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Bozic I, Lavrnja I. Thiamine and benfotiamine: Focus on their therapeutic potential. Heliyon 2023; 9:e21839. [PMID: 38034619 PMCID: PMC10682628 DOI: 10.1016/j.heliyon.2023.e21839] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 10/27/2023] [Accepted: 10/30/2023] [Indexed: 12/02/2023] Open
Abstract
Thiamine, also known as vitamin B1, is an essential nutrient that plays a crucial role in energy metabolism and overall health. It is a water-soluble vitamin that plays an important role in the conversion of carbohydrates into energy in the body. Thiamine is essential for the proper functioning of the nervous system, heart and muscles. Thiamine deficiency is a life-threatening disease that leads to various disorders and lesions in the nerves and brain, at least in vertebrates. Several thiamine precursors with higher bioavailability have been developed to compensate for thiamine deficiency, including benfotiamine. Benfotiamine is more bioavailable and has higher tissue penetration than thiamine. Studies have shown its antioxidant and anti-inflammatory potential in activated immune and glial cells. It also improves complications observed in type 2 diabetes and has beneficial effects in mouse models of neurodegenerative disease. Benfotiamine represents an off-the-shelf agent used to support nerve health, promote healthy aging and support glucose metabolism. Accordingly, the present review aimed to provide an overview of the neuroprotective effects of thiamine/benfotiamine in the context of inflammation and oxidative stress.
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Affiliation(s)
- Iva Bozic
- Institute for Biological Research "Sinisa Stankovic"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Irena Lavrnja
- Institute for Biological Research "Sinisa Stankovic"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
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Li X, Wang Z, Wang J, Lu J, Mao J, Han D, Li K. Measurement and Correlation of Solubility of Thiamine Nitrate in Three Binary Solvents and Thermodynamic Properties for the Solutions in Different Binary Mixtures at (278.15-313.15) K. Molecules 2023; 28:5012. [PMID: 37446674 DOI: 10.3390/molecules28135012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 06/14/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
The solubility of thiamine nitrate in {(methanol, acetone, isopropanol) + water} solvents will provide essential support for crystallization design and further theoretical studies. In this study, the solubility was experimentally measured over temperatures ranging from 278.15 to 313.15 K under atmospheric pressure using a dynamic method. The solubility increased with increasing temperature at a constant solvent composition. The dissolving capacity of thiamine nitrate in the three binary solvent mixtures at constant temperature in the low ratio of water ranked as water + methanol > water + acetone > water + isopropanol generally. Interestingly, in the high ratio of water systems, especially when the molar concentration of water was greater than 0.6, the dissolving capacity ranked as water + acetone > water + methanol > water + isopropanol. Additionally, the modified Apelblat equation, λh equation, van't Hoff equation and NRTL model were used to correlate the solubility data in binary mixtures. It turned out that all the selected thermodynamic models could give satisfactory results. Furthermore, the thermodynamic properties of the dissolution process of thiamine nitrate were also calculated based on the modified van't Hoff equation. The results indicate that the dissolution process of the thiamine nitrate in the selected solvents is all endothermic.
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Affiliation(s)
- Xinda Li
- State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
| | - Zhengjiang Wang
- Xi'an TPRI Water-Management & Environmental Protection Co., Ltd., Xi'an 710054, China
| | - Jing Wang
- Xi'an TPRI Water-Management & Environmental Protection Co., Ltd., Xi'an 710054, China
| | - Jiaqi Lu
- Xi'an TPRI Water-Management & Environmental Protection Co., Ltd., Xi'an 710054, China
| | - Jin Mao
- Xi'an TPRI Water-Management & Environmental Protection Co., Ltd., Xi'an 710054, China
| | - Dandan Han
- State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
| | - Kangli Li
- Institute of Shaoxing, Tianjin University, Shaoxing 312300, China
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Hadzi-Petrushev N, Angelovski M, Mladenov M. Advanced Glycation End Products and Diabetes. CONTEMPORARY ENDOCRINOLOGY 2023:99-127. [DOI: 10.1007/978-3-031-39721-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Fernandes ACF, Melo JB, Genova VM, Santana ÁL, Macedo G. Phytochemicals as Potential Inhibitors of Advanced Glycation End Products: Health Aspects and Patent Survey. RECENT ADVANCES IN FOOD, NUTRITION & AGRICULTURE 2022; 13:3-16. [PMID: 34053432 DOI: 10.2174/2212798412666210528130001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 02/17/2021] [Accepted: 03/06/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND The glycation of proteins and lipids synthesizes the advanced glycation end products (AGEs), i.e., substances that irreversibly damage macromolecules present in tissues and organs, which contribute to the impairment of biological functions. For instance, the accumulation of AGEs induces oxidative stress, the inflammatory responses, and consequently the on set/worsening of diseases, including obesity, asthma, cognitive impairment, and cancer. There is a current demand on natural and low-cost sources of anti-AGE agents. As a result, food phytochemicals presented promising results to inhibit glycation and consequently, the formation of AGEs. OBJECTIVE Here we describe how the AGEs are present in food via Maillard reaction and in organs via natural aging, as well as the effects of AGEs on the worsening of diseases. Also we described the methods used to detect AGEs in samples, and the current findings on the use of phytochemicals (phenolic compounds, phytosterols, carotenoids, terpenes and vitamins) as natural therapeuticals to inhibit health damages via inhibition of AGEs in vitro and in vivo. METHODS This manuscript reviewed publications available in the PubMed and Science Direct databases dated from the last 20 years on the uses of phytochemicals for the inhibition of AGEs. Recent patents on the use of anti-AGEs drugs were reviewed with the use of Google Advanced Patents database. RESULTS AND DISCUSSION There is no consensus about which concentration of AGEs in blood serum should not be hazardous to the health of individuals. Food phytochemicals derived from agroindustry wastes, including peanut skins, and the bagasses derived from citrus and grapes are promising anti-AGEs agents via scavenging of free radicals, metal ions, the suppression of metabolic pathways that induces inflammation, the activation of pathways that promote antioxidant defense, and the blocking of AGE connection with the receptor for advanced glycation endproducts (RAGE). CONCLUSION Phytochemicals derived from agroindustry are promising anti-AGEs, which can be included to replace synthetic drugs to inhibit AGE formation, and consequently to act as therapeutical strategy to prevent and treat diseases caused by AGEs, including diabetes, ovarian cancer, osteoporosis, and Alzheimer's disease.
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Affiliation(s)
- Annayara C F Fernandes
- Bioprocesses Laboratory, Food and Nutrition Department, School of Food Engineering, University of Campinas, UNICAMP, Campinas, SP, Brazil, Cidade Universitária "ZeferinoVaz", Rua Monteiro Lobato, 80, Campinas 13083-862, Brazil
| | - Jeane B Melo
- Bioprocesses Laboratory, Food and Nutrition Department, School of Food Engineering, University of Campinas, UNICAMP, Campinas, SP, Brazil, Cidade Universitária "ZeferinoVaz", Rua Monteiro Lobato, 80, Campinas 13083-862, Brazil
| | - Vanize M Genova
- Bioprocesses Laboratory, Food and Nutrition Department, School of Food Engineering, University of Campinas, UNICAMP, Campinas, SP, Brazil, Cidade Universitária "ZeferinoVaz", Rua Monteiro Lobato, 80, Campinas 13083-862, Brazil
| | - Ádina L Santana
- Bioprocesses Laboratory, Food and Nutrition Department, School of Food Engineering, University of Campinas, UNICAMP, Campinas, SP, Brazil, Cidade Universitária "ZeferinoVaz", Rua Monteiro Lobato, 80, Campinas 13083-862, Brazil.,264 Food Innovation Center, Nebraska Innovation Campus, University of Nebraska-Lincoln, 1901 N 21st street, Lincoln, NE, USA
| | - Gabriela Macedo
- Bioprocesses Laboratory, Food and Nutrition Department, School of Food Engineering, University of Campinas, UNICAMP, Campinas, SP, Brazil, Cidade Universitária "ZeferinoVaz", Rua Monteiro Lobato, 80, Campinas 13083-862, Brazil
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Lai SWT, Lopez Gonzalez EDJ, Zoukari T, Ki P, Shuck SC. Methylglyoxal and Its Adducts: Induction, Repair, and Association with Disease. Chem Res Toxicol 2022; 35:1720-1746. [PMID: 36197742 PMCID: PMC9580021 DOI: 10.1021/acs.chemrestox.2c00160] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Metabolism is an essential part of life that provides energy for cell growth. During metabolic flux, reactive electrophiles are produced that covalently modify macromolecules, leading to detrimental cellular effects. Methylglyoxal (MG) is an abundant electrophile formed from lipid, protein, and glucose metabolism at intracellular levels of 1-4 μM. MG covalently modifies DNA, RNA, and protein, forming advanced glycation end products (MG-AGEs). MG and MG-AGEs are associated with the onset and progression of many pathologies including diabetes, cancer, and liver and kidney disease. Regulating MG and MG-AGEs is a potential strategy to prevent disease, and they may also have utility as biomarkers to predict disease risk, onset, and progression. Here, we review recent advances and knowledge surrounding MG, including its production and elimination, mechanisms of MG-AGEs formation, the physiological impact of MG and MG-AGEs in disease onset and progression, and the latter in the context of its receptor RAGE. We also discuss methods for measuring MG and MG-AGEs and their clinical application as prognostic biomarkers to allow for early detection and intervention prior to disease onset. Finally, we consider relevant clinical applications and current therapeutic strategies aimed at targeting MG, MG-AGEs, and RAGE to ultimately improve patient outcomes.
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Affiliation(s)
- Seigmund Wai Tsuen Lai
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Edwin De Jesus Lopez Gonzalez
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Tala Zoukari
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Priscilla Ki
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Sarah C Shuck
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
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de Moraes RCM, Lima GCA, Cardinali CAEF, Gonçalves AC, Portari GV, Guerra-Shinohara EM, Leboucher A, Júnior JD, Kleinridders A, da Silva Torrão A. Benfotiamine protects against hypothalamic dysfunction in a STZ-induced model of neurodegeneration in rats. Life Sci 2022; 306:120841. [PMID: 35907494 DOI: 10.1016/j.lfs.2022.120841] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 07/13/2022] [Accepted: 07/22/2022] [Indexed: 10/16/2022]
Abstract
The neurodegeneration of Alzheimer's disease (AD) affects not only brain structures associate with cognition early in the progression of the disease, but other areas such as the hypothalamus, a region involved in the control of metabolism and appetite. In this context, we evaluated the effects of benfotiamine (BFT), a vitamin B1 analog that is being proposed as a therapeutical approach for AD-related cognitive alterations, which were induced by intracerebroventricular injection of streptozotocin (STZ). In addition to the already described effect of STZ on cognition, we show that this drug also causes metabolic changes which are linked to changes in hypothalamic insulin signaling and orexigenic and anorexigenic circuitries, as well as a decreased cellular integrated stress response. As expected, the supplementation with 150 mg/kg of BFT for 30 days increased blood concentrations of thiamine and its phosphate esters. This led to the prevention of body weight and fat loss in STZ-ICV-treated animals. In addition, we also found an improvement in food consumption, despite hypothalamic gene expression linked to anorexia after STZ exposure. Additionally, decreased apoptosis signaling was observed in the hypothalamus. In in vitro experiments, we noticed a high ability of BFT to increase insulin sensitivity in hypothalamic neurons. Furthermore, we also observed that BFT decreases the mitochondrial unfolded stress response damage by preventing the loss of HSP60 and reversed the mitochondria dysfunction caused by STZ. Taken together, these results suggest that benfotiamine treatment is a potential therapeutic approach in the treatment of hypothalamic dysfunction and metabolic disturbances associated with sporadic AD.
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Affiliation(s)
- Ruan Carlos Macêdo de Moraes
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil; Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Germany.
| | | | | | - Alisson Carvalho Gonçalves
- Federal Institute of Education, Science and Technology Goiano, Urutaí, GO, Brazil; Laboratory of Experimental Nutrition, Institute of Health Sciences, Federal University of Triângulo Mineiro, Brazil
| | - Guilherme Vannucchi Portari
- Laboratory of Experimental Nutrition, Institute of Health Sciences, Federal University of Triângulo Mineiro, Brazil
| | - Elvira Maria Guerra-Shinohara
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Brazil; Faculty of Pharmaceutical Sciences, Food and Nutrition, Federal University of Mato Grosso do Sul, Brazil
| | - Antoine Leboucher
- Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Germany
| | - José Donato Júnior
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil
| | - André Kleinridders
- Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Germany; Institute of Nutritional Science, Department of Molecular and Experimental Nutritional Medicine, University of Potsdam, Germany
| | - Andréa da Silva Torrão
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil
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Therapeutic potential of vitamin B 1 derivative benfotiamine from diabetes to COVID-19. Future Med Chem 2022; 14:809-826. [PMID: 35535731 DOI: 10.4155/fmc-2022-0040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Benfotiamine (S-benzoylthiamine-O-monophosphate), a unique, lipid-soluble derivative of thiamine, is the most potent allithiamine found in roasted garlic, as well as in other herbs of the genus Allium. In addition to potent antioxidative properties, benfotiamine has also been shown to be a strong anti-inflammatory agent with therapeutic significance to several pathological complications. Specifically, over the past decade or so, benfotiamine has been shown to prevent not only various secondary diabetic complications but also several inflammatory complications such as uveitis and endotoxemia. Recent studies also demonstrate that this compound could be used to prevent the symptoms associated with various infectious diseases such as HIV and COVID-19. In this review article, the authors discuss the significance of benfotiamine in the prevention of various pathological complications.
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Bönhof GJ, Sipola G, Strom A, Herder C, Strassburger K, Knebel B, Reule C, Wollmann JC, Icks A, Al-Hasani H, Roden M, Kuss O, Ziegler D. BOND study: a randomised double-blind, placebo-controlled trial over 12 months to assess the effects of benfotiamine on morphometric, neurophysiological and clinical measures in patients with type 2 diabetes with symptomatic polyneuropathy. BMJ Open 2022; 12:e057142. [PMID: 35115359 PMCID: PMC8814806 DOI: 10.1136/bmjopen-2021-057142] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Diabetic sensorimotor polyneuropathy (DSPN) affects approximately 30% of people with diabetes, while around half of cases are symptomatic. Currently, there are only few pathogenetically oriented pharmacotherapies for DSPN, one of which is benfotiamine, a prodrug of thiamine with a high bioavailability and favourable safety profile. While benfotiamine has shown positive effects in preclinical and short-term clinical studies, no long-term clinical trials are available to demonstrate disease-modifying effects on DSPN using a comprehensive set of disease-related endpoints. METHODS AND ANALYSIS The benfotiamine on morphometric, neurophysiological and clinical measures in patients with type 2 diabetes trial is a randomised double-blind, placebo-controlled parallel group monocentric phase II clinical trial to assess the effects of treatment with benfotiamine compared with placebo in participants with type 2 diabetes and mild to moderate symptomatic DSPN. Sixty participants will be 1:1 randomised to treatment with benfotiamine 300 mg or placebo two times a day over 12 months. The primary endpoint will be the change in corneal nerve fibre length assessed by corneal confocal microscopy (CCM) after 12 months of benfotiamine treatment compared with placebo. Secondary endpoints will include other CCM measures, skin biopsy and function indices, variables from somatic and autonomic nerve function tests, clinical examination and questionnaires, general health, health-related quality of life, cost, safety and blood tests. ETHICS AND DISSEMINATION The trial was approved by the competent authority and the local independent ethics committee. Trial results will be published in peer-reviewed journals, conference abstracts, and via online and print media. TRIAL REGISTRATION NUMBER DRKS00014832.
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Affiliation(s)
- Gidon J Bönhof
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Gundega Sipola
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Alexander Strom
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research, Partner Düsseldorf, Munich-Neuherberg, Germany
| | - Christian Herder
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Klaus Strassburger
- German Center for Diabetes Research, Partner Düsseldorf, Munich-Neuherberg, Germany
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Birgit Knebel
- German Center for Diabetes Research, Partner Düsseldorf, Munich-Neuherberg, Germany
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | | | | | - Andrea Icks
- Institute for Health Services Research and Health Economics, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Institute for Health Services Research and Health Economics, Centre for Health and Society, Medical Faculty and University Hospital Düsseldorf at Heinrich-Heine-University, Düsseldorf, Germany
| | - Hadi Al-Hasani
- German Center for Diabetes Research, Partner Düsseldorf, Munich-Neuherberg, Germany
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Oliver Kuss
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Centre for Health and Society, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - Dan Ziegler
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
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Yorek M. Treatment for Diabetic Peripheral Neuropathy: What have we Learned from Animal Models? Curr Diabetes Rev 2022; 18:e040521193121. [PMID: 33949936 PMCID: PMC8965779 DOI: 10.2174/1573399817666210504101609] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 01/07/2021] [Accepted: 02/13/2021] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Animal models have been widely used to investigate the etiology and potential treatments for diabetic peripheral neuropathy. What we have learned from these studies and the extent to which this information has been adapted for the human condition will be the subject of this review article. METHODS A comprehensive search of the PubMed database was performed, and relevant articles on the topic were included in this review. RESULTS Extensive study of diabetic animal models has shown that the etiology of diabetic peripheral neuropathy is complex, with multiple mechanisms affecting neurons, Schwann cells, and the microvasculature, which contribute to the phenotypic nature of this most common complication of diabetes. Moreover, animal studies have demonstrated that the mechanisms related to peripheral neuropathy occurring in type 1 and type 2 diabetes are likely different, with hyperglycemia being the primary factor for neuropathology in type 1 diabetes, which contributes to a lesser extent in type 2 diabetes, whereas insulin resistance, hyperlipidemia, and other factors may have a greater role. Two of the earliest mechanisms described from animal studies as a cause for diabetic peripheral neuropathy were the activation of the aldose reductase pathway and increased non-enzymatic glycation. However, continuing research has identified numerous other potential factors that may contribute to diabetic peripheral neuropathy, including oxidative and inflammatory stress, dysregulation of protein kinase C and hexosamine pathways, and decreased neurotrophic support. In addition, recent studies have demonstrated that peripheral neuropathy-like symptoms are present in animal models, representing pre-diabetes in the absence of hyperglycemia. CONCLUSION This complexity complicates the successful treatment of diabetic peripheral neuropathy, and results in the poor outcome of translating successful treatments from animal studies to human clinical trials.
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Affiliation(s)
- Mark Yorek
- Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242 USA
- Department of Veterans Affairs Iowa City Health Care System, Iowa City, IA, 52246 USA
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, 52242 USA
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The Role of Neurotropic B Vitamins in Nerve Regeneration. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9968228. [PMID: 34337067 PMCID: PMC8294980 DOI: 10.1155/2021/9968228] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 07/05/2021] [Indexed: 12/28/2022]
Abstract
Damage and regeneration naturally occur in the peripheral nervous system. The neurotropic B vitamins thiamine (B1), pyridoxine (B6), and cobalamin (B12) are key players, which maintain the neuronal viability in different ways. Firstly, they constantly protect nerves against damaging environmental influences. While vitamin B1 acts as a site-directed antioxidant, vitamin B6 balances nerve metabolism, and vitamin B12 maintains myelin sheaths. However, nerve injury occurs at times, because of an imbalance between protective factors and accumulating stress and noxae. This will result in the so-called Wallerian degeneration process. The presence of vitamins B1, B6, and B12 paves the way out to the following important regeneration by supporting the development of new cell structures. Furthermore, vitamin B1 facilitates the usage of carbohydrates for energy production, whereas vitamin B12 promotes nerve cell survival and remyelination. Absence of these vitamins will favor permanent nerve degeneration and pain, eventually leading to peripheral neuropathy.
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Zaheer A, Zaheer F, Saeed H, Tahir Z, Tahir MW. A Review of Alternative Treatment Options in Diabetic Polyneuropathy. Cureus 2021; 13:e14600. [PMID: 34040901 PMCID: PMC8139599 DOI: 10.7759/cureus.14600] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2021] [Indexed: 11/05/2022] Open
Abstract
Currently there is no recognized curative treatment for diabetic polyneuropathy (DPN). Strict glucose control and symptomatic pain relief are the first line management routes. DPN is a common complication of diabetes and has a major detrimental influence on the quality of life (QOL) for many patients. Due to the scope of the problem, it is imperative that treatment options which impede DPN's progression and restore sensorineural function should be researched comprehensively and made available to the masses at an economical cost. We reviewed a multitude of atypical treatment options for DPN including capsaicin, lidocaine, acupuncture, electrical nerve stimulation, alpha lipoic acid, benfotiamine, and acetyl-l-carnitine and explored the evidence to date regarding their safety and efficacy. Most of these options have been around for a long time and have promising pilot studies or small-scale trials focused on DPN treatment.
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Affiliation(s)
| | - Faizan Zaheer
- Medicine, Fatima Memorial Hospital College of Medicine and Dentistry, Lahore, PAK
| | | | - Zoya Tahir
- Pathology, Shaikh Zayed Hospital, Lahore, PAK
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Sambon M, Gorlova A, Demelenne A, Alhama-Riba J, Coumans B, Lakaye B, Wins P, Fillet M, Anthony DC, Strekalova T, Bettendorff L. Dibenzoylthiamine Has Powerful Antioxidant and Anti-Inflammatory Properties in Cultured Cells and in Mouse Models of Stress and Neurodegeneration. Biomedicines 2020; 8:biomedicines8090361. [PMID: 32962139 PMCID: PMC7555733 DOI: 10.3390/biomedicines8090361] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/03/2020] [Accepted: 09/16/2020] [Indexed: 12/14/2022] Open
Abstract
Thiamine precursors, the most studied being benfotiamine (BFT), have protective effects in mouse models of neurodegenerative diseases. BFT decreased oxidative stress and inflammation, two major characteristics of neurodegenerative diseases, in a neuroblastoma cell line (Neuro2a) and an immortalized brain microglial cell line (BV2). Here, we tested the potential antioxidant and anti-inflammatory effects of the hitherto unexplored derivative O,S-dibenzoylthiamine (DBT) in these two cell lines. We show that DBT protects Neuro2a cells against paraquat (PQ) toxicity by counteracting oxidative stress at low concentrations and increases the synthesis of reduced glutathione and NADPH in a Nrf2-independent manner. In BV2 cells activated by lipopolysaccharides (LPS), DBT significantly decreased inflammation by suppressing translocation of NF-κB to the nucleus. Our results also demonstrate the superiority of DBT over thiamine and other thiamine precursors, including BFT, in all of the in vitro models. Finally, we show that the chronic administration of DBT arrested motor dysfunction in FUS transgenic mice, a model of amyotrophic lateral sclerosis, and it reduced depressive-like behavior in a mouse model of ultrasound-induced stress in which it normalized oxidative stress marker levels in the brain. Together, our data suggest that DBT may have therapeutic potential for brain pathology associated with oxidative stress and inflammation by novel, coenzyme-independent mechanisms.
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Affiliation(s)
- Margaux Sambon
- Laboratory of Neurophysiology, GIGA-Neurosciences, University of Liège, 4000 Liège, Belgium; (M.S.); (J.A.-R.); (P.W.)
| | - Anna Gorlova
- Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD Maastricht, The Netherlands; (A.G.); (T.S.)
- Institute of Molecular Medicine Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia;
| | - Alice Demelenne
- Laboratory for the Analysis of Medicines, CIRM, Department of Pharmacy, University of Liège, 4000 Liège, Belgium; (A.D.); (M.F.)
| | - Judit Alhama-Riba
- Laboratory of Neurophysiology, GIGA-Neurosciences, University of Liège, 4000 Liège, Belgium; (M.S.); (J.A.-R.); (P.W.)
- Faculty of Sciences, University of Girona, 17004 Girona, Spain
| | - Bernard Coumans
- Laboratory of Molecular Regulation of Neurogenesis, GIGA-Stem Cell, University of Liège, 4000 Liège, Belgium; (B.C.); (B.L.)
| | - Bernard Lakaye
- Laboratory of Molecular Regulation of Neurogenesis, GIGA-Stem Cell, University of Liège, 4000 Liège, Belgium; (B.C.); (B.L.)
| | - Pierre Wins
- Laboratory of Neurophysiology, GIGA-Neurosciences, University of Liège, 4000 Liège, Belgium; (M.S.); (J.A.-R.); (P.W.)
| | - Marianne Fillet
- Laboratory for the Analysis of Medicines, CIRM, Department of Pharmacy, University of Liège, 4000 Liège, Belgium; (A.D.); (M.F.)
| | - Daniel C. Anthony
- Institute of Molecular Medicine Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia;
- Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK
| | - Tatyana Strekalova
- Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD Maastricht, The Netherlands; (A.G.); (T.S.)
- Institute of Molecular Medicine Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia;
| | - Lucien Bettendorff
- Laboratory of Neurophysiology, GIGA-Neurosciences, University of Liège, 4000 Liège, Belgium; (M.S.); (J.A.-R.); (P.W.)
- Correspondence: ; Tel.: +32-4-366-5967
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Fishman SL, Sonmez H, Basman C, Singh V, Poretsky L. The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review. Mol Med 2018; 24:59. [PMID: 30470170 PMCID: PMC6251169 DOI: 10.1186/s10020-018-0060-3] [Citation(s) in RCA: 202] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 11/04/2018] [Indexed: 12/18/2022] Open
Abstract
Background Traditional risk factors are insufficient to explain all cases of coronary artery disease (CAD) in patients with diabetes mellitus (DM). Advanced glycation end-products (AGEs) and their receptors may play important roles in the development and progression of CAD. Body Hyperglycemia is the hallmark feature of DM. An increase in the incidence of both micro-and macrovascular complications of diabetes has been observed with increased duration of hyperglycemia. This association persists even after glycemic control has been achieved, suggesting an innate mechanism of “metabolic memory.” AGEs are glycated proteins that may serve as mediators of metabolic memory due to their increased production in the setting of hyperglycemia and generally slow turnover. Elevated AGE levels can lead to abnormal cross linking of extracellular and intracellular proteins disrupting their normal structure and function. Furthermore, activation of AGE receptors can induce complex signaling pathways leading to increased inflammation, oxidative stress, enhanced calcium deposition, and increased vascular smooth muscle apoptosis, contributing to the development of atherosclerosis. Through these mechanisms, AGEs may be important mediators of the development of CAD. However, clinical studies regarding the role of AGEs and their receptors in advancing CAD are limited, with contradictory results. Conclusion AGEs and their receptors may be useful biomarkers for the presence and severity of CAD. Further studies are needed to evaluate the utility of circulating and tissue AGE levels in identifying asymptomatic patients at risk for CAD or to identify patients who may benefit from invasive intervention.
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Affiliation(s)
- Sarah Louise Fishman
- Division of Endocrinology, Department of Medicine, Lenox Hill Hospital, Northwell Health, 110 East 59th St #8B, New York, NY, 10022, USA
| | - Halis Sonmez
- Center for Diabetes and Endocrinology, 111 Salem Tpke, Norwich, CT, 06360, USA
| | - Craig Basman
- Department of Cardiology, Lenox Hill Hospital, Northwell Health, 100 East 77th St, New York, NY, 10065, USA
| | - Varinder Singh
- Department of Cardiology, Lenox Hill Hospital, Northwell Health, 100 East 77th St, New York, NY, 10065, USA
| | - Leonid Poretsky
- Division of Endocrinology, Department of Medicine, Lenox Hill Hospital, Northwell Health, 110 East 59th St #8B, New York, NY, 10022, USA.
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Chen JH, Lin X, Bu C, Zhang X. Role of advanced glycation end products in mobility and considerations in possible dietary and nutritional intervention strategies. Nutr Metab (Lond) 2018; 15:72. [PMID: 30337945 PMCID: PMC6180645 DOI: 10.1186/s12986-018-0306-7] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 09/21/2018] [Indexed: 02/08/2023] Open
Abstract
Advanced glycation end products (AGEs), a group of compounds that are formed by non-enzymatic reactions between carbonyl groups of reducing sugars and free amino groups of proteins, lipids or nucleic acids, can be obtained exogenously from diet or formed endogenously within the body. AGEs accumulate intracellularly and extracellularly in all tissues and body fluids and can cross-link with other proteins and thus affect their normal functions. Furthermore, AGEs can interact with specific cell surface receptors and hence alter cell intracellular signaling, gene expression, the production of reactive oxygen species and the activation of several inflammatory pathways. High levels of AGEs in diet as well as in tissues and the circulation are pathogenic to a wide range of diseases. With respect to mobility, AGEs accumulate in bones, joints and skeletal muscles, playing important roles in the development of osteoporosis, osteoarthritis, and sarcopenia with aging. This report covered the related pathological mechanisms and the potential pharmaceutical and dietary intervention strategies in reducing systemic AGEs. More prospective studies are needed to determine whether elevated serum AGEs and/or skin autofluorescence predict a decline in measures of mobility. In addition, human intervention studies are required to investigate the beneficial effects of exogenous AGEs inhibitors on mobility outcomes.
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Affiliation(s)
- Jie-Hua Chen
- Science and Technology Centre, By-Health Co. Ltd, No. 3 Kehui 3rd Street, No. 99 Kexue Avenue Central, Science City, Luogang District, Guangzhou, 510000 China
| | - Xu Lin
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
| | - Cuihong Bu
- Science and Technology Centre, By-Health Co. Ltd, No. 3 Kehui 3rd Street, No. 99 Kexue Avenue Central, Science City, Luogang District, Guangzhou, 510000 China
| | - Xuguang Zhang
- Science and Technology Centre, By-Health Co. Ltd, No. 3 Kehui 3rd Street, No. 99 Kexue Avenue Central, Science City, Luogang District, Guangzhou, 510000 China
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15
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Peripheral Neuropathy. Integr Med (Encinitas) 2018. [DOI: 10.1016/b978-0-323-35868-2.00013-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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16
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Spasov AA, Solov’eva OA, Kuznetsova VA. Protein Glycation During Diabetes Mellitus and the Possibility of its Pharmacological Correction (Review). Pharm Chem J 2017. [DOI: 10.1007/s11094-017-1627-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Kazi RS, Banarjee RM, Deshmukh AB, Patil GV, Jagadeeshaprasad MG, Kulkarni MJ. Glycation inhibitors extend yeast chronological lifespan by reducing advanced glycation end products and by back regulation of proteins involved in mitochondrial respiration. J Proteomics 2017; 156:104-112. [DOI: 10.1016/j.jprot.2017.01.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 12/27/2016] [Accepted: 01/23/2017] [Indexed: 11/26/2022]
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18
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Toxicity of Protein and DNA-AGEs in Neurodegenerative Diseases (NDDs) with Decisive Approaches to Stop the Deadly Consequences. PERSPECTIVES IN ENVIRONMENTAL TOXICOLOGY 2017. [DOI: 10.1007/978-3-319-46248-6_5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Targeting advanced glycation with pharmaceutical agents: where are we now? Glycoconj J 2016; 33:653-70. [PMID: 27392438 DOI: 10.1007/s10719-016-9691-1] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 05/11/2016] [Accepted: 05/26/2016] [Indexed: 02/06/2023]
Abstract
Advanced glycation end products (AGEs) are the final products of the Maillard reaction, a complex process that has been studied by food chemists for a century. Over the past 30 years, the biological significance of advanced glycation has also been discovered. There is mounting evidence that advanced glycation plays a homeostatic role within the body and that food-related Maillard products, intermediates such as reactive α-dicarbonyl compounds and AGEs, may influence this process. It remains to be understood, at what point AGEs and their intermediates become pathogenic and contribute to the pathogenesis of chronic diseases that inflict current society. Diabetes and its complications have been a major focus of AGE biology due to the abundance of excess sugar and α-dicarbonyls in this family of diseases. While further temporal information is required, a number of pharmacological agents that inhibit components of the advanced glycation pathway have already showed promising results in preclinical models. These therapies appear to have a wide range of mechanistic actions to reduce AGE load. Some of these agents including Alagebrium, have translated successfully to clinical trials, while others such as aminoguanidine, have had undesirable side-effect profiles. This review will discuss different pharmacological agents that have been used to reduce AGE burden in preclinical models of disease with a focus on diabetes and its complications, compare outcomes of those therapies that have reached clinical trials, and provide further rationale for the use of inhibitors of the glycation pathway in chronic diseases.
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Zhu Z, Varadi G, Carter SG. Pharmacokinetics of the transdermal delivery of benfotiamine. Acta Diabetol 2016; 53:317-22. [PMID: 26141141 DOI: 10.1007/s00592-015-0776-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 05/26/2015] [Indexed: 02/06/2023]
Abstract
AIMS Accumulation of advanced glycation endpoints is a trigger to the development of diabetic peripheral neuropathy, which is a common complication of diabetes. Oral administration of benfotiamine (BFT) has shown some preclinical and clinical promise as a treatment for diabetic peripheral neuropathy. The purpose of this study was to evaluate the method of transdermal delivery of BFT as a possible, viable route of administration for the treatment of diabetic peripheral neuropathy. METHODS A single application of 10 mg of BFT was given to guinea pigs topically. The levels of thiamine (T), thiamine monophosphate, thiamine diphosphate, S-benzoylthiamine and BFT were measured in the blood, skin and muscle at different time points within 24 h. RESULTS At the 24-h time point, following the single BFT dose, the T level was increased 10× in the blood, more than 7× in the skin and almost 4× in the muscle compared to the untreated animals. The total T content (total) was increased 7× in the blood, 17× in the skin and 3× in the muscle compared to the untreated animals. CONCLUSIONS This strong increase in the tissue levels of T and the associated metabolic derivatives levels found in the blood and local tissues following a single dose indicate that topically applied BFT may be a viable and advantageous delivery method for the treatment of diabetic peripheral neuropathy.
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Affiliation(s)
- Zhen Zhu
- BioChemics Inc., 99 Rosewood Drive, Suite 270, Danvers, MA, 01923-4537, USA.
| | - Gyula Varadi
- BioChemics Inc., 99 Rosewood Drive, Suite 270, Danvers, MA, 01923-4537, USA
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Mallipattu SK, Uribarri J. Advanced glycation end product accumulation: a new enemy to target in chronic kidney disease? Curr Opin Nephrol Hypertens 2015; 23:547-54. [PMID: 25160075 DOI: 10.1097/mnh.0000000000000062] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE OF REVIEW The critical role of advanced glycation end products (AGEs) in the progression of chronic diseases and their complications has recently become more apparent. This review summarizes the recent contributions to the field of AGEs in chronic kidney disease (CKD). RECENT FINDINGS Over the past 3 decades, AGEs have been implicated in the progression of CKD, and specifically diabetic nephropathy. Although numerous in-vitro and in-vivo studies highlight the detrimental role of AGEs accumulation in tissue injury, few prospective human studies or clinical trials show that inhibiting this process ameliorates disease. Nonetheless, recent studies have focused on the novel mechanisms that contribute to end-organ injury as a result of AGEs accumulation, as well as novel targets of therapy in kidney disease. SUMMARY As the prevalence and the incidence of CKD rises in the United States, it is essential to identify therapeutic strategies that either delay the progression of CKD or improve mortality in this population. The focus of this review is on highlighting the recent studies that advance our current understanding of the mechanisms mediating AGEs-induced CKD progression, as well as novel treatment strategies that have the potential to abrogate this disease process. VIDEO ABSTRACT http://links.lww.com/CONH/A12.
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Affiliation(s)
- Sandeep K Mallipattu
- aDivision of Nephrology, Department of Medicine, Stony Brook University bDivision of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA
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Ahmad S, Khan MS, Akhter F, Khan MS, Khan A, Ashraf JM, Pandey RP, Shahab U. Glycoxidation of biological macromolecules: a critical approach to halt the menace of glycation. Glycobiology 2014; 24:979-990. [PMID: 24946787 DOI: 10.1093/glycob/cwu057] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2025] Open
Abstract
Glycation is the result of covalent bonding of a free amino group of biological macromolecules with a reducing sugar, which results in the formation of a Schiff base that undergoes rearrangement, dehydration and cyclization to form a more stable Amadori product. The final products of nonenzymatic glycation of biomacromolecules like DNA, proteins and lipids are known as advanced glycation end products (AGEs). AGEs may be generated rapidly or over long times stimulated by distinct triggering mechanisms, thereby accounting for their roles in multiple settings and disease states. Both Schiff base and Amadori glycation products generate free radicals resulting in decline of antioxidant defense mechanisms and can damage cellular organelles and enzymes. This critical review primarily focuses on the mechanistic insight of glycation and the most probable route for the formation of glycation products and their therapeutic interventions. Furthermore, the prevention of glycation reaction using therapeutic drugs such as metformin, pyridoxamine and aminoguanidine (AG) are discussed with special emphasis on the novel concept of the bioconjugation of these drugs like, AG with gold nanoparticles (GNPs). At or above 10 mM concentration, AG is found to be toxic and therefore has serious health concerns, and the study warrants doing this novel bioconjugation of AG with GNPs. This approach might increase the efficacy of the AG at a reduced concentration with low or no toxicity. Using the concept of synthesis of GNPs with abovementioned drugs, it is assumed that toxicity of various drugs which are used at high doses can be minimized more effectively.
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Affiliation(s)
- Saheem Ahmad
- Department of Biosciences, Integral University, Lucknow, India
| | - M Salman Khan
- Department of Biosciences, Integral University, Lucknow, India
| | - Firoz Akhter
- Department of Biosciences, Integral University, Lucknow, India
| | - Mohd Sajid Khan
- Department of Biosciences, Integral University, Lucknow, India
| | - Amir Khan
- Glocal School of Life Sciences, Glocal University, Saharanpur, Uttar Pradesh, India
| | - J M Ashraf
- Department of Biotechnology, School of Biotechnology, Yeungnam University, Yeungnam, Republic of Korea
| | - Ramendra Pati Pandey
- Nano-Biotech Lab, Department of Zoology, Kirorimal College, University of Delhi, Delhi, India
| | - Uzma Shahab
- Department of Biochemistry, Central Drug Research Institute, Lucknow, India
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Hellwig M, Henle T. Backen, Altern, Diabetes: eine kurze Geschichte der Maillard-Reaktion. Angew Chem Int Ed Engl 2014. [DOI: 10.1002/ange.201308808] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Hellwig M, Henle T. Baking, ageing, diabetes: a short history of the Maillard reaction. Angew Chem Int Ed Engl 2014; 53:10316-29. [PMID: 25044982 DOI: 10.1002/anie.201308808] [Citation(s) in RCA: 325] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 12/12/2013] [Indexed: 01/11/2023]
Abstract
The reaction of reducing carbohydrates with amino compounds described in 1912 by Louis-Camille Maillard is responsible for the aroma, taste, and appearance of thermally processed food. The discovery that non-enzymatic conversions also occur in organisms led to intensive investigation of the pathophysiological significance of the Maillard reaction in diabetes and ageing processes. Dietary Maillard products are discussed as "glycotoxins" and thus as a nutritional risk, but also increasingly with regard to positive effects in the human body. In this Review we give an overview of the most important discoveries in Maillard research since it was first described and show that the complex reaction, even after over one hundred years, has lost none of its interdisciplinary actuality.
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Affiliation(s)
- Michael Hellwig
- Chair of Food Chemistry, Technische Universität Dresden, D-01062 Dresden (Germany) http://www.chm.tu-dresden.de/lc1
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Pácal L, Kuricová K, Kaňková K. Evidence for altered thiamine metabolism in diabetes: Is there a potential to oppose gluco- and lipotoxicity by rational supplementation? World J Diabetes 2014; 5:288-295. [PMID: 24936250 PMCID: PMC4058733 DOI: 10.4239/wjd.v5.i3.288] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 04/14/2014] [Accepted: 05/16/2014] [Indexed: 02/05/2023] Open
Abstract
Growing prevalence of diabetes (type 2 as well as type 1) and its related morbidity due to vascular complications creates a large burden on medical care worldwide. Understanding the molecular pathogenesis of chronic micro-, macro- and avascular complications mediated by hyperglycemia is of crucial importance since novel therapeutic targets can be identified and tested. Thiamine (vitamin B1) is an essential cofactor of several enzymes involved in carbohydrate metabolism and published data suggest that thiamine metabolism in diabetes is deficient. This review aims to point out the physiological role of thiamine in metabolism of glucose and amino acids, to present overview of thiamine metabolism and to describe the consequences of thiamine deficiency (either clinically manifest or latent). Furthermore, we want to explain why thiamine demands are increased in diabetes and to summarise data indicating thiamine mishandling in diabetics (by review of the studies mapping the prevalence and the degree of thiamine deficiency in diabetics). Finally, we would like to summarise the evidence for the beneficial effect of thiamine supplementation in progression of hyperglycemia-related pathology and, therefore, to justify its importance in determining the harmful impact of hyperglycemia in diabetes. Based on the data presented it could be concluded that although experimental studies mostly resulted in beneficial effects, clinical studies of appropriate size and duration focusing on the effect of thiamine supplementation/therapy on hard endpoints are missing at present. Moreover, it is not currently clear which mechanisms contribute to the deficient action of thiamine in diabetes most. Experimental studies on the molecular mechanisms of thiamine deficiency in diabetes are critically needed before clear answer to diabetes community could be given.
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Kulkarni MJ, Korwar AM, Mary S, Bhonsle HS, Giri AP. Glycated proteome: from reaction to intervention. Proteomics Clin Appl 2014. [PMID: 23184864 DOI: 10.1002/prca.201200101] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Glycation, a nonenzymatic reaction between reducing sugars and proteins, is a proteome wide phenomenon, predominantly observed in diabetes due to hyperglycemia. Glycated proteome of plasma, kidney, lens, and brain are implicated in the pathogenesis of various diseases, including diabetic complications, neurodegenerative diseases, cancer, and aging. This review discusses the strategies to characterize protein glycation, its functional implications in different diseases, and intervention strategies to protect the deleterious effects of protein glycation.
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Affiliation(s)
- Mahesh J Kulkarni
- Proteomics Facility, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Pune, India.
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Modulation of neuropathic pain in experimental diabetes mellitus. J Physiol Biochem 2014; 70:355-61. [DOI: 10.1007/s13105-013-0309-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Accepted: 12/19/2013] [Indexed: 01/17/2023]
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Stirban A, Gawlowski T, Roden M. Vascular effects of advanced glycation endproducts: Clinical effects and molecular mechanisms. Mol Metab 2013; 3:94-108. [PMID: 24634815 DOI: 10.1016/j.molmet.2013.11.006] [Citation(s) in RCA: 229] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2013] [Revised: 11/17/2013] [Accepted: 11/18/2013] [Indexed: 12/17/2022] Open
Abstract
The enhanced generation and accumulation of advanced glycation endproducts (AGEs) have been linked to increased risk for macrovascular and microvascular complications associated with diabetes mellitus. AGEs result from the nonenzymatic reaction of reducing sugars with proteins, lipids, and nucleic acids, potentially altering their function by disrupting molecular conformation, promoting cross-linking, altering enzyme activity, reducing their clearance, and impairing receptor recognition. AGEs may also activate specific receptors, like the receptor for AGEs (RAGE), which is present on the surface of all cells relevant to atherosclerotic processes, triggering oxidative stress, inflammation and apoptosis. Understanding the pathogenic mechanisms of AGEs is paramount to develop strategies against diabetic and cardiovascular complications.
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Affiliation(s)
- Alin Stirban
- Profil Institut für Stoffwechselforschung GmbH, Hellersbergstrasse 9, 41460 Neuss, Germany
| | - Thomas Gawlowski
- University of Paderborn, Warburger Str. 100, 33098 Paderborn, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany ; Division of Endocrinology and Diabetology, University Clinics Düsseldorf, 40225 Düsseldorf, Germany
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Double-blind, randomized placebo-controlled clinical trial of benfotiamine for severe alcohol dependence. Drug Alcohol Depend 2013; 133:562-70. [PMID: 23992649 PMCID: PMC3818307 DOI: 10.1016/j.drugalcdep.2013.07.035] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Revised: 07/26/2013] [Accepted: 07/27/2013] [Indexed: 12/16/2022]
Abstract
Alcohol dependence is associated with severe nutritional and vitamin deficiency. Vitamin B1 (thiamine) deficiency erodes neurological pathways that may influence the ability to drink in moderation. The present study examines tolerability of supplementation using the high-potency thiamine analog, benfotiamine (BF), and BF's effects on alcohol consumption in severely affected, self-identified, alcohol dependent subjects. A randomized, double-blind, placebo-controlled trial was conducted on 120 non-treatment seeking, actively drinking, alcohol dependent men and women volunteers (mean age=47 years) from the Kansas City area who met DSM-IV-TR criteria for current alcohol dependence. Subjects were randomized to receive 600 mg benfotiamine or placebo (PL) once daily by mouth for 24 weeks with 6 follow-up assessments scheduled at 4 week intervals. Side effects and daily alcohol consumption were recorded. Seventy (58%) subjects completed 24 weeks of study (N=21 women; N=49 men) with overall completion rates of 55% (N=33) for PL and 63% (N=37) for BF groups. No significant adverse events were noted and alcohol consumption decreased significantly for both treatment groups. Alcohol consumption decreased from baseline levels for 9 of 10 BF treated women after 1 month of treatment compared with 2 of 11 on PL. Reductions in total alcohol consumption over 6 months were significantly greater for BF treated women (BF: N=10, -611 ± 380 standard drinks; PL: N=11, -159 ± 562 standard drinks, p-value=0.02). BF supplementation of actively drinking alcohol dependent men and women was well-tolerated and may discourage alcohol consumption among women. The results do support expanded studies of BF treatment in alcoholism.
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Stirban A, Pop A, Fischer A, Heckermann S, Tschoepe D. Variability of skin autofluorescence measurement over 6 and 12 weeks and the influence of benfotiamine treatment. Diabetes Technol Ther 2013; 15:733-7. [PMID: 23964994 DOI: 10.1089/dia.2013.0103] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Measurements of skin autofluorescence (SAF) allow for a simple and noninvasive quantification of tissue advanced glycation end-products (AGEs), a marker linked to the risk of diabetes complications. The aim of this study was to test the repeatability of SAF over 6 and 12 weeks and to test whether benfotiamine, a thiamine prodrug suggested to reduce AGEs formation under hyperglycemic conditions, is able to attenuate SAF when administered over 6 weeks. PATIENTS AND METHODS In a double-blind, placebo-controlled, randomized, crossover study, 22 patients with type 2 diabetes mellitus (T2DM) received 900 mg/day benfotiamine or placebo for 6 weeks (washout period of 6 weeks between). At the beginning and at the end of each treatment period, SAF was assessed in the fasting state, as well as 2, 4, and 6 h following a mixed test meal. RESULTS The respective intra-individual and inter-individual variability of fasting SAF was 6.9% and 24.5% within 6 weeks and 10.9% and 23.1% within 12 weeks. The respective variability calculated for triplicate comparisons was 9.9% and 27.7%. A short-term therapy with benfotiamine did not influence SAF significantly, nor did we find a significant postprandial SAF increase. CONCLUSIONS In patients with T2DM, repeated, timely spaced SAF measurements have an intra-subject variability of below 11%. Using these data, sample sizes were calculated for interventional studies aiming at reducing SAF. Benfotiamine treatment for 6 weeks did not significantly influence SAF; for this, a longer-term therapy is probably needed.
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Affiliation(s)
- Alin Stirban
- Diabetes Clinic, Heart and Diabetes Center NR, Ruhr University Bochum, Bad Oeynhausen, Germany.
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31
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Are brain and heart tissue prone to the development of thiamine deficiency? Alcohol 2013; 47:215-21. [PMID: 23357554 DOI: 10.1016/j.alcohol.2012.12.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Revised: 08/20/2012] [Accepted: 12/29/2012] [Indexed: 11/21/2022]
Abstract
Thiamine deficiency is a continuing problem leading to beriberi and Wernicke's encephalopathy. The symptoms of thiamine deficiency develop in the heart, brain and neuronal tissue. Yet, it is unclear how rapid thiamine deficiency develops and which organs are prone to development of thiamine deficiency. We investigated these issues in a thiamine deficient animal model. Twenty-four male Lewis rats were fed a thiamine deficient diet, which contained 0.04% of normal thiamine intake. Six control rats were fed 200 μg of thiamine per day. Every week a group of six rats on the thiamine-deficient diet was sacrificed and blood, urine and tissue were stored. Blood and tissue transketolase activity, thiamine and thiamine metabolites were measured and PCR of thiamine transporter-1 (ThTr-1) was performed. Transketolase activity was significantly reduced in red blood cells, liver, lung, kidney and spleen tissue after two weeks of thiamine deficient diet. In brain tissue, transketolase activity was not reduced after up to four weeks of thiamine deficient diet. The amount of thiamine pyrophosphate was also significantly conserved in brain and heart tissue (decrease of 31% and 28% respectively), compared to other tissues (decrease of ~70%) after four weeks of thiamine deficient diet. There was no difference between tissues in ThTr-1 expression after four weeks of thiamine deficient diet. Despite the fact that the heart and the brain are predilection sites for complications from thiamine deficiency, these tissues are protected against thiamine deficiency. Other organs could be suffering from thiamine deficiency without resulting in clinical signs of classic thiamine deficiency in beriberi and Wernicke's encephalopathy.
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Gibson GE, Hirsch JA, Cirio RT, Jordan BD, Fonzetti P, Elder J. Abnormal thiamine-dependent processes in Alzheimer's Disease. Lessons from diabetes. Mol Cell Neurosci 2012; 55:17-25. [PMID: 22982063 DOI: 10.1016/j.mcn.2012.09.001] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2012] [Revised: 09/04/2012] [Accepted: 09/05/2012] [Indexed: 01/30/2023] Open
Abstract
Reduced glucose metabolism is an invariant feature of Alzheimer's Disease (AD) and an outstanding biomarker of disease progression. Glucose metabolism may be an attractive therapeutic target, whether the decline initiates AD pathophysiology or is a critical component of a cascade. The cause of cerebral regional glucose hypometabolism remains unclear. Thiamine-dependent processes are critical in glucose metabolism and are diminished in brains of AD patients at autopsy. Further, the reductions in thiamine-dependent processes are highly correlated to the decline in clinical dementia rating scales. In animal models, thiamine deficiency exacerbates plaque formation, promotes phosphorylation of tau and impairs memory. In contrast, treatment of mouse models of AD with the thiamine derivative benfotiamine diminishes plaques, decreases phosphorylation of tau and reverses memory deficits. Diabetes predisposes to AD, which suggests they may share some common mechanisms. Benfotiamine diminishes peripheral neuropathy in diabetic humans and animals. In diabetes, benfotiamine induces key thiamine-dependent enzymes of the pentose shunt to reduce accumulation of toxic metabolites including advanced glycation end products (AGE). Related mechanisms may lead to reversal of plaque formation by benfotiamine in animals. If so, the use of benfotiamine could provide a safe intervention to reverse biological and clinical processes of AD progression. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'.
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Affiliation(s)
- Gary E Gibson
- Department of Neurology and Neuroscience, Weill Cornell Medical College, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA.
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Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol 2012; 10:49. [PMID: 22748101 PMCID: PMC3527168 DOI: 10.1186/1477-7827-10-49] [Citation(s) in RCA: 977] [Impact Index Per Article: 75.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Accepted: 06/06/2012] [Indexed: 12/16/2022] Open
Abstract
Oxidative stress (OS), a state characterized by an imbalance between pro-oxidant molecules including reactive oxygen and nitrogen species, and antioxidant defenses, has been identified to play a key role in the pathogenesis of subfertility in both males and females. The adverse effects of OS on sperm quality and functions have been well documented. In females, on the other hand, the impact of OS on oocytes and reproductive functions remains unclear. This imbalance between pro-oxidants and antioxidants can lead to a number of reproductive diseases such as endometriosis, polycystic ovary syndrome (PCOS), and unexplained infertility. Pregnancy complications such as spontaneous abortion, recurrent pregnancy loss, and preeclampsia, can also develop in response to OS. Studies have shown that extremes of body weight and lifestyle factors such as cigarette smoking, alcohol use, and recreational drug use can promote excess free radical production, which could affect fertility. Exposures to environmental pollutants are of increasing concern, as they too have been found to trigger oxidative states, possibly contributing to female infertility. This article will review the currently available literature on the roles of reactive species and OS in both normal and abnormal reproductive physiological processes. Antioxidant supplementation may be effective in controlling the production of ROS and continues to be explored as a potential strategy to overcome reproductive disorders associated with infertility. However, investigations conducted to date have been through animal or in vitro studies, which have produced largely conflicting results. The impact of OS on assisted reproductive techniques (ART) will be addressed, in addition to the possible benefits of antioxidant supplementation of ART culture media to increase the likelihood for ART success. Future randomized controlled clinical trials on humans are necessary to elucidate the precise mechanisms through which OS affects female reproductive abilities, and will facilitate further explorations of the possible benefits of antioxidants to treat infertility.
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Affiliation(s)
- Ashok Agarwal
- Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA
| | | | - Beena J Premkumar
- Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Amani Shaman
- Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Sajal Gupta
- Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA
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Mallipattu SK, He JC, Uribarri J. Role of advanced glycation endproducts and potential therapeutic interventions in dialysis patients. Semin Dial 2012; 25:529-38. [PMID: 22548330 DOI: 10.1111/j.1525-139x.2012.01081.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
It has been nearly 100 years since the first published report of advanced glycation end products (AGEs) by the French chemist Maillard. Since then, our understanding of AGEs in diseased states has dramatically changed. Especially in the last 25 years, AGEs have been implicated in complications related to aging, neurodegenerative diseases, diabetes, and chronic kidney disease. Although AGE formation has been well characterized by both in vitro and in vivo studies, few prospective human studies exist demonstrating the role of AGEs in patients on chronic renal replacement therapy. As the prevalence of end-stage renal disease (ESRD) in the United States rises, it is essential to identify therapeutic strategies that either delay progression to ESRD or improve morbidity and mortality in this population. This article reviews the role of AGEs, especially those of dietary origin, in ESRD patients as well as potential therapeutic anti-AGE strategies in this population.
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Affiliation(s)
- Sandeep K Mallipattu
- Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA
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Smithline HA, Donnino M, Greenblatt DJ. Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects. BMC CLINICAL PHARMACOLOGY 2012; 12:4. [PMID: 22305197 PMCID: PMC3293077 DOI: 10.1186/1472-6904-12-4] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Accepted: 02/04/2012] [Indexed: 12/31/2022]
Abstract
BACKGROUND High dose oral thiamine may have a role in treating diabetes, heart failure, and hypermetabolic states. The purpose of this study was to determine the pharmacokinetic profile of oral thiamine hydrochloride at 100 mg, 500 mg and 1500 mg doses in healthy subjects. METHODS This was a randomized, double-blind, single-dose, 4-way crossover study. Pharmacokinetic measures were calculated. RESULTS The AUC₀₋₁₀ hr and C(max) values increased nonlinearly between 100 mg and 1500 mg. The slope of the AUC₀₋₁₀ hr vs dose, as well as the C(max) vs dose, plots are steepest at the lowest thiamine doses. CONCLUSION Our study demonstrates that high blood levels of thiamine can be achieved rapidly with oral thiamine hydrochloride. Thiamine is absorbed by both an active and nonsaturable passive process. TRIAL REGISTRATION ClinicalTrials.gov: NCT00981877.
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Affiliation(s)
- Howard A Smithline
- Department of Emergency Medicine, Tufts University School of Medicine and Baystate Medical Center, Springfield, MA, USA.
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Shoeb M, Ramana KV. Anti-inflammatory effects of benfotiamine are mediated through the regulation of the arachidonic acid pathway in macrophages. Free Radic Biol Med 2012; 52:182-90. [PMID: 22067901 PMCID: PMC3249497 DOI: 10.1016/j.freeradbiomed.2011.10.444] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2011] [Revised: 10/11/2011] [Accepted: 10/16/2011] [Indexed: 11/23/2022]
Abstract
Benfotiamine, a lipid-soluble analogue of vitamin B1, is a potent antioxidant that is used as a food supplement for the treatment of diabetic complications. Our recent study (U.C. Yadav et al., Free Radic. Biol. Med. 48:1423-1434, 2010) indicates a novel role for benfotiamine in the prevention of bacterial endotoxin, lipopolysaccharide (LPS)-induced cytotoxicity and inflammatory response in murine macrophages. Nevertheless, it remains unclear how benfotiamine mediates anti-inflammatory effects. In this study, we investigated the anti-inflammatory role of benfotiamine in regulating arachidonic acid (AA) pathway-generated inflammatory lipid mediators in RAW264.7 macrophages. Benfotiamine prevented the LPS-induced activation of cPLA2 and release of AA metabolites such as leukotrienes, prostaglandin E2, thromboxane 2 (TXB2), and prostacyclin (PGI2) in macrophages. Further, LPS-induced expression of AA-metabolizing enzymes such as COX-2, LOX-5, TXB synthase, and PGI2 synthase was significantly blocked by benfotiamine. Furthermore, benfotiamine prevented the LPS-induced phosphorylation of ERK1/2 and expression of transcription factors NF-κB and Egr-1. Benfotiamine also prevented the LPS-induced oxidative stress and protein-HNE adduct formation. Most importantly, compared to specific COX-2 and LOX-5 inhibitors, benfotiamine significantly prevented LPS-induced macrophage death and monocyte adhesion to endothelial cells. Thus, our studies indicate that the dual regulation of the COX and LOX pathways in AA metabolism could be a novel mechanism by which benfotiamine exhibits its potential anti-inflammatory response.
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Affiliation(s)
| | - Kota V Ramana
- Correspondence: Kota V Ramana, PhD, , Telephone (409)-772-2202, Fax: 409-772-9679 and mailing address: #6.614D BSB, Department of Biochemistry and Molecular biology, University of Texas Medical Branch, Galveston, Texas -77555, USA
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Tanaka T, Kono T, Terasaki F, Yasui K, Soyama A, Otsuka K, Fujita S, Yamane K, Manabe M, Usui K, Kohda Y. Thiamine prevents obesity and obesity-associated metabolic disorders in OLETF rats. J Nutr Sci Vitaminol (Tokyo) 2011; 56:335-46. [PMID: 21422702 DOI: 10.3177/jnsv.56.335] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
We previously found that thiamine mitigates metabolic disorders in spontaneously hypertensive rats, harboring defects in glucose and fatty acid metabolism. Mutation of thiamine transporter gene SLC19A2 is linked to type 2 diabetes mellitus. The current study extends our hypothesis that thiamine intervention may impact metabolic abnormalities in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, exhibiting obesity and metabolic disorders similar to human metabolic syndrome. Male OLETF rats (4 wk old) were given free access to water containing either 0.2% or 0% of thiamine for 21 and 51 wk. At the end of treatment, blood parameters and cardiac functions were analyzed. After sacrifice, organs weights, histological findings, and hepatic pyruvate dehydrogenase (PDH) activity in the liver were evaluated. Thiamine intervention averted obesity and prevented metabolic disorders in OLETF rats which accompanied mitigation of reduced lipid oxidation and increased hepatic PDH activity. Histological evaluation revealed that thiamine alleviated adipocyte hypertrophy, steatosis in the liver, heart, and skeletal muscle, sinusoidal fibrosis with formation of basement membranes (called pseudocapillarization) which accompanied significantly reduced expression of laminin β1 and nidogen-1 mRNA, interstitial fibrosis in the heart and kidney, fatty degeneration in the pancreas, thickening of the basement membrane of the vasculature, and glomerulopathy and mononuclear cell infiltration in the kidney. Cardiac and renal functions were preserved in thiamine treatment. Thiamine has a potential to prevent obesity and metabolic disorders in OLETF rats.
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Affiliation(s)
- Takao Tanaka
- Laboratory of Pharmacotherapy, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan
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Miranda-Massari JR, Gonzalez MJ, Jimenez FJ, Allende-Vigo MZ, Duconge J. Metabolic correction in the management of diabetic peripheral neuropathy: improving clinical results beyond symptom control. CURRENT CLINICAL PHARMACOLOGY 2011; 6:260-73. [PMID: 22082324 PMCID: PMC3682498 DOI: 10.2174/157488411798375967] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2011] [Revised: 06/07/2011] [Accepted: 09/23/2011] [Indexed: 12/28/2022]
Abstract
Current Clinical Management Guidelines of Diabetic Peripheral Neuropathy (DPN) are based on adequate glucose control and symptomatic pain relief. However, meticulous glycemic control could delay the onset or slow the progression of diabetic neuropathy in patients with DM type 2, but it does not completely prevent the progression of the disease. Complications of DPN as it continues its natural course, produce increasing pain and discomfort, loss of sensation, ulcers, infections, amputations and even death. In addition to the increased suffering, disability and loss of productivity, there is a very significant economic impact related to the treatment of DPN and its complications. In USA alone, it has been estimated that there are more than 5,000,000 patients suffering from DPN and the total annual cost of treating the disease and its complications is over $10,000 million dollars. In order to be able to reduce complications of DPN, it is crucial to improve or correct the metabolic conditions that lead to the pathology present in this condition. Pathophysiologic mechanisms implicated in diabetic neuropathy include: increased polyol pathway with accumulation of sorbitol and reduced Na+/K+-ATPase activity, microvascular damage and hypoxia due to nitric oxide deficit and increased oxygen free radical activity. Moreover, there is a decrease in glutathione and increase in homocysteine. Clinical trials in the last two decades have demonstrated that the use of specific nutrients can correct some of these metabolic derangements, improving symptom control and providing further benefits such as improved sensorium, blood flow and nerve regeneration. We will discuss the evidence on lipoic acid, acetyl-L-carnitine, benfotiamine and the combination of active B vitamins L-methylfolate, methylcobalamin and piridoxal-6-phosphate. In addition, we discuss the role of metformin, an important drug in the management of diabetes, and the presence of specific polymorphic genes, in the risk of developing DPN and how metabolic correction can reduce these risks.
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Affiliation(s)
- Jorge R. Miranda-Massari
- RECNAC 2 Project, University of Puerto Rico-Medical Sciences Campus, San Juan, Puerto Rico
- School of Pharmacy, Department of Pharmacy Practice, University of Puerto Rico-Medical Sciences Campus, San Juan, Puerto Rico
| | - Michael J. Gonzalez
- RECNAC 2 Project, University of Puerto Rico-Medical Sciences Campus, San Juan, Puerto Rico
- Graduate School of Public Health, Department of Human Development, Nutrition Program, University of Puerto Rico-Medical Sciences Campus, San Juan, Puerto Rico
| | - Francisco J. Jimenez
- School of Pharmacy, Department of Pharmacy Practice, University of Puerto Rico-Medical Sciences Campus, San Juan, Puerto Rico
| | - Myriam Z. Allende-Vigo
- School of Medicine, Department of Endocrinology, University of Puerto Rico-Medical Sciences Campus, San Juan, Puerto Rico
| | - Jorge Duconge
- RECNAC 2 Project, University of Puerto Rico-Medical Sciences Campus, San Juan, Puerto Rico
- Pharmaceutical Sciences, University of Puerto Rico-Medical Sciences Campus, San Juan, Puerto Rico
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Babizhayev MA, Deyev AI, Savel'Yeva EL, Lankin VZ, Yegorov YE. Skin beautification with oral non-hydrolized versions of carnosine and carcinine: Effective therapeutic management and cosmetic skincare solutions against oxidative glycation and free-radical production as a causal mechanism of diabetic complications and skin aging. J DERMATOL TREAT 2011; 23:345-84. [DOI: 10.3109/09546634.2010.521812] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Karachalias N, Babaei-Jadidi R, Rabbani N, Thornalley PJ. Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes. Diabetologia 2010; 53:1506-16. [PMID: 20369223 DOI: 10.1007/s00125-010-1722-z] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2009] [Accepted: 02/03/2010] [Indexed: 12/15/2022]
Abstract
AIMS/HYPOTHESIS The aim of this study was to quantify protein damage by glycation, oxidation and nitration in a rat model of diabetes at the sites of development of microvascular complications, including the effects of thiamine and benfotiamine therapy. METHODS Diabetes was induced in male Sprague-Dawley rats by 55 mg/kg streptozotocin and moderated by insulin (2 U twice daily). Diabetic and control rats were given thiamine or benfotiamine (7 or 70 mg kg(-1) day(-1)) over 24 weeks. Plasma, urine and tissues were collected and analysed for protein damage by stable isotopic dilution analysis MS. RESULTS There were two- to fourfold increases in fructosyl-lysine and AGE content of glomerular, retinal, sciatic nerve and plasma protein in diabetes. Increases in AGEs were reversed by thiamine and benfotiamine therapy but increases in fructosyl-lysine were not. Methionine sulfoxide content of plasma protein and 3-nitrotyrosine content of sciatic nerve protein were increased in diabetes. Plasma glycation free adducts were increased up to twofold in diabetes; the increases were reversed by thiamine. Urinary excretion of glycation, oxidation and nitration free adducts was increased by seven- to 27-fold in diabetes. These increases were reversed by thiamine and benfotiamine therapy. CONCLUSIONS/INTERPRETATION AGEs, particularly arginine-derived hydroimidazolones, accumulate at sites of microvascular complication development and have markedly increased urinary excretion rates in experimental diabetes. Thiamine and benfotiamine supplementation prevented tissue accumulation and increased urinary excretion of protein glycation, oxidation and nitration adducts. Similar effects may contribute to the reversal of early-stage clinical diabetic nephropathy by thiamine.
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Affiliation(s)
- N Karachalias
- Department of Biological Sciences, University of Essex, Central Campus, Wivenhoe Park, Colchester, Essex, UK
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Yadav UCS, Kalariya NM, Srivastava SK, Ramana KV. Protective role of benfotiamine, a fat-soluble vitamin B1 analogue, in lipopolysaccharide-induced cytotoxic signals in murine macrophages. Free Radic Biol Med 2010; 48:1423-34. [PMID: 20219672 PMCID: PMC2856750 DOI: 10.1016/j.freeradbiomed.2010.02.031] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Revised: 02/12/2010] [Accepted: 02/21/2010] [Indexed: 02/06/2023]
Abstract
This study was designed to investigate the molecular mechanisms by which benfotiamine, a lipid-soluble analogue of vitamin B1, affects lipopolysaccharide (LPS)-induced inflammatory signals leading to cytotoxicity in the mouse macrophage cell line RAW264.7. Benfotiamine prevented LPS-induced apoptosis, expression of the Bcl-2 family of proapoptotic proteins, caspase-3 activation, and PARP cleavage and altered mitochondrial membrane potential and release of cytochrome c and apoptosis-inducing factor and phosphorylation and subsequent activation of p38-MAPK, stress-activated kinases (SAPK/JNK), protein kinase C, and cytoplasmic phospholipase A2 in RAW cells. Further, phosphorylation and degradation of inhibitory kappaB and consequent activation and nuclear translocation of the redox-sensitive transcription factor NF-kappaB were significantly prevented by benfotiamine. The LPS-induced increased expression of cytokines and chemokines and the inflammatory marker proteins iNOS and COX-2 and their metabolic products NO and PGE(2) was also blocked significantly. Thus, our results elucidate the molecular mechanism of the anti-inflammatory action of benfotiamine in LPS-induced inflammation in murine macrophages. Benfotiamine suppresses oxidative stress-induced NF-kappaB activation and prevents bacterial endotoxin-induced inflammation, indicating that vitamin B1 supplementation could be beneficial in the treatment of inflammatory diseases.
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Affiliation(s)
- Umesh C S Yadav
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
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Watanabe M, Nakashima H, Ito K, Miyake K, Saito T. Improvement of dyslipidemia in OLETF rats by the prostaglandin I(2) analog beraprost sodium. Prostaglandins Other Lipid Mediat 2010; 93:14-9. [PMID: 20450981 DOI: 10.1016/j.prostaglandins.2010.04.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2009] [Revised: 04/12/2010] [Accepted: 04/27/2010] [Indexed: 10/19/2022]
Abstract
The Otsuka Long-Evans Tokushima Fatty (OLETF) rat was established as an animal model of human type 2 diabetes. Improvement of dyslipidemia by BPS has been confirmed in OLETF rats. The aim of this report is to clarify the mechanisms associated with improvement of dyslipidemia by BPS in OLETF rats. We divided male OLETF rats into three groups; 400microg/kg BPS treated (Group H), 200microg/kg BPS treated (Group L), and untreated control (Group C). After sacrifice, using the quantitative real-time PCR, we assayed the transcription levels of the HMG-CoA reductase (Hmgcr) for cholesterol biosynthesis, monoacylglycerol O-acyltransferase 1 (Mogat1) as TG synthetase, hepatic triglyceride lipase (Lipc) and lipoprotein lipase (Lpl) as triglycerides (TG) reductase in the liver. The mRNA expression of transketolase (Tkt) for pentose phosphate pathway (PPP) enzyme was also evaluated in the liver and kidney. Hmgcr and Mogat1 RNA expression levels were reduced in the livers and those of Tkt were increased in the kidney of BPS treated rats compared with those in untreated rats. The protein expressions of transketolase (Tkt) of BPS treated rats were similarly increased both in the kidney and liver. These results suggest that dyslipidemia was not improved by the acceleration of TG metabolism but by the suppression of activated cholesterol and TG biosyntheses in OLETF rats treated with BPS. High activity of Tkt induced by BPS may be involved in the suppression of such synthetic mechanisms.
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Affiliation(s)
- Maho Watanabe
- Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonann-ku, Fukuoka 814-0180, Japan
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Balakumar P, Rohilla A, Krishan P, Solairaj P, Thangathirupathi A. The multifaceted therapeutic potential of benfotiamine. Pharmacol Res 2010; 61:482-8. [PMID: 20188835 DOI: 10.1016/j.phrs.2010.02.008] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2010] [Revised: 02/17/2010] [Accepted: 02/17/2010] [Indexed: 12/14/2022]
Abstract
Thiamine, known as vitamin B(1), plays an essential role in energy metabolism. Benfotiamine (S-benzoylthiamine O-monophoshate) is a synthetic S-acyl derivative of thiamine. Once absorbed, benfotiamine is dephosphorylated by ecto-alkaline phosphatase to lipid-soluble S-benzoylthiamine. Transketolase is an enzyme that directs the precursors of advanced glycation end products (AGEs) to pentose phosphate pathway. Benfotiamine administration increases the levels of intracellular thiamine diphosphate, a cofactor necessary for the activation transketolase, resulting in the reduction of tissue level of AGEs. The elevated level of AGEs has been implicated in the induction and progression of diabetes-associated complications. Chronic hyperglycemia accelerates the reaction between glucose and proteins leading to the formation of AGEs, which form irreversible cross-links with many macromolecules such as collagen. In diabetes, AGEs accumulate in tissues at an accelerated rate. Experimental studies have elucidated that binding of AGEs to their specific receptors (RAGE) activates mainly monocytes and endothelial cells and consequently induces various inflammatory events. Moreover, AGEs exaggerate the status of oxidative stress in diabetes that may additionally contribute to functional changes in vascular tone control observed in diabetes. The anti-AGE property of benfotiamine certainly makes it effective for the treatment of diabetic neuropathy, nephropathy and retinopathy. Interestingly, few recent studies demonstrated additional non-AGE-dependent pharmacological actions of benfotiamine. The present review critically analyzed the multifaceted therapeutic potential of benfotiamine.
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Affiliation(s)
- Pitchai Balakumar
- Department of Pharmacology, SB College of Pharmacy, Sivakasi 626130, India.
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Jolivalt CG, Mizisin LM, Nelson A, Cunha JM, Ramos KM, Bonke D, Calcutt NA. B vitamins alleviate indices of neuropathic pain in diabetic rats. Eur J Pharmacol 2009; 612:41-7. [DOI: 10.1016/j.ejphar.2009.04.028] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2009] [Revised: 04/01/2009] [Accepted: 04/09/2009] [Indexed: 02/09/2023]
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Wong CY, Qiuwaxi J, Chen H, Li SW, Chan HT, Tam S, Shu XO, Lau CP, Kwong YL, Tse HF. Daily intake of thiamine correlates with the circulating level of endothelial progenitor cells and the endothelial function in patients with type II diabetes. Mol Nutr Food Res 2009; 52:1421-7. [PMID: 18925614 DOI: 10.1002/mnfr.200800056] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Our objective was to determine the relationships between levels of different dietary nutrients intake with circulating endothelial progenitor cells (EPC) and vascular endothelial function in type II diabetic patients. We studied the daily dietary nutrients intake, the numbers of circulating CD34(+)/KDR(+) EPC and CD133(+)/KDR(+) EPC and brachial artery flow-mediated dilation (FMD) in 88 diabetic patients without prior cardiovascular diseases and 91 sex- and age-matched controls. Compared with controls, diabetic patients had lower CD133(+)/KDR(+) EPC count (48.3 +/- 5.2 vs. 84.6 +/- 7.6/microL, p < 0.001), CD34(+)/KDR(+) EPC count (311 +/- 41 vs. 412 +/- 36/microL, p = 0.045), and FMD (2.54 +/- 0.37% vs. 5.46 +/- 0.47%, p < 0.001). After adjusted for age, sex, smoking history, body weight, hemoglobin A1c level, total calorie intake, other dietary vitamin intake, use of antihypertensives, and lipid lowering agents, a higher intake of thiamine was significantly associated with a higher level of circulating CD34(+)/KDR(+) EPC (beta = 0.49, p = 0.028) and CD133(+)/KDR(+) EPC (beta = 0.45, p = 0.037) in diabetic patients, but not in controls. Furthermore, an increased intake of thiamine from 1st to 4th quartile in diabetic patients independently predicted an absolute increase in FMD by 1.29% (p = 0.026, relative increase = 63.5%). This study demonstrated that daily thiamine intake was positively correlated with the circulating number of EPCs and FMD in patients with type II diabetes, independent of other dietary nutrients intake.
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Affiliation(s)
- Ching-Yuen Wong
- Cardiology Division, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
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Yadav UCS, Subramanyam S, Ramana KV. Prevention of endotoxin-induced uveitis in rats by benfotiamine, a lipophilic analogue of vitamin B1. Invest Ophthalmol Vis Sci 2009; 50:2276-82. [PMID: 19136698 DOI: 10.1167/iovs.08-2816] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
PURPOSE To study the amelioration of ocular inflammation in endotoxin-induced uveitis (EIU) in rats by benfotiamine, a lipid-soluble analogue of thiamine. METHODS EIU in Lewis rats was induced by subcutaneous injection of lipopolysaccharide (LPS) followed by treatment with benfotiamine. The rats were killed 3 or 24 hours after LPS injection, eyes were enucleated, aqueous humor (AqH) was collected, and the number of infiltrating cells, protein concentration, and inflammatory marker levels were determined. Immunohistochemical analysis of eye sections was performed to determine the expression of inducible-nitric oxide synthase (iNOS), cyclooxygenase (Cox)-2, protein kinase C (PKC), and transcription factor NF-kappaB. RESULTS Infiltrating leukocytes, protein concentrations, and inflammatory cytokines and chemokines were significantly elevated in the AqH of EIU rats compared with control rats, and benfotiamine treatment suppressed these increases. Similarly increased expression of inflammatory markers iNOS and Cox-2 in ciliary body and retinal wall was also significantly inhibited by benfotiamine. The increased phosphorylation of PKC and the activation of NF-kappaB in the ciliary body and in the retinal wall of EIU rat eyes were suppressed by benfotiamine. CONCLUSIONS These results suggest that benfotiamine suppresses oxidative stress-induced NF-kappaB-dependent inflammatory signaling leading to uveitis. Therefore, benfotiamine could be used as a novel therapeutic agent for the treatment of ocular inflammation, especially uveitis.
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Affiliation(s)
- Umesh C S Yadav
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555-0647, USA
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European Food Safety Authority (EFSA). Benfotiamine, thiamine monophosphate chloride and thiamine pyrophosphate chloride, as sources of vitamin B1 added for nutritional purposes to food supplements - Scientific Opinion of the Panel on Food Additives and Nutrient Sources added to Food (ANS). EFSA J 2008. [DOI: 10.2903/j.efsa.2008.864] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Bartlett HE, Eperjesi F. Nutritional supplementation for type 2 diabetes: a systematic review. Ophthalmic Physiol Opt 2008; 28:503-23. [DOI: 10.1111/j.1475-1313.2008.00595.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Beltramo E, Berrone E, Tarallo S, Porta M. Effects of thiamine and benfotiamine on intracellular glucose metabolism and relevance in the prevention of diabetic complications. Acta Diabetol 2008; 45:131-41. [PMID: 18581039 DOI: 10.1007/s00592-008-0042-y] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2008] [Accepted: 05/30/2008] [Indexed: 01/19/2023]
Abstract
Thiamine (vitamin B1) is an essential cofactor in most organisms and is required at several stages of anabolic and catabolic intermediary metabolism, such as intracellular glucose metabolism, and is also a modulator of neuronal and neuro-muscular transmission. Lack of thiamine or defects in its intracellular transport can cause a number of severe disorders. Thiamine acts as a coenzyme for transketolase (TK) and for the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes, enzymes which play a fundamental role for intracellular glucose metabolism. In particular, TK is able to shift excess fructose-6-phosphate and glycerhaldeyde-3-phosphate from glycolysis into the pentose-phosphate shunt, thus eliminating these potentially damaging metabolites from the cytosol. Diabetes might be considered a thiamine-deficient state, if not in absolute terms at least relative to the increased requirements deriving from accelerated and amplified glucose metabolism in non-insulin dependent tissues that, like the vessel wall, are prone to complications. A thiamine/TK activity deficiency has been described in diabetic patients, the correction of which by thiamine and/or its lipophilic derivative, benfotiamine, has been demonstrated in vitro to counteract the damaging effects of hyperglycaemia on vascular cells. Little is known, however, on the positive effects of thiamine/benfotiamine administration in diabetic patients, apart from the possible amelioration of neuropathic symptoms. Clinical trials on diabetic patients would be necessary to test this vitamin as a potential and inexpensive approach to the prevention and/or treatment of diabetic vascular complications.
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Affiliation(s)
- Elena Beltramo
- Department of Internal Medicine, University of Turin, Corso AM Dogliotti, 14, 10126, Turin, Italy.
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Stirban AO, Tschoepe D. Cardiovascular complications in diabetes: targets and interventions. Diabetes Care 2008; 31 Suppl 2:S215-21. [PMID: 18227488 DOI: 10.2337/dc08-s257] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Cardiovascular complications are mainly responsible for the high morbidity and mortality in people with diabetes. The awareness of physicians for the importance of primary prevention increased lately and numerous strategies have been developed. The spectrum ranges from pharmacologic treatment to vitamins and dietetic interventions. Some interesting concepts such as focusing on exogenous advanced glycation end products have emerged, but definitive results on their clinical relevance are still lacking. A major problem of the primary prevention is the choice of the method applied for screening, the criteria used to classify risk patients, as well as the choice of therapy. Guidelines provide goals to be achieved and offer alternatives for treatment, but the medical decision has to be made on an individualized basis. In this overview, we will comprehensively focus on the most important pathomechanisms and clinically relevant approaches, aiming at the early diagnosis and treatment of diabetes along with coronary heart disease. When primary prevention fails, we advocate a more aggressive treatment of critically ill patients, followed by optimal secondary prevention meeting on-target goals precisely.
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Affiliation(s)
- Alin O Stirban
- Heart and Diabetes Center, Ruhr-University Bochum, Bad Oeynhausen, Germany
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