CN116712533B - Application of SOSTDC1 protein in preparation of dermatological products - Google Patents
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- CN116712533B CN116712533B CN202310807786.7A CN202310807786A CN116712533B CN 116712533 B CN116712533 B CN 116712533B CN 202310807786 A CN202310807786 A CN 202310807786A CN 116712533 B CN116712533 B CN 116712533B
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Marine Sciences & Fisheries (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention provides an application of SOSTDC1 protein in preparing a product for treating skin diseases, and belongs to the technical field of biological medicines. Wherein the SOSTDC1 protein comprises a recombinant SOSTDC1 protein, or a mutant of the recombinant SOSTDC1 protein. The application of the SOSTDC1 protein in preparing a product for treating skin diseases proves that the SOSTDC1 recombinant protein can inhibit Wnt signal paths of skin tissues, so that keratinization of keratinocytes is reduced, symptoms such as hyperplasia and desquamation of epidermis are effectively blocked and delayed, and the treatment and delay of skin diseases including psoriasis and skin fibrosis based on the SOSTDC1 protein are realized.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of SOSTDC1 protein in preparation of a product for treating skin diseases.
Background
Psoriasis (Psoriasis), a common chronic inflammatory skin disease, is usually manifested by red plaques covered with white scales. These plaques are typically found on the scalp, elbows, knees and back, but may also occur on other body parts.
Psoriasis is an autoimmune disease, usually caused by a combination of genetic and environmental factors. Although psoriasis is not contagious, it can negatively impact the physical and psychological health of patients and current medical conditions cannot be completely cured.
Psoriasis is a chronic inflammatory skin disease characterized mainly by an immune-mediated scaling skin lesion, the main pathogenesis of which is hyper-proliferation of the epidermis caused by excessive activation of keratinocytes in the form of horny cells, and infiltration of inflammatory cells, resulting in localized inflammation. In the initial stage of psoriasis onset, local dendritic cells of skin respond to self antigen recognition and to produce cytokines such as IL23, IL1 beta, IL6, TNF alpha and the like, and further induce the production of CD 4T cells and gamma delta T cells IL-17A/F to promote the development of psoriasis. Keratinocytes play an important role in the development process of psoriasis, inflammatory factors act on basal lamina cells, induce the cells to divide continuously and increase value, obtain a large number of newly-born epidermal cells, and cause typical pathological changes of psoriasis such as epidermal hyperplasia, acanthosis and the like. Therefore, the research on the pathogenesis of the keratinocyte in the psoriasis is of great significance to clinical treatment and prognosis and improvement of the life quality of patients.
Traditional psoriasis treatment drugs mainly include: corticosteroids, vitamin D analogs, retinoids, calcineurin inhibitors, dithranol, methotrexate, cyclosporine, and the like; in recent years, biological agents have become an emerging therapy for psoriasis, including: anti-TNFα drugs, anti-IL 12/IL 23 antibodies, IL17 antibodies, and the like.
Although these biological agents have certain effects in the conventional treatment methods and therapeutic drugs, such drugs have problems of high price, possibility of opportunistic infections, and the like. Therefore, there is a great clinical need for a drug that can not only clearly base on the pathogenesis of psoriasis, but also achieve targeted therapy against psoriasis and reduce the cost of treatment.
Disclosure of Invention
To solve the above problems, the present invention provides the use of a SOSTDC1 protein comprising a recombinant SOSTDC1 protein, or a mutant of said recombinant SOSTDC1 protein, for the preparation of a product for the treatment of skin diseases.
Preferably, the SOSTDC1 protein is a secreted protein comprising at least one C-terminal cystine and at least one N-terminal secretion signal in the amino acid sequence.
Preferably, the amino acid sequence of the SOSTDC1 protein comprises any one of the following amino acid sequences: A. an amino acid sequence as shown in SEQ ID No. 1;
B. an amino acid sequence having at least 80% identity to the amino acid sequence shown in SEQ ID No. 1.
Preferably, the gene encoding the SOSTDC1 protein comprises: a nucleotide sequence as shown in SEQ ID No. 2; alternatively, the nucleotide sequence shown as SEQ ID No.2 is substituted, deleted and/or added with one or more nucleotides, the nucleotide sequence encoding the same active protein; alternatively, the nucleotide sequence encoding the amino acid sequence of SEQ ID No. 1.
Preferably, the product is a product of the SOSTDC1 protein for reducing keratinocyte keratinization by inhibiting Wnt signal path, thereby achieving the purpose of treating skin diseases.
Preferably, the skin disease comprises at least one of psoriasis and skin fibrosis.
Preferably, the SOSTDC1 protein is used in the product at a concentration of 100ng/mL to 1000ng/mL.
Preferably, the product is any one of a drug, a detection reagent, a kit and a diagnostic reagent;
the dosage forms of the medicine comprise paste, powder, tablet, capsule and granule.
Preferably, the drug is a keratinocyte-targeting drug; the medicament comprises at least one unit preparation; the SOSTDC1 protein is taken as an active ingredient in the unit preparation; the weight of the active ingredient in the unit formulation is n times the therapeutically effective dose of the active ingredient; wherein, the numerical range of n is 0.1-10.0; the effective therapeutic dose of the active ingredient is 0.1 mg/person to 20.0 mg/person.
Preferably, the medicament further comprises a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable carrier comprises: at least one of a sustained release agent, an excipient, a filler, a binder, a wetting agent, a disintegrating agent, an absorption enhancer, a surfactant and a lubricant.
The invention provides an application of SOSTDC1 protein in preparing a product for treating skin diseases, and belongs to the technical field of biological medicines. Wherein the SOSTDC1 protein comprises a recombinant SOSTDC1 protein, or a mutant of the recombinant SOSTDC1 protein. The application of the SOSTDC1 protein in preparing a product for treating skin diseases proves that the SOSTDC1 recombinant protein can inhibit Wnt signal paths of skin tissues, so that keratinization of keratinocytes is reduced, symptoms such as hyperplasia and desquamation of epidermis are effectively blocked and delayed, and the treatment and delay of skin diseases including psoriasis and skin fibrosis based on the SOSTDC1 protein are realized. Compared with the prior art, the invention has the following advantages and effects: (1) The main object of the present invention is to find new targets for the treatment or delay of psoriasis, in particular for targeting keratinization, to better prevent relapse after withdrawal and to reduce the risk of opportunistic infections; (2) According to the research, the SOSTDC1 recombinant protein can inhibit the Wnt signal path of skin tissues, so that the keratinization of keratinocytes is reduced, and the symptoms such as hyperplasia of epidermis, desquamation and the like are effectively blocked and delayed, so that the SOSTDC1 recombinant protein can be applied to the treatment of skin diseases, including psoriasis and skin fibrosis; (3) The SOSTDC1 has a plurality of proteins containing SOSTDC1 motif in human body, has very wide functions, and the SOSTDC1 has high expression level in human skin tissue, which suggests that SOSTDC1 is closely related to skin inflammatory diseases, and the invention discovers that SOSTDC1 interferes with keratinization process of psoriasis caused by keratinocyte through experiments, and is possible to be used as biological agent for treating or delaying psoriasis, therefore, the invention develops a novel pharmaceutical composition targeting psoriasis by taking SOSTDC1 recombinant protein as a core component has important research significance and wide economic market.
Drawings
FIG. 1 is a diagram showing cell grouping in PBS mice skin tissue of a single cell assay of example 1 of the present invention for experiments on SOSTDC1 expression in mice with IMQ-induced psoriasis;
FIG. 2 is a graph showing cell grouping in skin tissue of IMQ mice tested by single cell analysis of SOSTDC1 expression in IMQ-induced psoriatic mice in example 1 of the present invention;
FIG. 3 is a graph showing the grouping of SOSTDC1 positive cells in PBS mouse skin tissues from an experiment for single cell analysis of SOSTDC1 expression in IMQ-induced psoriatic mice in example 1 of the present invention;
FIG. 4 is a graph showing the grouping of SOSTDC1 positive cells in skin tissue of IMQ mice tested in the single cell assay of SOSTDC1 expression in IMQ-induced psoriatic mice in example 1 of the present invention;
FIG. 5 is an IMQ-induced SOSTDC1 of example 2 of the present invention eGFP Psoriasis characterization map of the fifth day of the back skin of mice in PBS group and IMQ group of mice in the experiments of the SOSTDC1 expression profile of psoriasis;
FIG. 6 is an IMQ-induced SOSTDC1 of example 2 of the present invention eGFP Daily severity index score (PASI) profile of psoriasis in the back skin of mice in PBS and IMQ groups tested for SOSTDC1 expression status of mice;
FIG. 7 is an IMQ-induced SOSTDC1 of example 2 of the present invention eGFP Flow chart (PBS) of CD45-SOSTDC1+ cells, CD45+ SOSTDC1+ cell ratios in skin tissue of mice psoriasis SOSTDC1 expression experiments;
FIG. 8 shows IMQ-induced SOSTDC1 in example 2 of the present invention eGFP Flow chart (IMQ) of the proportion of CD45-SOSTDC1+ cells, cd45+ SOSTDC1+ cells in skin tissue of mice psoriasis SOSTDC1 expression experiments;
FIG. 9 is an IMQ-induced SOSTDC1 of example 2 of the present invention eGFP Statistical plots of the proportion of CD45-SOSTDC1+ cells, cd45+ SOSTDC1+ cells in skin tissue from a mouse psoriasis SOSTDC1 expression profile experiment;
FIG. 10 shows IMQ-induced SOSTDC1 in example 2 of the present invention eGFP Flow chart (PBS) of the cd45+ cells, CD 45-cells proportion in the skin tissue SOSTDC1 positive cells of the mice psoriasis SOSTDC1 expression profile experiment;
FIG. 11 shows IMQ-induced SOSTDC1 in example 2 of the present invention eGFP Flow chart (IMQ) of the proportion of cd45+ cells, CD 45-cells in the skin tissue SOSTDC1 positive cells of the mice psoriasis SOSTDC1 expression profile experiment;
FIG. 12 shows IMQ-induced SOSTDC1 in example 2 of the present invention eGFP Statistical graphs of the proportion of CD45+ cells and CD 45-cells in SOSTDC1 positive cells of skin tissue of a mouse psoriasis SOSTDC1 expression condition experiment;
FIG. 13 is a SOSTDC1 from an experiment showing the effect of keratinocyte SOSTDC1 knockout on IMQ-induced psoriasis in example 3 of the present invention f/f Or K14-Cre SOSTDC1 f/f Psoriasis characterization map of the fifth day of the back skin of mice;
FIG. 14 is a graph showing the change in daily severity index score (PASI) of mice tested for the effect of keratinocyte SOSTDC1 knockout on IMQ-induced psoriasis in example 3 of the present invention;
FIG. 15 is a pathological diagram of H & E staining of mice tested for the effect of keratinocyte SOSTDC1 knockout on IMQ-induced psoriasis in example 3 of the present invention;
FIG. 16 is a Wnt signaling pathway diagram of an experiment showing the effect of SOSTDC1, a keratinocyte, on the skin tissue signaling pathway of IMQ-induced psoriasis mice in example 4 of the present invention;
FIG. 17 is a BMP signaling pathway diagram of an experiment showing the effect of SOSTDC1, a keratinocyte, on the skin tissue signaling pathway of IMQ-induced psoriasis mice in example 4 of the present invention;
FIG. 18 is a graph showing the pathway of the Keratification signal from the experiment of the effect of SOSTDC1, a keratinocyte, on the pathway of the skin tissue signal of IMQ-induced psoriasis mice in example 4 of the present invention;
FIG. 19 is a signal pathway diagram of a keratin filevent of the experiment of the effect of keratinocyte SOSTDC1 on the skin tissue signal pathway of IMQ-induced psoriasis mice in example 4 of the present invention;
FIG. 20 is a graph representing psoriasis on the fifth day of the intradermal injection of control agent (left) and SOSTDC1 protein (right) on the dorsal skin of mice tested for IMQ-induced experimental mice psoriasis in example 5 of the present invention;
FIG. 21 is a graph of the change in daily severity index score (PASI) of mice tested for SOSTDC1 effect on IMQ-induced experimental mice psoriasis in example 5 of the present invention;
FIG. 22 is a pathological diagram of H & E staining of mice with control reagents and SOSTDC1 protein of the effect of SOSTDC1 on IMQ-induced psoriasis in experimental mice in example 5 of the present invention.
The achievement of the objects, functional features and advantages of the present invention will be further described with reference to the accompanying drawings, in conjunction with the embodiments.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless defined otherwise hereinafter, all technical and scientific terms used in the detailed description of the invention are intended to be identical to what is commonly understood by one of ordinary skill in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
As used herein, the terms "comprising," "including," "having," "containing," or "involving" are inclusive or open-ended and do not exclude additional unrecited elements or method steps. The term "consisting of …" is considered to be a preferred embodiment of the term "comprising". If a certain group is defined below to contain at least a certain number of embodiments, this should also be understood to disclose a group that preferably consists of only these embodiments.
The indefinite or definite article "a" or "an" when used in reference to a singular noun includes a plural of that noun.
The following is provided merely to aid in the understanding of the present invention. These definitions should not be construed to have a scope less than understood by those skilled in the art.
The technical solution of the present invention is further described in detail below with reference to specific embodiments, but the present invention is not limited thereto, and any modifications made by anyone within the scope of the claims of the present invention are still within the scope of the claims of the present invention.
The invention provides an application of SOSTDC1 protein in preparing a product for treating skin diseases, wherein the SOSTDC1 protein comprises recombinant SOSTDC1 protein or a mutant of the recombinant SOSTDC1 protein.
Above, the SOSTDC1 protein may already include two types: (1) recombinant SOSTDC1 protein; (2) mutant of recombinant SOSTDC1 protein.
As described above, SOSTDC1 (sclerostin domain-containing protein 1) is a protein encoded by human gene SOSTDC1. SOSTDC1 is a secreted protein containing a domain similar to sclerostin (sclerostin) and is therefore classified as one of the members of the sclerostin family. SOSTDC1 is expressed in both embryonic development and adult tissue cells. Studies have shown that SOSTDC1 plays a role in many biological processes, including cell proliferation, cell cycle regulation, apoptosis, movement, tumorigenesis, and the like.
As described above, the recombinant SOSTDC1 protein refers to SOSTDC1 protein prepared by genetic engineering techniques. Specifically, it is SOSTDC1 protein produced in large scale in cell culture medium by eukaryotic cell expression system by inserting SOSTDC1 gene into suitable expression vector by recombinant DNA technology.
As described above, the mutant of the recombinant SOSTDC1 protein refers to a mutant which has been artificially introduced or deleted with certain nucleotides in the original SOSTDC1 gene sequence, thereby giving rise to a SOSTDC1 protein having an amino acid sequence different from that of the wild-type (i.e., natural form) SOSTDC1 protein. This approach can be used to make SOSTDC1 proteins more suitable for specific application scenarios, such as in the preparation of dermatological products, by altering the spatial configuration and biochemical properties of the protein.
In a word, the application of the SOSTDC1 protein in preparing a product for treating skin diseases can prove that the SOSTDC1 recombinant protein can inhibit Wnt signal paths of skin tissues, so that keratinization of keratinocytes is reduced, symptoms such as hyperplasia and desquamation of epidermis are effectively blocked and delayed, and the treatment and delay of skin diseases including psoriasis and skin fibrosis based on the SOSTDC1 protein are realized.
Compared with the prior art, the invention has the following advantages and effects: (1) The main object of the present invention is to find new targets for the treatment or delay of psoriasis, in particular for targeting keratinization, to better prevent relapse after withdrawal and to reduce the risk of opportunistic infections; (2) According to the research, the SOSTDC1 recombinant protein can inhibit the Wnt signal path of skin tissues, so that the keratinization of keratinocytes is reduced, and the symptoms such as hyperplasia of epidermis, desquamation and the like are effectively blocked and delayed, so that the SOSTDC1 recombinant protein can be applied to the treatment of skin diseases, including psoriasis and skin fibrosis; (3) The SOSTDC1 has a plurality of proteins containing SOSTDC1 motif in human body, has very wide functions, and the SOSTDC1 has high expression level in human skin tissue, which suggests that SOSTDC1 is closely related to skin inflammatory diseases, and the invention discovers that SOSTDC1 interferes with keratinization process of psoriasis caused by keratinocyte through experiments, and is possible to be used as biological agent for treating or delaying psoriasis, therefore, the invention develops a novel pharmaceutical composition targeting psoriasis by taking SOSTDC1 recombinant protein as a core component has important research significance and wide economic market.
Further, the SOSTDC1 protein is: a secreted protein comprising at least one C-terminal cystine and at least one N-terminal secretion signal in the amino acid sequence.
As described above, the SOSTDC1 protein is a secreted protein. Wherein the amino acid sequence comprises a C-terminal cystine and an N-terminal secretion signal.
The C-terminal cystine (cysteine) is an amino acid that differs from other amino acids in that it has a sulfur atom. In proteins, two Cysteine residues may form disulfide bonds, thereby stabilizing the three-dimensional structure of the protein.
The N-terminal secretion signal (signal peptide) is an amino acid sequence, which is located at the N-terminal of the protein and plays a role in the synthesis and transport process of the protein. It is capable of directing proteins through the endoplasmic reticulum membrane and being further processed and secreted into the extracellular environment. Thus, proteins comprising an N-terminal secretion signal are typically secreted proteins.
As mentioned above, in general, the amino acid sequence of SOSTDC1 protein contains only one C-terminal cystine and one N-terminal secretion signal. However, in some cases, it is possible to introduce additional C-terminal cystine and N-terminal secretion signals into the amino acid sequence of the SOSTDC1 protein by means of natural mutation or artificial engineering, etc.
If multiple C-terminal cysteines are present in the SOSTDC1 protein sequence, these Cys residues may form multiple disulfide bonds, further stabilizing the spatial configuration of the protein. Similarly, if multiple N-terminal signal peptides are present in the SOSTDC1 protein sequence, these signal peptides may allow the SOSTDC1 protein to be transported multiple times to the endoplasmic reticulum and golgi apparatus for processing and modification, and eventually be secreted into the extracellular environment.
Further, the amino acid sequence of the SOSTDC1 protein comprises any one of the following amino acid sequences: A. an amino acid sequence as shown in SEQ ID No. 1; B. an amino acid sequence having at least 80% identity to the amino acid sequence shown in SEQ ID No. 1.
The SOSTDC1 protein consists of 206 amino acids, is a secretory protein containing one C-terminal cystine and one N-terminal secretory signal, has a gene length of 621bp and a protein size of 21kDa.
In a preferred embodiment, the amino acid sequence of the SOSTDC1 protein comprises an amino acid sequence having at least 90% identity to the amino acid sequence as set forth in SEQ ID No. 1.
In a preferred embodiment, the amino acid sequence of the SOSTDC1 protein comprises an amino acid sequence having at least 99% identity to the amino acid sequence as set forth in SEQ ID No. 1.
Further, the gene encoding the SOSTDC1 protein may include any one of the following three nucleotide sequences: (1) a nucleotide sequence shown as SEQ ID No. 2; (2) Alternatively, the nucleotide sequence shown as SEQ ID No.2 is substituted, deleted and/or added with one or more nucleotides, the nucleotide sequence encoding the same active protein; (3) Alternatively, the nucleotide sequence encoding the amino acid sequence of SEQ ID No. 1.
Furthermore, the product is a product for reducing keratinocyte keratinization by inhibiting Wnt signal path of the SOSTDC1 protein so as to treat skin diseases.
The Wnt signaling pathway (window/integrated) is an important cell signaling pathway involved in many biological processes such as embryo development, tissue regeneration, and cell proliferation. The channel can regulate and control important processes related to cell survival such as cell proliferation, differentiation, polarity, apoptosis and the like. In mammals, the Wnt signaling pathway has two main branches: (1) A β -catenin (β -catenin) -dependent canonical Wnt signaling pathway and (2) a β -catenin (β -catenin) -independent non-canonical Wnt signaling pathway. After the classical Wnt signal channel is activated, beta-catenin (beta-catenin) enters the nucleus and activates a transcription factor Tcf/Lef, so that transcription of downstream genes is started, and life processes such as cell proliferation, cell differentiation and the like are affected. The Wnt signaling pathway plays an important role in normal physiological processes, and its deregulation is also associated with the occurrence and progression of many diseases, such as cancer, osteoporosis, etc.
The therapeutic effect of the product on skin diseases is achieved by inhibiting Wnt signal channels. The SOSTDC1 protein can reduce the keratinization of keratinocytes, thereby alleviating or treating certain skin diseases, because the Wnt signaling pathway plays an important role in the differentiation and proliferation of skin cells, while SOSTDC1 protein can inhibit the function of the signaling pathway. Thus, the product may have the effect of controlling excessive formation of keratin.
Further, the skin disease includes at least one of psoriasis and skin fibrosis.
Psoriasis (psoriasis) is a common chronic inflammatory skin disease characterized by the symptoms of red plaques, scales, itching, etc. on the skin. Skin fibrosis (skin fibrosis) is a disease of abnormal hyperplasia and scarring of the skin due to excessive fibroblast activity. Both of these diseases are one of the more common skin disorders.
Further, the psoriasis is psoriasis induced by imiquimod. Imiquimod (IMQ), having the formula: c (C) 14 H 16 N 4 Is a small molecule immunomodulator, and is used for treating diseases such as external genital organs and perianal warts. However, imiquimod has been found to cause psoriasis-like lesions and exacerbate the condition of psoriatic patients, and is widely used in the study of psoriasis pathogenesis and therapeutic targets. "psoriasis induced by imiquimod" may refer to a condition that results in the appearance of a psoriatic symptom in a patient through the use or contact of imiquimod. This type of psoriasis may also be referred to as drug-induced psoriasis. The psoriasis comprises psoriasis induced by Imiquimod (IMQ), and the SOSTDC1 protein can inhibit the Wnt signal path of skin tissues induced by IMQ, so that keratinization of keratinocytes is reduced, and further, the effect of delaying the pathogenesis of the psoriasis is shown.
Further, the SOSTDC1 protein in the product is used at a concentration of 100ng/mL-1000ng/mL. For example, it may be 100ng/mL, 200ng/mL, 300 ng/mL, 400 ng/mL, 500 ng/mL, 600 ng/mL, 700 ng/mL, 800 ng/mL, 900 ng/mL, 1000ng/mL, and the like.
In a preferred embodiment, the SOSTDC1 protein is used in the product at a concentration of 100ng/mL-500 ng/mL.
In a preferred embodiment, the SOSTDC1 protein is used in the product at a concentration of 100ng/mL-200ng/mL. For example, it may be 100ng/mL, 120 ng/mL, 140 ng/mL, 160 ng/mL, 180 ng/mL, 200ng/mL, and the like.
Further, the product is any one of a drug, a detection reagent, a kit and a diagnostic reagent.
Further, the drug is a keratinocyte-targeted drug.
The SOSTDC1 protein-containing medicament used in the treatment of skin diseases can act on cells responsible for keratinocytes in the skin, thereby regulating the metabolic process of the keratin and relieving or treating the skin diseases. Because keratinocytes are critical cells for keratinocyte formation and formation of the keratinous barrier in the skin, treatment of these cells can be effective in ameliorating various skin problems caused by abnormal keratinous metabolism, such as dryness, itching, scaling, acne, etc.
In particular, the agents mentioned herein may include topical keratolytic agents, etc. which promote the renewal of the stratum corneum on the skin surface and restore the normal function of the skin, thus achieving the aim of treating dermatological conditions.
The medicament comprises at least one unit preparation.
The medicine contains one or more unit preparations.
The SOSTDC1 protein is taken as an active ingredient in the unit preparation.
Further, the weight of the active ingredient in the unit formulation is n times the therapeutically effective dose of the active ingredient; wherein n has a value ranging from 0.1 to 10.0. For example, it may be 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0, etc.
In a preferred embodiment, n has a value in the range of 0.1 to 1.0.
Further, the effective therapeutic dose of the active ingredient is 0.1 mg/person/time to 20.0 mg/person/time. For example, it may be 0.1 mg/person/time, 0.2 mg/person/time, 0.3 mg/person/time, 0.4 mg/person/time, 0.6 mg/person/time, 0.8 mg/person/time, 1.0 mg/person/time, 2.0 mg/person/time, 4.0 mg/person/time, 6.0 mg/person/time, 8.0 mg/person/time, 10.0 mg/person/time, 12.0 mg/person/time, 14.0 mg/person/time, 16.0 mg/person/time, 18.0 mg/person/time, 20.0 mg/person/time, and the like.
In a preferred embodiment, the effective therapeutic dose of the active ingredient is 1.0 mg/person/time to 20.0 mg/person/time.
Further, the medicine also comprises a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable carrier comprises: at least one of a sustained release agent, an excipient, a filler, a binder, a wetting agent, a disintegrating agent, an absorption enhancer, a surfactant and a lubricant.
Further, the dosage forms of the medicine comprise paste, powder, tablet, capsule and granule. In addition, it may include, but is not limited to, injection, oral liquid preparation, external patch, spray, etc.
It is noted that, through research, the SOSTDC1 recombinant protein can not only relieve experimental mouse psoriasis, but also inhibit Wnt signal paths of skin tissues, relieve keratinization of keratinocytes, and can be used for treating or delaying psoriasis.
In a further embodiment of the invention, experimental mouse psoriasis caused by imiquimod (5% imq) can be effectively alleviated by administration of SOSTDC1 recombinant protein, and further SOSTDC1 is closely related to keratinocyte keratinization.
It should be noted that, according to the research, the SOSTDC1 recombinant protein has no obvious effect on healthy skin tissues, but the SOSTDC1 recombinant protein has good effect of treating or delaying psoriasis and can reduce keratinization, so that the SOSTDC1 recombinant protein can be used for preparing a medicament for treating or delaying psoriasis.
In conclusion, the SOSTDC1 recombinant protein can inhibit Wnt signal path of skin tissue, so that keratinization of keratinocyte is reduced, and symptoms such as epidermal hyperplasia, desquamation and the like are effectively blocked and delayed, so that the SOSTDC1 recombinant protein can be applied to treatment of skin diseases, including psoriasis and skin fibrosis.
The invention is further illustrated by the following specific examples, but it should be understood that these examples are for the purpose of illustration only and are not to be construed as limiting the invention in any way. Modifications of the method and apparatus of the invention, etc. within the scope of the claims may be made by those skilled in the art and are also considered to be within the scope of the invention. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art. The test methods for specific experimental conditions are not noted in the examples below, and are generally performed under conventional experimental conditions or under experimental conditions recommended by the manufacturer. The reagents and starting materials used in the present invention are commercially available unless otherwise specified.
The invention finds a new therapeutic target, namely SOSTDC1, in the process of researching the pathogenesis of psoriasis. StDC1 has been shown to inhibit the Wnt signaling pathway in skin tissue, thereby reducing keratinocyte keratinization, and effectively alleviating experimental mouse psoriasis caused by imiquimod (5% IMQ). It is understood that the effect of treating or delaying psoriasis can be achieved as long as the expression of SOSTDC1 gene can be up-regulated; thus, chemical agents up-regulate SOSTDC1 gene expression, except for the use of SOSTDC1 recombinant proteins, can also exert the same effect. Thus, SOSTDC1 recombinant proteins can be used for the preparation of a medicament for the treatment or delay of psoriasis.
Example 1: in this example, IMQ-induced psoriasis mouse SOSTDC1 expression was revealed by single cell sequencing experiments.
1. The experimental method comprises the following steps: (1) Wild male mice (C57 BL/6J,8 weeks old, beijing Vitrendy laboratory animal technologies Co., ltd.) were raised at the university laboratory animal center of North China. Animals were kept in a light-dark cycling feeding chamber for 12 hours at constant temperature and humidity. The feed and water can be eaten freely. All animal procedures were performed following procedures approved by the animal welfare ethics committee. (2) randomly dividing the mice into: PBS (control) and IMQ (imiquimod-dosed, psoriasis model group); wherein at least 4 mice per group. After 1 day of depilation of the backs (2 x2 cm) of the mice, the IMQ group was applied once daily with 62.5mg of IMQ cream (mass fraction 5%, purchased from the company of the pharmaceutical industry of gmbh) each time for 5 consecutive days to induce a psoriasis model. The skin of the back of the mouse was taken, after fat removal, digested into single cells by collagenase (Sigma Co., cat# C5138), and then single cell sequencing was performed.
2. Experimental results: as shown in fig. 1-4. FIGS. 1-4 show SOSTDC1 expression in skin tissue. Wherein, FIGS. 1 and 2 are cell grouping diagrams in PBS and IMQ mouse skin tissues; FIGS. 3 and 4 are cell clusters of SOSTDC1 positive cells in skin tissue.
Wherein, in the cell groupings of FIGS. 1 and 2, keratinocells are one type of keratinocyte-producing cell; epighelial refers to cells in Epithelial tissue, such as alveolar Epithelial cells, intestinal Epithelial cells, etc.; fibriplasts is a fibroblast, mainly responsible for the synthesis of collagen and other matrix components; hair follicle cells refers to hair follicle cells, including stem cells and different types of neuroendocrine cells; the Tcell is an immune cell, which belongs to a lymphocyte; sebaceous gland cells is a sebaceous gland cell; myeloid is a class of Myeloid-derived leukocytes including monocytes, macrophages, granulocytes, and the like; endothelial cells refers to endothelial cells, which mainly constitute the vessel wall; melanophytes are Melanocytes responsible for producing melanin color.
In addition, UMAP represents Uniform Manifold Approximation and Projection in FIGS. 1 and 2, which is a dimension-reduction algorithm, UMAP_1 and UMAP_2 in the abscissa and ordinate of the cell cluster map, which are the positions of cells in two-dimensional space calculated by the UMAP algorithm. These coordinates can help understand the relationships between different cell types in the dataset, as well as their changes in different physiological states; the relatively dark dots in FIGS. 3 and 4 represent cells with high sostdc1 expression; wherein the cells with high sostdc1 expression in fig. 3 correspond to keratinocytes and hair follicle cells in fig. 1; the cells with high sostdc1 expression in fig. 4 correspond to keratinocytes and hair follicle cells in fig. 2. (1) In the IMQ-induced psoriasis model, the UMAP cluster analysis shows that keratinocytes are significantly changed, which suggests that the keratinocytes play an important role in the occurrence and development of psoriasis. (2) Further analysis found that SOSTDC1 was mainly derived from keratinocytes in mouse skin tissue.
Example 2: in this example, it was experimentally demonstrated that IMQ induces mice psoriasis to inhibit SOSTDC1 expression, and that SOSTDC1 derived from keratinocytes is associated with psoriasis.
1. The experimental method comprises the following steps: (1) Male mouse (SOSTDC 1) eGFP Baioer chart pharmaceutical technology Co., ltdStructure) is randomly divided into: PBS and IMQ groups, at least 4 mice per group. After depilation of the back (2 x2 cm) of the mice for 1 day, 62.5mg of IMQ cream (mass fraction 5%, purchased from the company of the pharmaceutical industry, inc.) was applied once daily for 5 consecutive days to induce a psoriasis model. (2) daily record severity index (PASI) score: the cumulative fraction of erythema (0-4 min), flaking (0-4 min) and skin thickness (0-4 min). Mice were sacrificed 5 days after molding, the skin lesions were photographed, then skin tissues were isolated, fixed overnight in 4% paraformaldehyde solution, paraffin-embedded and sectioned for hematoxylin and eosin staining. Wherein, specific scoring criteria are as follows:
1) Erythema (0-4): as shown in the table below.
TABLE 1 erythema score criteria
2) Flake (0 min-4 min): as shown in the table below.
TABLE 2 Scale scoring criteria table
3) Skin thickness (0 min-4 min): as shown in the table below.
TABLE 3 skin thickness scoring criteria
2. Experimental results: the results are shown in FIGS. 5-12. FIGS. 5-12 show IMQ-induced SOSTDC1 eGFP The mouse psoriasis SOSTDC1 expression affects the experimental conditions. Wherein, figure 5 is a psoriasis characterization plot of the fifth day of the back skin of PBS group and IMQ group mice; FIG. 6 is a graph of changes in daily severity index score (PASI) for psoriasis on the back skin of PBS group and IMQ group mice; FIG. 7 shows CD45-SOSTDC1+ cells, CD45+ SOSTDC1+ cells in skin tissueFlow chart (PBS) of cell scale; FIG. 8 is a flow chart (IMQ) of CD45-SOSTDC1+ cells, CD45+ SOSTDC1+ cell ratios in skin tissue; FIG. 9 is a statistical plot of the proportion of CD45-SOSTDC1+ cells, CD45+ SOSTDC1+ cells in skin tissue; FIG. 10 is a flow chart (PBS) of the CD45+ cells, CD 45-cell ratios in SOSTDC1 positive cells of skin tissue; FIG. 11 is a flow chart (IMQ) of the proportion of CD45+ cells, CD 45-cells in SOSTDC1 positive cells of skin tissue; FIG. 12 is a statistical plot of the proportion of CD45+ cells and CD 45-cells in SOSTDC1 positive cells of skin tissue. (1) IMQ group compared to PBS group: the erythema and scales on the skin damage part are obviously increased; PASI score also increased significantly; (2) The higher proportion of CD45-SOSTDC1+ cells than CD45+ SOSTDC1+ cells suggests that CD45-SOSTDC1+ cells are significantly altered in the development and progression of psoriasis. Further analysis of the source of SOSTDC1 cells revealed that SOSTDC1 was predominantly derived from CD 45-cells. SOSTDC1 was shown to be expressed mainly in CD 45-cells of skin tissue. The above experimental results indicate that SOSTDC1 derived from keratinocytes is closely related to the occurrence of psoriasis.
Example 3: in this example, experiments were performed in which keratinocyte loss SOSTDC1 aggravates IMQ-induced psoriasis.
1. The experimental method comprises the following steps: (1) Taking SOSTDC1 f/f Mice (8 week old, siro Biotech Co., ltd.) or K14-Cre SOSTDC1 f/f Mice (8 weeks of age) at least 4 mice per group. After depilation of the back (2 x2 cm) of the mice for 1 day, 62.5mg of IMQ cream (mass fraction 5%, purchased from the company of the pharmaceutical industry, inc.) was applied once daily for 5 consecutive days to induce a psoriasis model. (2) daily record severity index (PASI) score: the cumulative fraction of erythema (0-4 min), flaking (0-4 min) and skin thickness (0-4 min). Mice were sacrificed 5 days after molding, the skin lesions were photographed, then skin tissues were isolated, fixed overnight in 4% paraformaldehyde solution, paraffin-embedded and sectioned for hematoxylin and eosin staining.
2. Experimental results: the results are shown in FIGS. 13-15. FIGS. 13-15 show keratinocyte-deficient SOSTDC1 against psoriasisIs the experimental condition. Wherein FIG. 13 is SOSTDC1 f/f Or K14-Cre SOSTDC1 f/f Psoriasis characterization map of the fifth day of the back skin of mice; FIG. 14 is a graph of mice daily severity index score (PASI) change; FIG. 15 is a drawing of mouse H&E staining pathology chart. Wherein K14-Cre SOSTDC1 f/f Mouse and SOSTDC1 f/f Comparison with mice: the erythema and scales on the skin damage part are obviously increased; PASI score also increased significantly; h&E staining showed a significant decrease and increase in epidermal hyperplasia.
Example 4: in this example, an experiment was performed in which keratinocyte-deficient SOSTDC1 activated the signaling pathway of skin tissue Wnt, keratinization.
1. The experimental method comprises the following steps: (1) Taking SOSTDC1 f/f Mouse, K14-Cre SOSTDC1 f/f Mice (8 weeks old) 3 mice per group. After depilation of the back (2 x2 cm) of the mice for 1 day, 62.5mg of IMQ cream (mass fraction 5%, purchased from the company of the pharmaceutical industry, inc.) was applied once daily for 5 consecutive days to induce a psoriasis model. (2) The same part of skin tissue of the mouse is taken, fat is removed, and transcriptome sequencing is performed.
2. Experimental results: the results are shown in FIG. 4. FIG. 4 shows that keratinocyte-deficient SOSTDC1 activates the Wnt, keratinization, keratin filevent signaling pathway in skin tissue. Wherein, fig. 16 is a Wnt signaling pathway diagram; FIG. 17 is a chart of BMP signaling pathway; FIG. 18 is a diagram of a isolation signal path; fig. 19 is a signal path diagram of a keratin filevent. Wherein K14-Cre SOSTDC1 f/f Mouse and SOSTDC1 f/f Comparison with mice: (1) Wnt, keratinization, keratin filevent signal pathway significance activation; (2) however, there was no significant change to BMP signaling pathway.
Example 5: in this example, an experimental mouse psoriasis progress verification experiment was performed with SOSTDC1 deferring IMQ induction.
1. The experimental method comprises the following steps: (1) Male mice (C57 BL/6J,8 weeks, beijing Vitolihua laboratory animal technologies Co., ltd.) were randomly divided into: vehicle group and Rm SOSTDC1 group, at least 5 mice per group. The backs (2X 2 cm) of the mice were dehaired for 1 day. Thereafter, the composition was applied once daily for 5 consecutive days with 62.5mg of IMQ cream (mass fraction 5%, purchased from Sichuan Ming's pharmaceutical Co., ltd.) each time to induce a psoriasis model. Wherein: A. rm SOSTDC1 group: mice were given intradermal injections of SOSTDC1 recombinant protein (in sterile water) every other day at a dose of 100 μg/kg. B. Control group: mice were given daily intradermal injections of equal amounts of sterile water. (2) daily record severity index (PASI) score: A. erythema (0-4); B. flakes (0 min-4 min); C. skin thickness (0 min-4 min); cumulative score of 3 items above. Mice were sacrificed 5 days after molding, the skin lesions were photographed, then skin tissues were isolated, fixed overnight in 4% paraformaldehyde solution, paraffin-embedded and sectioned for hematoxylin and eosin staining.
2. Experimental results: the results are shown in FIG. 5. Figure 5 shows the effect of SOSTDC1 on IMQ-induced experimental mouse psoriasis. Wherein, figure 20 is a psoriasis characterization plot of the fifth day of the back skin of mice injected intradermally with control agent (left) and SOSTDC1 protein (right); FIG. 21 is a graph of mice daily severity index score (PASI) change; FIG. 22 is a pathogenicity chart of H & E staining of mice with control reagents and SOSTDC1 protein. From the experimental results, it can be seen that the SOSTDC1 group compares with the Vehicle group: (1) the erythema and scales on the skin damage part are obviously reduced; (2) a significant reduction in mouse PASI score; (3) H & E staining showed a significant decrease in epidermal hyperplasia. SOSTDC1 was shown to delay the progression of IMQ-induced psoriasis in experimental mice.
In a word, the application of the SOSTDC1 protein in preparing a product for treating skin diseases proves that the SOSTDC1 recombinant protein can inhibit Wnt signal paths of skin tissues, so that keratinization of keratinocytes is reduced, symptoms such as epidermal hyperplasia, desquamation and the like are effectively blocked and delayed, and the treatment and delay of skin diseases including psoriasis and skin fibrosis based on the SOSTDC1 protein are realized.
While the preferred embodiments and examples of the present invention have been described, it should be noted that modifications and improvements, including but not limited to, adjustments of proportions, procedures, amounts and reaction vessels, may be made by those skilled in the art without departing from the inventive concept herein.
Claims (6)
1. The application of SOSTDC1 protein in preparing dermatological product is characterized in that,
the skin disease is psoriasis;
the amino acid sequence of the SOSTDC1 protein is the amino acid sequence shown in SEQ ID No. 1; and the gene encoding the SOSTDC1 protein is a nucleotide sequence shown as SEQ ID No. 2.
2. Use of a SOSTDC1 protein as claimed in claim 1 for the preparation of a product for the treatment of dermatological disorders, wherein said product is a product for the purpose of said SOSTDC1 protein of reducing keratinocyte keratinization by inhibiting Wnt signaling.
3. Use of a SOSTDC1 protein as claimed in claim 1 in the manufacture of a product for the treatment of skin disorders, wherein said SOSTDC1 protein is used in said product at a concentration of 100ng/mL to 1000ng/mL.
4. Use of a SOSTDC1 protein as claimed in claim 1 for the preparation of a product for the treatment of dermatological disorders, wherein said product is a medicament;
the dosage forms of the medicine comprise paste, powder, tablet, capsule and granule.
5. Use of a SOSTDC1 protein as claimed in claim 4 for the preparation of a product for the treatment of dermatological disorders, wherein said drug is a keratinocyte-targeting drug;
the medicament comprises at least one unit preparation;
the SOSTDC1 protein is taken as an active ingredient in the unit preparation;
the weight of the active ingredient in the unit formulation is n times the therapeutically effective dose of the active ingredient;
wherein, the numerical range of n is 1-10;
the effective therapeutic dose of the active ingredient is 0.1 mg/person to 20.0 mg/person.
6. Use of a SOSTDC1 protein as claimed in claim 4 in the manufacture of a product for the treatment of skin disorders, wherein said medicament further comprises a pharmaceutically acceptable carrier;
wherein the pharmaceutically acceptable carrier comprises: at least one of a sustained release agent, an excipient, a filler, a binder, a wetting agent, a disintegrating agent, an absorption enhancer, a surfactant and a lubricant.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1307637A (en) * | 1998-04-29 | 2001-08-08 | 吉尼西斯研究及发展有限公司 | Polynucleotides isolated from skin cells and methods of use thereof |
| CN101925611A (en) * | 2007-11-21 | 2010-12-22 | 安姆根有限公司 | Wise binding agents and epitopes |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1307637A (en) * | 1998-04-29 | 2001-08-08 | 吉尼西斯研究及发展有限公司 | Polynucleotides isolated from skin cells and methods of use thereof |
| CN101925611A (en) * | 2007-11-21 | 2010-12-22 | 安姆根有限公司 | Wise binding agents and epitopes |
Non-Patent Citations (2)
| Title |
|---|
| Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause profibrotic changes in linear morphoea fibroblasts;I. I. Badshah等;British Journal of Dermatology;第180卷(第5期);第1135-1149页 * |
| Mus musculus sclerostin domain containing 1 (Sostdc1), mRNA，NCBI Reference Sequence: NM_025312.3，1751bp mRNA linear;Choi RB等;NCBI genbank * |
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