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Singh A, Khushboo, Pandey M, Mattoo S, Pore SK, Bhattacharyya J. A glucose-responsive alginate-based hydrogel laden with modified GLP-1 and telmisartan ameliorates type 2 diabetes and reduces liver and kidney toxicities. J Mater Chem B 2025; 13:4419-4432. [PMID: 40095672 DOI: 10.1039/d4tb02261k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
The pathophysiology associated with type 2 diabetes mellitus (T2DM) includes insulin resistance, increased oxidative stress, a pro-inflammatory macrophage population, and dysfunction of pancreatic β cells in the islets of Langerhans, along with hepato- and nephro-toxicity. In this study, an injectable glucose-responsive hydrogel (Diabogel) was developed using alginate and 3-aminophenyl boronic acid to deliver modified glucagon-like peptide-1, insulinoma cell-derived extracellular vesicles, and telmisartan. Diabogel demonstrated cytocompatibility, decreased reactive oxygen species, enhanced insulin synthesis, and improved glucose uptake in vitro. In a high-fat diet/streptozotocin-induced murine model of T2DM, Diabogel lowered blood glucose levels, maintained body weight, and increased insulin expression. Furthermore, it promoted an anti-inflammatory microenvironment in the pancreas by regulating macrophage phenotype and the expression of NF-κB, supported cellular proliferation, and restored the pancreatic islets. In addition, Diabogel treatment significantly lowered the serum levels of pro-inflammatory cytokines and enhanced anti-inflammatory cytokines. Interestingly, Diabogel treatment also lowered diabetes-associated hepato- and nephro-toxicity. Taken together, Diabogel may serve as a potential approach for the treatment of T2DM, regulating blood glucose levels, restoring pancreatic β cell function, and reducing hepatic and renal toxicities.
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Affiliation(s)
- Anjali Singh
- Centre for Biomedical Engineering, Indian Institute of Technology, Delhi, New Delhi 110016, India.
- Department of Biomedical Engineering, All India Institute of Medical Science, Delhi, New Delhi 110016, India
| | - Khushboo
- Centre for Biomedical Engineering, Indian Institute of Technology, Delhi, New Delhi 110016, India.
- Department of Biomedical Engineering, All India Institute of Medical Science, Delhi, New Delhi 110016, India
| | - Monu Pandey
- Centre for Biomedical Engineering, Indian Institute of Technology, Delhi, New Delhi 110016, India.
- Department of Biomedical Engineering, All India Institute of Medical Science, Delhi, New Delhi 110016, India
| | - Shria Mattoo
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, Uttar Pradesh, India
| | - Subrata Kumar Pore
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, Uttar Pradesh, India
| | - Jayanta Bhattacharyya
- Centre for Biomedical Engineering, Indian Institute of Technology, Delhi, New Delhi 110016, India.
- Department of Biomedical Engineering, All India Institute of Medical Science, Delhi, New Delhi 110016, India
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Gupta RD, Haider MR, Roy S, Hashan MR, Baral A, Tamanna N, Mazumder A, Haider SS, Datta B. Association Between Abdominal Obesity, Body Mass Index, and Hypertension in India: Evidence From a Large Nationally Representative Data. J Clin Hypertens (Greenwich) 2025; 27:e70034. [PMID: 40101017 PMCID: PMC11917740 DOI: 10.1111/jch.70034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
Hypertension prevalence is rising among individuals with abdominal obesity in Southeast Asia, including India, but the relationship between abdominal obesity, body mass index (BMI), and hypertension remains underexplored. This study examines the association between these factors in a nationally representative Indian population aged 20-54 years (males: N = 78 832; females: N = 559 059). We analyzed data from the National Family Health Survey 2019-21 (NFHS-5). Hypertension was defined as a systolic blood pressure (SBP) ≥ 140 mm Hg, diastolic blood pressure (DBP) ≥ 90 mm Hg, or use of blood pressure-lowering medication. Abdominal obesity was defined by waist-hip ratio (>0.90 for men, >0.85 for women). BMI categories were underweight (<18.5 kg/m2), normal (18.5-<25.0 kg/m2), overweight (25.0-<30.0 kg/m2), and obese (≥30.0 kg/m2). Multivariable logistic regression adjusted for demographic and lifestyle factors was used to assess the link between BMI, abdominal obesity, and hypertension. Individuals with both obesity and abdominal obesity had significantly higher odds of hypertension, with males having 3.3 times (95% confidence interval [CI]: 2.9-3.7) and females 2.8 times (95% CI: 2.6-2.9) odds compared to those with normal BMI and no abdominal obesity. Both genders showed increased SBP and DBP by 3.0-5.0 mm Hg when abdominal obesity was present, regardless of BMI. Indian health programs should emphasize the risks of high BMI and abdominal obesity to reduce hypertension.
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Affiliation(s)
- Rajat Das Gupta
- BRAC James P Grant School of Public HealthBRAC UniversityDhakaBangladesh
- Department of Epidemiology and Biostatistics, Arnold School of Public HealthUniversity of South CarolinaColumbiaUSA
| | - Mohammad Rifat Haider
- Department of Health Policy and ManagementCollege of Public HealthUniversity of GeorgiaAthensGeorgiaUSA
| | - Simanta Roy
- Department of EpidemiologyRobert Stempel College of Public Health and Social WorkFlorida International UniversityMiamiFloridaUSA
| | - Mohammad Rashidul Hashan
- School of Medical, Health and Applied SciencesCentral Queensland UniversityRockhamptonAustralia
- Central Queensland Public Health UnitCentral Queensland Hospital and Health ServiceRockhamptonAustralia
- Ministry of Health and Family Welfare, Government of BangladeshDhakaBangladesh
| | - Amrit Baral
- Department of Public Health SciencesDivision of EpidemiologyUniversity of MiamiMiamiFloridaUSA
| | - Nowrin Tamanna
- Department of Epidemiology and Biostatistics, Arnold School of Public HealthUniversity of South CarolinaColumbiaUSA
| | - Ananna Mazumder
- Centre for International Public Health and Environmental ResearchBangladesh (CIPHER,B)DhakaBangladesh
- Jahurul Islam Medical College, BajitpurKishoreganjBangladesh
| | - Shams Shabab Haider
- Johns Hopkins Bloomberg School of Public HealthBaltimoreUSA
- Friendship NGODhakaBangladesh
| | - Biplab Datta
- Institute of Public and Preventive HealthAugusta UniversityAugustaGeorgiaUSA
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Li L, Xi L, Wang Q. Association between Chinese visceral adiposity index and risk of new-onset hypertension in middle-aged and older adults with prediabetes: evidence from a large national cohort study. Front Public Health 2025; 13:1509898. [PMID: 40013048 PMCID: PMC11861091 DOI: 10.3389/fpubh.2025.1509898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 01/27/2025] [Indexed: 02/28/2025] Open
Abstract
Purpose Chinese Visceral Adiposity Index (CVAI) has been found significantly associated with hypertension in general and type-2 diabetes adults. However, the predictive value of CVAI for the incidence of hypertension in adults with prediabetes is unclear. This study aimed to assess the predictive utility of the CVAI for the new onset of hypertension in middle-aged and older adult Chinese individuals with prediabetes. Methods A prospective cohort study was conducted involving participants aged 45 years and above with prediabetes from the 2011-2012 cohort of the China Health and Retirement Longitudinal Study (CHARLS). Logistic regression models were utilized to investigate the association between CVAI levels and the risk of new-onset hypertension. Results The study included 2,186 participants, among whom 444 (20.31%) developed hypertension. Significantly higher incidence rates of hypertension were observed in individuals belonging to the highest quartile group (Q4) compared to those in the lowest quartile group (Q1) of CVAI (29.41% vs. 14.69%, p < 0.001). Multivariate logistic regression analysis indicated that participants in Q4 had a 1.91-fold greater risk of hypertension development compared to those in Q1 (odds ratio (OR): 1.91, 95% confidence interval (CI): 1.49-2.45, p < 0.001). The area under the receiver operating characteristic (ROC) curve (AUC) demonstrated that CVAI exhibited superior performance in discriminating individuals at heightened risk of hypertension compared to other obesity-related indices (p < 0.001). A subgroup analysis revealed that age may modulate the relationship between CVAI and new-onset hypertension, with a more pronounced interaction observed among participants below 60 years of age (P for interaction: 0.026). Conclusion Elevated CVAI levels were significantly associated with an increased risk of developing hypertension. CVAI proves to be a reliable and effective tool for risk stratification in middle-aged and older adult Chinese individuals with prediabetes, underscoring its substantial implications for primary prevention of hypertension and public health strategies.
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Affiliation(s)
- Lanlan Li
- Department of Nephrology, Hospital of Xinjiang Production and Construction Corps, Urumqi, Xinjiang, China
- Department of Nephrology, Second Affiliated Hospital, Medical School of Shihezi University, Urumqi, Xinjiang, China
| | - Linqiang Xi
- Department of Cardiac Pacing and Electrophysiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- Department of Cardiology, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Dong Guan, Guangdong, China
| | - Qianhui Wang
- Department of Cardiac Pacing and Electrophysiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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Singh A, Pore SK, Bhattacharyya J. Encapsulation of telmisartan inside insulinoma-cell-derived extracellular vesicles outperformed biomimetic nanovesicles in modulating the pancreatic inflammatory microenvironment. J Mater Chem B 2024; 12:10294-10308. [PMID: 39269191 DOI: 10.1039/d4tb00808a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2024]
Abstract
Diabetes mellitus (DM) is a chronic metabolic condition, characterized by hyperglycaemia, oxidative imbalance, pancreatic β-cell death, and insulin insufficiency. Angiotensin II (Ang II) increases oxidative stress, inflammation, and apoptosis, and Ang II type 1 receptor (AT1R) blockers (ARBs) can ameliorate inflammatory response and oxidative stress. However, like other small-molecule drugs, free ARBs show poor in vivo efficacy and dose-limiting toxicities. Hence, in this study, we developed nano-formulations of telmisartan (TEL), an ARB, by encapsulating it inside a murine insulinoma cell-derived extracellular vesicle (nanoTEL) and a bio-mimetic lipid nanovesicle (lipoTEL). Both nano-formulations showed spherical morphology and sustained release of TEL. In vitro, nanoTEL restored oxidative equilibrium, attenuated reactive oxygen species levels, enhanced the uptake of glucose analogue, and increased the expression of glucose transporter protein 4 better than lipoTEL. In a streptozotocin-induced murine model of diabetes, nanoTEL lowered blood glucose levels, improved glucose tolerance, and promoted insulin synthesis and secretion significantly better than lipoTEL. Moreover, nanoTEL was found superior in ameliorating the pancreatic inflammatory microenvironment by regulating NF-κBp65, HIF-1α, and PPAR-γ expression; modulating IL-1β, IL-6, tumor necrosis factor-α, IL-10, and IL-4 levels and inducing the polarization of macrophage from M1 to M2. Further, nanoTEL administration induced angiogenesis and promoted the proliferation of pancreatic cells to restore the structural integrity of the islets of Langerhans more efficiently than lipoTEL. These findings collectively suggest that nanoTEL outperforms lipoTEL in restoring the function of pancreatic β-cells by modulating the pancreatic inflammatory microenvironment and show potential for the treatment of DM.
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Affiliation(s)
- Anjali Singh
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India
- Department of Biomedical Engineering, All India Institute of Medical Science Delhi, New Delhi 110029, India.
| | - Subrata Kumar Pore
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, 201313, India
| | - Jayanta Bhattacharyya
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India
- Department of Biomedical Engineering, All India Institute of Medical Science Delhi, New Delhi 110029, India.
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Leenders F, de Koning EJP, Carlotti F. Pancreatic β-Cell Identity Change through the Lens of Single-Cell Omics Research. Int J Mol Sci 2024; 25:4720. [PMID: 38731945 PMCID: PMC11083883 DOI: 10.3390/ijms25094720] [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: 03/15/2024] [Revised: 04/12/2024] [Accepted: 04/17/2024] [Indexed: 05/13/2024] Open
Abstract
The main hallmark in the development of both type 1 and type 2 diabetes is a decline in functional β-cell mass. This decline is predominantly attributed to β-cell death, although recent findings suggest that the loss of β-cell identity may also contribute to β-cell dysfunction. This phenomenon is characterized by a reduced expression of key markers associated with β-cell identity. This review delves into the insights gained from single-cell omics research specifically focused on β-cell identity. It highlights how single-cell omics based studies have uncovered an unexpected level of heterogeneity among β-cells and have facilitated the identification of distinct β-cell subpopulations through the discovery of cell surface markers, transcriptional regulators, the upregulation of stress-related genes, and alterations in chromatin activity. Furthermore, specific subsets of β-cells have been identified in diabetes, such as displaying an immature, dedifferentiated gene signature, expressing significantly lower insulin mRNA levels, and expressing increased β-cell precursor markers. Additionally, single-cell omics has increased insight into the detrimental effects of diabetes-associated conditions, including endoplasmic reticulum stress, oxidative stress, and inflammation, on β-cell identity. Lastly, this review outlines the factors that may influence the identification of β-cell subpopulations when designing and performing a single-cell omics experiment.
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Affiliation(s)
| | | | - Françoise Carlotti
- Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (F.L.); (E.J.P.d.K.)
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Cassandra Mkhize B, Mosili P, Sethu Ngubane P, Khathi A. The relationship between adipose tissue RAAS activity and the risk factors of prediabetes: a systematic review and meta-analysis. Adipocyte 2023; 12:2249763. [PMID: 37606270 PMCID: PMC10472858 DOI: 10.1080/21623945.2023.2249763] [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: 03/15/2023] [Revised: 07/29/2023] [Accepted: 08/11/2023] [Indexed: 08/23/2023] Open
Abstract
METHODS This systematic review was developed in compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-2020) standards. This was accomplished by searching clinical MeSH categories in MEDLINE with full texts, EMBASE, Web of Science, PubMed, Cochrane Library, Academic Search Complete, ICTRP and ClinicalTrial.gov. Reviewers examined all the findings and selected the studies that satisfied the inclusion criteria. The Downs and Black Checklist was used to assess for bias, followed by a Review Manager v5. A Forrest plot was used for the meta-analysis and sensitivity analysis. The protocol for this review was registered with PROSPERO CRD42022320252. RESULTS The clinical studies (n = 2) comprised 1065 patients with prediabetes and 1103 normal controls. The RAAS measurements were completed in the adipose tissue. The RAAS components, renin and aldosterone were higher in the prediabetic (PD) compared to the control [mean difference (MD) = 0.16, 95% CI 0.16 (-0.13, 0.45), p = 0.25]. Furthermore, the PD group demonstrated higher triglycerides mean difference [MD = 7.84, 95% CI 7.84 (-9.84, 25.51), p = 0.38] and increased BMI [MD = 0.13, 95% CI 0.13 (-0.74, 0.99), p = 0.77] compared to the control. The overall quality of the studies was fair with a median score and range of 17 (16-18). CONCLUSION The current study highlights the relationship between increased BMI, RAAS and insulin resistance which is a predictor of prediabetes. The renin is slightly higher in the prediabetes group without any statistical significance, aldosterone is rather negatively associated with prediabetes which may be attributed to the use of anti-hypertensive treatment.
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Affiliation(s)
| | - Palesa Mosili
- Department of Human Physiology, University of KwaZulu-Natal, Westville, South Africa
| | | | - Andile Khathi
- Department of Human Physiology, University of KwaZulu-Natal, Westville, South Africa
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Schreier B, Stern C, Rabe S, Mildenberger S, Gekle M. Assessment of the Role of Endothelial and Vascular Smooth Muscle EGFR for Acute Blood Pressure Effects of Angiotensin II and Adrenergic Stimulation in Obese Mice. Biomedicines 2023; 11:2241. [PMID: 37626737 PMCID: PMC10452314 DOI: 10.3390/biomedicines11082241] [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: 07/17/2023] [Revised: 08/05/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
(1) Background: Obesity is associated with hypertension because of endocrine dysregulation of the adrenergic and the renin-angiotensin-aldosterone systems. The epidermal growth factor receptor (EGFR) is an important signaling hub in the cardiovascular system. In this study, we investigate the role of smooth muscle cell (VSMC) and endothelial cell (EC) EGFRs for blood pressure homeostasis and acute vascular reactivity in vivo. (2) Methods: Mice with deletion of the EGFR in the respective cell type received either a high-fat (HFD) or standard-fat diet (SFD) for 18 weeks. Intravascular blood pressure was measured via a Millar catheter in anesthetized animals upon vehicle load, angiotensin II (AII) and phenylephrine (PE) stimulation. (3) Results: We confirmed that deletion of the EGFR in VSMCs leads to reduced blood pressure and a most probably compensatory heart rate increase. EC-EGFR and VSMC-EGFR had only a minor impact on volume-load-induced blood pressure changes in lean as well as in obese wild-type animals. Regarding vasoactive substances, EC-EGFR seems to have no importance for angiotensin II action and counteracting HFD-induced prolonged blood pressure increase upon PE stimulation. VSMC-EGFR supports the blood pressure response to adrenergic and angiotensin II stimulation in lean animals. The responsiveness to AII and alpha-adrenergic stimulation was similar in lean and obese animals despite the known enhanced activity of the RAAS and the sympathetic nervous system under a high-fat diet. (4) Conclusions: We demonstrate that EGFRs in VSMCs and to a lesser extent in ECs modulate short-term vascular reactivity to AII, catecholamines and volume load in lean and obese animals.
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Affiliation(s)
- Barbara Schreier
- Julius-Bernstein-Institute of Physiology, Martin-Luther-University Halle-Wittenberg, 06112 Halle, Germany
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Sankrityayan H, Rao PD, Shelke V, Kulkarni YA, Mulay SR, Gaikwad AB. Endoplasmic Reticulum Stress and Renin-Angiotensin System Crosstalk in Endothelial Dysfunction. Curr Mol Pharmacol 2023; 16:139-146. [PMID: 35232343 DOI: 10.2174/1874467215666220301113833] [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: 08/28/2021] [Revised: 12/15/2021] [Accepted: 12/16/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Vascular endothelial dysfunction (VED) significantly results in catastrophic cardiovascular diseases with multiple aetiologies. Variations in vasoactive peptides, including angiotensin II and endothelin 1, and metabolic perturbations like hyperglycaemia, altered insulin signalling, and homocysteine levels result in pathogenic signalling cascades, which ultimately lead to VED. Endoplasmic reticulum (ER) stress reduces nitric oxide availability, causes aberrant angiogenesis, and enhances oxidative stress pathways, consequently promoting endothelial dysfunction. Moreover, the renin-angiotensin system (RAS) has widely been acknowledged to impact angiogenesis, endothelial repair and inflammation. Interestingly, experimental studies at the preclinical level indicate a possible pathological link between the two pathways in the development of VED. Furthermore, pharmacological modulation of ER stress ameliorates angiotensin-II mediated VED as well as RAS intervention either through inhibition of the pressor arm or enhancement of the depressor arm of RAS, mitigating ER stress-induced endothelial dysfunction and thus emphasizing a vital crosstalk. CONCLUSION Deciphering the pathway overlap between RAS and ER stress may open potential therapeutic avenues to combat endothelial dysfunction and associated diseases. Several studies suggest that alteration in a component of RAS may induce ER stress or induction of ER stress may modulate the RAS components. In this review, we intend to elaborate on the crosstalk of ER stress and RAS in the pathophysiology of VED.
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Affiliation(s)
- Himanshu Sankrityayan
- Department of Pharmacy, Laboratory of Molecular Pharmacology, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan-333031, India
| | - Pooja Dhileepkumar Rao
- Department of Pharmacy, Laboratory of Molecular Pharmacology, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan-333031, India
| | - Vishwadeep Shelke
- Department of Pharmacy, Laboratory of Molecular Pharmacology, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan-333031, India
| | - Yogesh A Kulkarni
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai 400056, India
| | - Shrikant R Mulay
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Anil Bhanudas Gaikwad
- Department of Pharmacy, Laboratory of Molecular Pharmacology, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan-333031, India
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Mkhize BC, Mosili P, Ngubane PS, Sibiya NH, Khathi A. Diet-induced prediabetes: Effects on the activity of the renin-angiotensin-aldosterone system (RAAS) in selected organs. J Diabetes Investig 2021; 13:768-780. [PMID: 34619025 PMCID: PMC9077724 DOI: 10.1111/jdi.13690] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 09/14/2021] [Accepted: 10/04/2021] [Indexed: 11/30/2022] Open
Abstract
Derangements often observed with type 2 diabetes (T2D) are associated with disturbances in renin-angiotensin-aldosterone system (RAAS) activity. A positive correlation between local RAAS activity and the complications observed in T2D has been noted. However, the detrimental ramifications due to moderate hyperglycemia noted in prediabetes and the affected organ system and mechanistic pathways are not elucidated. Hence, this study investigated the effects of diet-induced prediabetes on RAAS in various organs. MATERIALS AND METHODS Male Sprague-Dawley rats were separated into two groups: non-pre-diabetic (NPD) through exposure to standard rat chow and diet-induced prediabetic (PD) group by exposure to a high-fat high carbohydrate diet for 32 weeks. RAAS activity in the skeletal muscle, adipose tissue, liver, pancreas and heart was determined through the analysis of RAAS components such as; renin, angiotensinogen, angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) via PCR as well as the quantification of angiotensin II and aldosterone concentration. Furthermore, NADPH oxidase, SOD and GPx1 concentrations were determined in the skeletal muscle, pancreas and heart in addition to the hepatic triglycerides. RESULTS The RAAS components were elevated in the PD group when compared to the NPD. This was further accompanied by increased NADPH oxidase and reduced SOD and GPx1 concentrations in the selected organs, in addition to the elevated hepatic triglycerides concentration in the PD by comparison to NPD. CONCLUSION Due to these observed changes, we suggest that local RAAS activity in the prediabetic state in selected organs elicits the derangements noted in T2D.
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Oza MJ, Laddha AP, Gaikwad AB, Mulay SR, Kulkarni YA. Role of dietary modifications in the management of type 2 diabetic complications. Pharmacol Res 2021; 168:105602. [PMID: 33838293 DOI: 10.1016/j.phrs.2021.105602] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 12/15/2022]
Abstract
Diabetes is a chronic metabolic disorder with a high rate of morbidity and mortality. Insufficient insulin secretion and insulin action are two major causes for the development of diabetes, which is characterized by a persistent increase in blood glucose level. Diet and sedentary life style play pivotal role in development of vascular complications in type 2 diabetes. Dietary modification is associated with a reprogramming of nutrient intake, which are proven to be effective for the management of diabetes and associated complications. Dietary modifications modulate various molecular key players linked with the functions of nutrient signalling, regulation of autophagy, and energy metabolism. It activates silent mating type information regulation 2 homolog1 (SIRT1) and AMP-activated protein kinase (AMPK). AMPK mainly acts as an energy sensor and inhibits autophagy repressor Mammalian target of rapamycin (mTOR) under nutritional deprivation. Under calorie restriction (CR), SIRT1 gets activated directly or indirectly and plays a central role in autophagy via the regulation of protein acetylation. Dietary modification is also effective in controlling inflammation and apoptosis by decreasing the level of pro-inflammatory cytokines like nuclear factor kappa- beta (NF-kβ), tissue growth factor-beta (TGF-β), tissue necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). It also improves glucose homeostasis and insulin secretion through beta cell regeneration. This indicates calorie intake plays a crucial role in the pathogenesis of type 2 diabetes-associated complications. The present review, emphasizes the role of dietary modifications in diabetes and associated complications.
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Affiliation(s)
- Manisha J Oza
- SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai 400056, India
| | - Ankit P Laddha
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai 400056, India
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India
| | - Shrikant R Mulay
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Yogesh A Kulkarni
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai 400056, India.
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Uyy E, Suica VI, Boteanu RM, Safciuc F, Cerveanu-Hogas A, Ivan L, Stavaru C, Simionescu M, Antohe F. Diabetic nephropathy associates with deregulation of enzymes involved in kidney sulphur metabolism. J Cell Mol Med 2020; 24:12131-12140. [PMID: 32935914 PMCID: PMC7579703 DOI: 10.1111/jcmm.15855] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/17/2020] [Accepted: 08/19/2020] [Indexed: 12/12/2022] Open
Abstract
Nephropathy is a major chronic complication of diabetes. A crucial role in renal pathophysiology is played by hydrogen sulphide (H2S) that is produced excessively by the kidney; however, the data regarding H2S bioavailability are inconsistent. We hypothesize that early type 1 diabetes (T1D) increases H2S production by a mechanism involving hyperglycaemia‐induced alterations in sulphur metabolism. Plasma and kidney tissue collected from T1D double transgenic mice were subjected to mass spectrometry‐based proteomic analysis, and the results were validated by immunological and gene expression assays.T1D mice exhibited a high concentration of H2S in the plasma and kidney tissue and histological, showed signs of subtle kidney fibrosis, characteristic for early renal disease. The shotgun proteomic analyses disclosed that the level of enzymes implicated in sulphate activation modulators, H2S‐oxidation and H2S‐production were significantly affected (ie 6 up‐regulated and 4 down‐regulated). Gene expression results corroborated well with the proteomic data. Dysregulation of H2S enzymes underly the changes occurring in H2S production, which in turn could play a key role in the initiation of renal disease. The new findings lead to a novel target in the therapy of diabetic nephropathy. Mass spectrometry data are available via ProteomeXchange with identifier PXD018053.
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Affiliation(s)
- Elena Uyy
- Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
| | - Viorel Iulian Suica
- Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
| | - Raluca Maria Boteanu
- Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
| | - Florentina Safciuc
- Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
| | - Aurel Cerveanu-Hogas
- Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
| | - Luminita Ivan
- Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
| | - Crina Stavaru
- "Cantacuzino" National Institute of Research and Development for Microbiology and Immunology, Bucharest, Romania
| | - Maya Simionescu
- Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
| | - Felicia Antohe
- Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
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Kim YH, Her AY, Jeong MH, Kim BK, Hong SJ, Kim S, Ahn CM, Kim JS, Ko YG, Choi D, Hong MK, Jang Y. Impacts of renin-angiotensin system inhibitors on two-year clinical outcomes in diabetic and dyslipidemic acute myocardial infarction patients after a successful percutaneous coronary intervention using newer-generation drug-eluting stents. Medicine (Baltimore) 2020; 99:e21289. [PMID: 32791710 PMCID: PMC7387038 DOI: 10.1097/md.0000000000021289] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
This study investigated the impacts of renin-angiotensin system inhibitors (RASIs) on 2-year clinical outcomes in diabetes and dyslipidemic acute myocardial infarction (AMI) patients after a successful percutaneous coronary intervention (PCI) using newer-generation drug-eluting stents (DESs).A total of 16,997 AMI patients were enrolled, and divided into four groups based on the presence or absence of diabetes and dyslipidemia as follows: diabetes -/dyslipidemia -(group A, 11,132 patients), diabetes +/dyslipidemia - (group B, 3,860 patients), diabetes -/dyslipidemia + (group C, 1,328 patients), and diabetes +/dyslipidemia + (group D, 677 patients). The clinical endpoint was the occurrence of major adverse cardiac events (MACEs), the composite of total death, recurrent myocardial infarction (re-MI), and any repeat revascularization, including target lesion revascularization (TLR), target vessel revascularization (TVR), and non-target vessel revascularization (non-TVR).After RASIs therapy, the cumulative incidences of MACEs (adjusted hazard ratio [aHR], 1.330; 95% confidence interval [CI], 1.022-1.732; P = .034), any repeat revascularization (aHR, 1.584; 95% CI, 1.092-2.298; P = .015), TLR, and TVR were significantly higher in group B than group C. However, the cumulative incidences of all-cause death, cardiac death, re-MI, and non-TVR were similar in groups B and C.In this study, under the newer-generation DESs era, repeat revascularization rate reduction benefit of RASIs therapy in diabetic AMI patients was lesser than that in dyslipidemic AMI patients. However, larger randomized controlled studies are needed to confirm these results in the future.
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Affiliation(s)
- Yong Hoon Kim
- Division of Cardiology, Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon
| | - Ae-Young Her
- Division of Cardiology, Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon
| | - Myung Ho Jeong
- Cardiovascular Center, Department of Cardiology, Chonnam National University Hospital, Gwangju
| | - Byeong-Keuk Kim
- Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul
| | - Sung-Jin Hong
- Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul
| | - Seunghwan Kim
- Division of Cardiology, Inje University College of Medicine, Haeundae Paik Hospital, Busan, South Korea
| | - Chul-Min Ahn
- Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul
| | - Jung-Sun Kim
- Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul
| | - Young-Guk Ko
- Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul
| | - Donghoon Choi
- Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul
| | - Myeong-Ki Hong
- Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul
| | - Yangsoo Jang
- Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul
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Kang T, Boland BB, Jensen P, Alarcon C, Nawrocki A, Grimsby JS, Rhodes CJ, Larsen MR. Characterization of Signaling Pathways Associated with Pancreatic β-cell Adaptive Flexibility in Compensation of Obesity-linked Diabetes in db/db Mice. Mol Cell Proteomics 2020; 19:971-993. [PMID: 32265294 PMCID: PMC7261816 DOI: 10.1074/mcp.ra119.001882] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 03/03/2020] [Indexed: 12/20/2022] Open
Abstract
The onset of obesity-linked type 2 diabetes (T2D) is marked by an eventual failure in pancreatic β-cell function and mass that is no longer able to compensate for the inherent insulin resistance and increased metabolic load intrinsic to obesity. However, in a commonly used model of T2D, the db/db mouse, β-cells have an inbuilt adaptive flexibility enabling them to effectively adjust insulin production rates relative to the metabolic demand. Pancreatic β-cells from these animals have markedly reduced intracellular insulin stores, yet high rates of (pro)insulin secretion, together with a substantial increase in proinsulin biosynthesis highlighted by expanded rough endoplasmic reticulum and Golgi apparatus. However, when the metabolic overload and/or hyperglycemia is normalized, β-cells from db/db mice quickly restore their insulin stores and normalize secretory function. This demonstrates the β-cell's adaptive flexibility and indicates that therapeutic approaches applied to encourage β-cell rest are capable of restoring endogenous β-cell function. However, mechanisms that regulate β-cell adaptive flexibility are essentially unknown. To gain deeper mechanistic insight into the molecular events underlying β-cell adaptive flexibility in db/db β-cells, we conducted a combined proteomic and post-translational modification specific proteomic (PTMomics) approach on islets from db/db mice and wild-type controls (WT) with or without prior exposure to normal glucose levels. We identified differential modifications of proteins involved in redox homeostasis, protein refolding, K48-linked deubiquitination, mRNA/protein export, focal adhesion, ERK1/2 signaling, and renin-angiotensin-aldosterone signaling, as well as sialyltransferase activity, associated with β-cell adaptive flexibility. These proteins are all related to proinsulin biosynthesis and processing, maturation of insulin secretory granules, and vesicular trafficking-core pathways involved in the adaptation of insulin production to meet metabolic demand. Collectively, this study outlines a novel and comprehensive global PTMome signaling map that highlights important molecular mechanisms related to the adaptive flexibility of β-cell function, providing improved insight into disease pathogenesis of T2D.
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Affiliation(s)
- Taewook Kang
- Protein research group, Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark; The Danish Diabetes Academy, Odense, Denmark
| | - Brandon B Boland
- The Kovler Diabetes Center, Department of Medicine Section of Endocrinology, Diabetes & Metabolism, University of Chicago, Chicago, Illinois 60637; Cardiovascular, Renal and Metabolic Disease, BioPharmaceuticals Research and Development, AstraZeneca Gaithersburg, Maryland 20878
| | - Pia Jensen
- Protein research group, Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark
| | - Cristina Alarcon
- The Kovler Diabetes Center, Department of Medicine Section of Endocrinology, Diabetes & Metabolism, University of Chicago, Chicago, Illinois 60637
| | - Arkadiusz Nawrocki
- Protein research group, Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark
| | - Joseph S Grimsby
- Cardiovascular, Renal and Metabolic Disease, BioPharmaceuticals Research and Development, AstraZeneca Gaithersburg, Maryland 20878
| | - Christopher J Rhodes
- The Kovler Diabetes Center, Department of Medicine Section of Endocrinology, Diabetes & Metabolism, University of Chicago, Chicago, Illinois 60637; Cardiovascular, Renal and Metabolic Disease, BioPharmaceuticals Research and Development, AstraZeneca Gaithersburg, Maryland 20878
| | - Martin R Larsen
- Protein research group, Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark.
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14
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Jahandideh F, Wu J. Perspectives on the Potential Benefits of Antihypertensive Peptides towards Metabolic Syndrome. Int J Mol Sci 2020; 21:E2192. [PMID: 32235782 PMCID: PMC7139547 DOI: 10.3390/ijms21062192] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/18/2020] [Accepted: 03/20/2020] [Indexed: 12/12/2022] Open
Abstract
In addition to the regulation of blood pressure, the renin-angiotensin system (RAS) also plays a key role in the onset and development of insulin resistance, which is central to metabolic syndrome (MetS). Due to the interplay between RAS and insulin resistance, antihypertensive compounds may exert beneficial effects in the management of MetS. Food-derived bioactive peptides with RAS blocking properties can potentially improve adipose tissue dysfunction, glucose intolerance, and insulin resistance involved in the pathogenesis of MetS. This review discusses the pathophysiology of hypertension and the association between RAS and pathogenesis of the MetS. The effects of bioactive peptides with RAS modulating effects on other components of the MetS are discussed. While the in vivo reports on the effectiveness of antihypertensive peptides against MetS are encouraging, the exact mechanism by which these peptides infer their effects on glucose and lipid handling is mostly unknown. Therefore, careful design of experiments along with standardized physiological models to study the effect of antihypertensive peptides on insulin resistance and obesity could help to clarify this relationship.
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Affiliation(s)
- Forough Jahandideh
- Department of Agricultural, Food and Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, Edmonton, AB T6G 2P5, Canada
- Cardiovascular Research Centre, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - Jianping Wu
- Department of Agricultural, Food and Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, Edmonton, AB T6G 2P5, Canada
- Cardiovascular Research Centre, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2S2, Canada
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15
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Advanced Glycation End Products: Potential Mechanism and Therapeutic Target in Cardiovascular Complications under Diabetes. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9570616. [PMID: 31885827 PMCID: PMC6925928 DOI: 10.1155/2019/9570616] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 11/25/2019] [Indexed: 01/08/2023]
Abstract
The occurrence and development of cardiovascular complications are predominantly responsible for the increased morbidity and mortality observed in patients with diabetes. Oxidative stress under hyperglycemia is currently considered the initial link to diabetic cardiovascular complications and a key node for the prevention and treatment of diabetes-related fatal cardiovascular events. Numerous studies have indicated that the common upstream pathway in the context of oxidative stress in the cardiovascular system under diabetic conditions is the interaction of advanced glycation end products (AGEs) with their receptors (RAGEs). Therefore, a further understanding of the relationship between oxidative stress and AGEs is of great significance for the prevention and treatment of cardiovascular complications in patients with diabetes. In this review, we will briefly summarize the recent research advances in diabetes with an emphasis on oxidative stress and its association with AGEs in diabetic cardiovascular complications.
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16
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Critical role of the endogenous renin-angiotensin system in maintaining self-renewal and regeneration potential of epidermal stem cells. Biochim Biophys Acta Mol Basis Dis 2019; 1865:2647-2656. [DOI: 10.1016/j.bbadis.2019.07.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 07/10/2019] [Accepted: 07/12/2019] [Indexed: 12/11/2022]
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17
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Sun L, Yu M, Zhou T, Zhang S, He G, Wang G, Gang X. Current advances in the study of diabetic cardiomyopathy: From clinicopathological features to molecular therapeutics (Review). Mol Med Rep 2019; 20:2051-2062. [PMID: 31322242 DOI: 10.3892/mmr.2019.10473] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 05/29/2019] [Indexed: 11/06/2022] Open
Abstract
The incidence of diabetes mellitus has become a major public health concern due to lifestyle alterations. Moreover, the complications associated with diabetes mellitus deeply influence the quality of life of patients. Diabetic cardiomyopathy (DC) is a type of diabetes mellitus complication characterized by functional and structural damage in the myocardium but not accompanied by coronary arterial disease. Currently, diagnosing and preventing DC is still a challenge for physicians due to its atypical symptoms. For this reason, it is necessary to summarize the current knowledge on DC, especially in regards to the underlying molecular mechanisms toward the goal of developing useful diagnostic approaches and effective drugs based on these mechanisms. There exist several review articles which have focused on these points, but there still remains a lot to learn from published studies. In this review, the features, diagnosis and molecular mechanisms of DC are reviewed. Furthermore, potential therapeutic and prophylactic drugs are discussed.
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Affiliation(s)
- Lin Sun
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Ming Yu
- Department of Cardiology, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Tong Zhou
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Siwen Zhang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Guangyu He
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Guixia Wang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Xiaokun Gang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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18
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Alam F, Shafique Z, Amjad ST, Bin Asad MHH. Enzymes inhibitors from natural sources with antidiabetic activity: A review. Phytother Res 2018; 33:41-54. [DOI: 10.1002/ptr.6211] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 09/10/2018] [Accepted: 09/13/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Fiaz Alam
- Department of Pharmacy COMSATS University Islamabad Pakistan
| | - Zainab Shafique
- Department of Pharmacy COMSATS University Islamabad Pakistan
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19
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Graus-Nunes F, Souza-Mello V. The renin-angiotensin system as a target to solve the riddle of endocrine pancreas homeostasis. Biomed Pharmacother 2018; 109:639-645. [PMID: 30404071 DOI: 10.1016/j.biopha.2018.10.191] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 10/30/2018] [Accepted: 10/31/2018] [Indexed: 10/27/2022] Open
Abstract
Local renin-angiotensin system (RAS) in the pancreas is linked to the modulation of glucose-stimulated insulin secretion (GSIS) in beta cells and insulin sensitivity in target tissues, emerging as a promising tool in the prevention and/or treatment of obesity, diabetes, and systemic arterial hypertension. Insulin resistance alters pancreatic islet cell distribution and morphology and hypertrophied islets exhibit upregulated angiotensin II type 1 receptor, which drives oxidative stress, apoptosis, and fibrosis, configuring beta cell dysfunction and diminishing islet lifespan. Pharmacological modulation of RAS has shown beneficial effects in diet-induced obesity model, mainly related to the translational potential that angiotensin receptor blockers and ECA2/ANG (1-7)/MAS receptor axis modulation have when it comes to islet preservation and type 2 diabetes prevention and/or treatment. This review describes the existing evidence for different approaches to blocking RAS elements in the management of insulin resistance and diabetes and focuses on islet remodeling and GSIS in rodents and humans.
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Affiliation(s)
- Francielle Graus-Nunes
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil.
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20
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Çetin Güvenç R, Ceran N, Güvenç TS, Tokgöz HC, Velibey Y. Right Ventricular Hypertrophy and Dilation in Patients With Human Immunodeficiency Virus in the Absence of Clinical or Echocardiographic Pulmonary Hypertension. J Card Fail 2018; 24:583-593. [PMID: 30195828 DOI: 10.1016/j.cardfail.2018.08.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 07/09/2018] [Accepted: 08/14/2018] [Indexed: 01/05/2023]
Abstract
BACKGROUND Involvement of right-sided heart chambers (RSHCs) in patients infected with human immunodeficiency virus (HIV) is common and is usually attributed to pulmonary arterial or venous hypertension (PH). However, myocardial involvement in patients with HIV is also common and might affect RSHCs even in the absence of overt PH. Our aim was to define morphologic and functional alterations in RSHC in patients with HIV and without PH. METHODS AND RESULTS A total of 50 asymptomatic patients with HIV and 25 control subjects without clinical or echocardiographic signs for PH were included in the study. Transthoracic echocardiography was used to obtain measurements. Patients with HIV had significantly increased right ventricular end-diastolic diameter (RVEDD) and right ventricular free wall thickness (RVFWT), as well as increased right atrial area and pulmonary arterial diameter, compared with control subjects. After adjustment for age, sex, and body surface area, RVFWT (average 1.81 mm, 95% confidence interval [CI] 0.35-3.26 mm) and RVEDD (average 6.82 mm, 95% CI 2.40-11.24 mm) were significantly higher in subjects infected with HIV. More patients with right ventricular hypertrophy were on antiretroviral treatment, and RVFWT was on average 1.3 mm higher (95% CI 0.24-2.37 mm) in patients on antiretroviral treatment after adjustment for confounders. CONCLUSIONS These findings suggest that alterations in RSHCs were present in patients with HIV without PH.
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Affiliation(s)
- Rengin Çetin Güvenç
- Division of Cardiology, Haydarpaşa Numune Research and Training Hospital, Istanbul, Turkey
| | - Nurgül Ceran
- Division of Infectious Disorders, Haydarpaşa Numune Research and Training Hospital, Istanbul, Turkey
| | - Tolga Sinan Güvenç
- Division of Cardiology, Dr Siyami Ersek Cardiovascular and Thoracic Surgery Research and Training Hospital, Istanbul, Turkey.
| | - Hacer Ceren Tokgöz
- Division of Cardiology, Haydarpaşa Numune Research and Training Hospital, Istanbul, Turkey
| | - Yalçin Velibey
- Division of Cardiology, Dr Siyami Ersek Cardiovascular and Thoracic Surgery Research and Training Hospital, Istanbul, Turkey
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21
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Pathophysiological Links Between Diabetes and Blood Pressure. Can J Cardiol 2018; 34:585-594. [DOI: 10.1016/j.cjca.2018.01.010] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 01/08/2018] [Accepted: 01/08/2018] [Indexed: 02/06/2023] Open
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22
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Sanni SJ, Lyngsø C, Gammeltoft S, Hansen JL. [Sar1, Ile4, Ile8]-angiotensin II Potentiates Insulin Receptor Signalling and Glycogen Synthesis in Hepatocytes. Basic Clin Pharmacol Toxicol 2018; 122:460-469. [PMID: 29136335 DOI: 10.1111/bcpt.12937] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 11/03/2017] [Indexed: 01/05/2025]
Abstract
The angiotensin II type I receptor (AT1R) is involved in the regulation of cardiovascular function. Excessive activation of AT1R by angiotensin II (Ang II) leads to cardiovascular disease and may be involved in the development of insulin resistance and diabetes. Functionally selective Ang II analogues, such as the [Sar1, Ile4, Ile8]-angiotensin II (SII Ang II) analogue, that only activate a subset of signalling networks have been demonstrated to have beneficial effects on cardiovascular function in certain settings, including lowering blood pressure and increasing cardiac performance. Here, we studied the effect of SII Ang II on insulin receptor (IR) signalling and glucose metabolism in primary rat hepatocytes. We show that long-term pre-treatment of hepatocytes with SII Ang II increased insulin-stimulated glycogen synthesis, while Ang II and the AT1R antagonist losartan had no effect. Insulin-stimulated suppression of hepatic glucose output was not affected by Ang II or SII Ang II. It is well known that insulin regulates glycogen synthesis and glucose output through Akt-mediated phosphorylation of glycogen synthase kinase α/β (GSK3α/β) and forkhead box protein O1 (FOXO1), respectively. In line with this, we show that SII Ang II potentiated insulin-stimulated phosphorylation of Akt and GSK3α/β, but not FOXO1. Furthermore, we demonstrate that the effect of SII Ang II on insulin-stimulated signalling and glycogen synthesis was dependent on Src and Gαq, as inhibitors of these proteins abolished the potentiating effect of SII Ang II. Thus, our results demonstrate that SII Ang II may have a positive effect on IR signalling and glucose metabolism in hepatocytes.
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Affiliation(s)
- Samra Joke Sanni
- Obesity Biology, Novo Nordisk A/S, Maalov, Denmark
- Department of Clinical Biochemistry, Glostrup Research Institute, Glostrup Hospital, Glostrup, Denmark
| | - Christina Lyngsø
- Department of Clinical Biochemistry, Glostrup Research Institute, Glostrup Hospital, Glostrup, Denmark
| | - Steen Gammeltoft
- Department of Clinical Biochemistry, Glostrup Research Institute, Glostrup Hospital, Glostrup, Denmark
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Abadir P, Hosseini S, Faghih M, Ansari A, Lay F, Smith B, Beselman A, Vuong D, Berger A, Tian J, Rini D, Keenahan K, Budman J, Inagami T, Fedarko N, Marti G, Harmon J, Walston J. Topical Reformulation of Valsartan for Treatment of Chronic Diabetic Wounds. J Invest Dermatol 2018; 138:434-443. [PMID: 29078982 PMCID: PMC10941026 DOI: 10.1016/j.jid.2017.09.030] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 09/05/2017] [Accepted: 09/07/2017] [Indexed: 02/07/2023]
Abstract
Chronic wounds are among the most devastating and difficult to treat consequences of diabetes. Dysregulation of the skin renin-angiotensin system is implicated in abnormal wound healing in diabetic and older adults. Given this, we sought to determine the effects of topical reformulations of the angiotensin type 1 receptor blockers losartan and valsartan and the angiotensin-converting enzyme inhibitor captopril on wound healing in diabetic and aged mice with further validation in older diabetic pigs. The application of 1% valsartan gel compared with other tested formulations and placebo facilitated and significantly accelerated closure time and increased tensile strength in mice, and was validated in the porcine model. One percent of valsartan gel-treated wounds also exhibited higher mitochondrial content, collagen deposition, phosphorylated mothers against decapentaplegic homologs 2 and 3 and common mothers against decapentaplegic homolog 4, alpha-smooth muscle actin, CD31, phospho-vascular endothelial growth factor receptor 2, and p42/44 mitogen-activated protein kinase. Knockout of the angiotensin subtype 2 receptors abolished the beneficial effects of angiotensin type 1 receptor blockers, suggesting a role for angiotensin subtype 2 receptors in chronic wound healing.
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Affiliation(s)
- Peter Abadir
- Division of Geriatrics Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
| | - Sayed Hosseini
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mahya Faghih
- Division of Geriatrics Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Amir Ansari
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Frank Lay
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Barbara Smith
- Cell Biology Imaging Facility, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Aleksandra Beselman
- Investigational Drug Service Pharmacy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Diep Vuong
- Division of Geriatrics Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Alan Berger
- Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jing Tian
- Department of Biostatistics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - David Rini
- Art as Applied to Medicine, Division of Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kevin Keenahan
- Department of Bioengineering Innovation, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Joshua Budman
- Department of Bioengineering Innovation, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Tadashi Inagami
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Neal Fedarko
- Division of Geriatrics Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Guy Marti
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Clinique Saint Jean, Melun, France
| | - John Harmon
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jeremy Walston
- Division of Geriatrics Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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24
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Cimmaruta D, Lombardi N, Borghi C, Rosano G, Rossi F, Mugelli A. Polypill, hypertension and medication adherence: The solution strategy? Int J Cardiol 2017; 252:181-186. [PMID: 29180263 DOI: 10.1016/j.ijcard.2017.11.075] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 09/18/2017] [Accepted: 11/21/2017] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Hypertension is an important global health challenge and a leading preventable risk factor for premature death and disability worldwide. In current cardiology practice, the main obstacles in the management of patients affected by hypertension are comorbidities and poor adherence to pharmacological treatments. The World Health Organization has recently highlighted increased adherence as a key development need for reducing cardiovascular disease. METHODS Principal observational and clinical trial data regarding adherence, reductions in cardiovascular risk and safety of the polypill approach are summarized and reviewed. CONCLUSIONS The polypill approach has been conclusively shown to increase adherence relative to usual care in all cardiovascular patients, furthermore, concomitant risk factor reductions have also been suggested. To date, the use of polypill could represent a solution strategy in patients affected by hypertension, comorbidities and non-adherence even though further studies, especially in the real-world settings, are needed in order to better understand its role in clinical practice.
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Affiliation(s)
- D Cimmaruta
- Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", University of Campania Region "Luigi Vanvitelli", Naples, Italy
| | - N Lombardi
- Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, Florence, Italy
| | - C Borghi
- Atherosclerosis Research Unit, Medicine & Surgery Sciences Dept., Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - G Rosano
- IRCCS San Raffaele Pisana, Rome, Italy; Cardiovascular and Cell Sciences Research Institute, St. George's University of London, London, United Kingdom
| | - F Rossi
- Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", University of Campania Region "Luigi Vanvitelli", Naples, Italy
| | - A Mugelli
- Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, Florence, Italy.
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25
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Noguchi R, Kaji K, Namisaki T, Moriya K, Kitade M, Takeda K, Kawaratani H, Okura Y, Aihara Y, Furukawa M, Mitoro A, Yoshiji H. Serum angiotensin-converting enzyme level for evaluating significant fibrosis in chronic hepatitis B. World J Gastroenterol 2017; 23:6705-6714. [PMID: 29085215 PMCID: PMC5643291 DOI: 10.3748/wjg.v23.i36.6705] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 05/01/2017] [Accepted: 06/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the diagnostic performance of angiotensin-converting enzyme (ACE) on significant liver fibrosis in patients with chronic hepatitis B (CHB). METHODS In total, 100 patients with CHB who underwent liver biopsy in our hospital were enrolled, and 70 patients except for 30 patients with hypertension, fatty liver or habitual alcoholic consumption were analyzed. We compared histological liver fibrosis and serum ACE levels and evaluated the predictive potential to diagnose significant liver fibrosis by comparison with several biochemical marker-based indexes such as the aspartate aminotransferase (AST)-to-platelet ratio index (APRI), the fibrosis index based on four factors (FIB-4), the Mac-2 binding protein glycosylation isomer (M2BPGi) level and the number of platelets (Plt). RESULTS Serum ACE levels showed moderately positive correlation with liver fibrotic stages (R2 = 0.181). Patients with significant, advanced fibrosis and cirrhosis (F2-4) had significantly higher serum ACE levels than those with early-stage fibrosis and cirrhosis (F0-1). For significant fibrosis (≥ F2), the 12.8 U/L cut-off value of ACE showed 91.7% sensitivity and 75.0% specificity. The receiver-operating characteristic (ROC) curves analysis revealed that the area under the curve (AUC) value of ACE was 0.871, which was higher than that of APRI, FIB-4, M2BPGi and Plt. CONCLUSION The serum ACE level could be a novel noninvasive, easy, accurate, and inexpensive marker of significant fibrosis stage in patients with CHB.
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Affiliation(s)
- Ryuichi Noguchi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Mitsuteru Kitade
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kosuke Takeda
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Yasushi Okura
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Yosuke Aihara
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Masanori Furukawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Akira Mitoro
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
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Angiotensin II type 2 receptor (AT2R) in renal and cardiovascular disease. Clin Sci (Lond) 2017; 130:1307-26. [PMID: 27358027 DOI: 10.1042/cs20160243] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 05/06/2016] [Indexed: 12/14/2022]
Abstract
Angiotensin II (Ang II) is well-considered to be the principal effector of the renin-angiotensin system (RAS), which binds with strong affinity to the angiotensin II type 1 (AT1R) and type 2 (AT2R) receptor subtype. However, activation of both receptors is likely to stimulate different signalling mechanisms/pathways and produce distinct biological responses. The haemodynamic and non-haemodynamic effects of Ang II, including its ability to regulate blood pressure, maintain water-electrolyte balance and promote vasoconstriction and cellular growth are well-documented to be mediated primarily by the AT1R. However, its biological and functional effects mediated through the AT2R subtype are still poorly understood. Recent studies have emphasized that activation of the AT2R regulates tissue and organ development and provides in certain context a potential counter-regulatory mechanism against AT1R-mediated actions. Thus, this review will focus on providing insights into the biological role of the AT2R, in particular its actions within the renal and cardiovascular system.
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Malek V, Gaikwad AB. Neprilysin inhibitors: A new hope to halt the diabetic cardiovascular and renal complications? Biomed Pharmacother 2017; 90:752-759. [DOI: 10.1016/j.biopha.2017.04.024] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Revised: 03/31/2017] [Accepted: 04/10/2017] [Indexed: 11/26/2022] Open
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Abstract
Wounds are among the most common, painful, debilitating and costly conditions in older adults. Disruption of the angiotensin type 1 receptors (AT1R), has been associated with impaired wound healing, suggesting a critical role for AT1R in this repair process. Biological functions of angiotensin type 2 receptors (AT2R) are less studied. We investigated effects of genetically disrupting AT2R on rate and quality of wound healing. Our results suggest that AT2R effects on rate of wound closure depends on the phase of wound healing. We observed delayed healing during early phase of wound healing (inflammation). An accelerated healing rate was seen during later stages (proliferation and remodeling). By day 12, fifty percent of AT2R−/− mice had complete wound closure as compared to none in either C57/BL6 or AT1R−/− mice. There was a significant increase in AT1R, TGFβ1 and TGFβ2 expression during the proliferative and remodeling phases in AT2R−/− mice. Despite the accelerated closure rate, AT2R−/− mice had more fragile healed skin. Our results suggest that in the absence of AT2R, wound healing rate is accelerated, but yielded worse skin quality. Elucidating the contribution of both of the angiotensin receptors may help fine tune future intervention aimed at wound repair in older individuals.
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Wołkow PP, Bujak-Giżycka B, Jawień J, Olszanecki R, Madej J, Rutowski J, Korbut R. Exogenous Angiotensin I Metabolism in Aorta Isolated from Streptozotocin Treated Diabetic Rats. J Diabetes Res 2016; 2016:4846819. [PMID: 27803936 PMCID: PMC5075625 DOI: 10.1155/2016/4846819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 08/31/2016] [Indexed: 11/30/2022] Open
Abstract
Purpose. Products of angiotensin (ANG) I metabolism may predispose to vascular complications of diabetes mellitus. Methods. Diabetes was induced with streptozotocin (75 mg/kg i.p.). Rat aorta fragments, isolated 4 weeks later, were pretreated with perindoprilat (3 μM), thiorphan (3 μM), or vehicle and incubated for 15 minutes with ANG I (1 μM). Products of ANG I metabolism through classical (ANG II, ANG III, and ANG IV) and alternative (ANG (1-9), ANG (1-7), and ANG (1-5)) pathways were measured in the buffer, using liquid chromatography-mass spectrometry. Results. Incubation with ANG I resulted in higher concentration of ANG II (P = 0.02, vehicle pretreatment) and lower of ANG (1-9) (P = 0.048, perindoprilat pretreatment) in diabetes. Preference for the classical pathway is suggested by higher ANG III/ANG (1-7) ratios in vehicle (P = 0.03), perindoprilat (P = 0.02), and thiorphan pretreated (P = 0.02) diabetic rat. Within the classical pathway, ratios of ANG IV/ANG II (P = 0.01) and of ANG IV/ANG III (P = 0.049), but not of ANG III/ANG II are lower in diabetes. Conclusions. Diabetes in rats led to preference toward deleterious (ANG II, ANG III) over protective (ANG IV, ANG (1-9), and ANG (1-7)) ANG I metabolites.
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Affiliation(s)
- P. P. Wołkow
- Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, Krakow, Poland
- *P. P. Wołkow:
| | - B. Bujak-Giżycka
- Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, Krakow, Poland
| | - J. Jawień
- Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
| | - R. Olszanecki
- Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
| | - J. Madej
- Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
| | - J. Rutowski
- Department of Pharmacology, Medical Faculty, University of Rzeszów, Rzeszów, Poland
| | - R. Korbut
- Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
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Abstract
Hypertension is a major cardiovascular risk factor that affects between 10-40% of the general population in an age dependent manner. The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure, fluid volume, and the vascular response to injury and inflammation 1. Chronic RAAS activation in the presence of sufficient sodium consumption leads to persistent hypertension, setting off a cascade of inflammatory, thrombotic, and atherogenic effects eventually leading to end-organ damage 2 3. Accordingly, numerous studies have demonstrated that elevated renin and/or aldosterone levels are predictors of adverse outcome in hypertension 4, heart failure 5 6, myocardial infarction 7, and renal insufficiency 8 and influence insulin resistance 9. Primary aldosteronism (PA) is the most common secondary form of hypertension with an estimated prevalence between 4 and 12% of hypertensives 10 11 12 and 11-20% in patients that are resistant to combined antihypertensive medication 13 14. Given the severe cardiovascular adverse effects of aldosterone excess that are independent of high blood pressure levels 15 16 17 18 detection and treatment of PA has important impact on clinical outcome and survival.
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Affiliation(s)
- M Reincke
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - F Beuschlein
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
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Steely AM, Callas PW, Bertges DJ. Renin-angiotensin-aldosterone-system inhibition is safe in the preoperative period surrounding carotid endarterectomy. J Vasc Surg 2015; 63:715-21. [PMID: 26603543 DOI: 10.1016/j.jvs.2015.09.048] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 09/28/2015] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Discontinuation of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) medications before surgery has been suggested because of the potentially deleterious effects of hypotension. We investigated the effect of preoperative ACEI and/or ARB use on early outcomes after carotid endarterectomy (CEA). METHODS We examined 3752 consecutive CEA patients within the Vascular Study Group of New England from September 2012 to September 2014 and compared outcomes for patients treated (n = 1772) or not treated (n = 1980) with ACEI and/or ARB preoperatively. Outcomes included perioperative need for intravenous vasoactive medication (IVBPmed) for hypotension or hypertension (HTN), major adverse cardiac events (MACEs), and the combined outcome of stroke or death. Adjusted analysis was performed using multivariable logistic regression of the crude cohort and by constructing a propensity score matched cohort (n = 1441). RESULTS ACEI and/or ARB users were more likely to be male (64% vs 59%; P = .001), with a higher prevalence of diabetes (41% vs 28%; P < .0001), HTN (97% vs 82%; P < .0001), coronary artery disease (31% vs 25%; P = .0001), congestive heart failure (10% vs 8%; P = .02), and asymptomatic carotid disease (59% vs 54%; P = .004). Patients who received ACEI and/or ARB preoperatively were more likely to be treated with aspirin (92% vs 88%; P = .0002) and statins (89% vs 85%; P = .001) preoperatively. In the unadjusted analysis, no significant differences were identified in hypotension that required IVBPmed (12% vs 11%; odds ratio [OR], 1.1; 95% confidence interval [CI], 0.9-1.4; P = .22), MACE (3% vs 2%; OR, 1.3; 95% CI, 0.8-1.9; P = .32), or stroke or death (3% vs 3%; OR, 1.0; 95% CI, 0.7-1.6; P = .89) for preoperative ACEI and/or ARB treated and nontreated patients, respectively. Preoperative ACEI and/or ARB usage was, however, associated with HTN that required IVBPmed (13% vs 10%; OR, 1.3; 95% CI, 1.1-1.6; P = .01). Analysis of the propensity score matched cohort revealed no significant differences in hypotension that required IVBPmed (12% vs 12%; OR, 1.0; 95% CI, 0.8-1.3; P = .86), MACE (3% vs 2%; OR, 1.1; 95% CI, 0.7-1.8; P = .62; ), or stroke or death (3% vs 3%; OR, 1.0; 95% CI, 0.7-1.6; P = .91) for patients treated or not treated with preoperative ACEI and/or ARB, respectively. ACEI and/or ARB remained associated with HTN that required IVBPmed (13% vs 10%; OR, 1.3; 95% CI, 1.0-1.7; P = .02). Results were similar after adjustment using logistic regression. The incidence of hospital length of stay >1 day was similar between ACEI and/or ARB treated and not treated patients (29% vs 32%; OR, 0.9; 95% CI, 0.8-1.1; P = .21). CONCLUSIONS Preoperative ACEI and/or ARB use was associated with marginally increased use of IVBPmed for HTN but not for hypotension and was not associated with increased MACE, stroke, or death. On the basis of these metrics, the use of preoperative ACEI and/or ARB appears safe before CEA.
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Affiliation(s)
- Andrea M Steely
- Division of Vascular Surgery, The University of Vermont Medical Center, Burlington, Vt
| | - Peter W Callas
- Division of Vascular Surgery, The University of Vermont Medical Center, Burlington, Vt
| | - Daniel J Bertges
- Division of Vascular Surgery, The University of Vermont Medical Center, Burlington, Vt.
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Pedersen M, Karlsen MA, Ankjærgaard KL, Jensen LT. Primary hyperaldosteronism diagnosed with adrenal vein sampling. Characteristics and follow-up after adrenalectomy in a Danish study. Scandinavian Journal of Clinical and Laboratory Investigation 2015; 76:45-50. [DOI: 10.3109/00365513.2015.1092047] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Kamber M, Papalazarou V, Rouni G, Papageorgopoulou E, Papalois A, Kostourou V. Angiotensin II inhibitor facilitates epidermal wound regeneration in diabetic mice. Front Physiol 2015; 6:170. [PMID: 26106332 PMCID: PMC4460301 DOI: 10.3389/fphys.2015.00170] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 05/20/2015] [Indexed: 11/14/2022] Open
Abstract
Tissue regeneration and wound healing are severely impaired in diabetes and are associated with poor circulation and dysfunctional blood vessels. Angiotensin II inhibitors are anti-hypertensive drugs used in clinical practice to regulate blood pressure and could affect tissue remodeling. We hypothesize that blocking angiotensin II, using Losartan, could facilitate tissue regeneration in diabetic mice. To this end, we established an experimental model of wound healing in streptozotocin-induced diabetic mice. Our data demonstrated that Losartan accelerates wound repair and normalizes wound stromal responses, having a beneficial role in wounds of diabetic individuals. Our findings highlight a potential therapeutic use of Losartan in improving wound repair in diabetic conditions.
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Affiliation(s)
- Maria Kamber
- Biomedical Sciences Research Centre "Alexander Fleming," Athens, Greece
| | | | - Georgia Rouni
- Biomedical Sciences Research Centre "Alexander Fleming," Athens, Greece
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Witzel II, Jelinek HF, Khalaf K, Lee S, Khandoker AH, Alsafar H. Identifying Common Genetic Risk Factors of Diabetic Neuropathies. Front Endocrinol (Lausanne) 2015; 6:88. [PMID: 26074879 PMCID: PMC4447004 DOI: 10.3389/fendo.2015.00088] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 05/13/2015] [Indexed: 12/13/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a global public health problem of epidemic proportions, with 60-70% of affected individuals suffering from associated neurovascular complications that act on multiple organ systems. The most common and clinically significant neuropathies of T2DM include uremic neuropathy, peripheral neuropathy, and cardiac autonomic neuropathy. These conditions seriously impact an individual's quality of life and significantly increase the risk of morbidity and mortality. Although advances in gene sequencing technologies have identified several genetic variants that may regulate the development and progression of T2DM, little is known about whether or not the variants are involved in disease progression and how these genetic variants are associated with diabetic neuropathy specifically. Significant missing heritability data and complex disease etiologies remain to be explained. This article is the first to provide a review of the genetic risk variants implicated in the diabetic neuropathies and to highlight potential commonalities. We thereby aim to contribute to the creation of a genetic-metabolic model that will help to elucidate the cause of diabetic neuropathies, evaluate a patient's risk profile, and ultimately facilitate preventative and targeted treatment for the individual.
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Affiliation(s)
- Ini-Isabée Witzel
- Biomedical Engineering Department, Khalifa University of Science, Technology and Research, Abu Dhabi, United Arab Emirates
| | - Herbert F. Jelinek
- Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia
- Centre for Research in Complex Systems, School of Community Health, Charles Sturt University, Albury, NSW, Australia
| | - Kinda Khalaf
- Biomedical Engineering Department, Khalifa University of Science, Technology and Research, Abu Dhabi, United Arab Emirates
| | - Sungmun Lee
- Biomedical Engineering Department, Khalifa University of Science, Technology and Research, Abu Dhabi, United Arab Emirates
| | - Ahsan H. Khandoker
- Biomedical Engineering Department, Khalifa University of Science, Technology and Research, Abu Dhabi, United Arab Emirates
- Electrical and Electronic Engineering Department, The University of Melbourne, Parkville, VIC, Australia
| | - Habiba Alsafar
- Biomedical Engineering Department, Khalifa University of Science, Technology and Research, Abu Dhabi, United Arab Emirates
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Harmon L, Chilton RJ, Spellman C. Reducing Cardiovascular Events and End-Organ Damage in Patients with Hypertension: New Considerations. Postgrad Med 2015; 123:7-17. [DOI: 10.3810/pgm.2011.03.2258] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Estacio RO. Renin-Angiotensin-Aldosterone System Blockade in Diabetes: Role of Direct Renin Inhibitors. Postgrad Med 2015; 121:33-44. [DOI: 10.3810/pgm.2009.05.2000] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Wyczalkowska-Tomasik A, Bartlomiejczyk I, Wirkowska A, Koperski L, Gornicka B, Paczek L. The Blocking on the Cathepsin B and Fibronectin Accumulation in Kidney Glomeruli of Diabetic Rats. Int J Endocrinol 2015; 2015:812825. [PMID: 26089895 PMCID: PMC4452094 DOI: 10.1155/2015/812825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 11/19/2014] [Indexed: 11/25/2022] Open
Abstract
Hyperglycemia results in the activation of tissue angiotensin II. Angiotensin II stimulates the synthesis of ECM proteins and causes a decrease activity of proteolytic enzymes. The aim of this study was to assess the impact of multilevel blocking of the RAAS, cathepsin B activity, and fibronectin accumulation in the glomerular in the rats diabetes model. Sixty male Wistar rats were initially included. Diabetes was induced by intravenous administration of streptozotocin. The animals were randomized to six groups of ten rats in group. Rats in the four groups were treated with inhibitors of the RAAS: enalapril (EN), losartan (LOS), enalapril plus losartan (EN + LOS), and spironolactone (SPIR); another group received dihydralazine (DIH) and the diabetic rats (DM) did not receive any drug. After six weeks, we evaluated blood pressure, 24 h urine collection, and blood for biochemical parameters and kidneys. In this study, fluorometric, ELISA, and immunohistochemical methods were used. Administration of EN + LOS increased activity of cathepsin B in homogenates of glomeruli compared to DM. Losartan treatment resulted in reduction of the ratio kidney weight/body weight compared to untreated diabetic rats. SPIR resulted in the increase activity of cathepsin B in the homogenate of glomeruli. The values of cathepsin B in the plasma of rats in all studied groups were similar and showed no tendency.
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Affiliation(s)
- Aleksandra Wyczalkowska-Tomasik
- Department of Immunology, Transplant Medicine and Internal Diseases, The Medical University of Warsaw, 02-006 Warsaw, Poland
- *Aleksandra Wyczalkowska-Tomasik:
| | - Irena Bartlomiejczyk
- Department of Immunology, Transplant Medicine and Internal Diseases, The Medical University of Warsaw, 02-006 Warsaw, Poland
| | - Agnieszka Wirkowska
- Department of Immunology, Transplant Medicine and Internal Diseases, The Medical University of Warsaw, 02-006 Warsaw, Poland
| | - Lukasz Koperski
- Department of Pathology, The Medical University of Warsaw, 02-004 Warsaw, Poland
| | - Barbara Gornicka
- Department of Pathology, The Medical University of Warsaw, 02-004 Warsaw, Poland
| | - Leszek Paczek
- Department of Immunology, Transplant Medicine and Internal Diseases, The Medical University of Warsaw, 02-006 Warsaw, Poland
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Czikora I, Feher A, Lucas R, Fulton DJR, Bagi Z. Caveolin-1 prevents sustained angiotensin II-induced resistance artery constriction and obesity-induced high blood pressure. Am J Physiol Heart Circ Physiol 2014; 308:H376-85. [PMID: 25527780 DOI: 10.1152/ajpheart.00649.2014] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The type 1 angiotensin II (ANG II) receptor (AT1R) undergoes internalization following stimulation by ANG II. Internalization reduces cell surface AT1Rs, and it is required for AT1R resensitization. In this process AT1R may interact with caveolin-1 (Cav1), the main scaffolding protein of caveolae. We hypothesized that the interaction between Cav1 and AT1R delays AT1R resensitization and thereby prevents sustained ANG II-induced resistance artery (RA) constriction under normal conditions and in experimental obesity. In rat and mouse skeletal muscle RA (diameter: ∼90-120 μm) ANG II-induced constrictions were reduced upon repeated (30-min apart) administrations. Upon disruption of caveolae with methyl-β-cyclodextrin or in RA of Cav1 knockout mice, repeated ANG II applications resulted in essentially maintained constrictions. In vascular smooth muscle cells, AT1R interacted with Cav1, and the degree of cell surface interactions was reduced by long-term (15-min), but not short-term (2-min), exposure to ANG II. When Cav1 was silenced, the amount of membrane-associated AT1R was significantly reduced by a short-term ANG II exposure. Moreover, Cav1 knockout mice fed a high-fat diet exhibited augmented and sustained RA constriction to ANG II and had elevated systemic blood pressure, when compared with normal or high-fat fed wild-type mice. Thus, Cav1, through a direct interaction, delays internalization and subsequent resensitization of AT1R. We suggest that this mechanism prevents sustained ANG II-induced RA constriction and elevated systemic blood pressure in diet-induced obesity.
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Affiliation(s)
- Istvan Czikora
- Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia
| | - Attila Feher
- Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia
| | - Rudolf Lucas
- Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia
| | - David J R Fulton
- Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia
| | - Zsolt Bagi
- Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia
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Riccioni G. The role of direct renin inhibitors in the treatment of the hypertensive diabetic patient. Ther Adv Endocrinol Metab 2013; 4:139-45. [PMID: 24143271 PMCID: PMC3799297 DOI: 10.1177/2042018813490779] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Hypertensive patients with diabetes exhibit an increased risk for cardiovascular complications, such as acute coronary syndrome, stroke, heart failure and chronic kidney disease (CKD). These two chronic diseases are linked to a high rate of morbidity and mortality and for this reason it is important for the clinician to recognize the need for effective treatment of hypertension, which can require combination therapy to achieve blood pressure (BP) goals. Direct renin inhibitors (DRIs) may be useful in combination with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) as they provide a more complete blockade of the renin-angiotensin-aldosterone system (RAAS), effectively suppressing residual angiotensin II production and the counter-regulatory increase in plasma renin activity observed in patients receiving monotherapy with ACEIs or ARBs. Some questions regarding the action of aliskiren in cardiovascular and renal disorders are open. In particular, the combination therapy of aliskiren and a RAAS blocker in diabetic hypertensive patients with CKD is controversial. Several published studies demonstrated that aliskiren is suitable for once-daily administration and its antihypertensive effect is comparable or superior to that of other antihypertensive agents at recommended doses, with a good tolerability profile. At the moment the association with ACEIs and ARBs is not recommended in patients with type 2 diabetes mellitus (T2DM) and renal impairment even if a recent published open-label study of low-dose aliskiren (150 mg/daily) in association with ACEIs or ARBs has demonstrated a good tolerability profile without the adverse events found in other studies. This review provides a brief overview of RAAS blocking, in particular the rationale and clinical evidence supporting the use of the DRI aliskiren, in high-risk patients with T2DM.
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Affiliation(s)
- Graziano Riccioni
- Intensive Cardiology Care Unit, San Camillo de Lellis Hospital, Via G. De Rogatis, 12, 71016 San Severo (FG), Italy
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Ren M, Hao S, Yang C, Zhu P, Chen L, Lin D, Li N, Yan L. Angiotensin II regulates collagen metabolism through modulating tissue inhibitor of metalloproteinase-1 in diabetic skin tissues. Diab Vasc Dis Res 2013; 10:426-35. [PMID: 23796502 DOI: 10.1177/1479164113485461] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
We investigated the effect of angiotensin II (Ang II) on matrix metalloproteinase-1 (MMP-1)/tissue inhibitor of metalloproteinase-1 (TIMP-1) balance in regulating collagen metabolism of diabetic skin. Skin tissues from diabetic model were collected, and the primary cultured fibroblasts were treated with Ang II receptor inhibitors before Ang II treatment. The collagen type I (Coll I) and collagen type III (Coll III) were measured by histochemistry. The expressions of transforming growth factor-β (TGF-β), MMP-1, TIMP-1 and propeptides of types I and III procollagens in skin tissues and fibroblasts were quantified using polymerase chain reaction (PCR), Western blot or enzyme-linked immunosorbent assay (ELISA). Collagen dysfunction was documented by changed collagen I/III ratio in streptozotocin (STZ)-injected mice compared with controls. This was accompanied by increased expression of TGF-β, TIMP-1 and propeptides of types I and III procollagens in diabetic skin tissues. In primary cultured fibroblasts, Ang II prompted collagen synthesis accompanied by increases in the expressions of TGF-β, TIMP-1 and types I and III procollagens, and these increases were inhibited by losartan, an Ang II type 1 (AT1) receptor blocker, but not affected by PD123319, an Ang II type 2 (AT2) receptor antagonist. These findings present evidence that Ang-II-mediated changes in the productions of MMP-1 and TIMP-1 occur via AT1 receptors and a TGF-β-dependent mechanism.
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Affiliation(s)
- Meng Ren
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
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Abstract
Arterial hypertension is a major cardiovascular risk factor that affects between 10 and 40% of the population in industrialized countries. Primary aldosteronism (PA) is the most common form of secondary hypertension with an estimated prevalence of around 10% in referral centers and 4% in a primary care setting. Despite its high prevalence until recently, the underlying genetic and molecular basis of this common disease had remained largely obscure. Over the past decade, a number of insights have been achieved that have relied on in vitro cellular systems, wild-type and genetically modified in vivo models, as well as clinical studies in well-characterized patient populations. This progress has been made possible by a number of independent technical developments including that of specific hormone assays that allow measurement in small sample volumes as well as genetic techniques that enable high-throughput sequencing of a large number of samples. Furthermore, animal models have provided important insights into the physiology of aldosterone regulation that have served as a starting point for investigation of mechanisms involved in autonomous aldosterone secretion. Finally, national and international networks that have built up registries and biobanks have been instrumental in fostering translational research endeavors in PA. Therefore, it is to be expected that in the near future, further pathophysiological mechanisms that result in autonomous aldosterone secretion will be unraveled.
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Affiliation(s)
- Felix Beuschlein
- Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, Germany.
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Chodavarapu H, Grobe N, Somineni HK, Salem ESB, Madhu M, Elased KM. Rosiglitazone treatment of type 2 diabetic db/db mice attenuates urinary albumin and angiotensin converting enzyme 2 excretion. PLoS One 2013; 8:e62833. [PMID: 23646149 PMCID: PMC3639987 DOI: 10.1371/journal.pone.0062833] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Accepted: 03/26/2013] [Indexed: 02/07/2023] Open
Abstract
Alterations within the renal renin angiotensin system play a pivotal role in the development and progression of cardiovascular and renal disease. Angiotensin converting enzyme 2 (ACE2) is highly expressed in renal tubules and has been shown to be renoprotective in diabetes. The protease, a disintegrin and metalloprotease (ADAM) 17, is involved in the ectodomain shedding of several transmembrane proteins including ACE2. Renal ACE2 and ADAM17 were significantly increased in db/db mice compared to controls. We investigated the effect of the insulin sensitizer, rosiglitazone, on albuminuria, renal ADAM17 protein expression and ACE2 shedding in db/db diabetic mice. Rosiglitazone treatment of db/db mice normalized hyperglycemia, attenuated renal injury and decreased urinary ACE2 and renal ADAM17 protein expression. Urinary excreted ACE2 is enzymatically active. Western blot analysis of urinary ACE2 demonstrated two prominent immunoreactive bands at approximately 70 & 90 kDa. The predominant immunoreactive band is approximately 20 kDa shorter than the one demonstrated for kidney lysate, indicating possible ectodomain shedding of active renal ACE2 in the urine. Therefore, it is tempting to speculate that renoprotection of rosiglitazone could be partially mediated via downregulation of renal ADAM17 and ACE2 shedding. In addition, there was a positive correlation between blood glucose, urinary albumin, plasma glucagon, and triglyceride levels with urinary ACE2 excretion. In conclusion, urinary ACE2 could be used as a sensitive biomarker of diabetic nephropathy and for monitoring the effectiveness of renoprotective medication.
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Affiliation(s)
- Harshita Chodavarapu
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States of America
| | - Nadja Grobe
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States of America
| | - Hari K. Somineni
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States of America
| | - Esam S. B. Salem
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States of America
| | - Malav Madhu
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States of America
| | - Khalid M. Elased
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States of America
- * E-mail:
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Nakamura Y, Fujimoto T, Ogawa Y, Namiki H, Suzuki S, Asano M, Sugita C, Mochizuki A, Miyazaki S, Tamaki K, Nagai Y, Inoue SI, Nagayama T, Kato M, Chiba K, Takasuna K, Nishi T. Lead optimization of 5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxyhexanamides to reduce a cardiac safety issue: discovery of DS-8108b, an orally active renin inhibitor. Bioorg Med Chem 2013; 21:3175-96. [PMID: 23598247 DOI: 10.1016/j.bmc.2013.03.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Revised: 03/11/2013] [Accepted: 03/15/2013] [Indexed: 01/26/2023]
Abstract
With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure-activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h.
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Affiliation(s)
- Yuji Nakamura
- Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
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Tiyerili V, Becher UM, Aksoy A, Lütjohann D, Wassmann S, Nickenig G, Mueller CFH. AT1-receptor-deficiency induced atheroprotection in diabetic mice is partially mediated via PPARγ. Cardiovasc Diabetol 2013; 12:30. [PMID: 23374104 PMCID: PMC3667017 DOI: 10.1186/1475-2840-12-30] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2012] [Accepted: 01/28/2013] [Indexed: 11/24/2022] Open
Abstract
Objective Peroxisome-proliferator–activated-receptor-γ (PPARγ) acts as a transcriptional regulator of multiple genes involved in glucose and lipid metabolism. In vitro studies showed that activated PPARγ suppresses AT1R-gene expression and vice versa. However, it has not yet been determined in vivo, whether AT1R-PPARγ-interactions play a relevant role in the pathogenesis of diabetic complications and specifically in accelerated atherosclerosis. Methods and results ApoE−/− and ApoE−/−/AT1R−/−-mice were rendered diabetic by intraperitoneal injections of streptozotocin. Diabetic and non-diabetic ApoE−/−-mice were further randomized to receive the AT1R antagonist telmisartan, the selective PPARγ antagonist GW9662, telmisartan and GW9662 or vehicle for 18 weeks. Diabetic and non-diabetic ApoE−/−/AT1R−/−-mice were randomized to receive either GW9662 or vehicle. GW9662 treatment in diabetic ApoE−/− and diabetic ApoE−/−/AT1−/−-mice resulted in the highest elevation of fasting blood glucose levels, whereas telmisartan treatment and AT1 deficiency in ApoE−/−-mice showed the lowest fasting blood glucose levels. Diabetic ApoE−/−-mice displayed severe impairment of endothelial function, enhanced oxidative stress and increased atherosclerotic lesion formation. ApoE−/−/AT1R−/− and telmisartan-treated ApoE−/−-mice showed a significantly better endothelial function, decreased oxidative stress and reduced atherosclerotic lesion formation. Treatment of diabetic ApoE−/− and ApoE−/−/AT1R−/−-mice with the selective PPARγ antagonist GW9662 omitted the atheroprotective effects of AT1R deficiency or AT1 antagonism. Conclusion Genetic disruption or pharmacological inhibition of the AT1R attenuates atherosclerosis and improves endothelial function in diabetic ApoE−/−-mice via the PPARγ pathway.
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Affiliation(s)
- Vedat Tiyerili
- Medizinische Klinik und Poliklinik II, Innere Medizin, Universitätsklinikum Bonn, Sigmund Freud Str, 25, 53105, Bonn, Germany.
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Nakamura Y, Fujimoto T, Ogawa Y, Sugita C, Miyazaki S, Tamaki K, Takahashi M, Matsui Y, Nagayama T, Manabe K, Mizuno M, Masubuchi N, Chiba K, Nishi T. Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor. ACS Med Chem Lett 2012; 3:754-8. [PMID: 24900544 DOI: 10.1021/ml300168e] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Accepted: 08/18/2012] [Indexed: 11/28/2022] Open
Abstract
A novel orally bioavailable renin inhibitor, DS-8108b (5), showing potent renin inhibitory activity and excellent in vivo efficacy is described. We report herein the synthesis and pharmacological effects of 5 including renin inhibitory activity in vitro, suppressive effects of ex vivo plasma renin activity (PRA) in cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in an animal model. Compound 5 demonstrated inhibitory activities toward human renin (IC50 = 0.9 nM) and human and monkey PRA (IC50 = 1.9 and 6.3 nM, respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in cynomolgus monkey on pretreatment with furosemide led to dose-dependent significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h.
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Affiliation(s)
- Yuji Nakamura
- Lead Discovery & Optimization Research Laboratories I, ‡Lead Discovery & Optimization Research Laboratories II, §Cardiovascular-Metabolics Research Laboratories, ∥Biological Research Laboratories, ⊥Drug Metabolism & Pharmacokinetics Research Laboratories, and #Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Teppei Fujimoto
- Lead Discovery & Optimization Research Laboratories I, ‡Lead Discovery & Optimization Research Laboratories II, §Cardiovascular-Metabolics Research Laboratories, ∥Biological Research Laboratories, ⊥Drug Metabolism & Pharmacokinetics Research Laboratories, and #Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Yasuyuki Ogawa
- Lead Discovery & Optimization Research Laboratories I, ‡Lead Discovery & Optimization Research Laboratories II, §Cardiovascular-Metabolics Research Laboratories, ∥Biological Research Laboratories, ⊥Drug Metabolism & Pharmacokinetics Research Laboratories, and #Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Chie Sugita
- Lead Discovery & Optimization Research Laboratories I, ‡Lead Discovery & Optimization Research Laboratories II, §Cardiovascular-Metabolics Research Laboratories, ∥Biological Research Laboratories, ⊥Drug Metabolism & Pharmacokinetics Research Laboratories, and #Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Shojiro Miyazaki
- Lead Discovery & Optimization Research Laboratories I, ‡Lead Discovery & Optimization Research Laboratories II, §Cardiovascular-Metabolics Research Laboratories, ∥Biological Research Laboratories, ⊥Drug Metabolism & Pharmacokinetics Research Laboratories, and #Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Kazuhiko Tamaki
- Lead Discovery & Optimization Research Laboratories I, ‡Lead Discovery & Optimization Research Laboratories II, §Cardiovascular-Metabolics Research Laboratories, ∥Biological Research Laboratories, ⊥Drug Metabolism & Pharmacokinetics Research Laboratories, and #Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Mizuki Takahashi
- Lead Discovery & Optimization Research Laboratories I, ‡Lead Discovery & Optimization Research Laboratories II, §Cardiovascular-Metabolics Research Laboratories, ∥Biological Research Laboratories, ⊥Drug Metabolism & Pharmacokinetics Research Laboratories, and #Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Yumi Matsui
- Lead Discovery & Optimization Research Laboratories I, ‡Lead Discovery & Optimization Research Laboratories II, §Cardiovascular-Metabolics Research Laboratories, ∥Biological Research Laboratories, ⊥Drug Metabolism & Pharmacokinetics Research Laboratories, and #Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Takahiro Nagayama
- Lead Discovery & Optimization Research Laboratories I, ‡Lead Discovery & Optimization Research Laboratories II, §Cardiovascular-Metabolics Research Laboratories, ∥Biological Research Laboratories, ⊥Drug Metabolism & Pharmacokinetics Research Laboratories, and #Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Kenichi Manabe
- Lead Discovery & Optimization Research Laboratories I, ‡Lead Discovery & Optimization Research Laboratories II, §Cardiovascular-Metabolics Research Laboratories, ∥Biological Research Laboratories, ⊥Drug Metabolism & Pharmacokinetics Research Laboratories, and #Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Makoto Mizuno
- Lead Discovery & Optimization Research Laboratories I, ‡Lead Discovery & Optimization Research Laboratories II, §Cardiovascular-Metabolics Research Laboratories, ∥Biological Research Laboratories, ⊥Drug Metabolism & Pharmacokinetics Research Laboratories, and #Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Noriko Masubuchi
- Lead Discovery & Optimization Research Laboratories I, ‡Lead Discovery & Optimization Research Laboratories II, §Cardiovascular-Metabolics Research Laboratories, ∥Biological Research Laboratories, ⊥Drug Metabolism & Pharmacokinetics Research Laboratories, and #Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Katsuyoshi Chiba
- Lead Discovery & Optimization Research Laboratories I, ‡Lead Discovery & Optimization Research Laboratories II, §Cardiovascular-Metabolics Research Laboratories, ∥Biological Research Laboratories, ⊥Drug Metabolism & Pharmacokinetics Research Laboratories, and #Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Takahide Nishi
- Lead Discovery & Optimization Research Laboratories I, ‡Lead Discovery & Optimization Research Laboratories II, §Cardiovascular-Metabolics Research Laboratories, ∥Biological Research Laboratories, ⊥Drug Metabolism & Pharmacokinetics Research Laboratories, and #Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
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Nakamura Y, Sugita C, Meguro M, Miyazaki S, Tamaki K, Takahashi M, Nagai Y, Nagayama T, Kato M, Suemune H, Nishi T. Design and optimization of novel (2S,4S,5S)-5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxy-2-isopropylhexanamides as renin inhibitors. Bioorg Med Chem Lett 2012; 22:4561-6. [DOI: 10.1016/j.bmcl.2012.05.092] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Revised: 05/23/2012] [Accepted: 05/29/2012] [Indexed: 11/28/2022]
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Antioxidants in kidney diseases: the impact of bardoxolone methyl. Int J Nephrol 2012; 2012:321714. [PMID: 22701794 PMCID: PMC3373077 DOI: 10.1155/2012/321714] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Revised: 04/02/2012] [Accepted: 04/10/2012] [Indexed: 01/16/2023] Open
Abstract
Drugs targeting the renin-angiotensin-aldosterone system (RAAS) are the mainstay of therapy to retard the progression of proteinuric chronic kidney disease (CKD) such as diabetic nephropathy. However, diabetic nephropathy is still the first cause of end-stage renal disease. New drugs targeted to the pathogenesis and mechanisms of progression of these diseases beyond RAAS inhibition are needed. There is solid experimental evidence of a key role of oxidative stress and its interrelation with inflammation on renal damage. However, randomized and well-powered trials on these agents in CKD are scarce. We now review the biological bases of oxidative stress and its role in kidney diseases, with focus on diabetic nephropathy, as well as the role of the Keap1-Nrf2 pathway and recent clinical trials targeting this pathway with bardoxolone methyl.
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Fournier PA, Arbour M, Cauchon E, Chen A, Chefson A, Ducharme Y, Falgueyret JP, Gagné S, Grimm E, Han Y, Houle R, Lacombe P, Lévesque JF, MacDonald D, Mackay B, McKay D, Percival MD, Ramtohul Y, St-Jacques R, Toulmond S. Design and synthesis of potent, isoxazole-containing renin inhibitors. Bioorg Med Chem Lett 2012; 22:2670-4. [DOI: 10.1016/j.bmcl.2012.03.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Revised: 03/02/2012] [Accepted: 03/05/2012] [Indexed: 11/27/2022]
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3,4-Diarylpiperidines as potent renin inhibitors. Bioorg Med Chem Lett 2012; 22:1953-7. [DOI: 10.1016/j.bmcl.2012.01.044] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Revised: 01/12/2012] [Accepted: 01/13/2012] [Indexed: 01/21/2023]
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50
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