessed using comet assay before and after 12 weeks of daily iron administration. Before the iron administration, the frequency of DNA strand breaks in the children with IDA was found to be lower than those in the control group (P < 0.05), but there was not a significant difference for frequency of Fpg-sensitive sites. After 12 weeks of iron administration, the frequency of both DNA strand breaks and Fpg-sensitive sites were found to be increased (P < 0.01). No significant association was determined between DNA damage parameters and hemoglobin, hematocrit, serum iron, total iron binding capacity, and ferritin. In conclusion, basal level of DNA strand breaks is at a low level in children with IDA. After iron administration, DNA strand breaks and Fpg-sensitive sites, which represent oxidatively damaged DNA, increased. However, this increase was unrelated to serum level of iron and ferritin.
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Hasbal C, Aksu BY, Himmetoglu S, Dincer Y, Koc EE, Hatipoglu S, Akcay T. DNA damage and glutathione level in children with asthma bronchiale: effect of antiasthmatic therapy. Pediatr Allergy Immunol 2010; 21:e674-8. [PMID: 19840299 DOI: 10.1111/j.1399-3038.2009.00959.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
When the production of reactive oxygen species (ROS) exceeds the capacity of antioxidant defences, a condition known as oxidative stress occurs and it has been implicated in many pathological conditions including asthma. Interaction of ROS with DNA may result in mutagenic oxidative base modifications such as 8-hydroxydeoxyguanosine (8-oxo-dGuo) and DNA strand breaks. Reduced glutathione (GSH) serves as a powerful antioxidant against harmful effects of ROS. The aim of this study was to describe DNA damage as level of DNA strand breaks and formamidopyrimidine DNA glycosylase (Fpg)-sensitive sites, which reflects oxidative DNA damage and GSH level in children with mild-to-moderate persistent asthma; and to examine the effect of antiasthmatic therapy on these DNA damage parameters and GSH level. Before and after 8 wk of antiasthmatic therapy blood samples were taken, DNA strand breaks and Fpg-sensitive sites in peripheral leukocytes were determined by comet assay, GSH level of whole blood was measured by spectrophotometric method. DNA strand breaks and Fpg-sensitive sites in the asthma group were found to be increased as compared with control group. GSH level in the asthma group was not significantly different from those in the control group. Levels of strand breaks, Fpg-sensitive sites and GSH were found to be decreased in the asthma group after the treatment. In conclusion, oxidative DNA damage (strand breaks and Fpg-sensitive sites) is at a high level in children with asthma. DNA damage parameters and GSH level were found to be decreased after therapy. Our findings imply that antiasthmatic therapy including glucocorticosteroids not only controls asthma but also decreases mutation risk in children with asthma bronchiale.
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Affiliation(s)
- Canan Hasbal
- Department of Pediatrics, Bakirkoy Dr. Sadi Konuk Education And Research Hospital, Istanbul, Turkey
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Glycaemic status in relation to oxidative stress and inflammation in well-controlled type 2 diabetes subjects. Br J Nutr 2009; 101:1423-6. [PMID: 19459227 DOI: 10.1017/s0007114508076204] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The aim of the present observational study was to investigate the relationships between glycaemic status and levels of oxidative stress and inflammation in well-controlled type 2 diabetes subjects. Metabolic variables (weight, BMI, waist circumference (waist), blood glucose, glycated Hb (HbA(1c)), insulin, blood lipids), biomarkers of oxidative stress (8-iso-PGF(2alpha), malondialdehyde, 8-oxo-7,8-dihydro-2'-deoxyguanosine, formamido pyrimidine glycosylase-sites, frequency of micronucleated erythrocytes, nitrotyrosine) and inflammatory markers (high sensitivity C-reactive protein (hsCRP), IL-6, cyclo-oxygenase-catalyzed PGF(2alpha)-metabolite) were measured. Fifty-six patients (thirty women and twenty-six men, age 62.3 (SD 7.0) years, HbA(1c) 6.1 (SD 0.9) %, BMI 28.3 (SD 3.8) kg/m(2), waist 99.6 (SD 11.1) cm) were included in the study. HbA(1c) (r 0.29, P=0.03) and blood glucose (r 0.33, P=0.01) correlated positively with 8-iso-PGF(2alpha). Positive correlations were also observed between HbA(1c) and nitrotyrosine (r 0.42, P=0.01), waist and hsCRP (r 0.37, P=0.005), hsCRP and IL-6 (r 0.61, P<0.0001) and between PGF(2alpha)-metabolite and 8-iso-PGF(2alpha) (r 0.27, P=0.048). The present study indicates that glycaemic status is associated with oxidative stress even in subjects with well-controlled type 2 diabetes. Furthermore, inflammation was more related to abdominal obesity than to glycaemic control. A large number of biomarkers of oxidative stress and inflammation were investigated, but only a few associations were found between the markers. This could be due to the fact that none of these biomarkers biosynthesises via similar pathways or simultaneously owing to their diverse nature and origin.
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Evaluation of chromosome aberrations, sister chromatid exchange and micronuclei in patients with type-1 diabetes mellitus. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2009; 676:1-4. [DOI: 10.1016/j.mrgentox.2009.02.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2008] [Revised: 02/16/2009] [Accepted: 02/20/2009] [Indexed: 11/20/2022]
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Differential action of methylselenocysteine in control and alloxan-diabetic rabbits. Chem Biol Interact 2009; 177:161-71. [DOI: 10.1016/j.cbi.2008.10.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2008] [Revised: 10/02/2008] [Accepted: 10/06/2008] [Indexed: 01/25/2023]
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Bagatini PB, Palazzo RP, Rodrigues MT, Costa CH, Maluf SW. Induction and removal of DNA damage in blood leukocytes of patients with type 2 diabetes mellitus undergoing hemodialysis. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2008; 657:111-5. [DOI: 10.1016/j.mrgentox.2008.08.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Revised: 08/06/2008] [Accepted: 08/07/2008] [Indexed: 01/06/2023]
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Winiarska K, Szymanski K, Gorniak P, Dudziak M, Bryla J. Hypoglycaemic, antioxidative and nephroprotective effects of taurine in alloxan diabetic rabbits. Biochimie 2008; 91:261-70. [PMID: 18957317 DOI: 10.1016/j.biochi.2008.09.006] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2008] [Accepted: 09/26/2008] [Indexed: 12/31/2022]
Abstract
The therapeutic potential of taurine was investigated under diabetic conditions. Alloxan diabetic rabbits were treated daily for three weeks with 1% taurine in drinking water. The following parameters were measured: 1) serum glucose, urea, creatinine and hydroxyl free radical (HFR) levels; 2) blood glutathione redox state; 3) urine albumin concentration; 4) hepatic and renal HFR levels, GSH/GSSG ratios and the activities of catalase, superoxide dismutase and the enzymes of glutathione metabolism; 5) renal NADPH oxidase activity; 6) the rates of renal and hepatic gluconeogenesis. Histological studies of kidneys were also performed. Taurine administration to diabetic rabbits resulted in 30% decrease in serum glucose level and the normalisation of diabetes-elevated rate of renal gluconeogenesis. It also decreased serum urea and creatinine concentrations, attenuated diabetes-evoked decline in GSH/GSSG ratio and abolished hydroxyl free radicals accumulation in serum, liver and kidney cortex. Animals treated with taurine exhibited elevated activities of hepatic gamma-glutamylcysteine syntetase and renal glutathione reductase and catalase. Moreover, taurine treatment evoked the normalisation of diabetes-stimulated activity of renal NADPH oxidase and attenuated both albuminuria and glomerulopathy characteristic of diabetes. In view of these data, it is concluded that: 1) diminished rate of renal gluconeogenesis seems to contribute to hypoglycaemic effect of taurine; 2) taurine-induced increase in the activities of catalase and the enzymes of glutathione metabolism is of importance for antioxidative action of this amino acid and 3) taurine nephroprotective properties might result from diminished renal NADPH oxidase activity. Thus, taurine seems to be beneficial for the therapy of both diabetes and diabetic nephropathy.
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Affiliation(s)
- Katarzyna Winiarska
- Department of Metabolic Regulation, Institute of Biochemistry, University of Warsaw, Poland.
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