Hernandezine, a natural herbal alkaloid, ameliorates type 2 diabetes by activating AMPK in two mouse models,Phytomedicine

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Hernandezine, a natural herbal alkaloid, ameliorates type 2 diabetes by activating AMPK in two mouse models
Phytomedicine ( IF 6.7 ) Pub Date : 2022-07-28 , DOI: 10.1016/j.phymed.2022.154366
Jing Bai ₁ , Shuai Zhang ₂ , Jinjing Cao ₂ , Hongbin Sun ₃ , Zhiguo Mang ₂ , Wei L Shen ₃ , Hao Li ₂

Affiliation

Background

AMP-activated protein kinase (AMPK) is an effective target for treating diabetes. However, successful drug development is delayed due to issues including toxicity. Plant-derived natural product AMPK activators have emerged as a new way to treat diabetes due to its potential low safety risks. Here, we studied the effect of hernandezine (HER), a natural product derived from Thalictrum, in activating AMPK and treating T2D in mouse models.

Method

We tested HER in various cells and tissues, including primary hepatocytes, skeletal myotubes cell lines, as well as major metabolic tissues from diabetic (db/db) and diet-induced obesity (DIO) model mice. The effect of HER on glucose uptake via AMPK in vitro and in vivo was confirmed utilizing cell transfection and adenovirus interference analysis. Tissue staining assessed the effect of HER on adipogenesis. Real-time quantitative polymerase chain reaction (real-time PCR) was applied to verify the effect of HER on transcription factors. Western blot analysis was used to determine the activation of phosphorylated AMPK and ACC pathways.

Results

Biochemically, we found that HER prevented pAMPK from dephosphorylation to prolong its activity, disproving previous direct activation model and providing a new model to explain HER-mediated AMPK activation. HER could be orally delivered to animals and has a 3-fold long half-life in vivo as compared to metformin. Importantly, long-term oral HER treatment potently reduced body weight and blood glucose in both type 2 diabetes mullitus (T2DM) mouse models by increasing glucose disposal and reducing lipogenesis, and appeared not to induce cardiac hypertrophy.

Conclusion

Natural product HER indirectly activates AMPK by suppressing its dephosphorylation. Oral HER effectively alleviated hyperglycemia and reduced body weight in T2D mouse models, appeared to have a low risk of causing cardiac hypertrophy, and might be a potential therapeutic option for T2DM.

中文翻译：

Hernandezine 是一种天然草本生物碱，通过在两种小鼠模型中激活 AMPK 来改善 2 型糖尿病

背景

AMP活化蛋白激酶（AMPK）是治疗糖尿病的有效靶点。然而，由于包括毒性在内的问题，成功的药物开发被推迟了。植物源性天然产物 AMPK 激活剂因其潜在的低安全风险而成为治疗糖尿病的新方法。在这里，我们研究了从Thalictrum中提取的天然产物 Hernandezine (HER)在小鼠模型中激活 AMPK 和治疗 T2D 的作用。

方法

我们在各种细胞和组织中测试了 HER，包括原代肝细胞、骨骼肌管细胞系，以及来自糖尿病 (db/db) 和饮食诱导的肥胖 (DIO) 模型小鼠的主要代谢组织。利用细胞转染和腺病毒干扰分析证实了 HER在体外和体内通过 AMPK 对葡萄糖摄取的影响。组织染色评估了 HER 对脂肪生成的影响。应用实时定量聚合酶链反应（real-time PCR）验证HER对转录因子的影响。Western印迹分析用于确定磷酸化AMPK和ACC途径的激活。

结果

在生化方面，我们发现 HER 阻止 pAMPK 去磷酸化以延长其活性，驳斥了以前的直接激活模型，并提供了解释 HER 介导的 AMPK 激活的新模型。与二甲双胍相比，HER 可口服递送至动物体内，其体内半衰期长 3 倍。重要的是，长期口服 HER 治疗通过增加葡萄糖处理和减少脂肪生成，有效降低了两种 2 型糖尿病 (T2DM) 小鼠模型的体重和血糖，并且似乎不会诱导心脏肥大。