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Sacubitril/valsartan promotes white adipose tissue browning in rats with metabolic syndrome through activation of mTORC1.

التفاصيل البيبلوغرافية
العنوان: Sacubitril/valsartan promotes white adipose tissue browning in rats with metabolic syndrome through activation of mTORC1.
المؤلفون: Nikolic M; Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.; Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, Kragujevac, Serbia., Jeremic N; Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, Kragujevac, Serbia.; Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.; Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia., Lazarevic N; Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, Kragujevac, Serbia.; Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.; Department of Human Pathology, 1st Moscow State Medical, University IM Sechenov, Moscow, Russia., Stojanovic A; Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, Kragujevac, Serbia.; Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia., Milojevic Samanovic A; Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, Kragujevac, Serbia.; Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia., Novakovic J; Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, Kragujevac, Serbia.; Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia., Zivkovic V; Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.; Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, Kragujevac, Serbia.; Department of Pharmacology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia., Nikolic M; Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia., Nedeljkovic N; Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia., Mitrovic S; Department of Pathology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia., Jakovljevic V; Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.; Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, Kragujevac, Serbia.; Department of Human Pathology, 1st Moscow State Medical, University IM Sechenov, Moscow, Russia.
المصدر: BioFactors (Oxford, England) [Biofactors] 2024 Jul-Aug; Vol. 50 (4), pp. 772-793. Date of Electronic Publication: 2024 Jan 29.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Ios Press Country of Publication: Netherlands NLM ID: 8807441 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-8081 (Electronic) Linking ISSN: 09516433 NLM ISO Abbreviation: Biofactors Subsets: MEDLINE
أسماء مطبوعة: Publication: Amsterdam : Ios Press
Original Publication: Oxford ; Washington, DC : Published for the International Union of Biochemistry by IRL Press, [c1988-
مواضيع طبية MeSH: Valsartan*/pharmacology , Biphenyl Compounds*/pharmacology , Adipose Tissue, White*/drug effects , Adipose Tissue, White*/metabolism , Metabolic Syndrome*/drug therapy , Metabolic Syndrome*/metabolism , Metabolic Syndrome*/pathology , Drug Combinations* , Aminobutyrates*/pharmacology , Rats, Wistar* , Mechanistic Target of Rapamycin Complex 1*/metabolism , Mechanistic Target of Rapamycin Complex 1*/antagonists & inhibitors , Mechanistic Target of Rapamycin Complex 1*/genetics , Tetrazoles*/pharmacology , Molecular Docking Simulation*, Animals ; Male ; Rats ; Adipose Tissue, Brown/drug effects ; Adipose Tissue, Brown/metabolism ; Uncoupling Protein 1/metabolism ; Uncoupling Protein 1/genetics ; Molecular Dynamics Simulation ; Neprilysin/metabolism ; Neprilysin/genetics ; Neprilysin/antagonists & inhibitors
مستخلص: In addition to their usual use in the treatment of cardiovascular disease, weak evidence is available for the potential of combined use of neprilysin inhibitor (sacubitril) and AT1 receptor antagonist (valsartan) to promote browning of white adipose tissue (WAT) in rats with metabolic syndrome (MetS). This study involved 32 male Wistar albino rats divided into four groups: CTRL-healthy control rats; ENT-healthy rats treated with sacubitril/valsartan; MS-rats with MetS; MS + ENT-rats with MetS treated with sacubitril/valsartan. After finishing the experimental protocol, different WAT depots were isolated for further analysis of molecular pathways. Molecular docking and molecular dynamics studies were used for in silico assessment of the binding affinity of sacubitril and valsartan towards subunits of mechanistic target of rapamycin complex 1 (mTORC1). Sacubitril/valsartan treatment markedly diminished morphological changes in adipose tissue, resulting in smaller lipid size and multilocular lipid droplet structure in WAT. We showed significantly higher protein expression of uncoupling protein-1 (UCP-1) and mTORC1 in WAT of MS + ENT rats, correlating with increased relative gene expression of browning-related markers in tissue of rats treated with sacubitril/valsartan compared with MS group of rats. In silico analysis showed that sacubitrilat and valsartan exhibited the highest binding affinity against mTOR and mLST8, forming stable complexes with these mTORC1 subunits. The observed results confirmed strong potential of combined sacubitril/valsartan treatment to increase browning markers expression in different WAT depots in MetS condition and to form permanent complexes with mTOR and mLST8 subunits over the time.
(© 2024 International Union of Biochemistry and Molecular Biology.)
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معلومات مُعتمدة: 04/22 Faculty of Medical Science, University of Kragujevac; 451-03-47/2023-01/200111 Ministry of Science, Technological Development and Innovation, Republic of Serbia
فهرسة مساهمة: Keywords: adipose tissue; browning; molecular docking; sacubitril; valsartan
المشرفين على المادة: 80M03YXJ7I (Valsartan)
0 (Biphenyl Compounds)
0 (Drug Combinations)
0 (Aminobutyrates)
WB8FT61183 (sacubitril and valsartan sodium hydrate drug combination)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
0 (Tetrazoles)
0 (Uncoupling Protein 1)
EC 3.4.24.11 (Neprilysin)
تواريخ الأحداث: Date Created: 20240129 Date Completed: 20240808 Latest Revision: 20240808
رمز التحديث: 20240808
DOI: 10.1002/biof.2040
PMID: 38284316
قاعدة البيانات: MEDLINE
الوصف
تدمد:1872-8081
DOI:10.1002/biof.2040