CN114728876A - 姜黄素类组合物及其处理肺纤维化的治疗潜力 - Google Patents
姜黄素类组合物及其处理肺纤维化的治疗潜力 Download PDFInfo
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- CN114728876A CN114728876A CN202080079524.8A CN202080079524A CN114728876A CN 114728876 A CN114728876 A CN 114728876A CN 202080079524 A CN202080079524 A CN 202080079524A CN 114728876 A CN114728876 A CN 114728876A
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Abstract
本发明公开了包含70％‑80％w/w四氢姜黄素类、10％‑20％w/w六氢姜黄素类和5％‑10％w/w八氢姜黄素类的组合物和其治疗应用。更具体地，本发明公开了包含70％‑80％w/w四氢姜黄素类、10％‑20％w/w六氢姜黄素类和5％‑10％w/w八氢姜黄素类的组合物在治疗性处理间质性肺病或肺纤维化中的用途。
Description
相关申请的交叉引用
这是一份要求于2019年10月15日提交的美国临时申请号62915068的优先权的非临时申请，其主题通过引用并入本文。
技术领域
本发明涉及姜黄素类组合物及其治疗应用。更具体地，本发明涉及包含四氢姜黄素类(THC)、六氢姜黄素类(HHC)和八氢姜黄素类(OHC)的组合物及其缓解肺纤维化症状的潜力。
背景技术
现有技术的描述
肺纤维化也称为间质性肺病(ILD)，是描述慢性肺部疾病的通用术语。它是由肺实质炎症和纤维化共同作用的结果(Kalchiem-Dekel等人,Interstitial Lung Disease andPulmonary Fibrosis:A Practical Approach for General Medicine Physicians withFocus on the Medical History,J Clin Med.2018Dec；7(12):476)。该病症以三种方式影响肺部：1)损伤肺组织、2)间质炎症和3)间质和肺泡中的纤维化。
ILD由各种环境、业余、职业或药物相关暴露或系统性自身免疫或结缔组织疾病(CTD)引起。化疗药物、抗心律失常药物、某些精神病学药物和一些抗生素(如环丙沙星)也已知会引起ILD。据报道，某些感染如CMV、HIV、细菌/真菌感染(肺炎、组织胞浆菌病和寄生虫感染(如肺吸虫)也会导致肺纤维化(Ross MH&Murray J.Occupational respiratorydisease in mining Occup Med(Lond).2004,54:304-310；Camus等人,Drug-induced andiatrogenic infiltrative lung disease Clin Chest Med.2004,25:479-519)。以下现有技术文献公开了ILD的重要病理特征。
i)Kalchiem-Dekel等人,Interstitial Lung Disease and PulmonaryFibrosis:A Practical Approach for General Medicine Physicians with Focus onthe Medical History,J Clin Med.2018Dec；7(12):476
ii)Raghu G,Brown KK.Interstitial lung disease:Clinical evaluation andkeys to an accurate diagnosis.Clin Chest Med.2004,25:409-419；
iii)King TE Jr.Clinical advances in the diagnosis and therapy of theinterstitial lung diseases.Am J Respir Crit Care Med.2005,172:268-279.
iv)Crystal等人,Interstitial lung disease:Current concepts ofpathogenesis,staging and therapy,The American Journal of Medicine,Volume 70,Issue 3,March1981,Pages 542-568
v)Harrison等人,Structural Features of Interstitial Lung Disease inSystemic Sclerosis,Am Rev Respir Dis,1991,144(3Pt 1):706-13.
ILD最常见的症状是呼吸急促，其随着疾病的严重程度恶化。ILD可引起多种并发症，包括肺动脉高压、呼吸衰竭和肺心病(右侧心力衰竭)。COVID-19感染的大流行已经影响了全世界的人口。COVID-19可能的并发症之一是肺纤维化，这会导致慢性呼吸困难、长期残疾并影响患者的生活质量。患者的临床、影像学和尸检报告显示肺纤维化，而现有的纤维化状况可能会使SARS-CoV-2感染复杂化(Zumla等人,“Reducing mortality from 2019-nCoV:host-directed therapies should be an option,”The Lancet,2020,395(10224):e35–e36；Ademola等人,Pulmonary Fibrosis in COVID-19Survivors:PredictiveFactors and Risk Reduction Strategies,Pulmonary Medicine,2020,Article ID6175964,10页)。已经描述了COVID-19中肺损伤的各种机制，其中涉及病毒和免疫介导的机制(Liu等人,“Overlapping and discrete aspects of the pathology andpathogenesis of the emerging human pathogenic coronaviruses SARS-CoV,MERS-CoV,and 2019-nCoV,”Journal of Medical Virology,vol.92,no.5,pp.491–494,2020)。进一步的氧化应激是增加COVID-19严重程度的主要因素，且抗氧化剂补充剂推荐用于针对COVID-19的治疗策略(Derouiche S,Oxidative Stress Associated with SARS-Cov-2(COVID-19)Increases the Severity of the Lung Disease-A Systematic Review.JInfect Dis Epidemiol,2020,6:121.doi.org/10.23937/2474-3658/1510121)。
ILD的治疗取决于疾病的诊断和严重程度。最常见的治疗方法包括施用抗生素和皮质类固醇。在某些情况下，还提供吸入氧气以减少由ILD引起的缺氧。硫唑嘌呤、N-乙酰半胱氨酸、环磷酰胺、环孢素、甲氨蝶呤、尼达尼布、吡非尼酮等药物也给药用于治疗ILD。ILD的晚期可能必须通过肺移植治疗。
由于ILD中的氧化还原失衡很严重，因此使用抗氧化剂进行治疗也有助于减轻疾病状况(Day B J,Antioxidants as Potential Therapeutics for Lung Fibrosis,Antioxid Redox Signal.2008；10(2):355–370)。据报道，源自药用植物的天然分子可减轻肺部炎症和相关疾病(Santana等人,Evidences of Herbal Medicine-Derived NaturalProducts Effects in Inflammatory Lung Diseases,Mediators Inflamm.2016；2016:2348968)。然而，仍然存在对在控制ILD症状方面非常有效的基于天然植物的组合物的工业需求。
从姜黄种中获得的化合物，特别是姜黄素类，以及它们在各种疾病和病症的治疗处理中的作用已得到充分证明。最近，姜黄素类的代谢物因其与姜黄素相似且优越的功效而备受关注(Majeed等人,Reductive Metabolites of Curcuminoids,NutrisciencePublishers LLC,2019)。姜黄素的还原代谢物如以STR#1表示的四氢姜黄素、以STR#2表示的六氢姜黄素和以STR#3表示的八氢姜黄素的药理活性尚待证实和开发用于工业应用。还原代谢物还包括四氢-去甲氧基姜黄素(STR#4)、四氢双-去甲氧基姜黄素(STR#5)、六氢-去甲氧基姜黄素(STR#6)、六氢双-去甲氧基姜黄素(STR#7)、八氢-去甲氧基姜黄素(STR#8)和八氢双-去甲氧基姜黄素(STR#9)。
姜黄素的这些还原代谢物通常被还原酶生物转化(Mimura等人，美国专利号US5266344；Pan等人，Biotransformation of curcumin through reduction andglucuronidation in mice,Drug Metab Dispos,1999,27(1):486-494)。它们也在自然界中被鉴定并从不同的植物来源中分离出来(Majeed等人，Reductive Metabolites ofCurcuminoids,Nutriscience Publishers LLC,2019)。本发明公开了一种组合物，其包含姜黄素类的代谢物，特别是四氢姜黄素、六氢姜黄素和八氢姜黄素，及其在肺纤维化处理中的治疗潜力。
本发明的主要目的是公开包含四氢姜黄素、六氢姜黄素和八氢姜黄素的组合物。
本发明的另一个目的是公开包含四氢姜黄素、六氢姜黄素和八氢姜黄素的组合物在间质性肺病的治疗性处理中的用途。
本发明实现了上述目的并提供了进一步的相关优点。
发明内容
在最优选实施方案中，本发明公开了包含70％-80％w/w四氢姜黄素类、10％-20％w/w六氢姜黄素类和5％-10％w/w八氢姜黄素类的组合物。
在另一优选实施方案中，本发明公开了在哺乳动物中治疗性处理间质性肺病的方法，所述方法包括向需要该治疗性处理的哺乳动物施用包含70％-80％w/w四氢姜黄素类、10％-20％w/w六氢姜黄素类和5％-10％w/w八氢姜黄素类的组合物的步骤。
在另一优选实施方案中，本发明公开了包含70％-80％w/w四氢姜黄素类、10％-20％w/w六氢姜黄素类和5％-10％w/w八氢姜黄素类的组合物在哺乳动物中治疗性处理间质性肺病的用途。
在另一优选实施方案中，本发明公开了在哺乳动物中抑制肥大细胞脱粒的方法，所述方法包括将肥大细胞与包含70％-80％w/w四氢姜黄素类、10％-20％w/w六氢姜黄素类和5％-10％w/w八氢姜黄素类的组合物接触的步骤以抑制组胺和细胞因子释放。
在另一优选实施方案中，本发明公开了包含70％-80％w/w四氢姜黄素类、10％-20％w/w六氢姜黄素类和5％-10％w/w八氢姜黄素类的组合物在哺乳动物中抑制肥大细胞脱粒的用途。
本发明的其他特征和优点将从以下更详细的描述中变得显而易见，这些描述通过示例的方式说明了本发明的原理。
附图简述
图1是显示用包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物处理的成纤维细胞中ROS减少的图示。***,P<0.001
图2是显示用包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物处理的肥大细胞组胺释放减少的图示。
图3是显示由IL1β诱导的肺上皮细胞(A549)细胞的上清液中，包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物对IL 6的减少的图示。
*表示P<0.05
图4A是显示使用包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物在淋巴细胞中观察到的炎症细胞积累减少的图示。***表示P<0.001
图4B是显示使用包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物在嗜酸性粒细胞中观察到的炎性细胞积累减少的图示。***表示P<0.001
图5是显示用包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物处理的动物肺裂解物中IL 6的相对基因表达的图示。***表示P<0.001
图6是显示用包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物处理的动物肺裂解物中IFN-γ的相对基因表达的图示。***表示P<0.001
图7是显示用包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物处理的动物肺MDA水平降低的图示。*表示P<0.05
图8是显示用包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物处理的动物的肺裂解物中SOD活性增加的图示。***表示P<0.001
图9是蛋白质印迹图像，显示用包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物处理的动物的肺裂解物中NRF-2蛋白的表达增加。
图10是显示用包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物处理的动物的肺裂解物中TGF-β表达降低的图示。*表示P<0.05
图11是肺切片的组织病理学图像，显示用包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物治疗的动物的肺部炎症减轻。
图12是肺切片的组织病理学图像，显示用包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物处理的动物中的胶原沉积减少。
图13是显示用包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物处理的动物肺中胶原沉积减少的图示。***表示P<0.001
图14是显示包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物处理的动物的肺裂解物中Col-1A的基因表达降低的图示。
优选实施方案的详述
在最优选实施方案中，本发明公开了包含70％-80％w/w四氢姜黄素类、10％-20％w/w六氢姜黄素类和5％-10％w/w八氢姜黄素类的组合物。在相关方面，所述四氢姜黄素类包括四氢姜黄素、四氢-去甲氧基姜黄素和四氢双-去甲氧基姜黄素。在另一相关方面，所述六氢姜黄素类进一步包括六氢姜黄素、六氢-去甲氧基姜黄素和六氢双-去甲氧基姜黄素。在另一相关实施方案中，所述六氢姜黄素类以外消旋形式存在或作为其两个手性(S或R)形式之一。在另一优选实施方案中，八氢姜黄素类进一步包括八氢姜黄素、八氢-去甲氧基姜黄素和八氢双-去甲氧基姜黄素。在另一相关实施方案中所述八氢姜黄素类以内消旋或右旋或左旋形式存在(所有形式都存在于本实施方案中，并声称是活性形式的一部分)。在另一相关方面，所述组合物进一步包含稳定剂、生物利用度增强剂和抗氧化剂、药物或营养学或化妆品可接受的赋形剂和增强剂。
在另一优选实施方案中，本发明公开了在哺乳动物中治疗性处理间质性肺病的方法，所述方法包括向需要该治疗性处理的哺乳动物施用包含70％-80％w/w四氢姜黄素类、10％-20％w/w六氢姜黄素类和5％-10％w/w八氢姜黄素类的组合物的步骤。在相关方面，所述四氢姜黄素类包括四氢姜黄素、四氢-去甲氧基姜黄素和四氢双-去甲氧基姜黄素。在另一相关方面，所述六氢姜黄素类进一步包括六氢姜黄素、六氢-去甲氧基姜黄素和六氢双-去甲氧基姜黄素。在另一优选实施方案中，八氢姜黄素类进一步包括八氢姜黄素、八氢-去甲氧基姜黄素和八氢双-去甲氧基姜黄素。在另一相关方面，所述治疗效果通过以下带来：减少胶原沉积，减少胶原1A基因表达，减少TGF-β水平，减少氧化应激和炎症，降低支气管肺泡灌洗(BAL)液中炎性细胞的积聚和抑制肥大细胞脱粒。在另一相关方面，所述组合物进一步包含稳定剂、生物利用度增强剂和抗氧化剂、药物或营养学或化妆品可接受的赋形剂和增强剂。在一个优选实施方案中，所述哺乳动物为人。
在另一优选实施方案中，本发明公开了包含70％-80％w/w四氢姜黄素类、10％-20％w/w六氢姜黄素类和5％-10％w/w八氢姜黄素类的组合物在哺乳动物中治疗性处理间质性肺病的用途。在相关方面，所述四氢姜黄素类包括四氢姜黄素、四氢-去甲氧基姜黄素和四氢双-去甲氧基姜黄素。在另一相关方面，所述六氢姜黄素类进一步包括六氢姜黄素、六氢-去甲氧基姜黄素和六氢双-去甲氧基姜黄素。在另一优选实施方案中，八氢姜黄素类进一步包括八氢姜黄素、八氢-去甲氧基姜黄素和八氢双-去甲氧基姜黄素。在另一相关方面，所述治疗效果通过以下带来：减少胶原沉积，减少胶原1A基因表达，降低TGF-β水平，减少氧化应激和炎症，降低支气管肺泡灌洗(BAL)液中炎性细胞的积聚和抑制肥大细胞脱粒。在另一相关方面，所述组合物进一步包含稳定剂、生物利用度增强剂和抗氧化剂、药物或营养学或化妆品可接受的赋形剂和增强剂。在一个优选实施方案中，所述哺乳动物为人。
在另一优选实施方案中，本发明公开了在哺乳动物中抑制肥大细胞脱粒的方法，所述方法包括将肥大细胞与包含70％-80％w/w四氢姜黄素类、10％-20％w/w六氢姜黄素类和5％-10％w/w八氢姜黄素类的组合物接触的步骤以抑制组胺和细胞因子释放。在相关方面，所述四氢姜黄素类包括四氢姜黄素、四氢-去甲氧基姜黄素和四氢双-去甲氧基姜黄素。在另一相关方面，所述六氢姜黄素类进一步包括六氢姜黄素、六氢-去甲氧基姜黄素和六氢双-去甲氧基姜黄素。在另一优选实施方案中，八氢姜黄素类进一步包括八氢姜黄素、八氢-去甲氧基姜黄素和八氢双-去甲氧基姜黄素。在另一相关方面，所述组合物进一步包含稳定剂、生物利用度增强剂和抗氧化剂、药物或营养学或化妆品可接受的赋形剂和增强剂。在一个优选实施方案中，所述哺乳动物为人。
在另一优选实施方案中，本发明公开了包含70％-80％w/w四氢姜黄素类、10％-20％w/w六氢姜黄素类和5％-10％w/w八氢姜黄素类的组合物在哺乳动物中抑制肥大细胞脱粒的用途。在相关实施方案中，肥大细胞脱粒的抑制通过以下带来：抑制组胺和细胞因子从肥大细胞释放。在相关方面，所述四氢姜黄素类包括四氢姜黄素、四氢-去甲氧基姜黄素和四氢双-去甲氧基姜黄素。在另一相关方面，所述六氢姜黄素类进一步包括六氢姜黄素、六氢-去甲氧基姜黄素和六氢双-去甲氧基姜黄素。在另一优选实施方案中，八氢姜黄素类进一步包括八氢姜黄素、八氢-去甲氧基姜黄素和八氢双-去甲氧基姜黄素。在另一相关方面，所述组合物进一步包含稳定剂、生物利用度增强剂和抗氧化剂、药物或营养学或化妆品可接受的赋形剂和增强剂。在一个优选实施方案中，所述哺乳动物为人。
在另一相关实施方案中所述生物利用度增强剂选自，但不限于，胡椒碱、槲皮素、大蒜萃取物、生姜提取物和柚皮苷。
在另一相关方面，一种或多种抗氧化剂和抗炎剂选自，但不限于，维生素A、D、E、K、C、B复合物、迷迭香酸、α硫辛酸、柔花酸、甘草酸、表没食子儿茶素没食子酸酯、植物多酚、光甘草定、辣木油、齐墩果酸、橄榄苦甙、鼠尾草酸、尿刊酸、八氢番茄红素、硫辛酸、硫辛酰胺、铁蛋白、得斯芬、胆红素、胆绿素、黑色素、泛醌、泛醇、抗坏血酸棕榈酸酯、抗坏血酸磷酸镁、抗坏血酸乙酸酯、生育酚和衍生物如维生素E乙酸酯、尿酸、α-葡萄基芸香苷、过氧化氢酶和超氧化物歧化酶、谷胱甘肽、硒化合物、丁基羟基苯甲醚(BHA)、丁基羟基甲苯(BHT)、偏亚硫酸氢钠(SMB)、没食子酸丙酯(PG)和氨基酸半胱氨酸。
阐述最优选实施方案的具体说明性示例包括在下文中。
实施例
实施例1：组合物
姜黄素类的还原代谢物即四氢姜黄素类、六氢姜黄素类和八氢姜黄素类通常通过还原酶和氢化进行生物转化(Mimura等人，美国专利号US 5266344；Pan等人，Biotransformation of curcumin through reduction and glucuronidation in mice,Drug Metab Dispos,1999,27(1):486-494)。它们也在自然界中被鉴定并从不同的植物来源中分离出来(Majeed等人，Reductive Metabolites of Curcuminoids,NutrisciencePublishers LLC,2019)。四氢姜黄素及其类似物四氢去甲氧基姜黄素、四氢双去甲氧基姜黄素已从姜属物种和姜黄属物种分离出来(Peng等人，Chemical constituents ofZingiber officinale(Zingeberaceae)。Yunnan Zhiwu Yanjiu，2007；29(1):125-128)。据报道，四氢去甲氧基姜黄素和四氢双去甲氧基姜黄素存在于Thai Zeodary(Curcumazedoaria)的根茎中(Matsuda等人,Anti-allergic principles from Thai zedoary:structural requirements of curcuminoids for inhibition of degranulation andeffect on the release of TNF-alpha and IL-4in RBL-2H3 cells.Bioorg med hem,2004；12(22):5891-5898)。四氢姜黄素也通过姜黄素的生物转化获得(Shimoda等人，Formation of tetrahydrocurcumin by reduction of curcumin withcultured plantcells of Marchantia polymmrpha,Nat Prod Commun,2012,7(4):529-530)。
六氢姜黄素类也是一种天然存在的植物代谢物，存在于姜黄、姜和Alpina的根和根茎中。六氢姜黄素类已从新鲜生姜的根茎中分离出来(Peng等人，Cytotoxic，cytoprotective and andoxidant effects of isolated phenolic Compounds fromfresh ginger，Fitoterapia，2012，83(3):568-585)。据报道，六氢姜黄素类以两种对映体形式(S&R)中的任何一种形式存在，也以外消旋混合物的形式存在(Majeed等人，ReductiveMetabolites of Curcuminoids,Nutriscience Publishers LLC,2019)。
类似地，八氢姜黄素类也从印尼莪术(C.xanthorrhiza)的根茎中分离出来(Uehara等人，Diarylheptanoids from the rhizomes of Curcuma xanthorrhiza andAlpinia officinarum,Chem Pharm Bull,1987,35(8):3298-3304)。八氢姜黄素也是通过氢化形式四氢姜黄素体内和微生物生物转化制备的(Majeed等人，Reductive Metabolitesof Curcuminoids,Nutriscience Publishers LLC,2019)
本发明中要求保护的组合物是使用以下氢化方法配制的：
将姜黄素类在溶剂丙酮中在氢气压力下在钯/碳存在下在室温下还原，直到起始材料不存在消失。产物分离为灰白色粉末，其包含四氢姜黄素、四氢去甲氧基姜黄素和四氢双去甲氧基姜黄素。此外，在钯/碳存在下，在特定温度和氢气压力下，在溶剂乙醇中将四氢姜黄素类选择性还原为六氢姜黄素类，直至起始材料消失。产物分离为灰白色粉末，其包含六氢姜黄素类和<5％的八氢姜黄素类。为了制备八氢姜黄素类，在钯/碳的存在下，在高温和氢气压力下，在溶剂乙醇中将四氢姜黄素类还原为八氢姜黄素类，直到原料完全转化。该产物被分离为灰白色粉末，主要是八氢姜黄素类和微量六氢姜黄素类。
四氢姜黄素类、六氢姜黄素类和八氢姜黄素类以以下比例混合:
表1：组合物
| 内含物 | 百分比(w/w) |
| 四氢姜黄素类 | 70-80 |
| 六氢姜黄素类 | 10-20 |
| 八氢姜黄素类 | 5-10 |
该组合物也可作为C3
Special从Sami Labs Limited商购。
实施例2：包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物的治疗潜力
与姜黄素类和四氢姜黄素类相比，通过评估其ORAC和ROS&DPPH清除潜力来测试包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物的治疗潜力。
氧自由基吸收能力测定(ORAC)：
将不同浓度的标准品(Trolox)(T5至T1)或测试样品(S3至S1)、APPH(2,2'-偶氮双(2-脒基丙烷二盐酸盐)和荧光素二钠染料添加到96孔暗板。在485/520nm(FluostarOptima Microplate Reader)下每1分钟记录荧光读数达35分钟(f1……f35)。曲线下面积(AUC)计算如下：
AUC＝(1+f1/f0+f2/f0+……+f35/f0)
净AUC是通过从样品的AUC中减去空白的AUC获得的。最终的ORAC值表示为每升或每克样品的微摩尔Trolox当量(μmol TE/g或μmol TE/L)。
DPPH(2,2-二苯基-1-苦基-肼基-水合物)自由基测定
将测试样品溶解在DMSO中并在50％甲醇中稀释以用于测定。在96孔板中将不同浓度的组合物和个体活性物质与甲醇中的DPPH溶液混合。将板在黑暗中孵育15分钟，并使用微板读取器(TECAN Ltd，
Switzerland)在540nm处测量吸光度。同时记录空白(DMSO、甲醇)和标准品(DMSO中的Trolox溶液)。
自由基清除活性计算如下，
％清除活性＝(B-C)-(S-C)/(B-C)*100
其中，B是参比溶液的吸光度，C是参比溶液空白(仅甲醇)的吸光度，S是测试溶液的吸光度，C是测试溶液空白的吸光度。用不同浓度筛选样品以确定抑制浓度(IC50，将DPPH吸光度降低50％的浓度)。结果列于表2：
表2：包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物(THO组合物)的ORAC和DPPH清除潜力
结果显示，与姜黄素类和四氢姜黄素类相比，包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物显示出更好的ORAC和DPPH清除，表明组合物具有更高的治疗功效。评估了该组合物本身的进一步的治疗活性。
细胞内活性氧物质(ROS)测定
将Swiss 3T3(5×104细胞/孔)细胞接种在96孔黑色微孔板中，并使其生长过夜。在有或没有DMEM 1％FBS中的不同浓度的样品的情况下，用H2O2(25mM)诱导细胞4小时。将新鲜制备的DCFH-DA试剂以10μg/孔的浓度添加到所有孔中，并在37℃下孵育30分钟。在BMGFluo Star Optima微板读取器中以485:520(Ex:Em)nm的波长记录荧光。相对于H2O2处理的对照细胞的荧光强度计算ROS清除的百分比。
结果(图1)表明该组合物在降低成纤维细胞中的ROS方面非常有效，IC50为29.64μg/mL。
实施例3-肺纤维化–体外测试
组合物在处理肺纤维化和抑制肥大细胞脱粒方面的潜力通过以下体外试验进行测试：
肥大细胞在处理和触发炎症反应和即时过敏反应方面发挥重要作用。它们释放多种炎症介质，如组胺、蛋白酶、趋化因子、细胞因子和花生四烯酸的代谢物，这些炎症介质作用于脉管系统、平滑肌、结缔组织、粘液腺和炎症细胞(Amin K,The role of mast cellsin allergic inflammation,Respiratory Medicine,2012；106；9-14)。据报道，与对照受试者相比，患有纤维化肺病的患者肺部的肥大细胞数量增加，并且与纤维化的严重程度呈正相关。此外，IPF患者BAL液中的组胺浓度比对照组高约10倍(Cruse等人,Mast cells inairway diseases and interstitial lung disease,Eur J Pharmacol.2016；778:125–138)。因此，必须抑制ILD受试者的肥大细胞脱粒。
测试了该组合物防止肥大细胞中组胺和细胞因子释放的能力。
组胺释放测试
P815细胞购自美国典型培养物保藏中心(ATCC,Manassas,VA,USA)，并在补充有10％(v/v)热灭活胎牛血清(FBS,Gibco,UK)的Dulbecco最小必需培养基(Gibco,UK)中培养，并保持在37℃的5％CO2培养箱中。当细胞达到80％融合时，将它们收获，重新悬浮在新鲜培养基中，并在24孔板中每孔接种5x105个细胞用于实验。
细胞用冰冷的HEPES缓冲的Tyrode溶液(包含0.1％牛血清白蛋白，不含Ca++和Mg++(由137mmol/L NaCl，5.6mmol/L葡萄糖，2.7mmol/L KC1，0.4mmol/L NaH2PO4，和10mmol/LHEPES构成[pH 7.4]))洗涤细胞后，将细胞用不同浓度的组合物以及30μg化合物48/80处理。孵育3小时后，将板置于冰上10分钟以终止脱粒。然后在以5000rpm离心5分钟后收集上清液。向50μL上清液中加入50μL 4N NaOH和10μL邻苯二甲醛(10mg/mL)，室温避光孵育10分钟。然后用50μL 1N HCl终止反应，并在390/460ex/em记录荧光。相对于化合物48/80处理的对照细胞的荧光强度计算组胺释放的百分比。
结果(图2)表明50μg/mL的组合物有效降低肥大细胞上清液中组胺的释放。
体外肺炎测定
将A549(1×104细胞/孔)细胞接种在96孔微孔板中并使其生长过夜。血清饥饿过夜后，在1％FBS RPMI 1％FBS培养基中，用IL1β(5ng/mL)在有或没有不同浓度的组合物的情况下预处理细胞4小时。此外，细胞仅用样品处理24小时。24小时后，收集上清液，按照制造商的说明通过ELISA(R&D Systems，Minneapolis，Minnesota，USA)测定IL6的水平。相对于IL1β处理的对照计算IL6的抑制百分比。
该组合物有效降低IL1β诱导的A549细胞上清液中IL 6(一种炎性细胞因子)的水平(图3)
该组合物在防止组胺释放和抑制肥大细胞脱粒方面非常有效，因此可用于治疗不同形式的过敏症。
实施例4：肺纤维化的体内研究
动物实验遵循的协议由机构动物伦理委员会根据印度的动物实验控制和监督委员会(CPCSEA)批准，符合印度政府的指导方针并符合美国国立卫生研究院出版的《实验动物的护理和使用指南》(NIH出版物，第8版，2011年)。将总共40只C57/BL6小鼠(6-8周龄)随机分为5组(平均体重20-22g)，每组8只小鼠。动物饲养在标准实验室条件下(温度23.5℃，湿度＝58–64％)，光照12小时且黑暗12小时的循环，以正常饮食和随意饮水喂养。
为了建立肺纤维化模型，实验小鼠通过气管内滴注施用单剂量5mg/kg体重的博来霉素，对照小鼠接受盐水。对于治疗性治疗，在博来霉素气管内给药后，从第3天开始，小鼠通过口服管饲法接受C3R混合物(20、40和80mg/kg)持续三周。在实验期结束时，将动物人道处死，收集器官、组织和血液用于进一步分析。记录所有动物的体重和器官重量。肺被解剖出来，称重，然后储存在RNA later或OCT中用于组织学分析
抗氧化和抗炎作用
支气管肺泡灌洗(BAL)。
通过将5ml无菌盐水气管内滴入肺部来收集BAL液(BALF)。然后将整个BALF以1500rpm的速度离心5分钟。离心后，使用血液分析仪分析残余悬浮液以测定总细胞、嗜中性粒细胞、嗜酸性粒细胞和淋巴细胞计数。
在接受治疗的动物的淋巴细胞(图4A)和嗜酸性粒细胞(图4B)中观察到的炎症细胞积累减少
同样，使用标准程序评估IL-6和IFN-γ水平。使用trizol方法从肺样品中提取RNA。将肺组织在液氮中匀浆，然后进行trizol提取和DNA酶以去除任何痕量的DNA。使用oligodT引物和Superscript III逆转录酶(cDNA合成试剂盒，InvitrogenTM)从RNA样品制备第一链cDNA。根据制造商的说明(Light
FastStart DNA Master SYBR Green I，Roche)，使用Light Cycler 96使用SYBR Green I荧光染料进行定量实时PCR(qRT-PCR)。用于分析的引物在表3中提供。18s基因用作管家基因。使用比较Ct(ΔΔCt)方法通过相对定量确定每个测试样品中靶基因的基因表达。
表3：IL-6和IFN-γ表达的引物列表
与博来霉素组相比，该组合物有效降低肺裂解物中IL 6(图5)和IFN-γ(图6)的相对基因表达
MDA
丙二醛是组织匀浆中的脂质过氧化终产物，根据Beuge和Aust.,1978的方法(进行了一些修改)测定。将组织匀浆与等体积的TBA-TCA-HCl溶液(0.5％TBA、20％TCA和0.25NHCl)混合。将混合物在沸水浴(95–100℃)中加热30分钟并立即冷却。将试管以10,000rpm离心10分钟，在532nm处读取上清液的吸光度。脂质过氧化物的水平表示为形成的μM MDA/mg蛋白质。
用该组合物处理的组中MDA水平显著降低(图7)
SOD
超氧化物歧化酶(SOD)，一种抗氧化酶，可催化超氧化物歧化为过氧化氢和氧气。它保护肺部免受导致肺纤维化等疾病的氧化损伤
SOD的活性是通过WST-1方法使用试剂盒按照制造商的说明(Elabsciences)测量的。黄嘌呤氧化酶(XO)催化WST-1与O2-反应生成水溶性甲臜染料。SOD催化超氧阴离子的歧化。SOD的活性与甲臜染料的量呈负相关。
该组合物显著增加了SOD的活性(图8)。
Nrf2表达
核因子红细胞2相关因子2(Nrf2)是抗氧化防御系统的关键调节因子，可保护细胞免受氧化应激。
将动物的冷冻肺均质化，并使用含有蛋白酶(1x蛋白酶抑制剂混合物-HI培养基)和磷酸酶(原钒酸钠1mM)的冰冷RIPA缓冲液裂解细胞。通过BCA方法(G-Biodciences，USA)评估蛋白质浓度。在变性10％聚丙烯酰胺凝胶(SDS-PAGE)中每个泳道上样细胞蛋白(100μg)。将分离的蛋白质转移到聚偏二氟乙烯膜(InvitrolonTM PVDF，Thermo FisherScientific，USA)并在5％脱脂奶粉中封闭2小时。然后将膜与适当稀释的抗小鼠一抗在4℃下孵育18小时，然后在37℃下与辣根过氧化物酶偶联的二抗(Thermo Scientific，USA)孵育2小时。通过ECL((Pierce ECL plus,Thermo Scientific，USA)检测免疫反应蛋白条带。使用Image J软件(1.52a版，美国国立卫生研究院)对免疫印迹进行定量。表4列出了用于实验的抗体
表4：抗体列表
与博来霉素诱导组相比，该组合物在恢复肺裂解物中NRF-2(一种调节抗氧化酶以防止组织氧化损伤的蛋白质)表达方面有效(图9)
TGF-β表达
TGF-β途径在肺纤维化中起关键作用。它诱导促进结缔组织增殖的生长因子的分泌，促进肺泡细胞中的上皮-间质转化(EMT)并调节金属蛋白酶活性和组织重塑。抑制TGF-β被批准用于特发性肺纤维化(IPF)的临床治疗(例如吡非尼酮)
在本发明中，肺匀浆中TGF-β的浓度是按照制造商的说明通过ELISA(R&D Systems(Minneapolis,Minnesota,USA)进行的。结果表示为肺匀浆每mg蛋白质的浓度。该组合物在40和80mg/kg体重时有效降低肺匀浆中TGF-β的浓度(图10)
组织学分析
对于苏木精和伊红染色，切片从肺组织的石蜡块上切下，该石蜡块以Bouin溶液预固定，并用Lillie-Mayer苏木精(Muto Pure Chemicals Co.，Ltd.，Japan)和伊红溶液(Wako Pure Chemical Industries)染色。为了可视化胶原蛋白沉积，Bouin固定肺切片使用天狼猩红溶液(Waldeck，Germany)染色。对于纤维化区域的定量分析，使用明场显微镜(Nikon Eclipse)捕获天狼星红染色切片的明场图像和图片，并使用ImageJ软件(美国国立卫生研究院，美国)测量。
在组织病理学分析中观察到肺部炎症显著减少(图11)。在给予组合物的组中，肺组织肺泡处的胶原沉积也显著减少(图12和图13)
还使用定量RT-PCR评估胶原1A基因表达。使用trizol方法从肺样本中提取RNA。将肺组织在液氮中匀浆，然后进行trizol提取和DNA酶以去除任何痕量的DNA。使用oligodT引物和Superscript III逆转录酶(cDNA合成试剂盒，InvitrogenTM)从RNA样品制备第一链cDNA。根据制造商的说明(Light
FastStart DNA Master SYBR Green I，Roche)，使用Light Cycler 96使用SYBR Green I荧光染料进行定量实时PCR(qRT-PCR)。用于分析的引物在表5中提供。18s基因用作管家基因。使用比较Ct(ΔΔCt)方法通过相对定量确定每个测试样品中靶基因的基因表达。
表5：引物列表
与博来霉素诱导组相比，该组合物有效降低肺裂解物中Col-1A(在结缔组织中发现的I型胶原蛋白)的相对基因表达(图14)。
总体而言，包含四氢姜黄素类、六氢姜黄素类和八氢姜黄素类的组合物在减少博莱霉素诱导的小鼠肺和纤维化中的纤维化和炎症标志物方面是有效的。它可以减少肥大细胞释放组胺，表明具有抗过敏活性。该组合物非常适合作为治疗呼吸系统疾病，包括ILD和SARS-CoV-2诱发的急性呼吸综合征的补充剂。
虽然已经参考优选实施方案描述了本发明，但是本领域技术人员应该清楚地理解本发明不限于此。相反，本发明的范围将仅结合所附权利要求来解释。
序列表
<110> Majeed, Muhammed
Nagabhushanam, Kalyanam
Mundkur, Lakshmi
Ramanujam, Rajendran
<120> 姜黄素类组合物及其处理肺纤维化的治疗潜力
<130> C3 reduct special
<160> 8
<170> PatentIn版本3.5
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<213> 人工序列
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<223> m Cola1的正向引物
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<213> 人工序列
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<213> 人工序列
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<211> 20
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<213> 人工序列
<220>
<223> IL6的反向引物
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Claims (20)
1.组合物，其包含70％-80％w/w四氢姜黄素类、10％-20％w/w六氢姜黄素类和5％-10％w/w八氢姜黄素类。
2.权利要求1所述的组合物，其中所述四氢姜黄素类包括四氢姜黄素、四氢-去甲氧基姜黄素和四氢双-去甲氧基姜黄素。
3.权利要求1所述的组合物，其中所述六氢姜黄素类包括六氢姜黄素、六氢-去甲氧基姜黄素和六氢双-去甲氧基姜黄素。
4.权利要求3所述的组合物，其中所述六氢姜黄素类以外消旋形式存在或作为其两个手性(S或R)形式之一。
5.权利要求1所述的组合物，其中所述八氢姜黄素类包括八氢姜黄素、八氢-去甲氧基姜黄素和八氢双-去甲氧基姜黄素。
6.权利要求5所述的组合物，其中所述八氢姜黄素类以内消旋形式或右旋或左旋形式存在。
7.权利要求1所述的组合物，其中所述组合物进一步包含稳定剂、生物利用度增强剂和抗氧化剂、药物或营养学或化妆品可接受的赋形剂和增强剂。
8.在哺乳动物中治疗性处理间质性肺病的方法，所述方法包括向需要该治疗性处理的哺乳动物施用包含70％-80％w/w四氢姜黄素类、10％-20％w/w六氢姜黄素类和5％-10％w/w八氢姜黄素类的组合物的步骤。
9.权利要求8所述的方法，其中所述四氢姜黄素类包括四氢姜黄素、四氢-去甲氧基姜黄素和四氢双-去甲氧基姜黄素。
10.权利要求8所述的方法，其中所述六氢姜黄素类包括六氢姜黄素、六氢-去甲氧基姜黄素和六氢双-去甲氧基姜黄素。
11.权利要求8所述的方法，其中八氢姜黄素类进一步包括八氢姜黄素、八氢-去甲氧基姜黄素和八氢双-去甲氧基姜黄素。
12.权利要求8所述的方法，其中所述治疗效果为减少胶原沉积，减少胶原1A基因表达，减少TGF-β水平，减少氧化应激和炎症，降低支气管肺泡灌洗(BAL)液中炎性细胞的积聚和抑制肥大细胞脱粒。
13.权利要求8所述的方法，其中所述组合物进一步包含稳定剂、生物利用度增强剂和抗氧化剂、药物或营养学或化妆品可接受的赋形剂和增强剂。
14.权利要求8所述的方法，其中所述哺乳动物为人。
15.在哺乳动物中抑制肥大细胞脱粒的方法，所述方法包括将肥大细胞与包含70％-80％w/w四氢姜黄素类、10％-20％w/w六氢姜黄素类和5％-10％w/w八氢姜黄素类的组合物接触的步骤，以抑制组胺和细胞因子释放。
16.权利要求15所述的方法，其中所述四氢姜黄素类包括四氢姜黄素、四氢-去甲氧基姜黄素和四氢双-去甲氧基姜黄素。
17.权利要求15所述的方法，其中所述六氢姜黄素类进一步包括六氢姜黄素、六氢-去甲氧基姜黄素和六氢双-去甲氧基姜黄素。
18.权利要求15所述的方法，其中八氢姜黄素类进一步包括八氢姜黄素、八氢-去甲氧基姜黄素和八氢双-去甲氧基姜黄素。
19.权利要求15所述的方法，其中所述组合物进一步包含稳定剂、生物利用度增强剂和抗氧化剂、药物或营养学或化妆品可接受的赋形剂和增强剂。
20.权利要求15所述的方法，其中所述哺乳动物为人。
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| CN202080079524.8A Pending CN114728876A (zh) | 2019-10-15 | 2020-10-15 | 姜黄素类组合物及其处理肺纤维化的治疗潜力 |
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| KR20230121791A (ko) * | 2020-12-17 | 2023-08-21 | 새미-사빈사 그룹 리미티드 | 섬유아세포-유사 활막세포 매개된 류마티스 관절염의효과적인 관리를 위한 조성물 |
| JP2024513775A (ja) * | 2021-03-25 | 2024-03-27 | サミ－サビンサ グループ リミテッド | 腎症を管理するための組成物及び方法 |
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| US11707438B2 (en) | 2023-07-25 |
| US20210106543A1 (en) | 2021-04-15 |
| US11491119B2 (en) | 2022-11-08 |
| JP2022551967A (ja) | 2022-12-14 |
| CA3153877C (en) | 2024-04-02 |
| CN114746102A (zh) | 2022-07-12 |
| US20210106544A1 (en) | 2021-04-15 |
| EP4045478A4 (en) | 2024-01-10 |
| WO2021076766A1 (en) | 2021-04-22 |
| JP2022553173A (ja) | 2022-12-22 |
| CA3153879A1 (en) | 2021-04-22 |
| EP4045478A1 (en) | 2022-08-24 |
| WO2021076771A1 (en) | 2021-04-22 |
| CA3153877A1 (en) | 2021-04-22 |
| EP4045071A4 (en) | 2023-11-29 |
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