CN116327771B - 一种用于治疗炎症及相关疾病的联合用药物 - Google Patents
一种用于治疗炎症及相关疾病的联合用药物 Download PDFInfo
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Abstract
本发明提供了一种用于治疗炎症及相关疾病的联合用药物，属于医药技术领域。本发明首次发现，烟酸和化合物9n均可通过HCAR2依赖Gi信号转导发挥抗炎作用，降低促炎因子水平，治疗炎症及其相关疾病(例如高血脂、心脑血管疾病以及脂类代谢异常)，减轻炎症引起的肺损伤和肝肾损伤。本发明首次发现本发明将烟酸和化合物9n联用，在增强烟酸治疗效果的同时，还降低了烟酸的施用剂量，可以减轻烟酸带来的副作用(例如血尿酸升高、胃肠道反应、皮肤潮红等)。
Description
技术领域
本发明属于医药技术领域，具体涉及一种用于治疗炎症及相关疾病的联合用药物。
背景技术
心脑血管疾病是威胁全球人类的死因之首，动脉粥样硬化是心脑血管疾病发生的主要病理基础和重要环节。动脉粥样硬化的发病机制复杂，其中，脂质代谢异常是动脉粥样硬化的主要病变基础。控制血脂是动脉粥样硬化常用的预防与治疗手段。
烟酸(niacin，NA)，又名维生素B3，化学名为3-吡啶甲酸，在人体内组成辅酶Ⅰ和辅酶Ⅱ并参与脂代谢等多种重要代谢过程。烟酸作为降血脂、预防心脑血管疾病以及脂类代谢异常的药物已有多年历史。人体正常的需求量为每天20mg，生理浓度的烟酸无法激动烟酸受体，临床通常采用大剂量口服(1～2g·d-1)用于降血脂与抗心脑血管疾病治疗。研究表明，烟酸可通过激动盐酸受体，促进胆固醇逆转运，发挥降脂功能，降低血清总胆固醇(TC)与甘油三酯(TG)，升高高密度脂蛋白胆固醇(HDL-C)，改善内皮细胞功能，抑制炎症反应，发挥抗心脑血管疾病作用。但是，一方面，大剂量口服烟酸，易导致血尿酸升高、胃肠道反应和皮肤潮红等副作用，降低了其临床用药依从性；另一方面，烟酸在抗炎、降血脂、预防心脑血管疾病以及脂类代谢异常等方面的药效要有待进一步的提高。为了克服上述问题，亟需开发出一种不仅能够减轻烟酸的副作用，还能够提高烟酸的治疗效果的药物。
发明内容
本发明的目的在于提供一种用于治疗炎症及相关疾病的联合用药物，以及HCAR2变构分子与烟酸联用在制备治疗炎症及其相关疾病的药物中的用途。
本发明提供了一种用于治疗炎症及相关疾病的联合用药物，它含有相同或不同规格单位制剂的用于同时或者分别给药的HCAR2变构分子和烟酸，以及药学上可接受的载体。
进一步地，所述HCAR2变构分子为化合物9n
进一步地，所述HCAR2变构分子与烟酸的摩尔比为1：(0.5～4)。
进一步地，所述HCAR2变构分子与烟酸的摩尔比为1：2。
进一步地，所述HCAR2变构分子与烟酸的质量比为1：(5～15)。
进一步地，所述HCAR2变构分子与烟酸的质量比为1：10。
本发明还提供了上述的联合用药物在制备治疗炎症及相关疾病的药物中的用途。
进一步地，所述炎症相关疾病为器官损伤、高血脂、心脑血管疾病或脂类代谢异常。
进一步地，所示器官损伤为肺损伤、肝损伤或肾损伤；所述心脑血管疾病为动脉粥样硬化。
进一步地，所述药物是降低烟酸引起的副作用的药物，所述副作用优选为血尿酸升高、胃肠道反应或皮肤潮红。
羟基羧酸受体2(HCAR2)也称为HM74、GPRl09A，是一种羟基羧酸受体，主要在脂肪细胞、免疫细胞、上皮细胞等表达。
化合物9n是一种已知的HCAR2变构分子。HCAR2变构分子指配体分子与HCAR2非底物结合位点结合，但对蛋白活性发挥重要调控的作用，即变构调节分子。
本发明首次发现，烟酸和化合物9n均可通过HCAR2依赖Gi信号转导发挥抗炎作用，降低促炎因子水平，治疗炎症及其相关疾病(例如高血脂、心脑血管疾病以及脂类代谢异常)，减轻炎症引起的肺损伤和肝肾损伤。
利用LPS刺激巨噬细胞诱导炎症模型，本发明首次发现烟酸和化合物9n联合使用的治疗效果优于单纯烟酸治疗或单纯化合物9n治疗。在相同剂量下，烟酸与化合物9n联合使用对炎症模型促炎因子的下调作用优于单独采用烟酸与单独采用化合物9n的作用之和，烟酸与化合物9n联合使用的抗炎效果发挥了协同增效的作用。
利用LPS诱导系统性炎症小鼠模型，本发明首次发现烟酸和化合物9n联合使用可以改善LPS诱导的系统性炎症小鼠的肝肾功能，减轻LPS诱导的系统性炎症小鼠的肺损伤和肝肾损伤。
本发明将烟酸和化合物9n联用，在增强烟酸治疗效果的同时，还降低了烟酸的施用剂量，可以减轻烟酸带来的副作用(例如血尿酸升高、胃肠道反应、皮肤潮红等)。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1.烟酸的抗炎效果：各组HCAR2、IL-1β、IL-6、TNF-α、MCP-1mRNA表达量。
图2.烟酸通过HCAR2抗炎的实验结果：各组HCAR2、IL-1β、IL-6、TNF-α、MCP-1mRNA表达量。
图3.化合物9n的抗炎效果：各组HCAR2、IL-1β、IL-6、TNF-α、MCP-1mRNA表达量。
图4.烟酸和化合物9n联用的抗炎效果：各组IL-1β、IL-6、TNF-α、MCP-1mRNA表达量。
图5.烟酸和化合物9n依赖Gi信号转导发挥抗炎作用的实验结果：各组IL-1β、IL-6、TNF-α、MCP-1mRNA表达量。
图6.化合物9n使HCAR2信号偏向Gi蛋白信号通路实验结果。
图7.烟酸和化合物9n联用对系统性炎症的肝肾功能保护作用：各组血肌酐(Scr)、血尿素氮(BUN)、丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)测试结果。
图8.烟酸和化合物9n联用对系统性炎症的肺组织和肾组织的病理损伤保护作用。
具体实施方式
本发明所用原料与设备均为已知产品，通过购买市售产品所得。
实施例1：烟酸的抗炎作用
1.实验方法
小鼠巨噬细胞系RAW264.7采用含有10％胎牛血清的高糖DMEM培养基，于37℃、5％CO2的细胞培养箱中培养。将处于生长对数期的RAW264.7细胞以3×104细胞/孔的浓度接种于96孔细胞培养板，置于培养箱中孵育，细胞贴壁生长至85％后，用100ng ml-1LPS处理RAW264.7细胞4小时构建炎症模型。在使用LPS诱导RAW264.7细胞前，用含有不同浓度的烟酸培养基(0，6.25，12.5，25，50，100，200μM)预处理细胞30分钟，收集各组细胞沉淀，用于后续检测。使用实时荧光RT-PCR检测HCAR2、IL-1β、IL-6、TNF-α、MCP-1mRNA表达量。
2.实验结果
结果如图1所示，可以看出，在LPS的处理下，炎症模型组较对照组HCAR2表达上调。与对照组比较，模型组IL-1β、IL-6、TNF-α、MCP-1的水平均有显著升高，差异具有统计学意义(P<0.05)；同时，与模型组相比，烟酸干预组IL-1β、IL-6、TNF-α、MCP-1的水平均有降低，差异具有统计学意义(P<0.05)，说明烟酸能抑制LPS诱导的巨噬细胞产生促炎因子，进而缓解炎症状态。
实施例2：烟酸通过HCAR2抗炎
1.实验方法
将巨噬细胞系RAW264.7接种至6孔板中，待细胞密度长至40％～60％时进行转染。转染前2h对细胞进行换液。通过siRNA沉默HCAR2，siRNA进行转染工作液的配制:将10μL浓度为20μM的HCAR2siRNA及其对照siRNA加至250μL的无血清培养基中，混匀，再将5～10μL的LipofectamineTM2000加至另外250μL的无血清培养基中，混匀，室温静置5分钟，再将两者混合，室温静置20分钟。从每孔中吸出500μL培养基弃去，再按每孔500μL将上述配制的混合液加入，混匀，4～6h后换液，转染48h。后用100ng ml-1LPS处理RAW264.7细胞4小时构建炎症模型。在使用LPS诱导RAW264.7细胞前，用含有25μM烟酸培养基预处理细胞30分钟，收集各组细胞沉淀，用于后续检测。使用实时荧光RT-PCR检测HCAR2、IL-1β、IL-6、TNF-α、MCP-1mRNA表达量。
2.实验结果
结果如图2所示，可以看出，沉默HCAR2后，炎症因子IL-1β、IL-6、TNF-α、MCP-1水平明显升高，与HCAR2沉默对照组比较，差异具有统计学意义(P<0.05)，说明烟酸经HCAR2对促炎细胞因子的产生具有负调控作用。
实施例3：化合物的9n抗炎作用
1.实验方法
100ng ml-1LPS处理RAW264.7细胞4小时构建炎症模型。在使用LPS诱导RAW264.7细胞前，用含有不同浓度的化合物9n培养基(0，6.25，12.5，25，50，100，200，400，800μM)预处理细胞30分钟，收集各组细胞沉淀，用于后续检测。使用实时荧光RT-PCR检测HCAR2、IL-1β、IL-6、TNF-α、MCP-1mRNA表达量。
2.实验结果
结果如图3所示，可以看出，在LPS的处理下，炎症模型组较对照组HCAR2蛋白表达上调。与对照组比较，模型组IL-1β、IL-6、TNF-α、MCP-1的水平均有显著升高，差异具有统计学意义(P<0.05)；同时，与模型组相比，化合物9n干预组IL-1β、IL-6、TNF-α、MCP-1的水平均有降低，差异具有统计学意义(P<0.05)，说明化合物9n能抑制LPS诱导的巨噬细胞产生促炎因子，进而缓解炎症状态。
实施例4：烟酸和化合物9n联用的抗炎效果
1.实验方法
100ng ml-1LPS处理RAW264.7细胞4小时构建炎症模型。在使用LPS诱导RAW264.7细胞前，分成采用三种方式进行预处理：(1)烟酸组：单用含有烟酸(25μM)的培养基预处理细胞30分钟；(2)化合物9n组：单用含有化合物9n(12.5μM)的培养基预处理细胞30分钟；(3)烟酸+化合物9n组：用含有不同浓度的化合物9n(6.25，12.5，25μM)和烟酸(25μM)的培养基预处理细胞30分钟。然后收集各组细胞沉淀，用于后续检测。使用实时荧光RT-PCR检测IL-1β、IL-6、TNF-α、MCP-1mRNA表达量。
2.实验结果
结果如图4所示，可以看出，与炎症模型组比较，烟酸组、化合物9n组、烟酸+化合物9n组炎症因子IL-1β、IL-6、TNF-α、MCP-1水平降低，差异具有统计学意义(P<0.05)，说明单用烟酸、单用化合物9n、烟酸和化合物9n联用均对促炎细胞因子的产生具有负调控作用。同时，与烟酸组、化合物9n组相比，烟酸+化合物9n组炎症因子IL-1β、IL-6、TNF-α、MCP-1水平显著降低，差异具有统计学意义(P<0.05)，说明化合物9n可以增强烟酸对促炎因子产生的负调控作用。
进一步地，以对促炎因子IL-1β的调控作用为例(图4)，炎症模型组IL-1β的表达量为549.13128，烟酸(25μM)组IL-1β的表达量为404.57217，化合物9n(12.5μM)组IL-1β的表达量为326.47527，烟酸(25μM)+化合物9n(12.5μM)组IL-1β的表达量为167.51812。计算发现，与炎症模型组相比，烟酸(25μM)组IL-1β的表达量降低了26.33％，化合物9n(12.5μM)组IL-1β的表达量降低了40.55％，烟酸(25μM)+化合物9n(12.5μM)组IL-1β的表达量降低了69.49％，也就是说，在相同剂量下，烟酸与化合物9n联用对炎症模型促炎因子IL-1β的下调作用优于单独采用烟酸与单独采用化合物9n的作用之和，烟酸与化合物9n联用的抗炎效果发挥了协同增效的作用。
实施例5：烟酸和化合物9n依赖Gi信号转导发挥抗炎作用
1.实验方法
利用百日咳毒素(PTX)抑制抑制性腺苷酸环化酶G蛋白(Gi/o)与HCAR2结合，阻断信号转导，从而判断烟酸和化合物9n激活HCAR2引起的下游信号通路。100ng ml-1PTX与RAW264.7细胞孵育16小时后，用化合物9n(12.5μM)和烟酸(25μM)培养基预处理细胞30分钟，最后用100ng ml-1LPS刺激细胞4小时，收集各组细胞沉淀，用于后续检测。使用实时荧光RT-PCR检测IL-1β、IL-6、TNF-α、MCP-1mRNA表达量。
2.实验结果
结果如图5所示，可以看出，与未使用PTX处理组比较，PTX处理组炎症因子IL-1β、IL-6、TNF-α、MCP-1水平升高，差异具有统计学意义(P<0.05)，说明烟酸和化合物9n与HCAR2结合后依赖Gi信号转导发挥抗炎作用。
实施例6：化合物9n使HCAR2信号偏向Gi蛋白信号通路
1.实验方法
使用GloSensor cAMP实验和基于NanoBiT生物传感器实验分别检测了Gi/o蛋白的激活和β-arrestin1的招募，进而探究化合物9n对烟酸激活HCAR2下游G蛋白信号和β-arrestin1信号的变构调控作用。对于GloSensor cAMP实验，将HCAR2与GloSensor报告质粒共侵染HEK293细胞，24小时后，收集细胞，均匀平铺于96孔板中，加入待测化合物9n(0，6.25，12.5，25，50，100nM)，室温孵育后，加入不同浓度的烟酸。最后用Synergy H1酶标仪检测荧光强度，表征G蛋白信号强弱。对于基于NanoBiT生物传感器检测β-arrestin1的招募实验，将融合LgBiT的β-arrestin1及融合SmBiT的HCAR2共同表达于HEK293细胞中，24小时后，收集细胞，均匀铺于96孔板中。检测方法同GloSensor cAMP实验。
2.实验结果
结果如图6所示。比较化合物9n对烟酸激活HCAR2下游G蛋白信号和β-arrestin1信号的强弱，发现化合物9n对烟酸激活HCAR2的Gi蛋白信号途径以剂量依赖性的方式增强，相反，对β-arrestin1的招募能力变构调控作用较弱。采用偏向性转导系数评估化合物9n对烟酸的变构调节Gi/o和β-arrestin1信号途径的偏向性，结果显示，烟酸诱导的G蛋白信号系数大于β-arrestin1信号系数，表明化合物9n变构调节烟酸偏向性激活Gi蛋白信号通路。
实施例7：烟酸和化合物9n联用对系统性炎症的肝肾功能保护作用
1.实验方法
8周龄的雄性C57BL/6J小鼠适应性喂养后，随机分为4组，每组8只。分别为:对照组(Control)、模型组(LPS)、烟酸组(LPS+Niaspan)和烟酸+化合物9n组(LPS+Niaspan+9n)。适应性喂养一周后，烟酸组(给药剂量：1000mg/kg)和烟酸(给药剂量：1000mg/kg)+化合物9n(给药剂量：100mg/kg)组小鼠灌服给药，对照组和模型组给予等量生理盐水。2小时后，对模型组和药物干预组小鼠进行腹腔注射LPS(10mg/kg)构建系统性炎症模型。造模8小时后，烟酸组(给药剂量：1000mg/kg)和烟酸(给药剂量：1000mg/kg)+化合物9n(给药剂量：100mg/kg)组小鼠再次灌服给药，对照组和模型组给予等量生理盐水。造模后16小时，处死小鼠，取血，解剖收集肺、肝脏和肾脏等器官。各组小鼠采集全血进行生化检测，包括血肌酐(Scr)、血尿素氮(BUN)、丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)。肺、肝脏和肾脏组织以4％的甲醛固定14d后，通过常规石蜡包埋、切片、HE染色并观察。
2.实验结果
全血生化检测结果如图7所示。与模型组比较，烟酸组和烟酸+化合物9n组的Scr、BUN、ALT和AST水平降低，差异具有统计学意义(P<0.05)，说明烟酸和烟酸+化合物9n可以改善LPS诱导的系统性炎症小鼠的肝肾功能。同时，与烟酸组相比，烟酸+化合物9n组Scr、BUN、ALT和AST水平显著降低，差异具有统计学意义(P<0.05)，说明化合物9n可以增强烟酸对肝肾功能的保护作用。
HE染色后组织形态学观察结果如图8所示，对照组小鼠肺部结构正常，无渗出液，且没有炎性细胞浸润等病理现象；与对照组比较，模型组肺组织结构松散，有大量炎性细胞浸润，可观察到肺泡壁间质明显增厚及出血等病理现象；烟酸组和烟酸+化合物9n组肺组织损伤有一定程度减轻，充血减轻，炎性细胞浸润减少，烟酸+化合物9n组病理损伤较烟酸组更轻。与对照组相比，模型组小鼠肾组织结构明显被破坏，有炎性细胞浸润，肾组织水肿明显；烟酸组和烟酸+化合物9n组肾组织损伤有一定程度减轻，水肿减轻，炎性细胞浸润减少，烟酸+化合物9n组病理损伤较烟酸组更轻。说明烟酸和化合物9n联合使用可以减轻LPS诱导的系统性炎症小鼠的肺损伤和肝肾损伤。
Claims (2)
1.联合用药物在制备减轻炎症引起的肺损伤、肝损伤或肾损伤的药物中的用途，其特征在于：所述联合用药物含有相同或不同规格单位制剂的用于同时或者分别给药的HCAR2变构分子和烟酸，以及药学上可接受的载体；所述HCAR2变构分子与烟酸的质量比为1：(5～15)；所述HCAR2变构分子为化合物9n
2.根据权利要求1所述的用途，其特征在于：所述HCAR2变构分子与烟酸的质量比为1：10。
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