荜茇宁与氟康唑联用对肥胖小鼠感染白念珠菌的保护作用  

Protective effect of combining wickerwork and fluconazole against Candida albicans infection in obese mice

作　　者：李欣祝 徐美玲 雷耀华 刘杉 王睿睿 庄馨瑛 LI Xinzhu;XU Meiling;LEI Yaohua;LIU Shan;WANG Ruirui;ZHUANG Xinying(College of Traditional Chinese Medicine,Yunnan University of Chinese Medicine,Yunnan Kunming 650500,China;Yunnan Province Engineering Laboratory for National Healthcare Theories&Products,Yunnan Kunming 650500,China;Key Laboratory of Applied Drug Delivery System&Preparation Technology,Yunnan Kunming 650500,China)

机构地区：[1]云南中医药大学中药学院,云南昆明650500 [2]云南省民族特色养生理论与健康产品工程实验室,云南昆明650500 [3]云南省高校外用给药系统与制剂技术研究重点实验室,云南昆明650500

出　　处：《中国医院药学杂志》2024年第23期2737-2742,共6页Chinese Journal of Hospital Pharmacy

基　　金：云南省中医药基础研究联合专项(编号:202301AZ070001-057)。

摘　　要：目的:探究肥胖合并白念珠菌(candida albicans,CA)感染的不良后果,同时进一步探讨氟康唑(fluconazol,FLC)与荜茇宁(piperlonguminine,GBN)联用的治疗效果。方法:构建高脂饮食(HFD)肥胖小鼠合并白念珠菌感染模型,给予不同药物治疗,监测小鼠死亡情况,检测脏器质量、肾脏载菌量和肾脏组织病理形态,检测血清脂质水平、腹腔灌洗液NETs水平以及肾脏组织炎症因子Tgf-β、IL-6、MCP-1、KC的表达水平。利用全反式维甲酸(ATRA)诱导HL-60细胞分化为类中性粒细胞(dHL-60),用GBN对dHL-60细胞进行预处理,给予佛波酯(PMA)刺激,检测细胞内活性氧(ROS)和NETs水平。结果:肥胖小鼠感染白念珠菌后生存率急剧下降,肾脏载菌量升高,血脂水平、中性粒细胞NETs水平和炎症因子水平均升高。FLC联合GBN治疗可将肥胖感染小鼠生存率恢复至100%,改善脏器指数,同时相比于单独应用FLC,肾脏载菌量、血脂水平、炎症水平和NETs水平都进一步降低。体外试验结果表明,GBN可降低PMA刺激类中性粒细胞生成的ROS和NETs水平。结论:肥胖小鼠感染白念珠菌后死亡率升高,同时体内伴有严重的炎症反应,GBN通过抑制中性粒细胞的活性氧生成和NETs释放调节机体炎症状态,与FLC联用改善肥胖小鼠的感染情况。OBJECTIVE To explore the adverse consequences of obesity plus Candida albicans(CA)infection and examine the therapeutic effect of fluconazol(FLC)in combination with piperlonguminine(GBN).METHODS A model of high-fat diet(HFD)obese mice plus invasive Candida albicans infection was constructed.Different drugs were dosed.Death,organ mass,renal load and renal histopathological morphology were detected.The serum levels of triglyceride(TG),total cholesterol(TC),low-density lipoprotein-C(LDL-C)and high-density lipoprotein-C(HDL-C)were measured.And the levels of neutrophil extracellular traps(NETs)in intraperitoneal lavage fluid were quantified,as well as the expressions of inflammatory factors transforming growth factor-beta(TGF-β),interleukin-6(IL-6),monocyte chemotactic protein-1(MCP-1)and keratinocyte-derived chemokine(KC)in renal tissues.In vitro assays were performed using all-trans retinoic acid(ATRA)for inducing differentiation of HL-60 cells into neutrophil-like granulocytes(dHL-60).dHL-60 cells were pre-treated with GBN and stimulated by phorbol ester(PMA).The intracellular levels of reactive oxygen species(ROS)and NETs were detected.RESULTS Obese mice infected with CA had dramatically lower survival,elevated renal load and higher levels of lipids and NETs.FLC in combination with GBN restored survival to 100%in obese infected mice and improved visceral indices,while further reducing renal load,lipids,inflammatory factors and NETs.In vitro results indicated that GBN reduced the levels of reactive oxygen species(ROS)and NETs generated by PMA-stimulated neutrophils.CONCLUSION CA infection in obese mice is associated with higher mortality and severe inflammatory response in vivo.GBN regulates the inflammatory state through suppressing ROS production and NETs release from neutrophils and ameliorates infection in obese mice in combination with FLC.

关 键 词：肥胖 白念珠菌 荜茇宁 炎症反应 

分 类 号：R285[医药卫生—中药学] R965[医药卫生—中医学]