阴阳双补方治疗骨转移癌痛作用机制的网络药理学研究Study on the Mechanism of Yinyang Shuangbu Formula in Treating Bone Metastasis Cancer Pain Based on Network Pharmacology
杨梦霞,毛昀,芦殿荣,朱世杰,周磊
摘要(Abstract):
目的 从网络药理学角度初步探究阴阳双补方治疗骨转移癌痛的潜在分子作用机制。方法 中药数据库筛阴阳双补方主要化合物,并利用Swiss Target Prediction数据库检索化合物对应靶点,通过GeneCards检索骨转移和癌痛两种疾病基因。通过韦恩分析将化合物靶点和两种疾病基因进行映射,得到潜在治疗靶点;利用Cytoscape3.8.2软件绘制多层次相互作用的“中药-化合物-潜在治疗靶点”网络图,并利用DAVID平台对潜在治疗靶点进行富集分析。结果 阴阳双补方主要化合物有88个,含673个药物靶点。骨转移癌疾病基因有483个、癌痛基因有858个,与药物靶点映射后得到94个潜在治疗靶点。阴阳双补方治疗骨转移癌痛的关键靶点为VEGFA、STAT3、ErbB2及AKT1等。通过富集分析发现,阴阳双补方治疗骨转移癌痛是通过调控PI3KAkt、FoxO、VEGF及mTOR等通路发挥抗炎、镇痛、调节神经系统的作用。结论 通过中药网络药理学发现“阴阳双补方”治疗骨转移癌痛的作用机制复杂,涉及多成分、多靶点和多通路,可能与抗炎、镇痛、调节神经系统等相关。
关键词(KeyWords): 肿瘤;骨转移;疼痛;网络药理;机制探讨;阴阳双补方
基金项目(Foundation): 国家自然科学基金面上项目(81973640);; 专利:一种治疗骨转移癌性躯体痛的中药组合物及其制备方法和应用(202110174580.6);; 中国中医科学院望京医院院级课题(WJYY2020-26)
作者(Author): 杨梦霞,毛昀,芦殿荣,朱世杰,周磊
参考文献(References):
- [1]Bouhassira D,Luporsi E,Krakowski I.Prevalence and incidence of chronic pain with or without neuropathic characteristics in patients with cancer[J].Pain,2017,158(6):1118-1125.
- [2]Li XM,Xiao WH,Yang P,et al.Psychological distress and cancer pain:Results from a controlled cross-sectional survey in China[J].Sci Rep,2017(7):39397.
- [3]Bennett MI.Mechanism-based cancer-pain therapy[J].Pain,2017,158(Suppl 1):S74-S78.
- [4]Candido KD,Kusper TM,Knezevic NN.New cancer pain treatment options[J].Curr Pain Headache Rep,2017,21(2):12.
- [5]毛昀.补肾类中药调节乳腺癌骨转移生态位的作用机制研究[D].北京:北京中医药大学,2021.
- [6]王稳,樊碧发.癌痛发生机制的研究进展[J].中国疼痛医学杂志,2021,27(8):616-618.
- [7]Li Z,Zhang J,Ren X,et al.The mechanism of quercetin in regulating osteoclast activation and the PAR2/TRPV1 signaling pathway in the treatment of bone cancer pain[J].Int JClin Exp Pathol,2018,11(11):5149-5156.
- [8]陈丹.山奈酚的抗炎镇痛作用及其机制研究[D].南京:南京中医药大学,2021.
- [9]Zhou YS,Cui Y,Zheng JX,et al.Luteolin relieves lung cancer-induced bone pain by inhibiting NLRP3 inflammasomes and glial activation in the spinal dorsal horn in mice[J].Phytomedicine,2022(96):153910.
- [10]Hulse RP.Role of VEGF-A in chronic pain[J].Oncotarget,2017,8(7):10775-10776.
- [11]Hulse RP,Beazley-Long N,Hua J,et al.Regulation of alternative VEGF-A m RNA splicing is a therapeutic target for analgesia[J].Neurobiol Dis,2014(71):245-259.
- [12]Hulse RP,Drake RA,Bates DO,et al.The control of alternative splicing by SRSF1 in myelinated afferents contributes to the development of neuropathic pain[J].Neurobiol Dis,2016(96):186-200.
- [13]Linher-Melville K,Sharma M,Nakhla P,et al.Inhibiting STAT3 in a murine model of human breast cancer-induced bone pain delays the onset of nociception[J].Mol Pain,2019(15):477.
- [14]Calvo M,Zhu N,Grist J,et al.Following nerve injury neuregulin-1 drives microglial proliferation and neuropathic pain via the MEK/ERK pathway[J].Glia,2011,59(4):554-568.
- [15]Lacroix-Fralish ML,Tawfik VL,Nutile-Mc Menemy N,et al.Neuregulin 1 is a pronociceptive cytokine that is regulated by progesterone in the spinal cord:implications for sex specific pain modulation[J].Eur J Pain,2008,12(1):94-103.
- [16]Jiang J,Zhang J,Yao P,et al.Activation of spinal neuregulin1-Erb B2 signaling pathway in a rat model of cancer-induced bone pain[J].Int J Oncol,2014,45(1):235-244.
- [17]袁翠堂,丁罡,廖志军,等.大鼠乳腺癌骨转移模型中PI3K/Akt信号通路参与诱导疼痛[J].实用癌症杂志,2016,31(3):349-358.
- [18]Zhao X,Liu Y,Zhu G,et al.SIRT1 downregulation mediated Manganese-induced neuronal apoptosis through activation of FOXO3a-Bim/PUMA axis[J].Sci Total Environ,2019(646):1047-1055.
- [19]Selvaraj D,Gangadharan V,Michalski CW,et al.A functional role for VEGFR1 expressed in peripheral sensory neurons in cancer pain[J].Cancer Cell,2015(27):780-796.
- [20]Asante CO,Wallace VC,Dickenson AH.Formalin-induced behavioural hypersensitivity and neuronal hyperexcitability are mediated by rapid protein synthesis at the spinal level[J].Mol Pain,2009(5):27.
- [21]Zhang W,Sun X-F,Bo J-H,et al.Activation of m TOR in the spinal cord is required for pain hypersensitivity induced by chronic constriction injury in mice[J].Pharmacol Biochem Behav,2013(111):64-70.
- [22]Argyriou P,Papageorgiou SG,Panteleon V,et al.Hypoxia-inducible factors in mantle cell lymphoma:implication for an activated m TORC1->HIF-1alpha pathway[J].Ann Hematol,2011(90):315-322.
- [23]Xie X,Ma L,Xi K,et al.Micro RNA-183 suppresses neuropathic pain and expression of AMPA receptors by targeting m TOR/VEGF signaling pathway[J].Cell Physiol Biochem,2017,41(1):181-192.