CN117815311A - 含玄参或其提取物的药物组合物及其用途 - Google Patents
含玄参或其提取物的药物组合物及其用途 Download PDFInfo
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- CN117815311A CN117815311A CN202311789423.1A CN202311789423A CN117815311A CN 117815311 A CN117815311 A CN 117815311A CN 202311789423 A CN202311789423 A CN 202311789423A CN 117815311 A CN117815311 A CN 117815311A
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- radix scrophulariae
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- figwort
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Abstract
本发明提供一种含玄参或其提取物的药物组合物及其用途，与由金银花、玄参、当归和甘草组成的组方相比，本发明的单药或其活性组分能够通过调节中性粒细胞活性，减少中性粒细胞迁移，以及减轻由不适当激活的中性粒细胞引起的免疫损伤，有效缓解急性痛风性关节炎(AGA)模型小鼠和胶原抗体诱导型关节炎(CAIA)模型小鼠以及胶原诱导型关节炎(CIA)模型小鼠的关节损伤。进一步证实了通过靶向中性粒细胞治疗中性粒细胞异常活化相关疾病的新策略是可行的。
Description
技术领域
本发明涉及医药领域，具体地涉及含玄参或其提取物的药物组合物及其用途，特别是用于调节中性粒细胞活性的用途，尤其涉及通过调节中性粒细胞活性治疗中性粒细胞异常活化相关疾病的用途。
背景技术
中性粒细胞是循环系统中最丰富的免疫细胞群体，占人体所有白细胞的40-70％。它们是固有免疫系统的重要组成部分，在体内发挥免疫监视、清除病原体和免疫调节等作用。当机体感染细菌后，中性粒细胞通过趋化作用被募集到感染部位；然后通过其吞噬、脱颗粒、呼吸爆发、中性粒细胞胞外诱捕网(NETs)释放等功能，清除病原体，或将病原体限制在局部、避免进一步扩散；中性粒细胞还可以通过释放炎症因子和趋化因子，进一步募集和活化单核/巨噬细胞、T细胞等其它免疫细胞，从而全面增强抗感染免疫水平。然而病原体一旦突破中性粒细胞屏障，发展成全身性脓毒症，中性粒细胞的过度活化会释放大量炎症因子，造成炎症因子风暴并抑制T细胞活化，进而导致患者多脏器功能衰竭及死亡。而近年来研究发现，中性粒细胞在机体局部的异常活化，也促进了类风湿关节炎(RA)、急性痛风性关节炎(AGA)等相关无菌性疾病的病程进展。
类风湿关节炎是一种常见的慢性全身性自身免疫性疾病，临床特征为持续性、对称性小关节病变。经典理论认为，类风湿关节炎是由T细胞、B细胞等获得性免疫细胞驱动形成的自身免疫性疾病。但中性粒细胞异常活化，也在类风湿关节炎发展的各个阶段发挥作用：①该细胞可以释放NETs，上面携带的瓜氨酸化组蛋白是刺激形成免疫复合物的主要自身抗原之一；②该细胞可以通过释放趋化因子，促进Th17细胞的分化和成熟，导致炎症免疫恶性循环；③该细胞作为效应细胞，在疾病活动期直接造成骨关节无菌性炎症损伤。类风湿关节炎的一线治疗包括常规抗炎药物和生物疾病缓解疗法，主要用于控制疼痛和炎症，但很少实现持续缓解。
急性痛风性关节炎(AGA)是由于体内嘌呤物质代谢异常、血尿酸水平升高，导致单钠尿酸盐(MSU)晶体沉积在关节滑膜、滑囊、软骨及其他组织中引起的反复发作性炎症疾病。主要表现为反复发作性关节红肿热痛与功能障碍，甚至关节畸形、尿酸性肾病等。沉积的MSU晶体通过活化单核/巨噬细胞，进而趋化中性粒细胞大量浸润至关节滑液和滑膜中，并发生爆发式级联扩增反应。浸润的中性粒细胞大量分泌IL-l、IL-8等细胞因子，以及溶酶体酶、氧自由基、花生酸类物质、骨髓相关蛋白S100A8/A9等，推动痛风急性炎症的进展。急性痛风性关节炎患者可长期服用减少尿酸合成的别嘌醇和促进尿酸盐排出的丙磺舒，预防关节炎的急性发作；非甾体类抗炎药、糖皮质激素和秋水仙碱，用于不同程度地改善症状。
玄参味甘、苦、咸，性微寒，归肺、胃、肾经；具有清热凉血，滋阴泻火的功效，主治温热病热入营血。临床用来治疗热病伤阴，舌绛烦渴，温毒发斑，津伤便秘，骨蒸劳嗽，目赤，咽痛，瘰疬，白喉，痈肿疮毒等。现代药理学研究表明，玄参具有抗炎、抗氧化、保肝、抗肿瘤、抗疲劳、降尿酸、抗抑郁、保护心肌细胞等药理活性，并对心血管系统、中枢神经系统以及免疫系统具有调节作用。用于治疗发热、肿胀、便秘、咽炎、喉炎、神经炎、喉咙痛、风湿等疾病。然而，目前并没有关于玄参调节中性粒细胞活性，特别是通过调节中性粒细胞活性治疗相关疾病的报道。
背景技术中的信息仅仅在于说明本发明的总体背景，不应视为承认或以任何形式暗示这些信息构成本领域一般技术人员所公知的现有技术。
发明内容
发明人致力于中药现代化研究，在大量深入研究后发现由金银花、玄参、当归和甘草组成的组方能够通过对中性粒细胞活性的调节作用来实现中性粒细胞异常活化相关关节炎症的有效治疗。在此基础上，发明人进一步深入研究并意外发现，与复方相比，当以玄参作为单药时其效果更优，这与传统理论的一般认知相反。至少部分地基于该发现完成了本发明。具体地，本发明包括以下内容。
本发明的第一方面，提供一种药物组合物，其用于调节中性粒细胞活性，进而防治疾病或疾病，其中，所述药物组合物包括玄参或其提取物。
在某些实施方案中，根据本发明所述的药物组合物，其中，所述提取物包括玄参的水提液和/或醇提液。
在某些实施方案中，根据本发明所述的药物组合物，其中，所述提取物包括玄参组分1：醇溶小分子、玄参组分2：玄参多糖。
在某些实施方案中，根据本发明所述的药物组合物，其中，所述玄参组分1醇溶小分子的制备包括：玄参水提液加入醇沉淀后取上清即得；所述玄参组分2多糖的制备包括：使玄参经醇沉、水溶后得到。
玄参水提液的制备不限定，例如可以通过使玄参粉于水中超声提取得到滤液，离心取上清；或通过常规水煎煮玄参得到水煎液，作为水提液。
在某些实施方案中，根据本发明所述的药物组合物，其中，玄参粉于水中超声时的温度为40-70℃。
本发明的第二方面，提供玄参或其提取物在制备调节中性粒细胞活性的药物中的用途。
在某些实施方案中，根据本发明所述的用途，其中，所述调节中性粒细胞的活性包括至少下述之一：
(1)抑制、延缓、延迟、降低、减少或减弱中性粒细胞趋化；
(2)抑制、延缓、延迟、降低或减少中性粒细胞外诱捕网NETs的形成。
(3)抑制、延缓、延迟、降低、减少或减弱中性粒细胞炎症因子；
本发明的第三方面，提供玄参或其提取物在制备与中性粒细胞异常活化相关的疾病或病症的药物中的用途。
在某些实施方案中，根据本发明所述的用途，其中，所述与中性粒细胞异常活化相关疾病或病症包括关节炎、脓毒症等；
优选地，所述关节炎包括急性痛风性关节炎、慢性关节炎、持续性对称性多关节炎和/或类风湿关节炎。
本发明的第四方面，提供一种用于体外调节中性粒细胞活性的方法，其中，使所述中性粒细胞与玄参或其提取物接触的步骤。
在本发明的研究中，建立了胶原诱导性关节炎(CIA)小鼠模型等多种模型来观察本组方及单药的疗效，发现与组方相比，其中的单药玄参在通过调节中性粒细胞活性治疗中性粒细胞异常活化相关疾病或病症的效果更优，这样的效果是完全预料不到的。
本发明制备了一种能够治疗炎症性疾病的单药及其活性组分，并通过实验证明了其抑制、降低、减少或减弱中性粒细胞的趋化、炎症因子，或抑制、降低或减少中性粒细胞外诱捕网NETs的形成，从而治疗类风湿关节炎或急性痛风性关节炎。
本发明得到的单药玄参或经提取得到的活性组分能够通过调节中性粒细胞活性有效缓解胶原诱导型关节炎(CIA)模型小鼠和胶原抗体诱导型关节炎(CAIA)模型小鼠以及急性痛风性关节炎(AGA)模型小鼠的损伤，减少中性粒细胞迁移到损伤的关节，以及减轻由不适当激活的中性粒细胞引起的免疫损伤。本发明证实了通过靶向中性粒细胞治疗中性粒细胞异常活化相关的疾病或病症的新策略是可行的。
附图说明
图1含本申请组方及玄参、玄参活性组分1(水提醇溶工艺制备获得)、玄参活性组分2(水提醇沉工艺制备获得)的药物血清体外抑制中性粒细胞趋化的结果。
图2示出了本申请组方及玄参、玄参活性组分1(水提醇溶工艺制备获得)、玄参活性组分2(水提醇沉工艺制备获得)减轻CIA小鼠关节红肿症状的结果。
图3示出了本申请组方及玄参、玄参活性组分1(水提醇溶工艺制备获得)、玄参活性组分2(水提醇沉工艺制备获得)给药后CIA小鼠关节病理改变情况。
图4为本申请组方及玄参、玄参活性组分1(水提醇溶工艺制备获得)、玄参活性组分2(水提醇沉工艺制备获得)给药后CIA小鼠关节骨Micro-CT扫描重建图像。
图5为玄参在中性粒细胞异常活化相关疾病中的作用机制。
具体实施方式
现详细说明本发明的多种示例性实施方式，该详细说明不应认为是对本发明的限制，而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。
应理解本发明中所述的术语仅仅是为描述特别的实施方式，并非用于限制本发明。另外，对于本发明中的数值范围，应理解为具体公开了该范围的上限和下限以及它们之间的每个中间值。在任何陈述值或陈述范围内的中间值以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本发明内。这些较小范围的上限和下限可独立地包括或排除在范围内。
除非另有说明，否则本文使用的所有技术和科学术语具有本发明所述领域的常规技术人员通常理解的相同含义。虽然本发明仅描述了优选的方法和材料，但是在本发明的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。本说明书中提到的所有文献通过引用并入，用以公开和描述与所述文献相关的方法和/或材料。在与任何并入的文献冲突时，以本说明书的内容为准。
本发明使用的术语“防治”指的是在疾病或机能紊乱发生之前或之后改善这种状况。与同等条件下未经治疗的参照组相比，按照任何标准技术来衡量，这种缓解或预防程度至少是5％、10％、20％、40％、50％、60％、80％、90％、95％或100％。
本发明中的药物可选的包含药学上可接受的赋形剂、载体或稀释剂，术语“药学上可接受的赋形剂、载体或稀释剂”指的是一种药学上可接受的材料、组合物或载体，如液体或固体填料、稀释剂、赋形剂、溶剂或封装材料，且该类药学上可接受的材料、组合物或载体参与将药剂从一个器官或身体的某一部位运载或运送至另一个器官或身体的另一部位。每种载体必须是“可接受的”，即指其与配方的其他成分相容且不损害患者。在药学上可接受的载体的部分示例如下：糖，如乳糖、葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物和类似物，如羧甲基纤维素钠、乙基纤维素和纤维素乙酸酯；西黄蓍胶粉；麦芽；明胶；滑石粉；赋形剂，如可可油和栓剂蜡；油，如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和豆油；二醇类，如丙二醇；多元醇，如甘油、山梨醇、甘露醇和聚乙二醇；酯类，如油酸乙酯和月桂乙酯；琼脂；缓冲剂，如氢氧化镁和氢氧化铝；褐藻酸；无热原水；等渗盐水；林格氏溶液；乙醇；磷酸盐缓冲液；以及药物制剂中使用的其他无毒且相容的物质。润湿剂、乳化剂和润滑剂，如十二烷基磺酸钠、硬脂酸镁、和聚氧乙烯-聚环氧丙烷共聚物以及着色剂、脱模剂、涂层剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂也可存在于组合物中。
本申请的药物的施用方式没有特别限制，代表性的施用方式包括但并不限于：口服、肌肉注射、静脉注射、静脉滴注、灌肠、喷雾、外敷、或腹腔注射。
用于口服给药的固体剂型包括片剂、丸剂、散剂、颗粒剂、或胶囊剂。在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种药物或组合物或活性组分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，组合物、药物、单药或活性组分也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳剂、溶液、悬浮剂、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
本申请中，用于肠胃外注射的药物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本申请中，用于局部给药的药物的剂型包括软膏剂、散剂、贴剂、喷雾剂和吸入剂。组合物、药物、单药或活性组分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本申请的药物可以单独给药，或者与其他治疗剂联合给药。其他治疗剂的实例包括但不限于能够用于炎症性疾病的小分子化合物或药物。
使用本申请的药物时，是将安全有效量的药物或其活性组分施用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
实施例1
一、实验步骤
1、中药制备
1.1组方水煎液的制备如下所述：
金银花90g，玄参90g，当归60g，甘草30g，十剂共270g。常规方法水煎两次药液合并，过滤，浓缩至600ml(0.45g/ml)。
1.2玄参水提液的制备如下所述：
玄参粉碎，并将玄参粉于40-70℃超声下水溶，过滤，离心取上清得到玄参水提液；或将玄参加水浸泡10-90分钟，煮沸后文火煎熬10-60分钟，倒出药液，药渣加适量水煎熬10-30分钟，合并两次水煎药液，过滤得玄参水提液。
1.3玄参组分1的制备如下所述：
玄参粉碎，超声下水溶，过滤，醇沉后收集上清，加压加热浓缩，得到醇溶小分子即玄参活性组分1。或玄参水煎液醇沉后收集上清，加压加热浓缩，得到醇溶小分子即玄参活性组分1。
1.4玄参组分2的制备如下所述：
玄参粉碎，超声下水溶，过滤，醇沉后收集沉淀，水浴蒸干浓缩得粗多糖即为玄参活性组分2。或玄参水煎液醇沉后收集沉淀，浓缩得粗多糖即为玄参活性组分2。
2.含药血清制备
组方含药血清组SD大鼠按临床等效剂量6倍剂量灌胃给药，玄参、玄参组分1、玄参组分2含药血清组大鼠给药剂量均为组方中相同玄参剂量换算。空白血清组大鼠灌胃给予生理盐水。每12h给药1次，共给药5次。末次给药1小时后取血分离血清，灭活。
3.中性粒细胞趋化检测
骨髓单细胞悬液预先分别在含有对照血清及组方含药血清的培养基中孵育1h，后以3*104/孔的细胞接种于趋化小室中，下室为含趋化因子培养基，于37℃孵箱培养3h。培养结束后，收集下室细胞于流式管中，加入抗体标记中性粒细胞，上机前加入计数微球beads，流式检测分析趋化至下室的中性粒细胞数。
4.活化后中性粒细胞形成NETs检测
细胞培养上清cf-DNA含量测定：
将骨髓分选的中性粒细胞105/孔接种在含有对照血清和组方含药血清的RPMI-1640培养基中，孵育1h；加入PMA刺激3h；加入DNaseⅠ将附着在细胞上的NETs切割打断。反应完成后加入EDTA终止酶反应；收集中性粒细胞的培养上清，采用PicoGreen试剂盒检测中性粒细胞培养上清中cf-DNA含量。
二、实验结果
1.组方、玄参及玄参组分1、组分2含药血清对中性粒细胞迁移的抑制作用
根据前期实验，20％剂量的含药血清干预为体外实验最佳给药浓度。体外中性粒细胞趋化实验结果显示，CXCL1、CXCL2刺激后，与对照组相比，更多的中性粒细胞趋化到下室。组方含药血清及玄参组分2含药血清有效抑制了CXCL1诱导的中性粒细胞趋化，玄参含药血清及玄参组分1含药血清均能显著抑制CXCL1及CXCL2诱导的中性粒细胞迁移(图1，表1)。
表1.组方、玄参、玄参组分1及玄参组分2含药血清对CXCL1、CXCL2趋化粒细胞的影响(MEAN±SEM)
注：#代表模型组与对照组有统计学差异，#，p<0.05；##，p<0.01；###，p<0.001。*代表给药组与模型组有统计学差异，*，p<0.05；**，p<0.01；***，p<0.001。
2.组方、玄参及玄参组分1、组分2含药血清抑制中性粒细胞NETs形成
中性粒细胞活化后会释放胞外诱捕网NETs，NETs中的蛋白酶释放会造成组织损伤，加重炎症反应。NETs被释放到外周，可以通过检测游离DNA(cf-DNA)含量反映中性粒细胞NETs的释放。实验结果显示，PMA刺激后，与对照组相比，中性粒细胞培养上清液中的cf-DNA含量显著升高，组方含药血清、单药玄参含药血清及玄参组分1、组分2含药血清均显著降低了中性粒细胞cf-DNA释放，抑制NETs形成。(表2)。
表2.组方、玄参、玄参组分含药血清对中性粒细胞cf-DNA(ng/mL)的影响(MEAN±SEM)
注：#代表模型组与对照组有统计学差异，#，p<0.05；##，p<0.01；###，p<0.001。*代表给药组与模型组有统计学差异，*，p<0.05；**，p<0.01；***，p<0.001。
实施例2
一、实验步骤
1、动物模型的建立
1.1胶原诱导型关节炎(CIA)小鼠模型建立
牛II型胶原蛋白和完全的弗氏佐剂冰水浴条件下以1:1的比例充分乳化，以滴加水中不扩散为度，Ⅱ型胶原的终浓度为1mg/mL。二次免疫使用不完全弗氏佐剂。DBA/1小鼠分别于第0天和第21天尾根部皮内注射乳化的胶原(100μL/只)诱导建立CIA小鼠模型。初次免疫后2周开始给药，给药剂量均为临床等效剂量。所有动物在关节炎指数评分开始下降后取材。取材后采用ELISA法检测血浆炎症因子、cf-DNA含量，关节炎症因子水平；实时荧光定量PCR检测关节中性粒细胞相关趋化因子表达；流式检测中性粒细胞比例变化；病理切片染色及Micro-CT检测小鼠关节病理损伤和骨质破坏情况。
1.2胶原抗体诱导型关节炎(CAIA)小鼠模型建立
选用7-8周龄雌性Balb/c小鼠。动物模型建立：第0d：尾静脉注射5克隆抗体合剂cocktail 150uL/只，第3d：腹腔注射LPS 70uL/只。尾静脉注射抗体后开始给药，给药剂量均为临床等效剂量。造模后每天对小鼠关节进行评分及肿胀度测量。关节评分及肿胀开始下降，炎症达到峰值后取材。
1.3急性痛风性关节炎(AGA)小鼠模型建立
研磨MSU晶体，过40μm筛，无菌生理盐水配制MSU晶体混悬液(50mg·mL-1)，采用30号针头的0.3mL注射器沿小鼠右踝关节外侧后方垂直穿刺进入踝关节腔，注入30μL MSU晶体混悬液；对照组同法注射等体积生理盐水。造模后单次给药，给药剂量均为临床等效剂量。造模后测量72h内踝关节肿胀度变化。后续实验相同方法造AGA模型，15h肿胀高峰时取材检测关节炎症因子表达。
2、观察及检测指标
2.1小鼠关节症状及评分、肿胀度
造模后观察记录动物的关节红肿症状。关节指数评分：0分：正常，关节无红肿；1分：足趾关节轻度红肿；2分：足趾关节和足跖肿胀；3分：踝以下足爪红肿；4分：包括踝关节在内的全足均红肿并伴功能障碍；AI＝四肢关节评分之和，总分为16分。每3天评分一次。游标卡尺测量小鼠腕踝关节直径，计算肿胀度，肿胀度＝测量直径-初始直径，关节肿胀度＝四肢关节肿胀度之和。
2.2关节组织病理学
HE染色观察关节炎症浸润情况，番红-O/固绿染色观察软骨破坏情况，Trap染色观察破骨细胞形成情况。
2.3影像学
小鼠踝关节Micro-CT扫描并进行三维重建成像，进行骨破坏评价。
2.4关节组织细胞因子表达及血浆中细胞因子含量
实时荧光定量PCR检测关节组织细胞因子的表达。使用Trizol提取总RNA。2-ΔΔCT法计算基因的相对表达。内参使用甘油醛-3-磷酸脱氢酶(GAPDH)。提取关节总蛋白，ELISA法检测小鼠关节炎症因子水平。小鼠取血分离血浆，CBA试剂盒检测血浆中多种细胞因子水平。
2.5血浆cf-DNA水平
小鼠眼球取血，分离血浆，采用PicoGreen试剂盒检测血浆中cf-DNA水平。
2.5小鼠脾脏、骨髓中性粒细胞比例
小鼠脾脏研磨制备单细胞悬液，PBS冲洗股骨制备骨髓单细胞悬液。使用抗小鼠CD11b-PercpCy5.5、Ly6G-BV510、CD48-PE Cy7抗体标记中性粒细胞，流式检测CIA小鼠脾脏及骨髓中性粒细胞比例变化。
二、实验结果
1.本申请组方、单药玄参及玄参中分离的组分对CIA小鼠的作用
1.1本申请组方对CIA小鼠有效，单药玄参及玄参组分1药效优于组方
表3-表4所示为CIA小鼠关节评分及肿胀度变化。二次免疫后第3天模型小鼠开始出现关节红肿，关节评分持续升高，二次免疫后第18天关节红肿基本达到峰值，关节肿胀维持至第27天后开始出现减轻，关节评分降低。关节肿胀度变化与评分基本一致。与模型组相比，本申请组方及单药玄参、玄参组分1、组分2均明显减轻了CIA小鼠关节肿胀程度，降低关节评分，且玄参及玄参组分1效果优于组方给药组。
表3.组方及玄参水煎液、玄参组分1、玄参组分2对CIA小鼠二次免疫后不同时间点关节评分的影响(MEAN±SEM)
注：#代表模型组与对照组有统计学差异，#，p<0.05；##，p<0.01；###，p<0.001。*代表给药组与模型组有统计学差异，*，p<0.05；**，p<0.01；***，p<0.001。
表4.组方及玄参水煎液、玄参组分1、玄参组分2对CIA小鼠二次免疫后不同时间点关节肿胀度(mm)的影响(MEAN±SEM)
注：#代表模型组与对照组有统计学差异，#，p<0.05；##，p<0.01；###，p<0.001。*代表给药组与模型组有统计学差异，*，p<0.05；**，p<0.01；***，p<0.001。
1.2本申请组方，单药玄参及玄参组分减轻CIA小鼠关节病理改变及骨破坏
组织病理学染色结果显示，CIA小鼠踝关节内炎性细胞浸润明显，并存在关节软骨结构破坏，破骨细胞大量形成。本申请组方，单药玄参及玄参组分均明显改善了关节组织病理学损伤(图2)。
Micro-CT结果示，在CIA小鼠的踝关节中存在明显的骨破坏，本申请组方，单药玄参及玄参组分给药组小鼠骨破坏程度明显减轻，且玄参组分改善CIA小鼠关节症状、病理及骨损伤较阳性药甲氨蝶呤、组方及单药玄参组均更明显(图3)。
1.3本申请组方，单药玄参及玄参组分减轻CIA小鼠全身及关节炎症
检测CIA小鼠血浆中细胞因子水平，结果如表5所示，CIA模型组小鼠血浆中TNF-α、IL-6、IFN-γ及MCP-1水平均显著升高，玄参给药明显降低了IL-6和MCP-1水平。玄参组分1组血浆IL-6水平较模型组显著下降，玄参组分2组血浆MCP-1水平较模型组显著下降。
关节组织炎症因子水平结果如表6所示，与对照组相比，模型组小鼠关节TNF-α、IL-1β及IL-6水平均显著上升。本申请组方及单药玄参均有效降低关节IL-1β和IL-6水平，玄参组分1给药后TNF-α、IL-6水平明显降低，玄参组分2有效降低炎症关节IL-6水平。
表5.组方及玄参水煎液、玄参组分对CIA小鼠血浆中细胞因子水平(pg/mL)的影响(MEAN±SEM)
注：#代表模型组与对照组有统计学差异，#，p<0.05；##，p<0.01；###，p<0.001。*代表给药组与模型组有统计学差异，*，p<0.05；**，p<0.01；***，p<0.001。
表6.组方及玄参水煎液、玄参组分对CIA小鼠关节骨组织炎症因子水平(pg/ug)的影响(MEAN±SEM)
注：#代表模型组与对照组有统计学差异，#，p<0.05；##，p<0.01；###，p<0.001。*代表给药组与模型组有统计学差异，*，p<0.05；**，p<0.01；***，p<0.001。
1.4本申请组方，单药玄参及玄参组分降低CIA小鼠血浆cf-DNA
表7所示为CIA小鼠血浆cf-DNA水平。与正常小鼠相比，CIA模型组小鼠血浆中cf-DNA水平显著升高，本申请组方及单药玄参、玄参组分2均显著降低了CIA小鼠血浆中cf-DNA水平。
表7.组方及玄参水煎液、玄参组分对CIA小鼠血浆cf-DNA(ng/mL)的影响(MEAN±SEM)
注：#代表模型组与对照组有统计学差异，#，p<0.05；##，p<0.01；###，p<0.001。*代表给药组与模型组有统计学差异，*，p<0.05；**，p<0.01；***，p<0.001。
1.5本申请组方、单药玄参及玄参组分降低CIA小鼠脾脏指数，减少中性粒细胞
取材后取小鼠脾脏，分析脾脏指数的改变，结果如表8所示。CIA模型组小鼠脾脏肿大，脾脏指数显著上升，给药后脾脏指数减小。进一步分析脾脏和骨髓中性粒细胞比例变化。结果如表9所示，CIA模型组小鼠骨髓及脾脏中性粒细胞比例显著增加，本申请组方减少了CIA小鼠脾脏中性粒细胞比例，玄参组分1显著减少骨髓及脾脏中性粒细胞比例，组分2减少骨髓中性粒细胞比例。提示本申请组方及玄参分离组分能有效调节CIA小鼠炎症状态下中性粒细胞的过度生成。
表8.组方及玄参水煎液、玄参组分对CIA小鼠脾脏指数(％)的影响(MEAN±SEM)
注：#代表模型组与对照组有统计学差异，#，p<0.05；##，p<0.01；###，p<0.001。*代表给药组与模型组有统计学差异，*，p<0.05；**，p<0.01；***，p<0.001。
表9.组方及玄参水煎液、玄参组分对CIA小鼠骨髓、脾脏中性粒细胞比例(％)的影响(MEAN±SEM)
注：#代表模型组与对照组有统计学差异，#，p<0.05；##，p<0.01；###，p<0.001。*代表给药组与模型组有统计学差异，*，p<0.05；**，p<0.01；***，p<0.001。
2.本申请组方及单药玄参对CAIA小鼠的作用
2.1本申请组方及单药玄参减轻CAIA小鼠关节肿胀
如表10所示，尾静脉注射抗体后，CAIA模型组小鼠第3天开始出现关节红肿，腹腔注射LPS加强免疫后关节肿胀程度显著增高，关节评分明显上升，第10天关节红肿基本达到峰值，而后关节肿胀程度出现下降，评分降低。与模型组相比，本申请组方及单药玄参均明显减轻了CAIA小鼠关节肿胀程度，降低关节评分，且玄参早期抑制关节肿胀较甲氨蝶呤及组方更明显。
表10.本申请组方及玄参对CAIA小鼠造模后不同时间点关节评分的影响(MEAN±SEM)
注：#代表模型组与对照组有统计学差异，#，p<0.05；##，p<0.01；###，p<0.001。*代表给药组与模型组有统计学差异，*，p<0.05；**，p<0.01；***，p<0.001。
2.2本申请组方及单药玄参抑制CAIA小鼠关节炎症因子及中性粒细胞趋化因子表达
实时定量PCR结果示(表11-12)，CAIA模型小鼠关节局部炎症因子TNF-α、IL-1β，趋化因子CXCL2、IL-8均有显著升高，本申请复方及单药玄参不同程度降低了炎症因子及趋化因子mRNA水平。
表11.本申请组方及玄参对CAIA小鼠关节炎症因子mRNA水平的影响(MEAN±SEM)
注：#代表模型组与对照组有统计学差异，#，p<0.05；##，p<0.01；###，p<0.001。*代表给药组与模型组有统计学差异，*，p<0.05；**，p<0.01；***，p<0.001。
表12.本申请组方及玄参对CAIA小鼠关节趋化因子mRNA水平的影响(MEAN±SEM)
注：#代表模型组与对照组有统计学差异，#，p<0.05；##，p<0.01；###，p<0.001。*代表给药组与模型组有统计学差异，*，p<0.05；**，p<0.01；***，p<0.001。
3.本申请组方及单药玄参对AGA小鼠的作用
如表13所示，与对照组相比，AGA模型组小鼠踝关节肿胀度明显升高，各给药组24h、48h、72h与模型组比较均有统计学差异。
根据课题组前期实验结果，AGA 15h肿胀高峰取材检测关节炎症因子及趋化因子表达情况，结果如表5所示。AGA模型15h关节中炎症因子TNF-α、IL-1β、IL-6及中性粒细胞趋化因子IL-8的mRNA水平均显著升高，各给药组不同程度地降低了关节中炎症因子及趋化因子的表达。
表13.本申请组方及玄参对AGA小鼠造模后不同时间点关节肿胀度(mm)的影响(MEAN±SEM)
注：#代表模型组与对照组有统计学差异，#，p<0.05；##，p<0.01；###，p<0.001。*代表给药组与模型组有统计学差异，*，p<0.05；**，p<0.01；***，p<0.001。
表14.本申请组方及单味药玄参对AGA小鼠关节炎症因子mRNA水平的影响(MEAN±SEM)
注：#代表模型组与对照组有统计学差异，#，p<0.05；##，p<0.01；###，p<0.001。*代表给药组与模型组有统计学差异，*，p<0.05；**，p<0.01；***，p<0.001。
从中性粒细胞体外趋化结果，本申请组方含药血清有效抑制了CXCL1诱导的中性粒细胞趋化，单药玄参及玄参活性组分1有效抑制CXCL1及CXCL2诱导的中性粒细胞趋化。
对中性粒细胞活化后培养上清cf-DNA进行检测，本申请组方含药血清、单药玄参含药血清及玄参活性组分含药血清均显著降低了中性粒细胞cf-DNA释放，抑制NETs形成。
从关节评分及肿胀度结果，本申请组方、玄参、玄参活性组分1和玄参活性组分2对CIA小鼠关节炎均有效，其中玄参活性组分1效果较其他给药组最佳，前期明显抑制CIA小鼠关节发病。取脾脏计算脾脏指数变化，造模后CIA模型小鼠脾脏指数显著增大，各给药组均明显降低脾指数。
对CIA小鼠骨髓、脾脏粒细胞比例进行流式细胞分析。CIA小鼠中性粒细胞比例增多，玄参活性组分1有效减少了CIA小鼠骨髓及脾脏中性粒细胞比例。
同时，通过AGA及CAIA小鼠两种关节炎模型，本申请组方及玄参均明显减轻AGA小鼠关节炎；且玄参单药在CAIA小鼠中效果优于本申请组方。
尽管本发明已经参考示例性实施方案进行了描述，但应理解本发明不限于公开的示例性实施方案。在不背离本发明的范围或精神的情况下，可对本发明说明书的示例性实施方案做多种调整或变化。权利要求的范围应基于最宽的解释以涵盖所有修改和等同结构与功能。
Claims (10)
1.一种药物组合物，其用于调节中性粒细胞活性，进而防治疾病或疾病，其特征在于，所述药物组合物包括玄参或其提取物。
2.根据权利要求1所述的药物组合物，其特征在于，所述提取物包括玄参的水提液和/或醇提液。
3.根据权利要求2所述的药物组合物，其特征在于，玄参水提液的加工包括：使玄参粉于40-70℃水中超声提取得到滤液，离心取上清得到水提液；或通过常规水煎煮玄参得到水煎液，作为水提液。
4.根据权利要求1所述的药物组合物，其特征在于，所述提取物包括玄参多糖、醇溶小分子。
5.根据权利要求4所述的药物组合物，其特征在于，所述玄参多糖的制备包括：使玄参水提液经醇沉，取沉淀水溶后得到；所述醇溶小分子的制备包括：使玄参水提液经醇沉后，取上清即得。
6.玄参或其提取物在制备调节中性粒细胞活性的药物中的用途。
7.根据权利要求6所述的用途，其特征在于，所述调节中性粒细胞活性包括至少下述之一：
(1)抑制、延缓、延迟、降低、减少或减弱中性粒细胞趋化；
(2)抑制、延缓、延迟、降低、减少或减弱中性粒细胞炎性因子；
(3)抑制、延缓、延迟、降低或减少中性粒细胞外诱捕网NETs的形成。
8.玄参或其提取物在制备与中性粒细胞异常活化相关的疾病或病症的药物中的用途。
9.根据权利要求8所述的用途，其特征在于，所述与中性粒细胞异常活化相关疾病或病症包括关节炎、脓毒症等；
优选地，所述关节炎包括急性痛风性关节炎、慢性关节炎、持续性对称性多关节炎和/或类风湿关节炎。
10.一种用于体外调节中性粒细胞活性的方法，其特征在于，使所述中性粒细胞与玄参或其提取物接触的步骤。
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