CN110856721A

CN110856721A - Application of tripterine in preparation of anti-scleroderma drugs

Info

Publication number: CN110856721A
Application number: CN201810964850.1A
Authority: CN
Inventors: 卢伟强; 姜兴武; 陈思; 刘明耀
Original assignee: East China Normal University; Bioray Laboratories Inc
Current assignee: East China Normal University; Bioray Laboratories Inc
Priority date: 2018-08-23
Filing date: 2018-08-23
Publication date: 2020-03-03

Abstract

The invention belongs to the field of medicines, and relates to application of tripterine in preparation of an anti-scleroderma medicine. Animal experiments prove that the tripterine can effectively relieve mouse scleroderma, and the effect of the tripterine is mainly shown in that infiltration of inflammatory cells at an affected part of the scleroderma and deposition of collagen can be relieved. The tripterine belongs to natural products, has high bioavailability and stable property, and has clinical use value. The tripterine is developed as a new scleroderma resisting medicine or an auxiliary component thereof, has obvious scleroderma resisting effect, is green and environment-friendly, and provides a new way and means for treating scleroderma diseases.

Description

Application of tripterine in preparation of anti-scleroderma drugs

Technical Field

The invention belongs to the field of medicines, and relates to application of tripterine in preparation of an anti-scleroderma medicine.

Background

Physical mechanical injury, infection caused by viruses and bacteria, exposure to toxins, and the like cause various degrees of tissue damage, and fibrosis generally occurs in the process of wound healing after tissue damage, which is caused by excessive tissue repair. Examples of conditions associated with tissue fibrosis are numerous and generally include the formation of skin scarring, liver fibrosis, kidney fibrosis (including diabetes-induced kidney disease), pulmonary interstitial fibrosis, glomerulonephritis, heart failure (ischemic and non-ischemic), scleroderma, and the like.

The pathogenesis of fibrosis is not completely understood, normally, fibroblast proliferation and function are tightly regulated by the body, but under pathological conditions such as persistent inflammation or tissue injury, tissue repair caused by connective tissue protein production continues, and when tissue repair is excessive, scarring occurs, resulting in fibrosis.

Systemic sclerosis, also known as systemic fibrosis or scleroderma, is an autoimmune disease, the most prominent external features being skin thickening and arteriolar damage due to collagen accumulation. Two forms of sclerosis are currently common in the clinic: local sclerosis and systemic sclerosis. Topical sclerosis affects mainly the skin of the face, hands and feet. Systemic sclerosis may also develop in internal organs including the kidney, heart, lung and gastrointestinal tract, in addition to the skin. The current data indicate that the 10-year survival rate for patients with localized systemic sclerosis is 75%; nearly 10% of the years have progressed to pulmonary hypertension in 10 to 20 years. The 10-year survival rate for systemic sclerosis patients is only 55%, the most common cause of death being failure of the lungs, heart and kidneys. In addition, these patients are at a slightly increased risk of developing cancer.

Tripterine is a pentacyclic triterpenoid compound with bioactivity separated from tripterygium wilfordii roots, and no report about the treatment effect of the tripterine on scleroderma diseases is found so far. The tripterine has high bioavailability and stable property, and has certain effect in treating chronic inflammation, autoimmune diseases, asthma and neurodegenerative diseases. The tripterine provided by the invention is intended to improve the symptoms of patients with diseases such as scleroderma by reducing infiltration of inflammatory cells and deposition of collagen.

Disclosure of Invention

The invention aims to provide a new application of tripterine in pharmacy, in particular to an application of tripterine in preparing a medicine for treating systemic sclerosis (scleroderma).

The invention aims to provide a new application of tripterine in pharmacy, in particular to an application of tripterine in preparing scleroderma treatment medicines. Wherein the scleroderma refers to increased skin thickness and collagen deposition.

In the invention, the tripterine can reduce collagen deposition and improve scleroderma symptoms by inhibiting the generation of inflammatory mediators.

Wherein the inflammatory mediators are TNF- α, TGF- β and IL-1 β.

The tripterine, also called Celastrol, has a structure shown in formula (I):

the relevant properties are as follows:

[ alternative name ] Celastrine

[ England name ] Celastrol

[ molecular formula ] C₂₉H₃₈O₄

[ molecular weight ] 450.61

[ CAS number ] 34157-83-0

[ MEANS FOR DETECTION ] HPLC ≥ 98%

[ PROPERTIES ] the product is a red needle-like crystal

[ EXTRACTION SOURCE ] root bark and stem bark delignification from Tripterygium wilfordii hook.f. Celastraceae.

[ physicochemical properties ] melting point 185-200 ℃, solubility in methanol, ethanol, acetone, ethyl acetate, chloroform, and insolubility in water.

The tripterine is purchased from Shanghai Shidande biotechnology limited company, and has the following goods number: ST 078801.

In the invention, the tripterine is injected into an animal individual (such as an abdominal cavity of a mouse), and the final concentration of the tripterine is 0.5-5 mg/kg. Preferably, the final concentration of the tripterine is 1 mg/kg.

According to the invention, the body weight of an induced systemic sclerosis (scleroderma) animal model is monitored, the content of collagen I (colla I), α smooth muscle actin (α -SMA) and hydroxyproline in tissues is detected, and the experimental result shows that the tripterine can reduce infiltration of inflammatory cells at an affected part of the scleroderma and deposition of collagen, so that the scleroderma symptom is improved.

The invention also provides application of the tripterine in preparing a medicament for inhibiting or treating inflammatory mediators generated in the scleroderma process.

Wherein the molecular formula of the tripterine is as follows: c₂₉H₃₈O₄The structure is shown as formula (I):

the invention also provides application of the tripterine in preparing a medicament for reducing or treating collagen deposited in the scleroderma process. Wherein the molecular formula of the tripterine is as follows: c₂₉H₃₈O₄Which isThe structure is shown as formula (I):

wherein the tripterine is used for reducing the hardness and/or thickness of the skin.

The invention has the beneficial effects that: the tripterine is developed as a new scleroderma resisting medicine or an auxiliary component thereof, has obvious scleroderma resisting effect, is green and environment-friendly, and provides a new way and means for treating scleroderma diseases. After 1mg/kg of tripterine treatment, the collagen deposition on the skin of mice can be obviously reduced, and compared with a control group, the hardness and the thickness of the skin are obviously reduced.

Drawings

FIG. 1 is a pathological graph of skin tissues of the control group stained by HE and animals administered with tripterine (1mg/kg) of example 1.

FIG. 2 is a pathological view of skin tissues of the control group stained with sirius red and animals administered with tripterine (1mg/kg) of example 1.

Detailed Description

The present invention will be described in further detail with reference to the following specific examples and drawings, and the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.

Example 1 tripterine alleviates bleomycin-induced scleroderma in mice.

In particular, tripterine can reduce bleomycin-induced skin thickness increase and collagen deposition.

(1) Laboratory animal

24 female Balb/c mice were housed in SPF grade. The light/dark is alternated every 12 hours, and drinking water is freely taken. The related guidelines of the management and protection of experimental animals are observed in the feeding and experimental processes. The experimental animals used in this experiment were purchased from slaick.

(2) Experimental grouping and processing

Balb/c female mice at 6-8 weeks were randomized into 3 groups of 8 mice each. Normal control groups were used: PBS + Vehicle; molding + drug control group: bleomycin (100 μ l, 1mg/ml in PBS buffer) induced scleroderma group, with BLM + Vehicle injected subcutaneously; modeling and tripterine treatment group: celastrol 1mg/kg intraperitoneal injection, BLM + Celastrol. Wherein the tripterine is dissolved in freshly prepared PBS containing 0.1% DMSO and 0.3% Tween-80, and equal volume of 0.1% DMSO and 0.3% Tween-80 PBS is administered to both the normal control group and the molding + drug control group.

The experimental period was four weeks during which body weight was monitored twice a week. At the end of the experimental period, the animals were treated with carbon dioxide asphyxiation and the back skin was quickly detached, the skin thickness was measured and fixed for tissue staining. The experimental results are shown in fig. 1 and 2.

Bleomycin (100 μ l, 1mg/ml in PBS buffer) treated with bleomycin induced a significant increase in skin thickness and collagen deposition in mice in the scleroderma group compared to the normal control group (PBS + Vehicle). However, the skin thickness of the mice in the molding + tripterine treatment group treated with tripterine was significantly improved.

The measurement of the content of the hydroxyproline and the results of the sirius red staining show that the content of the hydroxyproline and the accumulation of collagen are obviously increased in the bleomycin induced scleroderma group, and the modeling and tripterine treatment group is obviously improved, which shows that the content of the hydroxyproline and the accumulation of the collagen are obviously reduced by the treatment of the tripterine.

The present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.

Claims

1. The application of the tripterine in preparing the medicines for inhibiting or treating scleroderma is characterized in that the molecular formula of the tripterine is as follows: c₂₉H₃₈O₄The structure is shown as formula (I):

2. the use of claim 1, wherein said tripterine ameliorates scleroderma symptoms by inhibiting the production and/or infiltration of inflammatory mediators, reducing collagen deposition.

3. The use of claim 1, wherein said inflammatory mediator is TNF- α, TGF- β, IL-1 β.

4. The use of claim 1, wherein the tripterine is administered in an amount of 0.5-5mg per kg body weight of the subject.

5. The application of the tripterine in preparing the medicament for inhibiting or treating inflammatory mediators generated in the scleroderma process is characterized in that the molecular formula of the tripterine is as follows: c₂₉H₃₈O₄The structure is shown as formula (I):

6. the application of the tripterine in preparing the medicine for reducing or treating collagen deposited in the scleroderma process is characterized in that the molecular formula of the tripterine is as follows: c₂₉H₃₈O₄The structure is shown as formula (I):

7. the use of any one of claims 1 to 6, wherein the tripterine is used to reduce the stiffness and/or thickness of skin.