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Brossfield AV, McMahon DJ, Fernando J, Omeragic B, Majeed R, Agarwal S, Sroga GE, Wang B, Vashishth D, Rubin MR. The Effects of the AGE Inhibitor Pyridoxamine on Bone in Older Women With Type 2 Diabetes: A Randomized Clinical Trial. J Clin Endocrinol Metab 2025; 110:961-972. [PMID: 39376018 DOI: 10.1210/clinem/dgae700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 04/03/2024] [Accepted: 10/06/2024] [Indexed: 10/09/2024]
Abstract
CONTEXT Patients with type 2 diabetes (T2D) have reduced bone turnover and increased fractures. Advanced glycation end products (AGEs) impair osteoblasts and are implicated in diabetic fractures. Pyridoxamine (PM) is a vitamin B6 metabolite that inhibits formation of AGEs. OBJECTIVE We hypothesized that PM treatment in older patients with T2D, by inhibiting AGEs, would increase bone formation. METHODS This was a double-blind randomized controlled trial at an academic center. Older women with T2D were included (n = 55). Oral PM 200 mg twice daily for 1 year was given. The primary outcome was the change in the bone formation marker P1NP. Other outcomes were changes in bone resorption, bone mineral density (BMD), HbA1c, and skin autofluorescence (SAF), and in a bone biopsy subgroup, the correlation between bone fluorescent AGEs (fAGEs) and SAF. RESULTS P1NP increased 23.0% with PM (95% CI 9, 37; within group P = .028) vs 4.1% with placebo (-9, 17; within group P = .576; between groups P = .056). BMD increased at the femoral neck (PM 2.6 ± 5% vs placebo -0.9 ± 4%; between groups P = .007). Bone resorption markers and SAF did not change. HbA1c decreased (PM -0.38 ± 0.7% vs placebo 0.05 ± 1.7%; between groups P = .04). Within the PM group, the HbA1c change correlated inversely with the % P1NP change (r = -0.50, P = .034). Cortical bone biopsy fAGEs correlated with SAF (r = 0.86, P = .001). Adverse events were similar between groups. CONCLUSION PM tended to increase P1NP in older women with T2D, as well as increasing bone density and reducing HbA1c. Further studies are needed to investigate the potential of PM as a disease mechanism-directed approach to reduce fractures in T2D.
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Affiliation(s)
- Aiden V Brossfield
- Metabolic Bone Disease Unit, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Donald J McMahon
- Metabolic Bone Disease Unit, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Jason Fernando
- Metabolic Bone Disease Unit, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Beatriz Omeragic
- Metabolic Bone Disease Unit, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Rukshana Majeed
- Metabolic Bone Disease Unit, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Sanchita Agarwal
- Metabolic Bone Disease Unit, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Grazyna E Sroga
- Department of Biomedical Engineering, Shirley Ann Jackson, PhD Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
| | - Bowen Wang
- Department of Biomedical Engineering, Shirley Ann Jackson, PhD Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
| | - Deepak Vashishth
- Department of Biomedical Engineering, Shirley Ann Jackson, PhD Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
- Rensselaer-Icahn School of Medicine Center for Engineering and Precision Medicine, New York, NY 10029, USA
| | - Mishaela R Rubin
- Metabolic Bone Disease Unit, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
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D’Haese S, Claes L, Jaeken E, Deluyker D, Evens L, Heeren E, Haesen S, Vastmans L, Lambrichts I, Wouters K, Schalkwijk CG, Hansen D, Eijnde BO, Bito V. Pyridoxamine Alleviates Cardiac Fibrosis and Oxidative Stress in Western Diet-Induced Prediabetic Rats. Int J Mol Sci 2024; 25:8508. [PMID: 39126079 PMCID: PMC11312841 DOI: 10.3390/ijms25158508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024] Open
Abstract
Individuals with type 2 diabetes mellitus (T2DM) are at an increased risk for heart failure, yet preventive cardiac care is suboptimal in this population. Pyridoxamine (PM), a vitamin B6 analog, has been shown to exert protective effects in metabolic and cardiovascular diseases. In this study, we aimed to investigate whether PM limits adverse cardiac remodeling and dysfunction in rats who develop T2DM. Male rats received a standard chow diet or Western diet (WD) for 18 weeks to induce prediabetes. One WD group received additional PM (1 g/L) via drinking water. Glucose tolerance was assessed with a 1 h oral glucose tolerance test. Cardiac function was evaluated using echocardiography and hemodynamic measurements. Histology on left ventricular (LV) tissue was performed. Treatment with PM prevented the increase in fasting plasma glucose levels compared to WD-fed rats (p < 0.05). LV cardiac dilation tended to be prevented using PM supplementation. In LV tissue, PM limited an increase in interstitial collagen deposition (p < 0.05) seen in WD-fed rats. PM tended to decrease 3-nitrotyrosine and significantly lowered 4-hydroxynonenal content compared to WD-fed rats. We conclude that PM alleviates interstitial fibrosis and oxidative stress in the hearts of WD-induced prediabetic rats.
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Affiliation(s)
- Sarah D’Haese
- UHasselt, Cardio & Organ Systems (COST), Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (S.D.); (D.D.); (E.H.); (S.H.); (L.V.); (I.L.)
- Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands; (K.W.); (C.G.S.)
| | - Lisa Claes
- UHasselt, Cardio & Organ Systems (COST), Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (S.D.); (D.D.); (E.H.); (S.H.); (L.V.); (I.L.)
| | - Eva Jaeken
- UHasselt, Cardio & Organ Systems (COST), Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (S.D.); (D.D.); (E.H.); (S.H.); (L.V.); (I.L.)
| | - Dorien Deluyker
- UHasselt, Cardio & Organ Systems (COST), Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (S.D.); (D.D.); (E.H.); (S.H.); (L.V.); (I.L.)
| | - Lize Evens
- UHasselt, Cardio & Organ Systems (COST), Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (S.D.); (D.D.); (E.H.); (S.H.); (L.V.); (I.L.)
| | - Ellen Heeren
- UHasselt, Cardio & Organ Systems (COST), Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (S.D.); (D.D.); (E.H.); (S.H.); (L.V.); (I.L.)
| | - Sibren Haesen
- UHasselt, Cardio & Organ Systems (COST), Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (S.D.); (D.D.); (E.H.); (S.H.); (L.V.); (I.L.)
| | - Lotte Vastmans
- UHasselt, Cardio & Organ Systems (COST), Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (S.D.); (D.D.); (E.H.); (S.H.); (L.V.); (I.L.)
| | - Ivo Lambrichts
- UHasselt, Cardio & Organ Systems (COST), Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (S.D.); (D.D.); (E.H.); (S.H.); (L.V.); (I.L.)
| | - Kristiaan Wouters
- Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands; (K.W.); (C.G.S.)
| | - Casper G. Schalkwijk
- Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands; (K.W.); (C.G.S.)
| | - Dominique Hansen
- UHasselt, Faculty of Rehabilitation Sciences, REVAL Rehabilitation Research Centre, Agoralaan, 3590 Diepenbeek, Belgium;
- Department of Cardiology, Heart Centre Hasselt, Jessa Hospital, Stadsomvaart 11, 3500 Hasselt, Belgium
| | - BO Eijnde
- SMRc-Sports Medicine Research Center, BIOMED-Biomedical Research Institute, Faculty of Medicine & Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium;
- Division of Sport Science, Stellenbosch University, Stellenbosch 7602, South Africa
| | - Virginie Bito
- UHasselt, Cardio & Organ Systems (COST), Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (S.D.); (D.D.); (E.H.); (S.H.); (L.V.); (I.L.)
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Ooi H, Furukawa A, Takeuchi M, Koriyama Y. Toxic Advanced Glycation End-Products Inhibit Axonal Elongation Mediated by β-Tubulin Aggregation in Mice Optic Nerves. Int J Mol Sci 2024; 25:7409. [PMID: 39000515 PMCID: PMC11242247 DOI: 10.3390/ijms25137409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 06/23/2024] [Accepted: 07/02/2024] [Indexed: 07/16/2024] Open
Abstract
Advanced glycation end-products (AGEs) form through non-enzymatic glycation of various proteins. Optic nerve degeneration is a frequent complication of diabetes, and retinal AGE accumulation is strongly linked to the development of diabetic retinopathy. Type 2 diabetes mellitus is a major risk factor for Alzheimer's disease (AD), with patients often exhibiting optic axon degeneration in the nerve fiber layer. Notably, a gap exists in our understanding of how AGEs contribute to neuronal degeneration in the optic nerve within the context of both diabetes and AD. Our previous work demonstrated that glyceraldehyde (GA)-derived toxic advanced glycation end-products (TAGE) disrupt neurite outgrowth through TAGE-β-tubulin aggregation and tau phosphorylation in neural cultures. In this study, we further illustrated GA-induced suppression of optic nerve axonal elongation via abnormal β-tubulin aggregation in mouse retinas. Elucidating this optic nerve degeneration mechanism holds promise for bridging the knowledge gap regarding vision loss associated with diabetes mellitus and AD.
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Affiliation(s)
- Hayahide Ooi
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka 513-8670, Japan; (H.O.); (A.F.)
| | - Ayako Furukawa
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka 513-8670, Japan; (H.O.); (A.F.)
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-Machi, Kahoku 920-0293, Japan;
| | - Yoshiki Koriyama
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka 513-8670, Japan; (H.O.); (A.F.)
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Inoue H, Toriyama K, Takahira N, Murakami S, Miyamoto H, Suzuki T, Shiraishi A. Association between Moraxella keratitis and advanced glycation end products. Sci Rep 2024; 14:8024. [PMID: 38580798 PMCID: PMC10997605 DOI: 10.1038/s41598-024-58659-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 04/02/2024] [Indexed: 04/07/2024] Open
Abstract
Diabetes mellitus is recognized as a major predisposing factor for Moraxella keratitis. However, how diabetes mellitus contributes to Moraxella keratitis remains unclear. In this study, we examined Moraxella keratitis; based on the findings, we investigated the impact of advanced glycation end products (AGEs) deposition in the cornea of individuals with diabetic mellitus on the adhesion of Moraxella isolates to the cornea. A retrospective analysis of 27 culture-proven cases of Moraxella keratitis at Ehime University Hospital (March 2006 to February 2022) was performed. Moraxella isolates were identified using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Among the patients, 30.4% had diabetes mellitus and 22.2% had the predominant ocular condition of using steroid eye drops. The species identified were Moraxella nonliquefaciens in 59.3% and Moraxella lacunata in 40.7% of patients. To investigate the underlying mechanisms, we assessed the effects of M. nonliquefaciens adherence to simian virus 40-immortalized human corneal epithelial cells (HCECs) with or without AGEs. The results demonstrated the number of M. nonliquefaciens adhering to HCECs was significantly increased by adding AGEs compared with that in controls (p < 0.01). Furthermore, in the corneas of streptozotocin-induced diabetic C57BL/6 mice treated with or without pyridoxamine, an AGE inhibitor, the number of M. nonliquefaciens adhering to the corneas of diabetic mice was significantly reduced by pyridoxamine treatment (p < 0.05). In conclusion, the development of Moraxella keratitis may be significantly influenced by the deposition of AGEs on the corneal epithelium of patients with diabetes mellitus.
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Affiliation(s)
- Hidenori Inoue
- Department of Ophthalmology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Koji Toriyama
- Department of Ophthalmology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Naoko Takahira
- Department of Ophthalmology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Shinobu Murakami
- Clinical Laboratory Division, Ehime University Hospital, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Hitoshi Miyamoto
- Clinical Laboratory Division, Ehime University Hospital, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Takashi Suzuki
- Department of Ophthalmology, Toho University Graduate School of Medicine, 6-11-1, Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Atsushi Shiraishi
- Department of Ophthalmology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
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Wang B, Vashishth D. Advanced glycation and glycoxidation end products in bone. Bone 2023; 176:116880. [PMID: 37579812 PMCID: PMC10529863 DOI: 10.1016/j.bone.2023.116880] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 07/21/2023] [Accepted: 08/11/2023] [Indexed: 08/16/2023]
Abstract
Hyperglycemia and oxidative stress, enhanced in diabetes and aging, result in excessive accumulation of advanced glycation and glycoxidation end products (AGEs/AGOEs) in bone. AGEs/AGOES are considered to be "the missing link" in explaining increased skeletal fragility with diabetes, aging, and osteoporosis where increased fracture risk cannot be solely explained by bone mass and/or fall incidences. AGEs/AGOEs disrupt bone turnover and deteriorate bone quality through alterations of organic matrix (collagen and non-collagenous proteins), mineral, and water content. AGEs and AGOEs are also associated with bone fragility in other conditions such as Alzheimer's disease, circadian rhythm disruption, and cancer. This review explains how AGEs and AGOEs accumulate in bone and impact bone quality and bone fracture, and how AGES/AGOEs are being targeted in preclinical and clinical investigations for inhibition or removal, and for prediction and management of diabetic, osteoporotic and insufficiency fractures.
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Affiliation(s)
- Bowen Wang
- Shirley Ann Jackson Ph.D. Center of Biotechnology and Interdisciplinary Studies, Troy, NY 12180, USA; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
| | - Deepak Vashishth
- Shirley Ann Jackson Ph.D. Center of Biotechnology and Interdisciplinary Studies, Troy, NY 12180, USA; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA; Rensselaer - Icahn School of Medicine at Mount Sinai Center for Engineering and Precision Medicine, New York, NY 10019, USA.
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Bansal S, Burman A, Tripathi AK. Advanced glycation end products: Key mediator and therapeutic target of cardiovascular complications in diabetes. World J Diabetes 2023; 14:1146-1162. [PMID: 37664478 PMCID: PMC10473940 DOI: 10.4239/wjd.v14.i8.1146] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/21/2023] [Accepted: 05/22/2023] [Indexed: 08/11/2023] Open
Abstract
The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns. Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality. The cardiovascular diseases that accompany diabetes include angina, myocardial infarction, stroke, peripheral artery disease, and congestive heart failure. Among the various risk factors generated secondary to hyperglycemic situations, advanced glycation end products (AGEs) are one of the important targets for future diagnosis and prevention of diabetes. In the last decade, AGEs have drawn a lot of attention due to their involvement in diabetic patho-physiology. AGEs can be derived exogenously and endogenously through various pathways. These are a non-homogeneous, chemically diverse group of compounds formed non-enzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein, lipids, and nucleic acid. AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways. At the cellular level, they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation, inflammation, cellular proliferation, and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics. AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins; altering their structure, stability, and functions. Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities. In the present review, we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications. Furthermore, this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.
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Affiliation(s)
- Savita Bansal
- Department of Biochemistry, Institute of Home Sciences, University of Delhi, New Delhi 110016, India
| | - Archana Burman
- Department of Biochemistry, Institute of Home Economics, University of Delhi, New Delhi 110016, India
| | - Asok Kumar Tripathi
- Department of Biochemistry, University College of Medical Sciences, University of Delhi, New Delhi 110095, India
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Tian Z, Chen S, Shi Y, Wang P, Wu Y, Li G. Dietary advanced glycation end products (dAGEs): An insight between modern diet and health. Food Chem 2023; 415:135735. [PMID: 36863235 DOI: 10.1016/j.foodchem.2023.135735] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 02/06/2023] [Accepted: 02/15/2023] [Indexed: 03/04/2023]
Abstract
Advanced glycation end products (AGEs) are formed by a series of chemical reactions of amino acids, peptides, proteins, and ketones at normal temperature or heated non-enzymatic conditions. A large amount of AGEs derived from Maillard Reaction (MR) during the process of food heat-processing. After oral intake, dietary AGEs are converted into biological AGEs through digestion and absorption, and accumulated in almost all organs. The safety and health risk of dietary AGEs have attracted wide attention. Increasing evidence have shown that uptake of dietary AGEs is closely related to the occurrence of many chronic diseases, such as diabetes, chronic kidney disease, osteoporosis, and Alzheimer's disease. This review summarized the most updated information of production, bio-transport in vivo, detection technologies, and physiological toxicity of dietary AGEs, and also discussed approaches to inhibit dietary AGEs generation. Impressively, the future opportunities and challenges on the detection, toxicity, and inhibition of dietary AGEs are raised.
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Affiliation(s)
- Zhaoqing Tian
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China
| | - Shasha Chen
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China
| | - Yiheng Shi
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China
| | - Panpan Wang
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China
| | - Yongning Wu
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China; NHC Key Laboratory of Food Safety Risk Assessment, Food Safety Research Unit (2019RU014) of Chinese Academy of Medical Science, China National Center for Food Safety Risk Assessment, Beijing 100021, China
| | - Guoliang Li
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China.
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Smith PK, Venter C, O’Mahony L, Canani RB, Lesslar OJL. Do advanced glycation end products contribute to food allergy? FRONTIERS IN ALLERGY 2023; 4:1148181. [PMID: 37081999 PMCID: PMC10111965 DOI: 10.3389/falgy.2023.1148181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 03/06/2023] [Indexed: 04/07/2023] Open
Abstract
Sugars can bind non-enzymatically to proteins, nucleic acids or lipids and form compounds called Advanced Glycation End Products (AGEs). Although AGEs can form in vivo, factors in the Western diet such as high amounts of added sugars, processing methods such as dehydration of proteins, high temperature sterilisation to extend shelf life, and cooking methods such as frying and microwaving (and reheating), can lead to inordinate levels of dietary AGEs. Dietary AGEs (dAGEs) have the capacity to bind to the Receptor for Advanced Glycation End Products (RAGE) which is part of the endogenous threat detection network. There are persuasive epidemiological and biochemical arguments that correlate the rise in food allergy in several Western countries with increases in dAGEs. The increased consumption of dAGEs is enmeshed in current theories of the aetiology of food allergy which will be discussed.
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Affiliation(s)
- P. K. Smith
- Clinical Medicine and Menzies School of Research, Griffith University, Gold Coast, QLD, Australia
- Correspondence: P. K. Smith
| | - C. Venter
- Children’s Hospital Colorado, University of Colorado, Aurora, CO, United States
| | - L. O’Mahony
- Department of Medicine, School of Microbiology, APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - R. Berni Canani
- Department of Translational Medical Science and ImmunoNutritionLab at CEINGE-Advanced Biotechnologies, University of Naples “Federico II”, Naples, Italy
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Reeve EH, Kronquist EK, Wolf JR, Lee B, Khurana A, Pham H, Cullen AE, Peterson JA, Meza A, Colton Bramwell R, Villasana L, Machin DR, Henson GD, Walker AE. Pyridoxamine treatment ameliorates large artery stiffening and cerebral artery endothelial dysfunction in old mice. J Cereb Blood Flow Metab 2023; 43:281-295. [PMID: 36189840 PMCID: PMC9903220 DOI: 10.1177/0271678x221130124] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Age-related increases in large artery stiffness are associated with cerebrovascular dysfunction and cognitive impairment. Pyridoxamine treatment prevents large artery stiffening with advancing age, but the effects of pyridoxamine treatment on the cerebral vasculature or cognition is unknown. The purpose of this study was to investigate the effects of pyridoxamine on blood pressure, large artery stiffness, cerebral artery function, and cognitive function in old mice. Old male C57BL/6 mice consumed either pyridoxamine (2 g/L) or vehicle control in drinking water for ∼7.5 months and were compared with young male C57BL/6 mice. From pre- to post-treatment, systolic blood pressure increased in old control mice, but was maintained in pyridoxamine treated mice. Large artery stiffness decreased in pyridoxamine-treated mice but was unaffected in control mice. Pyridoxamine-treated mice had greater cerebral artery endothelium-dependent dilation compared with old control mice, and not different from young mice. Old control mice had impaired cognitive function; however, pyridoxamine only partially preserved cognitive function in old mice. In summary, pyridoxamine treatment in old mice prevented age-related increases in blood pressure, reduced large artery stiffness, preserved cerebral artery endothelial function, and partially preserved cognitive function. Taken together, these results suggest that pyridoxamine treatment may limit vascular aging.
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Affiliation(s)
- Emily H Reeve
- Department of Human Physiology, 3265, University of Oregon, Eugene, OR, USA
| | - Elise K Kronquist
- Department of Human Physiology, 3265, University of Oregon, Eugene, OR, USA
| | - Julia R Wolf
- Department of Human Physiology, 3265, University of Oregon, Eugene, OR, USA
| | - Byron Lee
- Department of Human Physiology, 3265, University of Oregon, Eugene, OR, USA
| | - Aleena Khurana
- Department of Human Physiology, 3265, University of Oregon, Eugene, OR, USA
| | - Hanson Pham
- Department of Human Physiology, 3265, University of Oregon, Eugene, OR, USA
| | - Abigail E Cullen
- Department of Human Physiology, 3265, University of Oregon, Eugene, OR, USA
| | - Jessica A Peterson
- Department of Human Physiology, 3265, University of Oregon, Eugene, OR, USA
| | - Antonio Meza
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | - R Colton Bramwell
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | | | - Daniel R Machin
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
- Department of Nutrition and Integrative Physiology, 7823, Florida State University, Tallahassee, FL, USA
| | - Grant D Henson
- Department of Human Physiology, 3265, University of Oregon, Eugene, OR, USA
| | - Ashley E Walker
- Department of Human Physiology, 3265, University of Oregon, Eugene, OR, USA
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
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Van den Eynde MDG, Houben AJHM, Scheijen JLJM, Linkens AMA, Niessen PM, Simons N, Hanssen NMJ, Kusters YHAM, Eussen SJMP, Miyata T, Stehouwer CDA, Schalkwijk CG. Pyridoxamine reduces methylglyoxal and markers of glycation and endothelial dysfunction, but does not improve insulin sensitivity or vascular function in abdominally obese individuals: A randomized double-blind placebo-controlled trial. Diabetes Obes Metab 2023; 25:1280-1291. [PMID: 36655410 DOI: 10.1111/dom.14977] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023]
Abstract
AIM To investigate the effects of pyridoxamine (PM), a B6 vitamer and dicarbonyl scavenger, on glycation and a large panel of metabolic and vascular measurements in a randomized double-blind placebo-controlled trial in abdominally obese individuals. MATERIALS AND METHODS Individuals (54% female; mean age 50 years; mean body mass index 32 kg/m2 ) were randomized to an 8-week intervention with either placebo (n = 36), 25 mg PM (n = 36) or 200 mg PM (n = 36). We assessed insulin sensitivity, β-cell function, insulin-mediated microvascular recruitment, skin microvascular function, flow-mediated dilation, and plasma inflammation and endothelial function markers. PM metabolites, dicarbonyls and advanced glycation endproducts (AGEs) were measured using ultra-performance liquid chromatography tandem mass spectrometry. Treatment effects were evaluated by one-way ANCOVA. RESULTS In the high PM dose group, we found a reduction of plasma methylglyoxal (MGO) and protein-bound Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), as compared to placebo. We found a reduction of the endothelial dysfunction marker soluble vascular cell adhesion molecule-1 (sVCAM-1) in the low and high PM dose group and of soluble intercellular adhesion molecule-1 (sICAM-1) in the high PM dose, as compared to placebo. We found no treatment effects on insulin sensitivity, vascular function or other functional outcome measurements. CONCLUSIONS This study shows that PM is metabolically active and reduces MGO, AGEs, sVCAM-1 and sICAM-1, but does not affect insulin sensitivity and vascular function in abdominally obese individuals. The reduction in adhesion markers is promising because these are important in the pathogenesis of endothelial damage and atherosclerosis.
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Affiliation(s)
- Mathias D G Van den Eynde
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht, The Netherlands
- Top Institute of Food and Nutrition (TIFN), Wageningen, The Netherlands
| | - Alfons J H M Houben
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht, The Netherlands
- Top Institute of Food and Nutrition (TIFN), Wageningen, The Netherlands
| | - Jean L J M Scheijen
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht, The Netherlands
| | - Armand M A Linkens
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht, The Netherlands
| | - Petra M Niessen
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht, The Netherlands
| | - Nynke Simons
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht, The Netherlands
| | - Nordin M J Hanssen
- Amsterdam Diabetes Center, Department of Internal and Vascular Medicine, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands
| | - Yvo H A M Kusters
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht, The Netherlands
| | - Simone J M P Eussen
- School for Cardiovascular Diseases (CARIM), Maastricht, The Netherlands
- Department of Epidemiology, Maastricht University, Maastricht, The Netherlands
- Care and Public Health Research Institute (CAPHRI), Maastricht, The Netherlands
| | - Toshio Miyata
- Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Coen D A Stehouwer
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht, The Netherlands
- Top Institute of Food and Nutrition (TIFN), Wageningen, The Netherlands
| | - Casper G Schalkwijk
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht, The Netherlands
- Top Institute of Food and Nutrition (TIFN), Wageningen, The Netherlands
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11
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Drug repurposing – A search for novel therapy for the treatment of diabetic neuropathy. Biomed Pharmacother 2022; 156:113846. [DOI: 10.1016/j.biopha.2022.113846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/27/2022] [Accepted: 10/06/2022] [Indexed: 11/23/2022] Open
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12
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Ooi H, Nasu R, Furukawa A, Takeuchi M, Koriyama Y. Pyridoxamine and Aminoguanidine Attenuate the Abnormal Aggregation of β-Tubulin and Suppression of Neurite Outgrowth by Glyceraldehyde-Derived Toxic Advanced Glycation End-Products. Front Pharmacol 2022; 13:921611. [PMID: 35721214 PMCID: PMC9204210 DOI: 10.3389/fphar.2022.921611] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 05/13/2022] [Indexed: 01/03/2023] Open
Abstract
Diabetes mellitus (DM) has been identified as a risk factor for the onset and progression of Alzheimer’s disease (AD). In our previous study, we demonstrated that glyceraldehyde (GA)-derived toxic advanced glycation end-products (toxic AGEs, TAGE) induced similar alterations to those observed in AD. GA induced dysfunctional neurite outgrowth via TAGE-β-tubulin aggregation, which resulted in the TAGE-dependent abnormal aggregation of β-tubulin and tau phosphorylation in human neuroblastoma SH-SY5Y cells. However, the effects of inhibitors of AGE formation on dysfunctional neurite outgrowth caused by GA-induced abnormalities in the aggregation of β-tubulin and tau phosphorylation remain unknown. Aminoguanidine (AG), an AGE inhibitor, and pyridoxamine (PM), a natural form of vitamin B6 (VB6), are effective AGE inhibitors. Therefore, the present study investigated whether AG or PM ameliorate TAGE-β-tubulin aggregation and the suppression of neurite outgrowth by GA. The results obtained showed that AG and PM inhibited the formation of TAGE-β-tubulin, mitigated the GA-induced suppression of neurite outgrowth, and reduced GA-mediated increases in tau phosphorylation levels. Collectively, these results suggest the potential of AG and PM to prevent the DM-associated onset and progression of AD.
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Affiliation(s)
- Hayahide Ooi
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
| | - Ryuto Nasu
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
| | - Ayako Furukawa
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Japan
| | - Yoshiki Koriyama
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
- *Correspondence: Yoshiki Koriyama,
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13
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Sarmah S, Roy AS. A review on prevention of glycation of proteins: Potential therapeutic substances to mitigate the severity of diabetes complications. Int J Biol Macromol 2022; 195:565-588. [DOI: 10.1016/j.ijbiomac.2021.12.041] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 12/03/2021] [Accepted: 12/05/2021] [Indexed: 12/21/2022]
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Chavda V, Chaurasia B, Deora H, Umana GE. Chronic Kidney disease and stroke: A Bi-directional risk cascade and therapeutic update. BRAIN DISORDERS 2021. [DOI: 10.1016/j.dscb.2021.100017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
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15
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Advanced Glycation End Products: New Clinical and Molecular Perspectives. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18147236. [PMID: 34299683 PMCID: PMC8306599 DOI: 10.3390/ijerph18147236] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/30/2021] [Accepted: 07/03/2021] [Indexed: 12/17/2022]
Abstract
Diabetes mellitus (DM) is considered one of the most massive epidemics of the twenty-first century due to its high mortality rates caused mainly due to its complications; therefore, the early identification of such complications becomes a race against time to establish a prompt diagnosis. The research of complications of DM over the years has allowed the development of numerous alternatives for diagnosis. Among these emerge the quantification of advanced glycation end products (AGEs) given their increased levels due to chronic hyperglycemia, while also being related to the induction of different stress-associated cellular responses and proinflammatory mechanisms involved in the progression of chronic complications of DM. Additionally, the investigation for more valuable and safe techniques has led to developing a newer, noninvasive, and effective tool, termed skin fluorescence (SAF). Hence, this study aimed to establish an update about the molecular mechanisms induced by AGEs during the evolution of chronic complications of DM and describe the newer measurement techniques available, highlighting SAF as a possible tool to measure the risk of developing DM chronic complications.
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16
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Van den Eynde MDG, Scheijen JLJM, Stehouwer CDA, Miyata T, Schalkwijk CG. Quantification of the B6 vitamers in human plasma and urine in a study with pyridoxamine as an oral supplement; pyridoxamine as an alternative for pyridoxine. Clin Nutr 2021; 40:4624-4632. [PMID: 34229268 DOI: 10.1016/j.clnu.2021.05.028] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 01/16/2021] [Accepted: 05/28/2021] [Indexed: 01/19/2023]
Abstract
BACKGROUND AND AIMS Vitamin B6 is involved in a large spectrum of physiological processes and comprises of the vitamers pyridoxamine (PM), pyridoxal (PL), pyridoxine (PN), and their phosphorylated derivatives including the biological active pyridoxal 5'-phosphate (PLP). While PN toxicity is known to complicate several treatments, PM has shown promise in relation to the treatment of metabolic and age-related diseases by blocking oxidative degradation and scavenging toxic dicarbonyl compounds and reactive oxygen species. We aimed to assess the metabolization of oral PM supplements in a single and three daily dose. MATERIALS AND METHODS We optimized and validated a method for the quantification of the B6 vitamers in plasma and urine using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Five healthy volunteers were recruited to study PM metabolization after a single oral dose of 200 mg PM or a three daily dose of 67 mg PM. A third protocol was implemented as control for dietary intake. Venous blood samples, 24 h urine and fasted second void urine samples were collected. RESULTS After a single oral dose of 200 mg PM, plasma PM increased in the first 3 h to a maximum of 2324 ± 266 nmol/L. While plasma PM levels returned to baseline after ~10 h of PM intake, PLP increased to a maximum of 2787 ± 329 nmol/L and reached a plateau. We found a small increase of PN to a maximum of 13.5 ± 2.1 nmol/L; it was nearly undetectable after ~12 h. With a three daily dose of 67 mg PM we observed an increase and decline of plasma PM, PL, and PN concentrations after each PM intake. PLP showed a similar increase as in the single dose protocol and accumulated over time. CONCLUSION In this study we showed high plasma levels of PM after oral PM supplementation. We found steadily increasing levels of the biologically active PLP, with minimal formation of PN. The B6 vitamer PM is an interesting supplement as an inhibitor of harmful processes in metabolic diseases and for the treatment of vitamin B6 deficiency. CLINICAL TRIAL REGISTRY The study was approved by the Medical Ethics Committee of Maastricht University (NL) and was registered at ClinicalTrials.gov as NCT02954588.
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Affiliation(s)
- Mathias D G Van den Eynde
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands; School for Cardiovascular Diseases (CARIM), Maastricht, the Netherlands
| | - Jean L J M Scheijen
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands; School for Cardiovascular Diseases (CARIM), Maastricht, the Netherlands
| | - Coen D A Stehouwer
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands; School for Cardiovascular Diseases (CARIM), Maastricht, the Netherlands
| | - Toshio Miyata
- Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Casper G Schalkwijk
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands; School for Cardiovascular Diseases (CARIM), Maastricht, the Netherlands.
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17
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Pereira ENGDS, Silvares RR, Rodrigues KL, Flores EEI, Daliry A. Pyridoxamine and Caloric Restriction Improve Metabolic and Microcirculatory Abnormalities in Rats with Non-Alcoholic Fatty Liver Disease. J Vasc Res 2021; 58:1-10. [PMID: 33535220 DOI: 10.1159/000512832] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 11/02/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION This study aims to examine the effect of a diet intervention and pyridoxamine (PM) supplementation on hepatic microcirculatory and metabolic dysfunction in nonalcoholic fatty liver disease (NAFLD). METHODS NAFLD in Wistar rats was induced with a high-fat diet for 20 weeks (NAFLD 20 weeks), and control animals were fed with a standard diet. The NAFLD diet intervention group received the control diet between weeks 12 and 20 (NAFLD 12 weeks), while the NAFLD 12 weeks + PM group also received PM. Fasting blood glucose (FBG) levels, body weight (BW), visceral adipose tissue (VAT), and hepatic microvascular blood flow (HMBF) were evaluated at the end of the protocol. RESULTS The NAFLD group exhibited a significant increase in BW and VAT, which was prevented by the diet intervention, irrespective of PM treatment. The FBG was elevated in the NAFLD group, and caloric restriction improved this parameter, although additional improvement was achieved by PM. The NAFLD group displayed a 31% decrease in HMBF, which was partially prevented by caloric restriction and completely prevented when PM was added. HMBF was negatively correlated to BW, FBG, and VAT content. CONCLUSION PM supplementation in association with lifestyle modifications could be an effective intervention for metabolic and hepatic vascular complications.
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Affiliation(s)
| | - Raquel Rangel Silvares
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil
| | - Karine Lino Rodrigues
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil
| | | | - Anissa Daliry
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil,
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18
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Glaeser JD, Ju D, Tawackoli W, Yang JH, Salehi K, Stefanovic T, Kanim LEA, Avalos P, Kaneda G, Stephan S, Metzger MF, Bae HW, Sheyn D. Advanced Glycation End Product Inhibitor Pyridoxamine Attenuates IVD Degeneration in Type 2 Diabetic Rats. Int J Mol Sci 2020; 21:E9709. [PMID: 33352698 PMCID: PMC7766438 DOI: 10.3390/ijms21249709] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/27/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is associated with advanced glycation end product (AGE) enrichment and considered a risk factor for intervertebral disc (IVD) degeneration. We hypothesized that systemic AGE inhibition, achieved using pyridoxamine (PM), attenuates IVD degeneration in T2DM rats. To induce IVD degeneration, lumbar disc injury or sham surgery was performed on Zucker Diabetic Sprague Dawley (ZDSD) or control Sprague Dawley (SD) rats. Post-surgery, IVD-injured ZDSD rats received daily PM dissolved in drinking water or water only. The resulting groups were SD uninjured, SD injured, ZDSD uninjured, ZDSD injured, and ZDSD injured + PM. Levels of blood glycation and disc degeneration were investigated. At week 8 post-surgery, glycated serum protein (GSP) levels were increased in ZDSDs compared to SDs. PM treatment attenuated this increase. Micro-MRI analysis demonstrated IVD dehydration in injured versus uninjured SDs and ZDSDs. In the ZDSD injured + PM group, IVD dehydration was diminished compared to ZDSD injured. AGE levels were decreased and aggrecan levels increased in ZDSD injured + PM versus ZDSD injured rats. Histological and immunohistochemical analyses further supported the beneficial effect of PM. In summary, PM attenuated GSP levels and IVD degeneration processes in ZDSD rats, demonstrating its potential to attenuate IVD degeneration in addition to managing glycemia in T2DM.
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Affiliation(s)
- Juliane D. Glaeser
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (J.D.G.); (D.J.); (W.T.); (J.H.Y.); (K.S.); (T.S.); (L.E.A.K.); (G.K.); (S.S.); (H.W.B.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Derek Ju
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (J.D.G.); (D.J.); (W.T.); (J.H.Y.); (K.S.); (T.S.); (L.E.A.K.); (G.K.); (S.S.); (H.W.B.)
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Wafa Tawackoli
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (J.D.G.); (D.J.); (W.T.); (J.H.Y.); (K.S.); (T.S.); (L.E.A.K.); (G.K.); (S.S.); (H.W.B.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Jae H. Yang
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (J.D.G.); (D.J.); (W.T.); (J.H.Y.); (K.S.); (T.S.); (L.E.A.K.); (G.K.); (S.S.); (H.W.B.)
- Korea University Guro Hospital, Seoul 08308, Korea
| | - Khosrowdad Salehi
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (J.D.G.); (D.J.); (W.T.); (J.H.Y.); (K.S.); (T.S.); (L.E.A.K.); (G.K.); (S.S.); (H.W.B.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Tina Stefanovic
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (J.D.G.); (D.J.); (W.T.); (J.H.Y.); (K.S.); (T.S.); (L.E.A.K.); (G.K.); (S.S.); (H.W.B.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Linda E. A. Kanim
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (J.D.G.); (D.J.); (W.T.); (J.H.Y.); (K.S.); (T.S.); (L.E.A.K.); (G.K.); (S.S.); (H.W.B.)
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Pablo Avalos
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Giselle Kaneda
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (J.D.G.); (D.J.); (W.T.); (J.H.Y.); (K.S.); (T.S.); (L.E.A.K.); (G.K.); (S.S.); (H.W.B.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Stephen Stephan
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (J.D.G.); (D.J.); (W.T.); (J.H.Y.); (K.S.); (T.S.); (L.E.A.K.); (G.K.); (S.S.); (H.W.B.)
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Melodie F. Metzger
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- The Orthopaedic Biomechanics Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Hyun W. Bae
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (J.D.G.); (D.J.); (W.T.); (J.H.Y.); (K.S.); (T.S.); (L.E.A.K.); (G.K.); (S.S.); (H.W.B.)
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Dmitriy Sheyn
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (J.D.G.); (D.J.); (W.T.); (J.H.Y.); (K.S.); (T.S.); (L.E.A.K.); (G.K.); (S.S.); (H.W.B.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Fuloria S, Subramaniyan V, Karupiah S, Kumari U, Sathasivam K, Meenakshi DU, Wu YS, Guad RM, Udupa K, Fuloria NK. A Comprehensive Review on Source, Types, Effects, Nanotechnology, Detection, and Therapeutic Management of Reactive Carbonyl Species Associated with Various Chronic Diseases. Antioxidants (Basel) 2020; 9:1075. [PMID: 33147856 PMCID: PMC7692604 DOI: 10.3390/antiox9111075] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 10/26/2020] [Accepted: 10/28/2020] [Indexed: 12/12/2022] Open
Abstract
Continuous oxidation of carbohydrates, lipids, and amino acids generate extremely reactive carbonyl species (RCS). Human body comprises some important RCS namely hexanal, acrolein, 4-hydroxy-2-nonenal, methylglyoxal, malondialdehyde, isolevuglandins, and 4-oxo-2- nonenal etc. These RCS damage important cellular components including proteins, nucleic acids, and lipids, which manifests cytotoxicity, mutagenicity, multitude of adducts and crosslinks that are connected to ageing and various chronic diseases like inflammatory disease, atherosclerosis, cerebral ischemia, diabetes, cancer, neurodegenerative diseases and cardiovascular disease. The constant prevalence of RCS in living cells suggests their importance in signal transduction and gene expression. Extensive knowledge of RCS properties, metabolism and relation with metabolic diseases would assist in development of effective approach to prevent numerous chronic diseases. Treatment approaches for RCS associated diseases involve endogenous RCS metabolizers, carbonyl metabolizing enzyme inducers, and RCS scavengers. Limited bioavailability and bio efficacy of RCS sequesters suggest importance of nanoparticles and nanocarriers. Identification of RCS and screening of compounds ability to sequester RCS employ several bioassays and analytical techniques. Present review describes in-depth study of RCS sources, types, properties, identification techniques, therapeutic approaches, nanocarriers, and their role in various diseases. This study will give an idea for therapeutic development to combat the RCS associated chronic diseases.
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Affiliation(s)
- Shivkanya Fuloria
- Faculty of Pharmacy, AIMST University, Kedah, Bedong 08100, Malaysia;
| | - Vetriselvan Subramaniyan
- Faculty of Medicine, Bioscience and Nursing, MAHSA University, Kuala Lumpur 42610, Malaysia; (V.S.); (Y.S.W.)
| | - Sundram Karupiah
- Faculty of Pharmacy, AIMST University, Kedah, Bedong 08100, Malaysia;
| | - Usha Kumari
- Faculty of Medicine, AIMST University, Kedah, Bedong 08100, Malaysia;
| | | | | | - Yuan Seng Wu
- Faculty of Medicine, Bioscience and Nursing, MAHSA University, Kuala Lumpur 42610, Malaysia; (V.S.); (Y.S.W.)
| | - Rhanye Mac Guad
- Faculty of Medicine and Health Science, University Malaysia Sabah, Kota Kinabalu 88400, Malaysia;
| | - Kaviraja Udupa
- Department of Neurophysiology, NIMHANS, Bangalore 560029, India;
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Prasad K, Bhanumathy KK. AGE-RAGE Axis in the Pathophysiology of Chronic Lower Limb Ischemia and a Novel Strategy for Its Treatment. Int J Angiol 2020; 29:156-167. [PMID: 33041612 DOI: 10.1055/s-0040-1710045] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
This review focuses on the role of advanced glycation end products (AGEs) and its cell receptor (RAGE) and soluble receptor (sRAGE) in the pathogenesis of chronic lower limb ischemia (CLLI) and its treatment. CLLI is associated with atherosclerosis in lower limb arteries. AGE-RAGE axis which comprises of AGE, RAGE, and sRAGE has been implicated in atherosclerosis and restenosis. It may be involved in atherosclerosis of lower limb resulting in CLLI. Serum and tissue levels of AGE, and expression of RAGE are elevated, and the serum levels of sRAGE are decreased in CLLI. It is known that AGE, and AGE-RAGE interaction increase the generation of various atherogenic factors including reactive oxygen species, nuclear factor-kappa B, cell adhesion molecules, cytokines, monocyte chemoattractant protein-1, granulocyte macrophage-colony stimulating factor, and growth factors. sRAGE acts as antiatherogenic factor because it reduces the generation of AGE-RAGE-induced atherogenic factors. Treatment of CLLI should be targeted at lowering AGE levels through reduction of dietary intake of AGE, prevention of AGE formation and degradation of AGE, suppression of RAGE expression, blockade of AGE-RAGE binding, elevation of sRAGE by upregulating sRAGE expression, and exogenous administration of sRAGE, and use of antioxidants. In conclusion, AGE-RAGE stress defined as a shift in the balance between stressors (AGE, RAGE) and antistressor (sRAGE) in favor of stressors, initiates the development of atherosclerosis resulting in CLLI. Treatment modalities would include reduction of AGE levels and RAGE expression, RAGE blocker, elevation of sRAGE, and antioxidants for prevention, regression, and slowing of progression of CLLI.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Kalpana K Bhanumathy
- Division of Oncology, Cancer Cluster Unit, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
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Pereira ENGDS, Silvares RR, Flores EEI, Rodrigues KL, Daliry A. Pyridoxamine improves metabolic and microcirculatory complications associated with nonalcoholic fatty liver disease. Microcirculation 2020; 27:e12603. [PMID: 31876010 DOI: 10.1111/micc.12603] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 12/19/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE We investigated the protective effects of pyridoxamine against metabolic and microcirculatory complications in nonalcoholic fatty liver disease. METHODS Nonalcoholic fatty liver disease was established by a high-fat diet administration over 28 weeks. Pyridoxamine was administered between weeks 20 and 28. The recruitment of leukocytes and the number of vitamin A-positive hepatic stellate cells were examined by in vivo microscopy. Laser speckle contrast imaging was used to evaluate microcirculatory hepatic perfusion. Thiobarbituric acid reactive substances measurement and RT-PCR were used for oxidative stress and inflammatory parameters. advanced glycation end products were evaluated by fluorescence spectroscopy. RESULTS The increase in body, liver, and fat weights, together with steatosis and impairment in glucose metabolism observed in the nonalcoholic fatty liver disease group were attenuated by pyridoxamine treatment. Regarding the hepatic microcirculatory parameters, rats with high-fat diet-induced nonalcoholic fatty liver disease showed increased rolling and adhesion of leukocytes, increased hepatic stellate cells activation, and decreased tissue perfusion, which were reverted by pyridoxamine. Pyridoxamine protected against the increased hepatic lipid peroxidation observed in the nonalcoholic fatty liver disease group. Pyridoxamine treatment was associated with increased levels of tumor necrosis factor alpha (TNF-α) mRNA transcripts in the liver. CONCLUSION Pyridoxamine modulates oxidative stress, advanced glycation end products, TNF-α transcripts levels, and metabolic disturbances, being a potential treatment for nonalcoholic fatty liver disease-associated microcirculatory and metabolic complications.
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Affiliation(s)
| | - Raquel Rangel Silvares
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | | | - Karine Lino Rodrigues
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Anissa Daliry
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
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Augustine J, Troendle EP, Barabas P, McAleese CA, Friedel T, Stitt AW, Curtis TM. The Role of Lipoxidation in the Pathogenesis of Diabetic Retinopathy. Front Endocrinol (Lausanne) 2020; 11:621938. [PMID: 33679605 PMCID: PMC7935543 DOI: 10.3389/fendo.2020.621938] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 12/21/2020] [Indexed: 12/31/2022] Open
Abstract
Lipids can undergo modification as a result of interaction with reactive oxygen species (ROS). For example, lipid peroxidation results in the production of a wide variety of highly reactive aldehyde species which can drive a range of disease-relevant responses in cells and tissues. Such lipid aldehydes react with nucleophilic groups on macromolecules including phospholipids, nucleic acids, and proteins which, in turn, leads to the formation of reversible or irreversible adducts known as advanced lipoxidation end products (ALEs). In the setting of diabetes, lipid peroxidation and ALE formation has been implicated in the pathogenesis of macro- and microvascular complications. As the most common diabetic complication, retinopathy is one of the leading causes of vision loss and blindness worldwide. Herein, we discuss diabetic retinopathy (DR) as a disease entity and review the current knowledge and experimental data supporting a role for lipid peroxidation and ALE formation in the onset and development of this condition. Potential therapeutic approaches to prevent lipid peroxidation and lipoxidation reactions in the diabetic retina are also considered, including the use of antioxidants, lipid aldehyde scavenging agents and pharmacological and gene therapy approaches for boosting endogenous aldehyde detoxification systems. It is concluded that further research in this area could lead to new strategies to halt the progression of DR before irreversible retinal damage and sight-threatening complications occur.
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Affiliation(s)
- Josy Augustine
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen’s University of Belfast, Belfast, United Kingdom
| | - Evan P. Troendle
- Department of Chemistry, King’s College London, London, United Kingdom
| | - Peter Barabas
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen’s University of Belfast, Belfast, United Kingdom
| | - Corey A. McAleese
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen’s University of Belfast, Belfast, United Kingdom
| | - Thomas Friedel
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen’s University of Belfast, Belfast, United Kingdom
| | - Alan W. Stitt
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen’s University of Belfast, Belfast, United Kingdom
| | - Tim M. Curtis
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen’s University of Belfast, Belfast, United Kingdom
- *Correspondence: Tim M. Curtis,
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Mazumder MAR, Hongsprabhas P, Thottiam Vasudevan R. In vitro and in vivo inhibition of maillard reaction products using amino acids, modified proteins, vitamins, and genistein: A review. J Food Biochem 2019; 43:e13089. [PMID: 31680276 DOI: 10.1111/jfbc.13089] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 09/21/2019] [Accepted: 09/23/2019] [Indexed: 01/02/2023]
Abstract
Maillard reaction is known to result in loss of nutrients, particularly that of essential amino acids; decrease in digestibility and safety issues due to the development of toxic compounds. Maillard reaction products are also known to cause oxidation of tissues and inflammation, thus increasing the risk of cardiovascular diseases and diabetes. The aim of this review is to present a detailed information about the role of foodborne constituents as antibrowning agents to significantly reduce the harmful compounds like advanced glycation end products (AGEs) during food processing. This review includes strategies involving addition of amino acids, aromatic compounds, vitamins, modification of amino acids, and reducing sugars as antibrowning agents to reduce the AGEs. The role of Food borne functional ingredients such as catechin, epicathechin, luteolin, and ferulic acids as inhibitors of AGEs is also discussed. Among the naturally occurring inhibitors, genistein could be a crucial and safe agent to reduce reactive intermediates. PRACTICAL APPLICATIONS: Maillard reaction leads to changes in food color, protein functionality, protein digestibility, and loss of nutrient from foods. Maillard reaction products (MRPs) is also reported to be associated with various inflammatory conditions and may contribute to the progress of chronic diseases, including diabetes. It is hence necessary to reduce the MRPs, in both food and biological products, to offset this phenomenon. Among the strategies adopted till date, chemical agents could inhibit reactive carbonyl species and reactive oxygen species, but also are known to elicit serious side effects. Dietary flavonoids could be a very good inhibitor of MRPs both in biological and in food systems. It could be suggested that dietary flavonoids and isoflavones can be used as antibrowning agents in food and pharmaceutical industries particularly for targeted and sustained release of hypoglycemic drug in the intestines.
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Affiliation(s)
- Md Anisur Rahman Mazumder
- Department of Food Processing Technology, School of Agriculture and Biosciences, Karunya Institute of Technology and Sciences, Coimbatore, India.,Department of Food Technology and Rural Industries, Faculty of Agricultural Engineering and Technology, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Parichat Hongsprabhas
- Department of Food Science and Technology, Faculty of Agro-Industry, Kasetsart University, Bangkok, Thailand
| | - Ranganathan Thottiam Vasudevan
- Department of Food Processing Technology, School of Agriculture and Biosciences, Karunya Institute of Technology and Sciences, Coimbatore, India
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Davies SS, May-Zhang LS, Boutaud O, Amarnath V, Kirabo A, Harrison DG. Isolevuglandins as mediators of disease and the development of dicarbonyl scavengers as pharmaceutical interventions. Pharmacol Ther 2019; 205:107418. [PMID: 31629006 DOI: 10.1016/j.pharmthera.2019.107418] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 09/20/2019] [Indexed: 12/13/2022]
Abstract
Products of lipid peroxidation include a number of reactive lipid aldehydes such as malondialdehyde, 4-hydroxy-nonenal, 4-oxo-nonenal, and isolevuglandins (IsoLGs). Although these all contribute to disease processes, the most reactive are the IsoLGs, which rapidly adduct to lysine and other cellular primary amines, leading to changes in protein function, cross-linking and immunogenicity. Their rapid reactivity means that only IsoLG adducts, and not the unreacted aldehyde, can be readily measured. This high reactivity also makes it challenging for standard cellular defense mechanisms such as aldehyde reductases and oxidases to dispose of them before they react with proteins and other cellular amines. This led us to seek small molecule primary amines that might trap and inactivate IsoLGs before they could modify cellular proteins or other endogenous cellular amines such as phosphatidylethanolamines to cause disease. Our studies identified 2-aminomethylphenols including 2-hydroxybenzylamine as IsoLG scavengers. Subsequent studies showed that they also trap other lipid dicarbonyls that react with primary amines such as 4-oxo-nonenal and malondialdehyde, but not hydroxyalkenals like 4-hydroxy-nonenal that preferentially react with soft nucleophiles. This review describes the use of these 2-aminomethylphenols as dicarbonyl scavengers to assess the contribution of IsoLGs and other amine-reactive lipid dicarbonyls to disease and as therapeutic agents.
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Affiliation(s)
- Sean S Davies
- Division of Clinical Pharmacology and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN, United States.
| | - Linda S May-Zhang
- Division of Clinical Pharmacology and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN, United States
| | - Olivier Boutaud
- Division of Clinical Pharmacology and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN, United States
| | - Venkataraman Amarnath
- Division of Clinical Pharmacology and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN, United States
| | - Annet Kirabo
- Division of Clinical Pharmacology and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN, United States
| | - David G Harrison
- Division of Clinical Pharmacology and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN, United States
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Nakamura T, Tsujimoto T, Yasuda K, Chujo D, Ohsugi M, Tanabe A, Ueki K, Kajio H. Poorly controlled type 2 diabetes with no progression of diabetes-related complications and low levels of advanced glycation end products: A Case report. Medicine (Baltimore) 2019; 98:e16573. [PMID: 31348288 PMCID: PMC6709306 DOI: 10.1097/md.0000000000016573] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
RATIONALE Previous studies have suggested that increased levels of advanced glycation end products (AGEs) and soluble receptor for AGE (sRAGE) are associated with diabetes-related complications. However, there is little evidence on the association between long-term levels of AGEs and sRAGE and progression of diabetes-related complications. PATIENT CONCERNS A 64-year-old man had poorly controlled type 2 diabetes, obesity, smoking, hypertension, and dyslipidemia. He had many risk factors for diabetes-related complications. DIAGNOSIS Despite poor glycemic control over 15 years, the patient did not exhibit diabetes-related complications. INTERVENTIONS We examined serum AGEs (CEL and MG-H1) and sRAGE levels in this patient over the past 10 years. OUTCOMES The patient maintained low serum AGEs and sRAGE levels. LESSONS AGEs and sRAGE levels may be associated with long-term development of diabetes-related complications.
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Affiliation(s)
- Tomoka Nakamura
- Department of Diabetes, Endocrinology, and Metabolism, Center Hospital
| | - Tetsuro Tsujimoto
- Department of Diabetes, Endocrinology, and Metabolism, Center Hospital
| | - Kazuki Yasuda
- Department of Metabolic Disorders, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine
- Department of Diabetes, Endocrinology and Metabolism, Kyorin University School of Medicine, Tokyo
| | - Daisuke Chujo
- Department of Diabetes, Endocrinology, and Metabolism, Center Hospital
- Center for Clinical Research, Toyama University Hospital, Toyama
| | - Mitsuru Ohsugi
- Department of Diabetes, Endocrinology, and Metabolism, Center Hospital
- Diabetes and Metabolism Information Center
| | - Akiyo Tanabe
- Department of Diabetes, Endocrinology, and Metabolism, Center Hospital
| | - Kohjiro Ueki
- Department of Diabetes, Endocrinology, and Metabolism, Center Hospital
- Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Hiroshi Kajio
- Department of Diabetes, Endocrinology, and Metabolism, Center Hospital
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AGE-RAGE stress: a changing landscape in pathology and treatment of Alzheimer's disease. Mol Cell Biochem 2019; 459:95-112. [PMID: 31079281 DOI: 10.1007/s11010-019-03553-4] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 05/04/2019] [Indexed: 12/27/2022]
Abstract
Numerous hypotheses including amyloid cascade, cholinergic, and oxidative have been proposed for pathogenesis of Alzheimer's disease (AD). The data suggest that advanced glycation end products (AGEs) and its receptor RAGE (receptor for AGE) are involved in the pathogenesis of AD. AGE-RAGE stress, defined as a balance between stressors (AGE, RAGE) and anti-stressors (sRAGE, AGE degraders) in favor of stressors, has been implicated in pathogenesis of diseases. AGE and its interaction with RAGE-mediated increase in the reactive oxygen species (ROS) damage brain because of its increased vulnerability to ROS. AGE and ROS increase the synthesis of amyloid β (Aβ) leading to deposition of Aβ and phosphorylation of tau, culminating in formation of plaques and neurofibrillary tangles. ROS increase the synthesis of Aβ, high-mobility group box 1(HMGB1), and S100 that interacts with RAGE to produce additional ROS resulting in enhancement of AD pathology. Elevation of ROS precedes the Aβ plaques formation. Because of involvement of AGE and RAGE in AD pathology, the treatment should be targeted at lowering AGE levels through reduction in consumption and formation of AGE, and lowering expression of RAGE, blocking of RAGE ligand binding, increasing levels of soluble RAGE (sRAGE), and use of antioxidants. The above treatment aspect of AD is lacking. In conclusion, AGE-RAGE stress initiates, and Aβ, HMGB1, and S100 enhance the progression of AD. Reduction of levels of AGE and RAGE, elevation of sRAGE, and antioxidants would be beneficial therapeutic modalities in the prevention, regression, and slowing of progression of AD.
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Prasad K. AGE-RAGE Stress in the Pathophysiology of Pulmonary Hypertension and its Treatment. Int J Angiol 2019; 28:71-79. [PMID: 31384104 DOI: 10.1055/s-0039-1687818] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Pulmonary hypertension (PH) is a rare and fatal disease characterized by elevation of pulmonary artery pressure ≥ 25 mm Hg. There are five groups of PH: (1) pulmonary artery (PA) hypertension (PAH), (2) PH due to heart diseases, (3) PH associated with lung diseases/hypoxia, (4) PH associated with chronic obstruction of PA, and (5) PH due to unclear and/or multifactorial mechanisms. The pathophysiologic mechanisms of group 1 have been studied in detail; however, those for groups 2 to 5 are not that well known. PH pathology is characterized by smooth muscle cells (SMC) proliferation, muscularization of peripheral PA, accumulation of extracellular matrix (ECM), plexiform lesions, thromboembolism, and recanalization of thrombi. Advanced glycation end products (AGE) and its receptor (RAGE) and soluble RAGE (sRAGE) appear to be involved in the pathogenesis of PH. AGE and its interaction with RAGE induce vascular hypertrophy through proliferation of vascular SMC, accumulation of ECM, and suppression of apoptosis. Reactive oxygen species (ROS) generated by interaction of AGE and RAGE modulates SMC proliferation, attenuate apoptosis, and constricts PA. Increased stiffness in the artery due to vascular hypertrophy, and vasoconstriction due to ROS resulted in PH. The data also suggest that reduction in consumption and formation of AGE, suppression of RAGE expression, blockage of RAGE ligand binding, elevation of sRAGE levels, and antioxidants may be novel therapeutic targets for prevention, regression, and slowing of progression of PH. In conclusion, AGE-RAGE stress may be involved in the pathogenesis of PH and the therapeutic targets should be the AGE-RAGE axis.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Canada
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Rajchgot T, Thomas SC, Wang JC, Ahmadi M, Balood M, Crosson T, Dias JP, Couture R, Claing A, Talbot S. Neurons and Microglia; A Sickly-Sweet Duo in Diabetic Pain Neuropathy. Front Neurosci 2019; 13:25. [PMID: 30766472 PMCID: PMC6365454 DOI: 10.3389/fnins.2019.00025] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Accepted: 01/11/2019] [Indexed: 12/11/2022] Open
Abstract
Diabetes is a common condition characterized by persistent hyperglycemia. High blood sugar primarily affects cells that have a limited capacity to regulate their glucose intake. These cells include capillary endothelial cells in the retina, mesangial cells in the renal glomerulus, Schwann cells, and neurons of the peripheral and central nervous systems. As a result, hyperglycemia leads to largely intractable complications such as retinopathy, nephropathy, hypertension, and neuropathy. Diabetic pain neuropathy is a complex and multifactorial disease that has been associated with poor glycemic control, longer diabetes duration, hypertension, advanced age, smoking status, hypoinsulinemia, and dyslipidemia. While many of the driving factors involved in diabetic pain are still being investigated, they can be broadly classified as either neuron -intrinsic or -extrinsic. In neurons, hyperglycemia impairs the polyol pathway, leading to an overproduction of reactive oxygen species and reactive nitrogen species, an enhanced formation of advanced glycation end products, and a disruption in Na+/K+ ATPase pump function. In terms of the extrinsic pathway, hyperglycemia leads to the generation of both overactive microglia and microangiopathy. The former incites a feed-forward inflammatory loop that hypersensitizes nociceptor neurons, as observed at the onset of diabetic pain neuropathy. The latter reduces neurons' access to oxygen, glucose and nutrients, prompting reductions in nociceptor terminal expression and losses in sensation, as observed in the later stages of diabetic pain neuropathy. Overall, microglia can be seen as potent and long-lasting amplifiers of nociceptor neuron activity, and may therefore constitute a potential therapeutic target in the treatment of diabetic pain neuropathy.
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Affiliation(s)
- Trevor Rajchgot
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - Sini Christine Thomas
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - Jo-Chiao Wang
- Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Maryam Ahmadi
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - Mohammad Balood
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - Théo Crosson
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - Jenny Pena Dias
- Johns Hopkins University School of Medicine, Division of Endocrinology, Diabetes and Metabolism, Baltimore, MD, United States
| | - Réjean Couture
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - Audrey Claing
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - Sébastien Talbot
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
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Antioxidant Supplementation in Renal Replacement Therapy Patients: Is There Evidence? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9109473. [PMID: 30774749 PMCID: PMC6350615 DOI: 10.1155/2019/9109473] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 12/15/2018] [Accepted: 12/20/2018] [Indexed: 12/26/2022]
Abstract
The disruption of balance between production of reactive oxygen species and antioxidant systems in favor of the oxidants is termed oxidative stress (OS). To counteract the damaging effects of prooxidant free radicals, all aerobic organisms have antioxidant defense mechanisms that are aimed at neutralizing the circulating oxidants and repair the resulting injuries. Antioxidants are either endogenous (the natural defense mechanisms produced by the human body) or exogenous, found in supplements and foods. OS is present at the early stages of chronic kidney disease, augments progressively with renal function deterioration, and is further exacerbated by renal replacement therapy. End-stage renal disease patients, on hemodialysis (HD) or peritoneal dialysis (PD), suffer from accelerated OS, which has been associated with increased risk for mortality and cardiovascular disease. During HD sessions, the bioincompatibility of dialyzers and dialysate trigger activation of white blood cells and formation of free radicals, while a significant loss of antioxidants is also present. In PD, the bioincompatibility of solutions, including high osmolality, elevated lactate levels, low pH, and accumulation of advanced glycation end-products trigger formation of prooxidants, while there is significant loss of vitamins in the ultrafiltrate. A number of exogenous antioxidants have been suggested to ameliorate OS in dialysis patients. Vitamins B, C, D, and E, coenzyme Q10, L-carnitine, a-lipoic acid, curcumin, green tea, flavonoids, polyphenols, omega-3 polyunsaturated fatty acids, statins, trace elements, and N-acetylcysteine have been studied as exogenous antioxidant supplements in both PD and HD patients.
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Rangel Silvares R, Nunes Goulart da Silva Pereira E, Eduardo Ilaquita Flores E, Lino Rodrigues K, Ribeiro Silva A, Gonçalves-de-Albuquerque CF, Daliry A. High-fat diet-induced kidney alterations in rats with metabolic syndrome: endothelial dysfunction and decreased antioxidant defense. Diabetes Metab Syndr Obes 2019; 12:1773-1781. [PMID: 31564943 PMCID: PMC6735540 DOI: 10.2147/dmso.s211253] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 06/11/2019] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION This study aimed to investigate changes in renal function and the AGE-RAGE axis in the kidney of a non-genetic animal model of metabolic syndrome (MetS) induced by high-fat diet (HFD). Additionally, we evaluated the protective effect of pyridoxamine (PM), a vitamin B6 analog with anti-AGE effects, in the context of diet-related renal endothelial dysfunction. METHODOLOGY In Wistar rats, the MetS animal model was induced by 20 or 28 weeks of HFD feeding. When indicated, a subgroup of animals was treated daily with PM (60 mg/kg) for 2 months. Tissue perfusion in renal microcirculation was examined by laser speckle contrast imaging. Oxidative stress was analyzed by thiobarbituric acid reactive species and the inflammatory markers by ELISA (TNF-α and IL-1β). Reverse transcription polymerase chain reaction was used to analyze eNOs, IL-6, vascular cell adhesion molecule (VCAM), NADPH oxidase subunit 47 (N47), catalase, and receptor for AGE (RAGE) gene expression. RESULTS Wistar rats fed a HFD showed negligible alteration in renal function, decrease in catalase mRNA transcripts and catalase enzyme activity compared to control (CTL) animals. Increased levels of IL-1β were observed in the kidney of MetS-induced rats. HFD-fed rats exhibited kidney endothelial dysfunction, with no significant differences in basal microvascular blood flow. PM significantly improved kidney vasorelaxation in HFD-fed rats. eNOS, VCAM, and RAGE gene expression and AGE content were not altered in kidneys of HFD-induced MetS rats in comparison to CTLs. CONCLUSIONS Our findings suggest that HFD-induced microvascular dysfunction precedes the decline in renal function, and could be related to antioxidant machinery defects and inflammation activation in the kidney. PM showed a vasoprotective effect, and thus, could be an important contributory factor in ameliorating diet-induced renal damage.
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Affiliation(s)
- Raquel Rangel Silvares
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| | | | - Edgar Eduardo Ilaquita Flores
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| | - Karine Lino Rodrigues
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| | - Adriana Ribeiro Silva
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| | - Cassiano Felipe Gonçalves-de-Albuquerque
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- Laboratory of Immunopharmacology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Anissa Daliry
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- Correspondence: Anissa DaliryInstituto Oswaldo Cruz, Fiocruz, Pavilhão Ozório de Almeida, Manguinhos, Rio de Janeiro, CEP: 21.040-360, RJ, BrazilEmail
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Milkovska-Stamenova S, Krieg L, Hoffmann R. Products of Early and Advanced Glycation in the Soy Milk Proteome. Mol Nutr Food Res 2018; 63:e1800725. [PMID: 30430721 DOI: 10.1002/mnfr.201800725] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 10/01/2018] [Indexed: 12/17/2022]
Abstract
SCOPE Thermal processing of soy milk kills pathogens and denatures anti-nutrition factors warranting microbiological safety, better digestibility, and longer storage. Additionally, Maillard reactions are triggered, yielding glycated proteins (Amadori/Heyns products) and a heterogeneous group of advanced glycation end-products (AGEs). These modifications alter the nutritional value, antigenicity, and digestibility of proteins. They also raise concerns about potentially toxic effects. This study aims at characterizing these modifications in proteins from different soy milk products. METHODS AND RESULTS Here, glycation and AGE-modification sites in the proteome of ultrahigh-temperature-treated natural soy milk, soy milk sweetened with hexose (fructose)-containing sweeteners (SSM), and sucrose as well as soy-based infant formulas (SIFs) from different manufacturers are reported for the first time. A bottom-up proteomic approach based on nano reversed-phase high-perfomance liquid chromatography-electrospray ionization-tandem mass spectrometry (nanoRP-HPLC-ESI-MS/MS) (collision-induced dissociation (CID) and electron transfer dissociation modes) identified 229 glycated peptides and 128 AGE-modified peptides resembling 53 proteins. The glycation sites are mainly derived from hexoses, whereas Nδ -carboxyethylarginine and methylglyoxal-derived hydroimidazolone are the main AGEs in soy milk. CONCLUSION The qualitative and quantitative data obtained here indicate that early glycation increases with harsher processing conditions (SIFs) and the addition of hexose-containing sweeteners (SSMs), whereas the latter sweeteners (but not the harsher processing) triggered more AGE modifications.
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Affiliation(s)
- Sanja Milkovska-Stamenova
- Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Leipzig, 04103, Germany.,Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig, 04103, Germany
| | - Laura Krieg
- Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Leipzig, 04103, Germany.,Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig, 04103, Germany
| | - Ralf Hoffmann
- Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Leipzig, 04103, Germany.,Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig, 04103, Germany
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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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Yamamura ET. Bioconversion of pyridoxine to pyridoxamine through pyridoxal using a Rhodococcus expression system. J Biosci Bioeng 2018; 127:79-84. [PMID: 30057158 DOI: 10.1016/j.jbiosc.2018.07.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 07/01/2018] [Accepted: 07/05/2018] [Indexed: 10/28/2022]
Abstract
Pyridoxamine, which is a form of vitamin B6, is a promising candidate for a prophylactic and/or remedy for diabetic complications. Pyridoxamine is chemically synthesized by an oxidative method in manufacturing. However, pyridoxamine production by bioconversion, which is generally preferable for environmental and energetic aspects, has been little investigated. Therefore, I aimed to produce pyridoxamine from pyridoxine, which is a readily and economically available starting material, by bioconversion using a Rhodococcus expression system. I found in the bioconversion of pyridoxine to pyridoxal, approximately 450 mM pyridoxal was produced from 500 mM pyridoxine using recombinant Rhodococcus erythropolis expressing the pyridoxine 4-oxidase gene derived from Mesorhizobium loti. Next, in the bioconversion of pyridoxal to pyridoxamine using recombinant R. erythropolis expressing the pyridoxamine-pyruvate aminotransferase gene derived from M. loti, the bioconversion rate was approximately 80% under the same conditions as pyridoxal production. Finally, in the bioconversion of pyridoxine to pyridoxamine through pyridoxal using recombinant R. erythropolis coexpressing the genes for pyridoxine 4-oxidase and pyridoxamine-pyruvate aminotransferase, the bioconversion rate was approximately 75%. Based on these findings, pyridoxamine production by bioconversion using a Rhodococcus expression system may be of interest for future industrial applications.
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Affiliation(s)
- Ei-Tora Yamamura
- Technical Department, Kyowa Pharma Chemical Co., Ltd., 530 Chokeiji, Takaoka, Toyama 933-8511, Japan.
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Abstract
OBJECTIVES Advanced glycation end-products (AGEs) are a post-translational modification of collagen that form spontaneously in the skeletal matrix due to the presence of reducing sugars, such as glucose. The accumulation of AGEs leads to collagen cross-linking, which adversely affects bone quality and has been shown to play a major role in fracture risk. Thus, intervening in the formation and accumulation of AGEs may be a viable means of protecting bone quality. METHODS An in vitro model was used to examine the efficacy of two AGE-inhibitors, aminoguanidine (AG) and pyridoxamine (PM), on ageing human cortical bone. Mid-diaphyseal tibial cortical bone segments were obtained from female cadavers (n = 20, age range: 57 years to 97 years) and randomly subjected to one of four treatments: control; glucose only; glucose and AG; or glucose and PM. Following treatment, each specimen underwent mechanical testing under physiological conditions via reference point indentation, and AGEs were quantified by fluorescence. RESULTS Treatment with AG and PM showed a significant decrease in AGE content versus control groups, as well as a significant decrease in the change in indentation distance, a reliable parameter for analyzing bone strength, via two-way analysis of variance (ANOVA) (p < 0.05). CONCLUSIONS The data suggest that AG and PM prevent AGE formation and subsequent biomechanical degradation in vitro. Modulation of AGEs may help to identify novel therapeutic targets to mitigate bone quality deterioration, especially deterioration due to ageing and in AGE-susceptible populations (e.g. diabetics).Cite this article: Bone Joint Res 2018;7:105-110.
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Affiliation(s)
- O Abar
- Department of Biology and Department of Orthopaedic Surgery
| | | | - S Y Tang
- Department of Biomedical Engineering and Department of Orthopaedic Surgery, Washington University in St Louis, 1 Brookings Drive, St. Louis, Missouri 63130, USA
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Prasad K, Mishra M. AGE-RAGE Stress, Stressors, and Antistressors in Health and Disease. Int J Angiol 2017; 27:1-12. [PMID: 29483760 DOI: 10.1055/s-0037-1613678] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Adverse effects of advanced glycation end-products (AGEs) on the tissues are through nonreceptor- and receptor-mediated mechanisms. In the receptor-mediated mechanism, interaction of AGEs with its cell-bound receptor of AGE (RAGE) increases generation of oxygen radicals, activates nuclear factor-kappa B, and increases expression and release of pro-inflammatory cytokines resulting in the cellular damage. The deleterious effects of AGE and AGE-RAGE interaction are coined as "AGE-RAGE stress." The body is equipped with defense mechanisms to counteract the adverse effects of AGE and RAGE through endogenous enzymatic (glyoxalase 1, glyoxalase 2) and AGE receptor-mediated (AGER1, AGER2) degradation of AGE, and through elevation of soluble receptor of AGE (sRAGE). Exogenous defense mechanisms include reduction in consumption of AGE, prevention of AGE formation, and downregulation of RAGE expression. We have coined AGE and RAGE as "stressors" and the defense mechanisms as "anti-stressors." AGE-RAGE stress is defined as a shift in the balance between stressors and antistressors in the favor of stressors. Measurements of stressors or antistressors alone would not assess AGE-RAGE stress. For true assessment of AGE-RAGE stress, the equation should include all the stressors and antistressors. The equation for AGE-RAGE stress, therefore, would be the ratio of AGE + RAGE/sRAGE + glyoxalase1 + glyoxalase 2 + AGER1 +AGER2. This is, however, not practical in patients. AGE-RAGE stress may be assessed simply by the ratio of AGE/sRAGE. A high ratio of AGE/sRAGE indicates a relative shift in stressors from antistressors, suggesting the presence of AGE-RAGE stress, resulting in tissue damage, initiation, and progression of the diseases and their complications.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology, University of Saskatchewan, College of Medicine, Saskatoon, Canada
| | - Manish Mishra
- Department of Physiology, University of Saskatchewan, College of Medicine, Saskatoon, Canada
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Pyridoxamine improves survival and limits cardiac dysfunction after MI. Sci Rep 2017; 7:16010. [PMID: 29167580 PMCID: PMC5700185 DOI: 10.1038/s41598-017-16255-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 11/09/2017] [Indexed: 01/13/2023] Open
Abstract
Advanced glycation end products (AGEs) play a key role in the progression of heart failure. Whether treatments limiting AGEs formation would prevent adverse left ventricular remodeling after myocardial infarction (MI) remain unknown. We investigated whether pyridoxamine (PM) could limit adverse cardiac outcome in MI. Rats were divided into MI, MI + PM and Sham. Echocardiography and hemodynamic parameters were used to assess cardiac function 8 weeks post-surgery. Total interstitial collagen, collagen I and collagen III were quantified using Sirius Red and polarized light microscopy. PM improved survival following LAD occlusion. Pre-treatment with PM significantly decreased the plasma AGEs levels. MI rats treated with PM displayed reduced left ventricular end-diastolic pressure and tau compared to untreated MI rats. Deformation parameters were also improved with PM. The preserved diastolic function was related to the reduced collagen content, in particular in the highly cross-linked collagen type I, mainly in the peri-infarct region, although not via TGF-β1 pathway. Our data indicate that PM treatment prevents the increase in AGEs levels and reduces collagen levels in a rat model of MI, resulting in an improved cardiac phenotype. As such, therapies targeting formation of AGEs might be beneficial in the prevention and/or treatment of maladaptive remodeling following MI.
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Szwergold B. A Hypothesis: Moderate Consumption of Alcohol Contributes to Lower Prevalence of Type 2 Diabetes Due to the Scavenging of Alpha-Dicarbonyls by Dietary Polyphenols. Rejuvenation Res 2017; 21:389-404. [PMID: 28891383 DOI: 10.1089/rej.2017.1974] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The world is experiencing an epidemic of type-2-diabetes mellitus (T2DM). This has led to increased morbidity and mortality, explosive growth in health care budgets, and an even greater adverse, if indirect, impact on societies and economies of affected countries. While genetic susceptibility to T2DM is a major determinant of its prevalence, changes in lifestyles also play a role. One such change has been a transition from traditional diets characterized by low caloric and high nutrient density to calorie-rich but nutrient-poor Western diets. Given this, one solution to the epidemic of T2DM would be to abandon Western diets and revert to traditional eating patterns. However, traditional diets cannot provide enough calories for the increasing global population, so transition from traditional to Western foodstuffs appears to be irreversible. Consequently, the only practical solution to problems caused by these changes is to modify Western diets, possibly by supplementing them with functional foods containing nutrients that would compensate for these dietary deficits. I present in this study a hypothesis to explain why shifts from traditional to Western diets have been so problematic and to suggest nutrients that may counteract these adverse effects. I postulate that the components of traditional diets that may compensate for deficiencies of Westerns diets are scavengers of reactive α-dicarbonyls produced as unavoidable by-products of glucose and lipid metabolism. Most important among these scavengers are some plant secondary metabolites: polyphenols, phlorotannins, and carotenoids. They are found in alcoholic beverages and are abundant in seasonings, cocoa, coffee, tea, whole grains, pigmented vegetables, fruits, and berries.
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Pereira A, Fernandes R, Crisóstomo J, Seiça RM, Sena CM. The Sulforaphane and pyridoxamine supplementation normalize endothelial dysfunction associated with type 2 diabetes. Sci Rep 2017; 7:14357. [PMID: 29085055 PMCID: PMC5662716 DOI: 10.1038/s41598-017-14733-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 10/10/2017] [Indexed: 01/01/2023] Open
Abstract
In this study we investigate pyridoxamine (PM) and/or sulforaphane (SFN) as therapeutic interventions to determine whether activators of NFE2-related factor 2 (Nrf2) can be used in addition with inhibitors of advanced glycation end products (AGE) formation to attenuate oxidative stress and improve endothelial dysfunction in type 2 diabetes. Goto-kakizaki (GK) rats, an animal model of non-obese type 2 diabetes, were treated with or without PM and/or SFN during 8 weeks and compared with age-matched Wistar rats. At the end of the treatment, nitric oxide (NO)-dependent and independent vasorelaxation in isolated aorta and mesenteric arteries were evaluated. Metabolic profile, NO bioavailability and vascular oxidative stress, AGE and Nrf2 levels were also assessed. Diabetic GK rats presented significantly lower levels of Nrf2 and concomitantly exhibited higher levels of oxidative stress and endothelial dysfunction. PM and SFN as monotherapy were capable of significantly improving endothelial dysfunction in aorta and mesenteric arteries decreasing vascular oxidative damage, AGE and HbA1c levels. Furthermore, SFN + PM proved more effective reducing systemic free fatty acids levels, normalizing endothelial function, NO bioavailability and glycation in GK rats. Activators of Nrf2 can be used therapeutically in association with inhibitors of AGE and cross-linking formation to normalize endothelial dysfunction in type 2 diabetes.
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Affiliation(s)
- Ana Pereira
- Physiology, IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Rosa Fernandes
- Ophthalmology, IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Joana Crisóstomo
- Physiology, IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Raquel M Seiça
- Physiology, IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Cristina M Sena
- Physiology, IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
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Kumar V, Bhatt PC, Rahman M, Al-Abbasi FA, Anwar F, Verma A. Umbelliferon-α-d-glucopyranosyl-(2 I→1 II)-α-Dglucopyranoside ameliorates Diethylnitrosamine induced precancerous lesion development in liver via regulation of inflammation, hyperproliferation and antioxidant at pre-clinical stage. Biomed Pharmacother 2017; 94:834-842. [PMID: 28802237 DOI: 10.1016/j.biopha.2017.07.047] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 06/22/2017] [Accepted: 07/11/2017] [Indexed: 11/18/2022] Open
Abstract
It is well documented that anomalous production of inflammatory proteins linked with most of the toxic expression and genesis of diverse chronic disease including cancer. Diethylnitrosamine (DEN) a well-known hepatotoxin and hepatocarcinogen, can induce oxidative stress and inflammatory reaction in it. Umbelliferone, secondary metabolites, is present in different plants and widely consumed by humans as medicine and food supplements. The aim of the current study was to scrutinize the chemoprotective potential of umbelliferon-α-d-glucopyranosyl-(2I→1II)-α-d-glucopyranoside (UFD) against DEN-induced hepatocellular carcinoma (HCC) in experimental rats. Single intraperitoneal injection of DEN (200mg/kg) was used for induction of HCC in rats and rats were grouped and orally treated with UFD (5, 10 and 20mg/kg) dose for 22 weeks. Parameters under investigation included hepatic, non-hepatic enzymes, oxidative stress, pro-inflammatory cytokines, COX-2 and NF-κB level along with histopathological examination in HCC rats. UFD exerted protective effect via reduction of oxidative stress, liver and non-liver parameters in a dose-dependent manner. It also reduced the expression of TNF-α, IL-1β, IL-6 and COX-2 in diseased rats. Our result revealed the essential repression of the inflammation cascade through modulation of nuclear factor-kappa B (NF-κB) signaling pathway.
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Affiliation(s)
- Vikas Kumar
- Natural Product Drug Discovery Laboratory, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad, 211007, Uttar Pradesh, India.
| | - Prakash Chandra Bhatt
- Centre for Advanced Research in Pharmaceutical Sciences, Microbial and Pharmaceutical Biotechnology Laboratory, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India
| | - Mahfoozur Rahman
- Natural Product Drug Discovery Laboratory, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad, 211007, Uttar Pradesh, India
| | - Fahad A Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Firoz Anwar
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Amita Verma
- Bio-organic & Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad, 211007, Uttar Pradesh, India
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Pyridoxamine scavenges protein carbonyls and inhibits protein aggregation in oxidative stress-induced human HepG2 hepatocytes. Biochem Biophys Res Commun 2017; 486:845-851. [DOI: 10.1016/j.bbrc.2017.03.147] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 03/27/2017] [Indexed: 01/03/2023]
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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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Prasad K, Mishra M. Do Advanced Glycation End Products and Its Receptor Play a Role in Pathophysiology of Hypertension? Int J Angiol 2017; 26:1-11. [PMID: 28255209 PMCID: PMC5330762 DOI: 10.1055/s-0037-1598183] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
There is a close relationship between arterial stiffness and blood pressure. The studies suggest that the advanced glycation end products (AGEs) and its cell receptor (RAGE) are involved in the arterial stiffness in two ways: changes in arterial structure and vascular function. Plasma levels of AGEs and expression of RAGE are elevated, while the levels of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) are lowered in patients with hypertension (HTN). There is a positive correlation between plasma levels of AGEs and arterial stiffness, and an inverse association between arterial stiffness/HTN, and serum levels of sRAGE and esRAGE. Various measures can reduce the levels of AGEs and expression of RAGE, and elevate sRAGE. Arterial stiffness and blood pressure could be reduced by lowering the serum levels of AGEs, and increasing the levels of sRAGE. Levels of AGEs can be lowered by reducing the consumption of AGE-rich diet, short duration of cooking in moist heat at low temperature, and cessation of cigarette smoking. Drugs such as aminoguanidine, vitamins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers, statins, and metformin inhibit AGE formation. Alagebrium, an AGE breakers reduces levels of AGEs. Clinical trials with some drugs tend to reduce stiffness. Systemic administration of sRAGE has beneficial effect in animal studies. In conclusion, AGE-RAGE axis is involved in arterial stiffness and HTN. The studies suggest that inhibition of AGEs formation, reduction of AGE consumption, blockade of AGE-RAGE interaction, suppression of RAGE expression, and exogenous administration of sRAGE may be novel therapeutic strategies for treatment of arterial stiffness and HTN.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology, College of Medicine, University of Saskatchewan, Saskatchewan, Canada
| | - Manish Mishra
- Department of Physiology, College of Medicine, University of Saskatchewan, Saskatchewan, Canada
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Pena-Polanco JE, Fried LF. Established and Emerging Strategies in the Treatment of Chronic Kidney Disease. Semin Nephrol 2016; 36:331-42. [DOI: 10.1016/j.semnephrol.2016.05.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Yagihashi S. Glucotoxic Mechanisms and Related Therapeutic Approaches. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2016; 127:121-49. [PMID: 27133148 DOI: 10.1016/bs.irn.2016.03.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Neuropathy is the earliest and commonest complication of diabetes. With increasing duration of diabetes, frequency and severity of neuropathy are worsened. Long-term hyperglycemia is therefore implicated in the development of this disorder. Nerve tissues require glucose energy to function and survive. Upon excessive glucose entry into the peripheral nerve, the glycolytic pathway and collateral glucose-utilizing pathways are overactivated and initiate adverse effects on nerve tissues. During hyperglycemia, flux through the polyol pathway, formation of advanced glycation end-products, production of free radicals, flux into the glucosamine pathway, and protein kinase C activity are all enhanced to negatively influence nerve function and structure. Suppression of these aberrant metabolic pathways has succeeded in prevention and inhibition of the development of neuropathy in animal models with diabetes. Satisfactory results were not attained, however, in patients with diabetes and further clinical trials are required. In this review, the author summarizes the hitherto proposed theories on the pathogenesis of diabetic neuropathy related to glucose metabolism and future prospects for the effective treatment of neuropathy.
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Affiliation(s)
- S Yagihashi
- Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
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Mochizuki S, Takano M, Sugano N, Ohtsu M, Tsunoda K, Koshi R, Yoshinuma N. The effect of B vitamin supplementation on wound healing in type 2 diabetic mice. J Clin Biochem Nutr 2016; 58:64-8. [PMID: 26798199 PMCID: PMC4706087 DOI: 10.3164/jcbn.14-122] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 08/03/2015] [Indexed: 12/15/2022] Open
Abstract
The aim of this study was to test the effects of B-group vitamin supplements on wound healing in diabetic mice. The mice in the experimental group were treated daily with 1 g/L B6, 1.25 mg/L B12, and 62.5 mg/L folic acid in their drinking water. Full-thickness excision wounds were created with 6-mm skin biopsy punches. Each wound closure was digitally photographed. Beginning on day 3 after wounding, the wound area in the diabetic mice was statistically larger than that of normal mice (p<0.05 vs diabetic mice). The diabetic mice treated with B vitamins displayed accelerated wound closure on day 3 (wound area 42.8 ± 11.3%, p<0.05). On day 9 after wounding, the wound area in the diabetic mice was also statistically larger than that of normal mice (p<0.05 vs diabetic mice). The diabetic mice treated with B vitamins displayed accelerated wound closure on day 3 (wound area 13.2 ± 16.8%, p<0.05). In addition, the high glucose level in the diabetic animals decreased significantly in response to B vitamin treatment. In conclusion, the results of this study indicate that B vitamin supplementation may improve wound healing in diabetic mice.
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Affiliation(s)
- Saeka Mochizuki
- Division of Applied Oral Sciences, Nihon University Graduate School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Mayuko Takano
- Department of Periodontology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Naoyuki Sugano
- Department of Periodontology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Mariko Ohtsu
- Division of Applied Oral Sciences, Nihon University Graduate School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Kou Tsunoda
- Division of Applied Oral Sciences, Nihon University Graduate School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Ryosuke Koshi
- Department of Periodontology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Naoto Yoshinuma
- Department of Periodontology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
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Stegen S, Sigal RJ, Kenny GP, Khandwala F, Yard B, De Heer E, Baelde H, Peersman W, Derave W. Aerobic and resistance training do not influence plasma carnosinase content or activity in type 2 diabetes. Am J Physiol Endocrinol Metab 2015; 309:E663-9. [PMID: 26389600 DOI: 10.1152/ajpendo.00142.2015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 08/04/2015] [Indexed: 01/03/2023]
Abstract
A particular allele of the carnosinase gene (CNDP1) is associated with reduced plasma carnosinase activity and reduced risk for nephropathy in diabetic patients. On the one hand, animal and human data suggest that hyperglycemia increases plasma carnosinase activity. On the other hand, we recently reported lower carnosinase activity levels in elite athletes involved in high-intensity exercise compared with untrained controls. Therefore, this study investigates whether exercise training and the consequent reduction in hyperglycemia can suppress carnosinase activity and content in adults with type 2 diabetes. Plasma samples were taken from 243 males and females with type 2 diabetes (mean age = 54.3 yr, SD = 7.1) without major microvascular complications before and after a 6-mo exercise training program [4 groups: sedentary control (n = 61), aerobic exercise (n = 59), resistance exercise (n = 63), and combined exercise training (n = 60)]. Plasma carnosinase content and activity, hemoglobin (Hb) A1c, lipid profile, and blood pressure were measured. A 6-mo exercise training intervention, irrespective of training modality, did not decrease plasma carnosinase content or activity in type 2 diabetic patients. Plasma carnosinase content and activity showed a high interindividual but very low intraindividual variability over the 6-mo period. Age and sex, but not Hb A1c, were significantly related to the activity or content of this enzyme. It can be concluded that the beneficial effects of exercise training on the incidence of diabetic complications are probably not related to a lowering effect on plasma carnosinase content or activity.
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Affiliation(s)
- Sanne Stegen
- Department of Movement and Sport Sciences, Ghent University, Ghent, Belgium
| | - Ronald J Sigal
- Departments of Medicine, Cardiac Sciences, and Community Health Sciences, Cumming School of Medicine, Faculties of Medicine and Kinesiology, University of Calgary, Calgary, Alberta, Canada; School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada; Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Glen P Kenny
- School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada; Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | | | - Benito Yard
- 5th Medical Department, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Emile De Heer
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; and
| | - Hans Baelde
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; and
| | - Wim Peersman
- Department of Family Medicine and Primary Health Care, Ghent University, Ghent, Belgium
| | - Wim Derave
- Department of Movement and Sport Sciences, Ghent University, Ghent, Belgium;
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47
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Sharma C, Kaur A, Thind SS, Singh B, Raina S. Advanced glycation End-products (AGEs): an emerging concern for processed food industries. Journal of Food Science and Technology 2015; 52:7561-76. [PMID: 26604334 DOI: 10.1007/s13197-015-1851-y] [Citation(s) in RCA: 160] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Revised: 04/12/2015] [Accepted: 04/22/2015] [Indexed: 01/02/2023]
Abstract
The global food industry is expected to increase more than US $ 7 trillion by 2014. This rise in processed food sector shows that more and more people are diverging towards modern processed foods. As modern diets are largely heat processed, they are more prone to contain high levels of advanced glycation end products (AGEs). AGEs are a group of complex and heterogeneous compounds which are known as brown and fluorescent cross-linking substances such as pentosidine, non-fluorescent cross-linking products such as methylglyoxal-lysine dimers (MOLD), or non-fluorescent, non-cross linking adducts such as carboxymethyllysine (CML) and pyrraline (a pyrrole aldehyde). The chemistry of the AGEs formation, absorption and bioavailability and their patho-biochemistry particularly in relation to different complications like diabetes and ageing discussed. The concept of AGEs receptor - RAGE is mentioned. AGEs contribute to a variety of microvascular and macrovascular complications through the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by engaging the receptor for advanced glycation end products (RAGE). Different methods of detection and quantification along with types of agents used for the treatment of AGEs are reviewed. Generally, ELISA or LC-MS methods are used for analysis of foods and body fluids, however lack of universally established method highlighted. The inhibitory effect of bioactive components on AGEs by trapping variety of chemical moieties discussed. The emerging evidence about the adverse effects of AGEs makes it necessary to investigate the different therapies to inhibit AGEs.
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Affiliation(s)
- Chetan Sharma
- Department of Food Science and Technology, Punjab Agricultural University, Ludhiana, India
| | - Amarjeet Kaur
- Department of Food Science and Technology, Punjab Agricultural University, Ludhiana, India
| | - S S Thind
- Department of Food Science and Technology, Punjab Agricultural University, Ludhiana, India
| | - Baljit Singh
- Department of Food Science and Technology, Punjab Agricultural University, Ludhiana, India
| | - Shiveta Raina
- Department of Microbiology, Punjab Agricultural University, Ludhiana, India
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48
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Zamani Z, Ghanei M, Panahi Y, Arjmand M, Sadeghi S, Mirkhani F, Parvin S, Salehi M, Sahebkar A, Vahabi F. Serum Metabolomic Profiling of Sulphur Mustard-Exposed Individuals Using (1)H Nuclear Magnetic Resonance Spectroscopy. Basic Clin Pharmacol Toxicol 2015; 118:77-82. [PMID: 26177671 DOI: 10.1111/bcpt.12441] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 06/30/2015] [Indexed: 12/01/2022]
Abstract
Sulphur mustard is an alkylating agent that reacts with different cellular components, causing acute and delayed complications that may remain for decades after exposure. This study aimed to identify differentially expressed metabolites between mustard-exposed individuals suffering from chronic complications compared with unexposed individuals as the control group. Serum samples were obtained from 15 mustard-exposed individuals and 15 apparently healthy unexposed individuals. Metabolomic profiling was performed using (1)H nuclear magnetic resonance spectroscopy, and analyses were carried out using Chenomex and MATLAB softwares. Metabolites were identified using Human Metabolome Database, and the main metabolic pathways were identified using MetaboAnalyst software. Chemometric analysis of serum samples identified 11 differentially expressed metabolites between mustard-exposed and unexposed groups. The main pathways that were influenced by sulphur mustard exposure were related to vitamin B6 (down-regulation), bile acid (up-regulation) and tryptophan (down-regulation) metabolism. Metabolism of vitamin B6, bile acids and tryptophan are the most severely impaired pathways in individuals suffering from chronic mustard-induced complications. These findings may find implications in the monitoring of exposed patients and identification of new therapeutic approaches.
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Affiliation(s)
- Zahra Zamani
- Biochemistry Department, Pasteur Institute of Iran, Tehran, Iran
| | - Mostafa Ghanei
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Yunus Panahi
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mohammad Arjmand
- Biochemistry Department, Pasteur Institute of Iran, Tehran, Iran
| | - Sedigheh Sadeghi
- Biochemistry Department, Pasteur Institute of Iran, Tehran, Iran
| | - Fatemeh Mirkhani
- Biochemistry Department, Pasteur Institute of Iran, Tehran, Iran
| | - Shahram Parvin
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Maryam Salehi
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farideh Vahabi
- Biochemistry Department, Pasteur Institute of Iran, Tehran, Iran
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49
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Dakshinamurti K. Vitamins and their derivatives in the prevention and treatment of metabolic syndrome diseases (diabetes),. Can J Physiol Pharmacol 2015; 93:355-62. [DOI: 10.1139/cjpp-2014-0479] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A cluster of inter-related conditions such as central obesity, dyslipidemia, impaired glucose metabolism, and hypertension is referred to as Metabolic Syndrome, which is a risk factor for the development of type-2 diabetes. The micro- and macro-vascular complications of diabetes contribute to its morbidity and mortality. In addition to its calcitropic effect, vitamin D is a regulator of gene expression as well as cell proliferation and differentiation. Various cross-sectional and longitudinal cohort studies have indicated a beneficial effect from vitamin D supplementation on the development of type-2 diabetes. Binding of retinol-bound retinol-binding protein to a membrane-binding protein suppresses insulin signaling. All-trans retinoic acid, a derivative of vitamin A, reverses these effects, resulting in increased insulin sensitivity, suppression of the phosphoenolpyruvate carboxy kinase (PEPCK) gene, and the induction of the glucokinase gene. Glucokinase and PEPCK are also regulated in opposite directions by the vitamin biotin, acting at the transcriptional level. Biotin also regulates the synthesis of insulin by the islet of Langerhans cells of the pancreas. The increase in advanced glycation end products (AGEs) is implicated in the initiation and progression of diabetes-associated microvascular diseases. Benfotiamine, a derivative of thiamine, and pyridoxamine, a vitamer of vitamin B6, both have anti-AGE properties, making them valuable therapeutic adjuvants in the treatment of diabetic complications. Thus, various vitamins and their derivatives have profound therapeutic potential in the prevention and treatment of type-2 diabetes.
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Affiliation(s)
- Krishnamurti Dakshinamurti
- St. Boniface Hospital Research Centre, Faculty of Medicine, University of Manitoba, 351 Tache Avenue Winnipeg, MB R2H 2A6, Canada
- St. Boniface Hospital Research Centre, Faculty of Medicine, University of Manitoba, 351 Tache Avenue Winnipeg, MB R2H 2A6, Canada
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50
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Quercetin as a finer substitute to aminoguanidine in the inhibition of glycation products. Int J Biol Macromol 2015; 77:188-92. [PMID: 25799884 DOI: 10.1016/j.ijbiomac.2015.03.021] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Revised: 03/10/2015] [Accepted: 03/14/2015] [Indexed: 11/20/2022]
Abstract
Non-enzymatic glycation is the addition of a free carbonyl group of a reducing sugar to the free amino groups of proteins, which results in the formation of early and advanced glycation end-products (AGEs). Glycation reaction is profoundly associated with diabetes and its secondary complications, such as nephropathy and neuropathy. Glyoxal is a carbonyl species that reacts rapidly with the free amino groups of proteins to form AGEs. While the formation of AGEs with various glycating agents has previously been demonstrated, no extensive studies have been conducted to assess the role of quercetin in all three stages of glycation (early, intermediate and late). In this study, we report the glycation of HSA (human serum albumin) and its characterization by several spectroscopic techniques. Furthermore, inhibition of products at all stages of glycation was studied by various assays. Spectroscopic analysis suggests structural perturbations in the HSA macromolecule as a result of modification, which might be due to the generation of free radicals and the formation of AGEs. Inhibition in the formation of glycation has established that quercetin is a better and a more potent antiglycating agent than aminoguanidine at all stages of glycation.
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