Aberrant activation of NLRP3 inflammasome has been implicated in the pathogenesis of diverse inflammation-related diseases, and pharmacological molecules targeting NLRP3 inflammasome are of considerable value to ident...Aberrant activation of NLRP3 inflammasome has been implicated in the pathogenesis of diverse inflammation-related diseases, and pharmacological molecules targeting NLRP3 inflammasome are of considerable value to identifying potential therapeutic interventions. Cardamonin(CDN), the major active ingredient of the traditional Chinese medicinal herb Alpinia katsumadai, has exerted an excellent anti-inflammatory activity, but the mechanism underlying this role is not fully understood. Here, we show that CDN blocks canonical and noncanonical NLRP3 inflammasome activation triggered by multiple stimuli. Moreover, the suppression of CDN on inflammasome activation is specific to NLRP3, not to NLRC4 or AIM2 inflammasome. Besides, the inhibitory effect is not dependent on the expression of NF-κB-mediated inflammasome precursor proteins. We also demonstrate that CDN suppresses the NLRP3 inflammasome through blocking ASC oligomerization and speckle formation in a dose-dependent manner.Importantly, CDN improves the survival of mice suffering from lethal septic shock and attenuates IL-1βproduction induced by LPS in vivo, which is shown to be NLRP3 dependent. In conclusion, our results identify CDN as a broad-spectrum and specific inhibitor of NLRP3 inflammasome and a candidate therapeutic drug for treating NLRP3 inflammasome-driven diseases.展开更多
小豆蔻明(cardamonin,CAR)的化学结构为2’,4’-二甲基-6’-甲氧基查尔酮,是一种主要存在于姜科山姜属植物草豆蔻种子中的黄酮类单体,生物活性广泛。由于其具有抗肿瘤作用,近年来倍受关注,并已有系列衍生物被合成。研究表明,CAR对多形...小豆蔻明(cardamonin,CAR)的化学结构为2’,4’-二甲基-6’-甲氧基查尔酮,是一种主要存在于姜科山姜属植物草豆蔻种子中的黄酮类单体,生物活性广泛。由于其具有抗肿瘤作用,近年来倍受关注,并已有系列衍生物被合成。研究表明,CAR对多形性胶质母细胞瘤、Lewis肺癌、乳腺癌、结肠癌和前列腺癌等肿瘤细胞的生长均有抑制作用,其作用机制涉及哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)通路、核因子κB(nuclear factor kappa B,NF-κB)信号通路、谷氨酰胺转氨酶2、内源性凋亡途径、信号转导与转录激活因子3(signal transducer and activator of transcription 3,STAT3)、E-钙黏蛋白(E-cadherin)、细胞自噬、β-catenin和细胞周期调控等。本文主要对CAR及其衍生物的抗肿瘤作用及其机制进行综述。展开更多
基金supported by the National Key Technology R&D Program(No.2017ZX09301022)the National Key Technology R&D Program(No.2015ZX09501-004-001-008)+1 种基金the BeijingNova program(No.Z181100006218001)the National Natural Science Foundation of China(No.81630100)
文摘Aberrant activation of NLRP3 inflammasome has been implicated in the pathogenesis of diverse inflammation-related diseases, and pharmacological molecules targeting NLRP3 inflammasome are of considerable value to identifying potential therapeutic interventions. Cardamonin(CDN), the major active ingredient of the traditional Chinese medicinal herb Alpinia katsumadai, has exerted an excellent anti-inflammatory activity, but the mechanism underlying this role is not fully understood. Here, we show that CDN blocks canonical and noncanonical NLRP3 inflammasome activation triggered by multiple stimuli. Moreover, the suppression of CDN on inflammasome activation is specific to NLRP3, not to NLRC4 or AIM2 inflammasome. Besides, the inhibitory effect is not dependent on the expression of NF-κB-mediated inflammasome precursor proteins. We also demonstrate that CDN suppresses the NLRP3 inflammasome through blocking ASC oligomerization and speckle formation in a dose-dependent manner.Importantly, CDN improves the survival of mice suffering from lethal septic shock and attenuates IL-1βproduction induced by LPS in vivo, which is shown to be NLRP3 dependent. In conclusion, our results identify CDN as a broad-spectrum and specific inhibitor of NLRP3 inflammasome and a candidate therapeutic drug for treating NLRP3 inflammasome-driven diseases.
文摘目的观察豆蔻明(Cardamonin,CDN)对肺纤维化小鼠的作用,并探究其对转化生长因子-β1(transforming growth factor-β1,TGF-β1)/smad信号通路的影响。方法将小鼠随机分为生理盐水(Sham)组、博莱霉素(Bleomycin,BLM)组、豆蔻明低剂量(low dose of Cardamonin,CDN-L)组、豆蔻明中剂量(medium dose of Cardamonin,CDN-M)组、豆蔻明高剂量(high dose of Cardamonin,CDN-H)组、地塞米松(dexamethasone,DXM)组;单次气管注射BLM诱导肺纤维化,计算肺指数;酶联免疫吸附法测血清肿瘤坏死因子(tumor necrosis factor-α,TNF-α)水平;试剂盒测肺组织羟脯氨酸(hydroxyproline,HYP)含量,苏木精-伊红、马松染色观察肺炎症程度及纤维化情况,RT-PCR法检测肺组织TGF-β1/smad信号通路相关基因表达情况。结果与Sham组相比,BLM组小鼠肺指数、Szapiel评分、Ashcroft评分明显升高(P<0.05),肺部炎症程度和纤维化程度严重。血清中TNF-α含量升高(P<0.05)、肺组织HYP水平升高(P<0.05),TGF-β1[(1.02±0.21)vs.(3.25±0.14)]、smad2[(1.00±0.05)vs.(1.63±0.09)]、smad3[(1.00±0.06)vs.(1.82±0.07)]、α-平滑肌肌动蛋白(α-smoothmuscleactin,α-SMA)[(1.00±0.10)vs.(2.15±0.10)]mRNA表达升高(P<0.05),上皮-钙黏蛋白(E-Cadherin)[(1.01±0.16)vs.(0.57±0.09)]mRNA水平降低(P<0.05)。CDN-M、CDN-H干预可减低小鼠肺指数,减轻炎性和肺纤维化,降低TNF-α、HYP水平(P<0.05),同时下调肺纤维小鼠肺组织中TGF-β1、smad2、smad3、α-SMA表达,上调E-Cadherin表达。CDN-L无明显治疗效果,CDN-H治疗作用与DXM相似。结论CDN可能通过TGF-β1/Smad通路介导上皮-间充质转化而发挥抗纤维化作用。
文摘目的制备小豆蔻明纳米混悬剂(cardamonin nanosuspensions,Car-NPs),研究其体外抗肿瘤活性。方法采用反溶剂沉淀联合高压均质法制备Car-NPs,以平均粒径及多分散指数(polydispersity index,PDI)为评价指标,对药载比、均质压力、均质次数进行单因素考察,利用Box-Behnken效应面设计法优化处方工艺;对最优处方工艺制备的Car-NPs进行表征,以动态光散射法测定平均粒径、粒度分布和ζ电位,在不同生理介质中监测粒径变化考察介质稳定性,透析法考察载药纳米粒的体外药物释放;通过细胞计数试剂盒-8(CCK-8)法测定并评估小豆蔻明游离药物及Car-NPs对人肝癌HepG2细胞、小鼠乳腺癌4T1细胞的体外细胞毒性。结果选用P188为稳定剂制备Car-NPs,最佳工艺处方为药载比4∶1,均质压力为65.37 MPa,均质次数11次;所制备的Car-NPs平均粒径为(198.5±5.4)nm,PDI为0.191±0.020,载药量为(62.54±0.13)%,包封率为(95.65±0.26)%,透射电子显微镜(TEM)下呈均一的圆球状;Car-NPs在PBS、5%葡萄糖、生理盐水、人工胃肠液中都能够稳定存在,满足口服和iv给药要求;以0.1%聚乙烯吡咯烷酮(PVP)为保护剂,Car-NPs冻干复溶后粒径基本不变,便于长期保存;Car-NPs在磷酸盐缓冲液中,呈现出先速释后缓释的两相释放曲线,释药过程符合一级释放方程,Q=1-e^−0.1048 t+73.586),R^(2)=0.9903。在168 h内累积释放率达到76.49%,而相同条件下小豆蔻明物理混悬液的累积释放率仅有22.65%;Car-NPs显著提高了小豆蔻明对4T1细胞[半数抑制浓度(IC_(50)),113.2μg/mL vs 33.89μg/mL,P<0.001]和HepG2细胞的杀伤作用(IC_(50),126.4μg/mL vs 52.94μg/mL,P<0.001)。结论采用Box-Behnken效应面法优化了Car-NPs的处方和工艺,所制备的Car-NPs有效解决了小豆蔻明难溶、难给药问题,冻干后便于长期保存。Car-NPs提高了小豆蔻明的体外释放度和对肿瘤细胞的杀伤作用,口服有望提高生物利用度;基于滞留效应(enhanced pe
文摘小豆蔻明(cardamonin,CAR)的化学结构为2’,4’-二甲基-6’-甲氧基查尔酮,是一种主要存在于姜科山姜属植物草豆蔻种子中的黄酮类单体,生物活性广泛。由于其具有抗肿瘤作用,近年来倍受关注,并已有系列衍生物被合成。研究表明,CAR对多形性胶质母细胞瘤、Lewis肺癌、乳腺癌、结肠癌和前列腺癌等肿瘤细胞的生长均有抑制作用,其作用机制涉及哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)通路、核因子κB(nuclear factor kappa B,NF-κB)信号通路、谷氨酰胺转氨酶2、内源性凋亡途径、信号转导与转录激活因子3(signal transducer and activator of transcription 3,STAT3)、E-钙黏蛋白(E-cadherin)、细胞自噬、β-catenin和细胞周期调控等。本文主要对CAR及其衍生物的抗肿瘤作用及其机制进行综述。
