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Jaruan O, Promsan S, Thongnak L, Pengrattanachot N, Phengpol N, Sutthasupha P, Lungkaphin A. Pyridoxine exerts antioxidant effects on kidney injury manifestations in high-fat diet-induced obese rats. Chem Biol Interact 2025; 415:111513. [PMID: 40239886 DOI: 10.1016/j.cbi.2025.111513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/21/2025] [Accepted: 04/14/2025] [Indexed: 04/18/2025]
Abstract
The modern diet contains a substantial level of fat which is believed to be one of the leading causes of the progression of kidney disease. Several studies have already demonstrated that consumption of a high-fat diet (HFD) induces inflammation and oxidative stress, causing activation of upstream mechanisms associated with kidney injury. For the prevention of such pathological events, a change in diet or the taking of nutritional supplements are recommended as alternative treatments. One of the forms of vitamin B6, pyridoxine (PN), has been shown to be an effective antioxidant and can also inhibit the formation of advanced-glycation end products (AGEs). In this study, the protective effects of PN (100 mg/kg/day for a period of eight weeks) against HFD-induced complications in obese rats were investigated. Rats fed on a HFD developed obesity which promoted inflammation, glucose intolerance, AGE receptor upregulation, oxidative stress, and kidney dysfunction. Intervention using PN mitigated obesity-related events and the impairment of kidney function by markedly reducing oxidative stress and also restoring the activity of antioxidant enzymes. Other studies have shown that some vitamin B6 derivatives inhibit the formation of AGEs but our study shows for the first time that PN exerted an antiglycative effect in this HFD-induced obesity model. Consequently, PN could potentially be a novel supplement for obese individuals to avoid kidney injury.
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Affiliation(s)
- Onanong Jaruan
- Department of Physiology, Faculty of Medicine Chiang Mai University, Chiang Mai, Thailand
| | - Sasivimon Promsan
- Department of Physiology, Faculty of Medicine Chiang Mai University, Chiang Mai, Thailand
| | - Laongdao Thongnak
- Department of Physiology, Faculty of Medicine Chiang Mai University, Chiang Mai, Thailand; Princess Srisavangavadhana College of Medicine, Chulabhorn Royal Academy, Bangkok, Thailand
| | | | - Nichakorn Phengpol
- Department of Physiology, Faculty of Medicine Chiang Mai University, Chiang Mai, Thailand
| | - Prempree Sutthasupha
- Department of Physiology, Faculty of Medicine Chiang Mai University, Chiang Mai, Thailand
| | - Anusorn Lungkaphin
- Department of Physiology, Faculty of Medicine Chiang Mai University, Chiang Mai, Thailand; Functional Foods for Health and Disease, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Functional Food Research Center for Well-Being, Multidisciplinary Research Institute, Chiang Mai University, Chiang Mai, Thailand.
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Siddiqui S, Ahmad R, Ahmad Y, Faizy AF, Moin S. Biophysical insight into the binding mechanism of epigallocatechin-3-gallate and cholecalciferol to albumin and its preventive effect against AGEs formation: An in vitro and in silico approach. Int J Biol Macromol 2024; 267:131474. [PMID: 38599429 DOI: 10.1016/j.ijbiomac.2024.131474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/24/2024] [Accepted: 04/06/2024] [Indexed: 04/12/2024]
Abstract
Advanced glycation end products (AGEs) are produced non-enzymatically through the process of glycation. Increased AGEs production has been linked to several diseases including polycystic ovary syndrome (PCOS). PCOS contributes to the development of secondary comorbidities, such as diabetes, cardiovascular complications, infertility, etc. Consequently, research is going on AGEs-inhibiting phytochemicals for their potential to remediate and impede the progression of hyperglycaemia associated disorders. In this study human serum albumin is used as a model protein, as albumin is predominantly present in follicular fluid. This article focusses on the interaction and antiglycating potential of (-)-Epigallocatechin-3-gallate (EGCG) and vitamin D in combination using various techniques. The formation of the HSA-EGCG and HSA-vitamin D complex was confirmed by UV and fluorescence spectroscopy. Thermodynamic analysis verified the spontaneity of reaction, and presence of hydrogen bonds and van der Waals interactions. FRET confirms high possibility of energy transfer. Cumulative antiglycation resulted in almost 60 % prevention in AGEs formation, decreased alterations at lysine and arginine, and reduced protein carbonylation. Secondary and tertiary structural changes were analysed by circular dichroism, Raman spectroscopy and ANS binding assay. Type and size of aggregates were confirmed by Rayleigh and dynamic light scattering, ThT fluorescence, SEM and SDS-PAGE. Effect on cellular redox status, DNA integrity and cytotoxicity was analysed in lymphocytes using dichlorofluorescein (DCFH-DA), DAPI and MTT assay which depicted an enhancement in antioxidant level by cumulative treatment. These findings indicate that EGCG and vitamin D binds strongly to HSA and have antiglycation ability which enhances upon synergism.
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Affiliation(s)
- Sana Siddiqui
- Department of Biochemistry, J.N.M.C., Faculty of Medicine, Aligarh Muslim University, Aligarh 202002, U.P., India
| | - Rizwan Ahmad
- Department of Biochemistry, J.N.M.C., Faculty of Medicine, Aligarh Muslim University, Aligarh 202002, U.P., India
| | - Yusra Ahmad
- Department of Biochemistry, J.N.M.C., Faculty of Medicine, Aligarh Muslim University, Aligarh 202002, U.P., India
| | - Abul Faiz Faizy
- Department of Biochemistry, J.N.M.C., Faculty of Medicine, Aligarh Muslim University, Aligarh 202002, U.P., India
| | - Shagufta Moin
- Department of Biochemistry, J.N.M.C., Faculty of Medicine, Aligarh Muslim University, Aligarh 202002, U.P., India.
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He H, Wei Q, Chang J, Yi X, Yu X, Luo G, Li X, Yang W, Long Y. Exploring the hypoglycemic mechanism of chlorogenic acids from Pyrrosia petiolosa (Christ) Ching on type 2 diabetes mellitus based on network pharmacology and transcriptomics strategy. JOURNAL OF ETHNOPHARMACOLOGY 2024; 322:117580. [PMID: 38104881 DOI: 10.1016/j.jep.2023.117580] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 11/05/2023] [Accepted: 12/10/2023] [Indexed: 12/19/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pyrrosia petiolosa (Christ) Ching (YBSW) is a Traditional Chinese medicine rich in chlorogenic acids. It is an important component in many Traditional Chinese medicinal hypoglycemic formulas and is commonly used by the Miao people to treat diabetes with good efficacy. Our previous research has suggested that chlorogenic acids may be the active ingredients in YBSW. AIM OF THE STUDY To explore the mechanisms underlying the anti-type 2 diabetes mellitus (T2DM) hypoglycemic effects of chlorogenic acids contained in YBSW. MATERIALS AND METHODS In vivo experiments, hematoxylin-eosin staining (HE) staining, and immunohistochemistry (IHC) were used to determine the effects of chlorogenic acids contained in YBSW in rats. mRNA expression profiling, microarray analysis, and network pharmacology were used to analyze the underlying mechanisms of the effects. Finally, apoptosis and changes in the related pathways were evaluated in vitro using a 3-(4,5-dimethyl-2-thia-zolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, quantitative real-time polymerase chain reaction, immunofluorescence (IF) assessment, and flow cytometry. RESULTS After the administration of isochlorogenic acid B, the levels of triglycerides, serum total cholesterol, and fasting blood glucose significantly decreased. HE and IHC staining revealed that isochlorogenic acid B significantly increased insulin expression in islet cells. Using network pharmacology and RNA-seq Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, we screened the advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) signaling pathway. We also verified that YBSW and its chlorogenic acid can inhibit apoptosis and downregulate the expression of related mRNA in the AGE-RAGE pathway in RIN-m5f cells. CONCLUSIONS YBSW exhibits a significant hypoglycemic effect, with chlorogenic acid being an effective component. The therapeutic effect of chlorogenic acids contained in YBSW is mainly realized by promoting insulin secretion and pancreatic tissue repair. Moreover, YBSW substantially mitigates apoptosis via the AGE-RAGE pathway in T2DM.
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Affiliation(s)
- Hanjiao He
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, No. 4 Dongqingnan Road, Huaxi District, Guiyang, Guizhou 550025, PR China
| | - Qing Wei
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, No. 4 Dongqingnan Road, Huaxi District, Guiyang, Guizhou 550025, PR China
| | - Jiao Chang
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, No. 4 Dongqingnan Road, Huaxi District, Guiyang, Guizhou 550025, PR China
| | - Xu Yi
- Second Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, No. 32 Feishan Road, Nanming District, Guiyang, Guizhou 550002, PR China
| | - Xiang Yu
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, No. 4 Dongqingnan Road, Huaxi District, Guiyang, Guizhou 550025, PR China
| | - Guoyong Luo
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, No. 4 Dongqingnan Road, Huaxi District, Guiyang, Guizhou 550025, PR China
| | - Xinfeng Li
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, No. 4 Dongqingnan Road, Huaxi District, Guiyang, Guizhou 550025, PR China.
| | - Wude Yang
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, No. 4 Dongqingnan Road, Huaxi District, Guiyang, Guizhou 550025, PR China.
| | - Yi Long
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, No. 4 Dongqingnan Road, Huaxi District, Guiyang, Guizhou 550025, PR China.
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Pearce B, Pearce K. Mitochondrial dysfunction and diabetes in South Africa: A review. ENDOCRINE AND METABOLIC SCIENCE 2024; 14:100157. [DOI: 10.1016/j.endmts.2024.100157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025] Open
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Horvat A, Vlašić I, Štefulj J, Oršolić N, Jazvinšćak Jembrek M. Flavonols as a Potential Pharmacological Intervention for Alleviating Cognitive Decline in Diabetes: Evidence from Preclinical Studies. Life (Basel) 2023; 13:2291. [PMID: 38137892 PMCID: PMC10744738 DOI: 10.3390/life13122291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/15/2023] [Accepted: 11/24/2023] [Indexed: 12/24/2023] Open
Abstract
Diabetes mellitus is a complex metabolic disease associated with reduced synaptic plasticity, atrophy of the hippocampus, and cognitive decline. Cognitive impairment results from several pathological mechanisms, including increased levels of advanced glycation end products (AGEs) and their receptors, prolonged oxidative stress and impaired activity of endogenous mechanisms of antioxidant defense, neuroinflammation driven by the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), decreased expression of brain-derived neurotrophic factor (BDNF), and disturbance of signaling pathways involved in neuronal survival and cognitive functioning. There is increasing evidence that dietary interventions can reduce the risk of various diabetic complications. In this context, flavonols, a highly abundant class of flavonoids in the human diet, are appreciated as a potential pharmacological intervention against cognitive decline in diabetes. In preclinical studies, flavonols have shown neuroprotective, antioxidative, anti-inflammatory, and memory-enhancing properties based on their ability to regulate glucose levels, attenuate oxidative stress and inflammation, promote the expression of neurotrophic factors, and regulate signaling pathways. The present review gives an overview of the molecular mechanisms involved in diabetes-induced cognitive dysfunctions and the results of preclinical studies showing that flavonols have the ability to alleviate cognitive impairment. Although the results from animal studies are promising, clinical and epidemiological studies are still needed to advance our knowledge on the potential of flavonols to improve cognitive decline in diabetic patients.
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Affiliation(s)
- Anđela Horvat
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
| | - Ignacija Vlašić
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
| | - Jasminka Štefulj
- Division of Molecular Biology, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
- Department of Psychology, Catholic University of Croatia, Ilica 242, 10000 Zagreb, Croatia
| | - Nada Oršolić
- Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia
| | - Maja Jazvinšćak Jembrek
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
- Department of Psychology, Catholic University of Croatia, Ilica 242, 10000 Zagreb, Croatia
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Pal R, Bhadada SK. AGEs accumulation with vascular complications, glycemic control and metabolic syndrome: A narrative review. Bone 2023; 176:116884. [PMID: 37598920 DOI: 10.1016/j.bone.2023.116884] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/22/2023]
Abstract
BACKGROUND Multiple pathogenetic mechanisms are involved in the genesis of various microvascular and macrovascular complications of diabetes mellitus. Of all these, advanced glycation end products (AGEs) have been strongly implicated. OBJECTIVES The present narrative review aims to summarize the available literature on the genesis of AGEs and their potential role in the causation of both micro- and macrovascular complications of diabetes mellitus. RESULTS Uncontrolled hyperglycemia triggers the formation of AGEs through non-enzymatic glycation reactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs accumulate in bloodstream and bodily tissues under chronic hyperglycemia. AGEs create irreversible cross-linkages of various intra- and extracellular molecules and activate the receptor for advanced glycation end products (RAGE), which stimulates downstream signaling pathways that generate reactive oxygen species (ROS) and contribute to oxidative stress. Additionally, intracellular glycation of mitochondrial respiratory chain proteins by AGEs contributes to the further generation of ROS, which, in turn, sets a vicious cycle that further promotes the production of endogenous AGEs. Through these pathways, AGEs play a principal role in the pathogenesis of various diabetic complications, including diabetic retinopathy, nephropathy, neuropathy, bone disease, atherosclerosis and non-alcoholic fatty liver disease. Multiple clinical studies and meta-analyses have revealed a positive association between tissue or circulating levels of AGEs and development of various diabetic complications. Besides, exogenous AGEs, primarily those derived from diets, promote insulin resistance, obesity, and metabolic syndrome. CONCLUSIONS AGEs, triggered by chronic hyperglycemia, play a pivotal role in the pathogenesis of various complications of diabetes mellitus.
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Affiliation(s)
- Rimesh Pal
- Department of Endocrinology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
| | - Sanjay K Bhadada
- Department of Endocrinology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India.
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Miao L, Liu C, Cheong MS, Zhong R, Tan Y, Rengasamy KRR, Leung SWS, Cheang WS, Xiao J. Exploration of natural flavones' bioactivity and bioavailability in chronic inflammation induced-type-2 diabetes mellitus. Crit Rev Food Sci Nutr 2023; 63:11640-11667. [PMID: 35821658 DOI: 10.1080/10408398.2022.2095349] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Diabetes, being the most widespread illness, poses a serious threat to global public health. It seems that inflammation plays a critical role in the pathophysiology of diabetes. This review aims to demonstrate a probable link between type 2 diabetes mellitus (T2DM) and chronic inflammation during its development. Additionally, the current review examined the bioactivity of natural flavones and the possible molecular mechanisms by which they influence diabetes and inflammation. While natural flavones possess remarkable anti-diabetic and anti-inflammatory bioactivities, their therapeutic use is limited by the low oral bioavailability. Several factors contribute to the low bioavailability, including poor water solubility, food interaction, and unsatisfied metabolic behaviors, while the diseases (diabetes, inflammation, etc.) causing even less bioavailability. Throughout the years, different strategies have been developed to boost flavones' bioavailability, including structural alteration, biological transformation, and innovative drug delivery system design. This review addresses current advancements in improving the bioavailability of flavonoids in general, and flavones in particular. Clinical trials were also analyzed to provide insight into the potential application of flavonoids in diabetes and inflammatory therapies.
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Affiliation(s)
- Lingchao Miao
- State Key Laboratory of Quality Control in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
| | - Conghui Liu
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Meang Sam Cheong
- State Key Laboratory of Quality Control in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
| | - Ruting Zhong
- State Key Laboratory of Quality Control in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
| | - Yi Tan
- State Key Laboratory of Quality Control in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
| | - Kannan R R Rengasamy
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, India
| | - Susan Wai Sum Leung
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Wai San Cheang
- State Key Laboratory of Quality Control in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
| | - Jianbo Xiao
- Department of Analytical and Food Chemistry, Faculty of Sciences, Universidade de Vigo, Nutrition and Bromatology Group, Ourense, Spain
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Zgutka K, Tkacz M, Tomasiak P, Tarnowski M. A Role for Advanced Glycation End Products in Molecular Ageing. Int J Mol Sci 2023; 24:9881. [PMID: 37373042 PMCID: PMC10298716 DOI: 10.3390/ijms24129881] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/02/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Ageing is a composite process that involves numerous changes at the cellular, tissue, organ and whole-body levels. These changes result in decreased functioning of the organism and the development of certain conditions, which ultimately lead to an increased risk of death. Advanced glycation end products (AGEs) are a family of compounds with a diverse chemical nature. They are the products of non-enzymatic reactions between reducing sugars and proteins, lipids or nucleic acids and are synthesised in high amounts in both physiological and pathological conditions. Accumulation of these molecules increases the level of damage to tissue/organs structures (immune elements, connective tissue, brain, pancreatic beta cells, nephrons, and muscles), which consequently triggers the development of age-related diseases, such as diabetes mellitus, neurodegeneration, and cardiovascular and kidney disorders. Irrespective of the role of AGEs in the initiation or progression of chronic disorders, a reduction in their levels would certainly provide health benefits. In this review, we provide an overview of the role of AGEs in these areas. Moreover, we provide examples of lifestyle interventions, such as caloric restriction or physical activities, that may modulate AGE formation and accumulation and help to promote healthy ageing.
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Affiliation(s)
- Katarzyna Zgutka
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University, Żołnierska 54, 70-210 Szczecin, Poland
| | - Marta Tkacz
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University, Żołnierska 54, 70-210 Szczecin, Poland
| | - Patrycja Tomasiak
- Institute of Physical Culture Sciences, University of Szczecin, 70-453 Szczecin, Poland
| | - Maciej Tarnowski
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University, Żołnierska 54, 70-210 Szczecin, Poland
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Reynaert NL, Vanfleteren LEGW, Perkins TN. The AGE-RAGE Axis and the Pathophysiology of Multimorbidity in COPD. J Clin Med 2023; 12:jcm12103366. [PMID: 37240472 DOI: 10.3390/jcm12103366] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 04/24/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a disease of the airways and lungs due to an enhanced inflammatory response, commonly caused by cigarette smoking. Patients with COPD are often multimorbid, as they commonly suffer from multiple chronic (inflammatory) conditions. This intensifies the burden of individual diseases, negatively affects quality of life, and complicates disease management. COPD and comorbidities share genetic and lifestyle-related risk factors and pathobiological mechanisms, including chronic inflammation and oxidative stress. The receptor for advanced glycation end products (RAGE) is an important driver of chronic inflammation. Advanced glycation end products (AGEs) are RAGE ligands that accumulate due to aging, inflammation, oxidative stress, and carbohydrate metabolism. AGEs cause further inflammation and oxidative stress through RAGE, but also through RAGE-independent mechanisms. This review describes the complexity of RAGE signaling and the causes of AGE accumulation, followed by a comprehensive overview of alterations reported on AGEs and RAGE in COPD and in important co-morbidities. Furthermore, it describes the mechanisms by which AGEs and RAGE contribute to the pathophysiology of individual disease conditions and how they execute crosstalk between organ systems. A section on therapeutic strategies that target AGEs and RAGE and could alleviate patients from multimorbid conditions using single therapeutics concludes this review.
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Affiliation(s)
- Niki L Reynaert
- Department of Respiratory Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands
| | - Lowie E G W Vanfleteren
- COPD Center, Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
| | - Timothy N Perkins
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Bao H, Cao J, Chen M, Chen M, Chen W, Chen X, Chen Y, Chen Y, Chen Y, Chen Z, Chhetri JK, Ding Y, Feng J, Guo J, Guo M, He C, Jia Y, Jiang H, Jing Y, Li D, Li J, Li J, Liang Q, Liang R, Liu F, Liu X, Liu Z, Luo OJ, Lv J, Ma J, Mao K, Nie J, Qiao X, Sun X, Tang X, Wang J, Wang Q, Wang S, Wang X, Wang Y, Wang Y, Wu R, Xia K, Xiao FH, Xu L, Xu Y, Yan H, Yang L, Yang R, Yang Y, Ying Y, Zhang L, Zhang W, Zhang W, Zhang X, Zhang Z, Zhou M, Zhou R, Zhu Q, Zhu Z, Cao F, Cao Z, Chan P, Chen C, Chen G, Chen HZ, Chen J, Ci W, Ding BS, Ding Q, Gao F, Han JDJ, Huang K, Ju Z, Kong QP, Li J, Li J, Li X, Liu B, Liu F, Liu L, Liu Q, Liu Q, Liu X, Liu Y, Luo X, Ma S, Ma X, Mao Z, Nie J, Peng Y, Qu J, Ren J, Ren R, Song M, Songyang Z, Sun YE, Sun Y, Tian M, Wang S, et alBao H, Cao J, Chen M, Chen M, Chen W, Chen X, Chen Y, Chen Y, Chen Y, Chen Z, Chhetri JK, Ding Y, Feng J, Guo J, Guo M, He C, Jia Y, Jiang H, Jing Y, Li D, Li J, Li J, Liang Q, Liang R, Liu F, Liu X, Liu Z, Luo OJ, Lv J, Ma J, Mao K, Nie J, Qiao X, Sun X, Tang X, Wang J, Wang Q, Wang S, Wang X, Wang Y, Wang Y, Wu R, Xia K, Xiao FH, Xu L, Xu Y, Yan H, Yang L, Yang R, Yang Y, Ying Y, Zhang L, Zhang W, Zhang W, Zhang X, Zhang Z, Zhou M, Zhou R, Zhu Q, Zhu Z, Cao F, Cao Z, Chan P, Chen C, Chen G, Chen HZ, Chen J, Ci W, Ding BS, Ding Q, Gao F, Han JDJ, Huang K, Ju Z, Kong QP, Li J, Li J, Li X, Liu B, Liu F, Liu L, Liu Q, Liu Q, Liu X, Liu Y, Luo X, Ma S, Ma X, Mao Z, Nie J, Peng Y, Qu J, Ren J, Ren R, Song M, Songyang Z, Sun YE, Sun Y, Tian M, Wang S, Wang S, Wang X, Wang X, Wang YJ, Wang Y, Wong CCL, Xiang AP, Xiao Y, Xie Z, Xu D, Ye J, Yue R, Zhang C, Zhang H, Zhang L, Zhang W, Zhang Y, Zhang YW, Zhang Z, Zhao T, Zhao Y, Zhu D, Zou W, Pei G, Liu GH. Biomarkers of aging. SCIENCE CHINA. LIFE SCIENCES 2023; 66:893-1066. [PMID: 37076725 PMCID: PMC10115486 DOI: 10.1007/s11427-023-2305-0] [Show More Authors] [Citation(s) in RCA: 167] [Impact Index Per Article: 83.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 02/27/2023] [Indexed: 04/21/2023]
Abstract
Aging biomarkers are a combination of biological parameters to (i) assess age-related changes, (ii) track the physiological aging process, and (iii) predict the transition into a pathological status. Although a broad spectrum of aging biomarkers has been developed, their potential uses and limitations remain poorly characterized. An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research: How old are we? Why do we get old? And how can we age slower? This review aims to address this need. Here, we summarize our current knowledge of biomarkers developed for cellular, organ, and organismal levels of aging, comprising six pillars: physiological characteristics, medical imaging, histological features, cellular alterations, molecular changes, and secretory factors. To fulfill all these requisites, we propose that aging biomarkers should qualify for being specific, systemic, and clinically relevant.
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Affiliation(s)
- Hainan Bao
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
| | - Jiani Cao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Mengting Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Min Chen
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Clinical Research Center of Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wei Chen
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Xiao Chen
- Department of Nuclear Medicine, Daping Hospital, Third Military Medical University, Chongqing, 400042, China
| | - Yanhao Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yu Chen
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Yutian Chen
- The Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Zhiyang Chen
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Ageing and Regenerative Medicine, Jinan University, Guangzhou, 510632, China
| | - Jagadish K Chhetri
- National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Yingjie Ding
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Junlin Feng
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jun Guo
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China
| | - Mengmeng Guo
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Chuting He
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Yujuan Jia
- Department of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan, 030001, China
| | - Haiping Jiang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Ying Jing
- Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
| | - Dingfeng Li
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China
| | - Jiaming Li
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jingyi Li
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Qinhao Liang
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430072, China
| | - Rui Liang
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, 300384, China
| | - Feng Liu
- MOE Key Laboratory of Gene Function and Regulation, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Sun Yat-sen University, Guangzhou, 510275, China
| | - Xiaoqian Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Zuojun Liu
- School of Life Sciences, Hainan University, Haikou, 570228, China
| | - Oscar Junhong Luo
- Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Jianwei Lv
- School of Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Jingyi Ma
- The State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Kehang Mao
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, 100871, China
| | - Jiawei Nie
- Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine (Shanghai), International Center for Aging and Cancer, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xinhua Qiao
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xinpei Sun
- Peking University International Cancer Institute, Health Science Center, Peking University, Beijing, 100101, China
| | - Xiaoqiang Tang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
| | - Jianfang Wang
- Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Qiaoran Wang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Siyuan Wang
- Clinical Research Institute, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Xuan Wang
- Hepatobiliary and Pancreatic Center, Medical Research Center, Beijing Tsinghua Changgung Hospital, Beijing, 102218, China
| | - Yaning Wang
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yuhan Wang
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Rimo Wu
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005, China
| | - Kai Xia
- Center for Stem Cell Biologyand Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China
- National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Fu-Hui Xiao
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China
- State Key Laboratory of Genetic Resources and Evolution, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Lingyan Xu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yingying Xu
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
| | - Haoteng Yan
- Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
| | - Liang Yang
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 510530, China
| | - Ruici Yang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuanxin Yang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China
| | - Yilin Ying
- Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital, Shanghai, 200025, China
| | - Le Zhang
- Gerontology Center of Hubei Province, Wuhan, 430000, China
- Institute of Gerontology, Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Weiwei Zhang
- Department of Cardiology, The Second Medical Centre, Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing, 100853, China
| | - Wenwan Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xing Zhang
- Key Laboratory of Ministry of Education, School of Aerospace Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Zhuo Zhang
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
- Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Min Zhou
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, China
| | - Rui Zhou
- Department of Nuclear Medicine and PET Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Qingchen Zhu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Zhengmao Zhu
- Department of Genetics and Cell Biology, College of Life Science, Nankai University, Tianjin, 300071, China
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Feng Cao
- Department of Cardiology, The Second Medical Centre, Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing, 100853, China.
| | - Zhongwei Cao
- State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
| | - Piu Chan
- National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
| | - Chang Chen
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Guobing Chen
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, 510632, China.
- Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, Guangzhou, 510000, China.
| | - Hou-Zao Chen
- Department of Biochemistryand Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
| | - Jun Chen
- Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Department of Integration of Chinese and Western Medicine, School of Basic Medical Science, Peking University, Beijing, 100191, China.
| | - Weimin Ci
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
| | - Bi-Sen Ding
- State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
| | - Qiurong Ding
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Feng Gao
- Key Laboratory of Ministry of Education, School of Aerospace Medicine, Fourth Military Medical University, Xi'an, 710032, China.
| | - Jing-Dong J Han
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, 100871, China.
| | - Kai Huang
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Clinical Research Center of Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Ageing and Regenerative Medicine, Jinan University, Guangzhou, 510632, China.
| | - Qing-Peng Kong
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.
- State Key Laboratory of Genetic Resources and Evolution, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
| | - Ji Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jian Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China.
| | - Xin Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Baohua Liu
- School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, 518060, China.
| | - Feng Liu
- Metabolic Syndrome Research Center, The Second Xiangya Hospital, Central South Unversity, Changsha, 410011, China.
| | - Lin Liu
- Department of Genetics and Cell Biology, College of Life Science, Nankai University, Tianjin, 300071, China.
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
- Institute of Translational Medicine, Tianjin Union Medical Center, Nankai University, Tianjin, 300000, China.
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300350, China.
| | - Qiang Liu
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China.
| | - Qiang Liu
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
- Tianjin Institute of Immunology, Tianjin Medical University, Tianjin, 300070, China.
| | - Xingguo Liu
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 510530, China.
| | - Yong Liu
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430072, China.
| | - Xianghang Luo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, China.
| | - Shuai Ma
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Xinran Ma
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
| | - Zhiyong Mao
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Jing Nie
- The State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Yaojin Peng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Jie Ren
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Ruibao Ren
- Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine (Shanghai), International Center for Aging and Cancer, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- International Center for Aging and Cancer, Hainan Medical University, Haikou, 571199, China.
| | - Moshi Song
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Zhou Songyang
- MOE Key Laboratory of Gene Function and Regulation, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Sun Yat-sen University, Guangzhou, 510275, China.
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
| | - Yi Eve Sun
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
| | - Yu Sun
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
- Department of Medicine and VAPSHCS, University of Washington, Seattle, WA, 98195, USA.
| | - Mei Tian
- Human Phenome Institute, Fudan University, Shanghai, 201203, China.
| | - Shusen Wang
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, 300384, China.
| | - Si Wang
- Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
| | - Xia Wang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
| | - Xiaoning Wang
- Institute of Geriatrics, The second Medical Center, Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Yan-Jiang Wang
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, 400042, China.
| | - Yunfang Wang
- Hepatobiliary and Pancreatic Center, Medical Research Center, Beijing Tsinghua Changgung Hospital, Beijing, 102218, China.
| | - Catherine C L Wong
- Clinical Research Institute, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China.
| | - Andy Peng Xiang
- Center for Stem Cell Biologyand Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China.
- National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Yichuan Xiao
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Zhengwei Xie
- Peking University International Cancer Institute, Health Science Center, Peking University, Beijing, 100101, China.
- Beijing & Qingdao Langu Pharmaceutical R&D Platform, Beijing Gigaceuticals Tech. Co. Ltd., Beijing, 100101, China.
| | - Daichao Xu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
| | - Jing Ye
- Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital, Shanghai, 200025, China.
| | - Rui Yue
- Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Cuntai Zhang
- Gerontology Center of Hubei Province, Wuhan, 430000, China.
- Institute of Gerontology, Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Hongbo Zhang
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Liang Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Weiqi Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Yong Zhang
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005, China.
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
| | - Yun-Wu Zhang
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361102, China.
| | - Zhuohua Zhang
- Key Laboratory of Molecular Precision Medicine of Hunan Province and Center for Medical Genetics, Institute of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, 410078, China.
- Department of Neurosciences, Hengyang Medical School, University of South China, Hengyang, 421001, China.
| | - Tongbiao Zhao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Yuzheng Zhao
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
- Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| | - Dahai Zhu
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005, China.
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
| | - Weiguo Zou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Gang Pei
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Biomedicine, The Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai, 200070, China.
| | - Guang-Hui Liu
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
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Hadzi-Petrushev N, Angelovski M, Mladenov M. Advanced Glycation End Products and Diabetes. CONTEMPORARY ENDOCRINOLOGY 2023:99-127. [DOI: 10.1007/978-3-031-39721-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Ravichandran G, Lakshmanan DK, Arunachalam A, Thilagar S. Food obesogens as emerging metabolic disruptors; A toxicological insight. J Steroid Biochem Mol Biol 2022; 217:106042. [PMID: 34890825 DOI: 10.1016/j.jsbmb.2021.106042] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 09/13/2021] [Accepted: 12/05/2021] [Indexed: 11/26/2022]
Abstract
Human food is composed of loads of chemicals derived naturally as well as unintentionally through environmental sources. Food additives added purposefully, play an important role in the palatability of foods. Most additives are synthetic whose essentiality in food processing is well-known however their health risks are not overlooked. The palatability of food should not only stimulate our eating desire alone but, also assure sufficient quality and safety. Application of food additives varies from region to region due to cultural or ethnic differences and the local food availability. There are about more than ten thousand chemicals allowed in food whereas due to weak enforcement, it becomes onerous for regulatory bodies identifying chemicals that are inadequately or not tested at all for safety. The hiking population and urbanization in many industrialized and developing countries resulted in life-style changes including culinary and eating choices. Particularly, the modern way of this globalised life demands ready-to-cook or ready-made foods, snacks, sweets, soft drinks, desserts, confectionery and so on. These sorts of food would be most uninteresting unless processed with additives. This puts food industries under demand to robustly supply foods that are either partially, fully or ultra-processed using plenty of additives. Recent research warns consuming food additives may result in serious health risks, not only for children but also for adults. Growing body of studies on food additives in various experimental animals, cell cultures, and human population suggest elevation of number of obesity and diabetes risk factors i.e. adiposity, dyslipidemia, weight gain, hyperglycaemia, insulin resistance, glucose intolerance, energy imbalance, hormonal intervention etc. Hence, it is important to identify and explore food obesogens or obesogenic food additives posing potential impact. Based on the recent toxicological findings, the review aspires to establish the association between exposure of food obesogen and metabolic disruption which may help filling knowledge gaps and distributing more knowledge, awareness and effective measures to implement treatment and preventive strategies for metabolic syndrome.
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Affiliation(s)
- Guna Ravichandran
- Department of Environmental Biotechnology, Bharathidasan University, Tiruchirappalli, India
| | - Dinesh Kumar Lakshmanan
- Department of Environmental Biotechnology, Bharathidasan University, Tiruchirappalli, India; Department of Biotechnology, Bannari Amman Institute of Technology, Sathyamangalam, Erode, India
| | - Abirami Arunachalam
- Department of Environmental Biotechnology, Bharathidasan University, Tiruchirappalli, India
| | - Sivasudha Thilagar
- Department of Environmental Biotechnology, Bharathidasan University, Tiruchirappalli, India.
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13
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Menon K, Cameron JD, de Courten M, de Courten B. Use of carnosine in the prevention of cardiometabolic risk factors in overweight and obese individuals: study protocol for a randomised, double-blind placebo-controlled trial. BMJ Open 2021; 11:e043680. [PMID: 33986049 PMCID: PMC8126302 DOI: 10.1136/bmjopen-2020-043680] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
INTRODUCTION Carnosine, an over the counter food supplement, has been shown to improve glucose metabolism as well as cardiovascular risk factors in animal and human studies through its anti-inflammatory, antioxidative, antiglycating and chelating properties. The aim of this study is to establish if carnosine supplementation improves obesity, insulin sensitivity, insulin secretion, cardiovascular risk factors including arterial stiffness and endothelial function, and other risk factors related to diabetes and cardiovascular disease in the overweight and obese population. METHODS AND ANALYSIS Fifty participants will be recruited to be enrolled in a double-blind randomised controlled trial. Eligible participants with a body mass index (BMI) between 25 and 40 kg/m2 will be randomly assigned to the intervention or placebo group. Following a medical review and oral glucose tolerance test to check eligibility, participants will then undergo testing. At baseline, participants will have anthropometric measurements (BMI, dual X-ray absorptiometry and peripheral quantitative CT scan), measurements of glucose metabolism (oral glucose tolerance test, intravenous glucose tolerance test and euglycaemic hyperinsulinaemic clamp), cardiovascular measurements (central blood pressure, endothelial function and arterial stiffness), a muscle and fat biopsy, physical activity measurement, liver fibroscan, cognitive function and questionnaires to assess dietary habits, sleep quality, depression, and quality of life. Following baseline assessments, participants will be randomised to either 2 g carnosine or placebo for 15 weeks. In the 15th week, all assessments will be repeated. The preplanned outcome metric is the change between baseline and follow-up measures. ETHICS AND DISSEMINATION This study is approved by the Human Research Ethics Committee of Monash Health and Monash University, Australia. TRIAL REGISTRATION NUMBER NCT02686996.
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Affiliation(s)
- Kirthi Menon
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - James D Cameron
- MonashHeart and Monash Cardiovascular Research Centre, Melbourne, Victoria, Australia
- School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia
| | - Maximilian de Courten
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
- Mitchell Institute, Victoria University, Melbourne, Victoria, Australia
| | - Barbora de Courten
- School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia
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14
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Rungratanawanich W, Qu Y, Wang X, Essa MM, Song BJ. Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury. Exp Mol Med 2021; 53:168-188. [PMID: 33568752 PMCID: PMC8080618 DOI: 10.1038/s12276-021-00561-7] [Citation(s) in RCA: 194] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 01/30/2023] Open
Abstract
Advanced glycation end products (AGEs) are potentially harmful and heterogeneous molecules derived from nonenzymatic glycation. The pathological implications of AGEs are ascribed to their ability to promote oxidative stress, inflammation, and apoptosis. Recent studies in basic and translational research have revealed the contributing roles of AGEs in the development and progression of various aging-related pathological conditions, such as diabetes, cardiovascular complications, gut microbiome-associated illnesses, liver or neurodegenerative diseases, and cancer. Excessive chronic and/or acute binge consumption of alcohol (ethanol), a widely consumed addictive substance, is known to cause more than 200 diseases, including alcohol use disorder (addiction), alcoholic liver disease, and brain damage. However, despite the considerable amount of research in this area, the underlying molecular mechanisms by which alcohol abuse causes cellular toxicity and organ damage remain to be further characterized. In this review, we first briefly describe the properties of AGEs: their formation, accumulation, and receptor interactions. We then focus on the causative functions of AGEs that impact various aging-related diseases. We also highlight the biological connection of AGE-alcohol-adduct formations to alcohol-mediated tissue injury. Finally, we describe the potential translational research opportunities for treatment of various AGE- and/or alcohol-related adduct-associated disorders according to the mechanistic insights presented.
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Affiliation(s)
- Wiramon Rungratanawanich
- grid.420085.b0000 0004 0481 4802Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892 USA
| | - Ying Qu
- grid.420085.b0000 0004 0481 4802Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892 USA
| | - Xin Wang
- Neuroapoptosis Drug Discovery Laboratory, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA 02115 USA
| | - Musthafa Mohamed Essa
- grid.412846.d0000 0001 0726 9430Department of Food Science and Nutrition, Aging and Dementia Research Group, College of Agricultural and Marine Sciences, Sultan Qaboos University, Al-Khoud, Muscat, Oman ,grid.412846.d0000 0001 0726 9430Aging and Dementia Research Group, Sultan Qaboos University, Muscat, Oman
| | - Byoung-Joon Song
- grid.420085.b0000 0004 0481 4802Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892 USA
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15
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Chung W, Promrat K, Wands J. Clinical implications, diagnosis, and management of diabetes in patients with chronic liver diseases. World J Hepatol 2020; 12:533-557. [PMID: 33033564 PMCID: PMC7522556 DOI: 10.4254/wjh.v12.i9.533] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/03/2020] [Accepted: 08/15/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus (DM) negatively affects the development and progression of chronic liver diseases (CLD) of various etiologies. Concurrent DM and CLD are also associated with worse clinical outcomes with respect to mortality, the occurrence of hepatic decompensation, and the development of hepatocellular carcinoma (HCC). Unfortunately, early diagnosis and optimal treatment of DM can be challenging, due to the lack of established clinical guidelines as well as the medical complexity of this patient population. We conducted an exploratory review of relevant literature to provide an up-to-date review for internists and hepatologists caring for this patient population. We reviewed the epidemiological and pathophysiological associations between DM and CLD, the impact of insulin resistance on the progression and manifestations of CLD, the pathogenesis of hepatogenic diabetes, as well as the practical challenges in diagnosis and monitoring of DM in this patient population. We also reviewed the latest clinical evidence on various pharmacological antihyperglycemic therapies with an emphasis on liver disease-related clinical outcomes. Finally, we proposed an algorithm for managing DM in patients with CLD and discussed the clinical and research questions that remain to be addressed.
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Affiliation(s)
- Waihong Chung
- Division of Gastroenterology, Department of Medicine, Rhode Island Hospital, Providence, RI 02905, United States.
| | - Kittichai Promrat
- Division of Gastroenterology and Hepatology, Providence VA Medical Center, Providence, RI 02908, United States
| | - Jack Wands
- Liver Research Center, The Warren Alpert Medical School of Brown University, Providence, RI 02903, United States
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16
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Zhang X, Fan Y, Luo Y, Jin L, Li S. Lipid Metabolism is the common pathologic mechanism between Type 2 Diabetes Mellitus and Parkinson's disease. Int J Med Sci 2020; 17:1723-1732. [PMID: 32714075 PMCID: PMC7378658 DOI: 10.7150/ijms.46456] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 06/18/2020] [Indexed: 02/07/2023] Open
Abstract
Although increasing evidence has suggested crosstalk between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM), the common mechanisms between the two diseases remain unclear. The aim of our study was to characterize the interconnection between T2DM and PD by exploring their shared biological pathways and convergent molecules. The intersections among the differentially expressed genes (DEGs) in the T2DM dataset GSE95849 and PD dataset GSE6613 from the Gene Expression Omnibus (GEO) database were identified as the communal DEGs between the two diseases. Then, an enrichment analysis, protein-protein interaction (PPI) network analysis, correlation analysis, and transcription factor-target regulatory network analysis were performed for the communal DEGs. As a result, 113 communal DEGs were found between PD and T2DM. They were enriched in lipid metabolism, including protein modifications that regulate metabolism, lipid synthesis and decomposition, and the biological effects of lipid products. All these pathways and their biological processes play important roles in both diseases. Fifteen hub genes identified from the PPI network could be core molecules. Their function annotations also focused on lipid metabolism. According to the correlation analysis and the regulatory network analysis based on the 15 hub genes, Sp1 transcription factor (SP1) could be a key molecule since it affected other hub genes that participate in the common mechanisms between PD and T2DM. In conclusion, our analyses reveal that changes in lipid metabolism could be a key intersection between PD and T2DM, and that SP1 could be a key molecule regulating these processes. Our findings provide novel points for the association between PD and T2DM.
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Affiliation(s)
- Xi Zhang
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
- Department of Neurology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Yu Fan
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Yuping Luo
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Lingjing Jin
- Department of Neurology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Siguang Li
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
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17
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Sergi D, Boulestin H, Campbell FM, Williams LM. The Role of Dietary Advanced Glycation End Products in Metabolic Dysfunction. Mol Nutr Food Res 2020; 65:e1900934. [PMID: 32246887 DOI: 10.1002/mnfr.201900934] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 03/09/2020] [Indexed: 12/13/2022]
Abstract
Advanced glycation end products (AGEs) are a heterogeneous group of molecules produced, non-enzymatically, from the interaction between reducing sugars and the free amino groups of proteins, nucleic acids, and lipids. AGEs are formed as a normal consequence of metabolism but can also be absorbed from the diet. They have been widely implicated in the complications of diabetes affecting cardiovascular health, the nervous system, eyes, and kidneys. Increased levels of AGEs are also detrimental to metabolic health and may contribute to the metabolic abnormalities induced by the Western diet, which is high in processed foods and represents a significant source of AGEs. While increased AGE levels are a consequence of diabetic hyperglycaemia, AGEs themselves activate signaling pathways, which compromise insulin signaling and pancreatic β-cell function, thus, contributing to the development of type 2 diabetes mellitus (T2DM). Furthermore, AGEs may also contribute to the obesogenic effects of the Western diet by promoting hypothalamic inflammation and disrupting the central control of energy balance. Here, the role of dietary AGEs in metabolic dysfunction is reviewed with a focus on the mechanisms underpinning their detrimental role in insulin resistance, pancreatic β-cell dysfunction, hypothalamic control of energy balance, and the pathogenesis of T2DM and obesity.
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Affiliation(s)
- Domenico Sergi
- Nutrition and Health Substantiation Group, Nutrition and Health Program, Health and Biosecurity, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Adelaide, SA, 5000, Australia.,Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5000, Australia
| | - Hakim Boulestin
- Rowett Institute, University of Aberdeen, Aberdeen, AB25 2ZD, UK
| | - Fiona M Campbell
- Rowett Institute, University of Aberdeen, Aberdeen, AB25 2ZD, UK
| | - Lynda M Williams
- Rowett Institute, University of Aberdeen, Aberdeen, AB25 2ZD, UK
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18
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Menon K, Marquina C, Liew D, Mousa A, de Courten B. Histidine-containing dipeptides reduce central obesity and improve glycaemic outcomes: A systematic review and meta-analysis of randomized controlled trials. Obes Rev 2020; 21:e12975. [PMID: 31828942 DOI: 10.1111/obr.12975] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/06/2019] [Accepted: 10/15/2019] [Indexed: 12/21/2022]
Abstract
Supplementation with histidine-containing dipeptides has been shown to improve obesity and glycaemic outcomes in animal and human studies. We conducted a systematic review and meta-analysis of randomized controlled trials to examine these effects. Electronic databases were searched investigating the effects of histidine-containing dipeptides supplementation on anthropometric and glycaemic outcomes. Meta-analyses were performed using random-effects models to calculate the weighted mean difference and 95% confidence interval. There were 30 studies for the systematic review and 23 studies pooled for meta-analysis. Histidine-containing dipeptide groups had a lower waist circumference (WMD [95% CI] = -3.53 cm [-5.65, -1.41], p = 0.001) and HbA1c level (WMD [95% CI] = -0.76% (8.5 mmol/mol) [-1.29% (14.3 mmol/mol), -0.24% (2.8 mmol/mol)], p = 0.004) at follow-up compared with controls. In sensitivity analyses of studies with low risk of bias, waist circumference, HbA1c, and fasting glucose levels (WMD [95% CI] = -0.63 mmol/L [-1.09, -0.18], p = 0.006) were significantly lower in intervention groups versus controls. There was also a trend toward lower fat mass (p = 0.09), insulin resistance (p = 0.07), and higher insulin secretion (p = 0.06) in intervention versus control groups. Supplementation with histidine-containing dipeptides may reduce central obesity and improve glycaemic outcomes. Further studies exploring histidine-containing dipeptide use in obesity and diabetes prevention and treatment are warranted.
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Affiliation(s)
- Kirthi Menon
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Clara Marquina
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Danny Liew
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Aya Mousa
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Barbora de Courten
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
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19
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Hypoglycemic activity of Phaseolus vulgaris (L.) aqueous extract in type 1 diabetic rats. CURRENT ISSUES IN PHARMACY AND MEDICAL SCIENCES 2019. [DOI: 10.2478/cipms-2019-0036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
The aim of the present study was to evaluate the hypoglycemic activity of the aqueous extract from the fruit walls of Phaseolus vulgaris pods and to examine the potential mechanism underlying the improvement of the glycemic level. In the course of the study, diabetes mellitus was induced in rats with a single intraperitoneal injection of streptozotocin (45 mg·kg−1 b.w.). Diabetic and control rats were then orally administered with a single-dose or repeated-dose (28 day) of P. vulgaris extract (200 mg·kg−1). Results show that the extract was found to possess significant hypoglycemic activity, and the study of glucose utilization by isolated rat hemidiaphragm suggests that the aqueous extract may enhance the peripheral utilization of glucose. The subsequent experiments have revealed that the P. vulgaris extract could increase glucose transporter 4 (GLUT-4) content in skeletal muscle cells of control and diabetic rats. Our data also indicate that the P. vulgaris extract did not affect the content of the insulin receptor, but significantly reduced the total tyrosine kinase activity in skeletal muscle cells of both experimental groups of rats. The present results clearly indicated that P. vulgaris extract may be beneficial for reducing hyperglycemia through its potency in regulation of glucose utilization via GLUT-4, but the current mechanism remains to be unidentified.
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20
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Comparison of Corneal Parameters of Children with Diabetes Mellitus and Healthy Children. J Ophthalmol 2019; 2019:2037072. [PMID: 31781373 PMCID: PMC6875226 DOI: 10.1155/2019/2037072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 09/20/2019] [Indexed: 12/05/2022] Open
Abstract
Purpose To compare differences in central corneal thickness (CCT), corneal curvature, and other corneal measurements of children with diabetes mellitus (DM) and healthy children, and to investigate related factors. Methods This was a case-control study. From January to February 2018, 50 children with diabetes mellitus were selected as a case group, and 46 healthy children and adolescents without diabetes mellitus were selected as a control group. Corneal topography and CCT were analyzed using a corneal topography measuring apparatus and biometrics (IOL Master). In the diabetic group, we analyzed whether age, course of disease, sex, glycosylated hemoglobin, triglyceride level, total cholesterol, body mass index (BMI), parental BMI, birth history, feeding history, pregnancy, or puerperal history were related to corneal morphology. Results There was a significant difference in CCT between groups, but no significant differences were found in corneal diameter, corneal curvature R1 or R2, or corneal topography. Central corneal thickness was not correlated with other clinical factors in the diabetes group. Conclusion Early screening and close follow-up of keratopathy in children with diabetes are imperative.
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Andreeva–Gateva PA, Mihaleva ID, Dimova II. Type 2 diabetes mellitus and cardiovascular risk; what the pharmacotherapy can change through the epigenetics. Postgrad Med 2019; 132:109-125. [DOI: 10.1080/00325481.2019.1681215] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Pavlina A. Andreeva–Gateva
- Department of Pharmacology and Toxicology, Faculty of Medicine, Medical University of Sofia, Sofia, Bulgaria
- Department of Pharmacology, Medical Faculty, Sofia University “St Kliment Ohridski”, Sofia, Bulgaria
| | - Ivelina D. Mihaleva
- Department of Pharmacology and Toxicology, Faculty of Medicine, Medical University of Sofia, Sofia, Bulgaria
| | - Ivanka I. Dimova
- Department of Medical Genetics, Faculty of Medicine, Medical University of Sofia, Sofia, Bulgaria
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22
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Adachi N, Kanazawa I, Tanaka KI, Takeno A, Notsu M, Tanaka S, Sugimoto T. Insulin-Like Growth Factor-I Protects Against the Detrimental Effects of Advanced Glycation End Products and High Glucose in Myoblastic C2C12 Cells. Calcif Tissue Int 2019; 105:89-96. [PMID: 30809689 DOI: 10.1007/s00223-019-00537-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 02/19/2019] [Indexed: 12/14/2022]
Abstract
Previous studies suggested that advanced glycation end products (AGEs) and insulin-like growth factor-I (IGF-I) are involved in the mechanism of diabetes-induced sarcopenia. In this study, we examined effects of treatments with AGEs and/or IGF-I for 24 h on myogenic differentiation and apoptosis in mouse myoblastic C2C12 cells. Real-time PCR and Western blot were performed to investigate mRNA and protein expressions, and apoptosis was examined by using a DNA fragment detection ELISA kit. AGE3 significantly decreased mRNA and protein expressions of MyoD and Myogenin, whereas IGF-I significantly increased them and attenuated the effects of AGE3. AGEs significantly decreased endogenous IGF-I mRNA expression and suppressed IGF-I-induced Akt activation. High glucose (22 mM) significantly increased mRNA expression of Rage, a receptor for AGEs, while IGF-I significantly decreased it. DNA fragment ELISA showed that AGE2 and AGE3 significantly increased apoptosis of C2C12 cells, whereas IGF-I significantly suppressed the AGE2- and AGE3-induced apoptosis. In contrast, high glucose enhanced AGE3-induced apoptosis. IGF-I significantly attenuated the effects of high glucose plus AGE3 on the mRNA and protein expressions of MyoD and Myogenin as well as the apoptosis. These findings indicate that AGEs inhibit myogenic differentiation and increase apoptosis in C2C12 cells, and that high glucose increases RAGE and enhances the AGE3-induced apoptosis, suggesting that AGEs and high glucose might contribute to the reduction of muscle mass and function. Moreover, IGF-I attenuated the detrimental effects of AGEs and high glucose in myoblastic cells; thus, IGF-I-Akt signal could be a therapeutic target of DM-induced sarcopenia.
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Affiliation(s)
- Naoko Adachi
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
| | - Ippei Kanazawa
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.
| | - Ken-Ichiro Tanaka
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
| | - Ayumu Takeno
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
| | - Masakazu Notsu
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
| | - Sayuri Tanaka
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
| | - Toshitsugu Sugimoto
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
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Wang T, Liu Y, Huang C, Mansai HAA, Wei W, Zhang X, Li X, Liu S, Yang S. Puerarin promotes MIN6 cell survival by reducing cellular reactive oxygen species. Mol Med Rep 2018; 17:7281-7286. [PMID: 29568901 DOI: 10.3892/mmr.2018.8731] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2017] [Accepted: 07/25/2017] [Indexed: 11/05/2022] Open
Abstract
Type 1 diabetes is caused by destruction of the pancreatic β‑cells and, to date, no cure has been developed. Promoting the survival of pancreatic β‑cells may be beneficial for patients with type 1 diabetes. Puerarin is an estrogen analogue that been demonstrated in previous studies to be able to decreased blood glucose in patients with type 1 diabetes. Similar results were demonstrated in previous studies which additionally demonstrated that puerarin was able to decreased blood glucose in type 1 diabetic mice by protecting pancreatic β‑cells. However, the mechanism underlying the function of puerarin in pancreatic β‑cells remains unclear. Therefore, the present study sought to investigate the detailed function of puerarin in pancreatic β‑cells. In the present study, H2O2 was used to induce apoptosis. It was observed that puerarin significantly decreased H2O2‑induced apoptosis in mouse insulinoma MIN6 cells. It was additionally observed that puerarin decreased the levels of intracellular reactive oxygen species and mitochondrial superoxide in MIN6 cells. The protective effect of puerarin was markedly decreased by 6‑aminonicotinamide, an inhibitor of glucose‑6‑phosphate dehydrogenase (G6PD). In conclusion, the results of the present study suggested that puerarin may increase the activity of G6PD, decreased the level of oxidative stress in MIN6 cells, protect mitochondria and promote MIN6 cell survival. Investigating the mechanism underlying the effect of puerarin in MIN6 cells may provide a novel approach for development of a cure for type 1 diabetes.
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Affiliation(s)
- Tianxi Wang
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Yijie Liu
- Division of Gastroenterology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Caoxin Huang
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Hussen Amir Ahmed Mansai
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Wenjing Wei
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Xiaofang Zhang
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Xuejun Li
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Suhuan Liu
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Shuyu Yang
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China
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The pathological role of advanced glycation end products-downregulated heat shock protein 60 in islet β-cell hypertrophy and dysfunction. Oncotarget 2018; 7:23072-87. [PMID: 27056903 PMCID: PMC5029611 DOI: 10.18632/oncotarget.8604] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 03/29/2016] [Indexed: 01/09/2023] Open
Abstract
Heat shock protein 60 (HSP60) is a mitochondrial chaperone. Advanced glycation end products (AGEs) have been shown to interfere with the β-cell function. We hypothesized that AGEs induced β-cell hypertrophy and dysfunction through a HSP60 dysregulation pathway during the stage of islet/β-cell hypertrophy of type-2-diabetes. We investigated the role of HSP60 in AGEs-induced β-cell hypertrophy and dysfunction using the models of diabetic mice and cultured β-cells. Hypertrophy, increased levels of p27Kip1, AGEs, and receptor for AGEs (RAGE), and decreased levels of HSP60, insulin, and ATP content were obviously observed in pancreatic islets of 12-week-old db/db diabetic mice. Low-concentration AGEs significantly induced the cell hypertrophy, increased the p27Kip1 expression, and decreased the HSP60 expression, insulin secretion, and ATP content in cultured β-cells, which could be reversed by RAGE neutralizing antibody. HSP60 overexpression significantly reversed AGEs-induced hypertrophy, dysfunction, and ATP reduction in β-cells. Oxidative stress was also involved in the AGEs-decreased HSP60 expression in β-cells. Pancreatic sections from diabetic patient showed islet hypertrophy, increased AGEs level, and decreased HSP60 level as compared with normal subject. These findings highlight a novel mechanism by which a HSP60-correlated signaling pathway contributes to the AGEs-RAGE axis-induced β-cell hypertrophy and dysfunction under diabetic hyperglycemia.
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25
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Age-related oxidative changes in pancreatic islets are predominantly located in the vascular system. Redox Biol 2017; 15:387-393. [PMID: 29331666 PMCID: PMC5772008 DOI: 10.1016/j.redox.2017.12.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Revised: 12/27/2017] [Accepted: 12/28/2017] [Indexed: 12/20/2022] Open
Abstract
Aged tissues usually show a decreased regenerative capacity accompanied by a decline in functionality. During aging pancreatic islets also undergo several morphological and metabolic changes. Besides proliferative and regenerative limitations, endocrine cells lose their secretory capacity, contributing to a decline in functional islet mass and a deregulated glucose homeostasis. This is linked to several features of aging, such as induction of cellular senescence or the formation of modified proteins, such as advanced glycation end products (AGEs) - the latter mainly examined in relation to hyperglycemia and in disease models. However, age-related changes of endocrine islets under normoglycemic and non-pathologic conditions are poorly investigated. Therefore, a characterization of pancreatic tissue sections as wells as plasma samples of wild-type mice (C57BL/6J) at various age groups (2.5, 5, 10, 15, 21 months) was performed. Our findings reveal that mice at older age are able to secret sufficient amounts of insulin to maintain normoglycemia. During aging the pancreatic islet area increased and the islet size doubled in 21 months old mice when compared to 2.5 months old mice, whereas the islet number was unchanged. This was accompanied by an age-dependent decrease in Ki-67 levels and pancreatic duodenal homeobox-1 (PDX-1), indicating a decline in proliferative and regenerative capacity of pancreatic islets with advancing age. In contrast, the number of p16Ink4a-positive nuclei within the islets was elevated starting from 10 months of age. Interestingly, AGEs accumulated exclusively in the islet blood vessels of old mice associated with increased amounts of inflammatory markers, such as the inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT). In summary, the age-related increase in islet size and area was associated with the induction of senescence, accompanied by an accumulation of non-enzymatically modified proteins in the islet vascular system.
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Impact of intracellular glyceraldehyde-derived advanced glycation end-products on human hepatocyte cell death. Sci Rep 2017; 7:14282. [PMID: 29079763 PMCID: PMC5660208 DOI: 10.1038/s41598-017-14711-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 10/16/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocyte cell death is a key feature of nonalcoholic steatohepatitis (NASH); however, the pathogenesis of NASH currently remains unclear. We aimed to investigate the effects of intracellular glyceraldehyde (GA)-derived advanced glycation end-products (GA-AGEs) on human hepatocyte cell death. The accumulation of intracellular GA-AGEs has been associated with the induction of DNA damage and hepatocyte necrotic cell death. Among intracellular GA-AGEs, caspase-3 has been identified as a GA-AGE-modified protein with abrogated protein function. Furthermore, the activation of caspase-3 and induction of hepatocyte apoptosis by camptothecin, a DNA-damaging agent, was suppressed by a treatment with GA. These results suggest the inhibitory effects of GA-AGE-modified caspase-3 on the induction of DNA-damage-induced apoptosis, which is associated with hepatocyte necrosis. Therefore, the suppression of necrosis, the inflammatory form of cell death, by the accumulation of GA-AGEs and GA-AGE-modified caspase-3 may represent a novel therapeutic target for the pathogenesis of NASH.
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TRB3 mediates advanced glycation end product-induced apoptosis of pancreatic β-cells through the protein kinase C β pathway. Int J Mol Med 2017; 40:130-136. [PMID: 28534945 PMCID: PMC5466392 DOI: 10.3892/ijmm.2017.2991] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 05/05/2017] [Indexed: 12/29/2022] Open
Abstract
Advanced glycation end products (AGEs), which accumulate in the body during the development of diabetes, may be one of the factors leading to pancreatic β-cell failure and reduced β-cell mass. However, the mechanisms responsible for AGE‑induced apoptosis remain unclear. This study identified the role and mechanisms of action of tribbles homolog 3 (TRB3) in AGE-induced β-cell oxidative damage and apoptosis. Rat insulinoma cells (INS-1) were treated with 200 µg/ml AGEs for 48 h, and cell apoptosis was then detected by TUNEL staining and flow cytometry. The level of intracellular reactive oxygen species (ROS) was measured by a fluorescence assay. The expression levels of receptor of AGEs (RAGE), TRB3, protein kinase C β2 (PKCβ2) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) were evaluated by RT-qPCR and western blot analysis. siRNA was used to knockdown TRB3 expression through lipofection, followed by an analysis of the effects of TRB3 on PKCβ2 and NOX4. Furthermore, the PKCβ2-specific inhibitor, LY333531, was used to analyze the effects of PKCβ2 on ROS levels and apoptosis. We found that AGEs induced the apoptosis of INS-1 cells and upregulated RAGE and TRB3 expression. AGEs also increased ROS levels in β-cells. Following the knockdown of TRB3, the AGE-induced apoptosis and intracellular ROS levels were significantly decreased, suggesting that TRB3 mediated AGE-induced apoptosis. Further experiments demonstrated that the knockdown of TRB3 decreased the PKCβ2 and NOX4 expression levels. When TRB3 was knocked down, the cells expressed decreased levels of PKCβ2 and NOX4. The PKCβ2‑specific inhibitor, LY333531, also reduced AGE-induced apoptosis and intracellular ROS levels. Taken together, our data suggest that TRB3 mediates AGE-induced oxidative injury in β-cells through the PKCβ2 pathway.
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Reynaert NL, Gopal P, Rutten EP, Wouters EF, Schalkwijk CG. Advanced glycation end products and their receptor in age-related, non-communicable chronic inflammatory diseases; Overview of clinical evidence and potential contributions to disease. Int J Biochem Cell Biol 2016; 81:403-418. [PMID: 27373680 DOI: 10.1016/j.biocel.2016.06.016] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 06/24/2016] [Accepted: 06/28/2016] [Indexed: 12/31/2022]
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Chang CC, Yuan W, Roan HY, Chang JL, Huang HC, Lee YC, Tsay HJ, Liu HK. The ethyl acetate fraction of corn silk exhibits dual antioxidant and anti-glycation activities and protects insulin-secreting cells from glucotoxicity. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 16:432. [PMID: 27809830 PMCID: PMC5294807 DOI: 10.1186/s12906-016-1382-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 10/07/2016] [Indexed: 11/10/2022]
Abstract
BACKGROUND In this study, we aimed to develop a Stigmata Maydis (corn silk) fraction with dual bio-activities against oxidative stress and protein glycation to protect β-cells from diabetes-induced failure. METHODS Corn silk fractions were prepared by partition and chemically characterised by thin-layer chromatography. Free radical scavenging assay, glycation assay, and cell-based viability test (neutral red) were employed to decide the best fraction. Cell death analysis was executed by annexin V/ Propidium iodide staining. Cell proliferation was measured by WST-1. Finally, β-cell function was evaluated by β-cell marker gene expression (RT-PCR) and acute insulin secretion test. RESULTS Four corn silk fractions were prepared from an ethanolic crude extract of corn silk. In vitro assays indicate ethyl acetate fraction (YMS-EA) was the most potent fraction. YMS-EA also attenuated the hydrogen peroxide- or methylglyoxal-induced induction of reactive oxygen species, reduction of cell viability, and inhibition of cell proliferation. However, YMS-EA was unable to prevent hydrogen peroxide-induced apoptosis or advanced glycation end-products-induced toxicity. Under hyperglycemic conditions, YMS-EA effectively reduced ROS levels, improved mRNA expression of insulin, glucokinase, and PDX-1, and enhanced glucose-stimulated insulin secretion. The similarity of bioactivities among apigenin, luteolin, and YMS-EA indicated that dual activities of YMS-EA might be derived from those compounds. CONCLUSIONS We concluded that YMS-EA fraction could be developed as a preventive food agent against the glucotoxicity to β-cells in Type 2 diabetes.
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Affiliation(s)
- Chia-Chuan Chang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC
| | - Wei Yuan
- Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan, ROC
| | - Hsiao-Yuh Roan
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Jia-Ling Chang
- Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan, ROC
| | - Hsiu-Chen Huang
- Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan, ROC
| | - Yu-Ching Lee
- The Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan, ROC
- The Ph.D. Program for Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC
| | - Huey Jen Tsay
- Institute of Neuroscience, Brain Research Centre, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Hui-Kang Liu
- Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan, ROC
- Ph.D Program for the Clinical Drug Discovery from Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei, Taiwan, ROC
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Tago K, Inoue KI, Ouchi M, Miura Y, Kubota K. Receptor for advanced glycation endproducts signaling cascades are activated in pancreatic fibroblasts, but not in the INS1E insulinoma cell line: Are mesenchymal cells major players in chronic inflammation? Islets 2016; 8:135-44. [PMID: 27415824 PMCID: PMC5029201 DOI: 10.1080/19382014.2016.1212146] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
The receptor for advanced glycation endproducts (RAGE) is a pattern recognition receptor that plays an important role in natural immunity. It is suggested that mesenchymal cells are the major players during inflammation. Previously, we reported that advanced glycation end products (AGE), known to be one of the ligands of RAGE, inhibited glucose-induced insulin secretion from ex vivo pancreatic islets, although the mechanism responsible remains largely unknown. In the present study, we examined the cascades operating downstream from RAGE using the insulinoma cell line INS1E and primary-cultured pancreatic fibroblasts as in vitro models for parenchymal (β) cells and mesenchymal cells, respectively. Phosphorylation of c-jun N-terminal kinase, inhibitor of nuclear factor κB kinase, and nuclear factor κB was stimulated by AGE or high mobility group binding 1 (HMGB1) in pancreatic fibroblasts, whereas no such effect was observed in INS1E cells. Expression of the Ccl5, Il-6, and Il-1b genes was increased by AGE/HMGB1 in fibroblasts, but not in INS1E cells. On the other hand, AGE inhibited the secretion of insulin from ex vivo pancreatic islets, and this effect was ameliorated by MK615, a Japanese apricot extract used as an anti-inflammatory agent. Glucose-induced insulin secretion from INS1E cells was not affected by direct administration of AGE/HMGB1, but was inhibited by fibroblast-conditioned medium. These results suggest that AGE suppresses glucose-induced insulin secretion from pancreatic islets through indirect mesenchymal RAGE signaling.
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Affiliation(s)
- Kazuma Tago
- Second Department of Surgery, Dokkyo Medical University, Shimotsuga, Tochigi, Japan
| | - Ken-ichi Inoue
- Center for Research Support, Dokkyo Medical University, Shimotsuga, Tochigi, Japan
| | - Motoshi Ouchi
- Department of Pharmacology and Toxicology, Dokkyo Medical University, Shimotsuga, Tochigi, Japan
| | - Yoshikazu Miura
- Laboratory of International Epidemiology, Dokkyo Medical University, Shimotsuga, Tochigi, Japan
| | - Keiichi Kubota
- Department of Gastroenterological Surgery, Dokkyo Medical University, Shimotsuga, Tochigi, Japan
- CONTACT Keiichi Kubota Department of Gastroenterological Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi, Japan
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Dong X, Zhang T, Liu Q, Zhu J, Zhao J, Li J, Sun B, Ding G, Hu X, Yang Z, Zhang Y, Li L. Beneficial effects of urine-derived stem cells on fibrosis and apoptosis of myocardial, glomerular and bladder cells. Mol Cell Endocrinol 2016; 427:21-32. [PMID: 26952874 DOI: 10.1016/j.mce.2016.03.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 02/17/2016] [Accepted: 03/02/2016] [Indexed: 12/19/2022]
Abstract
Urine-derived stem cells (USCs) are isolated from voided urine and display high proliferative activity and multiple differentiation potentials. The applicability of USCs in the treatment of bladder dysfunction and in cell-based urological tissue engineering has been demonstrated. Whether they could serve as a potential stem cell source for the treatment of diabetes mellitus (DM) and its complications has not been investigated. Here, we report the repairing and protective effects of USCs on pancreatic islets, the myocardium, the renal glomerulus and the bladder detrusor in diabetic rat models. Type 2 diabetic rat models were induced by means of a high fat diet and intraperitoneal injection with streptozotocin. USCs isolated from voided urine were administered via tail veins. The functional changes of pancreatic islets, left ventricle, glomerulus and bladder micturition were assessed by means of insulin tolerance tests, echocardiography, urine biochemical indexes and cystometry. The histologic changes were evaluated by hematoxylin and eosin staining, Masson's trichrome staining and TUNEL staining. Treatment with USCs significantly alleviated the histological destruction and functional decline. Although the USC treatment did not decrease fasting blood glucose to a significantly different level, the fibrosis and apoptosis of the myocardium, glomerulus and detrusor were significantly inhibited. This study indicates that administration of USCs may be useful for the treatment of the complications of DM.
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Affiliation(s)
- Xingyou Dong
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Teng Zhang
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Qian Liu
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Jingzhen Zhu
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Jiang Zhao
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Jia Li
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Bishao Sun
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Guolin Ding
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Xiaoyan Hu
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Zhenxing Yang
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Yuanyuan Zhang
- Wake Forest Institute of Regenerative Medicine, Wake Forest University, Winston Salem, NC, USA
| | - Longkun Li
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China.
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Baye E, Ukropcova B, Ukropec J, Hipkiss A, Aldini G, de Courten B. Physiological and therapeutic effects of carnosine on cardiometabolic risk and disease. Amino Acids 2016; 48:1131-49. [PMID: 26984320 DOI: 10.1007/s00726-016-2208-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 02/25/2016] [Indexed: 12/12/2022]
Abstract
Obesity, type 2 diabetes (T2DM) and cardiovascular disease (CVD) are the most common preventable causes of morbidity and mortality worldwide. They represent major public health threat to our society. Increasing prevalence of obesity and T2DM contributes to escalating morbidity and mortality from CVD and stroke. Carnosine (β-alanyl-L-histidine) is a dipeptide with anti-inflammatory, antioxidant, anti-glycation, anti-ischaemic and chelating roles and is available as an over-the-counter food supplement. Animal evidence suggests that carnosine may offer many promising therapeutic benefits for multiple chronic diseases due to these properties. Carnosine, traditionally used in exercise physiology to increase exercise performance, has potential preventative and therapeutic benefits in obesity, insulin resistance, T2DM and diabetic microvascular and macrovascular complications (CVD and stroke) as well as number of neurological and mental health conditions. However, relatively little evidence is available in humans. Thus, future studies should focus on well-designed clinical trials to confirm or refute a potential role of carnosine in the prevention and treatment of chronic diseases in humans, in addition to advancing knowledge from the basic science and animal studies.
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Affiliation(s)
- Estifanos Baye
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, 43-51 Kanooka Grove, Clayton, Melbourne, VIC, 3168, Australia.,Department of Public Health, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia
| | - Barbara Ukropcova
- Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia.,Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Jozef Ukropec
- Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Alan Hipkiss
- School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Giancarlo Aldini
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Barbora de Courten
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, 43-51 Kanooka Grove, Clayton, Melbourne, VIC, 3168, Australia. .,Diabetes and Vascular Medicine Unit, Monash Health, Clayton, VIC, 3168, Australia.
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You J, Wang Z, Xu S, Zhang W, Fang Q, Liu H, Peng L, Deng T, Lou J. Advanced Glycation End Products Impair Glucose-Stimulated Insulin Secretion of a Pancreatic β-Cell Line INS-1-3 by Disturbance of Microtubule Cytoskeleton via p38/MAPK Activation. J Diabetes Res 2016; 2016:9073037. [PMID: 27635403 PMCID: PMC5011238 DOI: 10.1155/2016/9073037] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 06/30/2016] [Indexed: 12/14/2022] Open
Abstract
Advanced glycation end products (AGEs) are believed to be involved in diverse complications of diabetes mellitus. Overexposure to AGEs of pancreatic β-cells leads to decreased insulin secretion and cell apoptosis. Here, to understand the cytotoxicity of AGEs to pancreatic β-cells, we used INS-1-3 cells as a β-cell model to address this question, which was a subclone of INS-1 cells and exhibited high level of insulin expression and high sensitivity to glucose stimulation. Exposed to large dose of AGEs, even though more insulin was synthesized, its secretion was significantly reduced from INS-1-3 cells. Further, AGEs treatment led to a time-dependent increase of depolymerized microtubules, which was accompanied by an increase of activated p38/MAPK in INS-1-3 cells. Pharmacological inhibition of p38/MAPK by SB202190 reversed microtubule depolymerization to a stabilized polymerization status but could not rescue the reduction of insulin release caused by AGEs. Taken together, these results suggest a novel role of AGEs-induced impairment of insulin secretion, which is partially due to a disturbance of microtubule dynamics that resulted from an activation of the p38/MAPK pathway.
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Affiliation(s)
- Jia You
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Zai Wang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Shiqing Xu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Wenjian Zhang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Qing Fang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Honglin Liu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Liang Peng
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Tingting Deng
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jinning Lou
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
- *Jinning Lou:
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Lan KC, Chiu CY, Kao CW, Huang KH, Wang CC, Huang KT, Tsai KS, Sheu ML, Liu SH. Advanced glycation end-products induce apoptosis in pancreatic islet endothelial cells via NF-κB-activated cyclooxygenase-2/prostaglandin E2 up-regulation. PLoS One 2015; 10:e0124418. [PMID: 25898207 PMCID: PMC4405342 DOI: 10.1371/journal.pone.0124418] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 03/13/2015] [Indexed: 12/23/2022] Open
Abstract
Microvascular complications eventually affect nearly all patients with diabetes. Advanced glycation end-products (AGEs) resulting from hyperglycemia are a complex and heterogeneous group of compounds that accumulate in the plasma and tissues in diabetic patients. They are responsible for both endothelial dysfunction and diabetic vasculopathy. The aim of this study was to investigate the cytotoxicity of AGEs on pancreatic islet microvascular endothelial cells. The mechanism underlying the apoptotic effect of AGEs in pancreatic islet endothelial cell line MS1 was explored. The results showed that AGEs significantly decreased MS1 cell viability and induced MS1 cell apoptosis in a dose-dependent manner. AGEs dose-dependently increased the expressions of cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase in MS1 cells. Treatment of MS1 cells with AGEs also resulted in increased nuclear factor (NF)-κB-p65 phosphorylation and cyclooxygenase (COX)-2 expression. However, AGEs did not affect the expressions of endoplasmic reticulum (ER) stress-related molecules in MS1 cells. Pretreatment with NS398 (a COX-2 inhibitor) to inhibit prostaglandin E2 (PGE2) production reversed the induction of cleaved caspase-3, cleaved PARP, and MS1 cell viability. Moreover, AGEs significantly increased the receptor for AGEs (RAGE) protein expression in MS1 cells, which could be reversed by RAGE neutralizing antibody. RAGE Neutralizing antibody could also reverse the induction of cleaved caspase-3 and cleaved PARP and decreased cell viability induced by AGEs. These results implicate the involvement of NF-κB-activated COX-2/PGE2 up-regulation in AGEs/RAGE-induced islet endothelial cell apoptosis and cytotoxicity. These findings may provide insight into the pathological processes within the pancreatic islet microvasculature induced by AGEs accumulation.
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Affiliation(s)
- Kuo-Cheng Lan
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chen-Yuan Chiu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chia-Wei Kao
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Kuo-How Huang
- Department of Urology, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan
| | - Ching-Chia Wang
- Department of Pediatrics, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan
| | - Kuo-Tong Huang
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Keh-Sung Tsai
- Departments of Laboratory Medicine, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan
| | - Meei-Ling Sheu
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Shing Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Pediatrics, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- * E-mail:
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Nowotny K, Jung T, Höhn A, Weber D, Grune T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 2015; 5:194-222. [PMID: 25786107 PMCID: PMC4384119 DOI: 10.3390/biom5010194] [Citation(s) in RCA: 748] [Impact Index Per Article: 74.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 02/06/2015] [Accepted: 03/02/2015] [Indexed: 12/25/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a very complex and multifactorial metabolic disease characterized by insulin resistance and β cell failure leading to elevated blood glucose levels. Hyperglycemia is suggested to be the main cause of diabetic complications, which not only decrease life quality and expectancy, but are also becoming a problem regarding the financial burden for health care systems. Therefore, and to counteract the continually increasing prevalence of diabetes, understanding the pathogenesis, the main risk factors, and the underlying molecular mechanisms may establish a basis for prevention and therapy. In this regard, research was performed revealing further evidence that oxidative stress has an important role in hyperglycemia-induced tissue injury as well as in early events relevant for the development of T2DM. The formation of advanced glycation end products (AGEs), a group of modified proteins and/or lipids with damaging potential, is one contributing factor. On the one hand it has been reported that AGEs increase reactive oxygen species formation and impair antioxidant systems, on the other hand the formation of some AGEs is induced per se under oxidative conditions. Thus, AGEs contribute at least partly to chronic stress conditions in diabetes. As AGEs are not only formed endogenously, but also derive from exogenous sources, i.e., food, they have been assumed as risk factors for T2DM. However, the role of AGEs in the pathogenesis of T2DM and diabetic complications—if they are causal or simply an effect—is only partly understood. This review will highlight the involvement of AGEs in the development and progression of T2DM and their role in diabetic complications.
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Affiliation(s)
- Kerstin Nowotny
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
| | - Tobias Jung
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
| | - Annika Höhn
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
| | - Daniela Weber
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
| | - Tilman Grune
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
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Sakalauskiene J, Kubilius R, Gleiznys A, Vitkauskiene A, Ivanauskiene E, Šaferis V. Relationship of clinical and microbiological variables in patients with type 1 diabetes mellitus and periodontitis. Med Sci Monit 2014; 20:1871-7. [PMID: 25294115 PMCID: PMC4199460 DOI: 10.12659/msm.890879] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND The aim of the study was to analyze how metabolic control of type 1 diabetes is related to clinical and microbiological periodontal parameters. MATERIAL AND METHODS The study involved 56 subjects aged from 19 to 50 years divided into 2 groups: healthy subjects (the H group), and diabetic (type 1 diabetes) patients with chronic untreated generalized periodontitis (the DM group). The glycosylated hemoglobin value (HbA1c) was determined using the UniCel DxC 800 SYNCHRON System (Beckman Coulter, USA), and the concentration in blood was measured by the turbidimetric immunoinhibition method. A molecular genetic assay (Micro-IDent plus, Germany) was used to detect periodontopathogenic bacteria in plaque samples. Periodontitis was confirmed by clinical and radiological examination. RESULTS Fusobacterium nucleatum, Capnocytophaga species, and Eikenella corrodens were the most frequently found bacteria in dental plaque samples (77.8%, 66.7%, and 33.4%, respectively), whereas Aggregatibacter actinomycetemcomitans was identified 40.7% less frequently in the DM group than in the H group. The strongest relationship was observed between the presence of 2 periodontal pathogens - F. nucleatum and Capnocytophaga spp. - and poorer metabolic control in type 1 diabetes patients (HbA1c) and all clinical parameters of periodontal pathology. CONCLUSIONS Periodontal disease was more evident in type 1 diabetic patients, and the prevalence of periodontitis was greatly increased in subjects with poorer metabolic control.
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Affiliation(s)
- Jurgina Sakalauskiene
- Department of Dental and Maxillofacial Orthopedics, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Ricardas Kubilius
- Department of Maxillofacial Surgery and Surgical Stomatology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Alvydas Gleiznys
- Department of Dental and Maxillofacial Orthopedics, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Astra Vitkauskiene
- Department of Laboratory Medicine, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Egle Ivanauskiene
- Department of Dental and Maxillofacial Orthopedics, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Viktoras Šaferis
- Department of Physics, Mathematics, and Biophysics, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
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Giacconi R, Simm A, Santos AN, Costarelli L, Malavolta M, Mecocci P, Piacenza F, Basso A, Fulop T, Rink L, Dedoussis G, Kanoni S, Herbein G, Jajte J, Mocchegiani E. Influence of +1245 A/G MT1A polymorphism on advanced glycation end-products (AGEs) in elderly: effect of zinc supplementation. GENES AND NUTRITION 2014; 9:426. [PMID: 25149676 DOI: 10.1007/s12263-014-0426-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Accepted: 08/09/2014] [Indexed: 11/25/2022]
Abstract
Advanced glycation end-products (AGEs) stimulate reactive oxygen species (ROS) generation and represent a risk factor for atherosclerosis, while their formation seems to be prevented by zinc. Metallothioneins (MT), zinc-binding proteins exert an antioxidant function by regulating intracellular zinc availability and protecting cells from ROS damages. +1245 A/G MT1A polymorphism was implicated in type 2 diabetes and in cardiovascular disease development as well as in the modulation of antioxidant response. The purpose of this study was to investigate the influence of +1245 A/G MT1A polymorphism on AGEs and ROS production and to verify the effect of zinc supplementation on plasma AGEs, zinc status parameters and antioxidant enzyme activity in relation to this SNP. One hundred and ten healthy subjects (72 ± 6 years) from the ZincAge study were supplied with zinc aspartate (10 mg/day for 7 weeks) and screened for +1245 MT1A polymorphism. +1245 MT1A G+ (Arginine) genotype showed higher plasma AGEs and ROS production in peripheral blood mononuclear cells (PBMCs) than G- (Lysine) one at the baseline. No significant changes after zinc supplementation were observed for AGEs, ROS and MT levels as well as for enzyme antioxidant activity in relation to the genotype. Among zinc status parameters, major increases were observed for the intracellular labile zinc (iZnL) and the NO-induced release of zinc in PBMCs, in G+ genotype as compared to G- one. In summary, +1245 G+ carriers showed increased plasma AGEs and ROS production in PBMCs at baseline and a higher improvement in iZnL after zinc intervention with respect to G- individuals.
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Affiliation(s)
- Robertina Giacconi
- Translation Research Center of Nutrition and Ageing, Italian National Research Centre on Aging (INRCA-IRCCS), Via Birarelli 8, 60121, Ancona, Italy,
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Boesten DMPHJ, Elie AGIM, Drittij-Reijnders MJ, den Hartog GJM, Bast A. Effect of Nɛ-carboxymethyllysine on oxidative stress and the glutathione system in beta cells. Toxicol Rep 2014; 1:973-980. [PMID: 28962310 PMCID: PMC5598217 DOI: 10.1016/j.toxrep.2014.06.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Revised: 06/19/2014] [Accepted: 06/20/2014] [Indexed: 11/25/2022] Open
Abstract
One of the pathways involved in the pathogenesis of diabetic complications is the formation of excessive levels of advanced glycation end (AGE) products. Nɛ-carboxymethyllysine (CML) is one of the best-characterized AGEs. Because little is known about the effects of AGEs on pancreatic beta cells, we investigated the effect of CML on human pancreatic cells and determined the activity and gene expression of glutathione system components. CML at a concentration of 0.5 mM induced cell death in human pancreatic beta cells, which was accompanied by increased intracellular oxidative stress. No changes in the gene expression of the receptor for AGEs (RAGE) were found, although an increase in the level of a target cytokine of RAGE after CML exposure was observed. Additionally we found that CML lowered the levels of GSH and affected the activity and expression of other components of the glutathione system. These changes indicate that the cells are even more vulnerable for oxidative stress after exposure to CML. Since beta cells are low in antioxidant enzymes and repair for oxidized DNA, CML, but most likely also other AGEs, accelerates beta cell dysfunction and increases beta cell death during chronic hyperglycemia.
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Affiliation(s)
| | - Atlanta G I M Elie
- Department of Toxicology, Maastricht University, Maastricht, The Netherlands
| | | | | | - Aalt Bast
- Department of Toxicology, Maastricht University, Maastricht, The Netherlands
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Shang SW, Yang JL, Huang F, Liu K, Liu BL. Modified Si-Miao-San ameliorates pancreatic B cell dysfunction by inhibition of reactive oxygen species-associated inflammation through AMP-kinase activation. Chin J Nat Med 2014; 12:351-60. [PMID: 24856758 DOI: 10.1016/s1875-5364(14)60043-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2013] [Indexed: 11/16/2022]
Abstract
AIM To observe the effect of modified Si-Miao-San (mSMS) on advanced glycation end products (AGEs)-induced pancreatic B cell dysfunction, as well as examining the underlying mechanisms. METHOD Pancreatic B cells (INS-1) were stimulated with advanced glycation end products (AGEs, 200 μg·mL(-1)) for 24 h to produce dysfunction in pancreatic B cells and the effects of mSMS observed on insulin secretion, NF-κB (p65) phosphorylation, reactive oxygen species (ROS) production, mitochondria membrane potential (Δψm), cell apoptosis, phosphorylation of AMP-kinase (AMPK), and caspase 3 activity. RESULTS The AGEs challenge resulted in increased basal insulin secretion, but decreased insulin secretion in response to high glucose, whereas this situation was reversed by mSMS treatment. AGEs stimulation induced NF-κB (p65) phosphorylation and reactive oxygen species (ROS) production, as well as Δψm collapse and cell apoptosis. mSMS inhibited ROS production and inhibited NF-κB activation by attenuating p65 phosphorylation. Meanwhile, AGEs-induced Δψm collapse and cell apoptosis were also reversed by mSMS treatment. Compound C, an inhibitor of AMP-Kinase (AMPK), abolished the beneficial effects of mSMS on the regulation of B cell function, indicating the involvement of AMPK. CONCLUSION mSMS ameliorated AGEs-induced B cell dysfunction by suppressing ROS-associated inflammation, and this action was related to its beneficial regulation of AMPK activity.
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Affiliation(s)
- Shu-Wan Shang
- State key laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 211198, China
| | - Jiang-Lin Yang
- State key laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 211198, China
| | - Fang Huang
- State key laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 211198, China
| | - Kang Liu
- State key laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 211198, China; Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicines, Nanjing 210046, China
| | - Bao-Lin Liu
- State key laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 211198, China; Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicines, Nanjing 210046, China.
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Gutierrez RMP, Flores JMM. Effect of chronic administration of hexane extract of Byrsonima crassifolia seed on B-cell and pancreatic oxidative parameters in streptozotocin-induced diabetic rat. AFRICAN JOURNAL OF TRADITIONAL, COMPLEMENTARY, AND ALTERNATIVE MEDICINES 2014; 11:231-6. [PMID: 25435601 DOI: 10.4314/ajtcam.v11i2.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND In Mexican traditional medicine, the seeds of Byrsonima crassifolia have been used in the treatment of diabetes, rheumatism and for wound healing. The aim was to evaluate the effect of seeds of B. crassifolia on insulin release from the pancreatic beta cells in streptozotocininduced diabetic rats. MATERIALS AND METHODS In the present study, we evaluated the beneficial effect of seeds B. crassifolia streptozotocin-induced type 1 diabetic rats. Insulin level; insulin sensitivity index, insulin content in pancreas, malonaldehyde, nitric oxide contents, oxidative stress parameters were assayed. Serum glucose levels were determined by the glucose oxidase method. To determine the insulin releasing activity, after extract treatment, the pancreas was excised. Pancreatic sections were processed for examination of insulin-releasing activity using an imunocytochemistry kit. RESULTS Administration of the hexane extract (200 and 400 mg/kg), exhibited a significant reduction in serum glucose. Administration of streptozotocin decreased the number of beta cells with insulin secretory activity in comparison with intact rats; but treatment with the B. crassifolia seed extract increased significantly the activity of the beta cells in comparison with the diabetic control rats. The extract decreased serum glucose in streptozotocin-induced diabetic rats and increased insulin release from the beta cells of the pancreas. CONCLUSION These finding suggest that B. crassifolia seed has beneficial effect for diabetes through decreasing blood glucose and lipid levels, increasing insulin sensitivity index and insulin content, up-regulating antioxidant enzyme activity and decreasing lipid peroxidation.
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Affiliation(s)
- Rosa Martha Perez Gutierrez
- Laboratory for Research on Natural Products, School of Chemical Engineering and Extractive Industries-IPN. Av. Instituto Politécnico Nacional, Unidad Profesional Adolfo Lopez Mateos CP 07758, Mexico D.F
| | - Jose Maria Mota Flores
- Laboratory for Research on Natural Products, School of Chemical Engineering and Extractive Industries-IPN. Av. Instituto Politécnico Nacional, Unidad Profesional Adolfo Lopez Mateos CP 07758, Mexico D.F
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Godoy-Matos AF. The role of glucagon on type 2 diabetes at a glance. Diabetol Metab Syndr 2014; 6:91. [PMID: 25177371 PMCID: PMC4148933 DOI: 10.1186/1758-5996-6-91] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Accepted: 08/20/2014] [Indexed: 12/25/2022] Open
Abstract
The opposite effects of insulin and glucagon in fuel homeostasis, the paracrine/endocrine inhibitory effects of insulin on glucagon secretion and the hyperglucagonemia in the pathogenesis of type 2 diabetes (T2D) have long been recognized. Inappropriately increased alpha-cell function importantly contributes to hyperglycemia and reflects the loss of tonic restraint normally exerted by high local concentrations of insulin on alpha-cells, possibly as a result of beta-cell failure and alpha-cell insulin resistance, but additional mechanisms, such as the participation of incretin hormones in this response, have also been suggested. Three classes of drugs already available for clinical use address the abnormalities of glucagon secretion in T2D, namely, the GLP-1 receptor agonists (GLP-1RA), the inhibitors of dipeptidyl peptidase-4 (DPP-4i) and the amylin agonist pramlintide; it has been proposed that the glucagonostatic and insulinotropic effects of GLP-1RA equally contribute to their hypoglycemic efficacy. In this review, the control of glucagon secretion and its participation in T2D pathogenesis are summarized.
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Affiliation(s)
- Amélio F Godoy-Matos
- Metabolism Unit, Instituto Estadual de Diabetes e Endocrinologia, Rio de Janeiro and Catholic University, Rio de Janeiro, Brazil
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42
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Bullon P, Newman HN, Battino M. Obesity, diabetes mellitus, atherosclerosis and chronic periodontitis: a shared pathology via oxidative stress and mitochondrial dysfunction? Periodontol 2000 2013; 64:139-53. [DOI: 10.1111/j.1600-0757.2012.00455.x] [Citation(s) in RCA: 192] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Cheng AS, Cheng YH, Chang TL. Resveratrol protects RINm5F pancreatic cells from methylglyoxal-induced apoptosis. J Funct Foods 2013. [DOI: 10.1016/j.jff.2013.07.021] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
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Gutierrez RMP. Effect of the hexane extract of Piper auritum on insulin release from β-cell and oxidative stress in streptozotocin-induced diabetic rat. Pharmacogn Mag 2013; 8:308-13. [PMID: 24082635 PMCID: PMC3785169 DOI: 10.4103/0973-1296.103661] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Revised: 01/21/2012] [Accepted: 11/22/2012] [Indexed: 12/01/2022] Open
Abstract
Background: The large-leafed perennial plant Piper auritum known as Hoja Santa, is used for its leaves that because of their spicy aromatic scent and flavor have an important presence in Mexican cuisine, and in many regions, this plant is known for its therapeutic properties. Materials and Methods: In the present study, we investigated the effect of hexane, chloroform and methanol extracts from Piper auritum on cell culture system and the effect in streptozotocin-induced type 1 diabetic rats treated by 28 days on the physiological, metabolic parameters and oxidative stress. Results: The hexane extract of P. auritum (HS) treatment significantly reduced the intake of both food, water and body weight loss as well as levels of blood glucose, serum cholesterol, triglycerides and increase HDL-cholesterol. After 4-week administration of HS antioxidant enzyme as SOD, CAT, GSH, GPx in pancreas were determined. These enzyme increased significantly compared with those of the diabetic rats control and normal animals. For all estimated, the results of HS treated groups leading to a restoration of the defense mechanism. The treatment also improves pancreatic TBARS–reactive substance level and serum NO and iNOS. To determine the insulin releasing activity, after extract treatment the serum and pancreatic sections were processed for examination of insulin-releasing activity using an immunocytochemistry kit. The results showed that administration of the hexane extract (200 and 400 mg/kg) exhibited a significant increase in serum and pancreas tissue insulin. Administration of streptozotocin decreased the insulin secretory activity in comparison with intact rats, but treatment with the HS extract increased significantly the activity of the beta cells in comparison with the diabetic control rats. The extract decreased serum glucose in streptozotocin-induced diabetic rats and increased insulin release from the beta cells of the pancreas. In cultured RIN-5F cells, we examined whether hexane extract of P. auritum would protect the pancreas-derived β-cells from oxidative stress. Moreover, HS could protect pancreatic β-cells from advanced glycation end products-induced oxidative stress. Conclusion: From these results, HS is suggested to show anti-diabetic effect by stimulating insulin-dependent and by protecting pancreatic β-cells from advanced glycation end products-induced oxidative stress.
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Affiliation(s)
- Rosa Martha Perez Gutierrez
- Laboratory of Natural Products Research, School of Chemical Engineering and Extractive Industries, IPN Avenue, National Polytechnic Institute S/N, Col Zacatenco, cp 07758. Maxico D.F
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45
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Feng L, Zhu M, Zhang M, Gu J, Jia X, Tan X, Gao C, Zhu Q. The protection of 4,4′-diphenylmethane-bis(methyl) carbamate from Cortex Mori on advanced glycation end product-induced endothelial dysfunction: Via inhibiting AGE formation or blocking AGEs–RAGE axis? Fitoterapia 2013; 89:239-49. [DOI: 10.1016/j.fitote.2013.06.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2013] [Revised: 05/25/2013] [Accepted: 06/01/2013] [Indexed: 10/26/2022]
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Song YM, Song SO, You YH, Yoon KH, Kang ES, Cha BS, Lee HC, Kim JW, Lee BW. Glycated albumin causes pancreatic β-cells dysfunction through autophagy dysfunction. Endocrinology 2013; 154:2626-39. [PMID: 23698718 DOI: 10.1210/en.2013-1031] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Growing evidence suggests that advanced glycation end-products (AGEs) are cytotoxic to pancreatic β-cells. The aims of this study were to investigate whether glycated albumin (GA), an early precursor of AGEs, would induce dysfunction in pancreatic β-cells and to determine which kinds of cellular mechanisms are activated in GA-induced β-cell apoptosis. Decreased viability and increased apoptosis were induced in INS-1 cells treated with 2.5 mg/mL GA under 16.7mM high-glucose conditions. Insulin content and glucose-stimulated secretion from isolated rat islets were reduced in 2.5 mg/mL GA-treated cells. In response to 2.5 mg/mL GA in INS-1 cells, autophagy induction and flux decreased as assessed by green fluorescent protein-microtubule-associated protein 1 light chain 3 dots, microtubule-associated protein 1 light chain 3-II conversion, and SQSTM1/p62 in the presence and absence of bafilomycin A1. Accumulated SQSTM1/p62 through deficient autophagy activated the nuclear factor-κB (p65)-inducible nitric oxide synthase-caspase-3 cascade, which was restored by treatment with small interfering RNA against p62. Small interfering RNA treatment against autophagy-related protein 5 significantly inhibited the autophagy machinery resulting in a significant increase in iNOS-cleaved caspase-3 expression. Treatment with 500μM 4-phenyl butyric acid significantly alleviated the expression of endoplasmic reticulum stress markers and iNOS in parallel with upregulated autophagy induction. However, in the presence of bafilomycin A1, the decreased viability of INS-1 cells was not recovered. Glycated albumin, an early precursor of AGE, caused pancreatic β-cell death by inhibiting autophagy induction and flux, resulting in nuclear factor-κB (p65)-iNOS-caspase-3 cascade activation as well as by increasing susceptibility to endoplasmic reticulum stress and oxidative stress.
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Affiliation(s)
- Young Mi Song
- Brain Korea 21 Project for Medical Science, Seoul 120-752, Korea
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Costal F, Oliveira E, Raposo A, Machado-Lima A, Peixoto E, Roma L, Santos L, Lopes Faria JB, Carpinelli AR, Giannella-Neto D, Passarelli M, Correa-Giannella ML. Dual effect of advanced glycation end products in pancreatic islet apoptosis. Diabetes Metab Res Rev 2013; 29:296-307. [PMID: 23315923 DOI: 10.1002/dmrr.2390] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Accepted: 12/18/2012] [Indexed: 12/26/2022]
Abstract
BACKGROUND Loss of β-cell function hastens deterioration of metabolic control in type 2 diabetes patients. Besides amyloid deposit and glucolipotoxicity, advanced glycation end products (AGEs) acting through their receptors (RAGE) seem to contribute to this process by promoting islet apoptosis. In order to investigate the role of AGEs in β-cell deterioration, we evaluated the temporal and dose effects of AGE compounds on apoptosis rate, reactive oxygen species generation and expression of pro-apoptotic and anti-apoptotic genes in cultured islets. METHODS Rat pancreatic islets were exposed or not for 24, 48, 72 and 96 h to albumin modified by glycoaldehyde. Apoptosis, reactive oxygen species and superoxide content and NADPH oxidase activity were evaluated as well as RNA expression of the genes Ager (codes for RAGE), Bax, Bcl2 and Nfkb1. RESULTS In 24 and 48 h, glycoaldehyde elicited a decrease in apoptosis rate in comparison with the control condition concomitantly with a reduction in Bax/Bcl2 RNA ratio and in Nfkb1 RNA expression. In contrast, after 72 and 96 h, glycoaldehyde promoted an increase in apoptosis rate concomitantly with an increase in Bax/Bcl2 RNA ratio and in Nfkb1 RNA expression. In 24 h, glycoaldehyde elicited a decrease in the islet content of reactive oxygen species, whereas after 48 and 72 h, it promoted an opposite effect, increasing superoxide generation. The NADPH oxidase inhibitor VAS2870 attenuated superoxide production, implicating NADPH oxidase as an important source of reactive oxygen species in islets exposed to AGEs. CONCLUSIONS Albumin modified by glycoaldehyde exerted a dual effect in cultured pancreatic islets, being protective against apoptosis after short exposure but pro-apoptotic after prolonged exposure.
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Affiliation(s)
- Flavia Costal
- Faculdade de Medicina da Universidade de São Paulo, Laboratório de Endocrinologia Celular e Molecular LIM-25, São Paulo, Brazil
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Jaganjac M, Tirosh O, Cohen G, Sasson S, Zarkovic N. Reactive aldehydes--second messengers of free radicals in diabetes mellitus. Free Radic Res 2013; 47 Suppl 1:39-48. [PMID: 23521622 DOI: 10.3109/10715762.2013.789136] [Citation(s) in RCA: 273] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Elevated levels of pro-oxidants and various markers of oxidative tissue damage were found in diabetic patients, indicating involvement of oxidative stress in the pathogenesis of diabetes mellitus (DM). On one side, physiological levels of reactive oxygen species (ROS) play an important role in redox signaling of various cells, while on the other, excessive ROS production can jeopardize the integrity and physiological functions of cellular macromolecules, in particular proteins, thus contributing to the pathogenesis of DM. Reactive aldehydes, especially 4-hydroxynonenal (HNE), are considered as second messengers of free radicals that act both as signaling molecules and as cytotoxic products of lipid peroxidation causing long-lasting biological consequences, in particular by covalent modification of macromolecules. Accordingly, the HNE and related reactive aldehydes may play important roles in the pathophysiology of DM, both in the development of the disease and in its progression and complications due to the following: (i) exposure of cells to supraphysiological levels of 4-hydroxyalkenals, (ii) persistent and sustained generation of 4-hydroxyalkenals that progressively affect vulnerable cells that lack an efficient bioactive aldehyde neutralization system, (iii) altered redox signaling influenced by reactive aldehydes, in particular by HNE, and (iv) induction of extracellular generation of similar aldehydes under secondary pathological conditions, such as low-grade inflammation.
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Affiliation(s)
- M Jaganjac
- Laboratory for Oxidative Stress, Rudjer Boskovic Institute, Zagreb, Croatia
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49
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Puddu A, Mach F, Nencioni A, Viviani GL, Montecucco F. An emerging role of glucagon-like peptide-1 in preventing advanced-glycation-end-product-mediated damages in diabetes. Mediators Inflamm 2013; 2013:591056. [PMID: 23365488 PMCID: PMC3556837 DOI: 10.1155/2013/591056] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 12/20/2012] [Accepted: 12/27/2012] [Indexed: 01/12/2023] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is a gut hormone produced in the intestinal epithelial endocrine L cells by differential processing of the proglucagon gene. Released in response to the nutrient ingestion, GLP-1 plays an important role in maintaining glucose homeostasis. GLP-1 has been shown to regulate blood glucose levels by stimulating glucose-dependent insulin secretion and inhibiting glucagon secretion, gastric emptying, and food intake. These antidiabetic activities highlight GLP-1 as a potential therapeutic molecule in the clinical management of type 2 diabetes, (a disease characterized by progressive decline of beta-cell function and mass, increased insulin resistance, and final hyperglycemia). Since chronic hyperglycemia contributed to the acceleration of the formation of Advanced Glycation End-Products (AGEs, a heterogeneous group of compounds derived from the nonenzymatic reaction of reducing sugars with free amino groups of proteins implicated in vascular diabetic complications), the administration of GLP-1 might directly counteract diabetes pathophysiological processes (such as pancreatic β-cell dysfunction). This paper outlines evidence on the protective role of GLP-1 in preventing the deleterious effects mediated by AGEs in type 2 diabetes.
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Affiliation(s)
- Alessandra Puddu
- Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, 16132 Genoa, Italy
| | - François Mach
- Division of Cardiology, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, Avenue de la Roseraie 64, 1211 Geneva, Switzerland
| | - Alessio Nencioni
- Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, 16132 Genoa, Italy
| | - Giorgio Luciano Viviani
- Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, 16132 Genoa, Italy
| | - Fabrizio Montecucco
- Division of Cardiology, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, Avenue de la Roseraie 64, 1211 Geneva, Switzerland
- First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, 16132 Genoa, Italy
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Gilbert ER, Liu D. Epigenetics: the missing link to understanding β-cell dysfunction in the pathogenesis of type 2 diabetes. Epigenetics 2012; 7:841-52. [PMID: 22810088 PMCID: PMC3427279 DOI: 10.4161/epi.21238] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Type 2 diabetes (T2D) is a growing health problem worldwide. While peripheral insulin resistance is common during obesity and aging in both animals and people, progression to T2D is largely due to insulin secretory dysfunction and significant apoptosis of functional β-cells, leading to an inability to compensate for insulin resistance. It is recognized that environmental factors and nutrition play an important role in the pathogenesis of diabetes. However, our knowledge surrounding molecular mechanisms by which these factors trigger β-cell dysfunction and diabetes is still limited. Recent discoveries raise the possibility that epigenetic changes in response to environmental stimuli may play an important role in the development of diabetes. In this paper, we review emerging knowledge regarding epigenetic mechanisms that may be involved in β-cell dysfunction and pathogenesis of diabetes, including the role of nutrition, oxidative stress and inflammation. We will mainly focus on the role of DNA methylation and histone modifications but will also briefly review data on miRNA effects on the pancreatic islets. Further studies aimed at better understanding how epigenetic regulation of gene expression controls β-cell function may reveal potential therapeutic targets for prevention and treatment of diabetes.
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Affiliation(s)
- Elizabeth R. Gilbert
- Department of Animal and Poultry Sciences; College of Agriculture and Life Sciences; Virginia Tech; Blacksburg, VA USA
| | - Dongmin Liu
- Department of Human Nutrition, Foods and Exercise; College of Agriculture and Life Sciences; Virginia Tech; Blacksburg, VA USA
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