Sahu Neha, Singh Nitesh, Arya Kamal Ram, Reddy Sabbu Sathish, Rai Amit Kumar, Shukla Vijaya, Pandey Jyotsana, Narender Tadigoppula, Tamrakar Akhilesh Kumar, Kumar Brijesh, Rajak Bikash Kumar, Malik Sumira, Rustagi Sarvesh
Department of Botany, University of Lucknow, Lucknow, India.
Botany Division, CSIR-Central Drug Research Institute, Lucknow, India.
Front Pharmacol. 2023 Mar 27;14:1073327. doi: 10.3389/fphar.2023.1073327. eCollection 2023.
Diabetes mellitus (DM) is a metabolic disorder that results in glucose accumulation in the blood, accompanied by the production of advanced glycation end products (AGEs) through glycation of cellular proteins. These AGEs interfere with insulin signaling and prevent GLUT4 membrane translocation, thereby promoting the accumulation of more glucose in the blood and causing post-diabetic complications. In this study, we examine the anti-diabetic potential of (Wall.) Drude, a well-known ethnomedicinal plant of the Indian Himalayas. Considering its various medicinal properties, we analyzed its ethanolic extract and various solvent fractions for antiglycation activity and antidiabetic potential, i.e., stimulation of GLUT4 translocation. The results showed that the extract and fractions exhibited increased antiglycation activity and an increased level of GLUT4 translocation. Analysis of a further 12 bioactive compounds of ethanolic extract, identified through LC-ESI-QTOF-MS/MS, revealed the presence of three new compounds: leucothol B, rhodoterpenoids A, and leucothol A. Moreover, we performed molecular docking of identified compounds against key proteins of diabetes mellitus: the sirtuin family of NAD (+)-dependent protein deacetylases 6 (SIRT6), aldose reductase (AR), and tyrosine kinase (TK). The results showed that flavonoid luteolin showed the best binding affinity ((-12.3 kcal/mol), followed by eriodictyol, astilbin, and syringaresinol. An ADMET study showed that luteolin, eriodictyol, astilbin, and syringaresinol may be promising drug candidates belonging to the flavonoid class of compounds, with no harmful effects and complying with all the drug-likeness guidelines. Furthermore, molecular dynamics (MD) simulations on a 50 ns timescale revealed that AR protein was most stable with luteolin throughout the simulation period. Therefore, this study reveals for the first time that plays an important role in insulin homeostasis, as shown in and studies.
糖尿病（DM）是一种代谢紊乱疾病，会导致血液中葡萄糖积累，并通过细胞蛋白糖基化产生晚期糖基化终产物（AGEs）。这些AGEs会干扰胰岛素信号传导，阻止葡萄糖转运蛋白4（GLUT4）向细胞膜转位，从而促使更多葡萄糖在血液中积累，引发糖尿病并发症。在本研究中，我们检测了印度喜马拉雅地区一种著名的民族药用植物——（Wall.）Drude的抗糖尿病潜力。鉴于其多种药用特性，我们分析了其乙醇提取物和不同溶剂萃取物的抗糖基化活性及抗糖尿病潜力，即对GLUT4转位的刺激作用。结果表明，提取物和萃取物的抗糖基化活性增强，GLUT4转位水平提高。通过液相色谱 - 电喷雾 - 四极杆飞行时间串联质谱（LC - ESI - QTOF - MS/MS）鉴定出乙醇提取物中的另外12种生物活性化合物，发现了三种新化合物：白千层醇B、红景天萜类化合物A和白千层醇A。此外，我们对鉴定出的化合物与糖尿病关键蛋白进行了分子对接：烟酰胺腺嘌呤二核苷酸（NAD(+)）依赖性蛋白脱乙酰酶6（SIRT6）的沉默调节蛋白家族、醛糖还原酶（AR）和酪氨酸激酶（TK）。结果表明，黄酮类化合物木犀草素表现出最佳结合亲和力（-12.3千卡/摩尔），其次是圣草酚、落新妇苷和紫丁香树脂醇。一项药物代谢及毒性预测（ADMET）研究表明，木犀草素、圣草酚、落新妇苷和紫丁香树脂醇可能是有前景的黄酮类化合物候选药物，无有害影响且符合所有类药指南。此外，在50纳秒时间尺度上进行的分子动力学（MD）模拟显示，在整个模拟期间，AR蛋白与木犀草素结合时最稳定。因此，本研究首次揭示，如在[具体研究1]和[具体研究2]中所示，[植物名称]在胰岛素稳态中起重要作用。
