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.

01 Oct 2019·The Journal of Steroid Biochemistry and Molecular BiologyQ2 · BIOLOGY

Retinoid X receptor-mediated neuroprotection via CYP19 upregulation and subsequent increases in estradiol synthesis

Q2 · BIOLOGY

Article

Author: Hikaru Sakurai ; Christoph F.A. Vogel ; Mayumi Tsuji ; Takeshi Yamazaki ; Yasuhiro Ishihara ; Ami Oguro

Increasing evidence has shown that one of the major neurosteroids, estradiol, has potent neuroprotective actions. We have reported that estradiol synthesis was enhanced when retinoic acid was added into rat hippocampal slice culture. In this study, we investigated the effects of a potent retinoid X receptor (RXR) agonist, bexarotene, on estrogen synthesis and neuroprotective action in hippocampal slices. Treatment with bexarotene increased estradiol levels as well as estrogen-synthesizing enzymes and CYP19 expression in hippocampal slice cultures. Bexarotene significantly suppressed neuronal cell death induced by oxygen-glucose deprivation (OGD)/reoxygenation. RXR agonists other than bexarotene, such as CD3254, also suppressed neuronal cell death accompanied by OGD/reoxygenation. The RXR antagonists HX531 and UVI3003 and the CYP19 inhibitor letrozole abolished the neuroprotection elicited by bexarotene, indicating that estradiol produced by RXR stimulation protects neurons from ischemic insult. The human brain-specific CYP19 promoter had 6 RXR half sites, and 2 of 6 half sites were responsible for CYP19 expression induced by bexarotene. Bexarotene increased the expression of catalase and glutathione peroxidase 1 and inhibited lipid peroxidation elicited by OGD/reoxygenation, suggesting that the antioxidative property of estrogen contributes to RXR-mediated neuroprotection. Bexarotene also suppressed neuronal injury induced by lipopolysaccharide in the hippocampal slices. Taken together, RXR stimulation can protect neurons via enhanced synthesis of estradiol with antioxidative mechanisms. The RXR-estrogen axis might be a novel mechanism-based strategy to prevent or ameliorate ischemic and/or inflammatory neuronal disorders.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Discovery	CN	Chengdu University of Traditional Chinese Medicine	01 Jun 2024

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