CN114259484A - Application of salvianolic acid A in preparing medicament for treating skin diseases - Google Patents
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Abstract
The invention relates to the field of traditional Chinese medicines, and discloses application of salvianolic acid A in preparing a medicine for treating skin diseases, namely application in preparing a medicine for treating skin inflammations, in particular psoriasis, wherein pharmacodynamic and mechanism researches show that the salvianolic acid A can play a role in treating psoriasis and other skin inflammations by inhibiting an IL-17A signal channel. Aiming at the disease model of psoriasis of mice induced by imiquimod, the salvianolic acid A can effectively improve the epidermal thickening, inflammatory cell infiltration and the level of inflammatory factors in skin of the skin damage tissues of the mice.
Description
Technical Field
The invention relates to the field of traditional Chinese medicines, relates to a new application of salvianolic acid A in skin diseases and skin injuries, and particularly relates to an application of salvianolic acid A in preparation of medicines for treating psoriasis.
Background
The skin is an important component of the human body, wraps the surface of the body, directly contacts with the external environment, has the functions of protecting, excreting, regulating body temperature, sensing external stimuli and the like, and is the largest organ in the human body organs. Is formed by tightly combining epidermis and dermis. About 16% of body weight. The adult skin area is about 1.2-2.0 square meters and the average thickness is 0.5-4.0 millimeters.
Psoriasis is a chronic recurrent disease, the cause of the disease is complex, the environment and genes lay the foundation for the occurrence and development of the disease, the psoriasis needs to be treated for a long time, and the psoriasis is easy to recur and cannot be cured radically. According to the Chinese psoriasis diagnosis and treatment guideline, the prevalence rate of psoriasis in Europe and America is 1% -3%, and the prevalence rate of psoriasis in 6 cities is 0.47% in 2008 investigation of China, so that about 840 million psoriasis patients in China are reckoned. Psoriasis is characterized clinically by repeated attacks of hyperkeratosis, scaling, erythema, and inflammatory cell infiltration, neovascularization, secretion of cytokines such as IL-6 and TNF-alpha. The current clinical therapy still cannot cure the psoriasis and has great side effect.
Salvianolic Acid A (SAA) is a water-soluble phenolic acid compound contained in dried root and rhizome of Salvia miltiorrhiza Bunge of Labiatae. Recent researches show that the SAA has obvious activity in the aspects of cardiovascular and cerebrovascular disease protection, liver injury resistance, diabetes and complications, tumor resistance and the like. However, the research of the salvianolic acid A as a medicament for treating immune diseases, particularly inflammatory diseases on the skin including psoriasis is not reported.
Disclosure of Invention
The purpose of the invention is as follows: the invention provides a new application of salvianolic acid A.
The invention discloses a medicine for treating psoriasis, which is prepared from Salvianolic acid A, which is an effective component of Salvia miltiorrhiza, and the mechanism of the medicine is related to an IL-17A signal channel which is an important signal channel for inhibiting and mediating skin inflammation. The deep mechanism research provides theoretical and experimental basis for the application of the salvianolic acid A in the clinical treatment of the skin diseases.
The technical scheme is as follows:
the application of salvianolic acid A in preparing medicines or cosmetics for treating skin diseases is disclosed, wherein the structural formula of salvianolic acid A is as follows.
The application is characterized in that the skin diseases are skin inflammation and skin injury.
The application is characterized in that the skin inflammation is diabetic dermatitis, contact dermatitis, eczema, rubella or urticaria.
Application of salvianolic acid A in preparing medicine for treating psoriasis is provided.
The application is that the salvianolic acid A is a medicinal preparation taking the salvianolic acid A as a main active substance.
The application is that the pharmaceutical preparation is tablets, capsules, granules, pellets, dripping pills, oral liquid, water injection, powder injection, infusion solution, ointment, gel or microemulsion.
Wherein the unit dosage of tablet, capsule, granule, pellet, dripping pill, oral liquid, and soft capsule is 5-100 mg.
Wherein the unit dosage of the injection, powder for injection and infusion solution is 1-50 mg.
The material basis of the medicinal preparation is salvianolic acid A, so the medicinal preparation has a good treatment effect on psoriasis.
Advantageous effects
1. The invention discovers that the salvianolic acid A has a treatment effect on the skin diseases for the first time, and can be applied to the treatment of the skin diseases and the additives of cosmetics. Specifically, the method comprises the following steps: the invention adopts imiquimod to induce and form a psoriasis-like skin lesion model of mice, and experimental results show that 2.5mg/kg of intraperitoneal injection can obviously reduce PASI scores, relieve skin thickening and reduce the expression levels of inflammatory cells and inflammatory factors in the skin.
2. The effect of salvianolic acid A on psoriasis is found to be related to the inhibition of IL-17A signaling pathway, an important signaling pathway for mediating skin inflammation. The IL17 family has 6 members: IL-17A (IL-17), IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25), and IL-17F. IL-17A is the prototype of the IL-17 family, with IL-17F having the highest homology to IL-17A, about 50%, both of which require binding to the common receptor IL-17RA to initiate signal transduction, and IL-17B-E having relatively poor homology to IL-17A, only 16% -30%. IL-17 family members function as homodimers or heterodimers. High levels of IL17 were associated with acute inflammatory responses, including psioriasis (psoriasis).
The psoriasis market is dominated by TNF-alpha blockers (anti-tumor necrosis factor mabs), including the best-marketed Enbrel (enrie, $ 86 billion sold in 2015) and Humira (tomaile, $ 140 billion sold worldwide in 2015), however up to 40% of patients are under-treated or non-responsive to TNF-blockers; according to the american Psoriasis Foundation (National Psoriasis Foundation) survey, up to 52% of patients are indicated to be dissatisfied with self-disease management. Therefore, IL-17 inhibitors have the ability to break the dominance of TNF inhibitors.
Currently, 2 drugs are marketed for treating psoriasis by IL-17A target: secukinumab of noval; ixekizumab littoral; also directed to the IL17 signaling pathway is a bispecific antibody, represented by ABT122 developed by AbbVie, which is directed against IL-17 and Tumor Necrosis Factor (TNF). The current clinical trial for ABT122 in the treatment of rheumatoid arthritis is in phase II. Additionally, CJM-112 manufactured by Nowa and CNTO-6785 manufactured by Morphosys, Bimekizumab manufactured by Yoshibiji corporation, have entered phase II clinical development.
Therefore, the invention finds that the salvianolic acid A treats the psoriasis through the IL-17A target, and has high clinical value and market value.
Description of the drawings:
FIG. 1 Salvianolic Acid A (SAA) ameliorates IMQ-induced psoriasis-like inflammatory lesions in mice. The mice were randomly divided into 4 groups, a normal group (Sham group), a model group (Imiguimod, IMQ group), and a SAA group (2.5mg/kg, 5 mg/kg). The normal group and the model group were given an equal amount of PBS, and the drug group was administered by intraperitoneal injection once a day at 200. mu.L each time according to the dose. In each group, except the normal group, the same amount of imiquimod cream was applied to the skin of the back of the mouse every day. Thereafter, the body weights of the mice were recorded daily and scored. Mice were sacrificed on day 4. A. Skin tissue damage such as skin scale, induration, erythema, etc. was clinically scored. B. Skin tissue samples were H & E stained and epidermal thickness was measured. C. Representative photograph of skin lesion site, representative result of H & E staining. Results are expressed as mean ± standard deviation.
FIG. 2 Salvianolic Acid A (SAA) ameliorates inflammatory infiltration in skin tissue of mice with IMQ-induced psoriasis-like lesions. Mice were randomly divided into 4 groups, a normal group (Sham group), a model group (Imiquimod, IMQ group), and a SAA group (2.5mg/kg, 5 mg/kg). The normal group and the model group were given an equal amount of PBS, and the drug group was administered by intraperitoneal injection once a day at 200. mu.L each time according to the dose. In each group, except the normal group, the same amount of imiquimod cream was applied to the skin of the back of the mouse every day. Thereafter, the body weights of the mice were recorded daily and scored. Mice were sacrificed on day 4, skin tissue sections were prepared, and immune cell infiltration in the skin of the mice was detected by immunofluorescence.
FIG. 3 Salvianolic Acid A (SAA) ameliorates inflammatory infiltration in skin tissue of mice with IMQ-induced psoriasis-like lesions. Mice were randomly divided into 4 groups, a normal group (Sham group), a model group (Imiquimod, IMQ group), and a SAA group (2.5mg/kg, 5 mg/kg). The normal group and the model group were given an equal amount of PBS, and the drug group was administered by intraperitoneal injection once a day at 200. mu.L each time according to the dose. In each group, except the normal group, the same amount of imiquimod cream was applied to the skin of the back of the mouse every day. Thereafter, the body weights of the mice were recorded daily and scored. Mice were sacrificed on day 4, skin tissue sections were prepared, and the expression levels of PCNA, KI-67, P-P65 in the skin of the mice were examined by immunohistochemistry.
FIG. 4 Salvianolic Acid A (SAA) improves IMQ-induced psoriasis-like lesion RNA sequencing KEGG pathway enrichment analysis. The mice were randomly divided into 4 groups, a normal group (Sham group), a model group (Imiquimod, IMQ group), and a SAA group (5 mg/kg). The normal group and the model group were given an equal amount of PBS, and the drug group was administered by intraperitoneal injection once a day at 200. mu.L each time according to the dose. In each group, except the normal group, the same amount of imiquimod cream was applied to the skin of the back of the mouse every day. Mice were sacrificed on day 4 and skin tissue was taken for RNA sequencing.
FIG. 5 cluster analysis of gene changes in Salvianolic Acid A (SAA) improved IMQ-induced psoriasis-like lesion RNA sequencing IL-17 signaling pathway and cytokine-cytokine receptor interaction signaling pathway. The mice were randomly divided into 4 groups, a normal group (Sham group), a model group (Imiquimod, IMQ group), and a SAA group (5 mg/kg). The normal group and the model group were given an equal amount of PBS, and the drug group was administered by intraperitoneal injection once a day at 200. mu.L each time according to the dose. In each group, except the normal group, the same amount of imiquimod cream was applied to the skin of the back of the mouse every day. Mice were sacrificed on day 4 and skin tissue was taken for RNA sequencing.
FIG. 6 Salvianolic Acid A (SAA) improves the expression of psoriasis-associated inflammatory factors, chemokines in IL-17A induced keratinocytes (HACAT); a is IL-6, B is cxcl-1, and C is cxcl-2.
FIG. 7 Salvianolic Acid A (SAA) ameliorates the increase in the rate of IL-17A-induced keratinocyte (HACAT) migration; a is a migration photograph, and B is migration rate result statistics.
Detailed Description
Example 1: intraperitoneal injection of salvianolic acid A for improving psoriasis-like inflammatory lesions of mice induced by imiquimod
The experimental method comprises the following steps:
1. experimental animals: C57/B6J female mice, 6-8 weeks, 18-22 g.
2. The experimental method comprises the following steps: normal female mice, C57/B6J, were anesthetized by intraperitoneal injection of 200-. The hair on the back of the mouse was shaved to form an exposed area of about 2cm × 2cm, which was randomly and evenly divided by body weight, and the shaving was performed 1 to 2 days before the actual experiment. Mice were weighed daily, observed for local skin changes, recorded by photography, and given a score of 0-3 based on psoriatic skin lesion area and severity of disease (PASI) scores, with a score of 0 on day one. Finally applying imiquimod emulsion, and applying 62.5mg of imiquimod cream to the skin at the hair shaving position of other groups except the normal control group: 3.125mg (5%)/mouse, 1 time daily for 4 consecutive days. And gives corresponding processing. Group 1: normal group, blank control, no treatment; group 2: model group, given imiquimod; group 3: dosing group, given imiquimod and injected i.p. with 2.5mg/kg SAA, group 4: dosing group, imiquimod was given and 5mg/kg SAA was i.p.. The normal group and the model group were given an equal amount of PBS, and the drug group was administered by intraperitoneal injection once a day at 200. mu.L each time according to the dose.
The materials were taken 4 days later, and the skin condition of the back of the mouse was photographed and recorded. Blood is taken from the eyeball, serum is separated, and the blood is stored at-80 ℃. Removing subcutaneous adipose tissue from skin lesion tissue, dividing into two parts, fixing one part in 4% paraformaldehyde solution, preparing paraffin section, extracting RNA from one part, and storing at-80 deg.C.
3. The evaluation method comprises the following steps:
the following mouse PASI criteria were established with reference to PASI (Psoriasis area and severity index) criteria to assess clinical severity: erythema; soaking; scales. Each feature was evaluated on a 0-3 point scale: 0 ═ none; 1 is mild; 2 is moderate; 3-severe. Each site was scored according to the following 3 skin lesion clinical characteristics:
erythema (erythema, E): red or dark red inflammatory plaques, fading of pressure. 0-no erythema visible; 1-is light red; 2-red; 3-extremely deep red.
Infiltration (I): the skin damage tends to spread around, the boundary is blurred, and the pressure is substantial. 0-skin lesions level with normal skin; 1-skin lesions are slightly elevated above normal skin surface; 2-moderate elevation, the edge of the plaque is round or slope type; 3-the skin lesions are highly thickened and the bulges are extremely obvious.
Desquamation/scaling (D): refers to the exfoliation of epidermal cells. 0-no visible scale on the surface; 1-scale is covered on the surface of part of the skin damage, and the fine scale is taken as the main part; 2-most of the skin damage surfaces are completely or incompletely covered with scales which are flaky; and 3, all the damaged surfaces are covered with scales, and the scales are thick and layered.
Exudation, dryness and itching were not counted in total.
Analysis of pharmacological test results
1. As shown in figure 1, the small molecular SAA injected into the abdominal cavity at 2.5mg/kg and 5mg/kg can obviously improve the psoriasis-like inflammatory skin lesion induced by imiquimod and improve the excessive proliferation of epidermal keratinocytes induced by IMQ, has no obvious toxic or side effect, and shows certain effectiveness and safety.
2. The small-molecule SAA of 2.5mg/kg and 5mg/kg is injected intraperitoneally, so that the immune infiltration condition in the psoriasis-like inflammatory skin lesion tissue induced by imiquimod can be remarkably improved, and the expression of CD4 and CD11b is reduced as shown in figure 2.
3. Immunohistochemical results indicate that the small molecule SAA injected into the abdominal cavity at 2.5mg/kg and 5mg/kg can obviously reduce the expression of proliferation-related proteins PCNA and KI-67 and reduce the expression of P-P65 in a proinflammatory signal pathway, as shown in figure 3.
The pharmacological studies provide sufficient evidence that the salvianolic acid A can improve the symptoms of psoriasis, prevent the occurrence and the development of psoriasis, improve the skin microenvironment of a psoriasis model and increase the stability of the immune microenvironment.
Example 2: RNA sequencing results show that salvianolic acid A alleviates psoriasis-like lesions mainly by inhibiting IL-17 signaling pathway in the imiquimod-induced animal model.
The experimental method comprises the following steps: the animal model was the same as in example 1; and (4) RNA sequencing.
The experimental results are as follows: as shown in fig. 4, the results of RNA sequencing KEGG pathway enrichment analysis of salvianolic acid a (saa) improved IMQ-induced psoriasis-like skin lesions showed that the IL-17 signaling pathway varied most significantly, followed by cytokine-cytokine receptor interaction signaling pathway. The results of the gene change cluster analysis are shown in FIG. 5.
Example 3: the salvianolic acid A improves the expression increase of inflammatory factors caused by IL-17A on a cell model.
The experimental method comprises the following steps: real-time reverse transcription fluorescent quantitative polymerase chain reaction (qRT-PCR).
HACAT cells were seeded into 12-well plates, DMEM containing 10% serum was added thereto and placed in CO2Culturing in a constant temperature incubator, changing into DMEM with 2% serum after adherence, adding IL-17a with the concentration of 25ng/mL and SAA with the concentration of 1. mu.M, 3. mu.M and 10. mu.M to each hole except a control hole, collecting cells after 12 hours, and extracting RNA, transcribing and amplifying by a Trizol method.
The experimental results are as follows: as shown in FIG. 6, 1. mu.M of SAA can reduce the increase in mRNA levels of IL-6, CXCL-1 and CXCL-2 caused by IL-17A.
Example 4: salvianolic acid A improves cell migration caused by IL-17A in the cell model.
The experimental method comprises the following steps: scratch test
HACAT cells were seeded into 12-well plates, DMEM containing 10% serum was added thereto and placed in CO2After the incubation in the incubator, the plate was scratched and replaced with 2% serum DMEM, 25ng/mL IL-17A and 5, 10. mu.M SAA were added to each well except for the control well, and the scratch was photographed at the same position for 0, 12, 24, 36, and 48 hours.
As a result of the experiment, SAA can inhibit the increase in cell migration rate caused by IL-17A, as shown in FIGS. 7A and B.
HaCaT is a cell line of immortalized keratinocytes derived from adult humans. HaCaT cells are used in a variety of studies because of their good in vitro differentiation and proliferation capabilities, as reproducible models to characterize human keratinocytes and to solve problems such as short culture life and inter-cell line variation. HaCaT cells can characterize a number of processes, for example, using them as a model system for the metabolism of vitamin D3 in skin. Therefore, the SAA can inhibit cell migration caused by IL-17A and has a therapeutic effect on skin diseases.
Claims (7)
1. The application of salvianolic acid A in preparing medicines or cosmetics for treating skin diseases is disclosed, wherein the structural formula of salvianolic acid A is as follows.
2. The use according to claim 1, wherein the skin disorder is skin inflammation or skin damage.
3. The use according to claim 2, wherein the skin inflammation is diabetic dermatitis, contact dermatitis, allergic dermatitis, eczema, urticaria, acne, whelk; the skin injury is diabetic foot, ultraviolet injury, and wound.
4. Application of salvianolic acid A in preparing medicine for treating psoriasis is provided.
5. The use according to any one of claims 1 to 4, wherein the salvianolic acid A is a pharmaceutical preparation of salvianolic acid A as a main active substance.
6. The use of claim 5, wherein the pharmaceutical formulation is a tablet, capsule, granule, pellet, drop pill, oral liquid, injection solution, powder for injection, infusion solution, ointment, gel or microemulsion.
7. The use of salvianolic acid A of claims 1, 2, 3, or 4, comprising the use of structural analogs, structural optimizers, structural modifications of salvianolic acid A in the preparation of said medicament or cosmetic.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115192589A (en) * | 2022-07-13 | 2022-10-18 | 滴可安(杭州)生物技术有限公司 | Application of neoisoliquiritin in preparation of psoriasis treatment medicine |
| CN117085006A (en) * | 2023-04-14 | 2023-11-21 | 天津天士力之骄药业有限公司 | Application of salvianolic acid Y in preparing medicament for treating urticaria |
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| KR20170073308A (en) * | 2015-12-18 | 2017-06-28 | 주식회사 엘지생활건강 | Composition for improving the skin |
| KR20190135263A (en) * | 2018-05-28 | 2019-12-06 | 충남대학교산학협력단 | Composition comprising salvianolic acid A for preventing or treating for inflammatory skin diseases |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20170073308A (en) * | 2015-12-18 | 2017-06-28 | 주식회사 엘지생활건강 | Composition for improving the skin |
| KR20190135263A (en) * | 2018-05-28 | 2019-12-06 | 충남대학교산학협력단 | Composition comprising salvianolic acid A for preventing or treating for inflammatory skin diseases |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115192589A (en) * | 2022-07-13 | 2022-10-18 | 滴可安(杭州)生物技术有限公司 | Application of neoisoliquiritin in preparation of psoriasis treatment medicine |
| CN117085006A (en) * | 2023-04-14 | 2023-11-21 | 天津天士力之骄药业有限公司 | Application of salvianolic acid Y in preparing medicament for treating urticaria |
| CN117085006B (en) * | 2023-04-14 | 2024-03-12 | 天津天士力之骄药业有限公司 | Application of salvianolic acid Y in preparing medicament for treating urticaria |
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