CN114699410A - Application of cepharanthine in preparing medicine for treating rheumatoid arthritis - Google Patents
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- CN114699410A CN114699410A CN202210057885.3A CN202210057885A CN114699410A CN 114699410 A CN114699410 A CN 114699410A CN 202210057885 A CN202210057885 A CN 202210057885A CN 114699410 A CN114699410 A CN 114699410A
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Images
Classifications
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- 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
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/59—Menispermaceae (Moonseed family), e.g. hyperbaena or coralbead
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- 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
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- 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
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- 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
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- 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]
Abstract
The invention discloses cepharanthine (A)Cepharanthine) A new application in treating rheumatoid arthritis belongs to the field of traditional Chinese medicine. The stephania sinica diels is prepared from stephania sinica diels (Chinese stephania sinica diels)Stephania cepharantha) The bisbenzylisoquinoline compound extracted from the extract shows good treatment effect on a mouse model of collagen-induced inflammatory arthritis, and has cell activity, migration capacity and signal for fibroblast-like synoviocytes of patients with rheumatoid arthritisThe transduction pathways have certain inhibiting effect, which shows that the stephania japonica extract has definite effect of resisting osteoarthritis diseases such as rheumatoid arthritis, and can be combined with auxiliary materials to prepare inflammatory diseases such as rheumatoid arthritis or be combined with other medicines for treating rheumatoid arthritis for application.
Description
Technical Field
The invention relates to a new application of an active component stephania sinica diels of a Chinese medicinal material stephania sinica diels, in particular to an application of the active component stephania sinica diels in preparing a medicament for treating rheumatoid arthritis, and belongs to the field of Chinese medicaments.
Background
Rheumatoid Arthritis (RA) is a chronic, autoimmune disease with synovitis as a major characteristic in clinical practice. WHO statistics indicate that about 1% of the world's population suffers from RA. The major pathological changes include synovitis and destruction of bone and cartilage in the joint, the latter being the direct cause of progressive rigidity, deformity, dysfunction and even disability of the joint. RA seriously harms human health and reduces the quality of life of people. Currently, the treatment of RA is mainly to relieve pain, control inflammation, improve joint function and protect organs, and the main measures include drug therapy, immune purification and surgical treatment, among which drug therapy is the most important and most widely used method. Clinically commonly used drugs include non-steroidal anti-inflammatory drugs (e.g., loxoprofen), glucocorticoid drugs (e.g., prednisone), immunosuppressive agents (e.g., methotrexate), and biologicals (e.g., Yixepu, adalimumab). However, the use of these drugs cannot avoid side effects, the non-steroidal anti-inflammatory drugs cause gastrointestinal discomfort and ulcers, the hormone use can cause osteoporosis, opportunistic infection and the like, and the immunosuppressive agents and biological agents comprehensively inhibit immunity, so that patients are easily infected. Therefore, there is a need for a safe and effective drug for controlling inflammation while protecting joint bones and cartilage.
Stephania japonica is Stephania japonica of MenispermaceaeStephania cepharantha) The root or stem leaf of the Chinese medicinal herb is one of the traditional Chinese medicinal materials in China. It is cold in nature and bitter in taste, has the functions of resisting tumor, resisting virus and raising white blood cell, is mainly used for tumor, virus infection, venomous snake bite, alopecia, leukopenia caused by radiotherapy and chemotherapy and the like, and has fresh reports of side effects. Besides, stephania japonica is also used as an important medicinal material for folk treatment of rheumatic arthralgia. The stem and root of stephania contain various alkaloids, one of the important active ingredients is Cepharanthine (CEP). The cepharanthine extracted from Stephania japonica is bisbenzylisoquinolineCompounds of the formula C37H38O9Molecular weight is 606.71, and its structure is as follows:
recent pharmacological research shows that CEP has strong anti-inflammatory effect. In a mouse lipopolysaccharide-induced acute lung injury model, CEP can reduce pathological changes in mice, and reduce the expression of various inflammatory cytokines such as Tumor Necrosis Factor (TNF) - α, Interleukin (IL) -1 β, and IL-6. CEP can inhibit the activation of microglia and inflammation induced by NLRP3 inflammasome, inhibit oxidative stress and show a certain treatment effect in a cerebral ischemia-reperfusion injury model. Meanwhile, the anti-inflammatory action of CEP can also protect tissues and cells and slow down the disease process. In sjogren's syndrome, CEP inhibits TNF- α -induced Matrix Metalloproteinase (MMP) -9 formation, protecting glandular cells and gland functions. In addition, CEP can inhibit proliferation and migration of vascular smooth muscle cells, inhibit activation of macrophages and express Inducible Nitric Oxide Synthase (iNOS) and Cyclooxygenase (COX) -2, and has certain effect of resisting atherosclerosis. CEP has the potential to inhibit osteoclast formation by modulating NF- κ B and NFAT cellular signaling pathways, thus being useful for the treatment of osteoclastic diseases. The above information suggests that CEP may have anti-inflammatory and immunomodulatory effects and have potential therapeutic effects in the treatment of rheumatoid arthritis. However, no study on the application of CEP as an antirheumatic in animal disease models of arthritis or in clinical applications has been found.
Disclosure of Invention
The invention provides a new application of cepharanthine, namely an application in preparing a medicament for treating rheumatoid arthritis.
The cepharanthine is a bisbenzylisoquinoline compound extracted from Chinese medicinal material cepharanthine.
The invention takes a collagen-induced arthritis mouse model (a world-recognized rheumatoid arthritis experimental animal model) and fibroblast-like synovial cells of rheumatoid arthritis patients as research objects to observe the treatment effect of the cepharanthine on the rheumatoid arthritis. Experiments prove that: (1) the celiac injection of cepharanthine (5 mg/kg) can obviously inhibit the collagen-induced arthritis of the joints of mice from generating inflammation and prevent the bone destruction; (2) the cepharanthine has certain inhibitory effect on cell activity, migration ability and signal transduction of rheumatoid arthritis fibroblast synoviocytes. Based on the research results, the cepharanthine is proved to have the efficacy of treating rheumatoid arthritis and can be used for preparing medicines for treating inflammatory diseases such as rheumatoid arthritis.
Drawings
FIG. 1 is a graph of the effect of cepharanthine on the joint score in a collagen-induced arthritis model mouse
FIG. 2 is a graph of normal mouse hindpaw
FIG. 3 is a graph of the hindpaw of a mouse with collagen-induced arthritis
FIG. 4 is a graph of the hind paw of a collagen-induced arthritis model mouse in the cepharanthine-treated group
FIG. 5 is a Micro-CT image of a normal mouse knee joint
FIG. 6 is a Micro-CT image of a mouse knee joint of a collagen-induced arthritis model
FIG. 7 is a Micro-CT image of knee joint of mouse as collagen-induced arthritis model in cepharanthine treatment group
FIG. 8 is an HE staining light microscope photograph (25X) of a normal mouse knee joint tissue section
FIG. 9 shows HE staining light microscope (25X) of pathological section of knee joint of collagen-induced arthritis-inducing model mouse
FIG. 10 is a HE stained light microscope (25X) of pathological section of knee joint tissue of stephania japonica collagen-induced arthritis model mouse
FIG. 11 is a pathological evaluation chart of mouse knee joint tissue section
FIG. 12 is a safranin-fast green staining light mirror image of a normal mouse knee joint tissue section (25X)
FIG. 13 is a safranin-fast green staining light mirror image of pathological section of knee joint tissue of collagen-induced arthritis-induced model mouse (25X)
FIG. 14 is a safranin-fast green staining light mirror image of a pathological section of knee joint of a mouse model of collagen-induced arthritis treated with cepharanthine (25X)
FIG. 15 is a graph showing the effect of cepharanthine on synovial fibroblast cell viability in rheumatoid arthritis patients
FIG. 16 is a graph showing the effect of cepharanthine on synovial fibroblast migration function in rheumatoid arthritis patients
FIG. 17 is a graph of the effect of cepharanthine on synovial fibroblast signal transduction pathway activation in rheumatoid arthritis patients.
Detailed Description
The invention will be better understood from the following examples. However, the contents of the embodiments are described only for illustrating the present invention, and should not be construed as limiting the present invention described in detail in the claims.
(I) Experimental method
1. Arthritis modeling and drug delivery
Repeatedly emulsifying the dissolved 2mg/ml bovine type II collagen with equal volume of complete (primary immunization) or incomplete (secondary immunization) Freund's adjuvant to prepare 1mg/ml emulsified liquid containing bovine type II collagen for molding. 21 male DBA1/J mice at 8 weeks of age were divided randomly into three groups: normal control group, model group and cepharanthine treatment group. The emulsion is injected into the place 1-2cm behind the tail root of the mouse intradermally for primary immunization by 0.1ml, and the injection day is recorded as d 0 days. 20 days after the primary immunization, the secondary immunization was performed in the same manner. Control mice were injected intradermally with an equal amount of saline. Collagen-induced arthritis (CIA) was modeled and intraperitoneal injection of cepharanthine (5 mg/kg) was started, with continuous daily dosing until the end of the experiment.
2. Clinical and pathological assessment of arthritis
Mice were evaluated daily for arthritis development and the degree of joint swelling was scored using a double blind method, with the following criteria: 0 point = no change; 1 point = swelling of the foot or enlarged articular nodules; 2 points = slight swelling and erythema of the foot; 3 points = marked swelling and erythema on the foot; 4 points = severe swelling or rigidity deformation of the foot. The sum of the clinical scores for the four feet was taken as the arthritis score for each mouse, with the highest score for each mouse being 16. Mice were sacrificed on day 40 post-molding and treated as follows: 1) Micro-CT examination was performed on the right knee joint of the mouse. 2) Taking the left knee joint of the mouse, fixing with formaldehyde, decalcifying, paraffin embedding and sectioning (5 mu m), staining with hematoxylin-eosin (H & E) and safranin-fast green, and sealing with neutral resin by a conventional method. The joint pathological injury index is as follows: score 0 = normal; 1 point = mild synovitis; 2 points = severe synovitis with pannus formation; 3 points = articular cartilage destruction; 4 points = bone destruction.
3. Rheumatoid arthritis fibroblast synoviocyte proliferation experiment
Fibroblast-like synoviocytes (FLS) of Rheumatoid Arthritis (RA) patients were isolated and cultured, and the RA FLS 3-8 with logarithmic phase increase was used instead. RA FLS were spread on 96-well plates at 37 ℃ with 5% CO2After 12h incubation, the supernatant was discarded, and then dimethyl sulfoxide (DMSO) and stephanine (20. mu.g/ml, 10. mu.g/ml, 5. mu.g/ml, 2.5. mu.g/ml, 1.25. mu.g/ml, 0.625. mu.g/ml, 0.313. mu.g/ml) were added, respectively, at 100. mu.l per well, with 3-5 replicate wells per group. After 24 or 48 hours of incubation, CCK-8 reagent was added and the absorbance value of each well was measured at OD450nm on an elisa to understand the effect of cepharanthine on the viability of RA FLS cells.
4. Rheumatoid arthritis fibroblast synovial cell migration experiment
The influence of cepharanthine on the migration ability of RA FLS was evaluated by a scratch test. RA FLS in logarithmic growth phase was first inoculated into 12-well plates (1X 10)5Per well) to achieve 90-100% cell binding. Cells were treated with different concentrations of cepharanthine 2h before scratching and controls were treated with the same volume of DMSO. The plate bottom, which was full of RA FLS, was scratched using 200 μ l of a gun tip, and then carefully washed 3 times with PBS. Low serum medium (DMEM containing 2% fetal bovine serum FBS) supplemented with stimulators Tumor Necrosis Factor (TNF) -alpha (10 ng/ml), TNF-alpha (10 ng/ml) + CEP (5. mu.g/ml, 2.5. mu.g/ml, 1.25. mu.g/ml) or CEP (5. mu.g/ml, 2.5. mu.g/ml, 1.25. mu.g/ml) was then added to the corresponding wells, respectively. Incubation is carried out at the temperature of 237 ℃ under 5% CO, and images are acquired and observed under an inverted microscope at 0h, 6h, 12h and 24h respectively, so as to observe the influence of CEP on the migration capacity of the RA FLS.
5. Detection of rheumatoid arthritis fibroblast synovial cell signal molecule
The effect of CEP on activation of RA FLS was understood by examining cell signaling pathways. RA FLS inoculated 6-well plate, each hole 2X 105 cells, make the cell binding degree reach 80-90%. Media containing 0.1% FBS was starved for 2h prior to stimulation and drug-treated groups were pretreated with the appropriate concentration of CEP. TNF-alpha (10 ng/ml) was then added to stimulate the cells for 15-20 minutes, the medium was immediately aspirated, washed 2 times with PBS, and the cells were lysed by adding RIPA lysate containing protease inhibitors and phosphatase inhibitors to extract the protein. Protein concentration was measured by BCA assay, followed by detection of phosphorylation levels of cell signaling molecules such as Erk1/2 and JNK by Western blot.
(II) results of the experiment
1. Effect of Cepharanthine on clinical Scoloritrin-induced arthritis model mice Scoloritrol
As can be seen from FIGS. 1 to 4, the hind paw of the joint of the model mouse was significantly inflamed, the joint score was significantly increased, and the difference was statistically significant, compared to the control group (A) ((B))P<0.05). While the hind paw of the cepharanthine-treated mice showed only slight redness and swelling, with a significant reduction in joint score, compared to the model mice (see below for the experimental data in the experimental data of the experimentalP<0.05). The result shows that the cepharanthine can obviously reduce the inflammation degree of the joints of a collagen-induced arthritis model mouse and reduce the clinical scores of the joints.
Joint imaging detection
As can be seen from fig. 5 to 7, the knee joints of the model mice have obvious bone destruction and the surfaces are different in concave and convex compared with the control mice; and the destruction of the knee joint of the mice in the cepharanthine treatment group is obviously reduced compared with the bone destruction of the mice in the model group, and the knee joint is very close to the control group. The results suggest that the stephanine treatment group can effectively protect the integrity of joint bones and reduce bone loss and damage.
Joint pathology detection
As shown in FIGS. 8 to 11, the cartilage of the knee joint of the normal group of mice was covered with 1 to 3 layers of normal synovial cells on both sides, and the articular cartilage and bone were not damaged. The synovium of the joints of the mice in the model group is obviously thickened, and a plurality of inflammatory cells infiltrate into the synovium and small blood vessels are formed.And joint synovial hyperplasia of mice in the cepharanthine treatment group is obviously reduced, and inflammatory cell infiltration area is obviously reduced compared with that of mice in the model group. As can be seen from FIG. 11, the arthritic pathology scores of the mice in the model group were significantly higher than those in the normal control group, and the differences were statistically significant (P<0.01). Compared with the model group mice, the arthritis pathological score of the stephania japonica treatment group mice is obviously reduced, and the stephania japonica treatment group mice have statistical difference (P)<0.05). As can be seen from FIGS. 12 to 14, the cartilage on the knee joint surface of the normal mice is complete and uniform, and the cartilage layer of the knee arthritis of the model mice is eroded and thinned, and the surface is uneven. The cartilage layer of knee joint of mice in the cepharanthine treatment group has no obvious erosion phenomenon, and is close to that of the normal group. The results show that the cepharanthine can effectively inhibit joint synovial hyperplasia, inflammatory cell infiltration and joint cartilage and bone destruction, and has the function of protecting joints.
Fibroblast synoviocytes cell viability assay
As shown in fig. 15, cepharanthine has some inhibitory effect on cell viability of RA FLS and is concentration dependent. At 48 hours, when the concentration of cepharanthine is 0.625 μ g/ml or more, the activity of RA FLS cells is significantly inhibited (P<0.05). And at 24 hours, when the concentration of the cepharanthine is 2.5 mu g/ml or more, the activity of the RA FLS cell is obviously inhibited (P<0.05). The result shows that the cepharanthine has certain inhibition effect on the activity of RA FLS cells.
Detection of fibroblast-like synovial cell migration ability
As shown in FIG. 16, cepharanthine inhibited the migration distance of RA FLS induced by TNF- α after 24 hours at all three concentrations, and the difference was statistically significant (P<0.05). And the migration ability of RA FLS gradually weakens with the increase of the concentration of cepharanthine. The result shows that the cepharanthine has certain inhibition effect on the migration capacity of RA FLS cells.
Fibroblast-like synoviocytes cell signaling pathway detection
As shown in FIG. 17, JNK, ERK1/2 were significantly phosphorylated in TNF- α stimulated RA FLS, indicating that two signaling pathways were activated. The phosphorylation levels of JNK and ERK1/2 in RA FLS under the stimulation of TNF-alpha are both remarkably inhibited by the cepharanthine with two concentrations, and the fact that the cepharanthine can inhibit the activation of the RA FLS by antagonizing JNK and ERK1/2 channels is suggested.
Claims (7)
1. A new pharmaceutical use of cepharanthine is characterized in that the cepharanthine is used for preparing drugs for treating rheumatoid arthritis.
2. Use according to claim 1, characterized in that: the cepharanthine is derived from the extract of the Chinese medicinal material cepharanthus.
3. Use according to claim 1, characterized in that: the cepharanthine is a bisbenzylisoquinoline compound extracted from the Chinese medicinal material cepharanthus spicata.
4. A pharmaceutical compound for treating rheumatoid arthritis is characterized by taking cepharanthine as a main active ingredient and containing cepharanthine (5.0-20.0 mg/kg) with an effective treatment dose.
5. A compound according to claim 4, characterized by comprising a therapeutically effective amount of cepharanthine in combination with adjuvants for use in a medicament or in combination with other medicaments for the treatment of rheumatoid arthritis.
6. A pharmaceutical composition according to claim 4, characterized by treating inflammatory diseases of the osteoarticular joints such as rheumatoid arthritis.
7. Osteoarthritis disorders according to claim 6, comprising: rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, reactive arthritis, psoriatic arthritis, inflammatory bowel disease arthritis, undifferentiated spondyloarthritis, gout, pseudogout, and osteoarthritis.
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| CN109771426A (en) * | 2019-02-26 | 2019-05-21 | 沈锋 | Application of the cepharanthine as the inhibitors of enzymes of ASPH |
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