Abstract：
The effective treatment of diabetes with comorbid depression is a big challenge so far. Honokiol, a bioactive compound from the dietary supplement Magnolia officinalis extract, possesses multiple health benefits. The present study aims to propose a network pharmacology-based method to elucidate potential targets of honokiol in treating diabetes with comorbid depression and related mechanisms. The antidepressant-like efficacy of honokiol was evaluated in high-fat diet (HFD) induced diabetic mice using animal behavior testing, immuno-staining and western blotting assay. Through network pharmacology analysis, retinoid X receptor alpha (RXRα) and vitamin D receptor (VDR) were identified as potential targets related to diabetes and depression. The stable binding conformation between honokiol and RXR/VDR was determined by molecular docking simulation. Moreover, hononkiol effectively alleviated depression-like behaviors in HFD diabetic mice, presented anti-diabetic and anti-neuroinflammatory functions, and protected the hippocampal neuroplasticity. Importantly, honokiol could activate RXR/VDR heterodimer in vivo. The beneficial effects of honokiol on HFD mice were significantly suppressed by UVI3003 (a RXR antagonist), while enhanced by calcitriol (a VDR agonist). Additionally, the disruption of autophagy in the hippocampus of HFD mice was ameliorated by honokiol, which was attenuated by UVI3003 but strengthened by calcitriol. Taken together, the data provide new evidence that honokiol exerts the antidepressant-like effect in HFD diabetic mice via activating RXR/VDR heterodimer to restore the balance of autophagy. Our findings indicate that the RXR/VDR-mediated signaling might be a potential target for treating diabetes with comorbid depression.
摘要：
到目前为止，有效治疗糖尿病合并抑郁症是一个巨大的挑战。和厚朴酚,一种来自膳食补充剂厚朴提取物的生物活性化合物，具有多种健康益处。本研究旨在提出一种基于网络药理学的方法，以阐明和厚朴酚治疗糖尿病合并抑郁症的潜在靶点及其相关机制。使用动物行为测试在高脂饮食（HFD）诱导的糖尿病小鼠中评估和厚朴酚的抗抑郁药样功效，免疫染色和蛋白质印迹测定。通过网络药理学分析,类视黄醇X受体α（RXRα）和维生素D受体（VDR）被确定为与糖尿病和抑郁症相关的潜在靶标。通过分子对接模拟确定和厚朴酚与RXR/VDR之间的稳定结合构象。此外，hononkiol有效缓解HFD糖尿病小鼠的抑郁样行为，呈现抗糖尿病和抗神经炎症功能，保护海马神经可塑性.重要的是,和厚朴酚可以在体内激活RXR/VDR异二聚体。和厚朴酚对HFD小鼠的有益作用被UVI3003（RXR拮抗剂）显著抑制，同时通过骨化三醇（VDR激动剂）增强。此外,和厚朴酚改善了HFD小鼠海马中自噬的破坏，UVI3003减弱，但骨化三醇增强。一起来看,这些数据提供了新的证据,证明和厚朴酚通过激活RXR/VDR异源二聚体恢复自噬平衡,在HFD糖尿病小鼠中发挥抗抑郁样作用.我们的发现表明，RXR/VDR介导的信号传导可能是治疗糖尿病合并抑郁症的潜在靶标。
