Ligandrol Ameliorates High-Fat Diet- and Streptozotocin-Induced Type 2 Diabetes Mellitus and Prevents Pancreatic Islets Degeneration.

IF 1.6 4区 医学 Q4 BIOCHEMICAL RESEARCH METHODS
Assay and drug development technologies Pub Date : 2024-11-01 Epub Date: 2024-11-06 DOI:10.1089/adt.2024.029
Deepa Sugumar, Ritaban Ghosh, Emdormi Rymbai, Jaikanth Chandrasekaran, Praveen Thaggikuppe Krishnamurthy, Ranjith S P, Shreya Sahu, Divakar Selvaraj
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引用次数: 0

Abstract

Androgen therapy has been shown to alleviate type 2 diabetes mellitus (T2DM) but is also associated with severe side effects such as prostate cancer. The present study aims to identify the best hit selective androgen receptor (AR) modulator by in silico studies and then investigates its antidiabetic effects in high-fat diet- and streptozotocin (STZ)-induced T2DM male rat model. Molecular docking and molecular dynamics (MD) studies were carried out using Maestro 13.1 and Desmond (2023-2024). Cytotoxicity and insulin secretion were measured in MIN6 cell lines. T2DM was induced using high-fat diet (HFD) for 4 weeks, followed by single STZ (40 mg/kg, intraperitoneally). OneTouch Ultra glucometer was used to measure fasting blood glucose. Gene expression was determined using reverse transcription polymerase chain reaction. Histopathology was carried out using hematoxylin and eosin stain. Through molecular docking, we identify ligandrol as a potential hit. Ligandrol showed a good binding affinity (-10.74 kcal/mol). MD showed that ligandrol is stable during the 100 ns simulation. Ligandrol increases insulin secretion in a dose-dependent manner in vitro in 2 h. Ligandrol (0.3 and 1 mg/kg, orally) significantly decreased the body weight and fasting blood glucose levels compared with the HFD and STZ group. Gene expression showed that ligandrol significantly increased the AR-targeted gene, neurogenic differentiation 1, compared with the HFD and STZ group. Histopathological staining studies showed that ligandrol prevents pancreatic islet degeneration compared with the HFD and STZ group. Our findings suggest that ligandrol's protective effect on pancreatic islets leading to its antidiabetic effect occurs through the activation of AR.

利甘定能改善高脂饮食和链脲佐菌素诱发的 2 型糖尿病并防止胰岛退化
雄激素疗法已被证明可以缓解 2 型糖尿病(T2DM),但也与前列腺癌等严重副作用相关。本研究旨在通过硅学研究确定最佳的选择性雄激素受体(AR)调节剂,然后研究其在高脂饮食和链脲佐菌素(STZ)诱导的 T2DM 雄性大鼠模型中的抗糖尿病作用。使用 Maestro 13.1 和 Desmond (2023-2024) 进行了分子对接和分子动力学(MD)研究。在 MIN6 细胞系中测量了细胞毒性和胰岛素分泌。使用高脂饮食(HFD)诱导 T2DM 4 周,然后腹腔注射单次 STZ(40 毫克/千克)。使用OneTouch Ultra血糖仪测量空腹血糖。使用反转录聚合酶链反应测定基因表达。组织病理学采用苏木精和伊红染色法。通过分子对接,我们确定配糖体为潜在的靶点。Ligandrol 显示出良好的结合亲和力(-10.74 kcal/mol)。MD 显示,配糖体在 100 ns 模拟期间是稳定的。与 HFD 和 STZ 组相比,Ligandrol(0.3 和 1 mg/kg,口服)能显著降低体重和空腹血糖水平。基因表达显示,与高纤维食物组和 STZ 组相比,利甘醇能显著增加 AR 靶向基因神经源性分化 1。组织病理学染色研究表明,与高脂饮食组和 STZ 组相比,利甘醇可防止胰岛变性。我们的研究结果表明,利甘醇对胰岛的保护作用是通过激活 AR 来实现的,从而产生抗糖尿病作用。
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来源期刊
Assay and drug development technologies
Assay and drug development technologies 医学-生化研究方法
CiteScore
3.60
自引率
0.00%
发文量
33
审稿时长
>12 weeks
期刊介绍: ASSAY and Drug Development Technologies provides access to novel techniques and robust tools that enable critical advances in early-stage screening. This research published in the Journal leads to important therapeutics and platforms for drug discovery and development. This reputable peer-reviewed journal features original papers application-oriented technology reviews, topical issues on novel and burgeoning areas of research, and reports in methodology and technology application. ASSAY and Drug Development Technologies coverage includes: -Assay design, target development, and high-throughput technologies- Hit to Lead optimization and medicinal chemistry through preclinical candidate selection- Lab automation, sample management, bioinformatics, data mining, virtual screening, and data analysis- Approaches to assays configured for gene families, inherited, and infectious diseases- Assays and strategies for adapting model organisms to drug discovery- The use of stem cells as models of disease- Translation of phenotypic outputs to target identification- Exploration and mechanistic studies of the technical basis for assay and screening artifacts
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