WO2023185448A1 - Utilisation de gallate de méthyle dans la préparation de médicaments destinés au traitement de l'arthrose - Google Patents
Utilisation de gallate de méthyle dans la préparation de médicaments destinés au traitement de l'arthrose Download PDFInfo
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- WO2023185448A1 WO2023185448A1 PCT/CN2023/081299 CN2023081299W WO2023185448A1 WO 2023185448 A1 WO2023185448 A1 WO 2023185448A1 CN 2023081299 W CN2023081299 W CN 2023081299W WO 2023185448 A1 WO2023185448 A1 WO 2023185448A1
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- osteoarthritis
- methyl gallate
- chondrocytes
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- drugs
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- FBSFWRHWHYMIOG-UHFFFAOYSA-N methyl 3,4,5-trihydroxybenzoate Chemical compound COC(=O)C1=CC(O)=C(O)C(O)=C1 FBSFWRHWHYMIOG-UHFFFAOYSA-N 0.000 title claims abstract description 132
- IBKQQKPQRYUGBJ-UHFFFAOYSA-N methyl gallate Natural products CC(=O)C1=CC(O)=C(O)C(O)=C1 IBKQQKPQRYUGBJ-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 201000008482 osteoarthritis Diseases 0.000 title claims abstract description 54
- 239000003814 drug Substances 0.000 title claims abstract description 26
- 229940079593 drug Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 210000001612 chondrocyte Anatomy 0.000 claims abstract description 71
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- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 2
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- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
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- 150000004702 methyl esters Chemical class 0.000 description 2
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- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- 208000020053 Abnormal inflammatory response Diseases 0.000 description 1
- 206010007710 Cartilage injury Diseases 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
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- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 208000003947 Knee Osteoarthritis Diseases 0.000 description 1
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 description 1
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 description 1
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- 239000002253 acid Substances 0.000 description 1
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- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
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- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
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- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
-
- 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
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to the field of medical technology, specifically the application of methyl gallate in the preparation of osteoarthritis therapeutic drugs.
- Osteoarthritis is one of the progressive chronic joint diseases with high disability and teratogenic rates worldwide. It is mainly characterized by the decrease of cartilage cells and the destruction and degradation of joint matrix. Current treatments mainly focus on alleviating clinical symptoms, and there is a lack of effective drugs to improve cartilage degeneration.
- traditional Chinese medicine has the advantages of accurate curative effect and minimal side effects. It has been used clinically, and the recovery of patients after combined treatment with traditional Chinese medicine is significantly better than that of conventional treatment alone. It shows that traditional Chinese medicine has good curative effect in treating osteoarthritis. But how to use traditional Chinese medicine to prevent and treat osteoarthritis is the direction of our research.
- chondrocyte apoptosis may lead to loss of extracellular matrix function and cartilage destruction.
- chondrocyte apoptosis is an inducer of cartilage degradation or a product of cartilage damage
- chondrocyte apoptosis is an important aspect of the pathogenesis of osteoarthritis. Therefore, articular chondrocyte apoptosis and abnormal inflammatory response are one of the initial diseases that lead to degenerative changes in joint tissues. How to alleviate the local inflammatory pressure in the joint and the induced chondrocyte apoptosis has become the key to treating this disease.
- Methyl gallate (Methyl gallate, whose structural formula is shown in Formula I) is a plant phenolic with antioxidant, anti-cancer and anti-inflammatory activities found in a variety of traditional Chinese medicines. It has also been reported that methyl gallate can regulate immune response, inhibit inflammation, and protect blood vessels.
- Chinese patent document CN114028376A discloses the use of MG in the preparation of NLRP3 pathway inhibitors for hyperuricemic nephropathy and/or gouty arthritis.
- Chinese patent document CN108530314A discloses a methyl gallate analog and its application in preparing anti-inflammatory drugs. However, there have been no reports on the application of methyl gallate in preparative osteoarthritis treatment drugs.
- the object of the present invention is to provide the application of methyl gallate in the preparation of osteoarthritis treatment drugs.
- the present invention discovers for the first time that methyl gallate protects chondrocytes by inhibiting the activation of the Pi3k/Akt signaling pathway, inhibiting chondrocyte apoptosis, thereby slowing down and treating osteoarthritis.
- methyl gallate is administered at the same time.
- PCR, Western Blot, and immunofluorescence are used to detect the apoptosis-related Pi3k/Akt signaling pathway, explore the changes in apoptosis expression downstream of Pi3k/Akt, and evaluate the protection of methyl gallate. role of chondrocytes;
- CCK-8 method is used to screen the optimal concentration of methyl gallate intervention
- Methyl gallate inhibits the catabolic ability of chondrocytes in osteoarthritis models
- Methyl gallate alleviates the synthetic ability of chondrocytes in osteoarthritis models
- Methyl gallate down-regulates the Pi3k/Akt pathway and affects chondrocyte function
- the first aspect of the present invention provides the use of methyl gallate in the preparation of osteoarthritis treatment drugs.
- osteoarthritis includes but is not limited to osteoarthritis induced by interleukin-1 ⁇ and/or under conditions stimulated by wind, cold and dampness.
- methyl gallate is used to prepare a medicine for slowing down and treating osteoarthritis caused by inflammation induction and/or damage to chondrocytes caused by wind, cold, and dampness stimulation.
- methyl gallate directly protects chondrocytes by reducing inflammation-induced and/or wind-cold-dampness stimulation damage to chondrocytes, thereby slowing down and treating osteoarthritis.
- methyl gallate protects chondrocytes by inhibiting the activation of the Pi3k/Akt signaling pathway, inhibiting chondrocyte apoptosis, thereby slowing down and treating osteoarthritis.
- a second aspect of the present invention provides the application of methyl gallate in the preparation of a medicine for reducing inflammation-induced and/or wind-cold-dampness stimulation to chondrocyte damage.
- a third aspect of the present invention provides the use of methyl gallate in the preparation of drugs that inhibit the activation of the Pi3k/Akt signaling pathway.
- a fourth aspect of the present invention provides a medicine for treating osteoarthritis, the active ingredient of which is gallic acid. acid methyl ester.
- the medicine also includes pharmaceutically acceptable carriers or excipients.
- the present invention discloses for the first time the protective effect of methyl gallate on chondrocytes in vitro and its application in the treatment of osteoarthritis.
- methyl gallate can reduce the damage of chondrocytes and directly protect chondrocytes; it can also target and inhibit the Pi3k/Akt signaling pathway that controls chondrocyte activation, thereby reducing the release of inflammatory factors.
- methyl gallate can also indirectly protect cartilage by reducing the inflammatory induction of osteoarthritis and/or the inhibition of chondrocyte vitality and apoptosis caused by wind, cold, and dampness stimulation, thereby treating and slowing down osteoarthritis.
- the present invention is supported by a large amount of experimental data, which shows that methyl gallate has a significant protective effect on chondrocytes and can play an important role in the treatment of osteoarthritis in the future.
- the present invention provides new ideas and reference for better understanding the pathological process of osteoarthritis and for the future development of drugs for treating osteoarthritis.
- Figure 1 shows the cytotoxicity test of methyl gallate on rat chondrocytes; A is the 24-hour CCK-8 test to evaluate the cell viability, and B is the 48-hour CCK-8 test to evaluate the cell viability.
- Figure 2 shows the ability of methyl gallate to inhibit the catabolism of chondrocytes in the osteoarthritis model;
- A is the RT-PCR detection of pro-inflammatory factors (IL-6, IL-1 ⁇ ) in SD rat chondrocytes after treatment. ) and catabolic ability (ADAMTS5, MMP13) mRNA expression.
- B is Western Blot to detect the protein expression of iNos, Cox-2 and MMP9 in SD rat chondrocytes after treatment.
- Figure 3 is a diagram showing the synthetic ability of chondrocytes in osteoarthritis model alleviated by methyl gallate;
- A is the immunofluorescence image of Col2 ⁇ 1 and DAPI (nucleus) in each group.
- B shows the fluorescence intensity of Col-2 ⁇ 1 in each group.
- C is Western Blot to detect the protein expression of Col2 ⁇ 1, Acan and Sox-9 in each group.
- Figure 4 is a diagram showing the effects of methyl gallate on the Pi3k/Akt pathway in chondrocytes.
- Figure 5 shows the effect of methyl gallate on chondrocyte apoptosis genes.
- Cartilage from the joints of the limbs of SD rats 24 hours after birth was removed, and chondrocytes were extracted. P1-2 generation cells were studied. CCK8 method was used to detect the cytotoxicity of methyl gallate on rat chondrocytes.
- Example 2 Protective effect of methyl gallate in osteoarthritis
- Cartilage from the joints of the limbs of SD rats 24 hours after birth was removed, and chondrocytes were extracted. P1-2 generation cells were studied.
- Preparation method of wind-cold dampness serum First, use the modified Hulth method + wind-cold-dampness artificial climate chamber intervention to establish a wind-cold-dampness osteoarthritis model (condition setting + humidity 95 ⁇ 2%, temperature 11 ⁇ 1°C, wind level 3 simulated wind-cold dampness environmental factors ), separate rat serum, and inactivate it for later use.
- control group IL-1 ⁇ 20ng/ml
- model group IL-1 ⁇ 20ng/ml
- wind-cold dampness serum group IL-1 ⁇ 20ng/ml+ wind-cold dampness serum 10%
- MG methyl gallate
- Figure 2 is a diagram showing the ability of methyl gallate to inhibit the catabolism of chondrocytes in osteoarthritis.
- pro-inflammatory factors IL-6, IL-1 ⁇
- catabolic indicators ADAMTS5, MMP13, iNos, The expression of Cox-2 and MMP9
- IL-6, IL-1 ⁇ pro-inflammatory factors
- ADAMTS5, MMP13, iNos The expression of Cox-2 and MMP9
- the expression of pro-inflammatory factors and catabolic indicators in the wind-cold-dampness serum group was further increased compared with the model group, indicating that IL-1 ⁇ combined with wind-cold-damp serum intervention can better simulate the inflammatory state of osteoarthritis
- after adding methyl gallate the expression of pro-inflammatory factors and catabolic indicators in chondrocytes significantly decreased, indicating that methyl gallate can inhibit osteoarthritis.
- the catabolic capacity of lower chondrocytes The catabolic capacity of lower chondrocytes.
- Figure 3 is a graph showing the synthetic ability of chondrocytes under the condition of methyl gallate relieving osteoarthritis.
- the results show that the expression of Col2 ⁇ 1, Acan and Sox-9 in the model group decreased compared with the control group, indicating that the chondrocytes after IL-1 ⁇ intervention The cartilage synthesis ability decreased; the expression of Col2 ⁇ 1, Acan and Sox-9 in the wind-cold-dampness serum group decreased significantly compared with the model group, indicating that the chondrocyte synthesis ability was further reduced after the intervention of IL-1 ⁇ combined with wind-cold-dampness serum; and after adding methyl gallate , the expression of synthetic indicators in chondrocytes increased significantly, indicating that methyl gallate can improve the synthetic ability of chondrocytes in osteoarthritis models under inflammatory conditions.
- FIG. 4 is a diagram showing the effects of methyl gallate on the Pi3k/Akt pathway in chondrocytes under osteoarthritis.
- the results show that the expression levels of p-Pi3k and p-AKT in the model group are higher than those in the control group; -The expression levels of Pi3k and p-AKT increased significantly compared with the model group, indicating that the intracellular Pi3k/Akt pathway was activated after the intervention of IL-1 ⁇ combined with wind-cold-dampness serum; and after adding methyl gallate, cartilage
- the expression of p-Pi3k and p-AKT in cells decreased, indicating that methyl gallate regulates the inactivation of the Pi3k/Akt signaling pathway in chondrocytes under inflammatory conditions and affects osteoarthritis.
- Figure 5 shows the effect of methyl gallate on chondrocyte apoptosis genes in osteoarthritis.
- the results show that the expression levels of Bax and Cleave-caspase 3 in the model group are higher than those in the control group, and the expression level of Bcl-2 is higher than that in the control group. group; the expression of Bax and Cleave-caspase3 in the wind-cold-dampness serum group was higher than that of the control group, and the expression of Bcl-2 was lower than that of the control group, indicating that intracellular apoptosis was obvious after the intervention of IL-1 ⁇ combined with wind-cold-dampness serum.
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
La présente invention se rapporte au domaine technique des médicaments, et en particulier, à une utilisation du gallate de méthyle dans la préparation de médicaments destinés au traitement de l'arthrose. Le gallate de méthyle peut soulager la lésion des chondrocytes, améliorer l'arthrose, et protéger directement les chondrocytes ; le gallate de méthyle peut également inhiber, de manière ciblée, une voie de signalisation Pi3k/Akt activée par des chondrocytes, ce qui permet de réduire la libération de facteurs inflammatoires. En outre, le gallate de méthyle peut également jouer un rôle dans la protection indirecte du cartilage en atténuant l'induction inflammatoire de l'arthrose et/ou l'inhibition de la viabilité des chondrocytes et l'apoptose provoquées par une stimulation par le vent, l'humidité et le froid, ce qui permet de traiter et de soulager l'arthrose. Afin de mieux comprendre le processus pathologique de l'arthrose, une nouvelle pensée et une nouvelle référence sont fournies pour le développement de médicaments destinés au traitement de l'arthrose dans le futur.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210322511.X | 2022-03-30 | ||
| CN202210322511.XA CN114931571A (zh) | 2022-03-30 | 2022-03-30 | 没食子酸甲酯在制备骨关节炎治疗药物中的应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2023185448A1 true WO2023185448A1 (fr) | 2023-10-05 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2023/081299 WO2023185448A1 (fr) | 2022-03-30 | 2023-03-14 | Utilisation de gallate de méthyle dans la préparation de médicaments destinés au traitement de l'arthrose |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN114931571A (fr) |
| WO (1) | WO2023185448A1 (fr) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114931571A (zh) * | 2022-03-30 | 2022-08-23 | 上海中医药大学附属曙光医院 | 没食子酸甲酯在制备骨关节炎治疗药物中的应用 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104884067A (zh) * | 2012-10-17 | 2015-09-02 | 甲基化物科学国际有限公司 | 包含s-腺苷甲硫氨酸及没食子酸酯的组合物 |
| CN108530314A (zh) * | 2018-05-23 | 2018-09-14 | 温州医科大学 | 一种没食子酸甲酯类似物及其应用 |
| WO2020050602A1 (fr) * | 2018-09-05 | 2020-03-12 | (주)루젠에스씨아이 | Système de criblage d'agents de traitement de maladies cartilagineuses à base d'une lignée cellulaire transformée par des éléments humains |
| CN114931571A (zh) * | 2022-03-30 | 2022-08-23 | 上海中医药大学附属曙光医院 | 没食子酸甲酯在制备骨关节炎治疗药物中的应用 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2013134126A (ru) * | 2011-01-10 | 2015-02-20 | ЕэСэМ ТЕКНОЛОДЖИС, ЛЛК | Способ снижения уровня с-концевого телопептида коллагена 2 типа |
| KR101401154B1 (ko) * | 2011-02-22 | 2014-05-30 | 경희대학교 산학협력단 | 메틸 갈레이트를 포함하는 조절 ｔ 세포 활성 억제용 약학적 조성물 |
| CN108863892B (zh) * | 2018-07-04 | 2022-04-05 | 温州医科大学 | 一种含酰胺结构的没食子酸甲酯类似物及应用 |
| CN114028376A (zh) * | 2021-09-17 | 2022-02-11 | 武汉翼博济生生物科技有限公司 | Mg在制备高尿酸血症肾病和/或痛风性关节炎的nlrp3通路抑制剂中的应用 |
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- 2022-03-30 CN CN202210322511.XA patent/CN114931571A/zh active Pending
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- 2023-03-14 WO PCT/CN2023/081299 patent/WO2023185448A1/fr unknown
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