CN113350342A - 犬尿喹啉酸在制备治疗骨质疏松相关疾病的药物中的用途 - Google Patents
犬尿喹啉酸在制备治疗骨质疏松相关疾病的药物中的用途 Download PDFInfo
- Publication number
- CN113350342A CN113350342A CN202110609117.XA CN202110609117A CN113350342A CN 113350342 A CN113350342 A CN 113350342A CN 202110609117 A CN202110609117 A CN 202110609117A CN 113350342 A CN113350342 A CN 113350342A
- Authority
- CN
- China
- Prior art keywords
- kyna
- osteoporosis
- bone
- disease associated
- kynurenine
- 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.)
- Pending
Links
- 208000001132 Osteoporosis Diseases 0.000 title claims abstract description 47
- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 title claims abstract description 20
- 201000010099 disease Diseases 0.000 title claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 13
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 33
- 230000037182 bone density Effects 0.000 claims abstract description 7
- 229940079593 drug Drugs 0.000 claims abstract description 7
- 230000036541 health Effects 0.000 claims abstract description 4
- HCZHHEIFKROPDY-UHFFFAOYSA-N kynurenic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC(=O)C2=C1 HCZHHEIFKROPDY-UHFFFAOYSA-N 0.000 claims description 132
- 210000000963 osteoblast Anatomy 0.000 claims description 26
- 210000002997 osteoclast Anatomy 0.000 claims description 26
- 230000000694 effects Effects 0.000 claims description 22
- 230000035800 maturation Effects 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 230000003247 decreasing effect Effects 0.000 claims description 5
- 230000004097 bone metabolism Effects 0.000 claims description 4
- 208000029725 Metabolic bone disease Diseases 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims 3
- 239000004480 active ingredient Substances 0.000 claims 2
- 238000013270 controlled release Methods 0.000 claims 2
- 239000003826 tablet Substances 0.000 claims 2
- 206010049088 Osteopenia Diseases 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 239000008187 granular material Substances 0.000 claims 1
- 239000003978 infusion fluid Substances 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 239000006191 orally-disintegrating tablet Substances 0.000 claims 1
- 239000006187 pill Substances 0.000 claims 1
- 208000001076 sarcopenia Diseases 0.000 claims 1
- 238000013268 sustained release Methods 0.000 claims 1
- 239000007939 sustained release tablet Substances 0.000 claims 1
- 239000012730 sustained-release form Substances 0.000 claims 1
- 239000006188 syrup Substances 0.000 claims 1
- 235000020357 syrup Nutrition 0.000 claims 1
- 230000006870 function Effects 0.000 abstract description 3
- 239000003937 drug carrier Substances 0.000 abstract description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 23
- 238000001514 detection method Methods 0.000 description 9
- 230000014509 gene expression Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 238000010172 mouse model Methods 0.000 description 9
- 210000002966 serum Anatomy 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 239000007928 intraperitoneal injection Substances 0.000 description 7
- 108020004999 messenger RNA Proteins 0.000 description 7
- 208000006386 Bone Resorption Diseases 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 230000024279 bone resorption Effects 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000003550 marker Substances 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 101710190440 Cytotoxin 1 Proteins 0.000 description 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 4
- VYVRIXWNTVOIRD-LRHBOZQDSA-N ciguatoxin CTX1B Chemical compound C([C@@]12[C@@H](C)[C@@H]([C@@H]3[C@H]([C@H]([C@H](C)[C@H]4O[C@H]5C[C@@H](C)C[C@H]6O[C@@]7(C)[C@H](O)C[C@H]8O[C@H]9C=C[C@H]%10O[C@H]%11C[C@@H]%12[C@H]([C@@H]([C@H]%13O[C@H](C=CC[C@@H]%13O%12)\C=C\[C@H](O)CO)O)O[C@@H]%11C=C[C@@H]%10O[C@@H]9C\C=C/C[C@@H]8O[C@@H]7C[C@@H]6O[C@@H]5C[C@@H]4O3)O)O2)C)[C@H](O)CO1 VYVRIXWNTVOIRD-LRHBOZQDSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 210000003141 lower extremity Anatomy 0.000 description 4
- 230000011164 ossification Effects 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- 210000001694 thigh bone Anatomy 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 230000002146 bilateral effect Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 210000000689 upper leg Anatomy 0.000 description 3
- 101150011252 CTSK gene Proteins 0.000 description 2
- 101100328884 Caenorhabditis elegans sqt-3 gene Proteins 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- 102000015775 Core Binding Factor Alpha 1 Subunit Human genes 0.000 description 2
- 108010024682 Core Binding Factor Alpha 1 Subunit Proteins 0.000 description 2
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 2
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 2
- 101150035730 Mmp9 gene Proteins 0.000 description 2
- 102100034404 Nuclear factor of activated T-cells, cytoplasmic 1 Human genes 0.000 description 2
- 101710151542 Nuclear factor of activated T-cells, cytoplasmic 1 Proteins 0.000 description 2
- 102000004067 Osteocalcin Human genes 0.000 description 2
- 108090000573 Osteocalcin Proteins 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000011532 immunohistochemical staining Methods 0.000 description 2
- 238000010603 microCT Methods 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- 101150014183 Alpl gene Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 101150065105 Cidec gene Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010068073 Kynurenine-oxoglutarate transaminase Proteins 0.000 description 1
- 208000030136 Marchiafava-Bignami Disease Diseases 0.000 description 1
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GVPNBCFOFXXEEN-UHFFFAOYSA-N OC(=O)c1cc(=O)c2ccccc2[nH]1.OC(=O)c1cc(=O)c2ccccc2[nH]1 Chemical compound OC(=O)c1cc(=O)c2ccccc2[nH]1.OC(=O)c1cc(=O)c2ccccc2[nH]1 GVPNBCFOFXXEEN-UHFFFAOYSA-N 0.000 description 1
- 108700038399 PGC-1 Proteins 0.000 description 1
- 102000017946 PGC-1 Human genes 0.000 description 1
- 206010039984 Senile osteoporosis Diseases 0.000 description 1
- RGCKGOZRHPZPFP-UHFFFAOYSA-N alizarin Chemical compound C1=CC=C2C(=O)C3=C(O)C(O)=CC=C3C(=O)C2=C1 RGCKGOZRHPZPFP-UHFFFAOYSA-N 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000033558 biomineral tissue development Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000018678 bone mineralization Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 201000000916 idiopathic juvenile osteoporosis Diseases 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- -1 intravenous infusion Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 229960003987 melatonin Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 238000009806 oophorectomy Methods 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- Engineering & Computer Science (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Rheumatology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Mycology (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Nutrition Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明属于生物医药领域,涉及犬尿喹啉酸的用途,具体而言涉及犬尿喹啉酸(KYNA)在制备治疗和/或预防骨质疏松的药物或保健品中的用途,KYNA表现出较好的增加骨密度,缓解骨骼微结构的作用。本发明还包括包含KYNA和药学上可接受的载体的药物或保健品。
Description
技术领域:
本发明属于生物医药领域,具体涉及犬尿喹啉酸(Kynurenic acid,KYNA)的用途。
背景技术:
骨质疏松是一种会导致骨量减少、骨密度降低,骨微结构发生改变的全身性骨代谢疾病,骨质疏松根据发病原因可以分为原发性和继发性。继发性一般是由其他疾病或药物引发的骨骼疾病,而原发性是随着年龄的增长必然发生的一种生理衰退型病变,包括绝经性、老年性和特发性三种类型的骨质疏松。绝经后骨质疏松多发生于55岁-65岁中老年女性,而老年性骨质疏松多发生于70岁以上老年人群,特发性骨质疏松多见于青少年和成年,多伴有家族遗传史。骨质疏松的发病率逐年增加之前的文献报道全球大约有2亿人患骨质疏松在中国,绝经女性占总人口的比例约占17%,这意味着患骨质疏松的绝经女性数量将大幅度增加。骨质疏松的主要特点为骨量大量丢失,包括骨矿物质与其基质比例减少;骨微结构由于骨组织形成和吸收失衡导致的退变,表现为骨小梁数量减少,骨小梁变细或发生断裂;骨的脆性增加、骨的力学强度降低,容易发生骨折等。这严重影响正常老年人的生活质量,也给社会的经济带来严重负担。
色氨酸是机体必须氨基酸,95%游离色氨酸通过犬尿氨酸途径进行代谢,其代谢产物可以参与机体炎症、免疫系统、神经元兴奋的调节。之前研究发现,色氨酸途径中如5-羟色胺、褪黑素、犬尿氨酸等代谢产物对骨代谢起到不同程度调控作用。其中犬尿氨酸作为犬尿氨酸途径的主要代谢产物,随年龄增加,外周血中KYN浓度显著增高,通过减少Hadc3/NCoR1表达增加脂质形成基因Cidec/PIin1表达从而抑制骨形成促进骨吸收加速骨量丢失。犬尿喹啉酸是KYN经犬尿氨酸氨基转移酶代谢所产生,Agudelo等人发现运动可激活骨骼肌中的PGC-1α1(gamma coactivator-1α1),促进KYN向KYNA转化,减少压力引起的KYN蓄积,缓解其对认知功能的毒性作用。此外,G protein-Coupled receptor(G蛋白偶联受体,GPCR)35(Gpr35)作为KYNA的受体,可调节细胞内Ca2+通路,KYNA激活Gpr35可促进细胞Ca2+的释放,因而KYNA可能在骨代谢过程中发挥重要作用。因此提示,运动过程中骨量的增加一方面可以与KYN在机体内蓄积降低所致,另一方面可能与KYNA具有的潜在促骨形成有关。
发明内容:
要解决的技术问题:
本发明要解决的问题是针对骨质疏松相关疾病寻找一种新的药物。
技术方案:
本发明的目的在于提供犬尿喹啉酸在生物医药领域的新用途,具体涉及其在制备治疗和/或预防骨质疏松的药物或保健品中的用途。本发明的实施例提供了犬尿喹啉酸(KYNA)在制备治疗和/或预防骨质疏松的药物或保健品中的用途。其中,所述药物或保健品可包含KYNA和药学上可接受的载体。所述药物的给药途径包括口服、肌肉注射、静脉输注、皮下注射及鞘内注射。为了更好的理解发明的本质,本发明开展了药理实验以证明KYNA在制药和保健领域的用途。经实验验证,本发明的KYNA在治疗和/或预防骨质疏松中,表现出较好的增加骨密度,缓解骨骼微结构的作用。
优点和效果:
(1)本发明的KYNA经动物实验验证对成骨细胞具有显著的促进作用,对于破骨细胞则呈现一定的抑制效果,因而能够调控机体的骨量平衡,具有防止骨质疏松的作用,可用于进一步制备治疗和/或预防骨质疏松的药物或保健品。
(2)本发明为目前治疗骨质疏松药物提供了一种全新的选择和思路,拓宽了治疗骨质疏松的选择领域。
附图说明:
图1a.KYNA显著抑制原代破骨细胞成熟。
图1b.KYNA显著抑制原代破骨细胞Trap阳性细胞数量。
图1c-f.KYNA显著抑制原代破骨细胞成熟标识物NFATc1(c)、Ctsk(d)、Mmp9(e)、Trap(f)mRNA的表达。
图2a.KYNA显著促进原代成骨细胞ALP浓度。
图2b.KYNA显著促进原代成骨细胞矿化过程。
图2c-f.KYNA显著促进原代成骨细胞活性标识物Runx2(c)、Col1(d)、Alpl(e)、Ocn(f)mRNA的表达。
图3a.KYNA治疗骨质疏松模型小鼠股骨骨小梁微结构增加模式图。
图3b.KYNA治疗骨质疏松模型小鼠股骨骨密度增加分析。
图3c.KYNA治疗骨质疏松模型小鼠股骨骨骼微结构缓解分析。
图4a-b.KYNA治疗骨质疏松模型小鼠股骨组织切片TRAP染色阳性面积显著降低。
图4c.KYNA治疗骨质疏松模型小鼠,血清中破骨细胞标识物CTX-1浓度显著下降。
图5a-b.KYNA治疗骨质疏松模型小鼠股骨组织切片Ocn阳性细胞数量显著增加。
图5c.KYNA治疗骨质疏松模型小鼠,血清中成骨细胞标识物P1NP浓度显著增加。
具体实施方式:
1.实验材料
1.1犬尿喹啉酸(KYNA)的准备
犬尿喹啉酸化学名称为4-羟基喹啉-2-甲酸(4-hydroxyquinoline-2-carboxylicacid),分子式为C10H7NO3,分子量为189.17g/mol,其化学结构式如下:
化学合成纯度大于99%的KYNA,将合成的KYNA粉末溶于DMSO中,配制浓度为5mM的KYNA溶液,分装后冷冻保存备用,使用时用DMSO稀释成相应浓度。
1.2骨质疏松小鼠模型的准备
国外学者Saville采用手术方式摘除大鼠的双侧卵巢后成功诱导骨质疏松症状,该手术去势法建模的重复性好,能够在相对较短的期限内成功构建,得到广泛的认可及推广。本发明即采用该手术去势法进行建模。具体操作如下:取10周大C57BI6雌鼠,在异弗烷麻醉情况下,背部开口,切去双侧卵巢以及连接的部分小鼠子宫,用3-0线进行缝合,并给予小鼠充足的水和食物进行饲养。
此外,之前研究显示,利用悬吊的方法使大鼠双下肢悬空、头低位,双下肢处于人工失重状态,保持双下肢失重状态3~4周后,大鼠双下肢股骨出现骨密度显著下降、骨矿物含量显著降低、骨小梁结构发生明显改变等骨质疏松的表现。因此我们使用尾悬吊方法进行应力减少型骨质疏松模型构建取4周大C57BI6雌鼠,把小鼠尾部悬吊14天,获取骨质疏松模型。
实施例一:犬尿喹啉酸(KYNA)在细胞中的作用
犬尿喹啉酸(KYNA)抑制破骨细胞、促进成骨细胞中作用
为了明确KYNA对成骨细胞和破骨细胞影响,我们将不同浓度的KYNA分别加入原代成骨细胞和原代破骨细胞中进行处理,对成骨细胞进行ALP染色和茜素红染色,同时检测原代成骨细胞中骨形成标识物mRNA基因表达情况。对破骨细胞进行Trap染色,同时检测出原代破骨细胞中骨吸收标识物mRNA基因表达情况。
犬尿喹啉酸(KYNA)抑制原代破骨细胞成熟。
为了验证KYNA对破骨细胞的作用,我们提取原代破骨细胞进行检测。在原代破骨细胞中,加入不同浓度的KYNA可以显著抑制破骨细胞成熟(图1a),TRAP阳性细胞数量显著降低(图1b),原代破骨细胞mRNA检测发现破骨细胞相关标识物NFATc1、Ctsk、Mmp9、Trap的表达显著降低(图1c-f)。
犬尿喹啉酸(KYNA)促进原代成骨细胞活性。
为了验证KYNA对成骨细胞的作用,我们提取原代成骨细胞进行检测。在原代成骨细胞中,加入不同浓度的KYNA,可以显著促进成骨细胞骨矿化过程(图2a-b),原代成骨细胞mRNA检测发现成骨细胞相关标识物Runx2、Col1、Alpl、Ocn的mRNA表达量显著增加(图2c-f)。以上表明,KYNA可以显著促进原代成骨细胞活性同时抑制破骨细胞成熟。
实施例二:犬尿喹啉酸(KYNA)在骨质疏松小鼠模型中的作用
为了验证KYNA对小鼠骨量的影响,我们采用10周大雌鼠,进行双侧卵巢切除手术,构建骨质疏松模型,在小鼠休息1周后,进行5mg/kg浓度KYNA腹腔注射,连续注射治疗4周后,取小鼠血清、骨骼组织进行检测。主要检测有小鼠股骨Micro-CT检测骨密度和骨骼微结构,小鼠血清中骨形成标识物P1NP和骨吸收标识物CTX-1,以及小鼠股骨组织切片进行Osteocalcin免疫组化染色,和Trap染色,分别明确成骨细胞活性和破骨细胞活性。
外源性腹腔注射犬尿喹啉酸(KYNA)显著缓解骨质疏松模型小鼠的骨量降低
在小鼠骨质疏松模型(OVX)构建后一周,进行5mg/kg每天一次的外源性KYNA腹腔注射,一共注射4周,治疗后收取小鼠股骨、血清等组织进行检测。Micro-CT检测发现,在KYNA治疗组中小鼠骨量与单纯OVX造模组显著增加,小鼠股骨骨骼微结构得到显著缓解(图3a-c)。以上表明,外源性注射KYNA治疗后,可以显著增加骨密度。
外源性腹腔注射犬尿喹啉酸(KYNA)显著抑制骨质疏松模型小鼠的破骨细胞骨吸收功能
在小鼠骨质疏松模型(OVX)构建后一周,进行5mg/kg每天一次的外源性KYNA腹腔注射,一共注射4周,治疗后收取小鼠股骨、血清等组织进行检测。血清学检测骨组织中破骨细胞活性CTX-1发现(图4c),小鼠KYNA治疗后,血清中CTX-1浓度显著降低,股骨组织切片破骨细胞活性染色(TRAP染色)表明(图4a,b),与OVX组相比,KYNA治疗组TRAP阳性面积显著降低。以上表明,外源性注射KYNA治疗后,可以显著通过抑制破骨细胞成熟抑制骨吸收。
外源性腹腔注射犬尿喹啉酸(KYNA)显著促进骨质疏松模型小鼠的成骨细胞骨吸收功能
在小鼠骨质疏松模型(OVX)构建后一周,进行5mg/kg每天一次的外源性KYNA腹腔注射,一共注射4周,治疗后收取小鼠股骨、血清等组织进行检测。血清学检测骨组织中成骨细胞活性P1NP发现(图5c),小鼠KYNA治疗后,血清中P1NP浓度显著增加,股骨组织切片成骨细胞活性Osteocalcin(Ocn)免疫组化染色发现(图5a,b),KYNA治疗组中Ocn阳性细胞数量较OVX组显著增加。以上表明,外源性注射KYNA治疗后,可以显著通过进成骨细胞活性从而增加骨吸收。
上述实验结果说明犬尿喹啉酸(KYNA)在骨质疏松模型小鼠中具有调控机体骨量平衡,缓解骨量丢失,具有防止骨质疏松的作用,对成骨细胞具有显著促进作用,对于破骨细胞呈现一定的抑制效果。
我们对尾悬吊方法获取的骨质疏松模型小鼠进行相同的实验,得出犬尿喹啉酸(KYNA)在骨质疏松小鼠模型中同样具有调控机体骨量平衡,缓解骨量丢失,具有防止骨质疏松的作用,对成骨细胞具有显著促进作用,对于破骨细胞呈现一定的抑制效果。
以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而脱离本发明技术方案的宗旨和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (7)
1.犬尿喹啉酸或其衍生物在制备治疗和/或预防骨代谢失衡相关的骨质减少疾病的药物或保健品中的应用。
2.根据权利要求1所述的应用,其特征在于,所述骨代谢失衡相关的骨质减少疾病是指原代成骨细胞活性降低相关疾病、破骨细胞成熟相关疾病、骨密度降低相关疾病、骨量降低相关疾病、骨质疏松症及骨质疏松相关疾病。
3.根据权利要求2所述的应用,其特征在于,所述骨质疏松相关疾病是指肌肉减少症。
4.根据权利要求1所述的应用,其特征在于,所述药物包含犬尿喹啉酸或其衍生物作为活性成分。
5.根据权利要求1所述的应用,其特征在于,所述药物还包含医药学上可接受的佐剂。
6.根据权利要求1所述的应用,其特征在于,所述药物的剂型为片剂、胶囊剂、口服液、糖浆、颗粒、滴丸、口腔崩解片、缓释片、控释片、缓释胶囊剂、控释胶囊剂、注射剂或输液剂。
7.权利要求1所述的应用中所使用的药物,其特征在于,所述药物包含犬尿喹啉酸或其衍生物作为活性成分。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110609117.XA CN113350342A (zh) | 2021-06-01 | 2021-06-01 | 犬尿喹啉酸在制备治疗骨质疏松相关疾病的药物中的用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110609117.XA CN113350342A (zh) | 2021-06-01 | 2021-06-01 | 犬尿喹啉酸在制备治疗骨质疏松相关疾病的药物中的用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113350342A true CN113350342A (zh) | 2021-09-07 |
Family
ID=77530774
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110609117.XA Pending CN113350342A (zh) | 2021-06-01 | 2021-06-01 | 犬尿喹啉酸在制备治疗骨质疏松相关疾病的药物中的用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113350342A (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117045652A (zh) * | 2023-08-28 | 2023-11-14 | 中国科学技术大学 | 犬尿喹啉酸在制备缓解和/或治疗神经性贪食症的药物中的应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109952102A (zh) * | 2016-09-05 | 2019-06-28 | 代谢研究所 | 使用色氨酸代谢物治疗肌肉萎缩 |
JP2021143171A (ja) * | 2020-03-12 | 2021-09-24 | 御木本製薬株式会社 | 破骨細胞活性抑制剤、破骨細胞遺伝子発現抑制剤 |
-
2021
- 2021-06-01 CN CN202110609117.XA patent/CN113350342A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109952102A (zh) * | 2016-09-05 | 2019-06-28 | 代谢研究所 | 使用色氨酸代谢物治疗肌肉萎缩 |
JP2021143171A (ja) * | 2020-03-12 | 2021-09-24 | 御木本製薬株式会社 | 破骨細胞活性抑制剤、破骨細胞遺伝子発現抑制剤 |
Non-Patent Citations (1)
Title |
---|
伍亚蓝: "GPR35调控骨重塑的分子机理研究", 《中国优秀博硕士学位论文全文数据库(硕士) 医药卫生科技辑》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117045652A (zh) * | 2023-08-28 | 2023-11-14 | 中国科学技术大学 | 犬尿喹啉酸在制备缓解和/或治疗神经性贪食症的药物中的应用 |
CN117045652B (zh) * | 2023-08-28 | 2024-05-28 | 中国科学技术大学 | 犬尿喹啉酸在制备缓解和/或治疗神经性贪食症的药物中的应用 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Liang et al. | Inhibition of RIPK1/RIPK3 ameliorates osteoclastogenesis through regulating NLRP3-dependent NF-κB and MAPKs signaling pathways | |
CN106994129A (zh) | 雷公藤甲素及其衍生物在制备治疗和/或预防肺损伤疾病的药物中的应用 | |
CN113350342A (zh) | 犬尿喹啉酸在制备治疗骨质疏松相关疾病的药物中的用途 | |
KR20080110776A (ko) | 아데노신 a₁ 수용체 길항제 및 항경련제의 공동 투여 | |
IE47331B1 (en) | Pharmaceutical composition | |
WO2013071696A1 (zh) | 人体五种正常碱基在制备肿瘤药物中的应用 | |
US7579331B2 (en) | Method of improved diuresis in individuals with impaired renal function | |
KR20150011379A (ko) | 옥시부티닌 투여를 위한 방법 및 조성물 | |
US20070014811A1 (en) | Agents For Treating Osteoporosis And Inhibiting Osteoclast Formation | |
CN101541323B (zh) | 吲唑甲氧基烷酸用于降低甘油三酯、胆固醇和葡萄糖水平的用途 | |
US20170128385A1 (en) | 7-hydroxy cannabidiol (7-oh-cbd) for use in the treatment of non-alcoholic fatty liver disease (nafld) | |
US11452710B1 (en) | Micronutrient and plant extract composition and method of improving bone health | |
CN112245424B (zh) | 一种没药烷倍半萜结构类似物在制备抗冠状病毒药物中的用途 | |
Wu et al. | Study on the mechanism of probucol nanosuspension on hyperlipidemic pancreatitis and regulation of blood lipid function | |
CN114191422A (zh) | 根皮素在制备抗抑郁药物中的应用 | |
WO2006026924A1 (fr) | Utilisation de ginsenoside dans le traitement du sida | |
WO2005079783A1 (ja) | 転写因子klf5の活性化抑制作用を有する医薬 | |
CN110075093A (zh) | 广藿香醇在制备抗抑郁症药物中的应用 | |
CN115501236B (zh) | 一种醋酸烯诺孕酮在制备降低肺部炎症性疾病的药物中的应用 | |
US11986507B1 (en) | Micronutrient composition to improve men's health | |
US20230404945A1 (en) | Application of alpha-asarone in preparation of medicine for preventing or treating hemorrhagic stroke | |
JP2017197436A (ja) | 神経筋接合部形成促進薬 | |
CN112107581A (zh) | 式i化合物在制备治疗肥胖及相关病症的药中的用途 | |
CN112807295A (zh) | 对羟基苯甲酸钠在制备治疗骨质疏松药物中的应用 | |
CN101323604B (zh) | 新的PPARα/γ双激动剂及其制备方法和用途 |
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 | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20210907 |
|
WD01 | Invention patent application deemed withdrawn after publication |