Dongli Li1, Chuipu Cai2, Yanfang Liao3, Qihui Wu3, Hanzhong Ke4, Pengfei Guo3, Qi Wang3, Banghan Ding5, Jiansong Fang6, Shuhuan Fang7. 1. Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510404, China. 2. Division of Data Intelligence, Department of Computer Science, Key Laboratory of Intelligent Manufacturing Technology of Ministry of Education, Shantou University, Shantou, China. 3. Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. 4. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, United States. 5. The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510404, China. 6. Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. Electronic address: fangjs@gzucm.edu.cn. 7. Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, 94305, United States. Electronic address: fangshuhuan@gzucm.edu.cn.
Abstract
BACKGROUND: Medicarpin is a natural pterocarpan-type phytoalexin widely distributed in many traditional Chinese medicines, such as Astragali Radix. A previous study showed that Astragali Radix demonstrated promising protective effects in neurons. However, there is no reported study on the neuroprotective function and the underlying mechanism of Medicarpin. PURPOSE: This study aimed to demonstrate the neuroprotective effect of Medicarpin on Alzheimer's disease (AD) and explore the therapeutic mechanisms. METHOD: First, we carried out animal behavioral tests and biochemical analysis to assess the anti-AD potential of Medicarpin for ameliorating spatial learning and memory and modulating cholinergic metabolism in scopolamine-induced amnesic mice. Subsequently, network proximity prediction was used to measure the network distance between the Medicarpin target network and AD-related endophenotype module. We identified Medicarpin-regulated AD pathological processes and highlighted the key disease targets via network analysis. Finally, experimental approaches including Nissl staining and Western blotting were conducted to validate our network-based findings. RESULT: In this study, we first observed that Medicarpin can ameliorate cognitive and memory dysfunction and significantly modulate cholinergic metabolism in scopolamine-induced amnesic mice. We then proposed an endophenotype network-based framework to comprehensively explore the AD therapeutic mechanisms of Medicarpin by integrating 25 AD-related endophenotype modules, gold-standard AD seed genes, an experimentally validated drug-target network of Medicarpin, and a global human protein-protein interactome. In silico prediction revealed that the effect of Medicarpin is highly relevant to neuronal apoptosis and synaptic plasticity, which was validated by experimental assays. Network analysis and Western blotting further identified two key targets, GSK-3β and MAPK14 (p38), in the AD-related protein regulatory network, which play key roles in the regulation of neuronal apoptosis and synaptic plasticity by Medicarpin. CONCLUSIONS: This study presented a powerful endophenotype network-based strategy to explore the mechanisms of action (MOAs) of new AD therapeutics, and first identified Medicarpin as a potential anti-AD candidate by targeting multiple pathways.
BACKGROUND:Medicarpin is a natural pterocarpan-type phytoalexin widely distributed in many traditional Chinese medicines, such as Astragali Radix. A previous study showed that Astragali Radix demonstrated promising protective effects in neurons. However, there is no reported study on the neuroprotective function and the underlying mechanism of Medicarpin. PURPOSE: This study aimed to demonstrate the neuroprotective effect of Medicarpin on Alzheimer's disease (AD) and explore the therapeutic mechanisms. METHOD: First, we carried out animal behavioral tests and biochemical analysis to assess the anti-AD potential of Medicarpin for ameliorating spatial learning and memory and modulating cholinergic metabolism in scopolamine-induced amnesicmice. Subsequently, network proximity prediction was used to measure the network distance between the Medicarpin target network and AD-related endophenotype module. We identified Medicarpin-regulated AD pathological processes and highlighted the key disease targets via network analysis. Finally, experimental approaches including Nissl staining and Western blotting were conducted to validate our network-based findings. RESULT: In this study, we first observed that Medicarpin can ameliorate cognitive and memory dysfunction and significantly modulate cholinergic metabolism in scopolamine-induced amnesicmice. We then proposed an endophenotype network-based framework to comprehensively explore the AD therapeutic mechanisms of Medicarpin by integrating 25 AD-related endophenotype modules, gold-standard AD seed genes, an experimentally validated drug-target network of Medicarpin, and a global human protein-protein interactome. In silico prediction revealed that the effect of Medicarpin is highly relevant to neuronal apoptosis and synaptic plasticity, which was validated by experimental assays. Network analysis and Western blotting further identified two key targets, GSK-3β and MAPK14 (p38), in the AD-related protein regulatory network, which play key roles in the regulation of neuronal apoptosis and synaptic plasticity by Medicarpin. CONCLUSIONS: This study presented a powerful endophenotype network-based strategy to explore the mechanisms of action (MOAs) of new AD therapeutics, and first identified Medicarpin as a potential anti-AD candidate by targeting multiple pathways.