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Chong ZZ, Souayah N. Crumbling Pathogenesis and Biomarkers for Diabetic Peripheral Neuropathy. Biomedicines 2025; 13:413. [PMID: 40002826 PMCID: PMC11853266 DOI: 10.3390/biomedicines13020413] [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: 01/12/2025] [Revised: 01/31/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Background: Diabetic sensorimotor polyneuropathy (DSP) is a common chronic diabetic complication. Traditionally, DSP was once considered irreversible with a typical loss of axon. However, the superimpose of acquired demyelination on axonal loss in DSP patients has been observed, implying that DSP may be preventable or reversible, particularly within a subgroup of patients exhibiting early-stage acquired demyelination, underscoring the critical importance of identifying early prognostic markers. Methods: We systemically review the literature on the roles of biomarkers in predicting DSP and monitoring the progress. The underlying mechanisms of biomarkers were also discussed. Results: The pathogenesis of DSP is multifaceted, with various pathological mechanisms contributing to its development. Key mechanisms include aberrant glucose metabolism and induction of oxidative stress and inflammation. Several pathological processes, such as disrupted glucose metabolism, nerve damage, impaired microcirculation, genetic variants, and microRNA dysregulation, lead to molecular and protein changes that may be detectable in blood and other biological compartments, thus serving as potential biomarkers for DSP progression. However, the utility of a biomarker depends on its predictive accuracy, practicality, and ease of measurement. Conclusions: Most biomarkers for predicting DSP have demonstrated suboptimal predictive value, and many lack established accuracy in forecasting DSP progression. Consequently, the diagnostic utility of any single biomarker remains limited. A comprehensive combination of biomarkers from various categories may hold incredible promise for accurate detection. As artificial intelligence (AI) techniques, especially machine learning, rapidly advance, these technologies may offer significant potential for developing diagnostic platforms to integrate and interpret complex biomarker data for DSP.
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Affiliation(s)
- Zhao Zhong Chong
- Department of Neurology, New Jersey Medical School, Rutgers University, 185 S. Orange Ave, Newark, NJ 07103, USA
| | - Nizar Souayah
- Department of Neurology, New Jersey Medical School, Rutgers University, 90 Bergen Street DOC 8100, Newark, NJ 07101, USA
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Zhang TY, Wang XN, Kuang HY, Zhang ZM, Xu CY, Zhao KQ, Ha-Si WY, Zhang C, Hao M. Association between all-cause mortality and vascular complications in U.S. adults with newly diagnosed type 2 diabetes (NHANES 1999-2018). Acta Diabetol 2025; 62:113-121. [PMID: 39096329 DOI: 10.1007/s00592-024-02342-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 07/15/2024] [Indexed: 08/05/2024]
Abstract
AIMS The impact of macrovascular and microvascular complications, the common vascular complications of type 2 diabetes, on long-term mortality has been well evaluated, but the impact of different complications of newly diagnosed type 2 diabetes (diagnosed within the past 2 years) on long-term mortality has not been reported. We aimed to investigate the relationship between all-cause mortality and vascular complications in U.S. adults (aged ≥ 20 years) with newly diagnosed type 2 diabetes. METHODS We used data from the 1999-2018 National Health and Nutritional Examination Surveys (NHANES). Cox proportional hazard models was used to assess hazard ratios (HR) and 95% confidence intervals for all-cause mortality. RESULTS A total of 928 participants were enrolled in this study. At a mean follow-up of 10.8 years, 181 individuals died. In the fully adjusted model, the hazard ratio (HR) (95% confidence interval [CI]) of all-cause mortality for individuals with any single complication compared with those with newly diagnosed type 2 diabetes without complications was 2.24 (1.37, 3.69), and for individuals with two or more complications was 5.34 (3.01, 9.46).Co-existing Chronic kidney disease (CKD) and diabetic retinopathy (DR) at baseline were associated with the highest risk of death (HR 6.07[2.92-12.62]), followed by CKD and cardiovascular disease (CVD) (HR 4.98[2.79-8.89]) and CVD and DR (HR 4.58 [1.98-10.57]). CONCLUSION The presence of single and combined diabetes complications exerts a long-term synergistic adverse impact on overall mortality in newly diagnosed U.S. adults with type 2 diabetes, underscoring the importance of comprehensive complication screening to enhance risk stratification and treatment.
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Affiliation(s)
- Tian-Yu Zhang
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, 23 You Zheng Street, Harbin, 150001, People's Republic of China
| | - Xue-Ning Wang
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, 23 You Zheng Street, Harbin, 150001, People's Republic of China
| | - Hong-Yu Kuang
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, 23 You Zheng Street, Harbin, 150001, People's Republic of China
| | - Zi-Meng Zhang
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, 23 You Zheng Street, Harbin, 150001, People's Republic of China
| | - Cheng-Ye Xu
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, 23 You Zheng Street, Harbin, 150001, People's Republic of China
| | - Kang-Qi Zhao
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, 23 You Zheng Street, Harbin, 150001, People's Republic of China
| | - Wu-Ying Ha-Si
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, 23 You Zheng Street, Harbin, 150001, People's Republic of China
| | - Cong Zhang
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, 23 You Zheng Street, Harbin, 150001, People's Republic of China
| | - Ming Hao
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, 23 You Zheng Street, Harbin, 150001, People's Republic of China.
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Ahmadi M, Ghafouri-Fard S, Najari-Hanjani P, Morshedzadeh F, Malakoutian T, Abbasi M, Akbari H, Amoli MM, Saffarzadeh N. "Hyperglycemic Memory": Observational Evidence to Experimental Inference. Curr Diabetes Rev 2025; 21:64-78. [PMID: 38369731 DOI: 10.2174/0115733998279869231227091944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/01/2023] [Accepted: 11/29/2023] [Indexed: 02/20/2024]
Abstract
Several epidemiological studies have appreciated the impact of "duration" and "level" of hyperglycemia on the initiation and development of chronic complications of diabetes. However, glycemic profiles could not fully explain the presence/absence and severity of diabetic complications. Genetic issues and concepts of "hyperglycemic memory" have been introduced as additional influential factors involved in the pathobiology of late complications of diabetes. In the extended phase of significant diabetes randomized, controlled clinical trials, including DCCT/EDIC and UKPDS, studies have concluded that the quality of glycemic or metabolic control at the early time around the diabetes onset could maintain its protective or detrimental impact throughout the following diabetes course. There is no reliable indication of the mechanism by which the transient exposure to a given glucose concentration level could evoke a consistent cellular response at target tissues at the molecular levels. Some biological phenomena, such as the production and the concentration of advanced glycation end products (AGEs), reactive oxygen species (ROS) and protein kinase C (PKC) pathway activations, epigenetic changes, and finally, the miRNAs-mediated pathways, may be accountable for the development of hyperglycemic memory. This work summarizes evidence from previous experiments that may substantiate the hyperglycemic memory soundness by its justification in molecular terms.
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Affiliation(s)
- Mohsen Ahmadi
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parisa Najari-Hanjani
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Firouzeh Morshedzadeh
- Department of Genetics, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Tahereh Malakoutian
- Department of Nephrology, Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohsen Abbasi
- Department of Emergency Medicine, Iran University of Medical Sciences, Tehran, Iran
- Hasheminejad Kidney Centre, Iran University of Medical Sciences, Anesthesiology Section, Tehran, Iran
| | - Hounaz Akbari
- Department of Nephrology, Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Mohammad Amoli
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Negin Saffarzadeh
- Department of Nephrology, Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Puhakka AM, Macharey G, Ziller V, Gissler M, Tekay A, Keil C, Hilfiker‐Kleiner D. Peripartum heart failure in Finland: A population-based record linkage study. ESC Heart Fail 2024; 11:4277-4284. [PMID: 39183443 PMCID: PMC11631313 DOI: 10.1002/ehf2.14996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 06/25/2024] [Accepted: 07/08/2024] [Indexed: 08/27/2024] Open
Abstract
AIMS Heart failure in late pregnancy and the postpartum period (HFPP) is a rare but potentially life-threatening condition, with peripartum cardiomyopathy (PPCM) being the most common subtype. This study aims to comprehensively investigate the prevalence of HFPP in the Finnish population and identify the underlying risk factors associated with its occurrence. METHODS We conducted a retrospective analysis using data from the Finnish Medical Birth Register and the Finnish Care Register for Health Care, covering 1996 to 2021. The dataset comprised 1 387 457 deliveries. HFPP cases were identified based on specific ICD-10 codes. To ensure the accuracy of our findings, we excluded cases with pre-existing cardiomyopathies and other significant cardiac diseases diagnosed before pregnancy. We employed logistic regression models to evaluate the associations between maternal factors and the incidence of HFPP. RESULTS We identified 159 cases of HFPP, resulting in an incidence rate of 11.5 per 100 000 deliveries. This incidence is comparable with rates reported in other Scandinavian countries and lower than those observed in Germany. Consistent with findings from European cohorts, our study confirmed that pregnancy-associated hypertensive disorders, particularly preeclampsia, as well as complications such as preterm delivery, twin pregnancy and elective caesarean section, are substantial risk factors for HFPP. These results support previous research linking angiogenic imbalance to the pathogenesis of PPCM. Significant risk factors for HFPP included maternal pre-pregnancy body mass index ≥35 [adjusted odds ratio (aOR) 2.04, 95% confidence interval (CI) 1.28-3.25, P = 0.003], history of maternal hypertensive disorder (aOR 2.44, 95% CI 1.22-4.88, P = 0.012), gestational hypertension without significant proteinuria (aOR 2.14, 95% CI 1.27-3.61, P = 0.004), preeclampsia (aOR 2.43, 95% CI 1.39-4.23, P = 0.002), type 1 or type 2 diabetes (aOR 3.27, 95% CI 1.66-6.45, P < 0.001) and twin pregnancy (aOR 2.74, 95% CI 1.37-5.49, P = 0.005). Additionally, extensive prepartum [odds ratio (OR) 2.86, 95% CI 1.18-6.98, P = 0.018] and postpartum blood loss (OR 2.50, 95% CI 1.44-5.02, P = 0.001) and maternal mental disorders (OR 7.39, 95% CI 4.10-13.31, P < 0.001) were significantly more common among HFPP patients. CONCLUSIONS The incidence of HFPP among women in Finland from 1996 to 2021 was low. HFPP exhibited a strong association with several risk factors, including preeclampsia, obesity, preterm delivery, twin pregnancy, elective caesarean section, multifoetal births, type 1 and type 2 diabetes, significant prepartum and postpartum blood loss and maternal mental health disorders. These findings underscore the importance of targeted interventions and careful monitoring in high-risk groups to mitigate the impact of HFPP on maternal health.
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Affiliation(s)
- Antti M. Puhakka
- Department of Obstetrics and GynecologyUniversity of Helsinki, Helsinki University HospitalHelsinkiFinland
| | - Georg Macharey
- Department of Obstetrics and GynecologyUniversity of Helsinki, Helsinki University HospitalHelsinkiFinland
| | - Volker Ziller
- Clinic for Gynecology and Obstetrics, Department of Endocrinology, Reproductive Medicine and OsteologyUniversity Hospital Gießen and Marburg, Philipps University MarburgMarburgGermany
- Department of Obstetrics and Perinatology, Clinic for Gynecology and ObstetricsUniversity Hospital Gießen and Marburg, Philipps University MarburgMarburgGermany
| | - Mika Gissler
- Department of Knowledge BrokersFinnish Institute of Health and Welfare (THL)HelsinkiFinland
- Academic Primary Health Care Centre, Region StockholmStockholmSweden
- Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
| | - Aydin Tekay
- Department of Obstetrics and GynecologyUniversity of Helsinki, Helsinki University HospitalHelsinkiFinland
| | - Corinna Keil
- Department of Obstetrics and Perinatology, Clinic for Gynecology and ObstetricsUniversity Hospital Gießen and Marburg, Philipps University MarburgMarburgGermany
- Faculty of Medicine BaldingerstraßePhilipps‐University MarburgMarburgGermany
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Pan X, Song Y, Liang Y, Feng G, Wang Z. Roseburia intestinalis: A possible target for vascular calcification. Heliyon 2024; 10:e39865. [PMID: 39524709 PMCID: PMC11550659 DOI: 10.1016/j.heliyon.2024.e39865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 10/22/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
With the advancement of metagenomics and metabolomics techniques, the crucial role of the gut microbiome in intestinal, cardiovascular, and metabolic disorders has been extensively explored. Vascular calcification (VC) is common in atherosclerosis, hypertension, diabetes mellitus, and chronic kidney disease. Moreover, it is a significant cause of cardiovascular diseases and mortality. Roseburia intestinalis, as a promising candidate for the next generation of probiotics, plays a substantial role in inhibiting the systemic inflammatory response and holds great potential in the treatment of intestinal diseases, cardiovascular diseases, and metabolic disorders. Its primary metabolite, butyrate, acts on specific receptors (GPR43, GPR41, GPR109a). It enters cells via transporters (MCT1, SMCT1), affecting gene expression through HDACs, PPARγ and Nrf2, promoting energy metabolism and changing the concentration of other metabolites (including AGEs, LPS, BHB) in the circulation to affect the body's life activities. In this paper, we focus on the possible mechanism of the primary metabolite butyrate of Roseburia intestinalis in inhibiting VC, which may become a potential therapeutic target for the treatment of VC and the ways to enhance its effect.
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Affiliation(s)
- Xinyun Pan
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
- Institue of Cardiovascular Diseases, Jiangsu University, Zhenjiang, 21200, China
| | - Yunjian Song
- Institue of Cardiovascular Diseases, Jiangsu University, Zhenjiang, 21200, China
| | - Yapeng Liang
- Department of Emergency, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Guoquan Feng
- Department of Imaging, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
- Institue of Cardiovascular Diseases, Jiangsu University, Zhenjiang, 21200, China
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Akgümüş A, Boyraz B, Balun A. The Role of Advanced Glycation End Products in Saphenous Vein Graft Failure. Med Princ Pract 2024; 34:87-95. [PMID: 39383854 PMCID: PMC11805552 DOI: 10.1159/000541879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 10/07/2024] [Indexed: 10/11/2024] Open
Abstract
OBJECTIVE We aimed to investigate the relationship between advanced glycation end product (AGE) levels in patients with saphenous vein graft (SVG) failure and in patients without SVG failure. SUBJECTS AND METHODS In our study, 55 patients with a history of previous coronary artery bypass grafting (CABG) surgery, who subsequently underwent coronary angiography for any reason and were found to have either SVG occlusion or significant lesions, were included as study patients. Additionally, 55 patients who have had CABG surgery without SVG failure for at least 1 year served as the control group. AGE values of the patients were measured using the skin autofluorescence method. RESULTS In our study results, we observed a significant difference in AGE levels between the two groups of patients with similar demographic characteristics (SVG failure groups AGE 3.2 [2.8-3.6] vs. control groups AGE 2.4 [2.1-2.7] p < 0.001). In the receiver operating characteristic curve analysis, we determined the ability of AGE levels to detect SVG failure with an area under the curve of 0.869. We found that in patients with AGE >3, it could detect SVG failure with a sensitivity of 70.9% and a specificity of 87.3%. CONCLUSIONS Our results demonstrate that AGE levels can predict SVG failure risk inexpensively, easily, and quickly. OBJECTIVE We aimed to investigate the relationship between advanced glycation end product (AGE) levels in patients with saphenous vein graft (SVG) failure and in patients without SVG failure. SUBJECTS AND METHODS In our study, 55 patients with a history of previous coronary artery bypass grafting (CABG) surgery, who subsequently underwent coronary angiography for any reason and were found to have either SVG occlusion or significant lesions, were included as study patients. Additionally, 55 patients who have had CABG surgery without SVG failure for at least 1 year served as the control group. AGE values of the patients were measured using the skin autofluorescence method. RESULTS In our study results, we observed a significant difference in AGE levels between the two groups of patients with similar demographic characteristics (SVG failure groups AGE 3.2 [2.8-3.6] vs. control groups AGE 2.4 [2.1-2.7] p < 0.001). In the receiver operating characteristic curve analysis, we determined the ability of AGE levels to detect SVG failure with an area under the curve of 0.869. We found that in patients with AGE >3, it could detect SVG failure with a sensitivity of 70.9% and a specificity of 87.3%. CONCLUSIONS Our results demonstrate that AGE levels can predict SVG failure risk inexpensively, easily, and quickly.
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Affiliation(s)
- Alkame Akgümüş
- Department of Cardiology, Faculty of Medicine, Bandırma Onyedi Eylül University, Balıkesir, Turkey
| | - Bedrettin Boyraz
- Cardiology Department, Medicalpark Hospital, Mudanya University, Bursa, Turkey
| | - Ahmet Balun
- Department of Cardiology, Faculty of Medicine, Bandırma Onyedi Eylül University, Balıkesir, Turkey
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Zhang T, Jiang D, Zhang X, Chen L, Jiang J, Zhang C, Li S, Li Q. The role of nonmyocardial cells in the development of diabetic cardiomyopathy and the protective effects of FGF21: a current understanding. Cell Commun Signal 2024; 22:446. [PMID: 39327594 PMCID: PMC11426003 DOI: 10.1186/s12964-024-01842-0] [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: 06/05/2024] [Accepted: 09/20/2024] [Indexed: 09/28/2024] Open
Abstract
Diabetic cardiomyopathy (DCM) represents a unique myocardial disease originating from diabetic metabolic disturbances that is characterized by myocardial fibrosis and diastolic dysfunction. While recent research regarding the pathogenesis and treatment of DCM has focused primarily on myocardial cells, nonmyocardial cells-including fibroblasts, vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and immune cells-also contribute significantly to the pathogenesis of DCM. Among various therapeutic targets, fibroblast growth factor 21 (FGF21) has been identified as a promising agent because of its cardioprotective effects that extend to nonmyocardial cells. In this review, we aim to elucidate the role of nonmyocardial cells in DCM and underscore the potential of FGF21 as a therapeutic strategy for these cells.
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Affiliation(s)
- Tianyi Zhang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Donghui Jiang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Xiao Zhang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Ligang Chen
- Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Jun Jiang
- Department of General Surgery (Thyroid Surgery), the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
- Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, 646000, Sichuan, China
| | - Chunxiang Zhang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, Sichuan, China.
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, 646000, Sichuan, China.
| | - Shengbiao Li
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, Sichuan, China.
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, 646000, Sichuan, China.
| | - Qiuhong Li
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, Sichuan, China.
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Kozakova M, Morizzo C, Penno G, Chiappino D, Palombo C. Diabetes-Related Changes in Carotid Wall Properties: Role of Triglycerides. J Clin Med 2024; 13:5654. [PMID: 39337141 PMCID: PMC11433327 DOI: 10.3390/jcm13185654] [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: 08/06/2024] [Revised: 09/07/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
Background/Objectives: This study compares the power of the radiofrequency (RF) signal reflected from the media layer (media power) of the common carotid artery (CCA) and the CCA stiffness between individuals with and without type 2 diabetes mellitus (T2DM). It also evaluates the associations of CCA media power with plasma glucose and lipid levels, as well as carotid stiffness. Methods: A total of 540 individuals, 115 with and 425 without T2DM (273 males, mean age = 64 ± 8 years) were studied using RF-based tracking of the right CCA. The following parameters were measured: CCA media thickness, luminal diameter, wall tensile stress (WTS), local pulse wave velocity (PWV), and media power. Results: Compared to the non-diabetic individuals, the T2DM patients had significantly higher CCA media thickness (652 ± 122 vs. 721 ± 138 microns, p < 0.005), luminal diameter (6.12 ± 0.78 vs. 6.86 ± 0.96 mm, p < 0.0005), media power (36.1 ± 4.8 vs. 39.3 ± 4.6, p < 0.0001), and PWV (7.65 ± 1.32 vs. 8.40 ± 1.89 m/s; p < 0.01), but comparable WTS (32.7 ± 10.4 vs. 33.1 ± 10.7 kPa; p = 0.25). In the entire population, CCA media power was independently associated with male sex, pulse pressure, current smoking, and T2DM; when T2DM was not included in the model, triglycerides emerged as an independent determinant of media power. The CCA PWV was independently associated with age, pulse pressure, media power, and T2DM. Conclusions: Our findings suggest the presence of structural changes in the arterial media of T2DM patients, leading to carotid stiffening and remodeling, aiming to preserve WTS. T2DM-related changes in arterial wall composition may be driven by high plasma triglyceride levels, which have previously been associated with both arterial stiffening and the incidence of CV events.
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Affiliation(s)
- Michaela Kozakova
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.K.); (G.P.)
- Esaote SpA, 16153 Genova, Italy
| | - Carmela Morizzo
- School of Medicine, Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, 56126 Pisa, Italy;
| | - Giuseppe Penno
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.K.); (G.P.)
| | - Dante Chiappino
- Fondazione Toscana G. Monasterio, Massa-Pisa, 56124 Pisa, Italy;
| | - Carlo Palombo
- School of Medicine, Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, 56126 Pisa, Italy;
- Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy
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Fewkes JJ, Dordevic AL, Murray M, Williamson G, Kellow NJ. Association between endothelial function and skin advanced glycation end-products (AGEs) accumulation in a sample of predominantly young and healthy adults. Cardiovasc Diabetol 2024; 23:332. [PMID: 39251982 PMCID: PMC11386354 DOI: 10.1186/s12933-024-02428-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Accepted: 08/31/2024] [Indexed: 09/11/2024] Open
Abstract
BACKGROUND In populations with chronic disease, skin autofluorescence (SAF), a measure of long-term fluorescent advanced glycation end-products (AGEs) accumulation in body tissues, has been associated with vascular endothelial function, measured using flow-mediated dilation (FMD). The primary aim of this study was to quantify the relationship between endothelial function and tissue accumulation of AGEs in adults from the general population to determine whether SAF could be used as a marker to predict early impairment of the endothelium. METHODS A cross-sectional study was conducted with 125 participants (median age: 28.5 y, IQR: 24.4-36.0; 54% women). Endothelial function was measured by fasting FMD. Skin AGEs were measured as SAF using an AGE Reader. Participant anthropometry, blood pressure, and blood biomarkers were also measured. Associations were evaluated using multivariable regression analysis and were adjusted for significant covariates. RESULTS FMD was inversely correlated with SAF (ρ = -0.50, P < 0.001) and chronological age (ρ = -0.51, P < 0.001). In the multivariable analysis, SAF, chronological age, and male sex were independently associated with reduced FMD (B [95% CI]; -2.60 [-4.40, -0.80]; -0.10 [-0.16, -0.03]; 1.40 [0.14, 2.67], respectively), with the multivariable model adjusted R2 = 0.31, P < 0.001. CONCLUSIONS Higher skin AGE levels, as measured by SAF, were associated with lower FMD values, in a predominantly young, healthy population. Additionally, older age and male participants exhibited significantly lower FMD values, corresponding with compromised endothelial function. These results suggest that SAF, a simple and inexpensive marker, could be used to predict endothelial impairment before the emergence of any structural artery pathophysiology or classic cardiovascular disease risk markers. TRIAL REGISTRATION The study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000821897) and concurrently entered into the WHO International Clinical Trials Registry Platform under the same ID number.
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Affiliation(s)
- Juanita J Fewkes
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia
- Victorian Heart Institute, Victoria Heart Hospital, 631 Blackburn Road, Clayton, VIC, 3168, Australia
| | - Aimee L Dordevic
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia
- Victorian Heart Institute, Victoria Heart Hospital, 631 Blackburn Road, Clayton, VIC, 3168, Australia
| | - Margaret Murray
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia
- School of Chemistry, Faculty of Science, Monash University, Clayton, VIC, 3800, Australia
| | - Gary Williamson
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia
- Victorian Heart Institute, Victoria Heart Hospital, 631 Blackburn Road, Clayton, VIC, 3168, Australia
| | - Nicole J Kellow
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia.
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
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10
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Mete G, Fidan Ç, Demirci A, Ozen Yalcin D, Devrim E, Elgun Ulkar S, Ozturk HS. Evaluation of serum arginine metabolic pathway markers in patients with bipolar disorder and schizophrenia. Int J Psychiatry Clin Pract 2024; 28:218-223. [PMID: 39955087 DOI: 10.1080/13651501.2025.2466506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 02/05/2025] [Accepted: 02/08/2025] [Indexed: 02/17/2025]
Abstract
OBJECTIVES Research on new serum parameters in bipolar disorder (BD) and schizophrenia is crucial for early diagnosis and understanding of disease pathophysiology. The arginine metabolic pathway has been found to be associated with several neuropsychiatric disorders in recent years. This study aims to investigate the role of serum markers involved in different steps of the arginine metabolic pathway in BD and schizophrenia. METHODS Sixty healthy volunteers, sixty patients with schizophrenia and sixty patients with BD were included in the study. We analysed ornithine decarboxylase (ODC), arginine decarboxylase (ADC) and agmatinase levels using enzyme-linked immunosorbent assay. Enzymatic colorimetric methods were used for nitric oxide (NO), nitric oxide synthase (NOS) and arginase measurement. RESULTS Serum agmatinase levels were significantly lower in BD and schizophrenia (p < 0.01). ODC and ADC levels were significantly lower in BD group compared to the control and schizophrenia groups (p < 0.001; p < 0.01). Serum NO levels were significantly higher and NOS levels were significantly lower in BD (p < 0.001; p < 0.05). Arginase levels were also lower in BD (p < 0.05). CONCLUSIONS Enzymes and substrates of the arginine metabolic pathway are promising markers in BD and schizophrenia. These markers can also be used to enable the diagnosis, when an adequate verbal communication is impossible.
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Affiliation(s)
- Gulsah Mete
- Department of Biochemistry, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Çigdem Fidan
- Department of Biochemistry, Faculty of Medicine, Ankara University, Ankara, Turkey
- Department of Biochemistry, Faculty of Medicine, Namık Kemal University, Tekirdağ, Turkey
| | - Adem Demirci
- Department of Psychiatry, Sincan Training and Research Hospital, Ankara, Turkey
| | - Demet Ozen Yalcin
- Department of Psychiatry, Sincan Training and Research Hospital, Ankara, Turkey
| | - Erdinc Devrim
- Department of Biochemistry, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Serenay Elgun Ulkar
- Department of Biochemistry, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Hasan Serdar Ozturk
- Department of Biochemistry, Faculty of Medicine, Ankara University, Ankara, Turkey
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11
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Pepe M, Addabbo F, Cecere A, Tritto R, Napoli G, Nestola PL, Cirillo P, Biondi-Zoccai G, Giordano S, Ciccone MM. Acute Hyperglycemia-Induced Injury in Myocardial Infarction. Int J Mol Sci 2024; 25:8504. [PMID: 39126075 PMCID: PMC11313474 DOI: 10.3390/ijms25158504] [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: 05/15/2024] [Revised: 07/29/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024] Open
Abstract
Acute hyperglycemia is a transient increase in plasma glucose level (PGL) frequently observed in patients with ST-elevation myocardial infarction (STEMI). The aim of this review is to clarify the molecular mechanisms whereby acute hyperglycemia impacts coronary flow and myocardial perfusion in patients with acute myocardial infarction (AMI) and to discuss the consequent clinical and prognostic implications. We conducted a comprehensive literature review on the molecular causes of myocardial damage driven by acute hyperglycemia in the context of AMI. The negative impact of high PGL on admission recognizes a multifactorial etiology involving endothelial function, oxidative stress, production of leukocyte adhesion molecules, platelet aggregation, and activation of the coagulation cascade. The current evidence suggests that all these pathophysiological mechanisms compromise myocardial perfusion as a whole and not only in the culprit coronary artery. Acute hyperglycemia on admission, regardless of whether or not in the context of a diabetes mellitus history, could be, thus, identified as a predictor of worse myocardial reperfusion and poorer prognosis in patients with AMI. In order to reduce hyperglycemia-related complications, it seems rational to pursue in these patients an adequate and quick control of PGL, despite the best pharmacological treatment for acute hyperglycemia still remaining a matter of debate.
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Affiliation(s)
- Martino Pepe
- Division of Cardiology, Department of Interdisciplinary Medicine (D.I.M.), University of Bari “Aldo Moro”, 70100 Bari, Italy (M.M.C.)
| | - Francesco Addabbo
- ASL Taranto, Local Health Authority of Taranto, Statistics and Epidemiology Unit, 74100 Taranto, Italy;
| | - Annagrazia Cecere
- Division of Cardiology, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, 35128 Padua, Italy;
| | - Rocco Tritto
- Division of Cardiology, Department of Interdisciplinary Medicine (D.I.M.), University of Bari “Aldo Moro”, 70100 Bari, Italy (M.M.C.)
| | - Gianluigi Napoli
- Division of Cardiology, Villa Verde Clinic, 74121 Taranto, Italy;
| | | | - Plinio Cirillo
- Department of Advanced Biomedical Sciences, Federico II University of Naples, 80131 Naples, Italy;
| | - Giuseppe Biondi-Zoccai
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy;
- Maria Cecilia Hospital, GVM Care & Research, 48032 Cotignola, Italy
| | - Salvatore Giordano
- Division of Cardiology, Department of Medical and Surgical Sciences, “Magna Graecia” University, 88100 Catanzaro, Italy;
| | - Marco Matteo Ciccone
- Division of Cardiology, Department of Interdisciplinary Medicine (D.I.M.), University of Bari “Aldo Moro”, 70100 Bari, Italy (M.M.C.)
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12
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Rojas A, Lindner C, Schneider I, Gonzalez I, Uribarri J. The RAGE Axis: A Relevant Inflammatory Hub in Human Diseases. Biomolecules 2024; 14:412. [PMID: 38672429 PMCID: PMC11048448 DOI: 10.3390/biom14040412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 03/21/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024] Open
Abstract
In 1992, a transcendental report suggested that the receptor of advanced glycation end-products (RAGE) functions as a cell surface receptor for a wide and diverse group of compounds, commonly referred to as advanced glycation end-products (AGEs), resulting from the non-enzymatic glycation of lipids and proteins in response to hyperglycemia. The interaction of these compounds with RAGE represents an essential element in triggering the cellular response to proteins or lipids that become glycated. Although initially demonstrated for diabetes complications, a growing body of evidence clearly supports RAGE's role in human diseases. Moreover, the recognizing capacities of this receptor have been extended to a plethora of structurally diverse ligands. As a result, it has been acknowledged as a pattern recognition receptor (PRR) and functionally categorized as the RAGE axis. The ligation to RAGE leads the initiation of a complex signaling cascade and thus triggering crucial cellular events in the pathophysiology of many human diseases. In the present review, we intend to summarize basic features of the RAGE axis biology as well as its contribution to some relevant human diseases such as metabolic diseases, neurodegenerative, cardiovascular, autoimmune, and chronic airways diseases, and cancer as a result of exposure to AGEs, as well as many other ligands.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile; (A.R.); (I.G.)
| | - Cristian Lindner
- Department of Radiology, Faculty of Medicine, University of Concepción, Concepción 4030000, Chile;
| | - Ivan Schneider
- Centre of Primary Attention, South Metropolitan Health Service, Santiago 3830000, Chile;
| | - Ileana Gonzalez
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile; (A.R.); (I.G.)
| | - Jaime Uribarri
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10021, USA
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13
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Naser N, Lonj CK, Rikard-Bell M, Sandow SL, Murphy TV. Advanced glycated end-products inhibit dilation through constitutive endothelial RAGE and Nox1/4 in rat isolated skeletal muscle arteries. Microcirculation 2024; 31:e12837. [PMID: 37985248 DOI: 10.1111/micc.12837] [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: 07/17/2023] [Revised: 10/17/2023] [Accepted: 11/07/2023] [Indexed: 11/22/2023]
Abstract
OBJECTIVE This study investigated the actions of advanced glycated end-products (AGE), their receptors (RAGE), and NAD(P)H oxidase (Nox) subtypes 1, 2, and 4 on mechanisms of endothelium-dependent dilation of the rat cremaster muscle artery (CMA). METHODS Immunofluorescence studies were used to examine expression of RAGE in rat arteries. ROS accumulation was measured using luminescence and fluorescence assays. Functional studies were performed using pressure myography. RESULTS High levels of RAGE expression were shown in the endothelial cells of the CMA, compared with low endothelial expression in middle cerebral and mesenteric arteries and the aorta. Exogenous AGE (in vitro glycated bovine serum albumin) stimulated H2O2 accumulation in CMA, which was prevented by the RAGE antagonist FPS-ZM1, the NAD(P)H oxidase (Nox) inhibitor apocynin and inhibited by the Nox1/4 inhibitor setanaxib, but not the Nox2 inhibitor GSK2795039. In functional studies, AGE inhibited vasodilation of CMA stimulated by acetylcholine, sodium nitroprusside, and the BKCa activator NS1619, but not adenosine-induced dilation. FPS-ZM1, apocynin, and setanaxib prevented the inhibitory effects of AGE on responses to acetylcholine and NS-1619. CONCLUSION These observations suggest RAGE are constitutively expressed in the endothelium of the rat CMA and may be activated by AGE to stimulate Nox1/4 and ROS formation with resulting inhibition of NO and BKCa-mediated endothelium-dependent dilation.
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Affiliation(s)
- Nadim Naser
- Physiology, School of Biomedical Sciences, UNSW Sydney, Sydney, Australia
| | - Chenchel K Lonj
- Physiology, School of Biomedical Sciences, UNSW Sydney, Sydney, Australia
| | - Matthew Rikard-Bell
- Physiology, School of Biomedical Sciences, UNSW Sydney, Sydney, Australia
- Townsville University Hospital, Townsville, Queensland, Australia
| | - Shaun L Sandow
- Biomedical Science, University of the Sunshine Coast, Maroochydore, Australia
- Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia
| | - Timothy V Murphy
- Physiology, School of Biomedical Sciences, UNSW Sydney, Sydney, Australia
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14
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Saemann L, Wernstedt L, Pohl S, Stiller M, Willsch J, Hofmann B, Veres G, Simm A, Szabó G. Impact of Age on Endothelial Function of Saphenous Vein Grafts in Coronary Artery Bypass Grafting. J Clin Med 2023; 12:5454. [PMID: 37685521 PMCID: PMC10487541 DOI: 10.3390/jcm12175454] [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: 07/27/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
BACKGROUND An intact and functionally preserved endothelial layer in the graft is crucial for myocardial perfusion and graft patency after coronary artery bypass grafting (CABG). We hypothesized that old age is a risk factor for decreased endothelial function of bypass grafts. Thus, we investigated the impact of age in patients treated with CABG on endothelial function in saphenous vein grafts. METHODS We mounted the saphenous vein graft segments of CABG patients < 70 (n = 33) and ≥70 (n = 40) years of age in organ bath chambers and exposed them to potassium chloride (KCl) and phenylephrine (PE) to test the receptor-independent and -dependent contractility, followed by exposure to acetylcholine (ACh) and sodium nitroprusside (SNP) to test the endothelial-dependent and -independent relaxation. RESULTS The maximal contraction induced by KCl (2.3 ± 1.8 vs. 1.8 ± 2 g) was stronger in patients ≥ 70 years of age. The relative contraction induced by PE in % of KCl (167 ± 64 vs. 163 ± 59%) was similar between groups. Patients aged < 70 years showed a higher endothelial-dependent relaxation induced by acetylcholine than patients ≥ 70 years (51 ± 27 vs. 42 ± 18%). The relaxation induced by SNP was similar between both groups. CONCLUSIONS The endothelial function of saphenous vein bypass grafts decreases during aging. Thus, age should be considered when improving graft maintenance.
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Affiliation(s)
- Lars Saemann
- Department of Cardiac Surgery, University Hospital Halle, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany (G.V.); (A.S.); (G.S.)
| | - Lena Wernstedt
- Department of Cardiac Surgery, University Hospital Halle, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany (G.V.); (A.S.); (G.S.)
| | - Sabine Pohl
- Department of Cardiac Surgery, University Hospital Halle, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany (G.V.); (A.S.); (G.S.)
| | - Markus Stiller
- Department of Cardiac Surgery, University Hospital Halle, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany (G.V.); (A.S.); (G.S.)
| | - Jan Willsch
- Department of Cardiac Surgery, University Hospital Halle, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany (G.V.); (A.S.); (G.S.)
| | - Britt Hofmann
- Department of Cardiac Surgery, University Hospital Halle, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany (G.V.); (A.S.); (G.S.)
| | - Gábor Veres
- Department of Cardiac Surgery, University Hospital Halle, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany (G.V.); (A.S.); (G.S.)
| | - Andreas Simm
- Department of Cardiac Surgery, University Hospital Halle, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany (G.V.); (A.S.); (G.S.)
| | - Gábor Szabó
- Department of Cardiac Surgery, University Hospital Halle, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany (G.V.); (A.S.); (G.S.)
- Department of Cardiac Surgery, Heidelberg University Hospital, 69120 Heidelberg, Germany
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15
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Bahadoran Z, Mirmiran P, Kashfi K, Ghasemi A. Vascular nitric oxide resistance in type 2 diabetes. Cell Death Dis 2023; 14:410. [PMID: 37433795 PMCID: PMC10336063 DOI: 10.1038/s41419-023-05935-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 06/18/2023] [Accepted: 06/28/2023] [Indexed: 07/13/2023]
Abstract
Vascular nitric oxide (NO•) resistance, manifested by an impaired vasodilator function of NO• in both the macro- and microvessels, is a common state in type 2 diabetes (T2D) associated with developing cardiovascular events and death. Here, we summarize experimental and human evidence of vascular NO• resistance in T2D and discuss its underlying mechanisms. Human studies indicate a ~ 13-94% decrease in the endothelium (ET)-dependent vascular smooth muscle (VSM) relaxation and a 6-42% reduced response to NO• donors, i.e., sodium nitroprusside (SNP) and glyceryl trinitrate (GTN), in patients with T2D. A decreased vascular NO• production, NO• inactivation, and impaired responsiveness of VSM to NO• [occurred due to quenching NO• activity, desensitization of its receptor soluble guanylate cyclase (sGC), and/or impairment of its downstream pathway, cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG)] are the known mechanisms underlying the vascular NO• resistance in T2D. Hyperglycemia-induced overproduction of reactive oxygen species (ROS) and vascular insulin resistance are key players in this state. Therefore, upregulating vascular NO• availability, re-sensitizing or bypassing the non-responsive pathways to NO•, and targeting key vascular sources of ROS production may be clinically relevant pharmacological approaches to circumvent T2D-induced vascular NO• resistance.
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Affiliation(s)
- Zahra Bahadoran
- Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parvin Mirmiran
- Department of Clinical Nutrition, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, 10031, USA
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Juin SK, Ouseph R, Gondim DD, Jala VR, Sen U. Diabetic Nephropathy and Gaseous Modulators. Antioxidants (Basel) 2023; 12:antiox12051088. [PMID: 37237955 DOI: 10.3390/antiox12051088] [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: 03/07/2023] [Revised: 05/05/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Diabetic nephropathy (DN) remains the leading cause of vascular morbidity and mortality in diabetes patients. Despite the progress in understanding the diabetic disease process and advanced management of nephropathy, a number of patients still progress to end-stage renal disease (ESRD). The underlying mechanism still needs to be clarified. Gaseous signaling molecules, so-called gasotransmitters, such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), have been shown to play an essential role in the development, progression, and ramification of DN depending on their availability and physiological actions. Although the studies on gasotransmitter regulations of DN are still emerging, the evidence revealed an aberrant level of gasotransmitters in patients with diabetes. In studies, different gasotransmitter donors have been implicated in ameliorating diabetic renal dysfunction. In this perspective, we summarized an overview of the recent advances in the physiological relevance of the gaseous molecules and their multifaceted interaction with other potential factors, such as extracellular matrix (ECM), in the severity modulation of DN. Moreover, the perspective of the present review highlights the possible therapeutic interventions of gasotransmitters in ameliorating this dreaded disease.
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Affiliation(s)
- Subir Kumar Juin
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Department of Microbiology & Immunology, Brown Cancer Center, Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Rosemary Ouseph
- Division of Nephrology & Hypertension, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Dibson Dibe Gondim
- Department of Pathology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Venkatakrishna Rao Jala
- Department of Microbiology & Immunology, Brown Cancer Center, Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Utpal Sen
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
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17
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Taguchi K, Fukami K. RAGE signaling regulates the progression of diabetic complications. Front Pharmacol 2023; 14:1128872. [PMID: 37007029 PMCID: PMC10060566 DOI: 10.3389/fphar.2023.1128872] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 03/07/2023] [Indexed: 03/18/2023] Open
Abstract
Diabetes, the ninth leading cause of death globally, is expected to affect 642 million people by 2040. With the advancement of an aging society, the number of patients with diabetes having multiple underlying diseases, such as hypertension, obesity, and chronic inflammation, is increasing. Thus, the concept of diabetic kidney disease (DKD) has been accepted worldwide, and comprehensive treatment of patients with diabetes is required. Receptor for advanced glycation endproducts (RAGE), a multiligand receptor, belonging to the immunoglobulin superfamily is extensively expressed throughout the body. Various types of ligands, including advanced glycation endproducts (AGEs), high mobility group box 1, S100/calgranulins, and nucleic acids, bind to RAGE, and then induces signal transduction to amplify the inflammatory response and promote migration, invasion, and proliferation of cells. Furthermore, the expression level of RAGE is upregulated in patients with diabetes, hypertension, obesity, and chronic inflammation, suggesting that activation of RAGE is a common denominator in the context of DKD. Considering that ligand–and RAGE–targeting compounds have been developed, RAGE and its ligands can be potent therapeutic targets for inhibiting the progression of DKD and its complications. Here, we aimed to review recent literature on various signaling pathways mediated by RAGE in the pathogenesis of diabetic complications. Our findings highlight the possibility of using RAGE–or ligand–targeted therapy for treating DKD and its complications.
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18
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Singh SK, Dwivedi SD, Yadav K, Shah K, Chauhan NS, Pradhan M, Singh MR, Singh D. Novel Biotherapeutics Targeting Biomolecular and Cellular Approaches in Diabetic Wound Healing. Biomedicines 2023; 11:biomedicines11020613. [PMID: 36831151 PMCID: PMC9952895 DOI: 10.3390/biomedicines11020613] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/12/2023] [Accepted: 02/15/2023] [Indexed: 02/22/2023] Open
Abstract
Wound healing responses play a major role in chronic inflammation, which affects millions of people around the world. One of the daunting tasks of creating a wound-healing drug is finding equilibrium in the inflammatory cascade. In this study, the molecular and cellular mechanisms to regulate wound healing are explained, and recent research is addressed that demonstrates the molecular and cellular events during diabetic wound healing. Moreover, a range of factors or agents that facilitate wound healing have also been investigated as possible targets for successful treatment. It also summarises the various advances in research findings that have revealed promising molecular targets in the fields of therapy and diagnosis of cellular physiology and pathology of wound healing, such as neuropeptides, substance P, T cell immune response cDNA 7, miRNA, and treprostinil growth factors such as fibroblast growth factor, including thymosin beta 4, and immunomodulators as major therapeutic targets.
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Affiliation(s)
- Suraj Kumar Singh
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur 492010, Chhattisgarh, India
| | - Shradha Devi Dwivedi
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur 492010, Chhattisgarh, India
| | - Krishna Yadav
- Raipur Institute of Pharmaceutical Educations and Research, Sarona, Raipur 492010, Chhattisgarh, India
| | - Kamal Shah
- Institute of Pharmaceutical Research, GLA University, Mathura 281406, Uttar Pradesh, India
| | | | - Madhulika Pradhan
- Gracious College of Pharmacy Abhanpur Raipur, Village-Belbhata, Taluka, Abhanpur 493661, Chhattisgarh, India
| | - Manju Rawat Singh
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur 492010, Chhattisgarh, India
| | - Deependra Singh
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur 492010, Chhattisgarh, India
- Correspondence:
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19
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Fujita N, Ishida M, Iwane T, Suganuma H, Matsumoto M, Hatakeyama S, Yoneyama T, Hashimoto Y, Mikami T, Itoh K, Ohyama C. Association between Advanced Glycation End-Products, Carotenoids, and Severe Erectile Dysfunction. World J Mens Health 2023:41.e17. [PMID: 36649922 DOI: 10.5534/wjmh.220154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 09/16/2022] [Accepted: 10/06/2022] [Indexed: 01/18/2023] Open
Abstract
PURPOSE To investigate the association between skin advanced glycation end-products (AGEs) levels, blood antioxidative vitamin and carotenoid concentrations, and severe erectile dysfunction (ED) in community-dwelling men. MATERIALS AND METHODS This cross-sectional study used the 5-Item International Index of Erectile Function to identify 335 community-dwelling men with ED. The accumulation of skin AGEs was assessed noninvasively by measuring skin autofluorescence. Background-adjusted multivariable logistic regression analyses using the inverse probability of treatment weighting method were performed to evaluate the effects of AGEs, vitamins, and carotenoids on severe ED. Moreover, multiple linear regression analyses were performed to assess the association between skin AGEs levels and serum carotenoid concentrations. RESULTS The median age of study participants was 57 years. Of the 335 men, 289 (86.3%) and 46 (13.7%) were classified into the mild/moderate and severe ED groups, respectively. Multivariable analyses revealed that skin AGEs levels, blood vitamins C and E, lutein, zeaxanthin, β-cryptoxanthin, α-carotene, β-carotene, total lycopene, and cis-lycopenes concentrations were significantly associated with severe ED, whereas all-trans lycopene concentrations were not. In the multiple linear regression analyses, serum zeaxanthin concentrations were negatively and significantly correlated with skin AGEs levels. CONCLUSIONS Higher skin AGEs levels and lower blood antioxidative vitamin and carotenoid concentrations were significantly associated with severe ED. Serum zeaxanthin levels were negatively and significantly correlated with skin AGEs levels, suggesting the possible effects of zeaxanthin on ED by decreasing tissue AGEs levels.
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Affiliation(s)
- Naoki Fujita
- Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
| | - Mizuri Ishida
- Innovation Center for Health Promotion, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Takuro Iwane
- Innovation Center for Health Promotion, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Hiroyuki Suganuma
- Nature & Wellness Research Department, Innovation Division, KAGOME CO., LTD., Nagoya, Japan
| | - Mai Matsumoto
- Nature & Wellness Research Department, Innovation Division, KAGOME CO., LTD., Nagoya, Japan
| | - Shingo Hatakeyama
- Department of Advanced Blood Purification Therapy, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Takahiro Yoneyama
- Department of Advanced Transplant and Regenerative Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Yasuhiro Hashimoto
- Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Tatsuya Mikami
- Innovation Center for Health Promotion, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Ken Itoh
- Department of Stress Response Science, Center for Advanced Medical Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Chikara Ohyama
- Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.,Department of Advanced Blood Purification Therapy, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.,Department of Advanced Transplant and Regenerative Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
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21
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Role of Nitric Oxide-Derived Metabolites in Reactions of Methylglyoxal with Lysine and Lysine-Rich Protein Leghemoglobin. Int J Mol Sci 2022; 24:ijms24010168. [PMID: 36613614 PMCID: PMC9820652 DOI: 10.3390/ijms24010168] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/14/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
Carbonyl stress occurs when reactive carbonyl compounds (RCC), such as reducing sugars, dicarbonyls etc., accumulate in the organism. The interaction of RCC carbonyl groups with amino groups of molecules is called the Maillard reaction. One of the most active RCCs is α-dicarbonyl methylglyoxal (MG) that modifies biomolecules forming non-enzymatic glycation products. Organic free radicals are formed in the reaction between MG and lysine or Nα-acetyllysine. S-nitrosothiols and nitric oxide (•NO) donor PAPA NONOate increased the yield of organic free radical intermediates, while other •NO-derived metabolites, namely, nitroxyl anion and dinitrosyl iron complexes (DNICs) decreased it. At the late stages of the Maillard reaction, S-nitrosoglutathione (GSNO) also inhibited the formation of glycation end products (AGEs). The formation of a new type of DNICs, bound with Maillard reaction products, was found. The results obtained were used to explain the glycation features of legume hemoglobin-leghemoglobin (Lb), which is a lysine-rich protein. In Lb, lysine residues can form fluorescent cross-linked AGEs, and •NO-derived metabolites slow down their formation. The knowledge of these processes can be used to increase the stability of Lb. It can help in better understanding the impact of stress factors on legume plants and contribute to the production of recombinant Lb for biotechnology.
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Prasad K. Involvement of AGE and Its Receptors in the Pathogenesis of Hypertension in Elderly People and Its Treatment. Int J Angiol 2022; 31:213-221. [PMID: 36588874 PMCID: PMC9803554 DOI: 10.1055/s-0042-1756175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Both systolic and diastolic blood pressures increase with age up to 50 to 60 years of age. After 60 years of age systolic pressure rises to 84 years of age but diastolic pressure remains stable or even decreases. In the oldest age group (85-99 years), the systolic blood pressure (SBP) is high and diastolic pressure (DBP) is the lowest. Seventy percent of people older than 65 years are hypertensive. This paper deals with the role of advanced glycation end products (AGE) and its cell receptor (RAGE) and soluble receptor (sRAGE) in the development of hypertension in the elderly population. Plasma/serum levels of AGE are higher in older people as compared with younger people. Serum levels of AGE are positively correlated with age, arterial stiffness, and hypertension. Low serum levels of sRAGE are associated with arterial stiffness and hypertension. Levels of sRAGE are negatively correlated with age and blood pressure. Levels of sRAGE are lower in patients with arterial stiffness and hypertension than patients with high levels of sRAGE. AGE could induce hypertension through numerous mechanisms including, cross-linking with collagen, reduction of nitric oxide, increased expression of endothelin-1, and transforming growth factor-β (TGF-β). Interaction of AGE with RAGE could produce hypertension through the generation of reactive oxygen species, increased sympathetic activity, activation of nuclear factor-kB, and increased expression of cytokines, cell adhesion molecules, and TGF- β. In conclusion, the AGE-RAGE axis could be involved in hypertension in elderly people. Treatment for hypertension in elderly people should be targeted at reduction of AGE levels in the body, prevention of AGE formation, degradation of AGE in vivo, downregulation of RAGE expression, blockade of AGE-RAGE interaction, upregulation of sRAGE expression, and use of antioxidants.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
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23
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Rao NL, Kotian GB, Shetty JK, Shelley BP, Dmello MK, Lobo EC, Shankar SP, Almeida SD, Shah SR. Receptor for Advanced Glycation End Product, Organ Crosstalk, and Pathomechanism Targets for Comprehensive Molecular Therapeutics in Diabetic Ischemic Stroke. Biomolecules 2022; 12:1712. [PMID: 36421725 PMCID: PMC9687999 DOI: 10.3390/biom12111712] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/03/2022] [Accepted: 11/05/2022] [Indexed: 08/10/2023] Open
Abstract
Diabetes mellitus, a well-established risk factor for stroke, is related to higher mortality and poorer outcomes following the stroke event. Advanced glycation end products(AGEs), their receptors RAGEs, other ligands, and several other processes contribute to the cerebrovascular pathomechanism interaction in the diabetes-ischemic stroke combination. Critical reappraisal of molecular targets and therapeutic agents to mitigate them is required to identify key elements for therapeutic interventions that may improve patient outcomes. This scoping review maps evidence on the key roles of AGEs, RAGEs, other ligands such as Leukotriene B4 (LTB4), High-mobility group box 1 (HMGB1) nuclear protein, brain-kidney-muscle crosstalk, alternate pathomechanisms in neurodegeneration, and cognitive decline related to diabetic ischemic stroke. RAGE, HMGB1, nitric oxide, and polyamine mechanisms are important therapeutic targets, inflicting common consequences of neuroinflammation and oxidative stress. Experimental findings on a number of existing-emerging therapeutic agents and natural compounds against key targets are promising. The lack of large clinical trials with adequate follow-up periods is a gap that requires addressing to validate the emerging therapeutic agents. Five therapeutic components, which include agents to mitigate the AGE-RAGE axis, improved biomarkers for risk stratification, better renal dysfunction management, adjunctive anti-inflammatory-antioxidant therapies, and innovative neuromuscular stimulation for rehabilitation, are identified. A comprehensive therapeutic strategy that features all the identified components is needed for outcome improvement in diabetic stroke patients.
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Affiliation(s)
- Nivedita L Rao
- Department of Biochemistry, Yenepoya Medical College, Yenepoya (deemed to be University), Mangalore 575018, Karnataka, India
| | - Greeshma B Kotian
- Department of Biochemistry, Yenepoya Medical College, Yenepoya (deemed to be University), Mangalore 575018, Karnataka, India
| | - Jeevan K Shetty
- Department of Biochemistry, School of Medicine, Royal College of Surgeons in Ireland Medical University of Bahrain, Muharraq 228, Bahrain
| | - Bhaskara P Shelley
- Department of Neurology, Yenepoya Medical College, Yenepoya (deemed to be University), Mangalore 575018, Karnataka, India
| | - Mackwin Kenwood Dmello
- Department of Public Health, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore 575018, Karnataka, India
| | - Eric C Lobo
- Department of Biochemistry, Yenepoya Medical College, Yenepoya (deemed to be University), Mangalore 575018, Karnataka, India
| | - Suchetha Padar Shankar
- College of Physiotherapy, Dayananda Sagar University, Bangalore 560111, Karnataka, India
| | - Shellette D Almeida
- School of Physiotherapy, D. Y. Patil (Deemed to be University), Navi Mumbai 400706, Maharashtra, India
| | - Saiqa R Shah
- Department of Biochemistry, Yenepoya Medical College, Yenepoya (deemed to be University), Mangalore 575018, Karnataka, India
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24
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Nasybullina EI, Pugachenko IS, Kosmachevskaya OV, Topunov AF. The Influence of Nitroxyl on Escherichia coli Cells Grown under Carbonyl Stress Conditions. APPL BIOCHEM MICRO+ 2022. [DOI: 10.1134/s0003683822050118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Zhang Z, Zhang Y, Yang D, Luo Y, Luo Y, Ru Y, Song J, Fei X, Chen Y, Li B, Jiang J, Kuai L. Characterisation of key biomarkers in diabetic ulcers via systems bioinformatics. Int Wound J 2022; 20:529-542. [PMID: 36181454 PMCID: PMC9885479 DOI: 10.1111/iwj.13900] [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: 03/09/2022] [Revised: 07/02/2022] [Accepted: 07/04/2022] [Indexed: 02/03/2023] Open
Abstract
Diabetic ulcers (DUs) are characterised by a high incidence and disability rate. However, its pathogenesis remains elusive. Thus, a deep understanding of the underlying mechanisms for the pathogenesis of DUs has vital implications. The weighted gene co-expression network analysis was performed on the main data from the Gene Expression Omnibus database. Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were adopted to analyse the potential biological function of the most relevant module. Furthermore, we utilised CytoHubba and protein-protein interaction network to identify the hub genes. Finally, the hub genes were validated by animal experiments in diabetic ulcer mice models. The expression of genes from the turquoise module was found to be strongly related to DUs. GO terms, KEGG analysis showed that biological functions are closely related to immune response. The hub genes included IFI35, IFIT2, MX2, OASL, RSAD2, and XAF1, which were higher in wounds of DUs mice than that in normal lesions. Additionally, we also demonstrated that the expression of hub genes was correlated with the immune response using immune checkpoint, immune cell infiltration, and immune scores. These data suggests that IFI35, IFIT2, MX2, OASL, RSAD2, and XAF1 are crucial for DUs.
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Affiliation(s)
- Zhan Zhang
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina,Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Ying Zhang
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina,Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Dan Yang
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina,Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Yue Luo
- Department of Integrated TCM and Western Medicine, Shanghai Skin Disease HospitalTongji UniversityShanghaiChina
| | - Ying Luo
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina,Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Yi Ru
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina,Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Jiankun Song
- Department of Integrated TCM and Western Medicine, Shanghai Skin Disease HospitalTongji UniversityShanghaiChina
| | - Xiaoya Fei
- Department of Integrated TCM and Western Medicine, Shanghai Skin Disease HospitalTongji UniversityShanghaiChina
| | - Yiran Chen
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina,Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Bin Li
- Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina,Department of Integrated TCM and Western Medicine, Shanghai Skin Disease HospitalTongji UniversityShanghaiChina
| | - Jingsi Jiang
- Department of Skin and Cosmetics Research, Shanghai Skin Disease HospitalTongji UniversityShanghaiChina
| | - Le Kuai
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina,Institute of DermatologyShanghai Academy of Traditional Chinese MedicineShanghaiChina
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26
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Coronary Microvascular Dysfunction in Diabetes Mellitus: Pathogenetic Mechanisms and Potential Therapeutic Options. Biomedicines 2022; 10:biomedicines10092274. [PMID: 36140374 PMCID: PMC9496134 DOI: 10.3390/biomedicines10092274] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/04/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetic patients are frequently affected by coronary microvascular dysfunction (CMD), a condition consisting of a combination of altered vasomotion and long-term structural change to coronary arterioles leading to impaired regulation of blood flow in response to changing cardiomyocyte oxygen requirements. The pathogenesis of this microvascular complication is complex and not completely known, involving several alterations among which hyperglycemia and insulin resistance play particularly central roles leading to oxidative stress, inflammatory activation and altered barrier function of endothelium. CMD significantly contributes to cardiac events such as angina or infarction without obstructive coronary artery disease, as well as heart failure, especially the phenotype associated with preserved ejection fraction, which greatly impact cardiovascular (CV) prognosis. To date, no treatments specifically target this vascular damage, but recent experimental studies and some clinical investigations have produced data in favor of potential beneficial effects on coronary micro vessels caused by two classes of glucose-lowering drugs: glucagon-like peptide 1 (GLP-1)-based therapy and inhibitors of sodium-glucose cotransporter-2 (SGLT2). The purpose of this review is to describe pathophysiological mechanisms, clinical manifestations of CMD with particular reference to diabetes, and to summarize the protective effects of antidiabetic drugs on the myocardial microvascular compartment.
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27
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Smith S, Normahani P, Lane T, Hohenschurz-Schmidt D, Oliver N, Davies AH. Pathogenesis of Distal Symmetrical Polyneuropathy in Diabetes. LIFE (BASEL, SWITZERLAND) 2022; 12:life12071074. [PMID: 35888162 PMCID: PMC9319251 DOI: 10.3390/life12071074] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 12/13/2022]
Abstract
Distal symmetrical polyneuropathy (DSPN) is a serious complication of diabetes associated with significant disability and mortality. Although more than 50% of people with diabetes develop DSPN, its pathogenesis is still relatively unknown. This lack of understanding has limited the development of novel disease-modifying therapies and left the reasons for failed therapies uncertain, which is critical given that current management strategies often fail to achieve long-term efficacy. In this article, the pathogenesis of DSPN is reviewed, covering pathogenic changes in the peripheral nervous system, microvasculature and central nervous system (CNS). Furthermore, the successes and limitations of current therapies are discussed, and potential therapeutic targets are proposed. Recent findings on its pathogenesis have called the definition of DSPN into question and transformed the disease model, paving the way for new research prospects.
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Affiliation(s)
- Sasha Smith
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Pasha Normahani
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Tristan Lane
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Department of Vascular Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
| | - David Hohenschurz-Schmidt
- Pain Research Group, Department of Surgery and Cancer, Imperial College London, London SW10 9NH, UK;
| | - Nick Oliver
- Section of Metabolic Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W2 1PG, UK;
- Division of Medicine and Integrated Care, Imperial College Healthcare NHS Trust, London W2 1NY, UK
| | - Alun Huw Davies
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London W6 8RF, UK
- Correspondence:
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Huang Y, Yue L, Qiu J, Gao M, Liu S, Wang J. Endothelial Dysfunction and Platelet Hyperactivation in Diabetic Complications Induced by Glycemic Variability. Horm Metab Res 2022; 54:419-428. [PMID: 35835141 PMCID: PMC9282943 DOI: 10.1055/a-1880-0978] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The development and progression of the complications of chronic diabetes mellitus are attributed not only to increased blood glucose levels but also to glycemic variability. Therefore, a deeper understanding of the role of glycemic variability in the development of diabetic complications may provide more insight into targeted clinical treatment strategies in the future. Previously, the mechanisms implicated in glycemic variability-induced diabetic complications have been comprehensively discussed. However, endothelial dysfunction and platelet hyperactivation, which are two newly recognized critical pathogenic factors, have not been fully elucidated yet. In this review, we first evaluate the assessment of glycemic variability and then summarise the roles of endothelial dysfunction and platelet hyperactivation in glycemic variability-induced complications of diabetes, highlighting the molecular mechanisms involved and their interconnections.
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Affiliation(s)
- Ye Huang
- Emergency Department, China Academy of Chinese Medical Sciences Xiyuan
Hospital, Beijing, China
| | - Long Yue
- Emergency Department, China Academy of Chinese Medical Sciences Xiyuan
Hospital, Beijing, China
| | - Jiahuang Qiu
- Research Center for Eco-Environmental Sciences, Chinese Academy of
Sciences, Beijing, China
| | - Ming Gao
- Research Center for Eco-Environmental Sciences, Chinese Academy of
Sciences, Beijing, China
| | - Sijin Liu
- Research Center for Eco-Environmental Sciences, Chinese Academy of
Sciences, Beijing, China
| | - Jingshang Wang
- Department of Traditional Chinese Medicine, Capital Medical University
Beijing Obstetrics and Gynecology Hospital, Beijing, China
- Correspondence Prof. Jingshang
Wang Capital Medical University Beijing Obstetrics and
Gynecology HospitalDepartment of Traditional Chinese
MedicineBeijingChina 18811213525
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29
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Advanced Glycation End-Products (AGEs): Formation, Chemistry, Classification, Receptors, and Diseases Related to AGEs. Cells 2022; 11:cells11081312. [PMID: 35455991 PMCID: PMC9029922 DOI: 10.3390/cells11081312] [Citation(s) in RCA: 276] [Impact Index Per Article: 92.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 01/27/2023] Open
Abstract
Advanced glycation end-products (AGEs) constitute a non-homogenous, chemically diverse group of compounds formed either exogeneously or endogeneously on the course of various pathways in the human body. In general, they are formed non-enzymatically by condensation between carbonyl groups of reducing sugars and free amine groups of nucleic acids, proteins, or lipids, followed by further rearrangements yielding stable, irreversible end-products. In the last decades, AGEs have aroused the interest of the scientific community due to the increasing evidence of their involvement in many pathophysiological processes and diseases, such as diabetes, cancer, cardiovascular, neurodegenerative diseases, and even infection with the SARS-CoV-2 virus. They are recognized by several cellular receptors and trigger many signaling pathways related to inflammation and oxidative stress. Despite many experimental research outcomes published recently, the complexity of their engagement in human physiology and pathophysiological states requires further elucidation. This review focuses on the receptors of AGEs, especially on the structural aspects of receptor-ligand interaction, and the diseases in which AGEs are involved. It also aims to present AGE classification in subgroups and to describe the basic processes leading to both exogeneous and endogeneous AGE formation.
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30
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Tuppad S, Medala K, Umesh M, Gaur A, Ganji V, Sakthivadivel V, Kumar P. Serum Adiponectin and Nitric Oxide Levels in Type II Diabetes and Its Correlation With Lipid Profile. Cureus 2022; 14:e24613. [PMID: 35664415 PMCID: PMC9149778 DOI: 10.7759/cureus.24613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2022] [Indexed: 11/15/2022] Open
Abstract
Introduction Various markers for diabetes have been identified in this new era of medicine, the most recent being adiponectin, which is primarily secreted from adipose tissue and has anti-diabetic, anti-inflammatory, and anti-atherogenic properties. It is also known to increase insulin sensitivity. Adiponectin deficiency or decreased secretion causes a variety of complications, including insulin resistance and the onset of type 2 diabetes mellitus (T2DM). One such complication of T2DM is endothelial dysfunction, which leads to decreased synthesis of nitric oxide (NO), another potent marker that normally disrupts key events in the progression of atherosclerosis. Aims and objectives The aim of the study was to compare and correlate serum adiponectin and nitric oxide levels with glycemic status in patients with T2DM and healthy controls. Materials and methods This comparative cross-sectional study included known cases of type II diabetes under group I and healthy age-matched controls under group II. Serum levels of adiponectin and nitric oxide were assessed in both the groups along with glycemic status [fasting blood sugar (FBS) and glycated hemoglobin (HbA1c)] and these parameters were compared between both groups using a t-test. Adiponectin and NO levels were correlated using Pearson's correlation with glycemic status in group I. Results The mean adiponectin levels in group I were 5.94 ± 1.490 μg/mL, which was significantly (p<0.00) less than in group II, 10.30 ±1.669 μg/mL. The mean NO levels in group I (42.98 ± 6.300 μmol/L) were also significantly (p<0.00) less than in group II (56.126 ± 7.579 μmol/L). FBS and HbA1C levels were significantly higher in group I than in group II. Conclusion Adiponectin and NO levels were significantly reduced in individuals with T2DM when compared to healthy controls. Therapeutic interventions that increase adiponectin and NO levels may be useful targets for improving diabetes control and reducing complications.
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Affiliation(s)
- Sangeeta Tuppad
- Physiology, Koppal Institute of Medical Sciences, Koppal, IND
| | - Kalpana Medala
- Physiology, All India Institute of Medical Sciences, Bibinagar, Hyderabad, IND
| | - Madhusudhan Umesh
- Physiology, All India Institute of Medical Sciences, Bibinagar, Hyderabad, IND
| | - Archana Gaur
- Physiology, All India Institute of Medical Sciences, Bibinagar, Hyderabad, IND
| | - Vidya Ganji
- Physiology, All India Institute of Medical Sciences, Bibinagar, Hyderabad, IND
| | | | - Prakash Kumar
- Physiology, Koppal Institute of Medical Sciences, Koppal, IND
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Revisiting Methodologies for In Vitro Preparations of Advanced Glycation End Products. Appl Biochem Biotechnol 2022; 194:2831-2855. [PMID: 35257316 DOI: 10.1007/s12010-022-03860-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 02/24/2022] [Indexed: 11/02/2022]
Abstract
Chronic elevation of sugar and oxidative stress generally results in development of advanced glycation end products (AGEs) in diabetic individuals. Accumulation of AGEs in an individual can give rise to the activation of several pathways that will ultimately lead to various complications. Such AGEs can also be prepared in an in vitro environment. For an in vitro preparation of advanced glycation end products (AGEs), proteins, lipids, or nucleic acids are generally required to be incubated with reducing sugars at a physiological temperature or higher depending upon the protocol optimized for its preparation. Certain other factors are also optimized and added to the buffer to hasten its preparation or alter the properties of prepared AGEs. Through this review, we intend to highlight the various studies related to the experimental procedures for the preparation of different types of AGEs. In addition, we present the comparative study of methodologies optimized for the preparation of AGEs.
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Prasad K, Khan AS, Bhanumathy KK. Does AGE-RAGE Stress Play a Role in the Development of Coronary Artery Disease in Obesity? Int J Angiol 2022; 31:1-9. [PMID: 35221846 PMCID: PMC8881108 DOI: 10.1055/s-0042-1742587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
This article deals with the role of AGE (advanced glycation end products)-RAGE (receptor for AGE) stress (AGE/sRAGE) in the development of coronary artery disease (CAD) in obesity. CAD is due to atherosclerosis in coronary artery. The serum/plasma levels of AGE and sRAGE are reduced, while AGE-RAGE stress and expression of RAGE are elevated in obese individuals. However, the levels of AGE are elevated in obese individuals with more than one metabolic syndrome. The increases in the AGE-RAGE stress would elevate the expression and production of atherogenic factors, including reactive oxygen species, nuclear factor-kappa B, cytokines, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial leukocyte adhesion molecules, monocyte chemoattractant protein-1, granulocyte-macrophage colony-stimulating factor, and growth factors. Low levels of sRAGE would also increase the atherogenic factors. The increases in the AGE-RAGE stress and decreases in the levels of sRAGE would induce development of atherosclerosis, leading to CAD. The therapeutic regimen for AGE-RAGE stress-induced CAD in obesity would include lowering of AGE intake, prevention of AGE formation, degradation of AGE in vivo, suppression of RAGE expression, blockade of AGE-RAGE interaction, downregulation of sRAGE expression, and use of antioxidants. In conclusion, the data suggest that AGE-RAGE stress is involved in the development of CAD in obesity, and the therapeutic interventions to reduce AGE-RAGE would be helpful in preventing, regressing, and slowing the progression of CAD in obesity.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada,Address for correspondence Kailash Prasad, MBBS, MD, PhD, DSc Department of Physiology (APP), College of Medicine, University of Saskatoon107 Wiggins Road, Saskatoon, SK, S7N 5E5Canada
| | - Amal S. Khan
- Community, Health and Epidemiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Kalpana K. Bhanumathy
- Division of Oncology, Cancer Cluster Unit, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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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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Jafarnejad S, Hooshiar S, Esmaili H, Taherian A. Exercise, Advanced Glycation End Products, and Their Effects on Cardiovascular Disorders: A Narrative Review. HEART AND MIND 2022. [DOI: 10.4103/hm.hm_31_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Wang M, Li Y, Li S, Lv J. Endothelial Dysfunction and Diabetic Cardiomyopathy. Front Endocrinol (Lausanne) 2022; 13:851941. [PMID: 35464057 PMCID: PMC9021409 DOI: 10.3389/fendo.2022.851941] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/14/2022] [Indexed: 12/22/2022] Open
Abstract
The cardiovascular complications contribute to a majority of diabetes associated morbidity and mortality, accounting for 44% of death in those patients with type 1 diabetes mellitus (DM) and 52% of deaths in type 2 DM. Diabetes elicits cardiovascular dysfunction through 2 major mechanisms: ischemic and non-ischemic. Non-ischemic injury is usually under-recognized although common in DM patients, and also a pathogenic factor of heart failure in those diabetic individuals complicated with ischemic heart disease. Diabetic cardiomyopathy (DCM) is defined as a heart disease in which the myocardium is structurally and functionally abnormal in the absence of coronary artery disease, hypertensive, valvular, or congenital heart disorders in diabetic patients, theoretically caused by non-ischemic injury solely. Current therapeutic strategies targeting DCM mainly address the increased blood glucose levels, however, the effects on heart function are disappointed. Accumulating data indicate endothelial dysfunction plays a critical role in the initiation and development of DCM. Hyperglycemia, hyperinsulinemia, and insulin resistance cause the damages of endothelial function, including barrier dysfunction, impaired nitric oxide (NO) activity, excessive reactive oxygen species (ROS) production, oxidative stress, and inflammatory dysregulation. In turn, endothelial dysfunction promotes impaired myocardial metabolism, intracellular Ca2+ mishandling, endoplasmic reticulum (ER) stress, mitochondrial defect, accumulation of advanced glycation end products, and extracellular matrix (ECM) deposit, leads to cardiac stiffness, fibrosis, and remodeling, eventually results in cardiac diastolic dysfunction, systolic dysfunction, and heart failure. While endothelial dysfunction is closely related to cardiac dysfunction and heart failure seen in DCM, clinical strategies for restoring endothelial function are still missing. This review summarizes the timely findings related to the effects of endothelial dysfunction on the disorder of myocardium as well as cardiac function, provides mechanical insights in pathogenesis and pathophysiology of DCM developing, and highlights potential therapeutic targets.
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Affiliation(s)
- Moran Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yongsheng Li
- Department of Emergency, Tongji Hospital, Tongji Medical College, Science and Technology, Huazhong University, Wuhan, China
- *Correspondence: Yongsheng Li, ; Sheng Li, ;
| | - Sheng Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Yongsheng Li, ; Sheng Li, ;
| | - Jiagao Lv
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Jeddi S, Yousefzadeh N, Kashfi K, Ghasemi A. Role of nitric oxide in type 1 diabetes-induced osteoporosis. Biochem Pharmacol 2021; 197:114888. [PMID: 34968494 DOI: 10.1016/j.bcp.2021.114888] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/09/2021] [Accepted: 12/09/2021] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D)-induced osteoporosis is characterized by decreased bone mineral density, bone quality, rate of bone healing, bone formation, and increased bone resorption. Patients with T1D have a 2-7-fold higher risk of osteoporotic fracture. The mechanisms leading to increased risk of osteoporotic fracture in T1D include insulin deficiency, hyperglycemia, insulin resistance, lower insulin-like growth factor-1, hyperglycemia-induced oxidative stress, and inflammation. In addition, a higher probability of falling, kidney dysfunction, weakened vision, and neuropathy indirectly increase the risk of osteoporotic fracture in T1D patients. Decreased nitric oxide (NO) bioavailability contributes to the pathophysiology of T1D-induced osteoporotic fracture. This review discusses the role of NO in osteoblast-mediated bone formation and osteoclast-mediated bone resorption in T1D. In addition, the mechanisms involved in reduced NO bioavailability and activity in type 1 diabetic bones as well as NO-based therapy for T1D-induced osteoporosis are summarized. Available data indicates that lower NO bioavailability in diabetic bones is due to disruption of phosphatidylinositol 3‑kinase/protein kinase B/endothelial NO synthases and NO/cyclic guanosine monophosphate/protein kinase G signaling pathways. Thus, NO bioavailability may be boosted directly or indirectly by NO donors. As NO donors with NO-like effects in the bone, inorganic nitrate and nitrite can potentially be used as novel therapeutic agents for T1D-induced osteoporosis. Inorganic nitrites and nitrates can decrease the risk for osteoporotic fracture probably directly by decreasing osteoclast activity, decreasing fat accumulation in the marrow cavity, increasing osteoblast activity, and increasing bone perfusion or indirectly, by improving hyperglycemia, insulin resistance, and reducing body weight.
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Affiliation(s)
- Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nasibeh Yousefzadeh
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, NY, USA.
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Zhan J, Chen C, Wang DW, Li H. Hyperglycemic memory in diabetic cardiomyopathy. Front Med 2021; 16:25-38. [PMID: 34921674 DOI: 10.1007/s11684-021-0881-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 06/25/2021] [Indexed: 12/26/2022]
Abstract
Cardiovascular diseases account for approximately 80% of deaths among individuals with diabetes mellitus, with diabetic cardiomyopathy as the major diabetic cardiovascular complication. Hyperglycemia is a symptom that abnormally activates multiple downstream pathways and contributes to cardiac hypertrophy, fibrosis, apoptosis, and other pathophysiological changes. Although glycemic control has long been at the center of diabetes therapy, multicenter randomized clinical studies have revealed that intensive glycemic control fails to reduce heart failure-associated hospitalization and mortality in patients with diabetes. This finding indicates that hyperglycemic stress persists in the cardiovascular system of patients with diabetes even if blood glucose level is tightly controlled to the normal level. This process is now referred to as hyperglycemic memory (HGM) phenomenon. We briefly reviewed herein the current advances that have been achieved in research on the underlying mechanisms of HGM in diabetic cardiomyopathy.
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Affiliation(s)
- Jiabing Zhan
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, China
| | - Chen Chen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, China.
| | - Huaping Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, China.
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Hansen L, Joseph G, Valdivia A, Taylor WR. Satellite Cell Expression of RAGE (Receptor for Advanced Glycation end Products) Is Important for Collateral Vessel Formation. J Am Heart Assoc 2021; 10:e022127. [PMID: 34689598 PMCID: PMC8751830 DOI: 10.1161/jaha.120.022127] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background The growth and remodeling of vascular networks is an important component of the prognosis for patients with peripheral artery disease. One protein that has been previously implicated to play a role in this process is RAGE (receptor for advanced glycation end products). This study sought to determine the cellular source of RAGE in the ischemic hind limb and the role of RAGE signaling in this cell type. Methods and Results Using a hind limb ischemia model of vascular growth, this study found skeletal muscle satellite cells to be a novel major cellular source of RAGE in ischemic tissue by both staining and cellular sorting. Although wild-type satellite cells increased tumor necrosis factor-α and monocyte chemoattractant protein-1 production in response to ischemia in vivo and a RAGE ligand in vitro, satellite cells from RAGE knockout mice lacked the increase in cytokine production both in vivo in response to ischemia and in vitro after stimuli with the RAGE ligand high-mobility group box 1. Furthermore, encapsulated wild-type satellite cells improved perfusion after hind limb ischemia surgery by both perfusion staining and vessel quantification, but RAGE knockout satellite cells provided no improvement over empty capsules. Conclusions Thus, RAGE expression and signaling in satellite cells is crucial for their response to stimuli and angiogenic and arteriogenic functions.
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Affiliation(s)
- Laura Hansen
- Division of Cardiology Department of Medicine Emory University Atlanta GA.,Division of Cardiology Atlanta Veterans Affairs Medical Center Decatur GA
| | - Giji Joseph
- Division of Cardiology Department of Medicine Emory University Atlanta GA
| | - Alejandra Valdivia
- Division of Cardiology Department of Medicine Emory University Atlanta GA
| | - W Robert Taylor
- Division of Cardiology Department of Medicine Emory University Atlanta GA.,Division of Cardiology Atlanta Veterans Affairs Medical Center Decatur GA.,The Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology and Emory University Atlanta GA
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Dimova R, Chakarova N, Grozeva G, Tankova T. The relationship between endogenous secretory RAGE and cardiac autonomic function in prediabetes. Int J Clin Pract 2021; 75:e14769. [PMID: 34473880 DOI: 10.1111/ijcp.14769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/30/2021] [Indexed: 11/26/2022] Open
Abstract
AIMS The putative protective role of esRAGE for cardiac autonomic function (CAF) remains unclear. To address this question, the present study has assessed the relationship of serum AGEs, sRAGE and esRAGE, and tissue AGEs with CAF in a high-risk population without diabetes. MATERIAL AND METHODS This study enrolled 48 subjects of mean age 52.7 ± 11.2 years and mean BMI 28.4 ± 6.3 kg/m2 , divided into two groups according to glucose tolerance: 16 with normal glucose tolerance (NGT) and 24 with prediabetes. A standard oral glucose tolerance test (OGTT) was performed. The glucose tolerance was defined according to 2006 WHO criteria. Fasting, 120-minutes glucose, lipids, creatinine, and HbA1c were measured. eGFR was calculated (CKD-EPI). Fasting, 120-minutes insulin (ECLIA method), advanced glycation end products (AGEs), plasma-soluble receptor for AGE (sRAGE), and endogenous secreted isoform of the receptor for AGE (esRAGE), (ELISA method) were assessed. HOMA-IR was calculated. Tissue AGEs were assessed by skin autofluorescence (AGE-Reader, DiagnOpticsTM). CAF was evaluated with ANX 3.0 autonomic nervous-monitoring system (ANSAR), applying deep breathing, Valsalva, and standing. RESULTS There was a significant decline in CAF in prediabetes in comparison with NGT. Serum and tissue AGEs, sRAGE, and esRAGE levels were similar between groups. On the matrix analysis, both sympathetic and parasympathetic activities at baseline and after standing and sympathetic tone during Valsalva were positively related to esRAGE in prediabetes. Multivariate regression analysis showed that esRAGE is an independent contributor to sympathetic, parasympathetic, and total autonomic tone in prediabetes accounting for about 28%, 34%, and 35% of their variances, respectively. CONCLUSION Our results have demonstrated that CAF is decreased in prediabetes. esRAGE, but not sRAGE, is reciprocally related to CAF, probably opposing the negative effects of glycation.
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Affiliation(s)
- Rumyana Dimova
- Division of Diabetology, Department of Endocrinology, Medical University Sofia, Sofia, Bulgaria
| | - Nevena Chakarova
- Division of Diabetology, Department of Endocrinology, Medical University Sofia, Sofia, Bulgaria
| | - Greta Grozeva
- Division of Diabetology, Department of Endocrinology, Medical University Sofia, Sofia, Bulgaria
| | - Tsvetalina Tankova
- Division of Diabetology, Department of Endocrinology, Medical University Sofia, Sofia, Bulgaria
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40
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Kong M, Lim YJ. Hemoglobin A1c level is a prognostic factor for locoregional recurrence in stage III non-small cell lung cancer patients treated with radiotherapy. Thorac Cancer 2021; 12:3032-3038. [PMID: 34599544 PMCID: PMC8590896 DOI: 10.1111/1759-7714.14174] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 11/27/2022] Open
Abstract
Background The level of hemoglobin A1c (HbA1c) might be associated with the severity of tumor hypoxia in patients with cancer. Here, we evaluated the association between the level of HbA1c and survival outcome in stage III non‐small cell lung cancer patients treated with radical radiotherapy. Methods We retrospectively analysed the clinical data of 104 patients with lung cancer treated with radiotherapy. The HbA1c levels of all patients were checked 1 week before the start of radiotherapy. Survival outcomes were analysed according to the HbA1c level. Results The 1‐, 2‐, and 3‐year locoregional recurrence‐free survival rates were 88.3%, 68.8%, and 63.0%, respectively, in the patient group with HbA1c levels ≤6% and 75.5%, 54.4%, and 41.8%, respectively, in the patient group with HbA1c levels >6% (p = 0.015). The HbA1c level remained a significant prognostic factor for locoregional recurrence‐free survival on multivariable analysis (hazard ratio = 2.014, 95% confidence interval = 1.088–3.726, p = 0.026). Conclusions Pretreatment HbA1c level is a significant prognostic factor for locoregional recurrence‐free survival in patients with stage III non‐small cell lung cancer treated with radical radiotherapy. Routine monitoring of pretreatment HbA1c levels and aggressive glycemic control may be considered to prevent the development of locoregional recurrence in these patients.
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Affiliation(s)
- Moonkyoo Kong
- Department of Radiation Oncology, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea
| | - Yu Jin Lim
- Department of Radiation Oncology, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea
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41
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Echouffo-Tcheugui JB, Guan J, Retnakaran R, Shah BR. Gestational Diabetes and Incident Heart Failure: A Cohort Study. Diabetes Care 2021; 44:dc210552. [PMID: 34385145 PMCID: PMC8929190 DOI: 10.2337/dc21-0552] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 07/15/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To assess whether gestational diabetes mellitus (GDM) is associated with an increased risk of heart failure (HF). RESEARCH DESIGN AND METHODS We conducted a population-based cohort study using information from the Ministry of Health and Long-Term Care of Ontario (Canada) health care administrative databases. We identified all women in Ontario with a GDM diagnosis with a live birth singleton delivery between 1 July 2007 and 31 March 2018. Women with diabetes or HF before pregnancy were excluded. GDM was defined based on laboratory test results and diagnosis coding. The primary outcome was incident HF hospitalization over a period extending from the index pregnancy until 31 March 2019. The secondary outcome was prevalent peripartum cardiomyopathy at index pregnancy. Estimates of association were adjusted for relevant cardiometabolic risk factors. RESULTS Among 906,319 eligible women (mean age 30 years [SD 5.6], 50,193 with GDM [5.5%]), there were 763 HF events over a median follow-up period of 7 years. GDM was associated with a higher risk of incident HF (adjusted hazard ratio [aHR] 1.62 [95% CI 1.28, 2.05]) compared with no GDM. This association remained significant after accounting for chronic kidney disease, postpartum diabetes, hypertension, and coronary artery disease (aHR 1.39 [95% CI 1.09, 1.79]). GDM increased the odds of peripartum cardiomyopathy (adjusted odds ratio 1.83 [95% CI 1.45, 2.33]). CONCLUSIONS In a large observational study, GDM was associated with an increased risk of HF. Consequently, diabetes screening during pregnancy is suggested to identify women at risk for HF.
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Affiliation(s)
- Justin B Echouffo-Tcheugui
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University, Baltimore, MD
- Welch Center for Prevention, Epidemiology, and Clinical Research, Department of Medicine, Johns Hopkins University, Baltimore, MD
| | - Jun Guan
- Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
| | - Ravi Retnakaran
- Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada
| | - Baiju R Shah
- Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada
- Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Institute for Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
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Uncovering the Protective Mechanism of the Volatile Oil of Acorus tatarinowii against Acute Myocardial Ischemia Injury Using Network Pharmacology and Experimental Validation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6630795. [PMID: 34239586 PMCID: PMC8241509 DOI: 10.1155/2021/6630795] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 04/13/2021] [Accepted: 04/21/2021] [Indexed: 11/17/2022]
Abstract
Acorus tatarinowii is a traditional aromatic resuscitation drug that can be clinically used to prevent cardiovascular diseases. The volatile oil of Acorus tatarinowii (VOA) possesses important medicinal properties, including protection against acute myocardial ischemia (MI) injury. However, the pharmacodynamic material basis and molecular mechanisms underlying this protective effect remain unclear. Using network pharmacology and animal experiments, we studied the mechanisms and pathways implicated in the activity of VOA against acute MI injury. First, VOA was extracted from three batches of Acorus tatarinowii using steam distillation, and then, its chemical composition was determined by GC-MS. Next, the components-targets and protein-protein interaction networks were constructed using systematic network pharmacology. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were also conducted in order to predict the possible pharmacodynamic mechanisms. Furthermore, animal experiments including ELISAs, histological examinations, and Western blots were performed in order to validate the pharmacological effects of VOA. In total, 33 chemical components were identified in VOA, and ß-asarone was found to be the most abundant component. Based on network pharmacology analysis, the therapeutic effects of VOA against myocardial ischemia might be mediated by signaling pathways involving COX-2, PPAR-α, VEGF, and cAMP. Overall, the obtained results indicate that VOA alleviates the pathological manifestations of isoproterenol-hydrochloride-induced myocardial ischemia in rats, including the decreased SOD (superoxide dismutase) content and increased LDH (lactic dehydrogenase) content. Moreover, the anti-MI effect of VOA might be attributed to the downregulation of the COX-2 protein that inhibits apoptosis, the upregulation of the PPAR-α protein that regulates energy metabolism, and the activation of VEGF and cAMP signaling pathways.
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Birukov A, Cuadrat R, Polemiti E, Eichelmann F, Schulze MB. Advanced glycation end-products, measured as skin autofluorescence, associate with vascular stiffness in diabetic, pre-diabetic and normoglycemic individuals: a cross-sectional study. Cardiovasc Diabetol 2021; 20:110. [PMID: 34176469 PMCID: PMC8236143 DOI: 10.1186/s12933-021-01296-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/03/2021] [Indexed: 02/06/2023] Open
Abstract
Background Advanced glycation end-products are proteins that become glycated after contact with sugars and are implicated in endothelial dysfunction and arterial stiffening. We aimed to investigate the relationships between advanced glycation end-products, measured as skin autofluorescence, and vascular stiffness in various glycemic strata. Methods We performed a cross-sectional analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, comprising n = 3535 participants (median age 67 years, 60% women). Advanced glycation end-products were measured as skin autofluorescence with AGE-Reader™, vascular stiffness was measured as pulse wave velocity, augmentation index and ankle-brachial index with Vascular Explorer™. A subset of 1348 participants underwent an oral glucose tolerance test. Participants were sub-phenotyped into normoglycemic, prediabetes and diabetes groups. Associations between skin autofluorescence and various indices of vascular stiffness were assessed by multivariable regression analyses and were adjusted for age, sex, measures of adiposity and lifestyle, blood pressure, prevalent conditions, medication use and blood biomarkers. Results Skin autofluorescence associated with pulse wave velocity, augmentation index and ankle-brachial index, adjusted beta coefficients (95% CI) per unit skin autofluorescence increase: 0.38 (0.21; 0.55) for carotid-femoral pulse wave velocity, 0.25 (0.14; 0.37) for aortic pulse wave velocity, 1.00 (0.29; 1.70) for aortic augmentation index, 4.12 (2.24; 6.00) for brachial augmentation index and − 0.04 (− 0.05; − 0.02) for ankle-brachial index. The associations were strongest in men, younger individuals and were consistent across all glycemic strata: for carotid-femoral pulse wave velocity 0.36 (0.12; 0.60) in normoglycemic, 0.33 (− 0.01; 0.67) in prediabetes and 0.45 (0.09; 0.80) in diabetes groups; with similar estimates for aortic pulse wave velocity. Augmentation index was associated with skin autofluorescence only in normoglycemic and diabetes groups. Ankle-brachial index inversely associated with skin autofluorescence across all sex, age and glycemic strata. Conclusions Our findings indicate that advanced glycation end-products measured as skin autofluorescence might be involved in vascular stiffening independent of age and other cardiometabolic risk factors not only in individuals with diabetes but also in normoglycemic and prediabetic conditions. Skin autofluorescence might prove as a rapid and non-invasive method for assessment of macrovascular disease progression across all glycemic strata. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-021-01296-5.
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Affiliation(s)
- Anna Birukov
- Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany. .,German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
| | - Rafael Cuadrat
- Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Elli Polemiti
- Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Fabian Eichelmann
- Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Matthias B Schulze
- Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany. .,German Center for Diabetes Research (DZD), München-Neuherberg, Germany. .,Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
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Khanam A, Ahmad S, Husain A, Rehman S, Farooqui A, Yusuf MA. Glycation and Antioxidants: Hand in the Glove of Antiglycation and Natural Antioxidants. Curr Protein Pept Sci 2021; 21:899-915. [PMID: 32039678 DOI: 10.2174/1389203721666200210103304] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/09/2019] [Accepted: 11/30/2019] [Indexed: 12/17/2022]
Abstract
The non-enzymatic interaction of sugar and protein resulting in the formation of advanced glycation end products responsible for cell signaling alterations ultimately leads to the human chronic disorders such as diabetes mellitus, cardiovascular diseases, cancer, etc. Studies suggest that AGEs upon interaction with receptors for advanced glycation end products (RAGE) result in the production of pro-inflammatory molecules and free radicals that exert altered gene expression effect. To date, many studies unveiled the potent role of synthetic and natural agents in inhibiting the glycation reaction at a lesser or greater extent. This review focuses on the hazards of glycation reaction and its inhibition by natural antioxidants, including polyphenols.
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Affiliation(s)
- Afreen Khanam
- IIRC-1, Laboratory of Glycation Biology and Metabolic Disorders, Integral University, Lucknow, India
| | - Saheem Ahmad
- IIRC-1, Laboratory of Glycation Biology and Metabolic Disorders, Integral University, Lucknow, India
| | - Arbab Husain
- IIRC-1, Laboratory of Glycation Biology and Metabolic Disorders, Integral University, Lucknow, India
| | - Shahnawaz Rehman
- IIRC-1, Laboratory of Glycation Biology and Metabolic Disorders, Integral University, Lucknow, India
| | - Alvina Farooqui
- Department of Bioengineering, Integral University, Lucknow, India
| | - Mohd Aslam Yusuf
- Department of Bioengineering, Integral University, Lucknow, India
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Oliveira JS, de Almeida C, de Souza ÂMN, da Cruz LD, Alfenas RCG. Effect of dietary advanced glycation end-products restriction on type 2 diabetes mellitus control: a systematic review. Nutr Rev 2021; 80:294-305. [PMID: 34010398 DOI: 10.1093/nutrit/nuab020] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
CONTEXT Reducing dietary advanced glycation end-products (AGEs) may favor diabetes control. OBJECTIVE Critically analyze studies about the effect of dietary AGEs restriction on inflammation, oxidative stress, and glycemic control in patients with type 2 diabetes mellitus (DM2). DATA SOURCE This systematic review was conducted according to PRISMA methodology. The PubMed, Web of Science, LILACS, and Cochrane Library databases were searched, using the terms "type 2 diabetes," "advanced glycation end products" and "diet." DATA EXTRACTION Seven original studies were included in this review. The duration of the studies ranged from 1 day to 16 weeks. All extracted data were compiled, compared, and critically analyzed. DATA ANALYSIS Glycemic variables were considered the primary outcomes. The secondary outcomes were glycation, inflammatory, and oxidative stress markers. CONCLUSION Although serum insulin, homeostasis model assessment of insulin resistance, and glycated hemoglobin values were lower after the consumption of AGEs restricted diets in most studies, there was a lack of unanimity regarding dietary AGEs' positive effect on inflammation, oxidative stress, and blood glucose. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration no. CRD42020152640.
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Affiliation(s)
- Julia S Oliveira
- J.S. Oliveira, C. Almeida, A.M.N. Souza, L.D. Cruz, and R.C.G. Alfenas are with Departamento de Nutrição e Saúde, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Carolina de Almeida
- J.S. Oliveira, C. Almeida, A.M.N. Souza, L.D. Cruz, and R.C.G. Alfenas are with Departamento de Nutrição e Saúde, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Ângela M N de Souza
- J.S. Oliveira, C. Almeida, A.M.N. Souza, L.D. Cruz, and R.C.G. Alfenas are with Departamento de Nutrição e Saúde, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Luciana D da Cruz
- J.S. Oliveira, C. Almeida, A.M.N. Souza, L.D. Cruz, and R.C.G. Alfenas are with Departamento de Nutrição e Saúde, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Rita C G Alfenas
- J.S. Oliveira, C. Almeida, A.M.N. Souza, L.D. Cruz, and R.C.G. Alfenas are with Departamento de Nutrição e Saúde, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
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46
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Yousefzadeh N, Jeddi S, Kashfi K, Ghasemi A. Diabetoporosis: Role of nitric oxide. EXCLI JOURNAL 2021; 20:764-780. [PMID: 34121973 PMCID: PMC8192884 DOI: 10.17179/excli2021-3541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 03/31/2021] [Indexed: 11/29/2022]
Abstract
Diabetoporosis, diabetic-related decreased bone quality and quantity, is one of the leading causes of osteoporotic fractures in subjects with type 2 diabetes (T2D). This is associated with lower trabecular and cortical bone quality, lower bone turnover rates, lower rates of bone healing, and abnormal posttranslational modifications of collagen. Decreased nitric oxide (NO) bioavailability has been reported within the bones of T2D patients and can be considered as one of the primary mechanisms by which diabetoporosis is manifested. NO donors increase trabecular and cortical bone quality, increase the rate of bone formation, accelerate the bone healing process, delay osteoporosis, and decrease osteoporotic fractures in T2D patients, suggesting the potential therapeutic implication of NO-based interventions. NO is produced in the osteoblast and osteoclast cells by three isoforms of NO synthase (NOS) enzymes. In this review, the roles of NO in bone remodeling in the normal and diabetic states are discussed. Also, the favorable effects of low physiological levels of NO produced by endothelial NOS (eNOS) versus detrimental effects of high pathological levels of NO produced by inducible NOS (iNOS) in diabetoporosis are summarized. Available data indicates decreased bone NO bioavailability in T2D and decreased expression of eNOS, and increased expression and activity of iNOS. NO donors can be considered novel therapeutic agents in diabetoporosis.
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Affiliation(s)
- Nasibeh Yousefzadeh
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, NY, USA
- PhD Program in Biology, City University of New York Graduate Center, New York,NY, USA
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Abstract
Coronary artery atherosclerosis and atherosclerotic plaque rupture cause coronary artery disease (CAD). Advanced glycation end products (AGE) and its cell receptor RAGE, and soluble receptor (sRAGE) and endogenous secretory RAGE (esRAGE) may be involved in the development of atherosclerosis. AGE and its interaction with RAGE are atherogenic, while sRAGE and esRAGE have antiatherogenic effects. AGE-RAGE stress is a ratio of AGE/sRAGE. A high AGE-RAGE stress results in development and progression of CAD and vice-versa. AGE levels in serum and skin, AGE/sRAGE in patients with CAD, and expression of RAGE in animal model of atherosclerosis were higher, while serum levels of esRAGE were lower in patients with CAD compared with controls. Serum levels of sRAGE in CAD patients were contradictory, increased or decreased. This contradictory data may be due to type of patients used, because the sRAGE levels are elevated in diabetics and end-stage renal disease. AGE/sRAGE ratio is elevated in patients with reduced or elevated levels of serum sRAGE. It is to stress that AGE, RAGE, sRAGE, or esRAGE individually cannot serve as universal biomarker. AGE and sRAGE should be measured simultaneously to assess the AGE-RAGE stress. The treatment of CAD should be targeted at reduction in AGE levels, prevention of AGE formation, degradation of AGE in vivo, suppression of RAGE expression, blockade of RAGE, elevation of sRAGE, and use of antioxidants. In conclusion, AGE-RAGE stress would initiate the development and progression of atherosclerosis. Treatment modalities would prevent, regress, and slow the progression of CAD.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, Canada
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48
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Deng L, Du C, Song P, Chen T, Rui S, Armstrong DG, Deng W. The Role of Oxidative Stress and Antioxidants in Diabetic Wound Healing. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8852759. [PMID: 33628388 PMCID: PMC7884160 DOI: 10.1155/2021/8852759] [Citation(s) in RCA: 278] [Impact Index Per Article: 69.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/29/2020] [Indexed: 12/16/2022]
Abstract
Foot ulcers are one of the most common and severe complication of diabetes mellitus with significant resultant morbidity and mortality. Multiple factors impair wound healing include skin injury, diabetic neuropathy, ischemia, infection, inadequate glycemic control, poor nutritional status, and severe morbidity. It is currently believed that oxidative stress plays a vital role in diabetic wound healing. An imbalance of free radicals and antioxidants in the body results in overproduction of reactive oxygen species which lead to cell, tissue damage, and delayed wound healing. Therefore, decreasing ROS levels through antioxidative systems may reduce oxidative stress-induced damage to improve healing. In this context, we provide an update on the role of oxidative stress and antioxidants in diabetic wound healing through following four perspectives. We then discuss several therapeutic strategies especially dietary bioactive compounds by targeting oxidative stress to improve wounds healing.
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Affiliation(s)
- Liling Deng
- Department of Endocrinology, Multidisciplinary Diabetic Foot Medical Center, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing 400014, China
| | - Chenzhen Du
- Department of Endocrinology, Multidisciplinary Diabetic Foot Medical Center, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing 400014, China
| | - Peiyang Song
- Department of Endocrinology, Multidisciplinary Diabetic Foot Medical Center, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing 400014, China
| | - Tianyi Chen
- Department of Endocrinology, Multidisciplinary Diabetic Foot Medical Center, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing 400014, China
| | - Shunli Rui
- Department of Endocrinology, Multidisciplinary Diabetic Foot Medical Center, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing 400014, China
| | - David G. Armstrong
- Department of Surgery, Keck School of Medicine of the University of Southern California, CA, USA
| | - Wuquan Deng
- Department of Endocrinology, Multidisciplinary Diabetic Foot Medical Center, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing 400014, China
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49
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McIntyre NJ, Shardlow A, Fluck RJ, McIntyre CW, Taal MW. Determinants of change in arterial stiffness over 5 years in early chronic kidney disease. Nephrol Dial Transplant 2021; 36:281-288. [PMID: 31532488 DOI: 10.1093/ndt/gfz170] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 07/17/2019] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Arterial stiffness (AS) is an established and potentially modifiable risk factor for cardiovascular disease associated with chronic kidney disease (CKD). There have been few studies to evaluate the progression of AS over time or factors that contribute to this, particularly in early CKD. We therefore investigated AS over 5 years in an elderly population with CKD Stage 3 cared for in primary care. METHODS A total of 1741 persons with an estimated glomerular filtration rate of 30-59 mL/min/1.73 m2 underwent detailed clinical and biochemical assessment at baseline and Years 1 and 5. Carotid to femoral pulse wave velocity (PWV) was measured to assess AS using a Vicorder device. RESULTS 970 participants had PWV assessments at baseline and 5 years. PWV increased significantly by a mean of 1.1 m/s (from 9.7 ± 1.9 to 10.8 ± 2.1 m/s). Multivariable linear regression analysis identified the following independent determinants of ΔPWV at Year 5: baseline age, diabetes status, baseline systolic blood pressure (SBP) and diastolic blood pressure, baseline PWV, ΔPWV at 1 year, ΔSBP over 5 years and Δserum bicarbonate over 5 years (R2 = 0.38 for the equation). CONCLUSIONS We observed a clinically significant increase in PWV over 5 years in a cohort with early CKD despite reasonably well-controlled hypertension. Measures of BP were identified as the most important modifiable determinant of ΔPWV, suggesting that interventions to prevent arterial disease should focus on improved control of BP, particularly in those who evidence an early increase in PWV. These hypotheses should now be tested in prospective trials.
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Affiliation(s)
- Natasha J McIntyre
- Centre for Kidney Research and Innovation, Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, UK
| | | | | | - Christopher W McIntyre
- Divison of Nephrology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.,Department of Nephrology, Victoria Hospital, London Health Sciences Centre, London, ON, Canada
| | - Maarten W Taal
- Centre for Kidney Research and Innovation, Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, UK.,Renal Unit, Royal Derby Hospital, Derby, UK
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Babel RA, Dandekar MP. A Review on Cellular and Molecular Mechanisms Linked to the Development of Diabetes Complications. Curr Diabetes Rev 2021; 17:457-473. [PMID: 33143626 DOI: 10.2174/1573399816666201103143818] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/08/2020] [Accepted: 10/12/2020] [Indexed: 11/22/2022]
Abstract
Modern lifestyle, changing eating habits and reduced physical work have been known to culminate into making diabetes a global pandemic. Hyperglycemia during the course of diabetes is an important causative factor for the development of both microvascular (retinopathy, nephropathy and neuropathy) and macrovascular (coronary artery disease, stroke and peripheral artery disease) complications. In this article, we summarize several mechanisms accountable for the development of both microvascular and macrovascular complications of diabetes. Several metabolic and cellular events are linked to the augmentation of oxidative stress like the activation of advanced glycation end products (AGE) pathway, polyol pathway, Protein Kinase C (PKC) pathway, Poly-ADP Ribose Polymerase (PARP) and hexosamine pathway. Oxidative stress also leads to the production of reactive oxygen species (ROS) like hydroxyl radical, superoxide anion and peroxides. Enhanced levels of ROS rescind the anti-oxidant defence mechanisms associated with superoxide dismutase, glutathione and ascorbic acid. Moreover, ROS triggers oxidative damages at the level of DNA, protein and lipids, which eventually cause cell necrosis or apoptosis. These physiological insults may be related to the microvascular complications of diabetes by negatively impacting the eyes, kidneys and the brain. While underlying pathomechanism of the macrovascular complications is quite complex, hyperglycemia associated atherosclerotic abnormalities like changes in the coagulation system, thrombin formation, fibrinolysis, platelet and endothelial function and vascular smooth muscle are well proven. Since hyperglycemia also modulates the vascular inflammation, cytokines, macrophage activation and gene expression of growth factors, elevated blood glucose level may play a central role in the development of macrovascular complications of diabetes. Taken collectively, chronic hyperglycemia and increased production of ROS are the miscreants for the development of microvascular and macrovascular complications of diabetes.
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Affiliation(s)
- Rishabh A Babel
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India
| | - Manoj P Dandekar
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India
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