دورية أكاديمية
أعرض في EDS

miR-200a-3p-enriched MSC-derived extracellular vesicles reverse erectile function in diabetic rats by targeting Keap1.

التفاصيل البيبلوغرافية
العنوان: miR-200a-3p-enriched MSC-derived extracellular vesicles reverse erectile function in diabetic rats by targeting Keap1.
المؤلفون: Zhang J; Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China., Zhao D; College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250199, China., Zang Z; Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China., Ruan Z; Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan 250021, China; Department of Urology, Tai'an City Central Hospital, Tai'an 271099, China., Fu Q; Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China; College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250199, China; Key Laboratory of Urinary Diseases in Universities of Shandong, Shandong First Medical University, Jinan 250021, China. Electronic address: qiangfu68@126.com., Zhang K; Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China. Electronic address: 270638805@qq.com.
المصدر: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Aug; Vol. 177, pp. 116964. Date of Electronic Publication: 2024 Jul 02.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 8213295 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1950-6007 (Electronic) Linking ISSN: 07533322 NLM ISO Abbreviation: Biomed Pharmacother Subsets: MEDLINE
أسماء مطبوعة: Publication: Paris : Editions Scientifiques Elsevier
Original Publication: New York, N.Y. : Masson Pub. USA, Inc., c1982-
مواضيع طبية MeSH: Diabetes Mellitus, Experimental*/complications , Diabetes Mellitus, Experimental*/metabolism , Erectile Dysfunction*/therapy , Erectile Dysfunction*/etiology , Erectile Dysfunction*/metabolism , Kelch-Like ECH-Associated Protein 1*/metabolism , Kelch-Like ECH-Associated Protein 1*/genetics , MicroRNAs*/genetics , MicroRNAs*/metabolism , Extracellular Vesicles*/metabolism , Rats, Sprague-Dawley* , Mesenchymal Stem Cells*/metabolism, Animals ; Male ; Rats ; Oxidative Stress ; Penile Erection ; Mesenchymal Stem Cell Transplantation/methods
مستخلص: Background: The administration of mesenchymal stem cells (MSCs) through intracavernous injection is a potential therapeutic approach for managing diabetes mellitus-induced erectile dysfunction (DMED). However, pulmonary embolism and tumorigenicity are fatal adverse events that limit the clinical application of MSCs. In this study, we examined the therapeutic efficacy and potential mechanism of MSC-derived extracellular vesicles (MSC-EVs).
Methods: In this study, forty 8-week-old male SpragueDawley (SD) rats were utilised. In the control group, ten rats were administered an intraperitoneal injection of PBS. STZ (60 mg/kg) was intraperitoneally injected into the remaining rats to establish a diabetes mellitus (DM) model. Afterwards, the diabetic rats were divided into three groups at random: the DM group (intracavernosal injection of PBS), the EVs group (intracavernosal injection of MSC-EVs), and the EVs-200a group (intracavernosal injection of miR-200a-3p-enriched extracellular vesicles). Erectile function was determined by measuring intracavernous pressure in real time and utilising electrical stimulation of the cavernous nerves. The smooth muscle content was evaluated through the investigation of penile tissue using immunofluorescence staining, Masson's trichrome staining, and western blotting after euthanasia. Superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) levels in the corpus cavernosum were measured via ELISA. In vitro, hydrogen peroxide (H 2 O 2 ) was used to induce oxidative stress. The viability of corpus cavernosum smooth muscle cells (ccSMCs) incubated with or without H 2 O 2 was measured using a CCK8 assay. Flow cytometry was used to assess the levels of reactive oxygen species (ROS) and apoptosis in ccSMCs. Furthermore, a dual-luciferase reporter assay was performed to validate the relationship between miR-200a-3p and Keap1.
Results: Reversal of erectile function was observed in the EVs groups, especially in the EVs-200a group. DM increased the MDA level and decreased the SOD and GSH levels. In the DM group, the expression of alpha-smooth muscle actin (α-SMA) and smooth muscle 22 alpha (SM22α) was decreased, and the expression of osteopontin (OPN) was increased. Western blotting revealed decreased Nrf2, HO-1, and Bcl2 expression and increased Keap1, Bax and cleaved caspase3 expression in the cavernous tissue. miR-200a-3p-enriched extracellular vesicles (EVs-200a) reversed these changes and inhibited the loss of smooth muscle content and cavernous fibrosis. In vitro, H 2 O 2 induced high ROS levels in ccSMCs and increased apoptosis, and these effects reversed by EVs-200a. H 2 O 2 reduced Nrf2, HO-1, and Bcl2 expression and increased Keap1, Bax and cleaved caspase-3 expression, and these effects were reversed by MSC-EVs, especially EVs-200a. The of dual-luciferase reporter assay results indicated that miR-200a-3p directly targeted Keap1 in a negative manner.
Conclusion: MSC-EVs, especially EVs-200a, alleviated erectile dysfunction in diabetic rats through the regulation of phenotypic switching, apoptosis and fibrosis. Mechanistically, miR-200a-3p targeted the Keap1/Nrf2 pathway to attenuate oxidative stress in diabetic rats.
Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest related to this research. There are no financial or personal relationships with other people or organizations that could have influenced the work presented in this manuscript. This includes employment, consultancies, honoraria, stock ownership, equity interests, patent-licensing arrangements, or any other potential conflicts of interest. All authors have approved the final manuscript and agree with its submission to Biomedicine & Pharmacotherapy
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
فهرسة مساهمة: Keywords: Diabetes mellitus; Erectile dysfunction; Extracellular vesicles; Stem cells
المشرفين على المادة: 0 (Kelch-Like ECH-Associated Protein 1)
0 (MicroRNAs)
0 (MIRN200 microRNA, rat)
0 (KEAP1 protein, rat)
تواريخ الأحداث: Date Created: 20240703 Date Completed: 20240727 Latest Revision: 20240727
رمز التحديث: 20240729
DOI: 10.1016/j.biopha.2024.116964
PMID: 38959607
قاعدة البيانات: MEDLINE
الوصف
تدمد:1950-6007
DOI:10.1016/j.biopha.2024.116964