摘要
针灸学如何传承精华,实现守正创新.本文在长期工作积累基础上,系统建立了源自针灸的靶标发现科学路径,包括经验传承、临床疗效、效应调节、生物过程、物质基础、靶标发现,并对未来可期的新药创制进行了展望.
Acupuncture has been an important therapy in traditional Chinese medicine(TCM) for more than 2000 years. However, based on the characteristics and advantages of acupuncture, how to promote further innovations and breakthroughs for the subject itself, as well as for Medicine and Life Sciences, is of great importance. Combined with our years of working in acupuncture, the life sciences, and our long-term practice in the prevention and treatment of asthma with acupuncture, scientific pipelines of target discovery originating from acupuncture have been systematically established, including experience inheritance, clinical efficacy, effect regulation, biological process, material basis, and target discovery. The acupuncture points GV14, BL12, and BL13 were selected based on the theory of traditional Chinese medicine in treating asthma, and the acupuncture therapy, named "three acupuncture points and five-needle method", is inherited from the national famous traditional Chinese medicine doctor, professor Jing-Ming Shao. With this method, acupuncture has achieved sound regulatory effects on mucosal and cellular immunity in patients with allergic asthma. The total efficacy of acupuncture for patients with allergic asthma at the end of one course of treatment was 85%. However, the concentration of cortisol in the plasma of asthmatic patients did not change significantly after the acupuncture. To identify the exact active biological processes, response genes and proteins of acupuncture in treating asthma, four tag libraries of serial analysis of gene expression(SAGE) were established from the lung tissues of control rats(CK), asthmatic rats(AS), asthmatic rats treated by acupuncture(ASAC), and control rats treated by acupuncture(CKAC). The results revealed that hundreds of differentially expressed genes and several critical biological processes were found using informatics tools, including antigen processing and presentation, toll-like receptor, regulation of actin cytoskeleton. Moreover, 21 specific genes of the acupuncture in treating asthma were detected using Venn diagrams, including metallothionein-2(MT-2). Our study further found that MT-2 protein expression was more than 50% lower in asthmatic lung tissue of ovalbumin(OVA)-induced asthmatic rats compared to control animals. However, acupuncture could significantly increase the MT-2 expression in lung tissue in a rat model of asthma. Consistently, injection of recombinant MT-2 into OVA-induced asthmatic rats through an external jugular vein rapidly reduced pulmonary resistance, to a greater extent than that achieved with the β2-agonist terbutaline. Mechanistic studies revealed that MT-2 bound to transgelin-2(TG-2, an actin-binding protein) on the membranes of airway smooth muscle cells(ASMCs), an interaction that was specifically required for MT-2 induced ASMC relaxation. Therefore, TG-2 has been considered to be a new target of acupuncture in treating asthma based on the clinical efficacy of acupuncture. We subsequently performed molecular docking analyses for more than 6000 compounds from an in-house database based on the nuclear magnetic resonance structure for the binding site of the TG-2 calponin-homology domain. Optimization of hit compounds led to the identification of the TG-2 agonist TSG12, which inhibited acetylcholine-induced contraction of rat ASMCs and reduced asthmatic pulmonary resistance in mice. TSG12 induced MYPT1 dephosphorylation and was shown to inactivate the Rho A-ROCK-MYPT1-MLC pathway, thereby causing ASMC relaxation. TSG12 inhalation(100 ng/kg) inhibited pulmonary resistance by more than 80% in asthmatic mice that had been challenged with house dust mite, and was more effective than the β-agonist isoproterenol. TSG12(1–100 ng/kg) similarly inhibited pulmonary resistance in OVA-challenged asthmatic mice, to a greater extent than that achieved with the β2-agonist terbutaline. Importantly, TSG12 also reduced acetylcholine-induced contraction of human ASMC in a dose-dependent manner, without signs of toxicity or desensitization. These results suggest that TG-2 agonists may represent a promising novel therapeutic approach for treating asthma, with potential clinical advantages over existing therapies. The above-mentioned target discovery originating from acupuncture is a vivid practice and concrete example of "Inheriting the essence, keeping integrity and innovation". The research of target discovery originating from acupuncture can not only clarify the scientific mechanism of acupuncture on the basis of inheritance, and actively promote the development of medicine and the life sciences, but also push forward for target discovery and drug development, and therefore extend new horizons for the innovation and development of acupuncture.
作者
杨永清
尹磊淼
朱维良
王宇
徐玉东
陈艳焦
Yongqing Yang;Leimiao Yin;Weiliang Zhu;Yu Wang;Yudong Xu;Yanjiao Chen(Shanghai Research Institute of Acupuncture and Meridian,Shanghai University of Traditional Chinese Medicine,Shanghai 200030,China;Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China)
出处
《科学通报》
EI
CAS
CSCD
北大核心
2020年第32期3520-3525,共6页
Chinese Science Bulletin
基金
国家自然科学基金(81973951,81922076,81873373,81973952,81872797,81774429)资助。
