CN109096360A - 一种治疗类风湿性关节炎的小分子化合物及其用途 - Google Patents
一种治疗类风湿性关节炎的小分子化合物及其用途 Download PDFInfo
- Publication number
- CN109096360A CN109096360A CN201710474946.5A CN201710474946A CN109096360A CN 109096360 A CN109096360 A CN 109096360A CN 201710474946 A CN201710474946 A CN 201710474946A CN 109096360 A CN109096360 A CN 109096360A
- Authority
- CN
- China
- Prior art keywords
- rheumatoid arthritis
- saponin
- small molecule
- molecule compound
- chonglou saponin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 206010039073 rheumatoid arthritis Diseases 0.000 title claims abstract description 20
- -1 small molecule compound Chemical class 0.000 title claims abstract description 10
- IUCHKMAZAWJNBJ-RCYXVVTDSA-N oleanolic acid 3-O-beta-D-glucosiduronic acid Chemical compound O([C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2C1(C)C)C)(C)CC[C@]1(CCC(C[C@H]14)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O IUCHKMAZAWJNBJ-RCYXVVTDSA-N 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 14
- 241000244987 Daiswa polyphylla Species 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- 238000002347 injection Methods 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 239000003405 delayed action preparation Substances 0.000 claims 1
- 210000000544 articulatio talocruralis Anatomy 0.000 abstract description 12
- 208000024891 symptom Diseases 0.000 abstract description 9
- 210000000988 bone and bone Anatomy 0.000 abstract description 8
- 230000007547 defect Effects 0.000 abstract description 7
- 230000008595 infiltration Effects 0.000 abstract description 6
- 238000001764 infiltration Methods 0.000 abstract description 6
- 206010003246 arthritis Diseases 0.000 abstract description 5
- 230000002757 inflammatory effect Effects 0.000 abstract description 5
- 210000000845 cartilage Anatomy 0.000 abstract description 4
- 102000008186 Collagen Human genes 0.000 abstract description 3
- 108010035532 Collagen Proteins 0.000 abstract description 3
- 241001465754 Metazoa Species 0.000 abstract description 3
- 229920001436 collagen Polymers 0.000 abstract description 3
- 206010060820 Joint injury Diseases 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract description 2
- 208000018937 joint inflammation Diseases 0.000 abstract description 2
- 230000006749 inflammatory damage Effects 0.000 abstract 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 18
- 101710115512 Nuclear receptor coactivator 5 Proteins 0.000 description 6
- 210000002540 macrophage Anatomy 0.000 description 6
- 230000002917 arthritic effect Effects 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 238000010603 microCT Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 210000001188 articular cartilage Anatomy 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 210000001258 synovial membrane Anatomy 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 description 3
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 229930182470 glycoside Natural products 0.000 description 3
- 150000002338 glycosides Chemical class 0.000 description 3
- 235000013402 health food Nutrition 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000000344 soap Substances 0.000 description 3
- 210000004233 talus Anatomy 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 2
- 206010051728 Bone erosion Diseases 0.000 description 2
- 206010007710 Cartilage injury Diseases 0.000 description 2
- 102000000503 Collagen Type II Human genes 0.000 description 2
- 108010041390 Collagen Type II Proteins 0.000 description 2
- 241000243575 Daiswa yunnanensis Species 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241001062009 Indigofera Species 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102000003777 Interleukin-1 beta Human genes 0.000 description 2
- 108090000193 Interleukin-1 beta Proteins 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 101000974353 Mus musculus Nuclear receptor coactivator 5 Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102100040247 Tumor necrosis factor Human genes 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000003044 adaptive effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000003356 anti-rheumatic effect Effects 0.000 description 2
- 239000003435 antirheumatic agent Substances 0.000 description 2
- 229960000190 bacillus calmette–guérin vaccine Drugs 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000005482 chemotactic factor Substances 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001364 upper extremity Anatomy 0.000 description 2
- 210000003857 wrist joint Anatomy 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- 241001061264 Astragalus Species 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 235000006533 astragalus Nutrition 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000001045 blue dye Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 210000003690 classically activated macrophage Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000006481 glucose medium Substances 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- 239000001044 red dye Substances 0.000 description 1
- 238000011268 retreatment Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 108010048734 sclerotin Proteins 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 210000002303 tibia Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nutrition Science (AREA)
- Mycology (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- General Health & Medical Sciences (AREA)
- Botany (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
本发明涉及一种治疗类风湿性关节炎的小分子化合物，其有效成分为重楼皂苷I，浓度为0.1‑10μM。本发明经动物实验证明，重楼皂苷I能减轻胶原诱导类风湿性关节炎小鼠的关节损伤和炎症浸润面积、骨量缺损和软骨缺损降低，减轻踝关节炎症损伤，能够改善类风湿性关节炎症状。本发明还公开了重楼皂苷I在制备类风湿性关节炎的药物或保健品中的用途。
Description
技术领域
本发明涉及一种治疗类风湿性关节炎的小分子化合物，并提出该化合物在制备各种形式的预防和治疗类风湿性关节炎的药物或保健食品中的应用。
背景技术
现有技术公开了类风湿性关节炎(Rheumatoid Arthritis，RA)是一种慢性、系统性、进行性、自身免疫性疾病，以广泛的持续存在的关节滑膜炎及对称性、破坏性的关节病变为特征。RA的治疗却非常困难，到目前为止，仍然缺乏安全有效的治疗药物。现代医学主要是抗炎及减轻后遗症，TNFα抑制剂Etanercept、Infliximab和Adalimumab等药物能够将一部分RA患者肿胀、触痛关节计数等客观症状指标减少到50％，但仍然有许多患者在初次治疗时对其不应答，或二次治疗失败，平均每年约有10％的患者因此停药。寻找安全有效的治疗药物成为RA研究亟待解决的重大问题。中医学在治疗RA方面历史悠久，积累了丰富的临床经验，在缓解和改善临床症状方面常能取得较好疗效。
巨噬细胞在类风湿关节炎疾病的发生、发展及演变中起着关键作用，疾病发病之初，巨噬细胞在滑膜内里和外层聚集，释放致炎因子和趋化因子，同时进行抗原呈递，募集Th1为主的淋巴细胞和B细胞。经过有效治疗后，M1巨噬细胞大量减少，疾病进入缓解期。因此抑制巨噬细胞炎症因子表达，对于RA具有重要的治疗意义。
发明内容
针对现有技术的上述不足，根据本发明的实施例，希望提供一种疗效确切的治疗类风湿性关节炎的小分子化合物，并提出其医药用途。
根据实施例，本发明技术方案提出的一种治疗类风湿性关节炎的小分子化合物，其有效成分为重楼皂苷I，浓度为0.1-10μM。重楼皂苷I是从中药百合科植物南重楼和北重楼Paris yunnanensis Franch的根茎中提取的有效成分，它可以减轻类风湿性关节炎小鼠的炎症浸润面积、骨量缺损和软骨缺损降低，减轻关节炎症损伤。
本发明技术方案的提出是基于重楼皂苷I作为类风湿性关节炎治疗药物，其在患者体液中的有效作用浓度为0.1-10μM。
本发明技术方案中，重楼皂苷I可与药物学上可接受的药物辅料混合形成散剂、膏剂、粉剂、针剂、水剂或注射剂。
本发明技术方案中，重楼皂苷I作为类风湿性关节炎治疗药物，为主要有效成分制备的各种形式的药物或保健食品，可以用于预防和治疗类风湿性关节炎。在使用时可以采取皮下、静脉注射或肛肠给药；注射液的使用可以任意选用生理盐水、葡萄糖、稳定剂、防腐剂、悬浮剂或乳化剂等。
本发明随后的实施例进行了动物实验，建立DBA/1小鼠CIA模型。DBA/1雌鼠6-8周，适应性饲养1周后，采用牛二型胶原和完全弗氏佐剂(卡介苗浓度为4mg/ml)，完全乳化后，尾椎附近背部皮肤皮内注射100μL(含100μg牛二型胶原)，42天后小鼠下肢(踝关节一下)或上肢(腕关节一下)可出现明显红肿，发病率为90％左右。DBA/1小鼠初次免疫42天后，将造模小鼠随机分为组，分为重楼皂苷I组和对照组，每组10只以上。重楼皂苷I组中将重楼皂苷I溶解在0.5％的羧甲基纤维素钠(CMC-Na)制备成混悬液，对照组为0.5％的CMC-Na。重楼皂苷I用量为8mg/kg。灌胃给药，每天一次，连续治疗7周。经动物实验关节炎症状评分，重楼皂苷I可以减轻关节炎评分，体内micro-CT检测结果表明，重楼皂苷I能使CIA小鼠踝关节骨侵蚀降低；组织形态学分析结果显示重楼皂苷I能减轻CIA小鼠踝关节炎症，减少骨侵蚀和软骨侵蚀。因此，以重楼皂苷I为主要有效成分制备的各种形式的药物或保健食品，可以用于预防和治疗类风湿性关节炎。
附图说明
图1为重楼皂苷I的结构简式。
图2动物关节炎症状评分图。
图3是动物实验体内的micro-CT检测结果图。
图4是动物实验体内的ABOG染色检测结果图。
图5是巨噬细胞体外实验qPCR检测结果图。
具体实施方式
下面结合附图和具体实施例，进一步阐述本发明。这些实施例应理解为仅用于说明本发明而不用于限制本发明的保护范围。在阅读了本发明记载的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等效变化和修改同样落入本发明权利要求所限定的范围。
本发明以下实施例中，重楼皂苷I(结构简式如图1所示)采用市售品或按照中药领域常用提取方法从中药百合科植物云南重楼Paris yunnanensis Franch的根茎中提取。
本发明以下实施例中，M为摩尔浓度，即mol/L；μM为微摩尔每升。
实施例
建立DBA/1小鼠CIA模型。DBA/1雌鼠6-8周，适应性饲养1周后，采用牛二型胶原和完全弗氏佐剂(卡介苗浓度为4mg/ml)，完全乳化后，尾椎附近背部皮肤皮内注射100μL(含100μg牛二型胶原)，42天后小鼠下肢(踝关节一下)或上肢(腕关节一下)可出现明显红肿，发病率为90％左右。DBA/1小鼠初次免疫42天后，将造模小鼠随机分为组，分为重楼皂苷I组和对照组，每组10只以上。重楼皂苷I组中重楼皂苷I溶解在0.5％的羧甲基纤维素钠(CMC-Na)制备成混悬液，对照组为0.5％的CMC-Na。重楼皂苷I用量为8mg/kg。灌胃给药，每天一次，连续治疗7周。取踝关节，进行关节炎症状评分，micro-CT检测踝关节骨量，关节切片阿尔辛兰-orange G(ABOG)染色观察炎性浸润和关节骨质和关节软骨破坏情况。
(一)进行动物实验关节炎症状评分。
关节炎症状评分标准如下，每一周观察一次，统计评分结果。
每只小鼠最低评分0分，最高评分为16分。
如图2所示，试验结果显示，在治疗第5周时，重楼皂苷I组的症状评分低于对照组(PPI，重楼皂苷I)。
(二)进行micro-CT检测。
动物踝关节取材后，10％多聚甲醛固定24h，转入75％酒精中，Micro-CT扫描，并三维重建。如图3所示，与WT小鼠相比，CIA小鼠踝关节距骨骨量明显减少。与CIA组比较，重楼皂苷I组小鼠踝关节距骨骨缺损明显减轻(PPI，重楼皂苷I)。
(三)进行动物实验的体内ABOG染色检测。
切片脱蜡至水→盐酸乙醇30sec→艾尔新蓝染液30min→水洗→2％盐酸乙醇分化2sec→水洗→氨水15sec→水洗→橙红染液1min→脱水透明→中性树胶封片。通风橱中放置4h后显微镜下观察。
艾尔新蓝可将关节软骨蓝染，如图4所示，在WT小鼠，可见完整的蓝染的踝关节软骨。但是在CIA小鼠踝关节，蓝染的软骨出现明显缺损，关节结构破坏。与CIA组比较，重楼皂苷I组关节软骨破坏明显减轻。测量关节软骨面积，显示重楼皂苷I显著减轻类风湿性关节炎的软骨缺损(PPI，重楼皂苷I)。对小鼠关节损伤程度进行评分(0-4分，4分：正常关节；3分轻度损伤关节，关节间隙尚存，无明显滑膜浸润；2分关节间隙变小，轻度滑膜浸润；1分，关节炎间隙消失，滑膜浸润明显，0分，关节融合，滑膜大量浸润，距骨破坏严重，评分越低表明关节炎损伤越严重)发现经过重楼皂苷I治疗之后，关节评分升高。
(四)进行细胞学实验，巨噬细胞炎症因子表达检测。
骨髓来源巨噬细胞(BMM)：采用PBS反复冲洗C57/BL6小鼠胫骨和股骨骨髓腔，红细胞裂解后，12孔板中，每孔铺下2×106细胞，加细胞入20ng/mlM-CSF(DMEM高糖培养基+20％FBS+1％LG+1％PS)1ml，3天后进行半换液，5天后贴壁细胞即为BMM.
重楼皂苷I(0.1μM、10μM)作用于BMM细胞3小时后，加入LPS(1μg/ml)和IFN-γ(100ng/ml)刺激巨噬细胞6小时后采用qPCR技术检测IL-1β、IL-6、TNF-α炎症因子的表达。如图5所示，发现LPS(1μg/ml)和IFN-γ(100ng/ml)刺激巨噬细胞高表达IL-1β、IL-6、TNF-α的mRNA，重楼皂苷I呈剂量依赖性抑制这些炎症因子的表达(PPI，重楼皂苷I)。
以上结果提示，重楼皂苷I抑制巨噬细胞炎症因子表达，减轻类风湿性关节炎小鼠关节炎症，减轻炎症对关节骨组织和软骨组织的损伤，说明重楼皂苷I是一个可用于防治类风湿性关节炎的药物。
Claims (4)
1.一种治疗类风湿性关节炎的小分子化合物，其特征是，有效成分为重楼皂苷I，浓度为0.1-10μM。
2.根据权利要求1所述的治疗类风湿性关节炎的小分子化合物，其特征是，重楼皂苷I与药物学上可接受的药物辅料混合形成散剂、膏剂、粉剂、针剂、水剂、肠溶缓释制剂或注射剂。
3.权利要求1或2所述的小分子化合物在制备防治类风湿性关节炎的药物或保健品中的用途。
4.根据权利要求3的用途，其特征是，重楼皂苷I的有效作用浓度为0.1-10μM。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710474946.5A CN109096360B (zh) | 2017-06-21 | 2017-06-21 | 一种治疗类风湿性关节炎的小分子化合物及其用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710474946.5A CN109096360B (zh) | 2017-06-21 | 2017-06-21 | 一种治疗类风湿性关节炎的小分子化合物及其用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109096360A true CN109096360A (zh) | 2018-12-28 |
| CN109096360B CN109096360B (zh) | 2021-05-07 |
Family
ID=64796160
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710474946.5A Active CN109096360B (zh) | 2017-06-21 | 2017-06-21 | 一种治疗类风湿性关节炎的小分子化合物及其用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109096360B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113181192A (zh) * | 2021-04-16 | 2021-07-30 | 陕西中医药大学 | 偏诺皂苷类化合物的应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101257909A (zh) * | 2005-07-06 | 2008-09-03 | 英国技术集团国际有限公司 | 核心2glcnac-t抑制剂 |
| CN101597317A (zh) * | 2008-06-05 | 2009-12-09 | 雷海民 | 重楼皂苷i的制备方法及其抑制血管生长的用途 |
| CN105796580A (zh) * | 2014-12-31 | 2016-07-27 | 上海中医药大学附属龙华医院 | 一种蛋白酶体活性抑制剂pi在制备防治骨肉瘤药物或保健食品中的应用 |
-
2017
- 2017-06-21 CN CN201710474946.5A patent/CN109096360B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101257909A (zh) * | 2005-07-06 | 2008-09-03 | 英国技术集团国际有限公司 | 核心2glcnac-t抑制剂 |
| CN101597317A (zh) * | 2008-06-05 | 2009-12-09 | 雷海民 | 重楼皂苷i的制备方法及其抑制血管生长的用途 |
| CN105796580A (zh) * | 2014-12-31 | 2016-07-27 | 上海中医药大学附属龙华医院 | 一种蛋白酶体活性抑制剂pi在制备防治骨肉瘤药物或保健食品中的应用 |
Non-Patent Citations (2)
| Title |
|---|
| 许晓莲: "重楼皂苷促成骨样细胞MC3T3-E1增殖作用及其机制", 《武警医学》 * |
| 陈临溪: "《细胞信号转导药理与临床》", 31 October 2014 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113181192A (zh) * | 2021-04-16 | 2021-07-30 | 陕西中医药大学 | 偏诺皂苷类化合物的应用 |
| CN113181192B (zh) * | 2021-04-16 | 2023-11-07 | 陕西中医药大学 | 偏诺皂苷类化合物的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109096360B (zh) | 2021-05-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109091477A (zh) | 治疗类风湿性关节炎的小分子化合物及其用途 | |
| CN109200039A (zh) | 治疗类风湿性关节炎的药物及其用途 | |
| CN103619333A (zh) | 钩吻素子在制备治疗类风湿性关节炎药物中的应用 | |
| CN104688881A (zh) | 一种治疗痔疮的中药组合物 | |
| CN101002857B (zh) | 一种中药组合物及其用途 | |
| CN101810686A (zh) | 一种用于治疗类风湿关节炎的配伍组合物及其制备方法 | |
| CN103446577A (zh) | 一种预防和治疗关节炎的药物组合物及其应用 | |
| CN101406688A (zh) | 一种治疗风湿、类风湿性关节炎的复方制剂 | |
| CN109096360A (zh) | 一种治疗类风湿性关节炎的小分子化合物及其用途 | |
| CN103405582A (zh) | 改善类风湿关节炎关节肿痛的中药组合物 | |
| CN112168904A (zh) | 一种治疗骨关节炎的中药复方制剂及其制备方法 | |
| CN103638359A (zh) | 一种治疗泌尿系结石的溶石排石汤 | |
| KR101321754B1 (ko) | 류마티스 관절염 및 골관절염의 개선 또는 치료를 위한 조성물 | |
| CN102293842A (zh) | 一种治疗溃疡性结肠炎的制剂及其制备方法 | |
| KR101533197B1 (ko) | 부테인을 포함하는 부종의 예방 또는 치료용 조성물 | |
| CN104257800A (zh) | 一种治疗痤疮的药剂 | |
| CN103316166A (zh) | 一种治疗痔疮的藏药及其制备方法 | |
| CN100367997C (zh) | 一种治疗痛风病的药物及其制备方法 | |
| US20160000844A1 (en) | A composition for improving joint health, or for preventing and treating rheumatoid arthritis and osteoarthritis | |
| CN104784650A (zh) | 一种用于临床护理胃溃疡的药物制剂 | |
| CN104189346A (zh) | 一种新型促胃肠动力的药物组合物及其制备方法 | |
| CN103768454A (zh) | 一种具有预防和治疗hiv/aids的组合物及其制备方法 | |
| CN109200055A (zh) | 一种治疗类风湿关节炎的药物及其用途 | |
| CN106039194A (zh) | 一种治疗放、化疗引起白细胞减少的复合制剂 | |
| KR20170133036A (ko) | 전립선염 치료용 중국 의약 연고 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |