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Jomova K, Raptova R, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Valko M. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging. Arch Toxicol 2023; 97:2499-2574. [PMID: 37597078 PMCID: PMC10475008 DOI: 10.1007/s00204-023-03562-9] [Citation(s) in RCA: 667] [Impact Index Per Article: 333.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 07/24/2023] [Indexed: 08/21/2023]
Abstract
A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or "good stress" and is characterized by low to mild levels of oxidants involved in the regulation of various biochemical transformations such as carboxylation, hydroxylation, peroxidation, or modulation of signal transduction pathways such as Nuclear factor-κB (NF-κB), Mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase, nuclear factor erythroid 2-related factor 2 (Nrf2) and other processes. Increased levels of ROS/RNS, generated from both endogenous (mitochondria, NADPH oxidases) and/or exogenous sources (radiation, certain drugs, foods, cigarette smoking, pollution) result in a harmful condition termed oxidative stress ("bad stress"). Although it is widely accepted, that many chronic diseases are multifactorial in origin, they share oxidative stress as a common denominator. Here we review the importance of oxidative stress and the mechanisms through which oxidative stress contributes to the pathological states of an organism. Attention is focused on the chemistry of ROS and RNS (e.g. superoxide radical, hydrogen peroxide, hydroxyl radicals, peroxyl radicals, nitric oxide, peroxynitrite), and their role in oxidative damage of DNA, proteins, and membrane lipids. Quantitative and qualitative assessment of oxidative stress biomarkers is also discussed. Oxidative stress contributes to the pathology of cancer, cardiovascular diseases, diabetes, neurological disorders (Alzheimer's and Parkinson's diseases, Down syndrome), psychiatric diseases (depression, schizophrenia, bipolar disorder), renal disease, lung disease (chronic pulmonary obstruction, lung cancer), and aging. The concerted action of antioxidants to ameliorate the harmful effect of oxidative stress is achieved by antioxidant enzymes (Superoxide dismutases-SODs, catalase, glutathione peroxidase-GPx), and small molecular weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine, and others). Perhaps one of the most effective low molecular weight antioxidants is vitamin E, the first line of defense against the peroxidation of lipids. A promising approach appears to be the use of certain antioxidants (e.g. flavonoids), showing weak prooxidant properties that may boost cellular antioxidant systems and thus act as preventive anticancer agents. Redox metal-based enzyme mimetic compounds as potential pharmaceutical interventions and sirtuins as promising therapeutic targets for age-related diseases and anti-aging strategies are discussed.
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Affiliation(s)
- Klaudia Jomova
- Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, Nitra, 949 74, Slovakia
| | - Renata Raptova
- Faculty of Chemical and Food Technology, Slovak University of Technology, Bratislava, 812 37, Slovakia
| | - Suliman Y Alomar
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Saleh H Alwasel
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50005, Hradec Kralove, Czech Republic
| | - Kamil Kuca
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50005, Hradec Kralove, Czech Republic
| | - Marian Valko
- Faculty of Chemical and Food Technology, Slovak University of Technology, Bratislava, 812 37, Slovakia.
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Baltusnikiene A, Staneviciene I, Jansen E. Beneficial and adverse effects of vitamin E on the kidney. Front Physiol 2023; 14:1145216. [PMID: 37007997 PMCID: PMC10050743 DOI: 10.3389/fphys.2023.1145216] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 03/01/2023] [Indexed: 03/17/2023] Open
Abstract
This article reviews the beneficial and adverse effects of high-dose vitamin E supplementation on the vitamin E status and renal function in human and rodent studies. The high doses of vitamin E, which can cause renal effects, were compared to upper limits of toxicity (UL) as established by various authorities worldwide. In recent mice studies with higher doses of vitamin E, several biomarkers of tissue toxicity and inflammation were found to be significantly elevated. In these biomarker studies, the severity of inflammation and the increased levels of the biomarkers are discussed together with the need to re-evaluate ULs, given the toxic effects of vitamin E on the kidney and emphasizing oxidative stress and inflammation. The controversy in the literature about vitamin E effects on the kidney is mainly caused by the dose-effects relations that do not give a clear view, neither in human nor animals studies. In addition, more recent studies on rodents with new biomarkers of oxidative stress and inflammation give new insights into possible mechanisms. In this review, the controversy is shown and an advice given on the vitamin E supplementation for renal health.
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Affiliation(s)
- Aldona Baltusnikiene
- Department of Biochemistry, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Inga Staneviciene
- Department of Biochemistry, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Eugène Jansen
- Retired from Centre for Health Protection, National Institute for Public Health and the Environment, Bilthoven, Netherlands
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3
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Hayashi D, Mouchlis VD, Okamoto S, Namba T, Wang L, Li S, Ueda S, Yamanoue M, Tachibana H, Arai H, Ashida H, Dennis EA, Shirai Y. Vitamin E functions by association with a novel binding site on the 67 kDa laminin receptor activating diacylglycerol kinase. J Nutr Biochem 2022; 110:109129. [PMID: 35977663 PMCID: PMC10243646 DOI: 10.1016/j.jnutbio.2022.109129] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 03/27/2022] [Accepted: 07/16/2022] [Indexed: 01/13/2023]
Abstract
It is generally recognized that the main function of α-tocopherol (αToc), which is the most active form of vitamin E, is its antioxidant effect, while non-antioxidant effects have also been reported. We previously found that αToc ameliorates diabetic nephropathy via diacylglycerol kinase alpha (DGKα) activation in vivo, and the activation was not related to the antioxidant effect. However, the underlying mechanism of how αToc activates DGKα have been enigmatic. We report that the membrane-bound 67 kDa laminin receptor (67LR), which has previously been shown to serve as a receptor for epigallocatechin gallate (EGCG), also contains a novel binding site for vitamin E, and its association with Vitamin E mediates DGKα activation by αToc. We employed hydrogen-deuterium exchange mass spectrometry (HDX/MS) and molecular dynamics (MD) simulations to identify the specific binding site of αToc on the 67LR and discovered the conformation of the specific hydrophobic pocket that accommodates αToc. Also, HDX/MS and MD simulations demonstrated the detailed binding of EGCG to a water-exposed hydrophilic site on 67LR, while in contrast αToc binds to a distinct hydrophobic site. We demonstrated that 67LR triggers an important signaling pathway mediating non-antioxidant effects of αToc, such as DGKα activation. This is the first evidence demonstrating a membrane receptor for αToc and one of the underlying mechanisms of a non-antioxidant function for αToc.
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Affiliation(s)
- Daiki Hayashi
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Kobe, Japan; Department of Pharmacology, and Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA
| | - Varnavas D Mouchlis
- Department of Pharmacology, and Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA
| | - Seika Okamoto
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Kobe, Japan
| | - Tomoka Namba
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Kobe, Japan
| | - Liuqing Wang
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Kobe, Japan
| | - Sheng Li
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Shuji Ueda
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Kobe, Japan
| | - Minoru Yamanoue
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Kobe, Japan
| | - Hirofumi Tachibana
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan
| | - Hiroyuki Arai
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo Japan
| | - Hitoshi Ashida
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Kobe, Japan
| | - Edward A Dennis
- Department of Pharmacology, and Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA
| | - Yasuhito Shirai
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Kobe, Japan.
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Li J, Yang K, Guo Y, Cao L, Cheng F, Zhang N. Material basis and action mechanism of Euryale Ferox Salisb in preventing and treating diabetic kidney disease. J Food Biochem 2022; 46:e14409. [PMID: 36165567 DOI: 10.1111/jfbc.14409] [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: 04/26/2022] [Revised: 07/14/2022] [Accepted: 08/30/2022] [Indexed: 01/13/2023]
Abstract
The aim of this study was to determine the chemical structure and mechanism of action of Euryale ferox Salisb (ES) in the prevention and treatment of diabetic kidney disease (DKD). The TCMSP, SymMap V2, CTD, DisGeNET, and GeneCards databases were searched for ES components, targets, and DKD targets using the network pharmacology method to identify common drug-disease targets. PPI analysis was used to identify hub genes, which were then followed by DKD clinical relevance, GO, KEGG analysis, and transcription factor prediction. Finally, molecular docking was performed. We discovered 24 components of ES and 72 objectives of ES, 9 of which were clinically relevant and primarily regulated by transcription factors such as HNF4A and PPARG. They are involved primarily in signal transduction, inflammatory responses, TNF regulation, apoptosis, MAPK, and other signaling pathways. The main components are oleic acid targeting the protein encoded by PPARA, LPL, FABP1, and vitamin E binding the protein encoded by MAPK1, TGFB1. In general, this approach provides an effective strategy in which ES acts primarily against DKD through oleic acid and vitamin E, targeting the protein encoded by PPARA, LPL, FABP1, MAPK1 to regulate TNF, apoptosis, MAPK, and other signaling pathways. PRACTICAL APPLICATIONS: Euryale ferox Salisb (ES) is well known for its use in medicine and food. Furthermore, ES contains many nutrients, whose pharmacological properties, including antidepressant, antioxidant, and anti-diabetic action, have been extensively demonstrated by numerous studies. In this article, through network pharmacology combined with clinical correlation analysis and molecular docking, the target and mechanism of ES in the treatment of diabetic kidney disease (DKD) were discussed, which clarified its mechanism at the molecular level. Provides a reference for the further development and utilization of ES.
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Affiliation(s)
- Jun Li
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Kaiping Yang
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Yunhui Guo
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Lukang Cao
- School of Pharmacy, Jinzhou Medical University, Jinzhou, China
| | - Fangling Cheng
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Nannan Zhang
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
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The Role of Diacylglycerol Kinase in the Amelioration of Diabetic Nephropathy. Molecules 2022; 27:molecules27206784. [PMID: 36296376 PMCID: PMC9607625 DOI: 10.3390/molecules27206784] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/05/2022] [Accepted: 10/07/2022] [Indexed: 12/02/2022] Open
Abstract
The drastic increase in the number of patients with diabetes and its complications is a global issue. Diabetic nephropathy, the leading cause of chronic kidney disease, significantly affects patients’ quality of life and medical expenses. Furthermore, there are limited drugs for treating diabetic nephropathy patients. Impaired lipid signaling, especially abnormal protein kinase C (PKC) activation by de novo-synthesized diacylglycerol (DG) under high blood glucose, is one of the causes of diabetic nephropathy. DG kinase (DGK) is an enzyme that phosphorylates DG and generates phosphatidic acid, i.e., DGK can inhibit PKC activation under diabetic conditions. Indeed, it has been proven that DGK activation ameliorates diabetic nephropathy. In this review, we summarize the involvement of PKC and DGK in diabetic nephropathy as therapeutic targets, and its mechanisms, by referring to our recent study.
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Eto E, Maeda Y, Sonoda N, Nakashima N, Kobayashi K, Takayanagi R, Ogawa Y, Inoguchi T. Association of serum total bilirubin levels with progressive renal decline and end-stage kidney disease: 10-year observational cohort study in Japanese patients with diabetes. PLoS One 2022; 17:e0271179. [PMID: 35819962 PMCID: PMC9275719 DOI: 10.1371/journal.pone.0271179] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 06/24/2022] [Indexed: 11/18/2022] Open
Abstract
Objective Previous reports have demonstrated the association of serum bilirubin levels with the progression of diabetic nephropathy. The objective of this study is to assess the association of basal bilirubin levels with progressive renal decline (PRD) and end-stage kidney disease (ESKD). Methods A total of 298 patients with diabetes who visited Kyushu University Hospital (Japan) were recruited and followed up for 10 years. PRD was defined as a negative change in estimated glomerular filtration ratio (eGFR) >3.7%/year, 2.5th percentile. Logistic regression analysis was performed to evaluate the association of total bilirubin levels with PRD and its cut-off point was determined by receiver operating characteristic (ROC) analysis. Kaplan-Meier method and Cox hazard regression analysis were used to evaluate the predictive ability of its cut-off point for ESKD. Results Logistic regression model showed that total bilirubin levels were significantly associated with PRD, and ROC analysis showed that its cut-off point was 0.5 mg/dL. Kaplan-Meier method showed that the percent of patients who reached two endpoints, composite endpoint (ESKD or doubling of creatinine level) or 30% eGFR decline, was significantly higher in the low bilirubin group than in the high bilirubin group (18.5% vs 11.0%, P = 0.045; 49.1% vs 42.1%, P = 0.045, respectively, log-rank test). Cox hazard regression models confirmed the independence of the predictive ability of its cut-off point. Conclusions Serum total bilirubin levels were negatively associated with PRD in diabetic nephropathy and its cut-off point was 0.5 mg/dL. It may be clinically useful for identifying patients at high risk of ESKD.
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Affiliation(s)
- Erina Eto
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasutaka Maeda
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Noriyuki Sonoda
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Naoki Nakashima
- Medical Information Center, Kyushu University Hospital, Fukuoka, Japan
| | - Kunihisa Kobayashi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryoichi Takayanagi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toyoshi Inoguchi
- Fukuoka City Health Promotion Support Center, Fukuoka City Medical Association, Fukuoka, Japan
- * E-mail:
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Nattagh-Eshtivani E, Gheflati A, Barghchi H, Rahbarinejad P, Hachem K, Shalaby MN, Abdelbasset WK, Ranjbar G, Olegovich Bokov D, Rahimi P, Gholizadeh Navashenaq J, Pahlavani N. The role of Pycnogenol in the control of inflammation and oxidative stress in chronic diseases: Molecular aspects. Phytother Res 2022; 36:2352-2374. [PMID: 35583807 DOI: 10.1002/ptr.7454] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/23/2022] [Accepted: 03/15/2022] [Indexed: 02/05/2023]
Abstract
The prevalence of chronic diseases has increased significantly with the rising trend of sedentary lifestyles, reduced physical activity, and dietary modifications in recent decades. Inflammation and oxidative stress play a key role in the pathophysiology of several chronic diseases, such as type II diabetes, cardiovascular diseases, and hepatic conditions. Therefore, reducing inflammation and oxidative stress may be beneficial in the prevention and treatment of various chronic disorders. Since chronic diseases are not completely curable, various methods have been proposed for their control. Complementary therapies and the use of natural antioxidant and antiinflammatory compounds are among these novel approaches. Pycnogenol (PYC) is a natural compound that could control inflammation and oxidative stress. Furthermore, some previous studies have shown that PYC could effectively reduce inflammation through signaling the downstream of insulin receptors, inhibiting the phosphorylation of the serine residues of insulin receptor substrate-1, reducing pro-inflammatory cytokines and oxidative stress indices through the stimulation of antioxidant pathways, increasing free radical scavenging activities, preventing lipid peroxidation, and protecting the erythrocytes in glucose-6-phosphate dehydrogenase-deficient individuals, although these effects have not been fully proved. The present study aimed to comprehensively review the evidence concerning the positive physiological and pharmacological properties of PYC, with an emphasis on the therapeutic potential of this natural component for enhancing human health.
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Affiliation(s)
- Elyas Nattagh-Eshtivani
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Gheflati
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hanieh Barghchi
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Pegah Rahbarinejad
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kadda Hachem
- Laboratory of Biotoxicology, Pharmacognosy and Biological Valorization of Plants (LBPVBP), Faculty of Sciences, University of Saida- Dr Moulay Tahar, Saida, Algeria
| | - Mohammed Nader Shalaby
- Biological Sciences and Sports Health Department, Faculty of Physical Education, Suez Canal University, Ismailia, Egypt
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Golnaz Ranjbar
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, Moscow, Russian Federation
- Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, Moscow, Russian Federation
| | - Pegah Rahimi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Naseh Pahlavani
- Health Sciences Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
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Rojo-Trejo MH, Robles-Osorio ML, Sabath E. Liposoluble vitamins A and E in kidney disease. World J Nephrol 2022; 11:96-104. [PMID: 35733655 PMCID: PMC9160709 DOI: 10.5527/wjn.v11.i3.96] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 08/15/2021] [Accepted: 04/21/2022] [Indexed: 02/06/2023] Open
Abstract
Kidney disease (KD) is characterized by the presence of elevated oxidative stress, and this is postulated as contributing to the high cardiovascular morbidity and mortality in these individuals. Chronic KD (CKD) is related to high grade inflammatory condition and pro-oxidative state that aggravates the progression of the disease by damaging primary podocytes. Liposoluble vitamins (vitamin A and E) are potent dietary antioxidants that have also anti-inflammatory and antiapoptotic functions. Vitamin deficits in CKD patients are a common issue, and multiple causes are related to them: Anorexia, dietary restrictions, food cooking methods, dialysis losses, gastrointestinal malabsorption, etc. The potential benefit of retinoic acid (RA) and α-tocopherol have been described in animal models and in some human clinical trials. This review provides an overview of RA and α tocopherol in KD.
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Affiliation(s)
| | | | - Ernesto Sabath
- Department of Renal Medicine, Nutrition School, Universidad Autónoma de Querétaro, Querétaro 76090, Mexico
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9
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General Health Benefits and Pharmacological Activities of Triticum aestivum L. Molecules 2022; 27:molecules27061948. [PMID: 35335312 PMCID: PMC8953994 DOI: 10.3390/molecules27061948] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/04/2022] [Accepted: 01/10/2022] [Indexed: 02/04/2023] Open
Abstract
Common wheat (Triticum aestivum), one of the world's most consumed cereal grains, is known for its uses in baking and cooking in addition to its medicinal uses. As this plant's medical benefits are enormous and scattered, this narrative review was aimed at describing the pharmacological activities, phytochemistry, and the nutritional values of Triticum aestivum. It is a good source of dietary fiber, resistant starch, phenolic acids, alkylresorcinols, lignans, and diverse antioxidant compounds such as carotenoids, tocopherols and tocotrienols. These constituents provide Triticum aestivum with a wide range of pharmacological properties, including anticancer, antimicrobial, antidiabetic, hypolipemic, antioxidant, laxative, and moisturizing effects. This review summarized the established benefits of wheat in human health, the mode of action, and different clinical, in vitro and in vivo studies for different varieties and cultivars. This review also gives an insight for future research into the better use of this plant as a functional food. More clinical trials, in vivo and in vitro studies are warranted to broaden the knowledge about the effect of Triticum aestivum on nutrition-related diseases prevention, and physical and mental well-being sustenance.
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10
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Hayashi D, Wang L, Ueda S, Yamanoue M, Ashida H, Shirai Y. The mechanisms of ameliorating effect of a green tea polyphenol on diabetic nephropathy based on diacylglycerol kinase α. Sci Rep 2020; 10:11790. [PMID: 32678222 PMCID: PMC7366667 DOI: 10.1038/s41598-020-68716-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 06/16/2020] [Indexed: 12/19/2022] Open
Abstract
Significant efforts have been made to ameliorate diabetic nephropathy (DN) by inhibiting protein kinase C. However, these efforts have not been successful in human trials, suggesting that novel therapeutic strategies are required. Thus far, it has been reported that green tea polyphenol epigallocatechin gallate (EGCg) improved albuminuria in DN in a human trial. Our previous study revealed that activation of diacylglycerol kinase α (DGKα) plays a crucial role in the amelioration of DN and that EGCg activates DGKα. Here, we investigated whether and how DGKα contributes to the amelioration of DN upon stimulation by EGCg by using streptozotocin-induced type 1 diabetic model mice. Our results revealed that EGCg ameliorated albuminuria in DN through DGKα in vivo, and methylated EGCg, which has higher absorption in the plasma improved albuminuria in DN effectively. Additionally, we showed that c-Src mediated EGCg-induced DGKα translocation and colocalized with the 67 kDa laminin receptor, which is an EGCg receptor. Furthermore, EGCg attenuated the loss of podocytes in DN by preventing a decrease in focal adhesion under high glucose conditions. Our results indicate that the DGKα pathway is an attractive therapeutic target and that activating this pathway is a novel strategy for treating DN.
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Affiliation(s)
- Daiki Hayashi
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Kobe University, Rokkodai-Cho 1-1, Nada-Ku, Kobe, 657-8501, Japan
| | - Liuqing Wang
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Kobe University, Rokkodai-Cho 1-1, Nada-Ku, Kobe, 657-8501, Japan
| | - Shuji Ueda
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Kobe University, Rokkodai-Cho 1-1, Nada-Ku, Kobe, 657-8501, Japan
| | - Minoru Yamanoue
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Kobe University, Rokkodai-Cho 1-1, Nada-Ku, Kobe, 657-8501, Japan
| | - Hitoshi Ashida
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Kobe University, Rokkodai-Cho 1-1, Nada-Ku, Kobe, 657-8501, Japan
| | - Yasuhito Shirai
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Kobe University, Rokkodai-Cho 1-1, Nada-Ku, Kobe, 657-8501, Japan.
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Affiliation(s)
- Hunjoo Ha
- Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung H. Kim
- Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea
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12
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Park JY, Ha SW, King GL. The Role of Protein Kinase C Activation in the Pathogenesis of Diabetic Vascular Complications. Perit Dial Int 2020. [DOI: 10.1177/089686089901902s37] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Many vascular diseases in diabetes are known to be associated with the activation of the diacylglycerol (OAG)protein kinase C (PKC) pathway. The major source of OAG that is elevated in diabetes is de novo synthesis from glycolytic intermediates. Among the various PKC isoforms, the β-isoform has been shown to be persistently activated in diabetic animals. Multiple lines of evidence have shown that many vascular alterations in diabetes such as a decrease in the activity of Na+-K+ -adenosine triphosphatase (Na+-K+-ATPase), and increases in extracellular matrix, cytokines, permeability, contractility, and cell proliferation -are caused by activation of PKC. Inhibition of PKC by two different kinds of PKC inhibitors, LY333531, a selective PKC-β-isoform inhibitor, and d-α-tocopherol, were able to prevent or reverse the various vascular dysfunctions in diabetic rats. These results have also provided in vivo evidence that OAG-PKC activation could be responsible for the hyperglycemia-induced vascular dysfunctions in diabetes. Clinical studies are now being performed to clarify the pathogenic roles of the OAG-PKC pathway in developing vascular complications in diabetic patients.
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Affiliation(s)
- Joong Yeol Park
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, U.S.A
| | - Sung-Woo Ha
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, U.S.A
| | - George L. King
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, U.S.A
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13
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Finno CJ, Peterson J, Kang M, Park S, Bordbari MH, Durbin-Johnson B, Settles M, Perez-Flores MC, Lee JH, Yamoah EN. Single-Cell RNA-seq Reveals Profound Alterations in Mechanosensitive Dorsal Root Ganglion Neurons with Vitamin E Deficiency. iScience 2019; 21:720-735. [PMID: 31733517 PMCID: PMC6864320 DOI: 10.1016/j.isci.2019.10.064] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 09/16/2019] [Accepted: 10/28/2019] [Indexed: 12/26/2022] Open
Abstract
Ninety percent of Americans consume less than the estimated average requirements of dietary vitamin E (vitE). Severe vitE deficiency due to genetic mutations in the tocopherol transfer protein (TTPA) in humans results in ataxia with vitE deficiency (AVED), with proprioceptive deficits and somatosensory degeneration arising from dorsal root ganglia neurons (DRGNs). Single-cell RNA-sequencing of DRGNs was performed in Ttpa-/- mice, an established model of AVED. In stark contrast to expected changes in proprioceptive neurons, Ttpa-/- DRGNs showed marked upregulation of voltage-gated Ca2+ and K+ channels in mechanosensitive, tyrosine-hydroxylase positive (TH+) DRGNs. The ensuing significant conductance changes resulted in reduced excitability in mechanosensitive Ttpa-/- DRGNs. A highly supplemented vitE diet (600 mg dl-α-tocopheryl acetate/kg diet) prevented the cellular and molecular alterations and improved mechanosensation. VitE deficiency profoundly alters the molecular signature and functional properties of mechanosensitive TH+ DRGN, representing an intriguing shift of the prevailing paradigm from proprioception to mechanical sensation.
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Affiliation(s)
- Carrie J Finno
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
| | - Janel Peterson
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Mincheol Kang
- Department of Physiology, School of Medicine, University of Nevada, Reno, Reno, NV 89557, USA
| | - Seojin Park
- Department of Physiology, School of Medicine, University of Nevada, Reno, Reno, NV 89557, USA
| | - Matthew H Bordbari
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Blythe Durbin-Johnson
- Bioinformatics Core Facility, Genome Center, University of California, Davis, CA 95616, USA
| | - Matthew Settles
- Bioinformatics Core Facility, Genome Center, University of California, Davis, CA 95616, USA
| | - Maria C Perez-Flores
- Department of Physiology, School of Medicine, University of Nevada, Reno, Reno, NV 89557, USA
| | - Jeong H Lee
- Department of Physiology, School of Medicine, University of Nevada, Reno, Reno, NV 89557, USA
| | - Ebenezer N Yamoah
- Department of Physiology, School of Medicine, University of Nevada, Reno, Reno, NV 89557, USA
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14
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Novel triazine-based pyrimidines suppress glomerular mesangial cells proliferation and matrix protein accumulation through a ROS-dependent mechanism in the diabetic milieu. Bioorg Med Chem Lett 2019; 29:1580-1585. [PMID: 31078409 DOI: 10.1016/j.bmcl.2019.04.052] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 04/29/2019] [Accepted: 04/30/2019] [Indexed: 11/20/2022]
Abstract
Diabetic nephropathy (DN) is one of the most serious complications of diabetes worldwide. It is depicted as the leading cause of end-stage renal disease. Oxidative stress plays a key role in hyperglycemia-induced DN. The preparation and characterization of novel mono-, di-, and trisubstituted-s-triazines endowed with uracil and/or thymine are described in this paper. The synthesis of the title compounds was realized through selective nucleophilic substitution reactions of cyanuric chloride with the corresponding hydrazide nucleobases. In this study, we assessed the effects of these derivatives on the progression of diabetic nephropathy. Our results show that trisubstituted-s-triazines endowed with acylhydrazides attenuate high-glucose induced glomerular mesangial cells proliferation and matrix protein accumulation in vitro. Notably, these derivatives also display anti-oxidative properties. This suggests that the novel trisubstituted-s-triazine derivatives provide renal protection through a reactive oxygen species (ROS)-dependent mechanism. Our data provide evidence that these derivatives may serve as potential therapeutic candidates in the treatment of DN.
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15
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Hayashi D, Tsumagari R, Liu K, Ueda S, Yamanoue M, Sakane F, Shirai Y. Screening of subtype-specific activators and inhibitors for diacylglycerol kinase. J Biochem 2019; 165:517-522. [DOI: 10.1093/jb/mvz008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 02/03/2019] [Indexed: 12/17/2022] Open
Affiliation(s)
- Daiki Hayashi
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Rokkodai-cho 1-1, Nada-ku, Kobe, Japan
| | - Ryosuke Tsumagari
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Rokkodai-cho 1-1, Nada-ku, Kobe, Japan
| | - Ke Liu
- Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba, Japan
| | - Shuji Ueda
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Rokkodai-cho 1-1, Nada-ku, Kobe, Japan
| | - Minoru Yamanoue
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Rokkodai-cho 1-1, Nada-ku, Kobe, Japan
| | - Fumio Sakane
- Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba, Japan
| | - Yasuhito Shirai
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Rokkodai-cho 1-1, Nada-ku, Kobe, Japan
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16
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Zingg JM. Vitamin E: Regulatory Role on Signal Transduction. IUBMB Life 2018; 71:456-478. [PMID: 30556637 DOI: 10.1002/iub.1986] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 11/20/2018] [Accepted: 11/21/2018] [Indexed: 01/02/2023]
Abstract
Vitamin E modulates signal transduction pathways by several molecular mechanisms. As a hydrophobic molecule located mainly in membranes it contributes together with other lipids to the physical and structural characteristics such as membrane stability, curvature, fluidity, and the organization into microdomains (lipid rafts). By acting as the main lipid-soluble antioxidant, it protects other lipids such as mono- and poly-unsaturated fatty acids (MUFA and PUFA, respectively) against chemical reactions with reactive oxygen and nitrogen species (ROS and RNS, respectively) and prevents membrane destabilization and cellular dysfunction. In cells, vitamin E affects signaling in redox-dependent and redox-independent molecular mechanisms by influencing the activity of enzymes and receptors involved in modulating specific signal transduction and gene expression pathways. By protecting and preventing depletion of MUFA and PUFA it indirectly enables regulatory effects that are mediated by the numerous lipid mediators derived from these lipids. In recent years, some vitamin E metabolites have been observed to affect signal transduction and gene expression and their relevance for the regulatory function of vitamin E is beginning to be elucidated. In particular, the modulation of the CD36/FAT scavenger receptor/fatty acids transporter by vitamin E may influence many cellular signaling pathways relevant for lipid homeostasis, inflammation, survival/apoptosis, angiogenesis, tumorigenesis, neurodegeneration, and senescence. Thus, vitamin E has an important role in modulating signal transduction and gene expression pathways relevant for its uptake, distribution, metabolism, and molecular action that when impaired affect physiological and patho-physiological cellular functions relevant for the prevention of a number of diseases. © 2018 IUBMB Life, 71(4):456-478, 2019.
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Affiliation(s)
- Jean-Marc Zingg
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida, USA
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17
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Preservation of renal function in chronic diabetes by enhancing glomerular glucose metabolism. J Mol Med (Berl) 2018; 96:373-381. [PMID: 29574544 DOI: 10.1007/s00109-018-1630-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 02/07/2018] [Accepted: 02/12/2018] [Indexed: 12/24/2022]
Abstract
Diabetic nephropathy (DN) affects approximately 30-40% of patients with type 1 (T1DM) and type 2 diabetes (T2DM). It is a major cause of end-stage renal disease (ESRD) for the developed world. Hyperglycemia and genetics are major causal factors for the initiation and progression of DN. Multiple abnormalities in glucose and mitochondrial metabolism induced by diabetes likely contribute to the severity of DN. Recent clinical studies in people with extreme duration of T1DM (> 50 years, Joslin Medalist Study) have supported the importance of endogenous protective factors to neutralize the toxic effects of hyperglycemia on renal and other vascular tissues. Using renal glomeruli from these patients (namely Medalists) with and without DN, we have shown the importance of increased glycolytic flux in decreasing the accumulation of glucose toxic metabolites, improving mitochondrial function, survival of glomerular podocytes, and reducing glomerular pathology. Activation of a key glycolytic enzyme, pyruvate kinase M2 (PKM2), resulted in the normalization of renal hemodynamics and mitochondrial and glomerular dysfunction, leading to the mitigation of glomerular pathologies in several mouse models of DN.
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18
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Hayashi D, Ueda S, Yamanoue M, Ashida H, Shirai Y. Amelioration of diabetic nephropathy by oral administration of d-α-tocopherol and its mechanisms. Biosci Biotechnol Biochem 2018; 82:65-73. [DOI: 10.1080/09168451.2017.1411184] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Abstract
Diabetic nephropathy (DN) is a diabetic vascular complication, and abnormal protein kinase C (PKC) activation from increased diacylglycerol (DG) production in diabetic hyperglycemia is one of the causes of DN. Diacylglycerol kinase (DGK) converts DG into phosphatidic acid. In other words, DGK can attenuate PKC activity by reducing the amount of DG. Recently, we reported that intraperitoneally administered d-α-tocopherol (vitamin E, αToc) induces an amelioration of DN in vivo through the activation of DGKα and the prevention of podocyte loss. However, the effect of the oral administration of αToc on DN in mice remains unknown. Here, we evaluated the effect of oral administration of αToc on DN and its molecular mechanism using streptozocin-induced diabetic mice. Consequently, the oral administration of αToc significantly ameliorated the symptoms of DN by preventing the loss of podocytes, and it was revealed that the inhibition of PKC activity was involved in this amelioration.
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Affiliation(s)
- Daiki Hayashi
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Kobe, Japan
| | - Shuji Ueda
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Kobe, Japan
| | - Minoru Yamanoue
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Kobe, Japan
| | - Hitoshi Ashida
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Kobe, Japan
| | - Yasuhito Shirai
- Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Kobe, Japan
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19
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Chen Y, Wu G, Xu M. The effect of L-thyroxine substitution on oxidative stress in early-stage diabetic nephropathy patients with subclinical hypothyroidism: a randomized double-blind and placebo-controlled study. Int Urol Nephrol 2017; 50:97-103. [PMID: 29196928 DOI: 10.1007/s11255-017-1756-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 11/20/2017] [Indexed: 12/29/2022]
Abstract
PURPOSE To study oxidative stress status of early type 2 diabetic nephropathy (DN) patients with subclinical hypothyroidism (SCH) and to assess effect of L-thyroxine therapy on the oxidative stress in these patients. METHODS It is a randomized double-blind and placebo-controlled trial. A total of 48 patients with early type 2 DN were included as Euthyroid group, and 92 early type 2 DN with SCH were selected and randomly assigned to L-thyroxine treatment group (LT4 group) and placebo group (SCH group). Changes in urinary albumin excretion rate (UAER), serum malondialdehyde (MDA), superoxide dismutase (SOD) activity, urine 8-hydroxyl deoxyguanosine (8-OHdG), serum creatinine, estimated glomerular filtration rate, and lipid profile before and after 24 weeks of follow-up were examined and compared. RESULTS The levels of UAER, MDA, 8-OHdG were higher, while the SOD activity was lower in DN patients with SCH than in DN patients (p < 0.05 for all). In the LT4 group, the levels of UAER, MDA, 8-OHdG decreased significantly (p < 0.05) to levels no longer different from the Euthyroid group. The SOD activity increased significantly. But in SCH group, the levels of mAlb, MDA, 8-OHdG were greater after 24 weeks of follow-up and greater than patients in the Euthyroid group. SOD activity decreased significantly after 24 weeks in the SCH group (p < 0.05). CONCLUSION Oxidative stress is greater in the DN patients with SCH, and SCH may exacerbate kidney injury in early DN patients. The LT4 treatment may decrease the oxidative stress and attenuate renal injury in DN patient with SCH.
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Affiliation(s)
- Yong Chen
- Department of Nephropathy, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology, 228 Jingui Road, Xianning, 437100, China
| | - Ganlin Wu
- Department of Medicine, School of Clinical Medicine Sciences, Hubei University of science and Technology, 88 Xianning Road, Xianning, 437100, China.
| | - Meirong Xu
- Department of Medicine, The Second Affiliated Hospital of Hubei University of Science and Technology, 58 Chahua Road, Xianning, 437100, China
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20
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Diacylglycerol Kinase alpha is Involved in the Vitamin E-Induced Amelioration of Diabetic Nephropathy in Mice. Sci Rep 2017; 7:2597. [PMID: 28572624 PMCID: PMC5453949 DOI: 10.1038/s41598-017-02354-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 04/10/2017] [Indexed: 02/05/2023] Open
Abstract
Diabetic nephropathy (DN) is one of vascular complications of diabetes and is caused by abnormal protein kinase C activation as a result of increased diacylglycerol (DG) production in diabetic hyperglycaemia. Diacylglycerol kinase (DGK) converts DG into phosphatidic acid. Therefore, it is expected that the activation of DGK would ameliorate DN. Indeed, it has been reported that vitamin E (VtE) ameliorates DN in rat by activating DGK, and we recently reported that VtE specifically activates DGKα isoform in vitro. However, whether DGKα is involved in the VtE-induced amelioration of DN in vivo remains unknown. Therefore, we investigated the VtE-induced amelioration of DN in wild-type (DGKα+/+) and DGKα–deficient (DGKα−/−) mice in which diabetes was induced by streptozocin. Several symptoms of DN were ameliorated by VtE treatment in the DGKα+/+ mice but not in the DGKα−/− mice. Moreover, transmission electron microscopy of glomeruli and immunofluorescent staining of glomerular epithelial cells (podocytes) indicated that VtE ameliorates podocyte pathology and prevents podocyte loss in the DGKα+/+ mice but not in the DGKα−/− mice. We showed that VtE can ameliorate DN in mice and that DGKα is involved in the VtE-induced amelioration of DN in vivo, suggesting that DGKα is an attractive therapeutic target for DN.
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21
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Noh H, Yu MR, Kim HJ, Lee JH, Park BW, Wu IH, Matsumoto M, King GL. Beta 2-adrenergic receptor agonists are novel regulators of macrophage activation in diabetic renal and cardiovascular complications. Kidney Int 2017; 92:101-113. [PMID: 28396116 DOI: 10.1016/j.kint.2017.02.013] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 02/06/2017] [Accepted: 02/09/2017] [Indexed: 01/01/2023]
Abstract
Macrophage activation is increased in diabetes and correlated with the onset and progression of vascular complications. To identify drugs that could inhibit macrophage activation, we developed a cell-based assay and screened a 1,040 compound library for anti-inflammatory effects. Beta2-adrenergic receptor (β2AR) agonists were identified as the most potent inhibitors of phorbol myristate acetate-induced tumor necrosis factor-α production in rat bone marrow macrophages. In peripheral blood mononuclear cells isolated from streptozotocin-induced diabetic rats, β2AR agonists inhibited diabetes-induced tumor necrosis factor-α production, which was prevented by co-treatment with a selective β2AR blocker. To clarify the underlying mechanisms, THP-1 cells and bone marrow macrophages were exposed to high glucose. High glucose reduced β-arrestin2, a negative regulator of NF-κB activation, and its interaction with IκBα. This subsequently enhanced phosphorylation of IκBα and activation of NF-κB. The β2AR agonists enhanced β-arrestin2 and its interaction with IκBα, leading to downregulation of NF-κB. A siRNA specific for β-arrestin2 reversed β2AR agonist-mediated inhibition of NF-κB activation and inflammatory cytokine production. Treatment of Zucker diabetic fatty rats with a β2AR agonist for 12 weeks attenuated monocyte activation as well as pro-inflammatory and pro-fibrotic responses in the kidneys and heart. Thus, β2AR agonists might have protective effects against diabetic renal and cardiovascular complications.
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MESH Headings
- Adrenergic beta-2 Receptor Agonists/pharmacology
- Adrenergic beta-2 Receptor Antagonists/pharmacology
- Animals
- Anti-Inflammatory Agents/pharmacology
- Diabetes Mellitus, Experimental/chemically induced
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/metabolism
- Diabetic Cardiomyopathies/chemically induced
- Diabetic Cardiomyopathies/genetics
- Diabetic Cardiomyopathies/metabolism
- Diabetic Cardiomyopathies/prevention & control
- Diabetic Nephropathies/chemically induced
- Diabetic Nephropathies/genetics
- Diabetic Nephropathies/metabolism
- Diabetic Nephropathies/prevention & control
- Fibrosis
- Humans
- Kidney/drug effects
- Kidney/metabolism
- Kidney/pathology
- Macrophage Activation/drug effects
- Macrophages/drug effects
- Macrophages/metabolism
- Male
- Myocardium/metabolism
- Myocardium/pathology
- NF-KappaB Inhibitor alpha/metabolism
- NF-kappa B/metabolism
- Phosphorylation
- Protein Kinase C/metabolism
- RNA Interference
- Rats, Sprague-Dawley
- Rats, Zucker
- Receptors, Adrenergic, beta-2/drug effects
- Receptors, Adrenergic, beta-2/genetics
- Receptors, Adrenergic, beta-2/metabolism
- Streptozocin
- THP-1 Cells
- Time Factors
- Transfection
- Tumor Necrosis Factor-alpha/metabolism
- beta-Arrestin 2/genetics
- beta-Arrestin 2/metabolism
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Affiliation(s)
- Hyunjin Noh
- Department of Internal Medicine, Soon Chun Hyang University, Seoul, Korea; Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea; Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
| | - Mi Ra Yu
- Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea
| | - Hyun Joo Kim
- Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea
| | - Ji Hye Lee
- Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea
| | - Byoung-Won Park
- Department of Internal Medicine, Soon Chun Hyang University, Seoul, Korea
| | - I-Hsien Wu
- Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Motonobu Matsumoto
- Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - George L King
- Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
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22
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Mehta V, Malairaman U. Flavonoids. PHARMACEUTICAL SCIENCES 2017. [DOI: 10.4018/978-1-5225-1762-7.ch022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Diabetes Mellitus is one of the major healthcare problems faced by the society today and has become alarmingly epidemic in many parts of the world. Despite enormous knowledge and technology advancement, available diabetes therapeutics only provide symptomatic relief by reducing blood glucose level, thereby, just slows down development and progression of diabetes and its associated complications. Thus, the need of the day is to develop alternate strategies that can not only prevent the progression but also reverse already “set-in” diabetic complications. Many flavonoids are reported, traditionally as well as experimentally, to be beneficial in averting diabetes and lowering risk of its accompanying complications. In the present chapter we have convened different flavonoids beneficial in diabetes and comorbid complications and discussed their mechanisms of action. Further, we conclude that coupling current therapeutics with flavonoids might provide exceptional advantage in the management of diabetes and its complications.
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Affiliation(s)
- Vineet Mehta
- Jaypee University of Information Technology, India
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23
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Mima A. Incretin-Based Therapy for Prevention of Diabetic Vascular Complications. J Diabetes Res 2016; 2016:1379274. [PMID: 26881236 PMCID: PMC4735992 DOI: 10.1155/2016/1379274] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 10/15/2015] [Accepted: 10/26/2015] [Indexed: 12/14/2022] Open
Abstract
Diabetic vascular complications are the most common cause of mortality and morbidity worldwide, with numbers of affected individuals steadily increasing. Diabetic vascular complications can be divided into two categories: macrovascular andmicrovascular complications. Macrovascular complications include coronary artery diseaseand cerebrovascular disease, while microvascular complications include retinopathy and chronic kidney disease. These complications result from metabolic abnormalities, including hyperglycemia, elevated levels of free fatty acids, and insulin resistance. Multiple mechanisms have been proposed to mediate the adverse effects of these metabolic disorders on vascular tissues, including stimulation of protein kinase C signaling and activation of the polyol pathway by oxidative stress and inflammation. Additionally, the loss of tissue-specific insulin signaling induced by hyperglycemia and toxic metabolites can induce cellular dysfunction and both macro- and microvascular complications characteristic of diabetes. Despite these insights, few therapeutic methods are available for the management of diabetic complications. Recently, incretin-based therapeutic agents, such as glucagon-like peptide-1 and dipeptidyl peptidase-4 inhibitors, have been reported to elicit vasotropic actions, suggesting a potential for effecting an actual reduction in diabetic vascular complications. The present review will summarize the relationship between multiple adverse biological mechanisms in diabetes and putative incretin-based therapeutic interventions intended to prevent diabetic vascular complications.
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Affiliation(s)
- Akira Mima
- Department of Nephrology, Nara Hospital, Kindai University Faculty of Medicine, Nara 630-0293, Japan
- *Akira Mima:
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24
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Gobbo MG, Dizeyi N, Abrahamsson PA, Bertilsson PA, Masitéli VS, Pytlowanciv EZ, Taboga SR, Góes RM. Influence of Melatonin on the Proliferative and Apoptotic Responses of the Prostate under Normal and Hyperglycemic Conditions. J Diabetes Res 2015; 2015:538529. [PMID: 26295055 PMCID: PMC4534615 DOI: 10.1155/2015/538529] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 06/22/2015] [Accepted: 06/24/2015] [Indexed: 01/23/2023] Open
Abstract
The antitumor properties of melatonin (MLT) are known for prostate cancer cells. This study investigated whether MLT affects prostate maturation and interferes with tissue injuries induced by diabetes. MLT was administered to Wistar rats from 5 weeks of age in the drinking water (10 μg/kg b.w.), and diabetes was induced at the 13th week by streptozotocin (4.5 mg/100g b.w., i.p.). The animals were euthanized in the 14th and 21st weeks. MLT reduced the immunostained cells for androgen receptor (AR) by 10% in younger rats. Diabetes decreased cell proliferation and increased apoptosis. MLT treatment impeded apoptosis (p = 0.02) and augmented proliferation (p = 0.0008) and PCNA content in prostate following long-term diabetes due to restoration of testosterone levels and expression of melatonin receptor type 1B. The effect of MLT (500 µM, 5 mM, and 10 mM) on androgen-dependent (22Rv1) and androgen-independent (PC3) cancer cells and human prostate epithelial cells (PNTA1) under normal and hyperglycemic conditions (HG, 450 mg/dL) was analyzed. Contrary to PNTA1 and 22Rv1 cells, MLT improved the proliferation of PC3 cells in hyperglycemic medium. The combined data indicated that MLT had proliferative and antiapoptotic effects in prostate cells subjected to HG levels and it seems to involve specific MLT pathways rather than AR.
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Affiliation(s)
- Marina G. Gobbo
- Department of Cell Biology, Institute of Biology, UNICAMP, Avenue Bertrand Russel, 6109 Campinas, SP, Brazil
| | - Nishtman Dizeyi
- Department of Clinical Sciences, Division of Urological Research, Skåne University Hospital, Lund University, 205 02 Malmö, Sweden
| | - Per-Anders Abrahamsson
- Department of Clinical Sciences, Division of Urological Research, Skåne University Hospital, Lund University, 205 02 Malmö, Sweden
| | - Per-Anders Bertilsson
- Department of Clinical Sciences, Division of Urological Research, Skåne University Hospital, Lund University, 205 02 Malmö, Sweden
| | - Viviane Sanches Masitéli
- Department of Biology, Institute of Biosciences, Humanities and Exact Sciences, UNESP, São José do Rio Preto, SP, Brazil
| | - Eloisa Zanin Pytlowanciv
- Department of Cell Biology, Institute of Biology, UNICAMP, Avenue Bertrand Russel, 6109 Campinas, SP, Brazil
| | - Sebastião R. Taboga
- Department of Biology, Institute of Biosciences, Humanities and Exact Sciences, UNESP, São José do Rio Preto, SP, Brazil
| | - Rejane M. Góes
- Department of Biology, Institute of Biosciences, Humanities and Exact Sciences, UNESP, São José do Rio Preto, SP, Brazil
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25
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Anaya HA, Yi FX, Boeldt DS, Krupp J, Grummer MA, Shah DM, Bird IM. Changes in Ca2+ Signaling and Nitric Oxide Output by Human Umbilical Vein Endothelium in Diabetic and Gestational Diabetic Pregnancies. Biol Reprod 2015. [PMID: 26203178 DOI: 10.1095/biolreprod.115.128645] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Diabetes (DM) complicates 3%-10% of pregnancies, resulting in significant maternal and neonatal morbidity and mortality. DM pregnancies are also associated with vascular dysfunction, including blunted nitric oxide (NO) output, but it remains unclear why. Herein we examine changes in endothelial NO production and its relationship to Ca(2+) signaling in endothelial cells of intact umbilical veins from control versus gestational diabetic (GDM) or preexisting diabetic subjects. We have previously reported that endothelial cells of intact vessels show sustained Ca(2+) bursting in response to ATP, and these bursts drive prolonged NO production. Herein we show that in both GDM and DM pregnancies, the incidence of Ca(2+) bursts remains similar, but there is a reduction in overall sustained phase Ca(2+) mobilization and a reduction in NO output. Further studies show damage has occurred at the level of NOS3 protein itself. Since exposure to DM serum is known to impair normal human umbilical vein endothelial cell (HUVEC) function, we further studied the ability of HUVEC to signal through Ca(2+) after they were isolated from DM and GDM subjects and maintained in culture for several days. These HUVEC showed differences in the rate of Ca(2+) bursting, with DM > GDM = control HUVEC. Both GDM- and DM-derived HUVEC showed smaller Ca(2+) bursts that were less capable of NOS3 activation compared to control HUVEC. We conclude that HUVEC from DM and GDM subjects are reprogrammed such that the Ca(2+) bursting peak shape and duration are permanently impaired. This may explain why ROS therapy alone is not effective in DM and GDM subjects.
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Affiliation(s)
- Heather A Anaya
- Perinatal Research Laboratories and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin, Madison, Wisconsin Rush University Medical Center, Section of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Chicago, Illinois
| | - Fu-Xian Yi
- Perinatal Research Laboratories and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Derek S Boeldt
- Perinatal Research Laboratories and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Jennifer Krupp
- Perinatal Research Laboratories and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin, Madison, Wisconsin Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Iowa Hospital and Clinics, Iowa City, Iowa
| | - Mary A Grummer
- Perinatal Research Laboratories and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Dinesh M Shah
- Perinatal Research Laboratories and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Ian M Bird
- Perinatal Research Laboratories and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
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Affiliation(s)
- Jean-Marc Zingg
- Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida 33136-6129;
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Hayashi D, Ueda S, Yamanoue M, Saito N, Ashida H, Shirai Y. Epigallocatechin-3-gallate activates diacylglycerol kinase alpha via a 67 kDa laminin receptor: A possibility of galloylated catechins as functional food to prevent and/or improve diabetic renal dysfunctions. J Funct Foods 2015. [DOI: 10.1016/j.jff.2015.04.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Dhall S, Do DC, Garcia M, Kim J, Mirebrahim SH, Lyubovitsky J, Lonardi S, Nothnagel EA, Schiller N, Martins-Green M. Generating and reversing chronic wounds in diabetic mice by manipulating wound redox parameters. J Diabetes Res 2014; 2014:562625. [PMID: 25587545 PMCID: PMC4284939 DOI: 10.1155/2014/562625] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 11/18/2014] [Accepted: 11/18/2014] [Indexed: 01/08/2023] Open
Abstract
By 2025, more than 500 M people worldwide will suffer from diabetes; 125 M will develop foot ulcer(s) and 20 M will undergo an amputation, creating a major health problem. Understanding how these wounds become chronic will provide insights to reverse chronicity. We hypothesized that oxidative stress (OS) in wounds is a critical component for generation of chronicity. We used the db/db mouse model of impaired healing and inhibited, at time of injury, two major antioxidant enzymes, catalase and glutathione peroxidase, creating high OS in the wounds. This was necessary and sufficient to trigger wounds to become chronic. The wounds initially contained a polymicrobial community that with time selected for specific biofilm-forming bacteria. To reverse chronicity we treated the wounds with the antioxidants α-tocopherol and N-acetylcysteine and found that OS was highly reduced, biofilms had increased sensitivity to antibiotics, and granulation tissue was formed with proper collagen deposition and remodeling. We show for the first time generation of chronic wounds in which biofilm develops spontaneously, illustrating importance of early and continued redox imbalance coupled with the presence of biofilm in development of wound chronicity. This model will help decipher additional mechanisms and potentially better diagnosis of chronicity and treatment of human chronic wounds.
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Affiliation(s)
- Sandeep Dhall
- Department of Cell Biology and Neuroscience, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA
- Bioengineering Interdepartmental Graduate Program, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA
| | - Danh C. Do
- Division of Biomedical Sciences, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA
| | - Monika Garcia
- Department of Cell Biology and Neuroscience, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA
| | - Jane Kim
- Department of Botany and Plant Sciences, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA
| | - Seyed H. Mirebrahim
- Department of Computer Science and Engineering, University of California, Riverside, Riverside, CA 92521, USA
| | - Julia Lyubovitsky
- Bioengineering Interdepartmental Graduate Program, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA
| | - Stefano Lonardi
- Department of Computer Science and Engineering, University of California, Riverside, Riverside, CA 92521, USA
| | - Eugene A. Nothnagel
- Department of Botany and Plant Sciences, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA
| | - Neal Schiller
- Division of Biomedical Sciences, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA
| | - Manuela Martins-Green
- Department of Cell Biology and Neuroscience, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA
- Bioengineering Interdepartmental Graduate Program, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA
- *Manuela Martins-Green:
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Marrazzo G, Barbagallo I, Galvano F, Malaguarnera M, Gazzolo D, Frigiola A, D'Orazio N, Li Volti G. Role of dietary and endogenous antioxidants in diabetes. Crit Rev Food Sci Nutr 2014; 54:1599-1616. [PMID: 24580561 DOI: 10.1080/10408398.2011.644874] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Diabetes affects different people of all ages, race, and sex. This is a condition characterized by a state of chronic hyperglycaemia that leads to an increase of intracellular oxidative stress linked to the overproduction of free radicals. In the present review, we focus our attention on the molecular mechanisms leading to oxidative stress-mediates complications with particular regard to central nervous system (CNS). Furthermore, the present review reports the effects of different kind of antioxidants with enzymatic and nonenzymatic action that may significantly decrease the intracellular free radicals' overproduction and prevents the hyperglycaemia-mediated complications.
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Affiliation(s)
- Giuseppina Marrazzo
- a Department of Drug Science, Section of Biochemistry , University of Catania , Catanina , Italy
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Abstract
Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the molecular mechanism involved and of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. Here we review the pathophysiological changes that occur in the kidney in response to hyperglycemia, including the cellular responses to high glucose and the responses in vascular, glomerular, podocyte, and tubular function. The molecular basis, characteristics, and consequences of the unique growth phenotypes observed in the diabetic kidney, including glomerular structures and tubular segments, are outlined. We delineate mechanisms of early diabetic glomerular hyperfiltration including primary vascular events as well as the primary role of tubular growth, hyperreabsorption, and tubuloglomerular communication as part of a "tubulocentric" concept of early diabetic kidney function. The latter also explains the "salt paradox" of the early diabetic kidney, that is, a unique and inverse relationship between glomerular filtration rate and dietary salt intake. The mechanisms and consequences of the intrarenal activation of the renin-angiotensin system and of diabetes-induced tubular glycogen accumulation are discussed. Moreover, we aim to link the changes that occur early in the diabetic kidney including the growth phenotype, oxidative stress, hypoxia, and formation of advanced glycation end products to mechanisms involved in progressive kidney disease.
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Affiliation(s)
- Volker Vallon
- Department of Medicine, University of California San Diego & VA San Diego Healthcare System, San Diego, California, USA.
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Mima A, Qi W, King GL. Implications of treatment that target protective mechanisms against diabetic nephropathy. Semin Nephrol 2013; 32:471-8. [PMID: 23062988 DOI: 10.1016/j.semnephrol.2012.07.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Diabetes results in vascular changes and dysfunction, and vascular complications are the leading cause of morbidity and mortality in diabetic patients. There has been a continual increase in the number of diabetic nephropathy patients and epidemic increases in the number of patients progressing to end-stage renal diseases. To identify targets for therapeutic intervention, most studies have focused on understanding how abnormal levels of glucose metabolites cause diabetic nephropathy, which is of paramount importance in devising strategies to combat the development and progression of diabetic nephropathy. However, less studied than the systemic toxic mechanisms, hyperglycemia and dyslipidemia might inhibit the endogenous vascular protective factors such as insulin, vascular endothelial growth factor, and platelet-derived growth factor. In this review, we highlight the importance of enhancing endogenous protective factors to prevent or delay diabetic nephropathy.
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Affiliation(s)
- Akira Mima
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
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Mima A, Matsubara T, Endo S, Murakami T, Hashimoto Y. Use of a polysulfone hemodialysis membrane may prevent recurrent posterior reversible encephalopathy syndrome in a patient undergoing hemodialysis. Int Urol Nephrol 2013; 46:255-60. [PMID: 23568662 DOI: 10.1007/s11255-013-0434-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 03/27/2013] [Indexed: 11/24/2022]
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Mima A. Inflammation and oxidative stress in diabetic nephropathy: new insights on its inhibition as new therapeutic targets. J Diabetes Res 2013; 2013:248563. [PMID: 23862164 PMCID: PMC3686081 DOI: 10.1155/2013/248563] [Citation(s) in RCA: 142] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Accepted: 05/15/2013] [Indexed: 12/16/2022] Open
Abstract
Diabetes and insulin resistance can greatly increase microvascular complications of diabetes including diabetic nephropathy (DN). Hyperglycemic control in diabetes is key to preventing the development and progression of DN. However, it is clinically very difficult to achieve normal glucose control in individual diabetic patients. Many factors are known to contribute to the development of DN. These include diet, age, lifestyle, or obesity. Further, inflammatory- or oxidative-stress-induced basis for DN has been gaining interest. Although anti-inflammatory or antioxidant drugs can show benefits in rodent models of DN, negative evidence from large clinical studies indicates that more effective anti-inflammatory and antioxidant drugs need to be studied to clear this question. In addition, our recent report showed that potential endogenous protective factors could decrease inflammation and oxidative stress, showing great promise for the treatment of DN.
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Affiliation(s)
- Akira Mima
- Department of Nephrology, Graduate School of Medicine, Institute of Health Biosciences, University of Tokushima, Tokushima 770-8503, Japan.
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Bensellam M, Laybutt DR, Jonas JC. The molecular mechanisms of pancreatic β-cell glucotoxicity: recent findings and future research directions. Mol Cell Endocrinol 2012; 364:1-27. [PMID: 22885162 DOI: 10.1016/j.mce.2012.08.003] [Citation(s) in RCA: 226] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Revised: 07/11/2012] [Accepted: 08/01/2012] [Indexed: 02/06/2023]
Abstract
It is well established that regular physiological stimulation by glucose plays a crucial role in the maintenance of the β-cell differentiated phenotype. In contrast, prolonged or repeated exposure to elevated glucose concentrations both in vitro and in vivo exerts deleterious or toxic effects on the β-cell phenotype, a concept termed as glucotoxicity. Evidence indicates that the latter may greatly contribute to the pathogenesis of type 2 diabetes. Through the activation of several mechanisms and signaling pathways, high glucose levels exert deleterious effects on β-cell function and survival and thereby, lead to the worsening of the disease over time. While the role of high glucose-induced β-cell overstimulation, oxidative stress, excessive Unfolded Protein Response (UPR) activation, and loss of differentiation in the alteration of the β-cell phenotype is well ascertained, at least in vitro and in animal models of type 2 diabetes, the role of other mechanisms such as inflammation, O-GlcNacylation, PKC activation, and amyloidogenesis requires further confirmation. On the other hand, protein glycation is an emerging mechanism that may play an important role in the glucotoxic deterioration of the β-cell phenotype. Finally, our recent evidence suggests that hypoxia may also be a new mechanism of β-cell glucotoxicity. Deciphering these molecular mechanisms of β-cell glucotoxicity is a mandatory first step toward the development of therapeutic strategies to protect β-cells and improve the functional β-cell mass in type 2 diabetes.
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Affiliation(s)
- Mohammed Bensellam
- Université catholique de Louvain, Institut de recherche expérimentale et clinique, Pôle d'endocrinologie, diabète et nutrition, Brussels, Belgium
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Chronic Administration of Oil Palm (Elaeis guineensis) Leaves Extract Attenuates Hyperglycaemic-Induced Oxidative Stress and Improves Renal Histopathology and Function in Experimental Diabetes. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:195367. [PMID: 23243433 PMCID: PMC3514844 DOI: 10.1155/2012/195367] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Accepted: 10/17/2012] [Indexed: 12/11/2022]
Abstract
Oil palm (Elaeis guineensis) leaves extract (OPLE) has antioxidant properties and because oxidative stress contributes to the pathogenesis of diabetic nephropathy (DN), we tested the hypothesis that OPLE prevents diabetes renal oxidative stress, attenuating injury. Sprague-Dawley rats received OPLE (200 and 500 mg kg(-1)) for 4 and 12 weeks after diabetes induction (streptozotocin 60 mg kg(-1)). Blood glucose level, body and kidney weights, urine flow rate (UFR), glomerular filtration rate (GFR), and proteinuria were assessed. Oxidative stress variables such as 8-hydroxy-2'-deoxyguanosine (8-OHdG), glutathione (GSH), and lipid peroxides (LPO) were quantified. Renal morphology was analysed, and plasma transforming growth factor-beta1 (TGF-β1) was measured. Diabetic rats demonstrated increase in blood glucose and decreased body and increased kidney weights. Renal dysfunction (proteinuria, elevations in UFR and GFR) was observed in association with increases in LPO, 8-OHdG, and TGF-β1 and a decrease in GSH. Histological evaluation of diabetic kidney demonstrated glomerulosclerosis and tubulointerstitial fibrosis. OPLE attenuated renal dysfunction, improved oxidative stress markers, and reduced renal pathology in diabetic animals. These results suggest OPLE improves renal dysfunction and pathology in diabetes by reducing oxidative stress; furthermore, the protective effect of OPLE against renal damage in diabetes depends on the dose of OPLE as well as progression of DN.
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36
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Paul MVS, Abhilash M, Varghese MV, Alex M, Harikumaran Nair R. Protective effects of α-tocopherol against oxidative stress related to nephrotoxicity by monosodium glutamate in rats. Toxicol Mech Methods 2012; 22:625-30. [DOI: 10.3109/15376516.2012.714008] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Fujita A, Yoh K, Shimohata H, Morito N, Ojima M, Okamura M, Takahashi S, Yamagata K. A Novel Diabetes Mellitus Mouse Model, MAFA-Deficient and Beta Cell-Specific MAFK-Overexpressing Hybrid Transgenic Mice, Developed Severe Diabetic Nephropathy and Improved with TCV-116 (Candesartan Cilexetil) Treatment. Exp Anim 2012; 61:49-57. [DOI: 10.1538/expanim.61.49] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Affiliation(s)
- Akiko Fujita
- Department of Nephrology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba
| | - Keigyou Yoh
- Department of Nephrology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba
| | - Homare Shimohata
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center
| | - Naoki Morito
- Department of Nephrology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba
| | - Masami Ojima
- Department of Anatomy and Embryology, Division of Biomedical Science, Faculty of Medicine, University of Tsukuba
| | - Midori Okamura
- Department of Anatomy and Embryology, Division of Biomedical Science, Faculty of Medicine, University of Tsukuba
| | - Satoru Takahashi
- Department of Anatomy and Embryology, Division of Biomedical Science, Faculty of Medicine, University of Tsukuba
| | - Kunihiro Yamagata
- Department of Nephrology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba
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Speeckaert MM, Speeckaert R, Van De Voorde L, Delanghe JR. Immunochemically unreactive albumin in urine: fiction or reality? Crit Rev Clin Lab Sci 2011; 48:87-96. [PMID: 21871001 DOI: 10.3109/10408363.2011.591366] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Urinary albumin measurements are currently not standardized due to a lack of a reference method and reference (primary and secondary [matrix]) material. Multiple molecular forms of albumin in urine are identified. Modification of albumin by proteolysis during passage through the urinary tract and chemical modification during specimen storage leads to the formation of albumin fragments. Multiple methods have been developed to quantify albuminuria and significant different results are reported dependent on the available assay. The current point of view of the National Kidney Disease Education Program - IFCC Working Group on Standardization of Albumin considers the immunoassay with polyclonal sera as the primary method of quantifying urine albumin. This article reviews the process of albumin fragmentation and focuses on the controversial topic of immuno-unreactive, nonimmunoreactive, or immunochemically nonreactive albumin fractions and its consequences for albumin analysis. We conclude that at present there are no hard arguments for measuring immunochemically unreactive albumin in urine. Immunoassays using polyclonal antisera for the detection of urinary albumin remain the gold standard. The development of a reference measurement procedure remains one of the challenges for the future.
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Affiliation(s)
- Marijn M Speeckaert
- Department of Clinical Chemistry, University of Ghent, Faculty of Medicine, Belgium
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Rodriguez F, Lopez B, Perez C, Fenoy FJ, Hernandez I, Stec DE, Volti GL, Salom MG. Chronic tempol treatment attenuates the renal hemodynamic effects induced by a heme oxygenase inhibitor in streptozotocin diabetic rats. Am J Physiol Regul Integr Comp Physiol 2011; 301:R1540-8. [DOI: 10.1152/ajpregu.00847.2010] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Heme oxygenase-1 (HO-1) is induced by oxidative stress and plays an important role in protecting the kidney from oxidant-mediated damage in the streptozotocin (STZ) rat model of type-1 diabetes mellitus (DM-1). HO-derived metabolites, presumably carbon monoxide (CO), mediate vasodilatory influences in the renal circulation, particularly in conditions linked to elevated HO-1 protein expression or diminished nitric oxide (NO) levels. We tested the hypothesis that diabetes increases oxidative stress and induces HO-1 protein expression, which contributes to regulate renal hemodynamics in conditions of low NO bioavailability. Two weeks after the induction of diabetes with STZ (65 mg/kg iv), Sprague-Dawley rats exhibited higher renal HO-1 protein expression, hyperglycemia, and elevated renal nitrotyrosine levels than control normoglycemic animals. In anesthetized diabetic rats, renal vascular resistance (RVR) was increased, and in vivo cortical NO levels were reduced ( P < 0.05) compared with control animals. Acute administration of the HO inhibitor Stannous mesoporphyrin (SnMP; 40 μmol/kg iv) did not alter renal hemodynamics in control rats, but greatly decreased glomerular filtration rate and renal blood flow, markedly increasing RVR in hyperglycemic diabetic rats. Chronic oral treatment with the SOD mimetic tempol prevented the elevation of nitrotyrosine, the HO-1 protein induction, and the increases in RVR induced by SnMP in the diabetic group, without altering basal NO concentrations or RVR. Increasing concentrations of a CO donor (CO-releasing molecule-A1) on pressurized renal interlobar arteries elicited a comparable relaxation in vessels taken from control or diabetic animals. These results suggest that oxidative stress-induced HO-1 exerts vasodilatory actions that partially maintain renal hemodynamics in uncontrolled DM-1.
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Affiliation(s)
- Francisca Rodriguez
- Department of Physiology, Murcia School of Medicine, University of Murcia, Murcia, Spain
| | - Bernardo Lopez
- Department of Physiology, Murcia School of Medicine, University of Murcia, Murcia, Spain
| | - Cayetano Perez
- Department of Physiology, Murcia School of Medicine, University of Murcia, Murcia, Spain
| | - Francisco J. Fenoy
- Department of Physiology, Murcia School of Medicine, University of Murcia, Murcia, Spain
| | - Isabel Hernandez
- Department of Physiology, Murcia School of Medicine, University of Murcia, Murcia, Spain
| | - David E. Stec
- Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi
| | - Giovanni Li Volti
- Department of Drug Sciences, Section of Biochemistry, Faculty of Pharmacy, University of Catania, Catania, Italy
| | - Miguel G. Salom
- Department of Physiology, Murcia School of Medicine, University of Murcia, Murcia, Spain
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Long-term dietary antioxidant cocktail supplementation effectively reduces renal inflammation in diabetic mice. Br J Nutr 2011; 106:1514-21. [PMID: 21736794 DOI: 10.1017/s0007114511001929] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Diabetic nephropathy is a serious complication for diabetic patients, yet the precise mechanism that underlies the development of diabetic complications remains unknown. We hypothesised that dietary antioxidant supplementation with single N-acetylcysteine (NAC) or vitamin C combined with either vitamin E or vitamin E and NAC improves diabetic renal inflammation through the modulation of blood glucose levels, oxidative stress and inflammatory response. Experimental animals were treated with alloxan monohydrate to induce diabetes. Mice were divided into five groups and supplemented with single or a combination of antioxidants. Body weights and blood glucose levels were measured once a week. After 8 weeks of dietary antioxidant supplementation, mice were killed and blood urea N (BUN) and plasma creatinine levels were measured to evaluate renal function. NF-κB protein was indirectly demonstrated by the phosphorylated IκBα (pIκBα) level, and the expressions of oxidative stress- and inflammatory response-related proteins were also determined. We demonstrated that dietary antioxidant supplementation decreased lipid peroxidation levels demonstrated by thiobarbituric acid-reacting substances, BUN and plasma creatinine levels in diabetic kidneys. Moreover, dietary antioxidant cocktail supplementation improved blood glucose levels and selectively regulated the expressions of Cu-Zn superoxide dismutase, haeme oxygenase-1, pIκBα, inducible NO synthase, cyclo-oxygenase-2 and C-reactive protein in diabetic kidneys effectively. These findings demonstrated that diabetic renal failure was associated with inflammatory responses induced by hyperglycaemia. In addition, results in the study suggest that antioxidant cocktail supplementation may have beneficial effects on diabetic nephropathy through selective reduction of blood glucose levels and inflammatory response.
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Fatehi-Hassanabad Z, Chan CB, Furman BL. Reactive oxygen species and endothelial function in diabetes. Eur J Pharmacol 2010; 636:8-17. [DOI: 10.1016/j.ejphar.2010.03.048] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2009] [Revised: 02/27/2010] [Accepted: 03/22/2010] [Indexed: 02/07/2023]
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Nakagawa T, Yokozawa T, Yamabe N, Rhyn DY, Goto H, Shimada Y, Shibahara N. Long-term treatment with Hachimi-jio-gan attenuates kidney damage in spontaneously diabetic WBN/Kob rats. J Pharm Pharmacol 2010; 57:1205-12. [PMID: 16105242 DOI: 10.1211/jpp.57.9.0016] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Abstract
Diabetes mellitus is now the most common cause of end-stage renal failure. In this study, the effects of Hachimi-jio-gan on diabetic kidney damage in spontaneously diabetic WBN/Kob rats were examined. Oral administration of Hachimi-jio-gan to WBN/Kob rats for 25 weeks significantly suppressed urinary protein excretion. It did not affect body weight loss or blood glucose levels, whereas it reversed the increase in kidney weight of WBN/Kob rats. Hachimi-jio-gan also reduced fibronectin and transforming growth factor β1 (TGF-β1) protein expression in the renal cortex. Furthermore, renal lipid peroxidation levels of WBN/Kob rats given Hachimi-jio-gan were significantly lower than those of untreated controls. Renal superoxide dismutase activity was elevated by Hachimi-jio-gan treatment in a dose-dependent manner. These results suggested that Hachimi-jio-gan could prevent diabetic kidney damage by reducing renal oxidative injury and expression of fibronectin and TGF-β1 proteins, which are all involved in the pathophysiology of diabetic nephropathy.
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Affiliation(s)
- Takako Nakagawa
- Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan
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Vitamin E. Antioxidants (Basel) 2010. [DOI: 10.1201/9781439822173.ch9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] Open
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Tan ALY, Sourris KC, Harcourt BE, Thallas-Bonke V, Penfold S, Andrikopoulos S, Thomas MC, O'Brien RC, Bierhaus A, Cooper ME, Forbes JM, Coughlan MT. Disparate effects on renal and oxidative parameters following RAGE deletion, AGE accumulation inhibition, or dietary AGE control in experimental diabetic nephropathy. Am J Physiol Renal Physiol 2009; 298:F763-70. [PMID: 20015941 DOI: 10.1152/ajprenal.00591.2009] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) generate ROS, and therefore this study evaluated the effects of RAGE deletion, decreasing AGE accumulation, or lowering dietary AGE content on oxidative parameters in diabetic nephropathy (DN). Control and diabetic male wild-type and RAGE-deficient (RAGE-/-) mice were fed high- or low-AGE diets, with two groups given the inhibitor of AGE accumulation, alagebrium chloride, and followed for 24 wk. Diabetic RAGE-/- mice were protected against albuminuria, hyperfiltration, glomerulosclerosis, decreased renal mitochondrial ATP production, and excess generation of both mitochondrial and cytosolic superoxide. Whereas glomerulosclerosis, tubulointerstitial expansion, and hyperfiltration were improved in diabetic mice treated with alagebrium, there was no effect on urinary albumin excretion. Both diabetic RAGE-/- and alagebrium-treated mice had an attenuation of renal RAGE expression and decreased renal and urinary AGE (carboxymethyllysine) levels. Low-AGE diets did not confer renoprotection, lower the AGE burden or renal RAGE expression, or improve cytosolic or mitochondrial superoxide generation. Renal uncoupling protein-2 gene expression and mitochondrial membrane potential were attenuated by all therapeutic interventions in diabetic mice. In the present study, diverse approaches to block the AGE-RAGE axis had disparate effects on DN, which has potential clinical implications for the way this axis should be targeted in humans.
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Affiliation(s)
- Adeline L Y Tan
- Juvenile Diabetes Research Foundation Einstein Centre for Diabetic Complications, Baker International Diabetes Institute Heart and Diabetes Research Institute, Melbourne, Victoria, Australia
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Sato S, Mukai Y, Yamate J, Norikura T, Morinaga Y, Mikame K, Funaoka M, Fujita S. Lignin-derived lignophenols attenuate oxidative and inflammatory damage to the kidney in streptozotocin-induced diabetic rats. Free Radic Res 2009; 43:1205-13. [DOI: 10.3109/10715760903247264] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Dávila-Esqueda ME, Vertiz-Hernández AA, Martínez-Morales F. Comparative Analysis of the Renoprotective Effects of Pentoxifylline and Vitamin E on Streptozotocin-Induced Diabetes Mellitus. Ren Fail 2009. [DOI: 10.1081/jdi-42728] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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Peroxisome proliferator-activated receptors in diabetic nephropathy. PPAR Res 2009; 2008:879523. [PMID: 19277201 PMCID: PMC2652581 DOI: 10.1155/2008/879523] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2008] [Accepted: 12/08/2008] [Indexed: 02/08/2023] Open
Abstract
Diabetic nephropathy is a leading cause of end-stage renal disease, which is increasing in incidence worldwide, despite intensive treatment approaches such as glycemic and blood pressure control in patients with diabetes mellitus. New therapeutic strategies are needed to prevent the onset of diabetic nephropathy. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostases. These agents might prevent the progression of diabetic nephropathy, since PPAR agonists improve dyslipidemia and insulin resistance. Furthermore, data from murine models suggest that PPAR agonists also have independent renoprotective effects by suppressing inflammation, oxidative stress, lipotoxicity, and activation of the renin-angiotensin system. This review summarizes data from clinical and experimental studies regarding the relationship between PPARs and diabetic nephropathy. The therapeutic potential of PPAR agonists in the treatment of diabetic nephropathy is also discussed.
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Brigelius-Flohé R. Vitamin E: the shrew waiting to be tamed. Free Radic Biol Med 2009; 46:543-54. [PMID: 19133328 DOI: 10.1016/j.freeradbiomed.2008.12.007] [Citation(s) in RCA: 162] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2008] [Revised: 11/28/2008] [Accepted: 12/03/2008] [Indexed: 12/16/2022]
Abstract
Vitamin E is the last of all vitamins whose essentiality is not yet understood. Its widely accepted role as a lipophilic antioxidant has been questioned, since proof of its in vivo relevance remained scarce. The influence of vitamin E on biomarkers of oxidative stress in vivo is inconsistent and metabolites of vitamin E having reacted as an antioxidant are hardly detectable. Novel functions of vitamin E include the regulation of enzymes, most of which are membrane bound or activated by membrane recruitment. Also, expression of genes responds to vitamin E. The search for a transcription factor common to all regulated genes failed so far and a receptor that specifically binds vitamin E has not yet been identified. According to microarray data, pathways preferentially affected by the vitamin E status are the inflammatory response and cellular traffic. A role of vitamin E in cellular trafficking could best explain the neurological symptoms seen in vitamin E deficiency. Emerging knowledge on vitamin E is compiled here with the perspective to unravel the molecular mechanisms that could more likely explain the essentiality of the vitamin than its ability to scavenge free radicals.
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Affiliation(s)
- Regina Brigelius-Flohé
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Biochemistry of Micronutrients, Nuthetal, Germany.
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Haidara MA, Mikhailidis DP, Rateb MA, Ahmed ZA, Yassin HZ, Ibrahim IM, Rashed LA. Evaluation of the effect of oxidative stress and vitamin E supplementation on renal function in rats with streptozotocin-induced Type 1 diabetes. J Diabetes Complications 2009; 23:130-136. [PMID: 18436458 DOI: 10.1016/j.jdiacomp.2008.02.011] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2007] [Revised: 02/09/2008] [Accepted: 02/28/2008] [Indexed: 02/05/2023]
Abstract
UNLABELLED We investigated the possible role of reactive oxygen species (ROS) on renal function in experimental diabetes. MATERIALS AND METHODS Seven groups of male rats were studied. Group I consisted of control animals. Diabetes was induced (by streptozotocin) in the animals in the other groups and they received either insulin or vitamin E (300 or 600 mg/kg), both insulin and vitamin E, or no treatment for 4 weeks. At the end of the study, blood pressure was measured and parameters of kidney function and oxidative stress were evaluated in serum and kidney tissue samples. RESULTS Diabetic animals had higher blood pressures; increased serum glucose, urea, creatinine, cyclic guanosine monophosphate (cGMP); increased kidney tissue levels of malondialdehyde and inducible nitric oxide synthetase (iNOS); and reduced serum glutathione peroxidase when compared with control animals. Blood glucose levels in diabetic animals were controlled by insulin and not by any dose of vitamin E alone. However, all other measured parameters improved towards control levels with either insulin or vitamin E in either dose. An additive beneficial effect was observed on the levels of iNOS and cGMP when both forms of treatment were used in diabetic animals. CONCLUSIONS We conclude that ROS may play an important role in diabetes-induced nephropathy in this rat model. Vitamin E supplementation in addition to insulin can have additive protective effects against deterioration of renal function in this model.
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Affiliation(s)
- Mohamed A Haidara
- Physiology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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