中药联合抗生素治疗感染性疾病的增效减毒机制研究策略
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摘要
抗生素疗效下降、毒副反应突出,多重耐药病原体增多使人类面临感染性疾病肆虐的严重威胁。积极应对威胁、确立有效防治方案已经成为全世界的迫切任务。中药治疗感染性疾病历史悠久、疗效确切,不仅抑杀病原体、消除毒素,而且对感染所致炎症、免疫异常、整体失调有治疗作用;抗生素主要抑杀病原体本身;中药与抗生素联用具有互补性,被认为是应对威胁的可行方案。临床观察发现中药对抗生素具有增效减毒潜力,揭示其机制是优化和推广方案的必要措施。首先采用系统药理学分子网络分析方法多层次、多维度预测中药联合抗生素治疗感染性疾病增效减毒的效应和机制,为进一步实证研究切入点和检测指标的选取提供依据;其次遵循中医药证对应用药原则,抗生素和中药各自单独及联合应用治疗特定证候状态的感染性疾病患者,除常规全面地评价两药联用的增效减毒效应之外,更采用多组学技术发现两药联用在分子水平的细微效应特征,并采用生物分子网络分析技术确定两药联用增效减毒的敏感、稳定的临床生物标志;然后以这些生物标志为线索,在感染性疾病动物模型体内和细胞水平溯源生物标志的生物转化过程和调控机制,并回归临床进行印证,从而揭示两者联用增效减毒机制,为联用方案的推广应用提供依据。
The decreased efficacy and severe side effects of antibiotics,as well the increase of multidrug resistant pathogens are seriously threatening human health. It has become an urgent task for the whole world to actively respond to threats and establish effective prevention and control plans. Traditional Chinese medicine( TCM) has a long history with exact curative effect in the treatment of infectious diseases. It not only inhibits pathogens and eliminates endotoxin,but also has therapeutic effect on inflammation,immune abnormality and overall disorder caused by infection. Antibiotics mainly inhibit the pathogen itself,while the combination of TCM and antibiotics is complementary with each other and is considered as a feasible solution to the challenges. Some clinical observations have shown that TCM has potentiality of enhancing antibiotics efficiency and reducing toxicity.Exploring its mechanism is the necessary measure to optimize and popularize treatment regimen. Firstly,multi-level and multi-dimensional systematic pharmacology network analysis methods are used to predict the mechanism of TCM combined with antibiotics in the treatment of infectious diseases,so as to provide the evidence for further empirical research and selection of test indicators. Then by following the principle of corresponding drug use in specific TCM syndromes,the antibiotics and TCM are individually and jointly applied to treat patients with specific syndrome conditions of infectious diseases. Besides routine and comprehensive evaluation of synergistic and attenuated effect of the combined drug use,multi-omics technique is also used to find the subtle effects of these two drugs at a molecular level. The sensitive and stable clinical biomarkers of synergism and attenuation of combined drug use are determined by using biomolecular network analysis technology. Finally,taking these biomarkers as clues,the biotransformation process and regulation mechanism of the biomarkers are traced back in animal models of infectious diseases and cell level,and all of these are clinically verified. As a result,the mechanism of efficacy enhancing and toxicity reducing of combined drug use can be revealed,providing basis for the promotion and application of such combined drug use.
The decreased efficacy and severe side effects of antibiotics,as well the increase of multidrug resistant pathogens are seriously threatening human health. It has become an urgent task for the whole world to actively respond to threats and establish effective prevention and control plans. Traditional Chinese medicine( TCM) has a long history with exact curative effect in the treatment of infectious diseases. It not only inhibits pathogens and eliminates endotoxin,but also has therapeutic effect on inflammation,immune abnormality and overall disorder caused by infection. Antibiotics mainly inhibit the pathogen itself,while the combination of TCM and antibiotics is complementary with each other and is considered as a feasible solution to the challenges. Some clinical observations have shown that TCM has potentiality of enhancing antibiotics efficiency and reducing toxicity.Exploring its mechanism is the necessary measure to optimize and popularize treatment regimen. Firstly,multi-level and multi-dimensional systematic pharmacology network analysis methods are used to predict the mechanism of TCM combined with antibiotics in the treatment of infectious diseases,so as to provide the evidence for further empirical research and selection of test indicators. Then by following the principle of corresponding drug use in specific TCM syndromes,the antibiotics and TCM are individually and jointly applied to treat patients with specific syndrome conditions of infectious diseases. Besides routine and comprehensive evaluation of synergistic and attenuated effect of the combined drug use,multi-omics technique is also used to find the subtle effects of these two drugs at a molecular level. The sensitive and stable clinical biomarkers of synergism and attenuation of combined drug use are determined by using biomolecular network analysis technology. Finally,taking these biomarkers as clues,the biotransformation process and regulation mechanism of the biomarkers are traced back in animal models of infectious diseases and cell level,and all of these are clinically verified. As a result,the mechanism of efficacy enhancing and toxicity reducing of combined drug use can be revealed,providing basis for the promotion and application of such combined drug use.
引文
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[27]TAN Y,LIU X R,ZHOU K,et al.The potential biomarkers to identify the development of steatosis in hyperuricemia[J].PLo S One,2017,11(2):e0149043.
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[30]Brown E D,Wright G D.Antibacterial drug discovery in the resistance era[J].Nature,2016,529(7586):336-343.
[31]San Millan A,Escudero J A,Gifford D R,et al.Multicopy plasmids potentiate the evolution of antibiotic resistance in bacteria[J].Nat Ecol Evol,2016,1(1):10.
[32]Tsang J.Bacterial plasmid addiction systems and their implications for antibiotic drug development[J].Postdoc J,2017,5(5):3-9.
[33]Venkatesan N,Perumal G,Doble M.Bacterial resistance in biofilm-associated bacteria[J].Future Microbiol,2015,10(11):1743-1750.
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[35]刘珏玲,杨伟峰,孙娅楠,等.痰热清注射液对耐甲氧西林金黄色葡萄球菌生物膜三维结构的影响[J].中国病原生物学杂志,2017,12(12):1152-1156.
[36]YANG W F,LIU J,Bla6ekovic'B,et al.In vitro antibacterial effects of Tanreqing injection combined with vancomycin or linezolid against methicillin-resistant Staphylococcus aureus[J].BMC Complement Altern Med,2018,18(1):169.
[2]施亚丽,徐福礼.抗生素耐药的发生机制及基本对策[J].人民军医,2012,55(3):196.
[3]O'neill J.Tackling drug-resistant infections globally:final report and recommendations[R].Government of the United Kingdom,2016.
[4]Prestinaci F,Pezzotti P,Pantosti A.Antimicrobial resistance:a global multifaceted phenomenon[J].Pathog Glob Health,2015,109(7):309-318.
[5]张俊华,张伯礼.感染性疾病的挑战与中医药替代研究[J].中国中药杂志,2017,42(8):1415-1417.
[6]刘天强,何健东,庄剑彬.中医药在预防抗生素滥用及其引起病症中的应用[J].亚太传统医药,2008,4(5):87-89.
[7]战旗,王蕊,李爽,等.中药抗菌作用研究现状[J].山东中医杂志,2014,33(8):697-698.
[8]侯江涛,李海文,刘凤斌,等.后抗生素时代中医药面临的机遇与挑战[J].现代中西医结合杂志,2015,24(19):2157-2159.
[9]黄琨明,杨志高,刘爱云,等.中药饮片对多重抗生素耐药细菌的抑菌作用[J].内蒙古中医药,2016,35(13):146-147.
[10]王萍,唐仕欢,苏瑾,等.基于整合药理学的中药现代研究进展[J].中国中药杂志,2018,43(7):1297-1302.
[11]LIU J L,LIU J J,SHEN F X,et al.Systems pharmacology analysis of synergy of TCM:an example using saffron formula[J].Sci Rep,2018,8(1):380.
[12]马程功,马跃荣.中医药证候动物模型的研究进展[J].成都中医药大学学报,2018,41(1):119-123.
[13]张弛,张戈,陈可冀,等.从疾病中医证候分类到分子模块分类[J].中国中西医结合杂志,2016,36(7):781-786.
[14]GUO H T,NIU X Y,GU Y,et al.Differential amino acid,carbohydrate and lipid metabolism perpetuations involved in a subtype of rheumatoid arthritis with Chinese medicine cold pattern[J].Int J Mol Sci,2016,17(10):E1757.
[15]WANG M,CHENG G,LU C,et al.Rheumatoid arthritis with deficiency pattern in traditional chinese medicine shows correlation with cold and hot patterns in gene expression profiles[J].Evid Based Complement Alternat Med,2013,2013:248650.
[16]Johnson CH,Ivanisevic J,Siuzdak G.Metabolomics:beyond biomarkers and towards mechanisms[J].Nat Rev Mol Cell Biol,2016,17(7):451-459.
[17]Nicholson J K,Connelly J,Lindon J C,et al.Metabonomics:a platform for studying drug toxicity and gene function[J].Nat Rev Drug Discov,2002,1(2):153-161.
[18]Cacciatore S,Loda M.Innovation in metabolomics to improve personalized healthcare[J].Ann N Y Acad Sci,2015,1346(1):57-62.
[19]浦绍艳,张鑫磊,蒋太交,等.宏基因组学研究方法及其在病原体检测中的应用[J].生物物理学报,2014,30(1):3-14.
[20]Taylor S L,Leong L E X,Mobegi F M,et al.Understanding the impact of antibiotic therapies on the respiratory tract resistome:a novel pooled-template metagenomic sequencing strategy[J].Multidiscip Respir Med,2018,13(Suppl 1):30.
[21]Rempe C S,Burris K P,Lenaghan S C,et al.The potential of systems biology to discover antibacterial mechanisms of plant phenolics[J].Front Microbiol,2017,8:422.
[22]谭勇,李健,肖诚,等.对证组分配伍是有毒中药控毒研究的重要途径[J].中国中西医结合杂志,2017,37(1):115-118.
[23]ZHANG C,JIANG M,ZHANG G,et al.Progress and perspectives of biomarker discovery in Chinese medicine research[J].Chin J Integr Med,2014,doi:10.1007/s11655-014-1848-9.
[24]Wikipedia contributors.Biomarker[EB/OL].https://en.wikipedia.org/wiki/Biomarker,2018-10-20/2018-10-28.
[25]TAN Y,LI J,LIU X R,et al.Deciphering the differential toxic responses of Radix aconiti lateralis praeparata in healthy and hydrocortisone-pretreated rats based on serum metabolic profiles[J].J Proteome Res,2013,12(1):513-524.
[26]TAN Y,JIA D M,LIN Z,et al.Potential metabolic biomarkers to identify interstitial lung abnormalities[J].Int J Mol Sci,2016,17(7):E1148.
[27]TAN Y,LIU X R,ZHOU K,et al.The potential biomarkers to identify the development of steatosis in hyperuricemia[J].PLo S One,2017,11(2):e0149043.
[28]SU T,TAN Y,Tsui M S,et al.Metabolomics reveals the mechanisms for the cardiotoxicity of Pinelliae Rhizoma and the toxicity-reducing effect of processing[J].Sci Rep,2016,doi:10.1038/srep34692.
[29]Johnson C H,Ivanisevic J,Siuzdak G.Metabolomics:beyond biomarkers and towards mechanisms[J].Nat Rev Mol Cell Biol,2016,17(7):451-459.
[30]Brown E D,Wright G D.Antibacterial drug discovery in the resistance era[J].Nature,2016,529(7586):336-343.
[31]San Millan A,Escudero J A,Gifford D R,et al.Multicopy plasmids potentiate the evolution of antibiotic resistance in bacteria[J].Nat Ecol Evol,2016,1(1):10.
[32]Tsang J.Bacterial plasmid addiction systems and their implications for antibiotic drug development[J].Postdoc J,2017,5(5):3-9.
[33]Venkatesan N,Perumal G,Doble M.Bacterial resistance in biofilm-associated bacteria[J].Future Microbiol,2015,10(11):1743-1750.
[34]de la Fuente-Nú1ez C,Reffuveille F,Fernández L,et al.Bacterial biofilm development as a multicellular adaptation:antibiotic resistance and new therapeutic strategies[J].Curr Opin Microbiol,2013,16(5):580-589.
[35]刘珏玲,杨伟峰,孙娅楠,等.痰热清注射液对耐甲氧西林金黄色葡萄球菌生物膜三维结构的影响[J].中国病原生物学杂志,2017,12(12):1152-1156.
[36]YANG W F,LIU J,Bla6ekovic'B,et al.In vitro antibacterial effects of Tanreqing injection combined with vancomycin or linezolid against methicillin-resistant Staphylococcus aureus[J].BMC Complement Altern Med,2018,18(1):169.