从白介素受体相关激酶反馈平衡调节与清热解毒中药抗脓毒症相关作用机制
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摘要
天然免疫TLR信号是机体防御病原体第一道防线,但过度活化失控导致脓毒症,因此,寻找其平衡的分子靶标和有效药物就显得尤其重要。白介素-1受体相关激酶(IRAKs)是TLR信号关键分子,它连接受体和下游转录因子,决定天然免疫的信号流向,影响其结局。研究发现,这些信号激酶可发生多态性表达,产生正性和负性的分子异构体,平衡机体防御和炎症。无疑,调控正负IRAK激酶平衡将成为防控脓毒症的新靶标。清热解毒中药具有免疫调节和抗炎活性,现代医学用分子生物学、病理学和免疫学的方法,从调控IRAK激酶信号中确证平衡天然免疫的内源性机制,阐明了清热解毒中药的物质基础和分子机制,为中药现代化提供了新的思路。
The TLR signaling of innate immune is the first line of defense of the host against pathogens, but excessive activation leads to sepsis. Therefore, to find molecular targets and effective drugs to balance innate immune is very important. Interleukin-1 receptorassociatd kinases(IRAKs) are the key molecules of TLR signal pathwayand it connects TLRs and transcript factors to decide the direction of innate immune signal and affect the outcome. Previous studies found that these IRAKs could express in polymorphism, resulting in producing negative variants, which balance the host defense and inflammation. No doubt, the regulation of negative or positive IRAK variants will become a new target for the prevention and control ofthe inflammtory imbalance. Traditional Chinese medicines ofclearing heatanddetoxicating have immunomodulatory and antiinflammatory activities, although our previous studies found that these drug can interfere with TLR signaling, but its material foundation and multitarget effects lack of a reasonable explain based on modern medicine. To this end, we use the methods of molecular biology, pathology and immunology to determine the endogenous mechanisms of balanced innate immune from the adapter protein polymorphism expression, further, use pharmacological methods to explore the substance basis and molecular mechanisms of traditional medicines ofclearing heatand detoxicating base on the target of regulation of IRAKs. In conclusion, our study will provide important experimental evidences to uncover the innate immune regulatory mechanism and relative drugs research, but also to provide new ideas for the modernization of traditional Chinese medicine.
The TLR signaling of innate immune is the first line of defense of the host against pathogens, but excessive activation leads to sepsis. Therefore, to find molecular targets and effective drugs to balance innate immune is very important. Interleukin-1 receptorassociatd kinases(IRAKs) are the key molecules of TLR signal pathwayand it connects TLRs and transcript factors to decide the direction of innate immune signal and affect the outcome. Previous studies found that these IRAKs could express in polymorphism, resulting in producing negative variants, which balance the host defense and inflammation. No doubt, the regulation of negative or positive IRAK variants will become a new target for the prevention and control ofthe inflammtory imbalance. Traditional Chinese medicines ofclearing heatanddetoxicating have immunomodulatory and antiinflammatory activities, although our previous studies found that these drug can interfere with TLR signaling, but its material foundation and multitarget effects lack of a reasonable explain based on modern medicine. To this end, we use the methods of molecular biology, pathology and immunology to determine the endogenous mechanisms of balanced innate immune from the adapter protein polymorphism expression, further, use pharmacological methods to explore the substance basis and molecular mechanisms of traditional medicines ofclearing heatand detoxicating base on the target of regulation of IRAKs. In conclusion, our study will provide important experimental evidences to uncover the innate immune regulatory mechanism and relative drugs research, but also to provide new ideas for the modernization of traditional Chinese medicine.
引文
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[23] 陈博,万敬员.“清法”理论的现代研究[J].中华中医药学刊,2016,34(9):2070-2072.
[24] B Dinda,S Dinda,S Dassharma,et al. Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders[J]. European Journal of Medicinal Chemistry,2017,131(5):68-80.
[25] 陈博,万敬员.小檗碱对氧化型低密度脂蛋白诱导巨噬细胞促炎细胞因子和活性氧的影响[J].中华中医药学刊,2017,35(11):2752-2755.
[26] L He,X Peng,J Zhu,et al.Mangiferin Attenuate Sepsis-Induced Acute Kidney Injury via Antioxidant and Anti-Inflammatory Effects[J].American Journal of Nephrology,2014, 40(5):441-450.
[27] Yang D, Chen W, Xiong J, et al. Interleukin 1 receptor-associated kinase 1 (IRAK1) mutation is a common, essential driver for Kaposi sarcoma herpesvirus lymphoma[J]. Proc Natl Acad Sci USA,2014,111(44): 4762-4768.
[28] Yin X, Gong X, Zhang L, et al. Glycyrrhetinic acid attenuates lipopolysaccharide-induced fulminant hepatic failure in d-galactosamine-sensitized mice by up-regulating expression of interleukin-1 receptor-associated kinase-M[J].Toxicol Appl Pharmacol, 2017, 320(1):8-16.
[29] Yin X, Gong X, Jiang R,et al. Emodin ameliorated lipopolysaccharide-induced fulminant hepatic failure by blockade of TLR4/MD2 complex expression in D-galactosamine-sensitized mice[J]. Int Immunopharmacol, 2014,23(1):66-72.
[30] Gong X, Huang D, Liu Y,et al.Pyrolysis and reutilization of plant residues after phytoremediation of heavy metals contaminated sediments: For heavy metals stabilization and dye adsorption[J]. Bioresour Technol, 2018, 253(1):64-71.
[31] Sperry JL, Zolin S, Zuckerbraun BS, et al.X chromosome-linked IRAK-1 polymorphism is a strong predictor of multiple organ failure and mortality postinjury[J].Ann Surg, 2014,260(4):698-703.
[32] Yin X, Gong X, Jiang R, et al. Emodin ameliorated lipopolysaccharide-induced fulminant hepatic failure by blockade of TLR4/MD2 complex expression in D-galactosamine-sensitized mice[J]. International immunopharmacology,2014,23(23): 66-72.
[33] Yuan Y,Gong X,Zhang L,et al. Chlorogenic acid ameliorated concanavalin A-induced hepatitis by suppression of Toll-like receptor 4 signaling in mice[J].IntImmunopharmacol,2017,44(3):97-104.
[2] Lee CC,Avalos AM,Ploegh HL.Accessory molecules for Toll-like receptors and their function [J].Nat Rev Immunol,2012,12(3):168-179.
[3] Nyholm SV,Graf J.Knowing your friends:invertebrate innate immunity fosters beneficial bacterial symbiose[J].Nat Rev Microbiol,2012,10(12):815-827.
[4] Rawlings DJ,Schwartz MA,Jackson SW,et al.Integration of B cell responses through Toll-like receptors and antigen receptors [J].Nat Rev Immunol,2012,12(4):282-294.
[5] Rakoff-Nahoum S,Bousvaros A.Innate and adaptive immune connections in inflammatory bowel diseases[J].Curr Opin Gastroenterol,2010,26(6):572-577.
[6] Midwood KS,Piccinini AM,Sacre S.Targeting.Toll-like receptors in autoimmunity[J].Curr Drug Targetss,2009,10(11):1139-1155.
[7] Bhesh Raj Sharma,Min Suk Kim,Dong Young,et al.Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members.Mol Cell.Nelumbo Nucifera leaf extract attenuated pancreatic β-cells toxicity induced by interleukin-1β and interferon-γ, and increased insulin secrection of pancreatic β-cells in streptozotocin-induced diabetic rats[J].Journal of Traditional Chinese Medicine,2016,36(1):71-77.
[8] Suhir H,Etzioni A.The role of Toll-like receptor signaling in human immunodeficiencies[J].Clinical reviews in allergy & immunology,2010,38(1):11-19.
[9] Flannery S,Bowie AG.The interleukin-1 receptor-associated kinases:critical regulators of innate immune signalling[J].Biochem Pharmacol,2010,80(12):1981-1991.
[10] Wang Z,Wesche H,Stevens T,et al.IRAK-4 inhibitors for inflammation[J].Curr Top Med Chem,2009,9(8):724-737.
[11] Dosch SF,Mahajan SD,Collins AR.SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-kappaB pathway in human monocyte macrophages in vitro[J].Virus Res,2009,142(1-2):19-27.
[12] Li K,Gong X,Kuang G,et al. Sesamin protects against renal ischemia reperfusion injury by promoting CD39-adenosine-A2AR signal pathway in mice[J].Am J Transl Res,2016,8(5):2245-2254.
[13] Wen peng, Dong Xianyue,Wang Shenghui,et al.Inhibitory effects of resveratrol on foam cell formation are mediated through monocyte chemotactic protein-1 and lipid metabolism-related proteins[J].International journal of molecular medicine,2014,33(5):1161-1168.
[14] Suhir H,Etzioni A.The role of Toll-like receptor signaling in human immunodeficiencies[J].Clinical reviews in allergy & immunology,2010,38(1):11-19.
[15] Flannery S, Bowie AG.The interleukin-1 receptor-associated kinases: critical regulators of innate immune signalling[J].Biochem Pharmacol,2010,80(12):1981-1991.
[16] Wang Z,Wesche H,Stevens T,et al.IRAK-4 inhibitors for inflammation[J].Curr Top Med Chem,2009,9(8):724-737.
[17] Dosch SF,Mahajan SD,Collins AR.SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-kappaB pathway in human monocyte macrophages in vitro[J].Virus Res,2009,142(1-2):19-27.
[18] Zhao H, Luo F, Li H, et al. Antinociceptive effect of tetrandrine on LPS-induced hyperalgesia via the inhibition of IKKβ phosphorylation and the COX-2/PGE pathway in mice[J]. Plos One,2014, 9(4):e94586.
[19] Kanzler H, Barrat FJ, Hessel EM, et al.Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists[J].Nat Med,2007,13(5):552-559.
[20] Hennessy EJ, Parker AE, O’Neill LA. Targeting Toll-like receptors: emerging therapeutics[J].Nat Rev Drug Discov,2010,9(4):293-307.
[21] H Huang, Z Cheng, H Shi,et al.Isolation and Characterization of Two Flavonoids,Engeletin and Astilbin, from the Leaves of Engelhardia roxburghiana and Their Potential Anti-inflammatory Properties Journal of Agricultural and Food[J]. Journal of Agricultural & Food Chemistry,2011,(59)9:4562-4569.
[22] 陈博,万敬员.中医临证思想在中药现代研究中的应用[J].中华中医药学刊,2015,33(4):828-830.
[23] 陈博,万敬员.“清法”理论的现代研究[J].中华中医药学刊,2016,34(9):2070-2072.
[24] B Dinda,S Dinda,S Dassharma,et al. Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders[J]. European Journal of Medicinal Chemistry,2017,131(5):68-80.
[25] 陈博,万敬员.小檗碱对氧化型低密度脂蛋白诱导巨噬细胞促炎细胞因子和活性氧的影响[J].中华中医药学刊,2017,35(11):2752-2755.
[26] L He,X Peng,J Zhu,et al.Mangiferin Attenuate Sepsis-Induced Acute Kidney Injury via Antioxidant and Anti-Inflammatory Effects[J].American Journal of Nephrology,2014, 40(5):441-450.
[27] Yang D, Chen W, Xiong J, et al. Interleukin 1 receptor-associated kinase 1 (IRAK1) mutation is a common, essential driver for Kaposi sarcoma herpesvirus lymphoma[J]. Proc Natl Acad Sci USA,2014,111(44): 4762-4768.
[28] Yin X, Gong X, Zhang L, et al. Glycyrrhetinic acid attenuates lipopolysaccharide-induced fulminant hepatic failure in d-galactosamine-sensitized mice by up-regulating expression of interleukin-1 receptor-associated kinase-M[J].Toxicol Appl Pharmacol, 2017, 320(1):8-16.
[29] Yin X, Gong X, Jiang R,et al. Emodin ameliorated lipopolysaccharide-induced fulminant hepatic failure by blockade of TLR4/MD2 complex expression in D-galactosamine-sensitized mice[J]. Int Immunopharmacol, 2014,23(1):66-72.
[30] Gong X, Huang D, Liu Y,et al.Pyrolysis and reutilization of plant residues after phytoremediation of heavy metals contaminated sediments: For heavy metals stabilization and dye adsorption[J]. Bioresour Technol, 2018, 253(1):64-71.
[31] Sperry JL, Zolin S, Zuckerbraun BS, et al.X chromosome-linked IRAK-1 polymorphism is a strong predictor of multiple organ failure and mortality postinjury[J].Ann Surg, 2014,260(4):698-703.
[32] Yin X, Gong X, Jiang R, et al. Emodin ameliorated lipopolysaccharide-induced fulminant hepatic failure by blockade of TLR4/MD2 complex expression in D-galactosamine-sensitized mice[J]. International immunopharmacology,2014,23(23): 66-72.
[33] Yuan Y,Gong X,Zhang L,et al. Chlorogenic acid ameliorated concanavalin A-induced hepatitis by suppression of Toll-like receptor 4 signaling in mice[J].IntImmunopharmacol,2017,44(3):97-104.
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