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Boo YC. Restoring Glutathione Homeostasis in Glycation-Related Eye Diseases: Mechanistic Insights and Therapeutic Interventions Beyond VEGF Inhibition. Antioxidants (Basel) 2025; 14:731. [PMID: 40563363 PMCID: PMC12189886 DOI: 10.3390/antiox14060731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2025] [Revised: 06/09/2025] [Accepted: 06/12/2025] [Indexed: 06/28/2025] Open
Abstract
Advanced glycation end-products (AGEs) and oxidative stress are recognized as central contributors to the pathogenesis of age-related or diabetic cataracts, diabetic retinopathy (DR), and age-related macular degeneration (AMD). These glycation-related diseases are characterized by impaired redox balance and decreased glutathione (GSH) levels. This review aims to examine the mechanistic links between AGEs and GSH depletion across ocular tissues by integrating in vitro, ex vivo, in vivo, and clinical studies relevant to this topic. The multiple levels of evidence highlight GSH homeostasis as both a biomarker and therapeutic target in glycation-related ocular disorders. Therapeutic strategies aimed at restoring GSH homeostasis under glycation stress are categorized into four mechanistic domains: (I) promoting GSH supply and synthesis, (II) enhancing GSH recycling, (III) mitigating glycation stress, and (IV) reducing oxidative and nitrosative stress. Most of these strategies have been explored via different approaches, and experimental findings with various interventions have shown promise in restoring GSH balance and mitigating AGE-induced damage. A pathological link between GSH depletion and vascular endothelial growth factor (VEGF) overexpression is observed in DR and wet AMD. GSH-centered interventions act upstream to modulate redox homeostasis while anti-VEGF therapies target downstream angiogenesis. This study supports the rationale for a dual-targeting strategy that combines redox-based interventions with VEGF inhibition in glycation-related ocular diseases.
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Affiliation(s)
- Yong Chool Boo
- Department of Molecular Medicine, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea; ; Tel.: +82-53-420-4946
- Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, The Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea
- Cell and Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
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Choi JY, Ha NG, Lee WJ, Boo YC. Synthetic and Natural Agents Targeting Advanced Glycation End-Products for Skin Anti-Aging: A Comprehensive Review of Experimental and Clinical Studies. Antioxidants (Basel) 2025; 14:498. [PMID: 40298870 PMCID: PMC12024170 DOI: 10.3390/antiox14040498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 04/17/2025] [Accepted: 04/18/2025] [Indexed: 04/30/2025] Open
Abstract
Advanced glycation end-products (AGEs) cause blood vessel damage and induce diabetic complications in various organs, such as the eyes, kidneys, nerves, and skin. As glycation stress causes aesthetic, physical, and functional changes in the skin, glycation-targeting skin anti-aging strategies are attracting attention in cosmetology and dermatology. The primary goal of this review is to understand the significance of glycation-induced skin aging and to examine the therapeutic potential of glycation-targeting strategies. This study covers experimental and clinical studies exploring various interventions to attenuate glycation-induced skin aging. Glycation stress decreases the viability of cells in culture media, the cell-mediated contraction of collagen lattices in reconstructed skin models, and the expression of fibrillin-1 at the dermo-epidermal junction in the skin explants. It also increases cross-links in tail tendon collagen in animals, prolonging its breakdown time. However, these changes are attenuated by several synthetic and natural agents. Animal and clinical studies have shown that dietary or topical administration of agents with antiglycation or antioxidant activity can attenuate changes in AGE levels (measured by skin autofluorescence) and skin aging parameters (e.g., skin color, wrinkles, elasticity, hydration, dermal density) induced by chronological aging, diabetes, high-carbohydrate diets, ultraviolet radiation, or oxidative stress. Therefore, the accumulating experimental and clinical evidence supports that dietary supplements or topical formulations containing one or more synthetic and natural antiglycation agents may help mitigate skin aging induced by AGEs.
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Affiliation(s)
- Joon Yong Choi
- Department of Biomedical Science, The Graduate School, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea;
- BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Nam Gyoung Ha
- Department of Dermatology, Kyungpook National University Hospital, Daegu 41944, Republic of Korea; (N.G.H.); (W.J.L.)
- Bio-Medical Research Institute, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
- Department of Dermatology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Weon Ju Lee
- Department of Dermatology, Kyungpook National University Hospital, Daegu 41944, Republic of Korea; (N.G.H.); (W.J.L.)
- Bio-Medical Research Institute, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
- Department of Dermatology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Yong Chool Boo
- Department of Biomedical Science, The Graduate School, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea;
- BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Dermatology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cell and Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
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Ma Y, Wang X, Lin S, King L, Liu L. The Potential Role of Advanced Glycation End Products in the Development of Kidney Disease. Nutrients 2025; 17:758. [PMID: 40077627 PMCID: PMC11902189 DOI: 10.3390/nu17050758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/10/2025] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
Advanced glycation end products (AGEs) represent a class of toxic and irreversible compounds formed through non-enzymatic reactions between proteins or lipids and carbonyl compounds. AGEs can arise endogenously under normal metabolic conditions and in pathological states such as diabetes, kidney disease, and inflammatory disorders. Additionally, they can be obtained exogenously through dietary intake, particularly from foods high in fat or sugar, as well as grilled and processed items. AGEs accumulate in various organs and have been increasingly recognized as significant contributors to the progression of numerous diseases, particularly kidney disease. As the kidney plays a crucial role in AGE metabolism and excretion, it is highly susceptible to AGE-induced damage. In this review, we provide a comprehensive discussion on the role of AGEs in the onset and progression of various kidney diseases, including diabetic nephropathy, chronic kidney disease, and acute kidney injury. We explore the potential biological mechanisms involved, such as AGE accumulation, the AGEs-RAGE axis, oxidative stress, inflammation, gut microbiota dysbiosis, and AGE-induced DNA damage. Furthermore, we discuss recent findings on the metabolic characteristics of AGEs in vivo and their pathogenic impact on renal function. Additionally, we examine the clinical significance of AGEs in the early diagnosis, treatment, and prognosis of kidney diseases, highlighting their potential as biomarkers and therapeutic targets. By integrating recent advancements in AGE research, this review aims to provide new insights and strategies for mitigating AGE-related renal damage and improving kidney disease management.
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Affiliation(s)
- Yibin Ma
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.M.); (X.W.); (S.L.); (L.K.)
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xinyu Wang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.M.); (X.W.); (S.L.); (L.K.)
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shan Lin
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.M.); (X.W.); (S.L.); (L.K.)
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lei King
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.M.); (X.W.); (S.L.); (L.K.)
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Liegang Liu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.M.); (X.W.); (S.L.); (L.K.)
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Jia T, Zhang X, Li L, Jiang X, Wang M. Relationship Between Serum HMGB1 and RAGE Levels and Restenosis in Type 2 Diabetes Mellitus Patients Complicated With Lower Extremity Vascular Disease: A Retrospective Study. Diabetes Metab Syndr Obes 2025; 18:315-325. [PMID: 39925465 PMCID: PMC11803418 DOI: 10.2147/dmso.s496360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 01/08/2025] [Indexed: 02/11/2025] Open
Abstract
Purpose To investigate the potential association between the serum concentrations of high mobility group protein B1 (HMGB1) and the receptor for advanced glycation end-products (RAGE) in relation to the occurrence of restenosis following interventional therapy for lower extremity vascular disease in patients diagnosed with type 2 diabetes mellitus (T2DM). Patients and Methods From March 2023 to January 2024, 96 T2DM patients with lower extremity vascular disease who underwent interventional therapy and 6-month follow-up in our hospital were studied. Patients were divided into in-stent restenosis (ISR) (n=38) and none-in-stent restenosis (NISR) (n=58) groups based on the occurrence of ISR. Pre-surgery demographics and serum levels of HMGB1, RAGE, glycated hemoglobin (HbA1c), and high-sensitivity C-reactive protein (hs-CRP) were analyzed. A Pearson correlation and multivariate Logistic regression were used to identify factors influencing restenosis. A predictive nomogram was built based on the identified factors. The receiver operating characteristic (ROC) curve analysis evaluated the predictive value of serum RAGE and HMGB1 for restenosis post-intervention. Results The ISR group exhibited statistically significant elevations in HbA1c, hs-CRP, HMGB1, and RAGE levels compared to the NISR group (P<0.05). Multivariate logistic regression analysis revealed that HMGB1 and RAGE were independent risk factors for restenosis in T2DM patients with lower extremity vascular disease undergoing interventional therapy. The predictive nomogram model developed specifically for this patient population demonstrated high accuracy. ROC curve analysis further emphasized the superior combined predictive value of HMGB1 and RAGE over individual biomarkers for restenosis after interventional therapy in this cohort. Conclusion Elevated preoperative serum levels of HMGB1 and RAGE in T2DM patients with lower extremity vascular disease are linked to restenosis following interventional therapy.
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Affiliation(s)
- Ting Jia
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
| | - Xuyan Zhang
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
| | - Li Li
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
| | - Xiaowan Jiang
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
| | - Mengjie Wang
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
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Guo X, Wang F, Zheng M, Li L, Li L, Wang J, Miao S, Ma S, Shi X. Network pharmacology and molecular docking to study the potential molecular mechanism of Qi Fu Yin for diabetic encephalopathy. J Biomol Struct Dyn 2025; 43:917-931. [PMID: 38047625 DOI: 10.1080/07391102.2023.2289038] [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: 06/06/2023] [Accepted: 08/29/2023] [Indexed: 12/05/2023]
Abstract
Diabetic encephalopathy is a chronic complication of diabetes that lacks an optimized treatment strategy. The present study sought to elucidate the potential molecular mechanism of Qi Fu Yin in improving diabetic encephalopathy through network pharmacology. The active components and target information of Qi Fu Yin were obtained from the TCMSP and Swiss target databases, while the target information of diabetic encephalopathy was sourced from Gene cards, OMIM, and Pharm Gkb databases. Enrichment analyses of KEGG and GO were conducted utilizing drug-disease common targets, while protein-protein interactions were predicted through the utilization of the STRING database platform. Subsequently, molecular docking was executed via Auto Dock Vina to authenticate the interaction between core components and core targets. The findings revealed that Qi Fu Yin exhibited 178 common targets with diabetic encephalopathy, and the enrichment analyses demonstrated that these targets were associated with lipid and atherosclerosis, AGE-RAGE signaling pathways, and other related pathways. The findings of the molecular docking indicated a favorable binding affinity between the active components of drug and the core targets, with EGF and quercetin exhibiting the most notable docking score. Additionally, the molecular dynamics simulation corroborated this high affinity. These results suggested that the active ingredients of Qi Fu Yin, including quercetin and kaempferol, may modulated the expression of genes such as IL10, TNF, EGF, and MMP2, thereby activating the AGE-RAGE signaling pathways and potentially serving as a therapeutic intervention for diabetic encephalopathy.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Xiaodi Guo
- Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, P. R. China
- The College of Life Sciences, Northwest University, Xi'an, P. R. China
| | - Feiyan Wang
- Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, P. R. China
| | - Meiling Zheng
- Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, P. R. China
| | - Liang Li
- Neurosurgery, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, P. R. China
| | - Long Li
- Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, P. R. China
| | - Jin Wang
- Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, P. R. China
| | - Shan Miao
- Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, P. R. China
| | - Shanbo Ma
- Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, P. R. China
| | - Xiaopeng Shi
- Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, P. R. China
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Rampanelli E, Romp N, Troise AD, Ananthasabesan J, Wu H, Gül IS, De Pascale S, Scaloni A, Bäckhed F, Fogliano V, Nieuwdorp M, Bui TPN. Gut bacterium Intestinimonas butyriciproducens improves host metabolic health: evidence from cohort and animal intervention studies. MICROBIOME 2025; 13:15. [PMID: 39833973 PMCID: PMC11744835 DOI: 10.1186/s40168-024-02002-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 12/10/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND The human gut microbiome strongly influences host metabolism by fermenting dietary components into metabolites that signal to the host. Our previous work has shown that Intestinimonas butyriciproducens is a prevalent commensal bacterium with the unique ability to convert dietary fructoselysine to butyrate, a well-known signaling molecule with proven health benefits. Dietary fructoselysine is an abundant Amadori product formed in foods during thermal treatment and is part of foods rich in dietary advanced glycation end products which have been associated with cardiometabolic disease. It is therefore of interest to investigate the causal role of this bacterium and fructoselysine metabolism in metabolic disorders. RESULTS We assessed associations of I. butyriciproducens with metabolic risk biomarkers at both strain and functional levels using a human cohort characterized by fecal metagenomic analysis. We observed that the level of the bacterial strain as well as fructoselysine fermentation genes were negatively associated with BMI, triglycerides, HbA1c, and fasting insulin levels. We also investigated the fructoselysine degradation capacity within the Intestinimonas genus using a culture-dependent approach and found that I. butyriciproducens is a key player in the butyrogenic fructoselysine metabolism in the gut. To investigate the function of I. butyriciproducens in host metabolism, we used the diet-induced obesity mouse model to mimic the human metabolic syndrome. Oral supplementation with I. butyriciproducens counteracted body weight gain, hyperglycemia, and adiposity. In addition, within the inguinal white adipose tissue, bacterial administration reduced inflammation and promoted pathways involved in browning and insulin signaling. The observed effects may be partly attributable to the formation of the short-chain fatty acids butyrate from dietary fructoselysine, as butyrate plasma and cecal levels were significantly increased by the bacterial strain, thereby contributing to the systemic effects of the bacterial treatment. CONCLUSIONS I. butyriciproducens ameliorates host metabolism in the context of obesity and may therefore be a good candidate for new microbiota-therapeutic approaches to prevent or treat metabolic diseases. Video Abstract.
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Affiliation(s)
- Elena Rampanelli
- Department of Experimental Vascular Medicine, Amsterdam UMC, Amsterdam, the Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, the Netherlands
| | - Nadia Romp
- Department of Experimental Vascular Medicine, Amsterdam UMC, Amsterdam, the Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, the Netherlands
| | - Antonio Dario Troise
- Proteomics, Metabolomics & Mass Spectrometry Laboratory, Institute for the Animal Production System in the Mediterranean Environment, National Research Council, 80055, Portici (Naples), Italy
| | | | - Hao Wu
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan Microbiome Center, and Human Phenome Institute, Fudan University, Shanghai, 200438, China
| | | | - Sabrina De Pascale
- Proteomics, Metabolomics & Mass Spectrometry Laboratory, Institute for the Animal Production System in the Mediterranean Environment, National Research Council, 80055, Portici (Naples), Italy
| | - Andrea Scaloni
- Proteomics, Metabolomics & Mass Spectrometry Laboratory, Institute for the Animal Production System in the Mediterranean Environment, National Research Council, 80055, Portici (Naples), Italy
| | - Fredrik Bäckhed
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Bruna Stråket 16, 41345, Gothenburg, Sweden
| | - Vincenzo Fogliano
- Department of Food Quality and Design, Wageningen University, Wageningen, the Netherlands
| | - Max Nieuwdorp
- Department of Experimental Vascular Medicine, Amsterdam UMC, Amsterdam, the Netherlands
| | - Thi Phuong Nam Bui
- Department of Experimental Vascular Medicine, Amsterdam UMC, Amsterdam, the Netherlands.
- Laboratory of Microbiology, Wageningen University, Wageningen, the Netherlands.
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Meybodi SMM, Karimi MA, Mousazadeh K, Khorsand K, Masoumi S, Pakmehr SA, Asadi Anar M, Samadi N, Poudineh M, Rahmanian M, Yaghoobpoor S, Rahimi A, Arbab Mojeni F, Banihashemian SZ, Masoodi M, Aghazadeh-Habashi K, Ghorbani A, Faridzadeh A, Deravi N. The influence of SGLT-2 inhibitors on lipid profiles in heart failure patients: a systematic review and meta-analysis. AMERICAN JOURNAL OF CARDIOVASCULAR DISEASE 2024; 14:295-305. [PMID: 39839562 PMCID: PMC11744213 DOI: 10.62347/aapz2726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 08/29/2024] [Indexed: 01/23/2025]
Abstract
BACKGROUND AND AIM Sodium-glucose cotransporter two inhibitors can reduce cardiovascular events by modulating lipid profiles in patients with heart failure, irrespective of diabetes status. In this study, we aimed to assess the effects of SGLT-2 inhibitors on the lipid profiles of patients with heart failure via a meta-analysis. METHODS The PubMed, Scopus, Web of Science, and Google Scholar databases were searched up to 2023 to retrieve relevant article titles, abstracts, and full texts. STATA software was used to conduct the meta-analysis. RESULT The Forest plot of fasting blood sugar levels in patients receiving SGLT-2 inhibitors differed significantly from those the in control group (mean difference = -0.08, 95% CI [-0.13, -0.02], P < 0.05). Analysis of lipid profile parameters, including total cholesterol, triglyceride, HDL, and LDL in patients with HF receiving SGLT-2 inhibitors, did not show a notable difference from the control group (P > 0.005). However, the mean difference was towards the reduction of LDL, cholesterol, and triglycerides and showed an increase in HDL levels. Egger's test for publication bias revealed some publication bias (P < 0.05). CONCLUSION Our topic analysis did not reveal any notable alterations in the lipid profile. To arrive at a more definite agreement, further research on subjects with heart failure is necessary because there is currently insufficient evidence.
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Affiliation(s)
- Seyed Mohammad Mahdi Meybodi
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN)Tehran, Iran
- Young Researchers and Elite Club, Islamic Azad UniversityTabriz Branch, Tabriz, Iran
| | | | | | | | - Samira Masoumi
- Islamic Azad University, Pharmaceutical Sciences Branch (IAUPS)Tehran, Iran
| | | | - Mahsa Asadi Anar
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical SciencesTehran, Iran
| | - Nahid Samadi
- Student Research Committee, Health Research Institute, Babol University of Medical SciencesBabol, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical SciencesZanjan, Iran
| | - Mohammad Rahmanian
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical SciencesTehran, Iran
| | - Shirin Yaghoobpoor
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical SciencesTehran, Iran
| | - Arash Rahimi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical SciencesTehran, Iran
| | - Fariba Arbab Mojeni
- Student Research Committee, School of Medicine, Mazandaran University of Medical SciencesSari, Iran
| | | | - Mina Masoodi
- Faculty of Medicine, Islamic Azad UniversityShahrood Branch, Shahrood, Iran
| | | | - Atousa Ghorbani
- Department of Biology, Faculty of Basic Sciences, Islamic Azad University, East Tehran Branch (Ghiamdasht)Tehran, Iran
| | - Arezoo Faridzadeh
- Department of Immunology and Allergy, School of Medicine, Mashhad University of Medical SciencesMashhad, Iran
- Immunology Research Center, Mashhad University of Medical SciencesMashhad, Iran
| | - Niloofar Deravi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical SciencesTehran, Iran
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Wei Y, Zhang Y, Sun J, Li W, Zhao X, Tian N, Cao Y, Xie J. Modulation of the receptor for advanced glycation end products pathway by natural polyphenols: A therapeutic approach to neurodegenerative diseases. FOOD BIOSCI 2024; 62:105511. [DOI: 10.1016/j.fbio.2024.105511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Sieńko D, Szabłowska-Gadomska I, Nowak-Szwed A, Rudziński S, Gofron M, Zygmunciak P, Lewandowska-Szumieł M, Zgliczyński WS, Czupryniak L, Mrozikiewicz-Rakowska B. The Potential of Mesenchymal Stem/Stromal Cells in Diabetic Wounds and Future Directions for Research and Therapy-Is It Time for Use in Everyday Practice? Int J Mol Sci 2024; 25:12171. [PMID: 39596237 PMCID: PMC11594847 DOI: 10.3390/ijms252212171] [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: 10/05/2024] [Revised: 10/30/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
The treatment of diabetic wounds is impaired by the intricate nature of diabetes and its associated complications, necessitating novel strategies. The utilization of mesenchymal stem/stromal cells (MSCs) as a therapeutic modality for chronic and recalcitrant wounds in diabetic patients is an active area of investigation aimed at enhancing its therapeutic potential covering tissue regeneration. The threat posed to the patient and their environment by the presence of a diabetic foot ulcer (DFU) is so significant that any additional therapeutic approach that opens new pathways to halt the progression of local changes, which subsequently lead to a generalized inflammatory process, offers a chance to reduce the risk of amputation or even death. This article explores the potential of MSCs in diabetic foot ulcer treatment, examining their mechanisms of action, clinical application challenges, and future directions for research and therapy.
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Affiliation(s)
- Damian Sieńko
- Department of Diabetology and Internal Diseases, Medical University of Warsaw, 02-097 Warsaw, Poland; (D.S.); (A.N.-S.); (L.C.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Ilona Szabłowska-Gadomska
- Laboratory for Cell Research and Application, Medical University of Warsaw, 02-097 Warsaw, Poland; (I.S.-G.); (S.R.); (M.L.-S.)
| | - Anna Nowak-Szwed
- Department of Diabetology and Internal Diseases, Medical University of Warsaw, 02-097 Warsaw, Poland; (D.S.); (A.N.-S.); (L.C.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Stefan Rudziński
- Laboratory for Cell Research and Application, Medical University of Warsaw, 02-097 Warsaw, Poland; (I.S.-G.); (S.R.); (M.L.-S.)
| | - Maksymilian Gofron
- Department of Urology, Municipal Complex Hospital, 42-200 Czestochowa, Poland;
| | - Przemysław Zygmunciak
- Department of Endocrinology, Centre of Postgraduate Medical Education, Bielanski Hospital, 01-809 Warsaw, Poland; (P.Z.); (W.S.Z.)
| | - Małgorzata Lewandowska-Szumieł
- Laboratory for Cell Research and Application, Medical University of Warsaw, 02-097 Warsaw, Poland; (I.S.-G.); (S.R.); (M.L.-S.)
- Department of Histology and Embryology, Medical University of Warsaw, 02-004 Warsaw, Poland
| | - Wojciech Stanisław Zgliczyński
- Department of Endocrinology, Centre of Postgraduate Medical Education, Bielanski Hospital, 01-809 Warsaw, Poland; (P.Z.); (W.S.Z.)
| | - Leszek Czupryniak
- Department of Diabetology and Internal Diseases, Medical University of Warsaw, 02-097 Warsaw, Poland; (D.S.); (A.N.-S.); (L.C.)
| | - Beata Mrozikiewicz-Rakowska
- Department of Endocrinology, Centre of Postgraduate Medical Education, Bielanski Hospital, 01-809 Warsaw, Poland; (P.Z.); (W.S.Z.)
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Hashiesh HM, Azimullah S, Nagoor Meeran MF, Saraswathiamma D, Arunachalam S, Jha NK, Sadek B, Adeghate E, Sethi G, Albawardi A, Al Marzooqi S, Ojha S. Cannabinoid 2 Receptor Activation Protects against Diabetic Cardiomyopathy through Inhibition of AGE/RAGE-Induced Oxidative Stress, Fibrosis, and Inflammasome Activation. J Pharmacol Exp Ther 2024; 391:241-257. [PMID: 38955492 DOI: 10.1124/jpet.123.002037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 06/22/2024] [Accepted: 06/25/2024] [Indexed: 07/04/2024] Open
Abstract
Oxidative stress, fibrosis, and inflammasome activation from advanced glycation end product (AGE)-receptor of advanced glycation end product (RAGE) interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study revealed the impact of β-caryophyllene (BCP) on activating cannabinoid type 2 receptors (CB2Rs) against diabetic complication, mainly cardiomyopathy and investigated the underlying cell signaling pathways in mice. The murine model of DCM was developed by feeding a high-fat diet with streptozotocin injections. After the development of diabetes, the animals received a 12-week oral BCP treatment at a dose of 50 mg/kg/body weight. BCP treatment showed significant improvement in glucose tolerance and insulin resistance and enhanced serum insulin levels in diabetic animals. BCP treatment effectively reversed the heart remodeling and restored the phosphorylated troponin I and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a expression. Ultrastructural examination showed reduced myocardial cell injury in DCM mice treated with BCP. The preserved myocytes were found to be associated with reduced expression of AGE/RAGE in DCM mice hearts. BCP treatment mitigated oxidative stress by inhibiting expression of NADPH oxidase 4 and activating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Also, BCP suppressed cardiac fibrosis and endothelial-to-mesenchymal transition in DCM mice by inhibiting transforming growth factor β (TGF-β)/suppressor of mothers against decapentaplegic (Smad) signaling. Further, BCP treatment suppressed nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in DCM mice and alleviated cellular injury to the pancreatic tissues evidenced by significant elevation of the number of insulin-positive cells. To demonstrate a CB2R-dependent mechanism of BCP, another group of DCM mice were pretreated with AM630, a CB2R antagonist. AM630 was observed to abrogate the beneficial effects of BCP in DCM mice. Taken together, BCP demonstrated the potential to protect the myocardium and pancreas of DCM mice mediating CB2R-dependent mechanisms. SIGNIFICANCE STATEMENT: BCP, a CB2R agonist, shows protection against DCM. BCP attenuates oxidative stress, inflammation, and fibrosis in DCM via activating CB2Rs. BCP mediating CB2R activation favorably modulates AGE/RAGE, PI3K/AKT/Nrf2β and TGF-β/Smad and (NLRP3) inflammasome in diabetic cardiomyopathy.
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Affiliation(s)
- Hebaallah Mamdouh Hashiesh
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Sheikh Azimullah
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Mohamed Fizur Nagoor Meeran
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Dhanya Saraswathiamma
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Seenipandi Arunachalam
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Niraj Kumar Jha
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Bassem Sadek
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Ernest Adeghate
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Gautam Sethi
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Alia Albawardi
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Saeeda Al Marzooqi
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Shreesh Ojha
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
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11
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Lee OYA, Wong ANN, Ho CY, Tse KW, Chan AZ, Leung GPH, Kwan YW, Yeung MHY. Potentials of Natural Antioxidants in Reducing Inflammation and Oxidative Stress in Chronic Kidney Disease. Antioxidants (Basel) 2024; 13:751. [PMID: 38929190 PMCID: PMC11201162 DOI: 10.3390/antiox13060751] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 06/13/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
Chronic kidney disease (CKD) presents a substantial global public health challenge, with high morbidity and mortality. CKD patients often experience dyslipidaemia and poor glycaemic control, further exacerbating inflammation and oxidative stress in the kidney. If left untreated, these metabolic symptoms can progress to end-stage renal disease, necessitating long-term dialysis or kidney transplantation. Alleviating inflammation responses has become the standard approach in CKD management. Medications such as statins, metformin, and GLP-1 agonists, initially developed for treating metabolic dysregulation, demonstrate promising renal therapeutic benefits. The rising popularity of herbal remedies and supplements, perceived as natural antioxidants, has spurred investigations into their potential efficacy. Notably, lactoferrin, Boerhaavia diffusa, Amauroderma rugosum, and Ganoderma lucidum are known for their anti-inflammatory and antioxidant properties and may support kidney function preservation. However, the mechanisms underlying the effectiveness of Western medications and herbal remedies in alleviating inflammation and oxidative stress occurring in renal dysfunction are not completely known. This review aims to provide a comprehensive overview of CKD treatment strategies and renal function preservation and critically discusses the existing literature's limitations whilst offering insight into the potential antioxidant effects of these interventions. This could provide a useful guide for future clinical trials and facilitate the development of effective treatment strategies for kidney functions.
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Affiliation(s)
- On Ying Angela Lee
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China; (O.Y.A.L.)
| | - Alex Ngai Nick Wong
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China; (O.Y.A.L.)
| | - Ching Yan Ho
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China; (O.Y.A.L.)
| | - Ka Wai Tse
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China; (O.Y.A.L.)
| | - Angela Zaneta Chan
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - George Pak-Heng Leung
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China;
| | - Yiu Wa Kwan
- The School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Martin Ho Yin Yeung
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China; (O.Y.A.L.)
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
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12
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Yang Y, Huang S, Ma Q, Li N, Li R, Wang Y, Liu H. Combined therapeutic strategy based on blocking the deleterious effects of AGEs for accelerating diabetic wound healing. Regen Biomater 2024; 11:rbae062. [PMID: 39323743 PMCID: PMC11424028 DOI: 10.1093/rb/rbae062] [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: 04/23/2024] [Accepted: 05/09/2024] [Indexed: 09/27/2024] Open
Abstract
Diabetic foot ulcer is a serious complication of diabetes. Excessive accumulation of advanced glycation end products (AGEs) is one of the critical pathogenic factors in postponing diabetic wound healing. The main pathogenic mechanisms of AGEs include inducing cellular dysfunction, prolonging inflammatory response, increasing oxidative stress and reducing endogenous nitric oxide (NO) production. Combination therapy of blocking the deleterious effects of AGEs and supplementing exogenous NO is hypothesized to promote diabetic wound healing. Here, we presented nanoparticles/hydrogel composite dressings to co-delivery rosiglitazone and S-nitroso glutathione into the wound bed. The designed co-delivery system augmented the survival of fibroblasts, reduced oxidative stress levels, reversed the change of mitochondrial membrane potential and decreased the proinflammatory cytokine expression. Local sustained release of therapeutic agents significantly improved the wound healing of diabetic rats including increasing the wound closure rate, alleviating inflammation, promoting collagen fiber production and angiogenesis. Our finding indicated this local deliver strategy aimed at inhibiting the toxic effects of AGEs has great clinical potential for diabetic wound treatment.
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Affiliation(s)
- Yang Yang
- Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Siwen Huang
- Department of Pharmaceutics, Wuya Collage of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Qing Ma
- Department of Pharmaceutics, Wuya Collage of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Ning Li
- Department of Pharmaceutics, Wuya Collage of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Runchu Li
- Beijing No. 4 High School International Campus, Beijing 100031, China
| | - Yongjun Wang
- Department of Pharmaceutics, Wuya Collage of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Hongzhuo Liu
- Department of Pharmaceutics, Wuya Collage of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
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13
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Anlar GG, Anwardeen N, Al Ashmar S, Pedersen S, Elrayess MA, Zeidan A. Metabolomics Profiling of Stages of Coronary Artery Disease Progression. Metabolites 2024; 14:292. [PMID: 38921428 PMCID: PMC11205943 DOI: 10.3390/metabo14060292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/02/2024] [Accepted: 01/06/2024] [Indexed: 06/27/2024] Open
Abstract
Coronary artery disease (CAD) and atherosclerosis pose significant global health challenges, with intricate molecular changes influencing disease progression. Hypercholesterolemia (HC), hypertension (HT), and diabetes are key contributors to CAD development. Metabolomics, with its comprehensive analysis of metabolites, offers a unique perspective on cardiovascular diseases. This study leveraged metabolomics profiling to investigate the progression of CAD, focusing on the interplay of hypercholesterolemia, hypertension, and diabetes. We performed a metabolomic analysis on 221 participants from four different groups: (I) healthy individuals, (II) individuals with hypercholesterolemia (HC), (III) individuals with both HC and hypertension (HT) or diabetes, and (IV) patients with self-reported coronary artery disease (CAD). Utilizing data from the Qatar Biobank, we combined clinical information, metabolomic profiling, and statistical analyses to identify key metabolites associated with CAD risk. Our data identified distinct metabolite profiles across the study groups, indicating changes in carbohydrate and lipid metabolism linked to CAD risk. Specifically, levels of mannitol/sorbitol, mannose, glucose, and ribitol increased, while pregnenediol sulfate, oleoylcarnitine, and quinolinate decreased with higher CAD risk. These findings suggest a significant role of sugar, steroid, and fatty acid metabolism in CAD progression and point to the need for further research on the correlation between quinolinate levels and CAD risk, potentially guiding targeted treatments for atherosclerosis. This study provides novel insights into the metabolomic changes associated with CAD progression, emphasizing the potential of metabolites as predictive biomarkers.
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Affiliation(s)
- Gulsen Guliz Anlar
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (G.G.A.); (S.A.A.); (S.P.)
| | - Najeha Anwardeen
- Biomedical Research Center (BRC), QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (N.A.); (M.A.E.)
| | - Sarah Al Ashmar
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (G.G.A.); (S.A.A.); (S.P.)
| | - Shona Pedersen
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (G.G.A.); (S.A.A.); (S.P.)
| | - Mohamed A. Elrayess
- Biomedical Research Center (BRC), QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (N.A.); (M.A.E.)
| | - Asad Zeidan
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (G.G.A.); (S.A.A.); (S.P.)
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Albar NY, Hassaballa H, Shikh H, Albar Y, Ibrahim AS, Mousa AH, Alshanberi AM, Elgebaly A, Bahbah EI. The interaction between insulin resistance and Alzheimer's disease: a review article. Postgrad Med 2024; 136:377-395. [PMID: 38804907 DOI: 10.1080/00325481.2024.2360887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 05/23/2024] [Indexed: 05/29/2024]
Abstract
Insulin serves multiple functions as a growth-promoting hormone in peripheral tissues. It manages glucose metabolism by promoting glucose uptake into cells and curbing the production of glucose in the liver. Beyond this, insulin fosters cell growth, drives differentiation, aids protein synthesis, and deters degradative processes like glycolysis, lipolysis, and proteolysis. Receptors for insulin and insulin-like growth factor-1 are widely expressed in the central nervous system. Their widespread presence in the brain underscores the varied and critical functions of insulin signaling there. Insulin aids in bolstering cognition, promoting neuron extension, adjusting the release and absorption of catecholamines, and controlling the expression and positioning of gamma-aminobutyric acid (GABA). Importantly, insulin can effortlessly traverse the blood-brain barrier. Furthermore, insulin resistance (IR)-induced alterations in insulin signaling might hasten brain aging, impacting its plasticity and potentially leading to neurodegeneration. Two primary pathways are responsible for insulin signal transmission: the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, which oversees metabolic responses, and the mitogen-activated protein kinase (MAPK) pathway, which guides cell growth, survival, and gene transcription. This review aimed to explore the potential shared metabolic traits between Alzheimer's disease (AD) and IR disorders. It delves into the relationship between AD and IR disorders, their overlapping genetic markers, and shared metabolic indicators. Additionally, it addresses existing therapeutic interventions targeting these intersecting pathways.
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Affiliation(s)
- Nezar Y Albar
- Internal Medicine Department, Dr. Samir Abbas Hospital, Jeddah, Saudi Arabia
| | | | - Hamza Shikh
- Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia
| | - Yassin Albar
- Fakeeh College of Medical Sciences, Jeddah, Saudi Arabia
| | | | - Ahmed Hafez Mousa
- Department of Neurosurgery, Postgraduate Medical Education, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
- Department of Neurosurgery, Rashid Hospital, Dubai Academic Health Cooperation, Dubai, United Arab Emirates
| | - Asim Muhammed Alshanberi
- Department of Community Medicine and Pilgrims Health Care, Umm Alqura University, Makkah, Saudi Arabia
- Medicine Program, Batterjee Medical College, Jeddah, Saudi Arabia
| | - Ahmed Elgebaly
- Smart Health Academic Unit, University of East London, London, UK
| | - Eshak I Bahbah
- Faculty of Medicine, Al-Azhar University, Damietta, Egypt
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15
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Wu J, Wan M, Jiang Z, Gong W, Zhou X. lncRNA FAS-AS1 served as a diagnostic biomarker of end-stage renal disease and mediated vascular calcification via regulating oxidative stress and inflammation. Gene 2024; 896:148035. [PMID: 38013128 DOI: 10.1016/j.gene.2023.148035] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 11/09/2023] [Accepted: 11/24/2023] [Indexed: 11/29/2023]
Abstract
PURPOSE Vascular calcification is a frequently occurring complication of end-stage renal disease (ESRD). This study focused on the significance of long non-coding RNA Fas cell surface death receptor-antisense 1(lncRNA FAS-AS1) in ESRD-related vascular calcification aiming to explore a potential biomarker for the detection. METHODS The study enrolled 65 healthy individuals, 79 ESRD patients (48 patients with vascular calcification), and 93 early-stage (I-IV) chronic kidney disease (CKD) patients. The expression of FAS-AS1 in serum was evaluated by real-time quantitative polymerase chain reaction (PCR). The diagnostic potential of FAS-AS1 was assessed in discriminating ESRD patients, vascular calcification, and the severity of vascular calcification. In vitro, the vascular smooth muscle cells (VSMCs) were treated with a hyperphosphatemia medium to evaluate the effect of FAS-AS1 on VSMCs calcification. RESULTS Elevated serum FAS-AS1 was observed in ESRD patients, which could discriminate from healthy individuals and early-stage CKD patients. FAS-AS1 was associated with the development of ESRD and the occurrence of vascular calcification. FAS-AS1 was also upregulated in vascular calcification patients, especially the patients with severe calcification, which showed diagnostic significance in evaluating vascular calcification degrees. Calcified VSMCs showed significantly increased levels of Ca2+, reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6), which was attenuated by silencing FAS-AS1. CONCLUSIONS FAS-AS1 discriminated ERSD patients and was associated with the occurrence of vascular calcification. The knockdown of FAS-AS1 suppressed hyperphosphatemia-induced vascular calcification via alleviating oxidative stress and inflammation.
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Affiliation(s)
- Jiaqi Wu
- Department of In-Patient Ultrasound, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Ming Wan
- Department of In-Patient Ultrasound, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Zhaopeng Jiang
- Department of In-Patient Ultrasound, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Wushuang Gong
- Department of In-Patient Ultrasound, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Xianli Zhou
- Department of In-Patient Ultrasound, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150081, China.
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16
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Miao L, Zhang X, Zhang H, Cheong MS, Chen X, Farag MA, Cheang WS, Xiao J. Baicalin ameliorates insulin resistance and regulates hepatic glucose metabolism via activating insulin signaling pathway in obese pre-diabetic mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 124:155296. [PMID: 38176276 DOI: 10.1016/j.phymed.2023.155296] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 12/12/2023] [Accepted: 12/16/2023] [Indexed: 01/06/2024]
Abstract
BACKGROUND Diabetes belongs to the most prevalent metabolic diseases worldwide, which is featured with insulin resistance, closely associated with obesity and urgently needs to be treated. Baicalin, belonging to natural flavonoids, has been reported to inhibit oxidative stress or inflammatoin. PURPOSE This study investigated the properties of baicalin on modulating abnormal glucolipid metabolism, as well as the underlying in-vitro and in-vivo mechanisms. METHODS Insulin-resistant (IR)-HepG2 cells were stimulated by dexamethasone (20 µM) and high glucose (50 mM) for 48 h and incubated with or without baicalin or metformin for another 16 h. Male C57BL/6 J mice were fed with a high-fat diet (HFD, 60 % kcal% fat) during the total 14 weeks. Obese mice were then administered with baicalin (50 and 100 mg/kg) or vehicle solution everyday through oral gavage during the last 4-week period. Moreover, baicalin metabolisms in vitro and in vivo were determined using UPLC/MS/MS to study its metabolism situation. RESULTS Exposure to dexamethasone and high glucose damaged the abilities of glycogen synthesis and glucose uptake with elevated oxidative stress and increased generation levels of advanced glycation end-products (AGEs) in HepG2 cells. These impairments were basically reversed by baicalin treatment. Four-week oral administration with baicalin ameliorated hyperglycemia and dyslipidemia in HFD-induced obese and pre-diabetic mice. Downregulation of IRS/PI3K/Akt signaling pathway accomplished with reduced GLUT4 expression and enhanced GSK-3β activity was observed in insulin resistant HepG2 cells as well as liver tissues from pre-diabetic mice; and such effect was prevented by baicalin. Moreover, baicalin and its matabolites were detected in IR-HepG2 cells and mouse plasma. CONCLUSION The study illustrated that baicalin alleviated insulin resistance by activating insulin signaling pathways and inhibiting oxidative stress and AGEs production, revealing the potential of baicalin to be a therapeutic natural flavonoid against hepatic insulin and glucose-lipid metabolic disturbance in pre-diabetes accompanied with obesity.
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Affiliation(s)
- Lingchao Miao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
| | - Xutao Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
| | - Haolin Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
| | - Meng Sam Cheong
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
| | - Xiaojia Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
| | - Mohamed A Farag
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Wai San Cheang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China.
| | - Jianbo Xiao
- Universidade de Vigo, Nutrition and Bromatology Group, Department of Analytical and Food Chemistry, Faculty of Sciences, Ourense 32004, Spain.
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Jain A, Kishore N. Glycation and drug binding by serum albumin. VITAMINS AND HORMONES 2024; 125:89-115. [PMID: 38997173 DOI: 10.1016/bs.vh.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/14/2024]
Abstract
Accumulation of glycation products in patients with hyperglycaemic conditions can lead to their reaction with the proteins in the human system such as serum albumin, haemoglobin, insulin, plasma lipoproteins, lens proteins and collagen among others which have important biological functions. Therefore, it is important to understand if glycation of these proteins affects their normal action not only qualitatively, but also importantly quantitatively. Glycation of human serum albumin can easily be carried out over period of weeks and its drug transportability may be examined, in addition to characterisation of the amadori products. A combination of ultrasensitive isothermal titration calorimetry, differential scanning calorimetry, spectroscopy and chromatography provides structure-property-energetics correlations which are important to obtain mechanistic aspects of drug recognition, conformation of the protein, and role of amadori products under conditions of glycation. The role of advance glycation end products is important in recognition of antidiabetic drugs. Further, the extent of glycation of the protein and its implication on drug transportability investigated by direct calorimetric methods enables unravelling mechanistic insights into role of functionality on drug molecules in the binding process, and hinderance in the recognition process, if any, as a result of glycation. It is possible that the drug binding ability of the protein under glycation conditions may not be adversely affected, or may even lead to strengthened ability. Rigorous studies on such systems with diverse functionality on the drug molecules is required which is essential in deriving guidelines for improvements in the existing drugs or in the synthesis of new molecular entities directed towards addressing diabetic conditions.
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Affiliation(s)
- Anu Jain
- Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India
| | - Nand Kishore
- Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India.
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Singh L, Kaur H, Chandra Arya G, Bhatti R. Neuroprotective potential of formononetin, a naturally occurring isoflavone phytoestrogen. Chem Biol Drug Des 2024; 103:e14353. [PMID: 37722967 DOI: 10.1111/cbdd.14353] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/17/2023] [Accepted: 09/04/2023] [Indexed: 09/20/2023]
Abstract
The increased prevalence of neurological illnesses is a burgeoning challenge to the public healthcare system and presents greater financial pressure. Formononetin, an O-methylated isoflavone, has gained a lot of attention due to its neuroprotective potential explored in several investigations. Formononetin is widely found in legumes and several types of clovers including Trifolium pratense L., Astragalus membranaceus, Sophora tomentosa, etc. Formononetin modulates various endogenous mediators to confer neuroprotection. It prevents RAGE activation that results in the inhibition of neuronal damage via downregulating the level of ROS and proinflammatory cytokines. Furthermore, formononetin also increases the expression of ADAM-10, which affects the pathology of neurodegenerative disease by lowering tau phosphorylation, maintaining synaptic plasticity, and boosting hippocampus neurogenesis. Besides these, formononetin also increases the expression of antioxidants, Nrf-2, PI3K, ApoJ, and LRP1. Whereas, reduces the expression of p65-NF-κB and proinflammatory cytokines. It also inhibits the deposition of Aβ and MAO-B activity. An inhibition of Aβ/RAGE-induced activation of MAPK and NOX governs the protection elicited by formononetin against inflammatory and oxidative stress-induced neuronal damage. Besides this, PI3K/Akt and ER-α-mediated activation of ADAM10, ApoJ/LRP1-mediated clearance of Aβ, and MAO-B inhibition-mediated preservation of dopaminergic neurons integrity are the major modulations produced by formononetin. This review covers the biosynthesis of formononetin and key molecular pathways modulated by formononetin to confer neuroprotection.
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Affiliation(s)
- Lovedeep Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India
- University Institute of Pharma Sciences, Chandigarh University, Mohali, India
| | - Harpreet Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India
| | - Girish Chandra Arya
- University Institute of Pharma Sciences, Chandigarh University, Mohali, India
| | - Rajbir Bhatti
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India
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Biswas A, Choudhury AD, Agrawal S, Bisen AC, Sanap SN, Verma SK, Kumar M, Mishra A, Kumar S, Chauhan M, Bhatta RS. Recent Insights into the Etiopathogenesis of Diabetic Retinopathy and Its Management. J Ocul Pharmacol Ther 2024; 40:13-33. [PMID: 37733327 DOI: 10.1089/jop.2023.0068] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2023] Open
Abstract
Purpose: Diabetic retinopathy (DR) is a microvascular retinal disease associated with chronic diabetes mellitus, characterized by the damage of blood vessels in the eye. It is projected to become the leading cause of blindness, given the increasing burden of the diabetic population worldwide. The diagnosis and management of DR pose significant challenges for physicians because of the involvement of multiple biochemical pathways and the complexity of ocular tissues. This review aims to provide a comprehensive understanding of the molecular pathways implicated in the pathogenesis of DR, including the polyo pathway, hexosamine pathway, protein kinase C (PKC), JAK/STAT signaling pathways, and the renin-angiotensin system (RAS). Methods: Academic databases such as PubMed, Scopus, Google Scholar and Web of Science was systematically searched using a carefully constructed search strategy incorporating keywords like "Diabetic Retinopathy," "Molecular Pathways," "Pharmacological Treatments," and "Clinical Trials" to identify relevant literature for the comprehensive review. Results: In addition to activating other inflammatory cascades, these pathways contribute to the generation of oxidative stress within the retina. Furthermore, it aims to explore the existing pharmacotherapy options available for the treatment of DR. In addition to conventional pharmacological therapies such as corticosteroids, antivascular endothelial growth factors, and nonsteroidal anti-inflammatory drugs (NSAIDs), this review highlights the potential of repurposed drugs, phyto-pharmaceuticals, and novel pipeline drugs currently undergoing various stages of clinical trials. Conclusion: Overall, this review serves as a technical exploration of the complex nature of DR, highlighting both established and emerging molecular pathways implicated in its pathogenesis. Furthermore, it delves into the available pharmacological treatments, as well as the promising repurposed drugs, phyto-pharmaceuticals, and novel drugs currently being evaluated in clinical trials, with a focus on their specific mechanisms of action.
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Affiliation(s)
- Arpon Biswas
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Jawaharlal Nehru University, New Delhi, India
| | - Abhijit Deb Choudhury
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Jawaharlal Nehru University, New Delhi, India
| | - Sristi Agrawal
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, New Delhi, India
| | - Amol Chhatrapati Bisen
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, New Delhi, India
| | - Sachin Nashik Sanap
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, New Delhi, India
| | - Sarvesh Kumar Verma
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Jawaharlal Nehru University, New Delhi, India
| | - Mukesh Kumar
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Jawaharlal Nehru University, New Delhi, India
| | - Anjali Mishra
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, New Delhi, India
| | - Shivansh Kumar
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Mridula Chauhan
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Rabi Sankar Bhatta
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
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Huang CY, Chen SH, Lin T, Liao YW, Chang YC, Chen CC, Yu CC, Chen CJ. Resveratrol attenuates advanced glycation end product-induced senescence and inflammation in human gingival fibroblasts. J Dent Sci 2024; 19:580-586. [PMID: 38303784 PMCID: PMC10829724 DOI: 10.1016/j.jds.2023.10.016] [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: 07/24/2023] [Revised: 10/13/2023] [Indexed: 02/03/2024] Open
Abstract
Background/purpose The accumulation of advanced glycation end products (AGEs) lead to a series of immune responses such as: increased oxidative stress and inflammation which contribute to the development of diabetic complications and periodontal disease. Resveratrol is a natural compound that has anti-oxidant and anti-inflammatory effects. Studies have found that diabetes-induced periodontitis is mainly caused by oxidative stress, aging and increased inflammation. In view of resveratrol has been proposed to have the ability in anti-oxidant and anti-inflammation in a variety of tissues. However, the role of resveratrol in diabetic periodontitis remains to be investigated. In this study, we aimed to investigate the role of resveratrol in preventing and treating diabetic periodontitis. Materials and methods First, cell proliferation was measured in AGEs-treated human gingival fibroblast with or without resveratrol. We examined the reactive oxygen species (ROS) generation, senescence-associated beta-galactosidase (SA-β-gal) and senescence marker p16 in human gingival fibroblasts (HGFs) stimulated with AGEs with or without the treatment of resveratrol. To determine whether resveratrol has the potential to regulate inflammaging which is mediated via the NF-κB signaling pathway and, the expression of p65 and p-IκB were also investigated. Furthermore, the concentration of interleukin (IL)-6 and IL-8 were also measured in AGEs-stimulated HGFs treated with or without resveratrol. Results ROS generation, cell senescence, and the secretion of IL-6 and IL-8 were significantly upregulated following the treatment of AGEs. However, the administration of resveratrol suppresses the generation of IL-6 and IL-8 and cell senescence via inhibiting NF-κB signaling pathway. Our results revealed that resveratrol inhibits inflammaging by downregulating NF-κB signaling pathway. Conclusion According to our findings, AGEs increase senescence and the production of proinflammatory cytokines in the gingiva, while the administration of resveratrol impedes inflammaging via suppressing NF-κB signaling pathway.
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Affiliation(s)
- Chao-Yen Huang
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
- Department of Emergency Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Szu-Han Chen
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
| | - Taichen Lin
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yi-Wen Liao
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yu-Cheng Chang
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Chun-Cheng Chen
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Cheng-Chia Yu
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chun-Jung Chen
- Division of Periodontics, Department of Dentistry, Chi Mei Medical Center, Tainan, Taiwan
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Chakraborty S, Verma A, Garg R, Singh J, Verma H. Cardiometabolic Risk Factors Associated With Type 2 Diabetes Mellitus: A Mechanistic Insight. Clin Med Insights Endocrinol Diabetes 2023; 16:11795514231220780. [PMID: 38148756 PMCID: PMC10750528 DOI: 10.1177/11795514231220780] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 11/27/2023] [Indexed: 12/28/2023] Open
Abstract
A complex metabolic condition referred to as Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR) and decreased insulin production. Obesity, dyslipidemia, hypertension, and chronic inflammation are just a few of the cardiometabolic illnesses that people with T2DM are more likely to acquire and results in cardiovascular issues. It is essential to comprehend the mechanistic insights into these risk variables in order to prevent and manage cardiovascular problems in T2DM effectively. Impaired glycemic control leads to upregulation of De novo lipogenesis (DNL), promote hepatic triglyceride (TG) synthesis, worsening dyslipidemia that is accompanied by low levels of high density lipoprotein cholesterol (HDL-C) and high amounts of small, dense low-density lipoprotein cholesterol (LDL-C) further developing atherosclerosis. By causing endothelial dysfunction, oxidative stress, and chronic inflammation, chronic hyperglycemia worsens already existing cardiometabolic risk factors. Vasoconstriction, inflammation, and platelet aggregation are caused by endothelial dysfunction, which is characterized by decreased nitric oxide production, increased release of vasoconstrictors, proinflammatory cytokines, and adhesion molecules. The loop of IR and endothelial dysfunction is sustained by chronic inflammation fueled by inflammatory mediators produced in adipose tissue. Infiltrating inflammatory cells exacerbate inflammation and the development of plaque in the artery wall. In addition, the combination of chronic inflammation, dyslipidemia, and IR contributes to the emergence of hypertension, a prevalent comorbidity in T2DM. The ability to target therapies and management techniques is made possible by improvements in our knowledge of these mechanistic insights. Aim of present review is to enhance our current understanding of the mechanistic insights into the cardiometabolic risk factors related to T2DM provides important details into the interaction of pathophysiological processes resulting in cardiovascular problems. Understanding these pathways will enable us to create efficient plans for the prevention, detection, and treatment of cardiovascular problems in T2DM patients, ultimately leading to better overall health outcomes.
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Affiliation(s)
- Snigdha Chakraborty
- Overseas R & D Centre, Overseas HealthCare Pvt Ltd., Phillaur, Punjab, India
| | - Anjali Verma
- Department of Food Technology and Nutrition, School of Agriculture, Lovely Professional University, Phagwara, Punjab, India
| | - Rajeev Garg
- IKG Punjab Technical University, Kapurthala, India
- Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela, Ropar, Punjab, India
- Guru Nanak Institute of Pharmacy, Dalewal, Hoshiarpur, Punjab, India
| | - Jyoti Singh
- Department of Food Technology and Nutrition, School of Agriculture, Lovely Professional University, Phagwara, Punjab, India
| | - Hitesh Verma
- Overseas R & D Centre, Overseas HealthCare Pvt Ltd., Phillaur, Punjab, India
- IKG Punjab Technical University, Kapurthala, India
- Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela, Ropar, Punjab, India
- Biofern Life Sciences Pvt Ltd, Karnataka, India
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Zhou X, Liu Z, Yang X, Feng J, Gins MS, Yan T, Han L, Zhang H. The Mechanism Underlying the Hypoglycemic Effect of Epimedin C on Mice with Type 2 Diabetes Mellitus Based on Proteomic Analysis. Nutrients 2023; 16:25. [PMID: 38201855 PMCID: PMC10780735 DOI: 10.3390/nu16010025] [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: 11/19/2023] [Revised: 12/12/2023] [Accepted: 12/13/2023] [Indexed: 01/12/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) has become a worldwide public health problem. Epimedin C is considered one of the most important flavonoids in Epimedium, a famous edible herb in China and Southeast Asia that is traditionally used in herbal medicine to treat diabetes. In the present study, the therapeutic potential of epimedin C against T2DM was ascertained using a mouse model, and the mechanism underlying the hypoglycemic activity of epimedin C was explored using a label-free proteomic technique for the first time. Levels of fasting blood glucose (FBG), homeostasis model assessment of insulin resistance (HOMA-IR), and oral glucose tolerance, as well as contents of malondialdehyde (MDA) and low-density lipoprotein cholesterol (LDL-C) in the 30 mg·kg-1 epimedin C group (EC30 group), were significantly lower than those in the model control group (MC group) (p < 0.05), while the contents of hepatic glycogen, insulin, and high-density lipoprotein cholesterol (HDL-C), as well as activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the EC30 group were notably higher than those in the MC group (p < 0.05). The structures of liver cells and tissues were greatly destroyed in the MC group, whereas the structures of cells and tissues were basically complete in the EC30 group, which were similar to those in the normal control group (NC group). A total of 92 differentially expressed proteins (DEPs) were enriched in the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. In the EC30 vs. MC groups, the expression level of cytosolic phosphoenolpyruvate carboxykinase (Pck1) was down-regulated, while the expression levels of group XIIB secretory phospholipase A2-like protein (Pla2g12b), apolipoprotein B-100 (Apob), and cytochrome P450 4A14 (Cyp4a14) were up-regulated. According to the KEGG pathway assay, Pck1 participated in the gluconeogenesis and insulin signaling pathways, and Pla2g12b, Apob, and Cyp4a14 were the key proteins in the fat digestion and fatty acid degradation pathways. Pck1, Pla2g12b, Apob, and Cyp4a14 seemed to play important roles in the prevention and treatment of T2DM. In summary, epimedin C inhibited Pck1 expression to maintain FBG at a relatively stable level, promoted Pla2g12b, Apob, and Cyp4a14 expressions to alleviate liver lipotoxicity, and protected liver tissues and cells from oxidant stress possibly by its phenolic hydroxyl groups.
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Affiliation(s)
- Xuexue Zhou
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, Academician and Expert Workstations in Puer City of Yunnan Province, College of Food Engineering and Nutritional Science, Provincial Research Station of Se-Enriched Foods in Hanyin County of Shaanxi Province, International Joint Research Center of Shaanxi Province for Food and Health Sciences, Shaanxi Normal University, Xi’an 710119, China (Z.L.); (T.Y.); (L.H.)
| | - Ziqi Liu
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, Academician and Expert Workstations in Puer City of Yunnan Province, College of Food Engineering and Nutritional Science, Provincial Research Station of Se-Enriched Foods in Hanyin County of Shaanxi Province, International Joint Research Center of Shaanxi Province for Food and Health Sciences, Shaanxi Normal University, Xi’an 710119, China (Z.L.); (T.Y.); (L.H.)
| | - Xiaohua Yang
- Research Station of Selenium-Enriched Tea of Shaanxi Province, Health Science Center, Xi’an Jiaotong University, Xi’an 710061, China
| | - Jing Feng
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, Academician and Expert Workstations in Puer City of Yunnan Province, College of Food Engineering and Nutritional Science, Provincial Research Station of Se-Enriched Foods in Hanyin County of Shaanxi Province, International Joint Research Center of Shaanxi Province for Food and Health Sciences, Shaanxi Normal University, Xi’an 710119, China (Z.L.); (T.Y.); (L.H.)
- Agrarian and Technological Institute, Peoples’ Friendship University of Russia, Moscow 119991, Russia;
| | - Murat Sabirovich Gins
- Agrarian and Technological Institute, Peoples’ Friendship University of Russia, Moscow 119991, Russia;
| | - Tingyu Yan
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, Academician and Expert Workstations in Puer City of Yunnan Province, College of Food Engineering and Nutritional Science, Provincial Research Station of Se-Enriched Foods in Hanyin County of Shaanxi Province, International Joint Research Center of Shaanxi Province for Food and Health Sciences, Shaanxi Normal University, Xi’an 710119, China (Z.L.); (T.Y.); (L.H.)
| | - Lei Han
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, Academician and Expert Workstations in Puer City of Yunnan Province, College of Food Engineering and Nutritional Science, Provincial Research Station of Se-Enriched Foods in Hanyin County of Shaanxi Province, International Joint Research Center of Shaanxi Province for Food and Health Sciences, Shaanxi Normal University, Xi’an 710119, China (Z.L.); (T.Y.); (L.H.)
| | - Huafeng Zhang
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, Academician and Expert Workstations in Puer City of Yunnan Province, College of Food Engineering and Nutritional Science, Provincial Research Station of Se-Enriched Foods in Hanyin County of Shaanxi Province, International Joint Research Center of Shaanxi Province for Food and Health Sciences, Shaanxi Normal University, Xi’an 710119, China (Z.L.); (T.Y.); (L.H.)
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Potra Cicalău GI, Ciavoi G, Scrobotă I, Marcu AO, Romanul I, Marian E, Vicaș LG, Ganea M. Assessing the Antioxidant Benefits of Topical Carvacrol and Magnolol Periodontal Hydrogel Therapy in Periodontitis Associated with Diabetes in Wistar Rats. Dent J (Basel) 2023; 11:284. [PMID: 38132422 PMCID: PMC10742747 DOI: 10.3390/dj11120284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/24/2023] [Accepted: 12/05/2023] [Indexed: 12/23/2023] Open
Abstract
It is well recognized that oxidative stress contributes to chronic stress-induced cytotoxicity, which is a major factor in the progression of many diseases, including periodontitis and diabetes. Formulas based on natural extracts with antioxidant properties are alternative treatment perspectives in the management of such diseases. The aim of our study was to assess how carvacrol and magnolol influence periodontitis associated with diabetes in Wistar rats. Ninety Wistar rats were distributed in nine groups: I-control group; II-diabetes group (D); III-periodontitis group (P); IV-periodontitis and diabetes group (PD); V-periodontitis and diabetes with vehicle alone (PDV); VI-periodontitis and diabetes treated with carvacrol (PDC); VII-periodontitis and diabetes treated with magnolol (PDM); VIII-periodontitis and diabetes treated with carvacrol and magnolol (PDCM); IX-healthy group with vehicle alone (CV). Blood malondialdehyde (MDA) levels and catalase activity levels (CAT) were measured as indicators of oxidative stress and antioxidant capacity, respectively. Where diabetes and periodontitis were induced, MDA was augmented and CAT was depleted significantly. Whether given alone (PDM) or in combination with carvacrol (PDCM), magnolol significantly decreased MDA. Between the PDM group and the PDCM group, there were no notable differences. In Wistar rats with periodontitis related to diabetes, topical use of hydrogels containing magnolol, either alone or in combination with carvacrol, may reduce oxidative stress.
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Affiliation(s)
- Georgiana Ioana Potra Cicalău
- Department of Dental Medicine, Faculty of Medicine and Pharmacy, University of Oradea, 1st Decembrie Street, 410073 Oradea, Romania; (G.I.P.C.); (G.C.); (I.R.)
| | - Gabriela Ciavoi
- Department of Dental Medicine, Faculty of Medicine and Pharmacy, University of Oradea, 1st Decembrie Street, 410073 Oradea, Romania; (G.I.P.C.); (G.C.); (I.R.)
| | - Ioana Scrobotă
- Department of Dental Medicine, Faculty of Medicine and Pharmacy, University of Oradea, 1st Decembrie Street, 410073 Oradea, Romania; (G.I.P.C.); (G.C.); (I.R.)
| | - Andreea Olivia Marcu
- Preclinics Department, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Ioana Romanul
- Department of Dental Medicine, Faculty of Medicine and Pharmacy, University of Oradea, 1st Decembrie Street, 410073 Oradea, Romania; (G.I.P.C.); (G.C.); (I.R.)
| | - Eleonora Marian
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 1st Decembrie Street, 410073 Oradea, Romania; (E.M.); (L.G.V.); (M.G.)
| | - Laura Grațiela Vicaș
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 1st Decembrie Street, 410073 Oradea, Romania; (E.M.); (L.G.V.); (M.G.)
| | - Mariana Ganea
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 1st Decembrie Street, 410073 Oradea, Romania; (E.M.); (L.G.V.); (M.G.)
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Khan R, Naseem I. Antiglycation, antifibrillation and antioxidative effects of para coumaric acid and vitamin D; an in-vitro and in-silico comparative-cum-synergistic approach. Biochim Biophys Acta Gen Subj 2023; 1867:130455. [PMID: 37678652 DOI: 10.1016/j.bbagen.2023.130455] [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: 07/04/2023] [Revised: 08/21/2023] [Accepted: 09/04/2023] [Indexed: 09/09/2023]
Abstract
Diabetes Mellitus is a metabolic disorder that results in impaired utilization of carbohydrates, lipids, and proteins. Severe hyperglycemia is its principal clinical symptom. Human serum albumin (HSA) is used as a model protein since it is viewed as a sign of glycaemic management because it is more likely to get glycated in diabetic people than other proteins. Para-coumaric acid (pCA), a phenolic acid, and Vitamin D (vit-D) are used as protective agents. In the present work, we deduce a synergistic-cum-comparative effect of pCA and vit-D, expecting some improvement in the efficacy of pCA when combined with vit-D. Methods employed are DPPH radical scavenging activity, In-vitro glycation of HSA, UV-vis spectroscopy, fluorescence analysis, and circular dichroism measurement. After treatment, increasein the absorbance and fluorescence intensity were reduced along with normalization of CD value. . The glycation-mediated fibrillation assessed by Congo-Red and Thioflavin T (ThT) were found to be diminishedwhen HSA was treated with equimolar concentration of p-CA and vit-D- treatment. Fructosamine adduct formation and lysine modificationwas also decreased, while inhibition to hemolysis and lipid peroxidation was found to increase upon treatment. The reactive oxygen species generation detection was also performed in lymphocytes treated with various protein samples. Docking results further confirmed theblocking some glycation-prone amino acids by both compounds. The study shows that the combination in the ratio of 1:1 has provided higher overall protection comparable to aminoguanidine (AG), the molecule which is utilized as a positive control.
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Affiliation(s)
- Rizwan Khan
- Department of Biochemistry, Life Sciences, Aligarh Muslim University, Aligarh 202002, UP, India
| | - Imrana Naseem
- Department of Biochemistry, Life Sciences, Aligarh Muslim University, Aligarh 202002, UP, India.
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Ediga HH, Hester P, Yepuri A, Reddy GB, Madala SK. Nε-Carboxymethyl-Lysine Modification of Extracellular Matrix Proteins Augments Fibroblast Activation. Int J Mol Sci 2023; 24:15811. [PMID: 37958795 PMCID: PMC10650592 DOI: 10.3390/ijms242115811] [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: 09/15/2023] [Revised: 10/24/2023] [Accepted: 10/28/2023] [Indexed: 11/15/2023] Open
Abstract
The extracellular matrix (ECM) is a dynamic complex protein network that provides structural integrity and plays an active role in shaping fibroblast behavior both in health and disease. Despite its essential functions, the impact of age-associated post-translational modifications on ECM-driven fibroblast activities such as proliferation, survival, fibroblast-to-myofibroblast transformation (FMT), and extracellular matrix production remains largely unknown. Nε-carboxymethyl-lysine (CML) is one of the well-characterized advanced glycation end-products (AGEs) that can occur on lysine residues within ECM proteins through non-enzymatic glycation. In this study, we determined the accumulation and the effects of the CML-modified ECM (CML-ECM) on fibroblast activation. Immunostainings and immunoblot analysis demonstrated significant increases in CML-AGE content in idiopathic pulmonary fibrosis (IPF) compared to age-matched healthy lungs. Gene expression analysis and fibroblast activation assays collectively implicate the ECM as a negative regulator of fibroblast activation. Notably, the CML modification of the ECM resulted in a significant decrease in its anti-fibrotic effects including proliferation, FMT, apoptosis, and ECM production. Together, the results of this study revealed an unexplored pathological role played by the CML-ECM on fibroblast activation, which has wide implications in IPF and other fibrotic diseases.
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Affiliation(s)
- Harshavardhana H. Ediga
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267-0564, USA (P.H.)
- Department of Biochemistry, ICMR-National Institute of Nutrition, Hyderabad 500007, India;
| | - Patrick Hester
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267-0564, USA (P.H.)
| | - Adithi Yepuri
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267-0564, USA (P.H.)
| | | | - Satish K. Madala
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267-0564, USA (P.H.)
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26
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Huang Z, Chu WK, Ng TK, Chen S, Liang J, Chen C, Xu Y, Xie B, Ke S, Liu Q, Chen W, Huang D. Protective effects of nattokinase against microvasculopathy and neuroinflammation in diabetic retinopathy. J Diabetes 2023; 15:866-880. [PMID: 37403338 PMCID: PMC10590680 DOI: 10.1111/1753-0407.13439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/25/2023] [Accepted: 06/12/2023] [Indexed: 07/06/2023] Open
Abstract
AIMS Diabetic retinopathy (DR) is a significant global public health concern. Alternative, safe, and cost-effective pharmacologic approaches are warranted. We aimed to investigate the therapeutic potential of nattokinase (NK) for early DR and the underlying molecular mechanism. METHODS A mouse model of diabetes induced by streptozotocin was utilized and NK was administered via intravitreal injection. Microvascular abnormities were evaluated by examining the leakage from blood-retinal barrier dysfunction and loss of pericytes. Retinal neuroinflammation was examined through the assessment of glial activation and leukostasis. The level of high mobility group box 1 (HMGB1) and its downstream signaling molecules was evaluated following NK treatment. RESULTS NK administration significantly improved the blood-retinal barrier function and rescued pericyte loss in the diabetic retinas. Additionally, NK treatment inhibited diabetes-induced gliosis and inflammatory response and protected retinal neurons from diabetes-induced injury. NK also improved high glucose-induced dysfunction in cultured human retinal micrangium endothelial cells. Mechanistically, NK regulated diabetes-induced inflammation partially by modulating HMGB1 signaling in the activated microglia. CONCLUSIONS This study demonstrated the protective effects of NK against microvascular damages and neuroinflammation in the streptozotocin-induced DR model, suggesting that NK could be a potential pharmaceutical agent for the treatment of DR.
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Affiliation(s)
- Zijing Huang
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongShantouChina
| | - Wai Kit Chu
- Department of Ophthalmology & Visual SciencesThe Chinese University of Hong KongHong KongChina
| | - Tsz Kin Ng
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongShantouChina
- Department of Ophthalmology & Visual SciencesThe Chinese University of Hong KongHong KongChina
- Shantou University Medical CollegeShantouChina
| | - Shaolang Chen
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongShantouChina
| | - Jiajian Liang
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongShantouChina
| | - Chong‐Bo Chen
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongShantouChina
| | - Yanxuan Xu
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongShantouChina
| | - Biyao Xie
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongShantouChina
- Shantou University Medical CollegeShantouChina
| | - Shuping Ke
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongShantouChina
- Shantou University Medical CollegeShantouChina
| | - Qingping Liu
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongShantouChina
| | - Weiqi Chen
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongShantouChina
| | - Dingguo Huang
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongShantouChina
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Zalewska A, Antonowicz B, Szulimowska J, Zieniewska-Siemieńczuk I, Leśniewska B, Borys J, Zięba S, Kostecka-Sochoń P, Żendzian-Piotrowska M, Lo Giudice R, Lo Giudice G, Żukowski P, Maciejczyk M. Mitochondrial Redox Balance of Fibroblasts Exposed to Ti-6Al-4V Microplates Subjected to Different Types of Anodizing. Int J Mol Sci 2023; 24:12896. [PMID: 37629077 PMCID: PMC10454109 DOI: 10.3390/ijms241612896] [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: 07/18/2023] [Revised: 08/12/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
Despite the high biocompatibility of titanium and its alloys, the need to remove titanium implants is increasingly being debated due to the potential for adverse effects associated with long-term retention. Therefore, new solutions are being sought to enhance the biocompatibility of titanium implants. One of them is to increase the thickness of the passive layer of the implant made of titanium dioxide. We were the first to evaluate the effect of hard-anodized (type II) Ti-6Al-4V alloy discs on the cytotoxicity, mitochondrial function, and redox balance of fibroblasts mitochondria compared to standard-anodized (type III) and non-anodized discs. The study used fibroblasts obtained from human gingival tissue. The test discs were applied to the bottom of 12-well plates. Cells were cultured for 24 h and 7, 14, and 21 days and mitochondria were isolated. We demonstrated the occurrence of oxidative stress in the mitochondria of fibroblasts of all tested groups, regardless of the presence and type of anodization. Type II anodization prevented changes in complex II activity (vs. control). The lowest degree of citrate synthase inhibition occurred in mitochondria exposed to titanium discs with type II anodization. In the last phase of culture, the presence of type II anodization reduced the degree of cytochrome c oxidase inhibition compared to the other tests groups and the control group, and prevented apoptosis. Throughout the experiment, the release of titanium, aluminium, and vanadium ions from titanium discs with a hard-anodized passive layer was higher than from the other titanium discs, but decreased with time. The obtained results proved the existence of dysfunction and redox imbalance in the mitochondria of fibroblasts exposed to hard-anodized titanium discs, suggesting the need to search for new materials perhaps biodegradable in tissues of the human body.
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Affiliation(s)
- Anna Zalewska
- Conservative Dentistry Department, Medical University in Bialystok, 15-278 Bialystok, Poland; (J.S.); (I.Z.-S.); (P.K.-S.)
| | - Bożena Antonowicz
- Dental Surgery Department, Medical University in Bialystok, 15-278 Bialystok, Poland;
| | - Julita Szulimowska
- Conservative Dentistry Department, Medical University in Bialystok, 15-278 Bialystok, Poland; (J.S.); (I.Z.-S.); (P.K.-S.)
| | - Izabela Zieniewska-Siemieńczuk
- Conservative Dentistry Department, Medical University in Bialystok, 15-278 Bialystok, Poland; (J.S.); (I.Z.-S.); (P.K.-S.)
| | - Barbara Leśniewska
- Department of Analytical and Inorganic Chemistry, University in Bialystok, 15-328 Bialystok, Poland;
| | - Jan Borys
- Department of Maxillofacial Surgery, Medical University in Bialystok, 15-278 Bialystok, Poland;
| | - Sara Zięba
- PhD School, Medical University in Bialystok, 15-278 Bialystok, Poland
| | - Paula Kostecka-Sochoń
- Conservative Dentistry Department, Medical University in Bialystok, 15-278 Bialystok, Poland; (J.S.); (I.Z.-S.); (P.K.-S.)
| | - Małgorzata Żendzian-Piotrowska
- Department of Hygiene, Epidemiology and Ergonomics, Medical University in Bialystok, 15-278 Bialystok, Poland; (M.Ż.-P.); (M.M.)
| | - Roberto Lo Giudice
- Department of Human Pathology of the Adult and Evolutive Age G. Barresi, Messina University, 98100 Messina, Italy;
| | - Giusseppe Lo Giudice
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Messina University, 98100 Messina, Italy;
| | - Piotr Żukowski
- Restorative Dentistry Department, Croydon University, London CR9 1DX, UK;
| | - Mateusz Maciejczyk
- Department of Hygiene, Epidemiology and Ergonomics, Medical University in Bialystok, 15-278 Bialystok, Poland; (M.Ż.-P.); (M.M.)
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Khan MI, Ashfaq F, Alsayegh AA, Hamouda A, Khatoon F, Altamimi TN, Alhodieb FS, Beg MMA. Advanced glycation end product signaling and metabolic complications: Dietary approach. World J Diabetes 2023; 14:995-1012. [PMID: 37547584 PMCID: PMC10401445 DOI: 10.4239/wjd.v14.i7.995] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 04/08/2023] [Accepted: 04/27/2023] [Indexed: 07/12/2023] Open
Abstract
Advanced glycation end products (AGEs) are a heterogeneous collection of compounds formed during industrial processing and home cooking through a sequence of nonenzymatic glycation reactions. The modern western diet is full of heat-treated foods that contribute to AGE intake. Foods high in AGEs in the contemporary diet include processed cereal products. Due to industrialization and marketing strategies, restaurant meals are modified rather than being traditionally or conventionally cooked. Fried, grilled, baked, and boiled foods have the greatest AGE levels. Higher AGE-content foods include dry nuts, roasted walnuts, sunflower seeds, fried chicken, bacon, and beef. Animal proteins and processed plant foods contain furosine, acrylamide, heterocyclic amines, and 5-hydroxymethylfurfural. Furosine (2-furoil-methyl-lysine) is an amino acid found in cooked meat products and other processed foods. High concentrations of carboxymethyl-lysine, carboxyethyl-lysine, and methylglyoxal-O are found in heat-treated nonvegetarian foods, peanut butter, and cereal items. Increased plasma levels of AGEs, which are harmful chemicals that lead to age-related diseases and physiological aging, diabetes, and autoimmune/inflammatory rheumatic diseases such as systemic lupus erythematosus and rheumatoid arthritis. AGEs in the pathophysiology of metabolic diseases have been linked to individuals with diabetes mellitus who have peripheral nerves with high amounts of AGEs and diabetes has been linked to increased myelin glycation. Insulin resistance and hyperglycemia can impact numerous human tissues and organs, leading to long-term difficulties in a number of systems and organs, including the cardiovascular system. Plasma AGE levels are linked to all-cause mortality in individuals with diabetes who have fatal or nonfatal coronary artery disease, such as ventricular dysfunction. High levels of tissue AGEs are independently associated with cardiac systolic dysfunction in diabetic patients with heart failure compared with diabetic patients without heart failure. It is widely recognized that AGEs and oxidative stress play a key role in the cardiovascular complications of diabetes because they both influence and are impacted by oxidative stress. All chronic illnesses involve protein, lipid, or nucleic acid modifications including crosslinked and nondegradable aggregates known as AGEs. Endogenous AGE formation or dietary AGE uptake can result in additional protein modifications and stimulation of several inflammatory signaling pathways. Many of these systems, however, require additional explanation because they are not entirely obvious. This review summarizes the current evidence regarding dietary sources of AGEs and metabolism-related complications associated with AGEs.
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Affiliation(s)
- Mohammad Idreesh Khan
- Department of Clinical Nutrition, College of Applied Health Sciences in Ar Rass, Qassim University, Ar Rass 51921, Saudi Arabia
| | - Fauzia Ashfaq
- Clinical Nutrition Department, Applied Medical Sciences College, Jazan University, Jazan 82817, Saudi Arabia
| | - Abdulrahman A Alsayegh
- Clinical Nutrition Department, Applied Medical Sciences College, Jazan University, Jazan 82817, Saudi Arabia
| | - Alshaimaa Hamouda
- Clinical Nutrition Department, Applied Medical Sciences College, Jazan University, Jazan 82817, Saudi Arabia
| | - Fahmida Khatoon
- Department of Biochemistry, College of Medicine, University of Hail, Hail 2240, Saudi Arabia
| | - Tahani Nasser Altamimi
- Department of Family and Community Medicine, College of Medicine, University of Hail, Hail 2240, Saudi Arabia
| | - Fahad Saad Alhodieb
- Department of Clinical Nutrition, College of Applied Health Sciences in Ar Rass, Qassim University, Ar Rass 51921, Saudi Arabia
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Yu T, Wang L, Zhang L, Deuster PA. Mitochondrial Fission as a Therapeutic Target for Metabolic Diseases: Insights into Antioxidant Strategies. Antioxidants (Basel) 2023; 12:1163. [PMID: 37371893 DOI: 10.3390/antiox12061163] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 05/22/2023] [Accepted: 05/25/2023] [Indexed: 06/29/2023] Open
Abstract
Mitochondrial fission is a crucial process in maintaining metabolic homeostasis in normal physiology and under conditions of stress. Its dysregulation has been associated with several metabolic diseases, including, but not limited to, obesity, type 2 diabetes (T2DM), and cardiovascular diseases. Reactive oxygen species (ROS) serve a vital role in the genesis of these conditions, and mitochondria are both the main sites of ROS production and the primary targets of ROS. In this review, we explore the physiological and pathological roles of mitochondrial fission, its regulation by dynamin-related protein 1 (Drp1), and the interplay between ROS and mitochondria in health and metabolic diseases. We also discuss the potential therapeutic strategies of targeting mitochondrial fission through antioxidant treatments for ROS-induced conditions, including the effects of lifestyle interventions, dietary supplements, and chemicals, such as mitochondrial division inhibitor-1 (Mdivi-1) and other mitochondrial fission inhibitors, as well as certain commonly used drugs for metabolic diseases. This review highlights the importance of understanding the role of mitochondrial fission in health and metabolic diseases, and the potential of targeting mitochondrial fission as a therapeutic approach to protecting against these conditions.
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Affiliation(s)
- Tianzheng Yu
- Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
| | - Li Wang
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
- Department of Pathology, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA
| | - Lei Zhang
- Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Patricia A Deuster
- Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA
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Li H, Li M, Dong S, Dong A, Wang J, Zhu Y, Deng Y, Chen S, Zhang M. Preliminary study of the interactive effects of coronary heart disease and lacunar infarction on renal function in patients with type 2 diabetes mellitus by gender. J Diabetes Complications 2023; 37:108477. [PMID: 37121118 DOI: 10.1016/j.jdiacomp.2023.108477] [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: 11/17/2022] [Revised: 04/10/2023] [Accepted: 04/11/2023] [Indexed: 05/02/2023]
Abstract
BACKGROUND Coronary heart disease (CHD) and lacunar infarction (LI) are the most common cardio- cerebrovascular complications of type 2 diabetes mellitus (T2DM) and a recognized risk factor for renal injury. Although a unidirectional association of CHD or LI with T2DM or the kidney has been demonstrated, however, it remains unknown whether there is an interactive effect of the coexistence of CHD and LI on renal function in T2DM patients. The aim of our study was to investigate the interaction between CHD and LI on renal function in gender-specific patients with T2DM and the association between cardio-cerebrovascular disease-related conventional serum markers and the estimated glomerular filtration rate (eGFR). METHODS We conducted a cross-sectional study in Beijing and Tianjin from April 2019 to August 2021. Participants with T2DM aged ≥18 years were asked to complete a one-to-one questionnaire and physical examination. RESULTS In this study, 389 eligible patients with T2DM were included, with a mean age of 63.04 ± 9.41 years, of whom 200 (51.41 %) were male. The proportions of patients with CHD, LI, and both CHD and LI were 28.53 %, 24.42 %, and 11.05 %, respectively. Compared to T2DM patients without either CHD or LI, those with both CHD and LI were found to have a significantly greater risk of reduced eGFR (OR: 12.82, 95 % CI 5.06-32.52, P < 0.001) than those with CHD alone (OR: 2.42, 95 % CI 1.37-3.00, P = 0.004) or LI alone (OR: 1.15, 95 % CI 0.61-2.18, P = 0.664). The combined presence of CHD and LI is associated with a significantly greater risk of decreased eGFR in female T2DM patients compared to their male counterparts. We found both multiplicative and additive effects in all T2DM patients; however, when stratified by sex, only multiplicative effects were observed. After controlling for interference from CHD, LI, and age, we found that total cholesterol (TC) was negatively correlated with eGFR in females (r = -0.156, P = 0.034), and low-density lipoprotein cholesterol (LDL-C) was negatively correlated with eGFR in males (r = -0.229, P = 0.001). CONCLUSION This study provides novel evidence that the synergistic effect of CHD and LI on renal injury in patients with T2DM is significantly greater than their individual effects. Women with T2DM who have both CHD and LI are at a 4.85-fold higher risk of decreased eGFR than men. Therefore, increased clinical attention should be given to preventing and treating vascular complications in T2DM patients, as well as aggressively reducing lipid levels, particularly TC and LDL-C, to delay or prevent renal dysfunction in T2DM patients.
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Affiliation(s)
- Hongdian Li
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Mingxuan Li
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Shaoning Dong
- Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
| | - Ao Dong
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jing Wang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuanyuan Zhu
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuanyuan Deng
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Shu Chen
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Mianzhi Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China; Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China.
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Lu HC, Lin T, Ng MY, Hsieh CW, Liao YW, Chen CC, Yu CC, Chen CJ. Anti-inflammaging effects of vitamin D in human gingival fibroblasts with advanced glycation end product stimulation. J Dent Sci 2023; 18:666-673. [PMID: 37021258 PMCID: PMC10068372 DOI: 10.1016/j.jds.2022.10.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/03/2022] [Indexed: 04/05/2023] Open
Abstract
Background/purpose :Both periodontal disease and diabetes mellitus (DM) are long-term inflammatory disorders that are highly prevalent and have a significant health impact. Inflammaging, a state of pre-aging and hyperinflammatory state has been acknowledged for its role in DM patients to have heightened risk of periodontitis. Numerous evidences revealed that inflammaging contributed by cell senescence, acceleration of inflammation and oxidative stress participates in the destruction of periodontium in DM. Abilities of vitamin D in suppressing inflammation and oxidative stress have been revealed in a range of tissues, however in DM’s gingival cells, the effect remain undefined. Materials and methods : Under the stimulation of advanced glycation end-products (AGEs), we assessed the cell proliferation in human gingival fibroblast (HGF), IL-6 and IL-8 secretions, cellular senescence expression and generation of reactive oxygen species (ROS) with or without vitamin D intervention. Following that, we examined the expression of Nrf2 and HO-1 to see if vitamin D was able to modulate the anti-oxidant signaling. A knockdown experiment was then conducted to proof the participation of Nrf2 on the secretion of pro-inflammatory IL-6 and IL-8. Results : Following the treatment of vitamin D, AGEs-elicited IL-6 and IL-8 production and cell senescence were dose-dependently repressed. Moreover, vitamin D attenuated AGEs-induced ROS in a dose-dependent pattern. Results from qRT-PCR demonstrated vitamin D reversed the suppression of Nrf2 and HO-1 induced by AGEs. Our findings revealed that the anti-inflammatory and anti-oxidant effect in vitamin D was mediated via the upregulation of Nrf2 expression. Conclusion : These data showed that high levels of AGEs in the gingiva lead to inflammaging reflected by increased pro-inflammatory cytokines, cell senescence expression and oxidative stress. Vitamin D supplementation can reduce oxidative stress and inflammation via the upregulation of Nrf2 signaling and hence, may be a potential approach for treatment of diabetes-associated periodontitis.
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Affiliation(s)
- Hung-Chieh Lu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
| | - Taichen Lin
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Min Yee Ng
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
| | - Chang-Wei Hsieh
- Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan
| | - Yi-Wen Liao
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Chun-Cheng Chen
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Cheng-Chia Yu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
- Corresponding author. Institute of Oral Sciences, Chung Shan Medical University, No.110, Sec.1, Jianguo N. Rd., Taichung 40201, Taiwan.
| | - Chun-Jung Chen
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Division of Periodontics, Department of Dentistry, Chi Mei Medical Center, Tainan, Taiwan
- Corresponding author. Division of Periodontics, Department of Dentistry, Chi Mei Medical Center, No. 901, Zhonghua Rd. Yongkang Dist., Tainan 71004, Taiwan.
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Terasaki M, Shibata K, Mori Y, Saito T, Matsui T, Ohara M, Fukui T, Hasumi K, Higashimoto Y, Nobe K, Yamagishi SI. SMTP-44D Inhibits Atherosclerotic Plaque Formation in Apolipoprotein-E Null Mice Partly by Suppressing the AGEs-RAGE Axis. Int J Mol Sci 2023; 24:ijms24076505. [PMID: 37047475 PMCID: PMC10094964 DOI: 10.3390/ijms24076505] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/24/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
SMTP-44D has been reported to have anti-oxidative and anti-inflammatory reactions, including reduced expression of receptor for advanced glycation end products (RAGE) in experimental diabetic neuropathy. Although activation of RAGE with its ligands, and advanced glycation end products (AGEs), play a crucial role in atherosclerotic cardiovascular disease, a leading cause of death in diabetic patients, it remains unclear whether SMTP-44D could inhibit experimental atherosclerosis by suppressing the AGEs–RAGE axis. In this study, we investigated the effects of SMTP-44D on atherosclerotic plaque formation and expression of AGEs in apolipoprotein-E null (Apoe−/−) mice. We further studied here whether and how SMTP-44D inhibited foam cell formation of macrophages isolated from Apoe−/− mice ex vivo. Although administration of SMTP-44D to Apoe−/− mice did not affect clinical or biochemical parameters, it significantly decreased the surface area of atherosclerotic lesions and reduced the atheromatous plaque size, macrophage infiltration, and AGEs accumulation in the aortic roots. SMTP-44D bound to immobilized RAGE and subsequently attenuated the interaction of AGEs with RAGE in vitro. Furthermore, foam cell formation evaluated by Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and gene expression of RAGE, cyclin-dependent kinase 5 (Cdk5) and CD36 in macrophages isolated from SMTP-44D-treated Apoe−/− mice were significantly decreased compared with those from saline-treated mice. Gene expression levels of RAGE and Cdk5 were highly correlated with each other, the latter of which was also positively associated with that of CD36. The present study suggests that SMTP-44D may inhibit atherosclerotic plaque formation in Apoe−/− mice partly by blocking the AGEs-RAGE-induced ox-LDL uptake into macrophages via the suppression of Cdk5-CD36 pathway.
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The Patient's Physiological Status at the Start Determines the Success of the Inpatient Cardiovascular Rehabilitation Program. J Clin Med 2023; 12:jcm12051735. [PMID: 36902521 PMCID: PMC10003145 DOI: 10.3390/jcm12051735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/11/2023] [Accepted: 02/13/2023] [Indexed: 02/24/2023] Open
Abstract
Multidisciplinary inpatient rehabilitation plays an important role in the recovery of patients with cardiovascular diseases (CVDs). Lifestyle changes, achieved by exercise, diet, weight loss and patient education programs, are the first steps to a healthier life. Advanced glycation end products (AGEs) and their receptor (RAGE) are known to be involved in CVDs. Clarification on whether initial AGE levels can influence the rehabilitation outcome is important. Serum samples were collected at the beginning and end of the inpatient rehabilitation stay and analyzed for parameters: lipid metabolism, glucose status, oxidative stress, inflammation and AGE/RAGE-axis. As result, a 5% increase in the soluble isoform RAGE (sRAGE) (T0: 891.82 ± 44.97 pg/mL, T1: 937.17 ± 43.29 pg/mL) accompanied by a 7% decrease in AGEs (T0: 10.93 ± 0.65 µg/mL, T1: 10.21 ± 0.61 µg/mL) was shown. Depending on the initial AGE level, a significant reduction of 12.2% of the AGE activity (quotient AGE/sRAGE) was observed. We found that almost all measured factors improved. Summarizing, CVD-specific multidisciplinary rehabilitation positively influences disease-associated parameters, and thus provides an optimal starting point for subsequent disease-modifying lifestyle changes. Considering our observations, the initial physiological situations of patients at the beginning of their rehabilitation stay seem to play a decisive role regarding the assessment of rehabilitation success.
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Maleki V, Abbaszadeh S, Seyyed Shoura SM, Sohrabnavi A, Sepandi M, Taghdir M. Potential roles of ellagic acid on metabolic variables in diabetes mellitus: A systematic review. Clin Exp Pharmacol Physiol 2023; 50:121-131. [PMID: 36222179 DOI: 10.1111/1440-1681.13729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 09/17/2022] [Accepted: 10/07/2022] [Indexed: 01/05/2023]
Abstract
Diabetes mellitus is a widespread endocrine disorder globally. Due to its antioxidant and anti-inflammatory properties, ellagic acid has the potential to improve the metabolic effects of chronic non-communicable diseases. This systematic review summarizes current evidence about the potential effects of ellagic acid on metabolic variables in diabetes mellitus. A comprehensive systematic literature search was conducted in databases such as PubMed, Scopus, EMBASE, ProQuest and Google Scholar from inception until March 2022. All animal studies and clinical trials were eligible for inclusion. Studies using in vitro models or published in a non-English language were excluded. Of 1320 articles, 23 were selected for assessment, including 21 animal studies and two randomized controlled trial studies. Following ellagic acid administration, findings reported improvement in FBS, HbA1c, insulin (20, 8 and 12 studies, respectively), TG, TC, HDL-C (13, 10 and 5 studies, respectively), MDA, GSH, CAT, SOD (11, 6, 3 and 4 studies, respectively), and TNF-α and IL-6 (6 and 3 studies, respectively). In conclusion, ellagic acid may improve glycaemic indicators, dyslipidaemia, oxidative stress and inflammation in diabetes mellitus. However, further clinical trials are needed to explore the mechanisms more precisely and to observe the applied consequences.
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Affiliation(s)
- Vahid Maleki
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.,Department of Nutrition and Food Hygiene, Faculty of Health, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Sepideh Abbaszadeh
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.,Department of Nutrition and Food Hygiene, Faculty of Health, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | | | - Asma Sohrabnavi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mojtaba Sepandi
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Maryam Taghdir
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.,Department of Nutrition and Food Hygiene, Faculty of Health, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Li H, Li M, Dong S, Zhang S, Dong A, Zhang M. Assessment of the association between genetic factors regulating thyroid function and microvascular complications in diabetes: A two-sample Mendelian randomization study in the European population. Front Endocrinol (Lausanne) 2023; 14:1126339. [PMID: 36926020 PMCID: PMC10011638 DOI: 10.3389/fendo.2023.1126339] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 02/15/2023] [Indexed: 03/08/2023] Open
Abstract
BACKGROUND Observational studies have identified a possible link between thyroid function and diabetic microangiopathy, specifically in diabetic kidney disease (DKD) and diabetic retinopathy (DR). However, it is unclear whether this association reflects a causal relationship. OBJECTIVE To assess the potential direct effect of thyroid characteristics on DKD and DR based on Mendelian randomization (MR). METHODS We conducted an MR study using genetic variants as an instrument associated with thyroid function to examine the causal effects on DKD and DR. The study included the analysis of 4 exposure factors associated with thyroid hormone regulation and 5 outcomes. Genomewide significant variants were used as instruments for standardized freethyroxine (FT4) and thyroid-stimulating hormone (TSH) levels within the reference range, standardized free triiodothyronine (FT3):FT4 ratio, and standardized thyroid peroxidase antibody (TPOAB) levels. The primary outcomes were DKD and DR events, and secondary outcomes were estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (ACR) in diabetes, and proliferative diabetic retinopathy (PDR). Satisfying the 3 MR core assumptions, the inverse-variance weighted technique was used as the primary analysis, and sensitivity analysis was performed using MR-Egger, weighted median, and MR pleiotropy residual sum and outlier techniques. RESULTS All outcome and exposure instruments were selected from publicly available GWAS data conducted in European populations. In inverse-variance weighted random-effects MR, gene-based TSH with in the reference range was associated with DKD (OR 1.44; 95%CI 1.04, 2.41; P = 0.033) and eGFR (β: -0.031; 95%CI: -0.063, -0.001; P = 0.047). Gene-based increased FT3:FT4 ratio, decreased FT4 with in the reference range were associated with increased ACR with inverse-variance weighted random-effects β of 0.178 (95%CI: 0.004, 0.353; P = 0.046) and -0.078 (95%CI: -0.142, -0.014; P = 0.017), respectively, and robust to tests of horizontal pleiotropy. However, all thyroid hormone instruments were not associated with DR and PDR at the genetic level. CONCLUSION In diabetic patients, an elevated TSH within the reference range was linked to a greater risk of DKD and decreased eGFR. Similarly, decreased FT4 and an increased FT3:FT4 ratio within the reference range were associated with increased ACR in diabetic patients. However, gene-based thyroid hormones were not associated with DR, indicating a possible pathway involving the thyroid-islet-renal axis. However, larger population studies are needed to further validate this conclusion.
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Affiliation(s)
- Hongdian Li
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Mingxuan Li
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Shaoning Dong
- Department of Nephrology, Tianjin academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
| | - Sai Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Ao Dong
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Mianzhi Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
- Department of Nephrology, Tianjin academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
- *Correspondence: Mianzhi Zhang,
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Low-Intensity Pulsed Ultrasound Counteracts Advanced Glycation End Products-Induced Corpus Cavernosal Endothelial Cell Dysfunction via Activating Mitophagy. Int J Mol Sci 2022; 23:ijms232314887. [PMID: 36499213 PMCID: PMC9740783 DOI: 10.3390/ijms232314887] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/13/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
Injury to corpus cavernosal endothelial cells (CCECs) is an important pathological basis of diabetes mellitus-induced erectile dysfunction (DMED), while low-intensity pulsed ultrasound (LIPUS) has been shown to improve erectile function in DMED. To further understand its therapeutic mechanism of action, in this study, we first demonstrated increased apoptosis and shedding in the CCECs of DMED patients, accompanied by significant mitochondrial injury by immunohistochemistry and electron microscopy of corpus cavernosum tissue. Next, we used advanced glycation end products (AGEs) to simulate the diabetic environment in vitro and found that AGES damaged mitochondria and inhibited angiogenesis in CCECs in a dose-dependent manner, while LIPUS treatment significantly reversed its effects. Mechanistic studies based on transcriptome sequencing showed that LIPUS significantly up-regulated LC3 and PARKIN protein levels in mitochondria, promoted mitophagy, and affected mitochondrial dynamics and reactive oxygen species (ROS) production. In addition, the protective effects of LIPUS were abrogated when mitophagy was inhibited by 3-methyladenine. In summary, LIPUS exerted potent inhibitory effects on AGES-induced CCEC failure via mitophagy, providing a theoretical basis for DMED treatment that encompasses the protection of endothelial structure and function.
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Lee BC, Choe YM, Suh GH, Choi IG, Lee JH, Kim HS, Hwang J, Yi D, Kim JW. A combination of midlife diabetes mellitus and the apolipoprotein E ε4 allele increase risk for cognitive decline. Front Aging Neurosci 2022; 14:1065117. [PMID: 36466611 PMCID: PMC9715424 DOI: 10.3389/fnagi.2022.1065117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 11/03/2022] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND It has been suggested that diabetes mellitus (DM) and the apolipoprotein E (APOE) ε4 allele (APOE4) increase the risk for Alzheimer's disease (AD) and cognitive decline. However, the evidence is sparse. We explored whether APOE4 status modulated the effects of midlife and late-life DM on global cognition of non-demented older adults. METHODS In all, 176 non-demented adults (age 65-90 years) were enrolled. All the participants underwent comprehensive clinical assessments including midlife and late-life DM evaluation and APOE genotyping. The global cognitive performance index was assessed by the total score (TS) of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery. RESULTS We found a significant midlife DM × APOE4 interaction effect on the global cognitive performance. Subgroup analyses indicated that an association between midlife DM and decreased global cognitive performance was apparent only in older adults who were APOE4-positive, and not in those with APOE4-negative. CONCLUSION Our findings from non-demented older adults suggest that midlife DM increases the risk for AD and cognitive decline, and this risk is modulated by APOE4 status. To prevent AD and cognitive decline, physicians should check for the possible coexistence of midlife DM and APOE4-positive status.
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Affiliation(s)
- Boung Chul Lee
- Department of Psychiatry, Hallym University College of Medicine, Chuncheon, South Korea
- Department of Neuropsychiatry, Hallym University Hangang Sacred Heart Hospital, Seoul, South Korea
| | - Young Min Choe
- Department of Psychiatry, Hallym University College of Medicine, Chuncheon, South Korea
- Department of Neuropsychiatry, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, South Korea
| | - Guk-Hee Suh
- Department of Psychiatry, Hallym University College of Medicine, Chuncheon, South Korea
- Department of Neuropsychiatry, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, South Korea
| | - Ihn-Geun Choi
- Department of Psychiatry, Hallym University College of Medicine, Chuncheon, South Korea
- Department of Psychiatry, Seoul W Psychiatric Office, Seoul, South Korea
| | - Jun Ho Lee
- Department of Neuropsychiatry, Seoul National University Hospital, Seoul, South Korea
| | - Hyun Soo Kim
- Department of Laboratory Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, South Korea
| | - Jaeuk Hwang
- Department of Psychiatry, Soonchunhyang University Seoul Hospital, Seoul, South Korea
| | - Dahyun Yi
- Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University, Seoul, South Korea
| | - Jee Wook Kim
- Department of Psychiatry, Hallym University College of Medicine, Chuncheon, South Korea
- Department of Neuropsychiatry, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, South Korea
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Topical application of melatonin accelerates the maturation of skin wounds and increases collagen deposition in a rat model of diabetes. J Tissue Viability 2022; 31:606-613. [DOI: 10.1016/j.jtv.2022.07.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 03/10/2022] [Accepted: 07/28/2022] [Indexed: 11/20/2022]
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Lee J, Yun JS, Ko SH. Advanced Glycation End Products and Their Effect on Vascular Complications in Type 2 Diabetes Mellitus. Nutrients 2022; 14:3086. [PMID: 35956261 PMCID: PMC9370094 DOI: 10.3390/nu14153086] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/22/2022] [Accepted: 07/26/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetes is well established as a chronic disease with a high health burden due to mortality or morbidity from the final outcomes of vascular complications. An increased duration of hyperglycemia is associated with abnormal metabolism. Advanced glycation end products (AGEs) are nonenzymatic glycated forms of free amino acids that lead to abnormal crosslinking of extra-cellular and intracellular proteins by disrupting the normal structure. Furthermore, the interaction of AGEs and their receptors induces several pathways by promoting oxidative stress and inflammation. In this review, we discuss the role of AGEs in diabetic vascular complications, especially type 2 DM, based on recent clinical studies.
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Affiliation(s)
- Jeongmin Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03391, Korea;
| | - Jae-Seung Yun
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, Korea;
| | - Seung-Hyun Ko
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, Korea;
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40
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Lee HW, Gu MJ, Yoo G, Choi IW, Lee SH, Kim Y, Ha SK. Glycolaldehyde induces synergistic effects on vascular inflammation in TNF-α-stimulated vascular smooth muscle cells. PLoS One 2022; 17:e0270249. [PMID: 35788200 PMCID: PMC9255721 DOI: 10.1371/journal.pone.0270249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/07/2022] [Indexed: 11/18/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory disease that contributes to disease progression is associated with the expression of adhesion molecules in vascular smooth muscle cells (VSMCs). Glycolaldehyde (GA) has been shown to impair cellular function in various disorders, including diabetes, and renal diseases. This study investigated the effect of GA on the expression of adhesion molecules in the mouse VSMC line, MOVAS-1. Co-incubation of VSMCs with GA (25–50 μM) dose-dependently increased the protein and mRNA level of Vcam-1 and ICAM-1. Additionally, GA upregulated intracellular ROS production and phosphorylation of MAPK and NK-κB. GA also elevated TNF-α-induced PI3K-AKT activation. Furthermore, GA enhanced TNF-α-activated IκBα kinase activation, subsequent IκBα degradation, and nuclear translocation of NF-κB. These findings suggest that GA stumulated VSMC adhesive capacity and the induction of VCAM-1 and ICAM-1 in VSMCs through inhibition of MAPK and NF-κB signaling pathways, providing insights into the effect of GA to induce inflammation within atherosclerotic lesions.
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Affiliation(s)
- Hee-Weon Lee
- Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Min Ji Gu
- Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Guijae Yoo
- Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - In-Wook Choi
- Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Sang-Hoon Lee
- Korea Food Research Institute, Wanju-gun, Republic of Korea
- Division of Food Biotechnology, University of Science and Technology, Daejeon, Korea
| | - Yoonsook Kim
- Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Sang Keun Ha
- Korea Food Research Institute, Wanju-gun, Republic of Korea
- Division of Food Biotechnology, University of Science and Technology, Daejeon, Korea
- * E-mail:
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41
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Chen K, Deng Y, Shang S, Li P, Liu L, Chen X. Network Pharmacology-Based Investigation of the Molecular Mechanisms of the Chinese Herbal Formula Shenyi in the Treatment of Diabetic Nephropathy. Front Med (Lausanne) 2022; 9:898624. [PMID: 35755045 PMCID: PMC9226379 DOI: 10.3389/fmed.2022.898624] [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: 03/17/2022] [Accepted: 05/05/2022] [Indexed: 11/13/2022] Open
Abstract
Background The Chinese herbal formula Shenyi (SY) is a prescription that was developed by the Department of Nephrology, Chinese People's Liberation Army General Hospital. This preparation is mainly used to treat chronic kidney disease (CKD) caused by Diabetic nephropathy (DN) and is effective. However, the active ingredients of SY, DN treatment-related molecular targets and the effector mechanisms are still unclear. Methods The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and the Traditional Chinese Medicine and Chemical Component Database of Shanghai Institute of Organic Chemistry were used to screen the active ingredients in SY, the TCMSP database and Swiss Target Prediction database were used to collect the targets of the active ingredients of SY, and the Gene Cards and Online Mendelian Inheritance in Man (OMIM) databases were used to screen for DN pathogenesis targets. The intersections of the component targets and disease targets were mapped to obtain the therapeutic targets. The METASCAPE database was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the therapeutic targets. Cytoscape 3.7.2 was used to analyze topological parameters and construct a network of SY for the treatment of DN. Results Sixty-two active ingredients and 497 active ingredient effector targets in SY, 3260 DN-related targets, and 271 SY treatments for DN targets were identified. Among these targets, 17 were core targets, including AKT1, tumor necrosis factor (TNF), interleukin-6 (IL6), and TP53. The GO and KEGG enrichment analyses show that SY's therapeutic effects for DN occur mainly through pathways such as advanced glycation end product (AGE)-RAGE, PI3K-Akt, and IL-17. Conclusion Multiple active ingredients in SY exhibit treatment effects on DN by affecting metabolism, inhibiting inflammation, and affecting cell structure growth.
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Affiliation(s)
- Keng Chen
- Clinical Medical School, Guangdong Pharmaceutical University, Guangzhou, China.,First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Yiyao Deng
- Department of Nephrology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Shunlai Shang
- First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Ping Li
- First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Linchang Liu
- First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China.,Department of Nephrology, Beijing Hospital of Integrated Traditional Chinese and Western Medicine, Beijing, China
| | - Xiangmei Chen
- Clinical Medical School, Guangdong Pharmaceutical University, Guangzhou, China.,First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
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Han AY, Ha SM, Shin YK, Seol GH. Ginsenoside Rg-1 prevents elevated cytosolic Ca 2+ via store-operated Ca 2+ entry in high-glucose-stimulated vascular endothelial and smooth muscle cells. BMC Complement Med Ther 2022; 22:166. [PMID: 35733160 PMCID: PMC9215051 DOI: 10.1186/s12906-022-03647-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/10/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Ginsenoside Rg-1 (Rg-1), a triterpenoid saponin abundantly present in Panax ginseng, is a type of naturally occurring steroid with known anti-diabetic and anti-inflammatory effects. In this study, we sought to confirm the effects and mechanisms of action of Rg-1 on store-operated Ca2+ entry (SOCE) in human vascular endothelial cell line (EA) and murine aortic vascular smooth muscle cell line (MOVAS) cells exposed to high glucose. METHODS Cytosolic Ca2+ concentrations in EA and MOVAS cells were measured by monitoring fluorescence of the ratiometric Ca2+-indicator, Fura-2 AM. RESULTS High glucose significantly increased Ca2+ influx by abnormally activating SOCE in EA and MOVAS cells. Notably, this high glucose-induced increase in SOCE was restored to normal levels in EA and MOVAS cells by Rg-1. Moreover, Rg-1 induced reductions in SOCE in cells exposed to high glucose were significantly inhibited by the plasma membrane Ca2+ ATPase (PMCA) blocker lanthanum, the Na+/K+-ATPase blocker ouabain, or the Na+/Ca2+ exchanger (NCX) blockers Ni2+ and KB-R7943. These observations suggest that the mechanism of action of Rg-1 inhibition of SOCE involves PMCA and Na+/K+-ATPase, and an increase in Ca2+ efflux via NCXs in both EA and MOVAS cells exposed to high glucose. CONCLUSIONS These findings indicate that Rg-1 may protect vascular endothelial and smooth muscle cells from Ca2+ increases following exposure to hyperglycemic conditions.
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Affiliation(s)
- A Young Han
- Department of Basic Nursing Science, College of Nursing, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea
- Department of Nursing, College of Life Science and Industry, Sunchon National University, Suncheon, Republic of Korea
| | - Su Min Ha
- Department of Basic Nursing Science, College of Nursing, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea
| | - You Kyoung Shin
- Department of Basic Nursing Science, College of Nursing, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea
| | - Geun Hee Seol
- Department of Basic Nursing Science, College of Nursing, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
- BK21 FOUR Program of Transdisciplinary Major in Learning Health Systems, Graduate School, Korea University, Seoul, Republic of Korea.
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Chopra A, Jayasinghe TN, Eberhard J. Are Inflamed Periodontal Tissues Endogenous Source of Advanced Glycation End-Products (AGEs) in Individuals with and without Diabetes Mellitus? A Systematic Review. Biomolecules 2022; 12:biom12050642. [PMID: 35625570 PMCID: PMC9138899 DOI: 10.3390/biom12050642] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/14/2022] [Accepted: 04/27/2022] [Indexed: 12/14/2022] Open
Abstract
Advanced glycation end-products (AGEs) are heterogeneous compounds formed when excess sugars condense with the amino groups of nucleic acids and proteins. Increased AGEs are associated with insulin resistance and poor glycemic control. Recently, inflamed periodontal tissues and certain oral bacteria were observed to increase the local and systemic AGE levels in both normoglycemic and hyperglycemic individuals. Although hyperglycemia induced AGE and its effect on the periodontal tissues is known, periodontitis as an endogenous source of AGE formation is not well explored. Hence, this systematic review is aimed to explore, for the first time, whether inflamed periodontal tissues and periodontal pathogens have the capacity to modulate AGE levels in individuals with or without T2DM and how this affects the glycemic load. Six electronic databases were searched using the following keywords: (Periodontitis OR Periodontal disease OR Periodontal Inflammation) AND (Diabetes mellitus OR Hyperglycemia OR Insulin resistance) AND Advanced glycation end products. The results yielded 1140 articles, of which 13 articles were included for the review. The results showed that the mean AGE levels in gingival crevicular fluid was higher in individuals with diabetes mellitus and periodontitis (521.9 pg/mL) compared to healthy individuals with periodontitis (234.84 pg/mL). The serum AGE levels in normoglycemic subjects having periodontitis was higher compared to those without periodontitis (15.91 ng/mL vs. 6.60 ng/mL). Tannerella forsythia, a common gram-negative anaerobe periodontal pathogen in the oral biofilm, was observed to produce methylglyoxal (precursor of AGE) in the gingival tissues. Increased AGE deposition and activate of AGE receptors was noted in the presence of periodontitis in both normoglycemic and hyperglycemic individuals. Hence, it can be concluded that periodontitis can modulate the local and systemic levels of AGE levels even in absence of hyperglycemia. This explains the bidirectional relationship between periodontitis and development of prediabetes, incident diabetes, poor glycemic control, and insulin resistance.
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Affiliation(s)
- Aditi Chopra
- Department of Periodontology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal 576104, India
- Correspondence:
| | - Thilini N. Jayasinghe
- The Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; (T.N.J.); (J.E.)
- School of Dentistry, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
| | - Joerg Eberhard
- The Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; (T.N.J.); (J.E.)
- School of Dentistry, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
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Oliveira AL, Medeiros ML, de Oliveira MG, Teixeira CJ, Mónica FZ, Antunes E. Enhanced RAGE Expression and Excess Reactive-Oxygen Species Production Mediates Rho Kinase-Dependent Detrusor Overactivity After Methylglyoxal Exposure. Front Physiol 2022; 13:860342. [PMID: 35418871 PMCID: PMC8996136 DOI: 10.3389/fphys.2022.860342] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 03/11/2022] [Indexed: 12/23/2022] Open
Abstract
Methylglyoxal (MGO) is a highly reactive dicarbonyl compound implicated in diabetes-associated diseases. In vascular tissues, MGO induces the formation of advanced glycation end products (AGEs) that bounds its receptor RAGE, initiating the downstream tissue injury. Outside the cardiovascular system, MGO intake produces mouse voiding dysfunction and bladder overactivity. We have sought that MGO-induced bladder overactivity is due to activation of AGE-RAGE-reactive-oxygen species (ROS) signaling cascade, leading to Rho kinase activation. Therefore, female mice received 0.5% MGO orally for 12 weeks, after which in vitro bladder contractions were evaluated in the presence or not of superoxide dismutase (PEG-SOD) or the Rho kinase inhibitor Y27632. Treatment with MGO significantly elevated the serum levels of MGO and fluorescent AGEs, as well as the RAGE immunostaining in the urothelium, detrusor, and vascular endothelium. RAGE mRNA expression in the bladder was also higher in the MGO group. Methylglyoxal significantly increased the ROS production in both urothelium and detrusor smooth muscle, with the increases in detrusor markedly higher than urothelium. The bladder activity of superoxide dismutase (SOD) was significantly reduced in the MGO group. Gene expressions of L-type Ca2+ channels, RhoA, ROCK-1, and ROCK-2 in bladder tissues were significantly elevated in the MGO group. Increased bladder contractions to electrical-field stimulation, carbachol α,β-methylene ATP, and extracellular Ca2+ were observed after MGO exposure, which was significantly reduced by prior incubation with either PEG-SOD or Y27632. Overall, our data indicate serum MGO accumulation elevates the AGEs levels and activates the RAGE-ROS signaling leading to Rho kinase-induced muscle sensitization, ultimately leading to detrusor overactivity.
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Affiliation(s)
- Akila L Oliveira
- Department of Pharmacology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Matheus L Medeiros
- Department of Pharmacology, University of Campinas (UNICAMP), Campinas, Brazil
| | | | - Caio Jordão Teixeira
- Department of Physiology and Biophysics, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Fabíola Z Mónica
- Department of Pharmacology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Edson Antunes
- Department of Pharmacology, University of Campinas (UNICAMP), Campinas, Brazil
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45
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Sinha S, Haque M. Insulin Resistance Is Cheerfully Hitched with Hypertension. Life (Basel) 2022; 12:564. [PMID: 35455055 PMCID: PMC9028820 DOI: 10.3390/life12040564] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/08/2022] [Accepted: 04/08/2022] [Indexed: 12/15/2022] Open
Abstract
Cardiovascular diseases and type 2 diabetes mellitus (T2DM) have risen steadily worldwide, particularly in low-income and developing countries. In the last hundred years, deaths caused by cardiovascular diseases increased rapidly to 35-40%, becoming the most common cause of mortality worldwide. Cardiovascular disease is the leading cause of morbidity and mortality in type 2 diabetes mellitus (T2DM), which is aggravated by hypertension. Hypertension and diabetes are closely interlinked since they have similar risk factors such as endothelial dysfunction, vascular inflammation, arterial remodeling, atherosclerosis, dyslipidemia, and obesity. Patients with high blood pressure often show insulin resistance and have a higher risk of developing diabetes than normotensive individuals. It has been observed that over the last 30 years, the prevalence of insulin resistance (IR) has increased significantly. Accordingly, hypertension and insulin resistance are strongly related to an increased risk of impaired glucose tolerance, diabetes, cardiovascular diseases (CVD), and endocrine disorders. Common mechanisms, for instance, upregulation of the renin-angiotensin-aldosterone system, oxidative stress, inflammation, and activation of the immune system, possibly have a role in the association between diabetes and hypertension. Altogether these abnormalities significantly increase the risk of developing type 2 diabetes.
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Affiliation(s)
- Susmita Sinha
- Department of Physiology, Khulna City Medical College and Hospital, 33 KDA Avenue, Hotel Royal Mor, Khulna Sadar, Khulna 9100, Bangladesh;
| | - Mainul Haque
- The Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kem Perdana Sungai Besi, Kuala Lumpur 57000, Malaysia
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Retinitis Pigmentosa (RP): The Role of Oxidative Stress in the Degenerative Process Progression. Biomedicines 2022; 10:biomedicines10030582. [PMID: 35327384 PMCID: PMC8945005 DOI: 10.3390/biomedicines10030582] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/20/2022] [Accepted: 02/23/2022] [Indexed: 02/05/2023] Open
Abstract
Purpose: Retinitis Pigmentosa is a term that includes a group of inherited bilateral and progressive retinal degenerations, with the involvement of rod photoreceptors, which frequently leads to blindness; oxidative stress may be involved in the degeneration progression as proposed by several recent studies. The goal of this study is to evaluate whether circulating free radicals taken from capillary blood are related to one of the most important features of Retinitis pigmentosa that can affect frequently patients: cystoid macular oedema (CME). Materials: A total of 186 patients with Retinitis Pigmentosa (range: 25−69 years) were enrolled; all patients completed an ophthalmologic examination and SD-OCT at baseline and were divided into three subgroups according to the SD-OCT features. ROS blood levels were determined using FORT with monitoring of free oxygen radicals. Results: Test levels of free oxygen radicals were significantly increased, almost twice, in RP patients showing cystoid macular oedema and significantly increased compared to the control group. (p < 0.001). Discussion: Our findings suggest that oxidative stress may speed cone photoreceptors’ morphological damage (CMT); because long lasting oxidative stress in the RP may cause oxidative damage, with animal models of RP suggesting this is a micromolecular mechanism of photoreceptors’ (cone) death, it can be similar to cone damage in human RP eyes. The limitations of this paper are the relatively small sample, the horizontal design of the study, and the lack of data about the levels of ROS in the vitreous body.
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Mishra N, Kaur G, Saxena S. External Limiting Membrane, Photoreceptor Ellipsoid Zone Disruption, and Retinal Pigment Epithelium Alterations in Diabetic Retinopathy. ANNALS OF THE NATIONAL ACADEMY OF MEDICAL SCIENCES (INDIA) 2022. [DOI: 10.1055/s-0042-1742585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
Abstract
Objective Diabetic retinopathy (DR), a microvascular complication of diabetes, is a leading cause of preventable blindness. Spectral domain optical coherence tomography (SD-OCT) provides cross-sectional and topographical imaging of the retina. SD-OCT resolves outer retinal layers into three hyperreflective bands—external limiting membrane (ELM), ellipsoid zone (EZ), and retinal pigment epithelium (RPE). In this article, we have studied the role of these outer retinal layers in structural and molecular changes taking place in DR.
Materials and Methods Articles with clinical features, pathogenesis, diagnosis, and treatment of DR were thoroughly studied. Articles were searched on PubMed, MEDLINE, and Cochrane Library from 2000 to 2020. Studies focusing on the role of ELM, EZ, and RPE in pathogenesis of DR based on SD-OCT were included.
Results The long-standing hyperglycemia leads to protein glycosylation resulting in formation of advanced glycation end products (AGEs). AGEs have an impact through their effect on retinal microvasculature, vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1, nitrosative and oxidative stress, and vitamin D and calcium metabolism. All these factors have been linked with disruption of outer retinal layers. AGEs lead to vascular endothelial dysfunction and release of proangiogenic factors by increasing the expression of VEGF in retinal pericytes and RPE cells. This leads to leakage and fluid accumulation resulting in diabetic macular edema (DME). In DME, there is sequential disruption of ELM and EZ and decrease in visual acuity (VA). The RPE alterations have been reported to be associated with the severity of DR and decrease in VA. Anti-VEGF therapy, most common treatment of DME, leads to restoration of barrier effect of ELM, it was found to be restored first followed by EZ restoration. Newer anti-AGEs agents and their receptor blockers are being developed which have a positive effect on maintaining the health of RPE.
Conclusion A complex molecular association exists between the structural changes in ELM, EZ, and RPE in DR. SD-OCT is an indispensable tool to study these changes as integrity of these outer layers of retina is essential for maintaining visual function of retina in DR.
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Affiliation(s)
- Nibha Mishra
- Department of Ophthalmology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Gurkiran Kaur
- Department of Ophthalmology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Sandeep Saxena
- Department of Ophthalmology, King George's Medical University, Lucknow, Uttar Pradesh, India
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48
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Matsumoto T, Taguchi K, Kobayashi T. Relationships between advanced glycation end products (AGEs), vasoactive substances, and vascular function. J Smooth Muscle Res 2022; 57:94-107. [PMID: 35095032 PMCID: PMC8795595 DOI: 10.1540/jsmr.57.94] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) are major cell types that control vascular function, and hence dysfunction of these cells plays a key role in the development and progression of vasculopathies. Abnormal vascular responsiveness to vasoactive substances including vasoconstrictors and vasodilators has been observed in various arteries in diseases including diabetes, hypertension, chronic kidney diseases, and atherosclerosis. Several substances derived from ECs tightly control vascular function, such as endothelium-derived relaxing and contracting factors, and it is known that abnormal vascular signaling of these endothelium-derived substances is often observed in various diseases. Derangement of signaling in VSMCs and altered function influence vascular reactivity to vasoactive substances and tone, which are important determinants of vascular resistance and blood pressure. However, understanding the molecular mechanisms underlying abnormalities of vascular functions in pathological states is difficult because multiple substances interact in the development of these processes. Advanced glycation end products (AGEs), a heterogeneous group of bioactive compounds, are thought to contribute to vascular dysfunction, which in turn cause the development of several diseases including diabetes, hypertension, stroke, and atherosclerosis. A growing body of evidence suggests that AGEs could affect these cells and modulate vascular function. This study is focused on the link between AGEs and functions of ECs and VSMCs, particularly the modulative effects of AGEs on vascular reactivities to vasoactive substances.
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Affiliation(s)
- Takayuki Matsumoto
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Kumiko Taguchi
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Tsuneo Kobayashi
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
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Gao Y, Xu Y, Yin J. Selenomethionine Ameliorates Cognitive Impairment, Decreases Hippocampal Oxidative Stress and Attenuates Dysbiosis in D-Galactose-Treated Mice. Antioxidants (Basel) 2022; 11:antiox11010111. [PMID: 35052615 PMCID: PMC8772940 DOI: 10.3390/antiox11010111] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/25/2021] [Accepted: 12/28/2021] [Indexed: 02/04/2023] Open
Abstract
The prevalence of age-related cognitive impairment is increasing as the proportion of older individuals in the population grows. It is therefore necessary and urgent to find agents to prevent or ameliorate age-related cognitive impairment. Selenomethionine (SeMet) is a natural amino acid occurring in yeast and Brazil nuts. It mitigates cognitive impairment in an Alzheimer’s disease mouse model, however, whether it works on age-related cognitive impairment remains unknown. In this study, SeMet significantly improved the performance of D-galactose-treated mice in the novel object recognition test, passive avoidance task and Morris water maze test. SeMet reversed D-galactose-induced reduction of hippocampal acetylcholine levels, suppression of choline acetyltransferase activity and activation of acetyl cholinesterase. It decreased D-galactose-induced oxidative stress and increased the selenoprotein P levels in the hippocampus. Besides, it attenuated D-galactose-induced dysbiosis by increasing the α-diversity and modulating the taxonomic structure. Correlations between certain taxa and physiological parameters were observed. Our results provide evidence of the effectiveness of SeMet on ameliorating D-galactose-induced cognitive impairment and suggest SeMet has potential to be used in the prevention or adjuvant treatment of age-related cognitive impairment.
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Affiliation(s)
| | - Yongquan Xu
- Correspondence: (Y.X.); (J.Y.); Tel.: +86-571-8665-0594 (Y.X.); +86-571-8665-0031 (J.Y.)
| | - Junfeng Yin
- Correspondence: (Y.X.); (J.Y.); Tel.: +86-571-8665-0594 (Y.X.); +86-571-8665-0031 (J.Y.)
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50
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Sheikh MH, Errede M, d'Amati A, Khan NQ, Fanti S, Loiola RA, McArthur S, Purvis GSD, O'Riordan CE, Ferorelli D, Dell'Erba A, Kieswich J, Reutelingsperger C, Maiorano E, Yaqoob M, Thiemermann C, Baragetti A, Catapano AL, Norata GD, Marelli-Berg F, Virgintino D, Solito E. Impact of metabolic disorders on the structural, functional, and immunological integrity of the blood-brain barrier: Therapeutic avenues. FASEB J 2022; 36:e22107. [PMID: 34939700 DOI: 10.1096/fj.202101297r] [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: 08/13/2021] [Revised: 11/04/2021] [Accepted: 12/03/2021] [Indexed: 12/23/2022]
Abstract
Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high-fat high-sugar diet mimicking obesity-induced type 2 diabetes mellitus (T2DM) in humans, we show that pro-inflammatory mediators and altered immune responses damage the blood-brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment. Together the disruption to the structural and functional integrity of the BBB results in enhanced transmigration of leukocytes across the BBB that could contribute to an initiation of a neuroinflammatory response through activation of microglia. Using a humanized in vitro model of the BBB and T2DM patient post-mortem brains, we show the translatable applicability of our results. We find a leaky BBB phenotype in T2DM patients can be attributed to a loss of junctional proteins through changes in inflammatory mediators and MMP/TIMP levels, resulting in increased leukocyte extravasation into the brain parenchyma. We further investigated therapeutic avenues to reduce and restore the BBB damage caused by HFHS-feeding. Pharmacological treatment with recombinant annexin A1 (hrANXA1) or reversion from a high-fat high-sugar diet to a control chow diet (dietary intervention), attenuated T2DM development, reduced inflammation, and restored BBB integrity in the animals. Given the rising incidence of diabetes worldwide, understanding metabolic-disease-associated brain microvessel damage is vital and the proposed therapeutic avenues could help alleviate the burden of these diseases.
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Affiliation(s)
- Madeeha H Sheikh
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Mariella Errede
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari School of Medicine, Bari, Italy
| | - Antonio d'Amati
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari School of Medicine, Bari, Italy.,Department of Emergency and Organ Transplantation, Section of Anatomic Pathology, University of Bari, Bari, Italy
| | - Noorafza Q Khan
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Silvia Fanti
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Rodrigo A Loiola
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Laboratoire de la Barrière Hémato-Encéphalique, Faculty Jean Perrin, EA 2465, Université d'Artois, Arras, France
| | - Simon McArthur
- Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Gareth S D Purvis
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
| | - Caroline E O'Riordan
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Davide Ferorelli
- Department of Interdisciplinary Medicine, Section of Legal Medicine, University of Bari, Bari, Italy
| | - Alessandro Dell'Erba
- Department of Interdisciplinary Medicine, Section of Legal Medicine, University of Bari, Bari, Italy
| | - Julius Kieswich
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Chis Reutelingsperger
- Cardiovascular Research Institute, Maastricht University, Maastricht, The Netherlands
| | - Eugenio Maiorano
- Department of Emergency and Organ Transplantation, Section of Anatomic Pathology, University of Bari, Bari, Italy
| | - Magdi Yaqoob
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Christoph Thiemermann
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Andrea Baragetti
- Department of Pharmacological and Biomolecular Sciences, Milan University, Milan, Italy.,IRCCS Multimedica, Sesto San Giovanni, Italy
| | - Alberico Luigi Catapano
- Department of Pharmacological and Biomolecular Sciences, Milan University, Milan, Italy.,IRCCS Multimedica, Sesto San Giovanni, Italy
| | - Giuseppe Danilo Norata
- Department of Pharmacological and Biomolecular Sciences, Milan University, Milan, Italy.,IRCCS Multimedica, Sesto San Giovanni, Italy.,S.I.S.A. Centre for the Study of Atherosclerosis-Bassini Hospital, Cinisello Balsamo, Italy
| | - Federica Marelli-Berg
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Daniela Virgintino
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari School of Medicine, Bari, Italy
| | - Egle Solito
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Department of Medicina Molecolare e Biotecnologie Mediche, University of Naples "Federico II", Naples, Italy
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