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Adeshara K, Parente EB, Harjutsalo V, Lehto M, Sandholm N, Groop PH. Relationship between sRAGE and obesity in individuals with type 1 diabetes during a median follow-up of 6.3 years. Diabetologia 2025:10.1007/s00125-025-06440-4. [PMID: 40301129 DOI: 10.1007/s00125-025-06440-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 03/07/2025] [Indexed: 05/01/2025]
Abstract
AIMS/HYPOTHESIS Soluble receptor for advanced glycation end products (sRAGE) has been inversely linked to obesity, which is defined by excess of total body fat. However, body fat accumulation is also relevant for health. In this study, we investigated associations between sRAGE and obesity in individuals with type 1 diabetes over 6.3 years of follow-up. METHODS The study included 3886 adults with type 1 diabetes from the FinnDiane study. Serum sRAGE concentrations were determined by ELISA. Central obesity was defined on the basis of waist/height ratio (WHtR), and general obesity on the basis of BMI. The Kruskal-Wallis test was used to assess the differences in baseline BMI, WHtR and sRAGE concentrations, comparing the groups stratified by albuminuria status. Changes in BMI and WHtR were calculated over time and Wilcoxon rank test was used for comparisons. Linear regression, adjusted for sex, age, albuminuria and HbA1c, was used for assessing the association of sRAGE with obesity measures at baseline, and with changes over time. RESULTS Over a median follow-up of 6.3 years, BMI changed by a median Δ of 0.76 kg/m2 (IQR -0.39 to 2.07; p<0.001) and WHtR by a median Δ of 0.019 (IQR -0.007 to 0.05; p<0.001). The change in BMI was observed in 67% of the individuals, and WHtR in 68% of them. Baseline sRAGE was inversely associated with BMI (r2=0.07, β -0.174; p<0.001) and WHtR (r2=0.16, β -0.179; p<0.001) in the overall cohort. These relationships remained consistent across subgroups stratified by albuminuria status, including no, moderate and severe albuminuria (all p<0.001). However, sRAGE was not associated with changes in BMI or WHtR over time. CONCLUSIONS/INTERPRETATION sRAGE is inversely associated with both general and central obesity, as represented by BMI and WHtR, independent of kidney disease, suggesting sRAGE is a biomarker of obesity. However, sRAGE is not associated with the changes in BMI and WHtR over a 6.3 year follow-up. Future research with longer follow-up is merited to understand how sRAGE correlates with body fat accumulation.
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Affiliation(s)
- Krishna Adeshara
- Folkhälsan Research Center, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Erika B Parente
- Folkhälsan Research Center, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Boehringer Ingelheim International GmbH, Ingelheim, Germany
| | - Valma Harjutsalo
- Folkhälsan Research Center, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Markku Lehto
- Folkhälsan Research Center, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Niina Sandholm
- Folkhälsan Research Center, Helsinki, Finland.
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland.
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
| | - Per-Henrik Groop
- Folkhälsan Research Center, Helsinki, Finland.
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland.
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia.
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
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Vianello E, Beltrami AP, Aleksova A, Janjusevic M, Fluca AL, Corsi Romanelli MM, La Sala L, Dozio E. The Advanced Glycation End-Products (AGE)-Receptor for AGE System (RAGE): An Inflammatory Pathway Linking Obesity and Cardiovascular Diseases. Int J Mol Sci 2025; 26:3707. [PMID: 40332316 PMCID: PMC12028226 DOI: 10.3390/ijms26083707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 03/31/2025] [Accepted: 04/11/2025] [Indexed: 05/08/2025] Open
Abstract
The AGE (advanced glycation end-products)-RAGE (receptor for AGE) system is a pro-inflammatory pathway that contributes to the pathogenesis of obesity and obesity-related cardiovascular disorders (CVD). Circulating AGE and the soluble form of RAGE (sRAGE) has been suggested as a potential biomarker of CVD related to obesity. In this study, we aim to (1) summarize the current knowledge about the role of obesity in the onset and progression of CVD, (2) discuss the role of the AGE-RAGE system as a pathway promoting obesity and linking obesity to CVD, and (3) highlight available strategies for reducing AGE-RAGE system activation and the associated beneficial effects.
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Affiliation(s)
- Elena Vianello
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy; (E.V.); (M.M.C.R.); (L.L.S.)
- Experimental Laboratory for Research on Organ Damage Biomarkers, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy
| | - Antonio P. Beltrami
- Department of Medicine, Università degli Studi di Udine, 33100 Udine, Italy;
- Azienda Sanitaria Universitaria Friuli Centrale, 33100 Udine, Italy
| | - Aneta Aleksova
- Department of Medical Surgical and Health Sciences, Università degli Studi di Trieste, 34129 Trieste, Italy; (A.A.); (M.J.); (A.L.F.)
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina, 34100 Trieste, Italy
| | - Milijana Janjusevic
- Department of Medical Surgical and Health Sciences, Università degli Studi di Trieste, 34129 Trieste, Italy; (A.A.); (M.J.); (A.L.F.)
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina, 34100 Trieste, Italy
| | - Alessandra L. Fluca
- Department of Medical Surgical and Health Sciences, Università degli Studi di Trieste, 34129 Trieste, Italy; (A.A.); (M.J.); (A.L.F.)
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina, 34100 Trieste, Italy
| | - Massimiliano M. Corsi Romanelli
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy; (E.V.); (M.M.C.R.); (L.L.S.)
- Department of Clinical and Experimental Pathology, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy
| | - Lucia La Sala
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy; (E.V.); (M.M.C.R.); (L.L.S.)
- IRCCS Multimedica, 20138 Milan, Italy
| | - Elena Dozio
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy; (E.V.); (M.M.C.R.); (L.L.S.)
- Experimental Laboratory for Research on Organ Damage Biomarkers, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy
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3
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Zhao H, Lv J, Chen B, He F, Wang Q, Xie D, Koyama H, Zhang C, Cheng J. RAGE deficiency obstructs high uric acid-induced oxidative stress and inflammatory response. Int Immunopharmacol 2025; 151:114316. [PMID: 39987631 DOI: 10.1016/j.intimp.2025.114316] [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: 11/26/2024] [Revised: 02/13/2025] [Accepted: 02/13/2025] [Indexed: 02/25/2025]
Abstract
Hyperuricemia is a metabolic disorder primarily associated with gout and implicated in various metabolic inflammatory diseases. While the role of monosodium urate crystals triggering inflammation has been well-documented, recent findings suggest that soluble high uric acid (HUA) also induces pro-inflammatory cytokine production in human monocytes. However, the comprehensive effects of HUA levels on macrophage dysfunction and the underlying mechanisms remain underexplored. This study employs urate oxidase knockout (UOX-KO) and receptor for advanced glycation end products deficiency (RAGE-/-) mouse models to elucidate macrophage function and its mechanistic pathways. Our results demonstrate that HUA promotes M1 polarization and migration of macrophages while impairing their phagocytic ability. This process is mediated through the high mobility group box 1 (HMGB1)-RAGE- ROS axis. Notably, RAGE deficiency in bone marrow-derived cells partially mediates these effects. Pathologically, elevated HMGB1 and monocyte chemoattractant protein 1 levels in pancreatic islets increases macrophage infiltration in UOX-KO mice. Treatment with the FPS-ZM1, as a pharmacological RAGE inhibitor, effectively decreases serum UA levels, ameliorates islet inflammation and insulin resistance. These findings suggest that soluble HUA serves as a pro-inflammatory trigger through the HMGB1-RAGE-ROS axis, and that RAGE inhibition may mitigate these effects by decreasing inflammatory macrophage infiltration in the islets. Additionally, the influence of UA on macrophages extends beyond gout, potentially contributing to the pathogenesis of other metabolic inflammatory conditions, such as atherosclerosis, non-alcoholic steatohepatitis, obesity, and hyperlipidemia.
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Affiliation(s)
- Hairong Zhao
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, China; Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Jiamin Lv
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Binyang Chen
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Furong He
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Qiang Wang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - De Xie
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Hidenori Koyama
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Chenggui Zhang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, China.
| | - Jidong Cheng
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China; Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Japan.
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Drygała S, Żendzian-Piotrowska M, Radzikowski M, Zalewska A, Maciejczyk M. Inhibition of protein glycation by vasodilatory β-blockers - In vitro studies and in silico analyses. Biomed Pharmacother 2025; 185:117976. [PMID: 40080999 DOI: 10.1016/j.biopha.2025.117976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 03/07/2025] [Accepted: 03/07/2025] [Indexed: 03/15/2025] Open
Abstract
Glycation is defined as a non-enzymatic reaction wherein reducing sugars interact with amino acid residues present in proteins, resulting in the formation of advanced glycation end-products (AGE). This biochemical phenomenon is linked to several pathological conditions, particularly cardiovascular disease (CVD) and diabetes, as it significantly contributes to the onset of endothelial dysfunction and inflammation. Given these connections, vasodilatory β-blockers (VBB) have garnered interest due to their multifaceted pharmacological effects that extend beyond traditional β-adrenergic blockade. These agents not only enhance endothelial function but also exhibit notable antioxidant and anti-inflammatory properties, which may be associated with their capacity to inhibit glycation processes. In our study, we examined these properties through an in vitro and in silico study utilizing bovine serum albumin (BSA) as a model with multiple carbohydrates and aldehydes as glycation agents. Furthermore, we evaluated the binding affinity of VBB to BSA and pro-inflammatory proteins via molecular docking. The results indicated that while VBB were effective in diminishing the rates of protein glycation their effectiveness was generally lower than that of aminoguanidine, a recognized anti-glycation agent. In contrast, molecular docking analyses suggested that the anti-inflammatory properties of VBB may be due to their competition with glycation agents for binding sites on BSA, as well as their interactions with proteins integral to the activation of pro-inflammatory signaling pathways.
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Affiliation(s)
- Szymon Drygała
- Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Bialystok 15-089, Poland
| | | | - Michał Radzikowski
- Biochemistry of Civilization Diseases' Students' Scientific Club at the Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Bialystok 15-089, Poland
| | - Anna Zalewska
- Department of Restorative Dentistry, Medical University of Bialystok, Bialystok 15-089, Poland
| | - Mateusz Maciejczyk
- Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Bialystok 15-089, Poland.
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Hansman DS, Du J, Casson RJ, Peet DJ. Eye on the horizon: The metabolic landscape of the RPE in aging and disease. Prog Retin Eye Res 2025; 104:101306. [PMID: 39433211 PMCID: PMC11833275 DOI: 10.1016/j.preteyeres.2024.101306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 10/23/2024]
Abstract
To meet the prodigious bioenergetic demands of the photoreceptors, glucose and other nutrients must traverse the retinal pigment epithelium (RPE), a polarised monolayer of cells that lie at the interface between the outer retina and the choroid, the principal vascular layer of the eye. Recent investigations have revealed a metabolic ecosystem in the outer retina where the photoreceptors and RPE engage in a complex exchange of sugars, amino acids, and other metabolites. Perturbation of this delicate metabolic balance has been identified in the aging retina, as well as in age-related macular degeneration (AMD), the leading cause of blindness in the Western world. Also common in the aging and diseased retina are elevated levels of cytokines, oxidative stress, advanced glycation end-products, increased growth factor signalling, and biomechanical stress - all of which have been associated with metabolic dysregulation in non-retinal cell types and tissues. Herein, we outline the role of these factors in retinal homeostasis, aging, and disease. We discuss their effects on glucose, mitochondrial, lipid, and amino acid metabolism in tissues and cell types outside the retina, highlighting the signalling pathways through which they induce these changes. Lastly, we discuss promising avenues for future research investigating the roles of these pathological conditions on retinal metabolism, potentially offering novel therapeutic approaches to combat age-related retinal disease.
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Affiliation(s)
- David S Hansman
- School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
| | - Jianhai Du
- Department of Ophthalmology and Visual Sciences, Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV 26506, USA
| | - Robert J Casson
- Discipline of Ophthalmology and Visual Science, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Daniel J Peet
- School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
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6
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Semchyshyn H. Fructose-mediated AGE-RAGE axis: approaches for mild modulation. Front Nutr 2024; 11:1500375. [PMID: 39698244 PMCID: PMC11652219 DOI: 10.3389/fnut.2024.1500375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 11/20/2024] [Indexed: 12/20/2024] Open
Abstract
Fructose is a valuable and healthy nutrient when consumed at normal levels (≤50 g/day). However, long-term consumption of excessive fructose and elevated endogenous production can have detrimental health impacts. Fructose-initiated nonenzymatic glycation (fructation) is considered as one of the most likely mechanisms leading to the generation of reactive species and the propagation of nonenzymatic processes. In the later stages of glycation, poorly degraded advanced glycation products (AGEs) are irreversibly produced and accumulated in the organism in an age- and disease-dependent manner. Fructose, along with various glycation products-especially AGEs-are present in relatively high concentrations in our daily diet. Both endogenous and exogenous AGEs exhibit a wide range of biological effects, mechanisms of which can be associated with following: (1) AGEs are efficient sources of reactive species in vivo, and therefore can propagate nonenzymatic vicious cycles and amplify glycation; and (2) AGEs contribute to upregulation of the specific receptor for AGEs (RAGE), amplifying RAGE-mediated signaling related to inflammation, metabolic disorders, chronic diseases, and aging. Therefore, downregulation of the AGE-RAGE axis appears to be a promising approach for attenuating disease conditions associated with RAGE-mediated inflammation. Importantly, RAGE is not specific only to AGEs; it can bind multiple ligands, initiating a complex RAGE signaling network that is not fully understood. Maintaining an appropriate balance between various RAGE isoforms with different functions is also crucial. In this context, mild approaches related to lifestyle-such as diet optimization, consuming functional foods, intake of probiotics, and regular moderate physical activity-are valuable due to their beneficial effects and their ability to mildly modulate the fructose-mediated AGE-RAGE axis.
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Affiliation(s)
- Halyna Semchyshyn
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine
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Wu J, Tang L, Zheng F, Chen X, Li L. A review of the last decade: pancreatic cancer and type 2 diabetes. Arch Physiol Biochem 2024; 130:660-668. [PMID: 37646618 DOI: 10.1080/13813455.2023.2252204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/04/2023] [Accepted: 08/21/2023] [Indexed: 09/01/2023]
Abstract
Pancreatic cancer (PC) is a prevalent gastrointestinal tumour known for its high degree of malignancy, resulting in a mere 10% five-year survival rate for most patients. Over the past decade, a growing body of research has shed light on the intricate bidirectional association between PC and Type 2 diabetes (T2DM). The collection of PC- and T2DM-related articles is derived from two comprehensive databases, namely WOS (Web of Science Core Collection) and CNKI (China National Knowledge Infrastructure). This article discusses the last 10 years of research trends in PC and T2DM and explores their potential regulatory relationship as well as related medications.
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Affiliation(s)
- Jiaqi Wu
- Nanfang Hospital, Southern Medical University, Guangzhou, China
- School of Nursing, Southern Medical University, Guangzhou, China
| | - Liang Tang
- Department of General Medicine, Zhuzhou Central Hospital, Zhuzhou, China
| | - Feng Zheng
- Department of Anatomy, University of Otago, Dunedin, New Zealand
| | - Xun Chen
- Department of the Trauma center, Zhuzhou Central Hospital, Zhuzhou, China
- Department of hepatobiliary surgery, Zhuzhou Central Hospital, Zhuzhou, China
| | - Lei Li
- Department of Pathology, University of Otago, Dunedin, New Zealand
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Moreno-Navarrete JM, Leal Y, Rosell-Díaz M, Fernández-Real JM. Soluble receptors for advanced glycation endproducts are predictors of insulin sensitivity and affected by weight loss. Nutr Diabetes 2024; 14:88. [PMID: 39424781 PMCID: PMC11489772 DOI: 10.1038/s41387-024-00345-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 09/30/2024] [Accepted: 10/03/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND Mice experiments have underscored the efficacy of pharmacological inhibition of advanced glycation endproducts (AGEs) through the use of soluble receptors for advanced glycation endproducts (sRAGE) in mitigating obesity-linked metabolic disruptions and insulin resistance. However, human studies have presented conflicting findings regarding the correlation between circulating sRAGE levels and insulin resistance, as well as glucose tolerance. Here, we aimed to delve deeper into the relationship between sRAGE levels and systemic insulin sensitivity. METHODS Plasma sRAGE levels, hyperinsulinemic-euglycemic clamp, and continuous glucose monitoring were measured in two independent cross-sectional case-control studies [cohort 1 (n = 180) and cohort 2 (n = 124)]. In addition, a subgroup of 42 participants with obesity were followed for 12 months. In 14 of these participants, weight loss was achieved through bariatric surgery intervention. RESULTS Our results revealed a significant association between plasma sRAGE levels and both insulin sensitivity and glycemic control parameters, even after adjustments for age, sex, and BMI. Furthermore, longitudinal analysis demonstrated that interventions aimed at weight loss led to reductions in fasting glucose and HbA1c levels, concurrently with increases in sRAGE levels. CONCLUSIONS These findings underscore that sRAGE levels were strongly associated with insulin sensitivity and glycemic control, suggesting a possible role of sRAGE in preserving insulin sensitivity and maintaining glycemic control, which should be confirmed in further studies.
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Affiliation(s)
- José María Moreno-Navarrete
- Nutrition, Eumetabolism and Health Group, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Av. França 30, 17007, Girona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain.
- Department of Medical Sciences, School of Medicine, University of Girona, 17003, Girona, Spain.
| | - Yenny Leal
- Nutrition, Eumetabolism and Health Group, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Av. França 30, 17007, Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain
- Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Av. França, s/n, 17007, Girona, Spain
| | - Marisel Rosell-Díaz
- Nutrition, Eumetabolism and Health Group, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Av. França 30, 17007, Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain
- Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Av. França, s/n, 17007, Girona, Spain
| | - José Manuel Fernández-Real
- Nutrition, Eumetabolism and Health Group, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Av. França 30, 17007, Girona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain.
- Department of Medical Sciences, School of Medicine, University of Girona, 17003, Girona, Spain.
- Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Av. França, s/n, 17007, Girona, Spain.
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9
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Kanikowska D, Kanikowska A, Strojny Z, Kawka E, Zawada A, Rutkowski R, Litwinowicz M, Sato M, Grzymisławski M, Bręborowicz A, Witowski J, Korybalska K. Assessment of EN-RAGE, sRAGE, and its isoforms: cRAGE, esRAGE in obese patients treated by moderate caloric restriction combined with physical activity conducted in hospital condition. Cytokine 2024; 180:156665. [PMID: 38823153 DOI: 10.1016/j.cyto.2024.156665] [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: 03/19/2024] [Revised: 05/15/2024] [Accepted: 05/24/2024] [Indexed: 06/03/2024]
Abstract
BACKGROUND AGEs, their receptor (RAGE), and the extracellular newly identified receptor for AGEs product-binding protein (EN-RAGE) are implicated in the pathogenesis of inflammation. AIM We analyzed serum EN-RAGE, soluble RAGE (sRAGE), and their isoforms: endogenous secretory - esRAGE and cleaved - cRAGE concentrations in lean controls (n = 74) and in patients with obesity (n = 71) treated for three weeks with moderate calorie restriction (CR) combined with physical activity in a hospital condition. METHODS Using the ELISA method, serum sRAGE, esRAGE, and EN-RAGE were measured before and after CR. RESULTS The serum level of sRAGE and esRAGE in patients with obesity was lower than that in non-obese individuals, contrary to cRAGE. EN-RAGE concentration was about three times higher in obese patients. Gradually, a rise in BMI resulted in sRAGE, esRAGE reduction, and EN-RAGE increase. The sRAGE concentration was sex-dependent, indicating a higher value in lean men. A moderate negative correlation was observed between BMI and all RAGE isoforms, whereas EN-RAGE displays a positive correlation. CR resulted in an expected decrease in anthropometric, metabolic, and proinflammatory parameters and EN-RAGE, but no RAGE isoforms. The ratio EN-RAGE/sRAGE was higher in obese humans than in control and was not modified by CR. CONCLUSION Obesity decreases sRAGE and esRAGE and increases EN-RAGE concentration. Moderate CR and physical activity by decreasing inflammation reduces EN-RAGE but is insufficient to increase sRAGE and esRAGE to the extent observed in lean patients. EN-RAGE instead of sRAGE could be helpful to indicate a better outcome of moderate dietary intervention in obese subjects.
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Affiliation(s)
- Dominika Kanikowska
- Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland.
| | - Alina Kanikowska
- Department of Internal Diseases, Metabolism and Nutrition, Poznań University of Medical Science, Poznań, Poland
| | - Zofia Strojny
- Department of Conservative Dentistry and Endodontics, Poznań University of Medical Sciences, Poznań, Poland
| | - Edyta Kawka
- Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland
| | - Agnieszka Zawada
- Department of Internal Diseases, Metabolism and Nutrition, Poznań University of Medical Science, Poznań, Poland
| | - Rafał Rutkowski
- Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland
| | - Monika Litwinowicz
- Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland
| | - Maki Sato
- Institutional Research, Aichi Medical University School of Medicine, Aichi, Japan
| | - Marian Grzymisławski
- Department of Internal Diseases, Metabolism and Nutrition, Poznań University of Medical Science, Poznań, Poland
| | - Andrzej Bręborowicz
- Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland; Collegium Medicum, Zielona Góra University, Zielona Góra, Poland
| | - Janusz Witowski
- Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland
| | - Katarzyna Korybalska
- Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland
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Brunnthaler L, Hammond TG, Pereyra D, Santol J, Probst J, Laferl V, Resch U, Aiad M, Janoschek AS, Gruenberger T, Hackl H, Starlinger P, Assinger A. HMGB1-Mediated Cell Death-A Crucial Element in Post-Hepatectomy Liver Failure. Int J Mol Sci 2024; 25:7150. [PMID: 39000266 PMCID: PMC11241647 DOI: 10.3390/ijms25137150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 06/19/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024] Open
Abstract
Liver resection (LR) is the primary treatment for hepatic tumors, yet posthepatectomy liver failure (PHLF) remains a significant concern. While the precise etiology of PHLF remains elusive, dysregulated inflammatory processes are pivotal. Therefore, we explored the theragnostic potential of extracellular high-mobility-group-box protein 1 (HMGB1), a key damage-associated molecular pattern (DAMP) released by hepatocytes, in liver recovery post LR in patients and animal models. Plasma from 96 LR patients and liver tissues from a subset of 24 LR patients were analyzed for HMGB1 levels, and associations with PHLF and liver injury markers were assessed. In a murine LR model, the HMGB1 inhibitor glycyrrhizin, was administered to assess its impact on liver regeneration. Furthermore, plasma levels of keratin-18 (K18) and cleaved cytokeratin-18 (ccK18) were quantified to assess suitability as predictive biomarkers for PHLF. Patients experiencing PHLF exhibited elevated levels of intrahepatic and circulating HMGB1, correlating with markers of liver injury. In a murine LR model, inhibition of HMGB1 improved liver function, reduced steatosis, enhanced regeneration and decreased hepatic cell death. Elevated levels of hepatic cell death markers K18 and ccK18 were detected in patients with PHLF and correlations with levels of circulating HMGB1 was observed. Our study underscores the therapeutic and predictive potential of HMGB1 in PHLF mitigation. Elevated HMGB1, K18, and ccK18 levels correlate with patient outcomes, highlighting their predictive significance. Targeting HMGB1 enhances liver regeneration in murine LR models, emphasizing its role in potential intervention and prediction strategies for liver surgery.
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Affiliation(s)
- Laura Brunnthaler
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria; (L.B.); (J.S.); (U.R.)
| | - Thomas G. Hammond
- Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, 4055 Basel, Switzerland;
- Clinical Pharmacology and Safety Sciences, AstraZeneca, Cambridge CB4 0WG, UK
| | - David Pereyra
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria; (D.P.); (V.L.); (M.A.); (A.S.J.)
| | - Jonas Santol
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria; (L.B.); (J.S.); (U.R.)
- Department of Surgery, HPB Center, Viennese Health Network, Clinic Favoriten and Sigmund Freud Private University, 1100 Vienna, Austria; (J.P.); (T.G.)
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Joel Probst
- Department of Surgery, HPB Center, Viennese Health Network, Clinic Favoriten and Sigmund Freud Private University, 1100 Vienna, Austria; (J.P.); (T.G.)
| | - Valerie Laferl
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria; (D.P.); (V.L.); (M.A.); (A.S.J.)
| | - Ulrike Resch
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria; (L.B.); (J.S.); (U.R.)
| | - Monika Aiad
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria; (D.P.); (V.L.); (M.A.); (A.S.J.)
| | - Anna Sofie Janoschek
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria; (D.P.); (V.L.); (M.A.); (A.S.J.)
| | - Thomas Gruenberger
- Department of Surgery, HPB Center, Viennese Health Network, Clinic Favoriten and Sigmund Freud Private University, 1100 Vienna, Austria; (J.P.); (T.G.)
| | - Hubert Hackl
- Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Patrick Starlinger
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria; (D.P.); (V.L.); (M.A.); (A.S.J.)
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Alice Assinger
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria; (L.B.); (J.S.); (U.R.)
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11
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Rojas A, Lindner C, Schneider I, Gonzalez I, Uribarri J. The RAGE Axis: A Relevant Inflammatory Hub in Human Diseases. Biomolecules 2024; 14:412. [PMID: 38672429 PMCID: PMC11048448 DOI: 10.3390/biom14040412] [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: 03/04/2024] [Revised: 03/21/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024] Open
Abstract
In 1992, a transcendental report suggested that the receptor of advanced glycation end-products (RAGE) functions as a cell surface receptor for a wide and diverse group of compounds, commonly referred to as advanced glycation end-products (AGEs), resulting from the non-enzymatic glycation of lipids and proteins in response to hyperglycemia. The interaction of these compounds with RAGE represents an essential element in triggering the cellular response to proteins or lipids that become glycated. Although initially demonstrated for diabetes complications, a growing body of evidence clearly supports RAGE's role in human diseases. Moreover, the recognizing capacities of this receptor have been extended to a plethora of structurally diverse ligands. As a result, it has been acknowledged as a pattern recognition receptor (PRR) and functionally categorized as the RAGE axis. The ligation to RAGE leads the initiation of a complex signaling cascade and thus triggering crucial cellular events in the pathophysiology of many human diseases. In the present review, we intend to summarize basic features of the RAGE axis biology as well as its contribution to some relevant human diseases such as metabolic diseases, neurodegenerative, cardiovascular, autoimmune, and chronic airways diseases, and cancer as a result of exposure to AGEs, as well as many other ligands.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile; (A.R.); (I.G.)
| | - Cristian Lindner
- Department of Radiology, Faculty of Medicine, University of Concepción, Concepción 4030000, Chile;
| | - Ivan Schneider
- Centre of Primary Attention, South Metropolitan Health Service, Santiago 3830000, Chile;
| | - Ileana Gonzalez
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile; (A.R.); (I.G.)
| | - Jaime Uribarri
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10021, USA
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12
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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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13
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Arivazhagan L, Popp CJ, Ruiz HH, Wilson RA, Manigrasso MB, Shekhtman A, Ramasamy R, Sevick MA, Schmidt AM. The RAGE/DIAPH1 axis: mediator of obesity and proposed biomarker of human cardiometabolic disease. Cardiovasc Res 2024; 119:2813-2824. [PMID: 36448548 PMCID: PMC11484493 DOI: 10.1093/cvr/cvac175] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 12/07/2023] Open
Abstract
Overweight and obesity are leading causes of cardiometabolic dysfunction. Despite extensive investigation, the mechanisms mediating the increase in these conditions are yet to be fully understood. Beyond the endogenous formation of advanced glycation endproducts (AGEs) in overweight and obesity, exogenous sources of AGEs accrue through the heating, production, and consumption of highly processed foods. Evidence from cellular and mouse model systems indicates that the interaction of AGEs with their central cell surface receptor for AGE (RAGE) in adipocytes suppresses energy expenditure and that AGE/RAGE contributes to increased adipose inflammation and processes linked to insulin resistance. In human subjects, the circulating soluble forms of RAGE, which are mutable, may serve as biomarkers of obesity and weight loss. Antagonists of RAGE signalling, through blockade of the interaction of the RAGE cytoplasmic domain with the formin, Diaphanous-1 (DIAPH1), target aberrant RAGE activities in metabolic tissues. This review focuses on the potential roles for AGEs and other RAGE ligands and RAGE/DIAPH1 in the pathogenesis of overweight and obesity and their metabolic consequences.
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Affiliation(s)
- Lakshmi Arivazhagan
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Collin J Popp
- Center for Healthful Behavior Change, Department of Population Health, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Henry H Ruiz
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Robin A Wilson
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Michaele B Manigrasso
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Alexander Shekhtman
- Department of Chemistry, The State University of New York at Albany, Albany, NY 12222, USA
| | - Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Mary Ann Sevick
- Center for Healthful Behavior Change, Department of Population Health, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
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14
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Ye D, Miyoshi A, Ushitani T, Kadoya M, Igeta M, Konishi K, Shoji T, Yasuda K, Kitaoka S, Yagi H, Kuroda E, Yamamoto Y, Cheng J, Koyama H. RAGE in circulating immune cells is fundamental for hippocampal inflammation and cognitive decline in a mouse model of latent chronic inflammation. Brain Behav Immun 2024; 116:329-348. [PMID: 38142917 DOI: 10.1016/j.bbi.2023.12.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 11/29/2023] [Accepted: 12/19/2023] [Indexed: 12/26/2023] Open
Abstract
BACKGROUND Latent chronic inflammation has been proposed as a key mediator of multiple derangements in metabolic syndrome (MetS), which are increasingly becoming recognized as risk factors for age-related cognitive decline. However, the question remains whether latent chronic inflammation indeed induces brain inflammation and cognitive decline. METHODS A mouse model of latent chronic inflammation was constructed by a chronic subcutaneous infusion of low dose lipopolysaccharide (LPS) for four weeks. A receptor for advanced glycation end products (RAGE) knockout mouse, a chimeric myeloid cell specific RAGE-deficient mouse established by bone marrow transplantation and a human endogenous secretory RAGE (esRAGE) overexpressing adenovirus system were utilized to examine the role of RAGE in vivo. The cognitive function was examined by a Y-maze test, and the expression level of genes was determined by quantitative RT-PCR, western blot, immunohistochemical staining, or ELISA assays. RESULTS Latent chronic inflammation induced MetS features in C57BL/6J mice, which were associated with cognitive decline and brain inflammation characterized by microgliosis, monocyte infiltration and endothelial inflammation, without significant changes in circulating cytokines including TNF-α and IL-1β. These changes as well as cognitive impairment were rescued in RAGE knockout mice or chimeric mice lacking RAGE in bone marrow cells. P-selectin glycoprotein ligand-1 (PSGL-1), a critical adhesion molecule, was induced in circulating mononuclear cells in latent chronic inflammation in wild-type but not RAGE knockout mice. These inflammatory changes and cognitive decline induced in the wild-type mice were ameliorated by an adenoviral increase in circulating esRAGE. Meanwhile, chimeric RAGE knockout mice possessing RAGE in myeloid cells were still resistant to cognitive decline and brain inflammation. CONCLUSIONS These findings indicate that RAGE in inflammatory cells is necessary to mediate stimuli of latent chronic inflammation that cause brain inflammation and cognitive decline, potentially by orchestrating monocyte activation via regulation of PSGL-1 expression. Our results also suggest esRAGE-mediated inflammatory regulation as a potential therapeutic option for cognitive dysfunction in MetS with latent chronic inflammation.
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Affiliation(s)
- Dasen Ye
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Akio Miyoshi
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Tomoe Ushitani
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Manabu Kadoya
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Masataka Igeta
- Department of Biostatistics, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Kosuke Konishi
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Takuhito Shoji
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Koubun Yasuda
- Department of Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Shiho Kitaoka
- Department of Pharmacology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Hideshi Yagi
- Department of Anatomy and Cell Biology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Etsushi Kuroda
- Department of Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Jidong Cheng
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan; Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Hidenori Koyama
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan.
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15
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Jiang S, Xia N, Buonfiglio F, Böhm EW, Tang Q, Pfeiffer N, Olinger D, Li H, Gericke A. High-fat diet causes endothelial dysfunction in the mouse ophthalmic artery. Exp Eye Res 2024; 238:109727. [PMID: 37972749 DOI: 10.1016/j.exer.2023.109727] [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: 07/13/2023] [Revised: 10/27/2023] [Accepted: 11/13/2023] [Indexed: 11/19/2023]
Abstract
Obesity is a significant health concern that leads to impaired vascular function and subsequent abnormalities in various organs. The impact of obesity on ocular blood vessels, however, remains largely unclear. In this study, we examined the hypothesis that obesity induced by high-fat diet produces vascular endothelial dysfunction in the ophthalmic artery. Mice were subjected to a high-fat diet for 20 weeks, while age-matched controls were maintained on a standard diet. Reactivity of isolated ophthalmic artery segments was assessed in vitro. Reactive oxygen species (ROS) were quantified in cryosections by dihydroethidium (DHE) staining. Redox gene expression was determined in ophthalmic artery explants by real-time PCR. Furthermore, the expression of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), the receptor for advanced glycation end products (RAGE), and of the lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) was determined in cryosections using immunofluorescence microscopy. Ophthalmic artery segments from mice on a high-fat diet exhibited impaired vasodilation responses to the endothelium-dependent vasodilator acetylcholine, while endothelium-independent responses to nitroprusside remained preserved. DHE staining intensity in the vascular wall was notably stronger in mice on a high-fat diet. Messenger RNA expression for NOX2 was elevated in the ophthalmic artery of mice subjected to high fat diet. Likewise, immunostainings revealed increased expression of NOX2 and of RAGE, but not of LOX-1. These findings suggest that a high-fat diet triggers endothelial dysfunction by inducing oxidative stress in the ophthalmic artery via involvement of RAGE and NOX2.
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Affiliation(s)
- Subao Jiang
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Ning Xia
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Francesco Buonfiglio
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Elsa W Böhm
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Qi Tang
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Norbert Pfeiffer
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Dominik Olinger
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Huige Li
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Adrian Gericke
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
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16
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Li D, Ju F, Wang H, Fan C, Jacob JC, Gul S, Zaliani A, Wartmann T, Polidori MC, Bruns CJ, Zhao Y. Combination of the biomarkers for aging and cancer? - Challenges and current status. Transl Oncol 2023; 38:101783. [PMID: 37716258 PMCID: PMC10514562 DOI: 10.1016/j.tranon.2023.101783] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 09/04/2023] [Accepted: 09/07/2023] [Indexed: 09/18/2023] Open
Abstract
The proportion of patients diagnosed with cancer has been shown to rise with the increasing aging global population. Advanced age is a major risk factor for morbidity and mortality in older adults. As individuals experience varying health statuses, particularly with age, it poses a challenge for medical professionals in the cancer field to obtain standardized treatment outcomes. Hence, relying solely on chronological age and disease-related parameters is inadequate for clinical decision-making for elderly patients. With functional, multimorbidity-related, and psychosocial changes that occur with aging, oncologic diseases may develop and be treated differently from younger patients, leading to unique challenges in treatment efficacy and tolerance. To overcome this challenge, personalized therapy using biomarkers has emerged as a promising solution. Various categories of biomarkers, including inflammatory, hematological, metabolic, endocrine, and DNA modification-related indicators, may display features related to both cancer and aging, aiding in the development of innovative therapeutic approaches for patients with cancer in old age. Furthermore, physical functional measurements as non-molecular phenotypic biomarkers are being investigated for their potential complementary role in structured multidomain strategies to combat age-related diseases such as cancer. This review provides insight into the current developments, recent discoveries, and significant challenges in cancer and aging biomarkers, with a specific focus on their application in advanced age.
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Affiliation(s)
- Dai Li
- Department of General, Visceral, Tumor and Transplantation Surgery, University Hospital of Cologne, Kerpener Straße 62, 50937 Cologne, Germany; Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Feng Ju
- Department of General, Visceral, Tumor and Transplantation Surgery, University Hospital of Cologne, Kerpener Straße 62, 50937 Cologne, Germany
| | - Han Wang
- Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Chunfu Fan
- Medical faculty, University of Cologne, Germany
| | | | - Sheraz Gul
- Fraunhofer Institute for Translational Medicine and Pharmacology, Schnackenburgallee 114, d-22525 Hamburg, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hamburg Site, Schnackenburgallee 114, d-22525 Hamburg, Germany
| | - Andrea Zaliani
- Fraunhofer Institute for Translational Medicine and Pharmacology, Schnackenburgallee 114, d-22525 Hamburg, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hamburg Site, Schnackenburgallee 114, d-22525 Hamburg, Germany
| | - Thomas Wartmann
- Department of General, Visceral und Vascular Surgery, Otto von Guericke University, Magdeburg, Leipziger Str. 44, Magdeburg, 39120, Germany
| | - Maria Cristina Polidori
- Ageing Clinical Research, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress-Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne Germany
| | - Christiane J Bruns
- Department of General, Visceral, Tumor and Transplantation Surgery, University Hospital of Cologne, Kerpener Straße 62, 50937 Cologne, Germany; Center for Integrated Oncology (CIO) Aachen, Bonn, Cologne and Düsseldorf, Cologne, Germany
| | - Yue Zhao
- Department of General, Visceral, Tumor and Transplantation Surgery, University Hospital of Cologne, Kerpener Straße 62, 50937 Cologne, Germany.
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17
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Carr KD, Weiner SP, Vasquez C, Schmidt AM. Involvement of the Receptor for Advanced Glycation End Products (RAGE) in high fat-high sugar diet-induced anhedonia in rats. Physiol Behav 2023; 271:114337. [PMID: 37625475 PMCID: PMC10592025 DOI: 10.1016/j.physbeh.2023.114337] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/08/2023] [Accepted: 08/21/2023] [Indexed: 08/27/2023]
Abstract
Clinical and basic science investigation indicates a link between insulin resistance and anhedonia. Previous results of this laboratory point to impaired nucleus accumbens (NAc) insulin signaling as an underpinning of diet-induced anhedonia, based on use of a glucose lick microstructure assay. The present study evaluated whether advanced glycation end products (AGEs) and their receptor (RAGE), known to mediate obesogenic diet-induced inflammation and pathological metabolic conditions, are involved in this behavioral change. Six weeks maintenance of male and female rats on a high fat-high sugar liquid diet (chocolate Ensure) increased body weight gain, and markedly increased circulating insulin and leptin, but induced anhedonia (decreased first minute lick rate and lick burst size) in males only. In these subjects, anhedonia correlated with plasma concentrations of insulin. Although the diet did not alter plasma or NAc AGEs, or the expression of RAGE in the NAc, marginally significant correlations were seen between anhedonia and plasma content of several AGEs and NAc RAGE. Importantly, a small molecule RAGE antagonist, RAGE229, administered twice daily by oral gavage, prevented diet-induced anhedonia. This beneficial effect was associated with improved adipose function, reflected in the adiponectin/leptin ratio, and increased pCREB/total CREB in the NAc, and a shift in the pCREB correlation with pThr34-DARPP-32 from near-zero to strongly positive, such that both phospho-proteins correlated with the rescued hedonic response. This set of findings suggests that the receptor/signaling pathway and cell type underlying the RAGE229-mediated increase in pCREB may mediate anhedonia and its prevention. The possible role of adipose tissue as a locus of diet-induced RAGE signaling, and source of circulating factors that target NAc to modify hedonic reactivity are discussed.
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Affiliation(s)
- Kenneth D Carr
- Departments of Psychiatry, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, United States; Departments of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, United States.
| | - Sydney P Weiner
- Departments of Psychiatry, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, United States
| | - Carolina Vasquez
- Departments of Psychiatry, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, United States; Departments of Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, United States
| | - Ann Marie Schmidt
- Departments of Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, United States
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18
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Taheri F, Vasheghani-Farahani A, Honarkar-Shafie E, Poorhosseini H, Yaseri M, Hosseinzadeh-Attar MJ. Effect of diet low in advanced glycation end products on appetite, body composition, and brown adipose tissue markers in patients with coronary artery disease treated with angioplasty: A randomized controlled trial. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2023; 28:75. [PMID: 38152071 PMCID: PMC10751513 DOI: 10.4103/jrms.jrms_293_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/18/2023] [Accepted: 07/17/2023] [Indexed: 12/29/2023]
Abstract
Background Recent changes in dietary habits have resulted in increased intake of advanced glycation end products (AGEs), which are known to have a predominant contribution to the pathogenesis and complications of coronary artery disease (CAD). AGEs are also thought to induce weight gain by affecting appetite, energy expenditure, and brown adipose tissue (BAT). Here, we investigated whether the restriction of dietary AGEs could affect appetite, body composition, anthropometric indices, and BAT-derived markers in CAD patients treated with angioplasty. Materials and Methods Forty-two stented CAD patients were randomly allocated into two groups that received either a low-AGEs or a control diet for 12 weeks. At baseline and postintervention, fasting blood samples were analyzed for total AGEs, nesfatin-1, and BAT-derived markers (fibroblast growth factor 21 and neuregulin 4). Subjective appetite ratings and body composition were evaluated using the Visual Analog Scale (VAS) and bioelectric impedance analysis. Anthropometric indices, including fat mass index (FMI), abdominal volume index (AVI), and body adiposity index (BAI), were calculated through the relevant formula. Results Restricting dietary AGEs for 12 weeks could cause a significant reduction in weight, FMI, AVI, and BAI (P < 0.05) compared to the comparison group. In addition, VAS data analyses indicated a significant decrease in the sense of hunger and prospective food intake (P < 0.05) in the intervention group compared to the comparison group. No significant difference was seen in the measured biochemical markers between the two groups. Conclusion This study indicated that the low-AGEs diet could decrease appetite, weight, and anthropometric indices in stented CAD patients.
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Affiliation(s)
- Fatemeh Taheri
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Vasheghani-Farahani
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Elaheh Honarkar-Shafie
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamidreza Poorhosseini
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Yaseri
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Miranda ER, Mey JT, Blackburn BK, Chaves AB, Fuller KNZ, Perkins RK, Ludlow AT, Haus JM. Soluble RAGE and skeletal muscle tissue RAGE expression profiles in lean and obese young adults across differential aerobic exercise intensities. J Appl Physiol (1985) 2023; 135:849-862. [PMID: 37675469 PMCID: PMC10642519 DOI: 10.1152/japplphysiol.00748.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 08/22/2023] [Accepted: 08/24/2023] [Indexed: 09/08/2023] Open
Abstract
Nearly 40% of Americans have obesity and are at increased risk for developing type 2 diabetes. Skeletal muscle is responsible for >80% of insulin-stimulated glucose uptake that is attenuated by the inflammatory milieu of obesity and augmented by aerobic exercise. The receptor for advanced glycation endproducts (RAGE) is an inflammatory receptor directly linking metabolic dysfunction with inflammation. Circulating soluble isoforms of RAGE (sRAGE) formed either by proteolytic cleavage (cRAGE) or alternative splicing (esRAGE) act as decoys for RAGE ligands, thereby counteracting RAGE-mediated inflammation. We aimed to determine if RAGE expression or alternative splicing of RAGE is altered by obesity in muscle, and whether acute aerobic exercise (AE) modifies RAGE and sRAGE. Young (20-34 yr) participants without [n = 17; body mass index (BMI): 22.6 ± 2.6 kg/m2] and with obesity (n = 7; BMI: 32.8 ± 2.9 kg/m2) performed acute aerobic exercise (AE) at 40%, 65%, or 80% of maximal aerobic capacity (V̇o2max; mL/kg/min) on separate visits. Blood was taken before and 30 min after each AE bout. Muscle biopsy samples were taken before, 30 min, and 3 h after the 80% V̇o2max AE bout. Individuals with obesity had higher total RAGE and esRAGE mRNA and RAGE protein (P < 0.0001). In addition, RAGE and esRAGE transcripts correlated to transcripts of the NF-κB subunit P65 (P < 0.05). There was no effect of AE on total RAGE or esRAGE transcripts, or RAGE protein (P > 0.05), and AE tended to decrease circulating sRAGE in particular at lower intensities of exercise. RAGE expression is exacerbated in skeletal muscle with obesity, which may contribute to muscle inflammation via NF-κB. Future work should investigate the consequences of increased skeletal muscle RAGE on the development of obesity-related metabolic dysfunction and potential mitigating strategies.NEW & NOTEWORTHY This study is the first to investigate the effects of aerobic exercise intensity on circulating sRAGE isoforms, muscle RAGE protein, and muscle RAGE splicing. sRAGE isoforms tended to diminish with exercise, although this effect was attenuated with increasing exercise intensity. Muscle RAGE protein and gene expression were unaffected by exercise. However, individuals with obesity displayed nearly twofold higher muscle RAGE protein and gene expression, which positively correlated with expression of the P65 subunit of NF-κB.
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Affiliation(s)
- Edwin R Miranda
- School of Kinesiology, University of Michigan, Ann Arbor, Michigan, United States
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, United States
| | - Jacob T Mey
- Integrated Physiology and Molecular Metabolism, Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States
| | - Brian K Blackburn
- Applied Health Sciences and Kinesiology, Humboldt State University, Arcata, California, United States
| | - Alec B Chaves
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States
| | - Kelly N Z Fuller
- Division of Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Ryan K Perkins
- Department of Kinesiology, California State University Chico, Chico, California, United States
| | - Andrew T Ludlow
- School of Kinesiology, University of Michigan, Ann Arbor, Michigan, United States
| | - Jacob M Haus
- School of Kinesiology, University of Michigan, Ann Arbor, Michigan, United States
- Applied Health Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
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20
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Ramasamy R, Shekhtman A, Schmidt AM. RAGE/DIAPH1 and atherosclerosis through an evolving lens: Viewing the cell from the "Inside - Out". Atherosclerosis 2023; 394:117304. [PMID: 39492058 PMCID: PMC11309734 DOI: 10.1016/j.atherosclerosis.2023.117304] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 08/11/2023] [Accepted: 09/15/2023] [Indexed: 08/13/2024]
Abstract
BACKGROUND AND AIMS In hyperglycemia, inflammation, oxidative stress and aging, Damage Associated Molecular Patterns (DAMPs) accumulate in conditions such as atherosclerosis. Binding of DAMPs to receptors such as the receptor for advanced glycation end products (RAGE) activates signal transduction cascades that contribute to cellular stress. The cytoplasmic domain (tail) of RAGE (ctRAGE) binds to the formin Diaphanous1 (DIAPH1), which is important for RAGE signaling. This Review will detail the evidence linking the RAGE/DIAPH1 signaling pathway to atherosclerosis and envisages future therapeutic opportunities from the "inside-out" point of view in affected cells. METHODS PubMed was searched using a variety of search terms, including "receptor for advanced glycation end products" along with various combinations including "and atherosclerosis," "soluble RAGE and atherosclerosis," "statins and RAGE," "PPAR and RAGE" and "SGLT2 inhibitor and RAGE." RESULTS In non-diabetic and diabetic mice, antagonism or global deletion of Ager (the gene encoding RAGE) retards progression and accelerates regression of atherosclerosis. Global deletion of Diaph1 in mice devoid of the low density lipoprotein receptor (Ldlr) significantly attenuates atherosclerosis; mice devoid of both Diaph1 and Ldlr display significantly lower plasma and liver concentrations of cholesterol and triglyceride compared to mice devoid of Ldlr. Associations between RAGE pathway and human atherosclerosis have been identified based on relationships between plasma/serum concentrations of RAGE ligands, soluble RAGEs and atherosclerosis. CONCLUSIONS Efforts to target RAGE/DIAPH1 signaling through a small molecule antagonist therapeutic strategy hold promise to quell accelerated atherosclerosis in diabetes and in other forms of cardiovascular disease.
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Affiliation(s)
- Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, NYU Langone Medical Center, NY, USA
| | - Alexander Shekhtman
- Department of Chemistry, The State University of New York at Albany, Albany, NY, USA
| | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, NYU Langone Medical Center, NY, USA.
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21
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Ghosh AR, Bandopadhyay P, Sarkar J, Khanna S, Chaudhuri T, Tantia O, Chakrabarti P, Ganguly D. Mitochondrial sourcing of interferogenic ligands and an autoantigen in human obesity-associated metaflammation. Obesity (Silver Spring) 2023; 31:2229-2234. [PMID: 37496088 DOI: 10.1002/oby.23805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 04/26/2023] [Accepted: 04/28/2023] [Indexed: 07/28/2023]
Abstract
OBJECTIVE Visceral adipose tissue (VAT) inflammation contributes to metabolic dysregulation in obesity. VAT recruitment and activation of plasmacytoid dendritic cells (pDCs) through toll-like receptor 9 (TLR9) recognition of self-DNA, leading to induction of type I interferons, are crucial innate triggers for this VAT inflammation. It was hypothesized that mitochondrial DNA (mtDNA) can contribute to TLR9 activation in VAT-recruited pDCs in obesity, and this study aimed to identify the carrier protein for ligand access to TLR9 and to explore whether this also provides for a source of autoantigens in this context. METHODS VAT samples, used for gene expression studies as well as adipose explant cultures, were collected from patients with obesity (n = 54) and lean patients (n = 10). Supernatants from human pDC cultures, treated with adipose explant culture supernatants, were used for interferon α ELISA. Venous plasma, from patients with (n = 114) and without (n = 45) obesity, was used for an ELISA for autoantibodies. RESULTS MtDNA from VAT in obesity, in complex with mitochondrial transcription factor A protein (TFAM), acts as interferogenic ligands for pDCs. Humoral autoreactivity against TFAM is also induced in obesity. CONCLUSIONS Interferogenic ligands and an autoantigen can be sourced from dysfunctional mitochondria in VAT of humans with obesity. Further therapeutic and prognostic potential for this immune mechanism in obesity warrants exploration.
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Affiliation(s)
- Amrit Raj Ghosh
- Translational Research Unit of Excellence, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Purbita Bandopadhyay
- Translational Research Unit of Excellence, CSIR-Indian Institute of Chemical Biology, Kolkata, India
- Academy of Scientific and Innovative Research, Ghaziabad, India
| | - Jit Sarkar
- Department of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Shashi Khanna
- Institute of Laparoscopic Surgery Hospitals, Kolkata, India
| | | | - Om Tantia
- Institute of Laparoscopic Surgery Hospitals, Kolkata, India
| | - Partha Chakrabarti
- Academy of Scientific and Innovative Research, Ghaziabad, India
- Department of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Dipyaman Ganguly
- Translational Research Unit of Excellence, CSIR-Indian Institute of Chemical Biology, Kolkata, India
- Academy of Scientific and Innovative Research, Ghaziabad, India
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22
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Liu B, Meng Q, Gao X, Sun H, Xu Z, Wang Y, Zhou H. Lipid and glucose metabolism in senescence. Front Nutr 2023; 10:1157352. [PMID: 37680899 PMCID: PMC10481967 DOI: 10.3389/fnut.2023.1157352] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 08/09/2023] [Indexed: 09/09/2023] Open
Abstract
Senescence is an inevitable biological process. Disturbances in glucose and lipid metabolism are essential features of cellular senescence. Given the important roles of these types of metabolism, we review the evidence for how key metabolic enzymes influence senescence and how senescence-related secretory phenotypes, autophagy, apoptosis, insulin signaling pathways, and environmental factors modulate glucose and lipid homeostasis. We also discuss the metabolic alterations in abnormal senescence diseases and anti-cancer therapies that target senescence through metabolic interventions. Our work offers insights for developing pharmacological strategies to combat senescence and cancer.
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Affiliation(s)
- Bin Liu
- Department of Urology II, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Qingfei Meng
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China
| | - Xin Gao
- Department of Urology II, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Huihui Sun
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China
| | - Zhixiang Xu
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China
| | - Yishu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China
| | - Honglan Zhou
- Department of Urology II, The First Hospital of Jilin University, Changchun, Jilin, China
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23
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Ragazzi E, Burlina S, Cosma C, Chilelli NC, Lapolla A, Sartore G. Anti-diabetic combination therapy with pioglitazone or glimepiride added to metformin on the AGE-RAGE axis: a randomized prospective study. Front Endocrinol (Lausanne) 2023; 14:1163554. [PMID: 37635976 PMCID: PMC10453795 DOI: 10.3389/fendo.2023.1163554] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 07/26/2023] [Indexed: 08/29/2023] Open
Abstract
Introduction The ratio between advanced glycation end products (AGEs) and soluble form of receptor (s-RAGE) has been proposed as a risk marker for renal and cardiovascular diseases. The aim of this study was to evaluate in the diabetes condition the influence of two different oral anti-diabetic treatments on the AGE/s-RAGE ratio, during a 5-year observation period. Methods Seventy-three patients with type 2 diabetes mellitus were randomly assigned to a drug therapy with pioglitazone or glimepiride, combined to metformin. Each subject was evaluated at baseline and after 5 years of treatment. Results In both groups s-RAGE levels did not significantly vary, while the levels of AGE and AGE/s-RAGE were both significantly reduced, basal compared to 5-year values. Within pioglitazone group, as well within glimepiride group, significant variations (Δ, as difference between 5 years of treatment minus basal) were observed for AGE (Δ= -21.1±13.4 µg/ml, P<0.001 for pioglitazone; Δ= -14.4±11.4 µg/ml, P<0.001 for glimepiride) and in AGE/s-RAGE (Δ= -0.037±0.022 µg/pg, P<0.001 for pioglitazone; Δ= -0.024±0.020µg/pg, P<0.001 for glimepiride), suggesting an average decrease of the parameters by more than 50% in both treatments. Pioglitazone was more effective than glimepiride in reducing AGE/s-RAGE ratio after 5 years of therapy. Conclusion These data can help to explain the benefits of oral anti-diabetic therapy in relation to the reduction of cardiovascular risk, as suggested by variations in AGE/s-RAGE ratio as biochemical marker of endothelial function; in particular, treatment with pioglitazone seems to offer greater long-term benefit on AGE-RAGE axis.
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Affiliation(s)
- Eugenio Ragazzi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Silvia Burlina
- Department of Medicine – DIMED, University of Padova, Padova, Italy
| | - Chiara Cosma
- Department of Medicine – DIMED, University of Padova, Padova, Italy
| | | | | | - Giovanni Sartore
- Department of Medicine – DIMED, University of Padova, Padova, Italy
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24
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Muoio MG, Pellegrino M, Rapicavoli V, Talia M, Scavo G, Sergi V, Vella V, Pettinato S, Galasso MG, Lappano R, Scordamaglia D, Cirillo F, Pulvirenti A, Rigiracciolo DC, Maggiolini M, Belfiore A, De Francesco EM. RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer. Breast Cancer Res 2023; 25:84. [PMID: 37461077 PMCID: PMC10351154 DOI: 10.1186/s13058-023-01686-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 07/11/2023] [Indexed: 07/20/2023] Open
Abstract
The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated whether RAGE contributes to the oncogenic actions of Insulin, which plays a key role in BC progression particularly in obese and diabetic patients. Analysis of the publicly available METABRIC study, which collects gene expression and clinical data from a large cohort (n = 1904) of BC patients, revealed that RAGE and the Insulin Receptor (IR) are co-expressed and associated with negative prognostic parameters. In MCF-7, ZR75 and 4T1 BC cells, as well as in patient-derived Cancer-Associated Fibroblasts, the pharmacological inhibition of RAGE as well as its genetic depletion interfered with Insulin-induced activation of the oncogenic pathway IR/IRS1/AKT/CD1. Mechanistically, IR and RAGE directly interacted upon Insulin stimulation, as shown by in situ proximity ligation assays and coimmunoprecipitation studies. Of note, RAGE inhibition halted the activation of both IR and insulin like growth factor 1 receptor (IGF-1R), as demonstrated in MCF-7 cells KO for the IR and the IGF-1R gene via CRISPR-cas9 technology. An unbiased label-free proteomic analysis uncovered proteins and predicted pathways affected by RAGE inhibition in Insulin-stimulated BC cells. Biologically, RAGE inhibition reduced cell proliferation, migration, and patient-derived mammosphere formation triggered by Insulin. In vivo, the pharmacological inhibition of RAGE halted Insulin-induced tumor growth, without affecting blood glucose homeostasis. Together, our findings suggest that targeting RAGE may represent an appealing opportunity to blunt Insulin-induced oncogenic signaling in BC.
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Affiliation(s)
- M G Muoio
- Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122, Catania, Italy
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | - M Pellegrino
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | - V Rapicavoli
- Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122, Catania, Italy
| | - M Talia
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | - G Scavo
- Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122, Catania, Italy
| | - V Sergi
- Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122, Catania, Italy
| | - V Vella
- Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122, Catania, Italy
| | - S Pettinato
- Breast Unit Breast Surgery, Garibaldi-Nesima Hospital, 95122, Catania, Italy
| | - M G Galasso
- Pathological Anatomy Unit, Garibaldi-Nesima Hospital, 95122, Catania, Italy
| | - R Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | - D Scordamaglia
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | - F Cirillo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | - A Pulvirenti
- Bioinformatics Unit, Department of Clinical and Experimental Medicine, University of Catania, 95131, Catania, Italy
| | - D C Rigiracciolo
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139, Milan, Italy
| | - M Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy.
| | - A Belfiore
- Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122, Catania, Italy
| | - E M De Francesco
- Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122, Catania, Italy.
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Garza-Campos A, Prieto-Correa JR, Domínguez-Rosales JA, Hernández-Nazará ZH. Implications of receptor for advanced glycation end products for progression from obesity to diabetes and from diabetes to cancer. World J Diabetes 2023; 14:977-994. [PMID: 37547586 PMCID: PMC10401444 DOI: 10.4239/wjd.v14.i7.977] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/31/2023] [Accepted: 04/17/2023] [Indexed: 07/12/2023] Open
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are chronic pathologies with a high incidence worldwide. They share some pathological mechanisms, including hyperinsulinemia, the production and release of hormones, and hyperglycemia. The above, over time, affects other systems of the human body by causing tissue hypoxia, low-grade inflammation, and oxidative stress, which lay the pathophysiological groundwork for cancer. The leading causes of death globally are T2DM and cancer. Other main alterations of this pathological triad include the accumulation of advanced glycation end products and the release of endogenous alarmins due to cell death (i.e., damage-associated molecular patterns) such as the intracellular proteins high-mobility group box protein 1 and protein S100 that bind to the receptor for advanced glycation products (RAGE) - a multiligand receptor involved in inflammatory and metabolic and neoplastic processes. This review analyzes the latest advanced reports on the role of RAGE in the development of obesity, T2DM, and cancer, with an aim to understand the intracellular signaling mechanisms linked with cancer initiation. This review also explores inflammation, oxidative stress, hypoxia, cellular senescence, RAGE ligands, tumor microenvironment changes, and the “cancer hallmarks” of the leading tumors associated with T2DM. The assimilation of this information could aid in the development of diagnostic and therapeutic approaches to lower the morbidity and mortality associated with these diseases.
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Affiliation(s)
- Andrea Garza-Campos
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Roberto Prieto-Correa
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Alfredo Domínguez-Rosales
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Zamira Helena Hernández-Nazará
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
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26
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Gutowska K, Czajkowski K, Kuryłowicz A. Receptor for the Advanced Glycation End Products ( RAGE) Pathway in Adipose Tissue Metabolism. Int J Mol Sci 2023; 24:10982. [PMID: 37446161 DOI: 10.3390/ijms241310982] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/22/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Advanced glycation end products (AGEs) are mediators in the process of cellular dysfunction in response to hyperglycemia. Numerous data indicate that the accumulation of AGEs in the extracellular matrix plays a key role in the development of obesity-related adipose tissue dysfunction. Through binding of their membrane receptor (RAGE), AGEs affect numerous intracellular pathways and impair adipocyte differentiation, metabolism, and secretory activity. Therefore, inhibiting the production and accumulation of AGEs, as well as interfering with the metabolic pathways they activate, may be a promising therapeutic strategy for restoring normal adipose tissue function and, thus, combating obesity-related comorbidities. This narrative review summarizes data on the involvement of the RAGE pathway in adipose tissue dysfunction in obesity and the development of its metabolic complications. The paper begins with a brief review of AGE synthesis and the RAGE signaling pathway. The effect of the RAGE pathway on adipose tissue development and activity is then presented. Next, data from animal and human studies on the involvement of the RAGE pathway in obesity, diabetes, and cardiovascular diseases are summarized. Finally, therapeutic perspectives based on interference with the RAGE pathway are discussed.
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Affiliation(s)
- Klaudia Gutowska
- II Faculty and Clinic of Obstetrics and Gynaecology, Medical University of Warsaw, 00-315 Warsaw, Poland
- Doctoral School, Medical University of Warsaw, Zwirki i Wigury 81, 02-091 Warsaw, Poland
| | - Krzysztof Czajkowski
- II Faculty and Clinic of Obstetrics and Gynaecology, Medical University of Warsaw, 00-315 Warsaw, Poland
| | - Alina Kuryłowicz
- Department of Human Epigenetics, Mossakowski Medical Research Centre PAS, 02-106 Warsaw, Poland
- Department of General Medicine and Geriatric Cardiology, Medical Centre of Postgraduate Education, 00-401 Warsaw, Poland
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Wilson RA, Arivazhagan L, Ruiz HH, Zhou B, Qian K, Manigrasso MB, Bernadin R, Mangar K, Shekhtman A, Li H, Ramasamy R, Schmidt AM. Pharmacological antagonism of receptor for advanced glycation end products signaling promotes thermogenesis, healthful body mass and composition, and metabolism in mice. Obesity (Silver Spring) 2023; 31:1825-1843. [PMID: 37231626 PMCID: PMC10790363 DOI: 10.1002/oby.23774] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 02/14/2023] [Accepted: 02/28/2023] [Indexed: 05/27/2023]
Abstract
OBJECTIVE Optimal body mass and composition as well as metabolic fitness require tightly regulated and interconnected mechanisms across tissues. Disturbances in these regulatory networks tip the balance between metabolic health versus overweight and obesity and their complications. The authors previously demonstrated roles for the receptor for advanced glycation end products (RAGE) in obesity, as global- or adipocyte-specific deletion of Ager (the gene encoding RAGE) protected mice from high-fat diet-induced obesity and metabolic dysfunction. METHODS To explore translational strategies evoked by these observations, a small molecule antagonist of RAGE signaling, RAGE229, was administered to lean mice and mice with obesity undergoing diet-induced weight loss. Body mass and composition and whole body and adipose tissue metabolism were examined. RESULTS This study demonstrates that antagonism of RAGE signaling reduced body mass and adiposity and improved glucose, insulin, and lipid metabolism in lean male and female mice and in male mice with obesity undergoing weight loss. In adipose tissue and in human and mouse adipocytes, RAGE229 enhanced phosphorylation of protein kinase A substrates, which augmented lipolysis, mitochondrial function, and thermogenic programs. CONCLUSIONS Pharmacological antagonism of RAGE signaling is a potent strategy to optimize healthful body mass and composition and metabolic fitness.
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Affiliation(s)
- Robin A. Wilson
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Lakshmi Arivazhagan
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Henry H. Ruiz
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Boyan Zhou
- Departments of Population Health (Biostatistics) and Environmental Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Kun Qian
- Departments of Population Health (Biostatistics) and Environmental Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Michaele B. Manigrasso
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Rollanda Bernadin
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Kaamashri Mangar
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Alexander Shekhtman
- Department of Chemistry, State University of New York, Albany, New York, USA
| | - Huilin Li
- Departments of Population Health (Biostatistics) and Environmental Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
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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: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [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: 13] [Impact Index Per Article: 6.5] [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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Kim Y. Blood and Tissue Advanced Glycation End Products as Determinants of Cardiometabolic Disorders Focusing on Human Studies. Nutrients 2023; 15:nu15082002. [PMID: 37111220 PMCID: PMC10144557 DOI: 10.3390/nu15082002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 04/29/2023] Open
Abstract
Cardiometabolic disorders are characterised by a cluster of interactive risk determinants such as increases in blood glucose, lipids and body weight, as well as elevated inflammation and oxidative stress and gut microbiome changes. These disorders are associated with onset of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). T2DM is strongly associated with CVD. Dietary advanced glycation end products (dAGEs) attributable from modern diets high in sugar and/or fat, highly processed foods and high heat-treated foods can contribute to metabolic etiologies of cardiometabolic disorders. This mini review aims to determine whether blood dAGEs levels and tissue dAGEs levels are determinants of the prevalence of cardiometabolic disorders through recent human studies. ELISA (enzyme-linked immunosorbent assay), high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) for blood dAGEs measurement and skin auto fluorescence (SAF) for skin AGEs measurement can be used. Recent human studies support that a diet high in AGEs can negatively influence glucose control, body weight, blood lipid levels and vascular health through the elevated oxidative stress, inflammation, blood pressure and endothelial dysfunction compared with a diet low in AGEs. Limited human studies suggested a diet high in AGEs could negatively alter gut microbiota. SAF could be considered as one of the predictors affecting risks for cardiometabolic disorders. More intervention studies are needed to determine how dAGEs are associated with the prevalence of cardiometabolic disorders through gut microbiota changes. Further human studies are conducted to find the association between CVD events, CVD mortality and total mortality through SAF measurement, and a consensus on whether tissue dAGEs act as a predictor of CVD is required.
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Affiliation(s)
- Yoona Kim
- Department of Food and Nutrition, Institute of Agriculture and Life Science, Gyeongsang National University, 501 Jinju-daero, Jinju 52828, Gyeongsangnam-do, Republic of Korea
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Vanfleteren LE, Weidner J, Franssen FM, Gaffron S, Reynaert NL, Wouters EF, Spruit MA. Biomarker-based clustering of patients with chronic obstructive pulmonary disease. ERJ Open Res 2023; 9:00301-2022. [PMID: 36755966 PMCID: PMC9900445 DOI: 10.1183/23120541.00301-2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 10/16/2022] [Indexed: 11/25/2022] Open
Abstract
Rationale COPD has been associated repeatedly with single biomarkers of systemic inflammation, ignoring the complexity of inflammatory pathways. This study aimed to cluster patients with COPD based on systemic markers of inflammatory processes and to evaluate differences in their clinical characterisation and examine how these differences may relate to altered biological pathways. Methods 213 patients with moderate-to-severe COPD in a clinically stable state were recruited and clinically characterised, which included a venous blood sample for analysis of serum biomarkers. Patients were clustered based on the overall similarity in systemic levels of 57 different biomarkers. To determine interactions among the regulated biomarkers, protein networks and biological pathways were examined for each patient cluster. Results Four clusters were identified: two clusters with lower biomarker levels (I and II) and two clusters with higher biomarker levels (III and IV), with only a small number of biomarkers with similar trends in expression. Pathway analysis indicated that three of the four clusters were enriched in Rage (receptor for advanced glycation end-products) and Oncostatin M pathway components. Although the degree of airflow limitation was similar, the clinical characterisation of clusters ranged from 1) better functional capacity and health status and fewer comorbidities; 2) more underweight, osteoporosis and static hyperinflation; 3) more metabolically deranged; and 4) older subjects with worse functional capacity and higher comorbidity load. Conclusions These new insights may help to understand the functionally relevant inflammatory interactions in the pathophysiology of COPD as a heterogeneous disease.
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Affiliation(s)
- Lowie E.G.W. Vanfleteren
- COPD Center, Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Gothenburg, Sweden,Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,Corresponding author: Lowie Vanfleteren ()
| | - Julie Weidner
- Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Frits M.E. Franssen
- Department of Research and Development, CIRO+, Horn, The Netherlands,Department of Respiratory Medicine, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands,NUTRIM School of Nutrition and Translational Research in Metabolism, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | | | - Niki L. Reynaert
- Department of Respiratory Medicine, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands,NUTRIM School of Nutrition and Translational Research in Metabolism, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - Emiel F.M. Wouters
- Department of Research and Development, CIRO+, Horn, The Netherlands,Department of Respiratory Medicine, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands,NUTRIM School of Nutrition and Translational Research in Metabolism, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands,Ludwig Boltzmann Institute for Lung Health, Vienna, Austria
| | - Martijn A. Spruit
- Department of Research and Development, CIRO+, Horn, The Netherlands,Department of Respiratory Medicine, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands,NUTRIM School of Nutrition and Translational Research in Metabolism, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
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Du Z, Wu J, Feng Z, Ma X, Zhang T, Shu X, Xu J, Wang L, Luo M, Wu J. RAGE displays sex-specific differences in obesity-induced adipose tissue insulin resistance. Biol Sex Differ 2022; 13:65. [PMID: 36348465 PMCID: PMC9641909 DOI: 10.1186/s13293-022-00476-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 10/31/2022] [Indexed: 11/10/2022] Open
Abstract
Background The receptor for advanced glycation end products (RAGE) plays an important role in obesity-associated insulin sensitivity. We have also previously reported that RAGE deficiency improved insulin resistance in obesity-induced adipose tissue. The current study was aimed to elucidate the sex-specific mechanism of RAGE deficiency in adipose tissue metabolic regulation and systemic glucose homeostasis. Methods RAGE-deficient (RAGE−/−) mice were fed a high-fat diet (HFD) and subjected to glucose and insulin tolerance tests. Subcutaneous adipose tissue (sAT) was collected, and macrophage polarization was assessed by quantitative real-time PCR. Immunoblotting was performed to evaluate the insulin signaling in adipose tissues. Results Under HFD feeding conditions, body weight and adipocyte size of female RAGE deficient (RAGE−/−) were markedly lower than that of male mice. Female RAGE−/− mice showed significantly improved glucose and insulin tolerance compared to male RAGE−/− mice, accompanied with increased M2 macrophages polarization. Expressions of genes involved in anti-oxidant and browning were up-regulated in adipose tissues of female RAGE−/− mice. Moreover, insulin-induced AKT phosphorylation was significantly elevated in adipose tissue in female RAGE−/− mice compared to male RAGE−/− mice. Conclusions Our findings suggest that RAGE-mediated adipose tissue insulin resistance is sex-specific, which is associated with different expression of genes involved in anti-oxidant and browning and insulin-induced AKT phosphorylation. Supplementary Information The online version contains supplementary material available at 10.1186/s13293-022-00476-6.
Female RAGE−/− mice showed significantly improved glucose and insulin tolerance compared to male RAGE−/− mice. Female RAGE deficiency promotes M2 macrophage polarization in adipose tissues. Female RAGE deficiency prevents oxidative stress in adipose tissues. Female RAGE deficiency protects insulin-AKT signaling in adipose tissues.
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Delangre E, Oppliger E, Berkcan S, Gjorgjieva M, Correia de Sousa M, Foti M. S100 Proteins in Fatty Liver Disease and Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms231911030. [PMID: 36232334 PMCID: PMC9570375 DOI: 10.3390/ijms231911030] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 01/27/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent and slow progressing hepatic pathology characterized by different stages of increasing severity which can ultimately give rise to the development of hepatocellular carcinoma (HCC). Besides drastic lifestyle changes, few drugs are effective to some extent alleviate NAFLD and HCC remains a poorly curable cancer. Among the deregulated molecular mechanisms promoting NAFLD and HCC, several members of the S100 proteins family appear to play an important role in the development of hepatic steatosis, non-alcoholic steatohepatitis (NASH) and HCC. Specific members of this Ca2+-binding protein family are indeed significantly overexpressed in either parenchymal or non-parenchymal liver cells, where they exert pleiotropic pathological functions driving NAFLD/NASH to severe stages and/or cancer development. The aberrant activity of S100 specific isoforms has also been reported to drive malignancy in liver cancers. Herein, we discuss the implication of several key members of this family, e.g., S100A4, S100A6, S100A8, S100A9 and S100A11, in NAFLD and HCC, with a particular focus on their intracellular versus extracellular functions in different hepatic cell types. Their clinical relevance as non-invasive diagnostic/prognostic biomarkers for the different stages of NAFLD and HCC, or their pharmacological targeting for therapeutic purpose, is further debated.
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Stephen SJ, Bailey S, D'Erminio DN, Krishnamoorthy D, Iatridis JC, Vashishth D. Bone matrix quality in a developing high-fat diet mouse model is altered by RAGE deletion. Bone 2022; 162:116470. [PMID: 35718325 PMCID: PMC9296598 DOI: 10.1016/j.bone.2022.116470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 06/07/2022] [Accepted: 06/07/2022] [Indexed: 11/20/2022]
Abstract
Overweightness and obesity in adolescents are epidemics linked to chronic low-grade inflammation and elevated fracture risk. The increased fracture risk observed in overweight/obese adolescence contrasts the traditional concept that high body mass is protective against fracture, and thus highlights the need to determine why weight gain becomes detrimental to fracture during growth and maturity. The Receptor for Advanced Glycation End products (RAGE) is a central inflammatory regulator that can influence bone metabolism. It remains unknown how RAGE removal impacts skeletal fragility in overweightness/obesity, and whether increased fracture risk in adolescents could result from low-grade inflammation deteriorating bone quality. We characterized the multiscale structural, mechanical, and chemical properties of tibiae extracted from adolescent C57BL/6J (WT) and RAGE null (KO) mice fed either low-fat (LF) or high-fat (HF) diet for 12 weeks starting at 6 weeks of age using micro-computed tomography, strength, Raman spectroscopy, and nanoindentation. Overweight/obese WT HF mice possessed degraded mineral-crystal quality and increased matrix glycoxidation in the form of pentosidine and carboxymethyl-lysine, with HF diet in females only showing reduced cortical surface expansion and TMD independently of RAGE ablation. Furthermore, in contrast to males, HF diet in females led to more material damage and plastic deformation. RAGE KO mitigated glycoxidative matrix accumulation, preserved mineral quantity, and led to increased E/H ratio in females. Taken together, these results highlight the complex, multi-scale and sex-dependent relationships between bone quality and function under overweightness, and identifies RAGE-controlled glycoxidation as a target to potentially preserve matrix quality and mechanical integrity.
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Affiliation(s)
- Samuel J Stephen
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Stacyann Bailey
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Danielle N D'Erminio
- Leni and Peter W. May Department of Orthopaedics, Ichan School of Medicine at Mount Sinai, New York, NY, USA
| | - Divya Krishnamoorthy
- Leni and Peter W. May Department of Orthopaedics, Ichan School of Medicine at Mount Sinai, New York, NY, USA
| | - James C Iatridis
- Leni and Peter W. May Department of Orthopaedics, Ichan School of Medicine at Mount Sinai, New York, NY, USA
| | - Deepak Vashishth
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies Rensselaer Polytechnic Institute, Troy, NY, USA.
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Thiagarajan D, Quadri N, Jawahar S, Zirpoli H, Del Pozo CH, López-Díez R, Hasan SN, Yepuri G, Gugger PF, Finlin BS, Kern PA, Gabbay K, Schmidt AM, Ramasamy R. Aldose reductase promotes diet-induced obesity via induction of senescence in subcutaneous adipose tissue. Obesity (Silver Spring) 2022; 30:1647-1658. [PMID: 35894077 DOI: 10.1002/oby.23496] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 05/09/2022] [Accepted: 05/12/2022] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Aldose reductase (AKR1B1 in humans; Akr1b3 in mice), a key enzyme of the polyol pathway, mediates lipid accumulation in the murine heart and liver. The study objective was to explore potential roles for AKR1B1/Akr1b3 in the pathogenesis of obesity and its complications. METHODS The study employed mice treated with an inhibitor of aldose reductase or mice devoid of Akr1b3 were used to determine their response to a high-fat diet. The study used subcutaneous adipose tissue-derived adipocytes to investigate mechanisms by which AKR1B1/Akr1b3 promotes diet-induced obesity. RESULTS Increased expression of aldose reductase and senescence in the adipose tissue of humans and mice with obesity were demonstrated. Genetic deletion of Akr1b3 or pharmacological blockade of AKRIB3 with zopolrestat reduced high-fat-diet-induced obesity, attenuated markers of adipose tissue senescence, and increased lipolysis. CONCLUSIONS AKR1B1/Akr1b3 modulation of senescence in subcutaneous adipose tissue contributes to aberrant metabolic responses to high-fat feeding. These data unveil new opportunities to target these pathways to combat obesity.
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Affiliation(s)
- Devi Thiagarajan
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
- Saha Cardiovascular Research Center, Department of Physiology, University of Kentucky, Lexington, Kentucky, USA
| | - Nosirudeen Quadri
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Shabnam Jawahar
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Hylde Zirpoli
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Carmen Hurtado Del Pozo
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Raquel López-Díez
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Syed Nurul Hasan
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Gautham Yepuri
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Paul F Gugger
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Brian S Finlin
- Center for Clinical and Translational Sciences, University of Kentucky, Lexington, Kentucky, USA
| | - Philip A Kern
- Center for Clinical and Translational Sciences, University of Kentucky, Lexington, Kentucky, USA
| | | | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
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D’Erminio DN, Krishnamoorthy D, Lai A, Hoy RC, Natelson DM, Poeran J, Torres A, Laudier DM, Nasser P, Vashishth D, Illien-Jünger S, Iatridis JC. High fat diet causes inferior vertebral structure and function without disc degeneration in RAGE-KO mice. J Orthop Res 2022; 40:1672-1686. [PMID: 34676612 PMCID: PMC9021327 DOI: 10.1002/jor.25191] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 08/12/2021] [Accepted: 09/30/2021] [Indexed: 02/04/2023]
Abstract
Back pain and spinal pathologies are associated with obesity in juveniles and adults, yet studies identifying causal relationships are lacking and none investigate sex differences. This study determined if high fat (HF) diet causes structural and functional changes to vertebrae and intervertebral discs (IVDs); if these changes are modulated in mice with systematic ablation for the receptor for advanced glycation endproducts (RAGE-KO); and if these changes are sex-dependent. Wild-type (WT) and RAGE-KO mice were fed a low fat (LF) or HF diet for 12 weeks starting at 6 weeks, representing the juvenile population. HF diet led to weight/fat gain, glucose intolerance, and increased cytokine levels (IL-5, MIG, and RANTES); with less fat gain in RAGE-KO females. Most importantly, HF diet reduced vertebral trabecular bone volume fraction and compressive and shear moduli, without a modifying effect of RAGE-KO, but with a more pronounced effect in females. HF diet caused reduced cortical area fraction only in WT males. Neither HF diet nor RAGE-KO affected IVD degeneration grade. Biomechanical properties of coccygeal motion segments were affected by RAGE-KO but not diet, with some interactions identified. In conclusion, HF diet resulted in inferior vertebral structure and function with some sex differences, no IVD degeneration, and few modifying effects of RAGE-KO. These structural and functional deficiencies with HF diet provide further evidence that diet can affect spinal structures and may increase the risk for spinal injury and degeneration with aging and additional stressors. Back pain and spinal pathologies are associated with obesity in juveniles and adults, yet studies identifying causal relationships are lacking and none investigate sex differences.
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Affiliation(s)
- Danielle N D’Erminio
- Leni & Peter W. May Dept. of Orthopaedics, Mount Sinai Health System, New York, NY
- Dept. of Biomedical Engineering, The City College of New York at CUNY, NY, NY
| | - Divya Krishnamoorthy
- Leni & Peter W. May Dept. of Orthopaedics, Mount Sinai Health System, New York, NY
- 3DBio Therapeutics, New York, NY
| | - Alon Lai
- Leni & Peter W. May Dept. of Orthopaedics, Mount Sinai Health System, New York, NY
| | - Robert C Hoy
- Leni & Peter W. May Dept. of Orthopaedics, Mount Sinai Health System, New York, NY
| | - Devorah M Natelson
- Leni & Peter W. May Dept. of Orthopaedics, Mount Sinai Health System, New York, NY
| | - Jashvant Poeran
- Dept. of Population Health Science & Policy, and Medicine, Mount Sinai Health System, New York, NY
| | - Andrew Torres
- Leni & Peter W. May Dept. of Orthopaedics, Mount Sinai Health System, New York, NY
| | - Damien M Laudier
- Leni & Peter W. May Dept. of Orthopaedics, Mount Sinai Health System, New York, NY
| | - Philip Nasser
- Leni & Peter W. May Dept. of Orthopaedics, Mount Sinai Health System, New York, NY
| | - Deepak Vashishth
- Ctr. for Biotechnology & Interdisciplinary Studies, Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY
| | - Svenja Illien-Jünger
- Leni & Peter W. May Dept. of Orthopaedics, Mount Sinai Health System, New York, NY
- Emory University School of Medicine, Department of Orthopaedics, Atlanta, GA
| | - James C Iatridis
- Leni & Peter W. May Dept. of Orthopaedics, Mount Sinai Health System, New York, NY
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George S, Jean-Baptiste W, Yusuf Ali A, Inyang B, Koshy FS, George K, Poudel P, Chalasani R, Goonathilake MR, Waqar S, Mohammed L. The Role of Type 2 Diabetes in Pancreatic Cancer. Cureus 2022; 14:e26288. [PMID: 35898377 PMCID: PMC9308974 DOI: 10.7759/cureus.26288] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 06/24/2022] [Indexed: 11/05/2022] Open
Abstract
The incidence of type 2 diabetes mellitus (T2DM) and its potential complications, such as cancers, are increasing worldwide at an astounding rate. There are many factors such as obesity, diabetes, alcohol consumption, and the adoption of sedentary lifestyles that are driving pancreatic cancer (PC) to become one of the leading causes of cancer mortality in the United States. PC is notorious for its generic symptoms and late-stage presentation with rapid metastasis. The connection between T2DM and the risk of PC development is multifaceted and complex. Some of the proposed theories reveal that chronic inflammation, insulin resistance, hyperinsulinemia, hyperglycemia, and abnormalities in the insulin and insulin-like growth factor axis (IGF) contribute to the disease association between these two conditions. This literature review aims to highlight relevant studies and explore the molecular mechanisms involved in the etiology of diabetes and its impact on PC development, as well as the role of anti-diabetic agents on PC. Despite extensive studies, the exact interaction between T2DM and PC remains obscure and will need further investigation. According to current knowledge, there is a substantial link between diabetes, obesity, and dietary patterns in the development and progression of PC. Consequently, focusing our efforts on preventive measures by reducing modifiable risk factors remains the most effective strategy to reduce the risk of PC at this time. Antidiabetic drugs can have various effects on the occurrence and prognosis of PC with metformin offering a clear benefit of inhibiting PC and insulin increasing the risk of PC. The development of future novel therapies will require a deeper knowledge of the triggering mechanisms and interplay between these two disease states.
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Arivazhagan L, López-Díez R, Shekhtman A, Ramasamy R, Schmidt AM. Glycation and a Spark of ALEs (Advanced Lipoxidation End Products) - Igniting RAGE/Diaphanous-1 and Cardiometabolic Disease. Front Cardiovasc Med 2022; 9:937071. [PMID: 35811725 PMCID: PMC9263181 DOI: 10.3389/fcvm.2022.937071] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 05/30/2022] [Indexed: 12/25/2022] Open
Abstract
Obesity and non-alcoholic fatty liver disease (NAFLD) are on the rise world-wide; despite fervent advocacy for healthier diets and enhanced physical activity, these disorders persist unabated and, long-term, are major causes of morbidity and mortality. Numerous fundamental biochemical and molecular pathways participate in these events at incipient, mid- and advanced stages during atherogenesis and impaired regression of established atherosclerosis. It is proposed that upon the consumption of high fat/high sugar diets, the production of receptor for advanced glycation end products (RAGE) ligands, advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs), contribute to the development of foam cells, endothelial injury, vascular inflammation, and, ultimately, atherosclerosis and its consequences. RAGE/Diaphanous-1 (DIAPH1) increases macrophage foam cell formation; decreases cholesterol efflux and causes foam cells to produce and release damage associated molecular patterns (DAMPs) molecules, which are also ligands of RAGE. DAMPs stimulate upregulation of Interferon Regulatory Factor 7 (IRF7) in macrophages, which exacerbates vascular inflammation and further perturbs cholesterol metabolism. Obesity and NAFLD, characterized by the upregulation of AGEs, ALEs and DAMPs in the target tissues, contribute to insulin resistance, hyperglycemia and type two diabetes. Once in motion, a vicious cycle of RAGE ligand production and exacerbation of RAGE/DIAPH1 signaling ensues, which, if left unchecked, augments cardiometabolic disease and its consequences. This Review focuses on RAGE/DIAPH1 and its role in perturbation of metabolism and processes that converge to augur cardiovascular disease.
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Affiliation(s)
- Lakshmi Arivazhagan
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States
| | - Raquel López-Díez
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States
| | - Alexander Shekhtman
- Department of Chemistry, The State University of New York at Albany, Albany, NY, United States
| | - Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States
| | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States,*Correspondence: Ann Marie Schmidt
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Wang Q, Xi Y, Chen B, Zhao H, Yu W, Xie D, Liu W, He F, Xu C, Cheng J. Receptor of Advanced Glycation End Products Deficiency Attenuates Cisplatin-Induced Acute Nephrotoxicity by Inhibiting Apoptosis, Inflammation and Restoring Fatty Acid Oxidation. Front Pharmacol 2022; 13:907133. [PMID: 35712715 PMCID: PMC9196246 DOI: 10.3389/fphar.2022.907133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/12/2022] [Indexed: 11/17/2022] Open
Abstract
Cisplatin is a widely used and potent anti-neoplastic agent, but severe and inescapable side effects in multiple normal tissues and organs limit its application, especially nephrotoxicity. Molecular mechanisms of cisplatin nephrotoxicity involve mitochondrial damage, oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis, necroptosis, etc. Receptor of advanced glycation end products (RAGE) is a multiligand pattern recognition receptor, engaged in inflammatory signaling and mitochondrial homeostasis. Whether inhibition of RAGE alleviates cisplatin-induced nephropathy has not been investigated. Here, we revealed that RAGE deficiency attenuates cisplatin-induced acute nephrotoxicity, as evidenced by reduced apoptosis, inflammation, lipid accumulation, restored mitochondrial homeostasis and fatty acid oxidation in renal tubular epithelial cells (TECs). In vitro studies showed that, the RAGE-specific inhibitor FPS-ZM1 attenuated the cisplatin-induced decrease of cell viability and fatty acid oxidation in the normal rat renal TEC line NRK-52E cells. Taken together, RAGE knockout mitigated cisplatin-induced acute nephrotoxicity by inhibiting apoptosis, inflammation, and restoring fatty acid oxidation in TECs, suggesting that RAGE inhibition could be a therapeutic option for cisplatin-induced acute nephrotoxicity.
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Affiliation(s)
- Qiang Wang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China.,Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, China
| | - Yuemei Xi
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China.,Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, China
| | - Binyang Chen
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China.,Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, China
| | - Hairong Zhao
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China.,Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, China
| | - Wei Yu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China.,Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, China
| | - De Xie
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China.,Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, China
| | - Weidong Liu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China.,Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, China
| | - Furong He
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China.,Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, China
| | - Chenxi Xu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China.,Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, China
| | - Jidong Cheng
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China.,Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, China
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Sabbatinelli J, Castiglione S, Macrì F, Giuliani A, Ramini D, Vinci MC, Tortato E, Bonfigli AR, Olivieri F, Raucci A. Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study. Cardiovasc Diabetol 2022; 21:95. [PMID: 35668468 PMCID: PMC9169316 DOI: 10.1186/s12933-022-01535-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 05/26/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Advanced glycation end-products (AGEs) and their interaction with the receptor for advanced glycation end-products (RAGE) play a pivotal role in the development and progression of type 2 diabetes. In this retrospective cohort study, we explored the association of circulating levels of soluble RAGE (sRAGE) isoforms, i.e., endogenous secretory esRAGE and cleaved cRAGE, AGEs and their respective ratios with 15-year all-cause mortality in type 2 diabetes. METHODS Baseline AGEs and sRAGE isoforms concentration were measured by ELISA in 362 patients with type 2 diabetes and in 125 age- and gender-matched healthy control subjects (CTR). Independent predictors of mortality were determined using Cox proportional-hazards models and used to build and validate a nomogram for all-cause mortality prediction in type 2 diabetes. RESULTS AGEs, total sRAGE, cRAGE and the AGEs/sRAGE and AGEs/esRAGE ratios were significantly increased in patients with type 2 diabetes compared to CTR (p < 0.001). In CTR subjects, but not in type 2 diabetes patients, a significant negative correlation between cRAGE and age was confirmed (p = 0.003), whereas the AGEs/sRAGE (p = 0.032) and AGEs/cRAGE (p = 0.006) ratios were positively associated with age. At an average follow-up of 15 years (4,982 person-years), 130 deaths were observed. The increase in the AGEs/cRAGE ratio was accompanied by a higher risk of all-cause mortality in patients with type 2 diabetes (HR per each SD increment = 1.30, 95% CI 1.15-1.47; p < 0.001). Moreover, sRAGE was associated with the development of major adverse cardiovascular events (MACE) in type 2 diabetes patients without previous MACE (OR for each SD increase: 1.48, 95% CI 1.11-1.89). A nomogram based on age, sex, HbA1c, systolic blood pressure, and the AGEs/cRAGE ratio was built to predict 5-, 10- and 15-year survival in type 2 diabetes. Patients were categorized into quartiles of the monogram scores and Kaplan-Meier survival curves confirmed the prognostic accuracy of the model (log-rank p = 6.5 × 10- 13). CONCLUSIONS The ratio between AGEs and the cRAGE isoform is predictive of 15-year survival in patients with type 2 diabetes. Our data support the assessment of circulating AGEs and soluble RAGE isoforms in patients with type 2 diabetes as predictors of MACE and all-cause mortality.
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Affiliation(s)
- Jacopo Sabbatinelli
- Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
- Laboratory Medicine Unit, Azienda Ospedaliero Universitaria "Ospedali Riuniti", Ancona, Italy
| | - Stefania Castiglione
- Experimental Cardio-Oncology and Cardiovascular Aging Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy
| | - Federica Macrì
- Experimental Cardio-Oncology and Cardiovascular Aging Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy
| | - Angelica Giuliani
- Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy.
| | - Deborah Ramini
- Clinical Laboratory and Molecular Diagnostic, IRCCS INRCA, Ancona, Italy
| | - Maria Cristina Vinci
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Milan, Italy
| | - Elena Tortato
- Metabolic Diseases and Diabetology Department, IRCCS INRCA, Ancona, Italy
| | | | - Fabiola Olivieri
- Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
- Clinical Laboratory and Molecular Diagnostic, IRCCS INRCA, Ancona, Italy
| | - Angela Raucci
- Experimental Cardio-Oncology and Cardiovascular Aging Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy
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Popp CJ, Zhou B, Manigrasso MB, Li H, Curran M, Hu L, St-Jules DE, Alemán JO, Vanegas SM, Jay M, Bergman M, Segal E, Sevick MA, Schmidt AM. Soluble Receptor for Advanced Glycation End Products (sRAGE) Isoforms Predict Changes in Resting Energy Expenditure in Adults with Obesity during Weight Loss. Curr Dev Nutr 2022; 6:nzac046. [PMID: 35542387 PMCID: PMC9071542 DOI: 10.1093/cdn/nzac046] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/17/2022] [Accepted: 03/24/2022] [Indexed: 01/05/2023] Open
Abstract
Background Accruing evidence indicates that accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) play a significant role in obesity and type 2 diabetes. The concentrations of circulating RAGE isoforms, such as soluble RAGE (sRAGE), cleaved RAGE (cRAGE), and endogenous secretory RAGE (esRAGE), collectively sRAGE isoforms, may be implicit in weight loss and energy compensation resulting from caloric restriction. Objectives We aimed to evaluate whether baseline concentrations of sRAGE isoforms predicted changes (∆) in body composition [fat mass (FM), fat-free mass (FFM)], resting energy expenditure (REE), and adaptive thermogenesis (AT) during weight loss. Methods Data were collected during a behavioral weight loss intervention in adults with obesity. At baseline and 3 mo, participants were assessed for body composition (bioelectrical impedance analysis) and REE (indirect calorimetry), and plasma was assayed for concentrations of sRAGE isoforms (sRAGE, esRAGE, cRAGE). AT was calculated using various mathematical models that included measured and predicted REE. A linear regression model that adjusted for age, sex, glycated hemoglobin (HbA1c), and randomization arm was used to test the associations between sRAGE isoforms and metabolic outcomes. Results Participants (n = 41; 70% female; mean ± SD age: 57 ± 11 y; BMI: 38.7 ± 3.4 kg/m2) experienced modest and variable weight loss over 3 mo. Although baseline sRAGE isoforms did not predict changes in ∆FM or ∆FFM, all baseline sRAGE isoforms were positively associated with ∆REE at 3 mo. Baseline esRAGE was positively associated with AT in some, but not all, AT models. The association between sRAGE isoforms and energy expenditure was independent of HbA1c, suggesting that the relation was unrelated to glycemia. Conclusions This study demonstrates a novel link between RAGE and energy expenditure in human participants undergoing weight loss.This trial was registered at clinicaltrials.gov as NCT03336411.
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Affiliation(s)
- Collin J Popp
- Center for Healthful Behavior Change, Department of Population Health, New York University Langone Health, New York, NY, USA
| | - Boyan Zhou
- Division of Biostatistics, Department of Population Health, New York University Langone Health, New York, NY, USA
| | - Michaele B Manigrasso
- Diabetes Research Program, Department of Medicine, New York University Langone Health, New York, NY, USA
| | - Huilin Li
- Division of Biostatistics, Department of Population Health, New York University Langone Health, New York, NY, USA
| | - Margaret Curran
- Center for Healthful Behavior Change, Department of Population Health, New York University Langone Health, New York, NY, USA
| | - Lu Hu
- Center for Healthful Behavior Change, Department of Population Health, New York University Langone Health, New York, NY, USA
| | - David E St-Jules
- Department of Nutrition, University of Nevada, Reno, Reno, NV, USA
| | - José O Alemán
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, New York University Langone Health, New York, NY, USA
| | - Sally M Vanegas
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, New York University Langone Health, New York, NY, USA
| | - Melanie Jay
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, New York University Langone Health, New York, NY, USA
| | - Michael Bergman
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, New York University Langone Health, New York, NY, USA
| | - Eran Segal
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel
| | - Mary A Sevick
- Center for Healthful Behavior Change, Department of Population Health, New York University Langone Health, New York, NY, USA
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, New York University Langone Health, New York, NY, USA
| | - Ann M Schmidt
- Diabetes Research Program, Department of Medicine, New York University Langone Health, New York, NY, USA
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Ramasamy R, Shekhtman A, Schmidt AM. The RAGE/DIAPH1 Signaling Axis & Implications for the Pathogenesis of Diabetic Complications. Int J Mol Sci 2022; 23:ijms23094579. [PMID: 35562970 PMCID: PMC9102165 DOI: 10.3390/ijms23094579] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/13/2022] [Accepted: 04/17/2022] [Indexed: 02/08/2023] Open
Abstract
Increasing evidence links the RAGE (receptor for advanced glycation end products)/DIAPH1 (Diaphanous 1) signaling axis to the pathogenesis of diabetic complications. RAGE is a multi-ligand receptor and through these ligand-receptor interactions, extensive maladaptive effects are exerted on cell types and tissues targeted for dysfunction in hyperglycemia observed in both type 1 and type 2 diabetes. Recent evidence indicates that RAGE ligands, acting as damage-associated molecular patterns molecules, or DAMPs, through RAGE may impact interferon signaling pathways, specifically through upregulation of IRF7 (interferon regulatory factor 7), thereby heralding and evoking pro-inflammatory effects on vulnerable tissues. Although successful targeting of RAGE in the clinical milieu has, to date, not been met with success, recent approaches to target RAGE intracellular signaling may hold promise to fill this critical gap. This review focuses on recent examples of highlights and updates to the pathobiology of RAGE and DIAPH1 in diabetic complications.
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Affiliation(s)
- Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA;
| | - Alexander Shekhtman
- Department of Chemistry, The State University of New York at Albany, Albany, NY 12222, USA;
| | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA;
- Correspondence:
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Liu W, Li Z, Feng C, Hu S, Yang X, Xiao K, Nong Q, Xiao Q, Wu K, Li XQ, Cao W. The structures of two polysaccharides from Angelica sinensis and their effects on hepatic insulin resistance through blocking RAGE. Carbohydr Polym 2022; 280:119001. [PMID: 35027136 DOI: 10.1016/j.carbpol.2021.119001] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/02/2021] [Accepted: 12/07/2021] [Indexed: 02/08/2023]
Abstract
This study found two novel homogeneous polysaccharides from Angelica sinensis, APS-1I and APS-2II, binding to RAGE with a dissociation constant of 2.02 ± 0.2 and 85.92 ± 0.2 μM, respectively. APS-1I is a 17.0 kDa heteropolysaccharide, whose backbone is composed of α-1,6-Glcp, α-1,3,6-Glcp, α-1,2-Glcp, α-1,4-Galp, and α-1,3-Rhap, and whose two branches contain α-1,3,5-Araf, α-1,3-Araf, α-1,4-Galp, β-1,3-Galp, and β-1,4-Glcp. APS-2II is a 10.0 kDa linear glucan, that contains α-1,6-Glcp, α-1,3-Glcp, α-1,2-Glcp, and α-T-Glcp. In vitro, APS-1I demonstrated better promotion on glucose absorption and stronger repression on p-IRS-1 (Ser307), p-IRS-2 (Ser731), p-JNK, and p-P38 than APS-2II in insulin resistance (IR)-HepG2 cells. Furthermore, APS-1I treatment couldn't further decrease the inhibition on the phosphorylation of JNK and P38 produced by RAGE siRNA in IR-HepG2 cells. In vivo, APS-1I markedly improved IR and reversed the livers RAGE-JNK/p38-IRS signaling in high-fat-diet and streptozotocin-induced diabetic rats, suggesting that APS-1I could be a potential agent for improving IR in type 2 diabetes.
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Affiliation(s)
- Wenjuan Liu
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Zezhi Li
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Caixia Feng
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Shengwei Hu
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Xin Yang
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Kaimin Xiao
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Qiuna Nong
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Qianhan Xiao
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Kehan Wu
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China
| | - Xiao-Qiang Li
- Department of Pharmacology and Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Wei Cao
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China; Department of Pharmacology and Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
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Prasad K, Khan AS, Bhanumathy KK. Does AGE-RAGE Stress Play a Role in the Development of Coronary Artery Disease in Obesity? Int J Angiol 2022; 31:1-9. [PMID: 35221846 PMCID: PMC8881108 DOI: 10.1055/s-0042-1742587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
This article deals with the role of AGE (advanced glycation end products)-RAGE (receptor for AGE) stress (AGE/sRAGE) in the development of coronary artery disease (CAD) in obesity. CAD is due to atherosclerosis in coronary artery. The serum/plasma levels of AGE and sRAGE are reduced, while AGE-RAGE stress and expression of RAGE are elevated in obese individuals. However, the levels of AGE are elevated in obese individuals with more than one metabolic syndrome. The increases in the AGE-RAGE stress would elevate the expression and production of atherogenic factors, including reactive oxygen species, nuclear factor-kappa B, cytokines, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial leukocyte adhesion molecules, monocyte chemoattractant protein-1, granulocyte-macrophage colony-stimulating factor, and growth factors. Low levels of sRAGE would also increase the atherogenic factors. The increases in the AGE-RAGE stress and decreases in the levels of sRAGE would induce development of atherosclerosis, leading to CAD. The therapeutic regimen for AGE-RAGE stress-induced CAD in obesity would include lowering of AGE intake, prevention of AGE formation, degradation of AGE in vivo, suppression of RAGE expression, blockade of AGE-RAGE interaction, downregulation of sRAGE expression, and use of antioxidants. In conclusion, the data suggest that AGE-RAGE stress is involved in the development of CAD in obesity, and the therapeutic interventions to reduce AGE-RAGE would be helpful in preventing, regressing, and slowing the progression of CAD in obesity.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada,Address for correspondence Kailash Prasad, MBBS, MD, PhD, DSc Department of Physiology (APP), College of Medicine, University of Saskatoon107 Wiggins Road, Saskatoon, SK, S7N 5E5Canada
| | - Amal S. Khan
- Community, Health and Epidemiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Kalpana K. Bhanumathy
- Division of Oncology, Cancer Cluster Unit, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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Simvastatin Improves Microcirculatory Function in Nonalcoholic Fatty Liver Disease and Downregulates Oxidative and ALE-RAGE Stress. Nutrients 2022; 14:nu14030716. [PMID: 35277075 PMCID: PMC8838100 DOI: 10.3390/nu14030716] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 01/11/2022] [Accepted: 01/14/2022] [Indexed: 12/12/2022] Open
Abstract
Increased reactive oxidative stress, lipid peroxidation, inflammation, and fibrosis, which contribute to tissue damage and development and progression of nonalcoholic liver disease (NAFLD), play important roles in microcirculatory disorders. We investigated the effect of the modulatory properties of simvastatin (SV) on the liver and adipose tissue microcirculation as well as metabolic and oxidative stress parameters, including the advanced lipoxidation end product–receptors of advanced glycation end products (ALE-RAGE) pathway. SV was administered to an NAFLD model constructed using a high-fat–high-carbohydrate diet (HFHC). HFHC caused metabolic changes indicative of nonalcoholic steatohepatitis; treatment with SV protected the mice from developing NAFLD. SV prevented microcirculatory dysfunction in HFHC-fed mice, as evidenced by decreased leukocyte recruitment to hepatic and fat microcirculation, decreased hepatic stellate cell activation, and improved hepatic capillary network architecture and density. SV restored basal microvascular blood flow in the liver and adipose tissue and restored the endothelium-dependent vasodilatory response of adipose tissue to acetylcholine. SV treatment restored antioxidant enzyme activity and decreased lipid peroxidation, ALE-RAGE pathway activation, steatosis, fibrosis, and inflammatory parameters. Thus, SV may improve microcirculatory function in NAFLD by downregulating oxidative and ALE-RAGE stress and improving steatosis, fibrosis, and inflammatory parameters.
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Merhi Z, Du XQ, Charron MJ. Postnatal weaning to different diets leads to different reproductive phenotypes in female offspring following perinatal exposure to high levels of dietary advanced glycation end products. F&S SCIENCE 2022; 3:95-105. [PMID: 35559999 DOI: 10.1016/j.xfss.2021.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 11/30/2021] [Accepted: 12/02/2021] [Indexed: 06/15/2023]
Abstract
OBJECTIVE To examine, following perinatal exposure to a diet high in advanced glycation end products (AGEs), whether the use of standard AGE-free mouse chow during the postweaning period alters metabolism and reproduction differently than exposure to a diet low in AGEs. DESIGN Experimental animal study. SETTING University-based research laboratory. ANIMAL(S) Female CD1 mice. INTERVENTION(S) Seven-week-old mice were placed on a diet either low or high in AGEs perinatally, before mating and then during pregnancy and lactation. All offspring were weaned onto an AGE-free normal chow. MAIN OUTCOME MEASURE(S) Growth curve, liver and abdominal fat weight, insulin and glucose tolerance tests, vaginal opening, estrous cyclicity, and serum levels of antimüllerian hormone, leptin, and adiponectin were assessed. Ovarian histologic examination for follicular count and gene expression was also performed. RESULT(S) Compared with the mice exposed to a diet low in AGEs, the mice exposed to a diet high in AGEs showed lower body weight in pups, lower liver weight, delayed vaginal opening, higher serum antimüllerian hormone levels, lower primordial and secondary follicle pools, and higher ovarian Fshr messenger RNA levels. CONCLUSION(S) Following weaning, perinatal AGEs can target puberty onset and folliculogenesis differently to standard mouse chow.
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Affiliation(s)
- Zaher Merhi
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, SUNY Downstate Health Sciences University, Brooklyn, New York; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York.
| | - Xiu Quan Du
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York
| | - Maureen J Charron
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York; Department of Obstetrics, Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, New York; Department of Medicine and the Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, New York
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Jafarnejad S, Hooshiar S, Esmaili H, Taherian A. Exercise, Advanced Glycation End Products, and Their Effects on Cardiovascular Disorders: A Narrative Review. HEART AND MIND 2022. [DOI: 10.4103/hm.hm_31_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Hernandez-Castillo C, Shuck SC. Diet and Obesity-Induced Methylglyoxal Production and Links to Metabolic Disease. Chem Res Toxicol 2021; 34:2424-2440. [PMID: 34851609 DOI: 10.1021/acs.chemrestox.1c00221] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The obesity rate in the United States is 42.4% and has become a national epidemic. Obesity is a complex condition that is influenced by socioeconomic status, ethnicity, genetics, age, and diet. Increased consumption of a Western diet, one that is high in processed foods, red meat, and sugar content, is associated with elevated obesity rates. Factors that increase obesity risk, such as socioeconomic status, also increase consumption of a Western diet because of a limited access to healthier options and greater affordability of processed foods. Obesity is a public health threat because it increases the risk of several pathologies, including atherosclerosis, diabetes, and cancer. The molecular mechanisms linking obesity to disease onset and progression are not well understood, but a proposed mechanism is physiological changes caused by altered lipid peroxidation, glycolysis, and protein metabolism. These metabolic pathways give rise to reactive molecules such as the abundant electrophile methylglyoxal (MG), which covalently modifies nucleic acids and proteins. MG-adducts are associated with obesity-linked pathologies and may have potential for biomonitoring to determine the risk of disease onset and progression. MG-adducts may also play a role in disease progression because they are mutagenic and directly impact protein stability and function. In this review, we discuss how obesity drives metabolic alterations, how these alterations lead to MG production, the association of MG-adducts with disease, and the potential impact of MG-adducts on cellular function.
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Affiliation(s)
- Carlos Hernandez-Castillo
- Department of Diabetes and Cancer Metabolism, Beckman Research Institute of City of Hope, Duarte, California 91010, United States
| | - Sarah C Shuck
- Department of Diabetes and Cancer Metabolism, Beckman Research Institute of City of Hope, Duarte, California 91010, United States
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Tandon P, Abrams ND, Carrick DM, Chander P, Dwyer J, Fuldner R, Gannot G, Laughlin M, McKie G, PrabhuDas M, Singh A, Tsai SYA, Vedamony MM, Wang C, Liu CH. Metabolic Regulation of Inflammation and Its Resolution: Current Status, Clinical Needs, Challenges, and Opportunities. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 207:2625-2630. [PMID: 34810268 PMCID: PMC9996538 DOI: 10.4049/jimmunol.2100829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 09/29/2021] [Indexed: 02/05/2023]
Abstract
Metabolism and inflammation have been viewed as two separate processes with distinct but critical functions for our survival: metabolism regulates the utilization of nutrients, and inflammation is responsible for defense and repair. Both respond to an organism's stressors to restore homeostasis. The interplay between metabolic status and immune response (immunometabolism) plays an important role in maintaining health or promoting disease development. Understanding these interactions is critical in developing tools for facilitating novel preventative and therapeutic approaches for diseases, including cancer. This trans-National Institutes of Health workshop brought together basic scientists, technology developers, and clinicians to discuss state-of-the-art, innovative approaches, challenges, and opportunities to understand and harness immunometabolism in modulating inflammation and its resolution.
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Affiliation(s)
- Pushpa Tandon
- National Cancer Institute, National Institutes of Health, Rockville, MD;
| | - Natalie D Abrams
- National Cancer Institute, National Institutes of Health, Rockville, MD
| | | | - Preethi Chander
- National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
| | - Johanna Dwyer
- Office of Dietary Supplements, National Institutes of Health, Bethesda, MD
| | - Rebecca Fuldner
- National Institute of Aging, National Institutes of Health, Bethesda, MD
| | - Gallya Gannot
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD
| | - Maren Laughlin
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - George McKie
- National Eye Institute, National Institutes of Health, Bethesda, MD
| | - Mercy PrabhuDas
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD
| | - Anju Singh
- National Cancer Institute, National Institutes of Health, Rockville, MD
| | - Shang-Yi Anne Tsai
- National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD
| | - Merriline M Vedamony
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD; and
| | - Chiayeng Wang
- National Cancer Institute, National Institutes of Health, Rockville, MD
| | - Christina H Liu
- National Institute of General Medical Sciences, National Institutes of Health, Bethesda, MD
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Role of RAGE in obesity-induced adipose tissue inflammation and insulin resistance. Cell Death Discov 2021; 7:305. [PMID: 34686659 PMCID: PMC8536716 DOI: 10.1038/s41420-021-00711-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/22/2021] [Accepted: 10/11/2021] [Indexed: 12/14/2022] Open
Abstract
Obesity is known to be associated with adipose tissue inflammation and insulin resistance. Importantly, in obesity, the accumulation of proinflammatory macrophages in adipose tissue correlates with insulin resistance. We hypothesized that the receptor for advanced glycation end products (RAGE) and associated ligands are involved in adipose tissue insulin resistance, and that the activation of the AGE–RAGE axis plays an important role in obesity-associated inflammation. C57BL/6J mice (WT) and RAGE deficient (RAGE−/−) mice were fed a high fat diet (HFD) and subjected to glucose and insulin tolerance tests. Epdidymal adipose tissue (eAT) was collected and adipose stromal vascular cells isolated using flow cytometry. Visceral adipose tissue macrophage polarization was assessed by quantitative real time PCR. Immunoblotting was performed to evaluate the insulin signaling in adipose tissues. In additional studies, cell trafficking was assessed by injecting labeled blood monocytes into recipient mice. RAGE−/− mice displayed improved insulin sensitivity and glucose tolerance, accompanied by decreased body weight and eAT mass. Exogenous methylglyoxal (MGO) impaired insulin-stimulated AKT signaling in adipose tissues from WT mice fed a normal chow diet, but not in RAGE−/− mice. In contrast, in obese mice, treatment with MGO did not reduce insulin-induced phosphorylation of AKT in WT-HFD mice. Moreover, insulin-induced AKT phosphorylation was found to be impaired in adipose tissue from RAGE−/−-HFD mice. RAGE−/− mice displayed improved inflammatory profiles and evidence for increased adipose tissue browning. This observation is consistent with the finding of reduced plasma levels of FFA, glycerol, IL-6, and leptin in RAGE−/− mice compared to WT mice. Collectively the data demonstrate that RAGE-mediated adipose tissue inflammation and insulin-signaling are potentially important mechanisms that contribute to the development of obesity-associated insulin resistance.
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