CN113730390B - Use of compounds for promoting repair of skin lesions - Google Patents
Use of compounds for promoting repair of skin lesions Download PDFInfo
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- CN113730390B CN113730390B CN202111044412.1A CN202111044412A CN113730390B CN 113730390 B CN113730390 B CN 113730390B CN 202111044412 A CN202111044412 A CN 202111044412A CN 113730390 B CN113730390 B CN 113730390B
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- 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
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present application relates to the use of polyether compounds for the preparation of medicaments or pharmaceutical compositions for the promotion of epithelial tissue repair and/or regeneration. The application proves that compared with the existing similar product human recombinant EGF and rehabilitation new, the polyether compound polydecalinmycin containing decalin structure has better injury repair promoting effect, small molecular weight, small dosage and single component. In addition, the compound can be synthesized by adopting a microbial gene modification fermentation method, has high component content, simple extraction and separation process, lower required production cost and use cost and technical advancement.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to application of a compound in the aspect of promoting epithelial tissue repair and/or regeneration.
Background
The skin acts as an external epithelium of the human body and is the organ most challenged by a range of external stress factors throughout the life cycle. Worldwide, annual accidental injuries and surgical procedures can cause hundreds of millions of skin wounds. According to statistics of world health organization, about 900 ten thousand people burn and scald in 2017. In addition to acute wounds, a variety of common diseases such as diabetic foot, aging, obesity, vascular disease, cancer, infection, etc., are observed in the complications of which there is a general pathological phenomenon in which skin wounds heal slowly or do not heal completely, which is a steady growing trend in more than 1% of people worldwide. The healing time of wounds is closely related to susceptibility to infection, pain duration, hospitalization time and scar occurrence, and the burden of skin wound treatment will become heavier, both from a human health and from an economic standpoint.
In the skin injury repair process, the abnormality of any link can seriously influence the normal progress of injury repair. Thus, delicate skin repair mechanisms are often affected by numerous factors, such as age, nutritional status, endocrine changes, local blood circulation, infection, ionizing radiation, drugs, systemic diseases, and the like. When the superficial surface of the wound and the loss of the epidermal cells are slight, the organism can be repaired by the mechanism, so that most of structures and functions of the epidermis are recovered. However, in wounds with more tissue cell loss and oversized wounds, the regenerated epidermis is difficult to repair the wounds completely, and the organism fills the wounds by connective tissues and loses the original tissue structure and function. In addition, the problem of insufficient healing capacity of chronic wounds is equally troublesome. For example, in diabetes, diabetic foot morbidity is about 25%, which severely impairs the repair rate of wounds due to damaged tissue cells and abnormal metabolism caused by abnormal hyperglycemia. Obesity often coexisting with diabetes is unfavorable for wound microangiogenesis due to thick skin fat, and the wound is easy to cause fat liquefaction to generate infection, so that the wound recovery speed of obese people is slower. In the aging population, the wound healing rate due to aging is also significantly slowed down due to the decline of cell compensatory functions, in particular the decline of stem cell self-renewal function and impaired cell clearance. Promoting healing of these acute and chronic wounds to achieve maximum restoration of tissue function is a major concern for clinical care.
In clinical treatment, skin wound repair is mainly directed to the treatment and administration of acute and chronic skin wounds. The American cockroach extract single prescription-rehabilitation new liquid developed based on the advantages of the traditional Chinese medicine in China is commonly used for treating trauma, peptic ulcer, burn, bedsore and the like. The new medicine recombinant bovine basic fibroblast growth factor (rb-bFGF) of the genetic engineering class I of China promotes wound healing, and is mainly used for burn, chronic ulcer on the body surface, fresh wound (including trauma, skin-supply wound, operation wound and the like). However, the traditional Chinese medicine compound has complex components, an undefined target and difficult quality control; the polypeptide and the recombinant protein have high preparation cost, are easy to hydrolyze and have unstable curative effect. The small molecular compound has the advantages of definite components, difficult degradation, low preparation cost and the like. To date, small molecule compounds have not been used for clinical treatment of wounds. Small molecule compounds that seek to improve or enhance the endogenous regenerative capacity of the skin are a great need in medicine and society.
Disclosure of Invention
The invention provides the use of the compound polydecalinmycin, its chelated form, its hydrated form or its pharmaceutically acceptable salts or esters for the preparation of a medicament or pharmaceutical composition for promoting epithelial tissue repair and/or regeneration.
In some embodiments, the compound Polydecalinmycin (PDM) has the structure shown in formula I:
in some embodiments, compound PDM has the formula C 43 H 70 O 8 Molecular weight 714, which is structurally shown in FIG. 1.
In some embodiments, the compound polydecalinmycin is synthetic or obtained from a microbial fermentation culture.
In some embodiments, the compound polydecalinmycin is obtained from a microbial fermentation culture.
In some embodiments, the microorganism is selected from a mutant strain of Streptomyces sp.scsio 03032 with deletion of the spmO (tryptophan oxidase) gene.
In some embodiments, the microorganism is selected from the mutant SPM257.
In some embodiments, PDM may be prepared as described in chinese patent application 202010499605.5.
The epidermis of mammalian skin is a continuous, multi-layered epithelium that is regenerated by a great deal. In the physiological state, the epidermis is continually senescent and sloughed off, while basal cell division, proliferation and differentiation continue to take place [1]. Thus, the skin possesses a delicate, complex, orderly set of mechanisms to protect itself and restore tissue integrity when damaged, a process that is accomplished by the co-coordination of a variety of cells and cytokines [2]. The process of skin injury repair can be divided into four phases: hemostasis→inflammation→epidermal tissue regeneration→epidermal remodeling. Among these, epidermal tissue regeneration is the most important stage in the whole set of repair mechanisms. At this stage, the granulation tissue, consisting of fibroblasts at the sprouting site of the new capillaries, grows from the edges and bottom of the wound and spreads towards the center and surface of the defect, filling the recessed wound, becoming a new substrate for the migration of later keratinocytes (keratinocytes). The basal keratinocytes then begin to proliferate, migrate from the wound edge to the wound center under the clot, forming a monolayer of epithelial cells on the granulation tissue, and eventually proliferate, differentiating into squamous epithelium. During this period, fibroblasts from the periphery of the wound and bone marrow are activated by macrophages, secreting collagen, and forming scars; wherein a portion of the fibroblasts differentiate into myofibroblasts, promoting wound edge condensation. Indeed, the ability of the epidermis to self-renew, repair is largely maintained by the stem cells of the substrate. Epidermal stem cells possess a strong self-renewal capacity, complete self-renewal by asymmetric division, and form a new daughter cell, a transiently expanded cell. The transiently expanded cells continue to divide, expand, migrate upward to form other cell layers, such as spiny cell layers, granulosa cell layers, etc. [1]. During wound repair, cells involved in repair secrete a variety of cytokines including EGF, TGF-beta, FGF, VEGF, and the like, which in turn regulate cell proliferation, migration, and differentiation [3]. However, skin wounds often heal poorly due to severe tissue defects or inadequate repair mechanisms. In order to solve the problem, in addition to preventing wound infection, effective clinical treatment means are not available at present. Searching a key target for repairing skin injury, clarifying a repairing mechanism, and being beneficial to finding a safe and effective skin injury treatment scheme. In one embodiment of the present invention, it was demonstrated that polyether compound PDM significantly promotes cell proliferation of human epidermal keratinocytes (HACAT) and human embryonic kidney epithelial cells (HEK 293), mouse epidermal fibroblasts (MDF) and human embryonic fibroblasts (MEF), and is dose dependent.
In some embodiments, the polyether compound is used at a concentration of 10 to 1000nM.
In some embodiments, the promotion of epithelial tissue repair and/or regeneration comprises promotion of repair and/or regeneration of a skin wound or scar.
In some embodiments, the skin wound is selected from the group consisting of a wound, a burn, a scald, an ulcer.
In some embodiments, the wound is selected from a excision wound, a cut, a puncture wound, or a puncture wound.
In some embodiments, the medicament or pharmaceutical composition is formulated for topical or transdermal administration, oral administration, intravenous injection, intramuscular injection.
In some embodiments, the medicament or pharmaceutical composition is formulated as a gel, spray, paste, cream, lotion, ointment, oil, aqueous solution, suspension, dispersion, patch, adhesive, bandage, dressing, depot or reservoir.
In some embodiments, the method of making the compound PDM comprises the steps of:
s1, preparing a fermentation culture of spmO gene deletion mutant SPM 257;
s2, adding macroporous resin into the fermentation culture prepared in the step S1, and continuing fermentation;
s3, after the fermentation in the step S2 is finished, filtering the prepared mixture to obtain macroporous resin adsorbed with fermentation metabolites;
s4, eluting the macroporous resin prepared in the step S3, concentrating the eluent to obtain a water mixed solution, and extracting the water mixed solution, wherein an extraction layer is the total extract;
s5, performing silica gel column chromatography on the total extract prepared in the step S4, using chloroform/methanol as an eluent, collecting a fraction Fr.1 eluted by a gradient of 92:8 of chloroform/methanol volume ratio, passing through a column, eluting by using chloroform/methanol volume ratio of 1:1 as a mobile phase, concentrating to obtain a fraction Fr.1-1 containing polydecamycin, separating and purifying the fraction Fr.1-1 by the column, and eluting to obtain the compound polydecamycin.
Specifically, the preparation method comprises the following steps:
a. preparing a fermentation culture of spmO gene deletion mutant SPM257, adding macroporous resin into a fermentation culture medium, separating the macroporous resin adsorbed with fermentation metabolites from fermentation liquor and mycelium after the culture is finished, eluting the macroporous resin by acetone, distilling and concentrating eluent to obtain water mixed liquor, extracting the water mixed liquor by butanone, and concentrating a butanone extraction layer to obtain a total extract;
b. subjecting the total extract to silica gel column chromatography, performing gradient elution by using chloroform/methanol as an eluent from a volume ratio of 100:0-0:100, collecting a fraction Fr.1 eluted by the gradient of the volume ratio of chloroform/methanol of 92:8, eluting by using a sephadex column by using the volume ratio of chloroform/methanol of 1:1 as a mobile phase, concentrating to obtain a fraction Fr.1-1 containing polydecalinmycin, separating and purifying the fraction Fr.1-1 by using the sephadex column, and eluting by using methanol as the mobile phase to obtain the compound polydecalinmycin.
More specifically, in one embodiment, the preparation method includes the steps of:
a. preparing a fermentation culture of spmO gene deletion mutant SPM257, inoculating the activated mutant SPM257 into a seed culture medium, culturing at 28 ℃ and 200rpm for 72 hours to obtain a seed solution, inoculating the seed solution into the fermentation culture medium at 10%v/v of inoculum size, shaking and culturing at 28 ℃ and 200rpm for 5 days, adding sterilized Amberlite XAD-16 macroporous resin into the culture medium, continuously culturing for 2 days, and mixing the macroporous resin adsorbed with fermentation metabolites with the fermentation brothSeparating from mycelium, eluting macroporous resin with acetone, distilling and concentrating the eluent to obtain water mixed solution, extracting the water mixed solution with butanone, and concentrating the butanone extraction layer to obtain total extract. The seed culture medium comprises 10g of soluble starch, 4g of yeast extract powder, 2g of bacteriological peptone and 30g of sea salt, and water is added to fix the volume to 1L, and the pH value is 7.0; the fermentation medium consists of 10g of soluble starch and K 2 HPO 4 1g，MgSO 4 ·7H 2 O 1g，(NH 4 ) 2 SO 4 2g，CaCO 3 2g, proper trace elements, water and pH 7.0.
b. Subjecting the total extract to silica gel column chromatography, performing gradient elution by using chloroform/methanol as an eluent from a volume ratio of 100:0-0:100, collecting a fraction Fr.1 eluted by the gradient of 92:8 of chloroform/methanol, eluting by using a Sephadex column Sephadex LH-20 and using chloroform/methanol volume ratio of 1:1 as a mobile phase, concentrating to obtain a fraction Fr.1-1 containing polydecamycin, separating and purifying the fraction Fr.1-1 by using a Sephadex LH-20 column, and eluting by using methanol as the mobile phase to obtain the compound polydecamycin.
Drawings
Fig. 1 is a structural formula of Polydecalinmycin (PDM) in some embodiments;
FIGS. 2-A, 2-B, 2-C, and 2-D show that Polydecalinmycin (PDM) significantly promotes proliferation of human epidermal keratinocytes (HACAT), human embryonic kidney epithelial cells (HEK 293), mouse epidermal fibroblasts (MDF), and human embryonic fibroblasts (MEF), respectively;
FIG. 3-A shows representative pictures of the BALB/C mouse skin lesion healing promoting effect of day Polydecalinmycin (PDM), EGF and rehabilitation new (KFX) from day 0 to day 14. FIG. 3-B shows the quantitative results for wound area of all mice in each group;
FIG. 4-A shows the BSK-Lepr promoting EGF on days 0, 16, 24 and Polydecalinmycin (PDM) em2Cd479 Representative pictures of skin injury healing effect in mice/Gpt. FIG. 4-B shows the quantitative results for wound area of all mice in each group.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples, which do not represent limitations on the scope of the present invention. Some insubstantial modifications and adaptations of the invention based on the inventive concept by others remain within the scope of the invention. Those skilled in the art may make modifications to the compounds that are contemplated, for example, modifications (e.g., derivatives of the compounds) that do not affect the nature and function of the compounds to some extent.
The invention is tested on in vitro cell and mouse animal models, and the test scheme is a conventional method.
Example 1 MTS method evaluation of Polydecalinmycin (PDM) in vitro proliferation-promoting Activity on human epidermal keratinocytes (HACAT), human embryonic kidney epithelial cells (HEK 293), mouse epidermal fibroblasts (MDF) and human embryonic fibroblasts (MEF)
Cells in logarithmic growth were seeded in 96-well plates with 5000 cells per well and cultured for 24 hours, after which complete medium containing different concentrations of Polydecalinmycin (PDM) was added for 72 hours. MTS assay (20. Mu.L/well) was added and incubated for 4 hours. Absorbance (OD value) was measured at 490nm wavelength using a microplate reader. Relative cell proliferation rate (relative cell viability) = (OD Dosing group -OD Blank group )/(OD Control group -OD Blank group )*100％。
TABLE 1 concentration of PDM added to different cells (unit: nM)
As shown in FIG. 2, polydecalinmycin (PDM) significantly promoted proliferation of HACAT, HEK293, MDF, MEF cells, and the optimal dose was approximately in the range of 500-1000nM and was dose dependent.
EXAMPLE 2 repair of BALB/C mouse skin injury model by Polydecalinmycin (PDM)
BALB/C mice (females, 6-8 weeks old, body weight 20-25 g) were anesthetized, shaved on their backs and were dehaired using depilatory cream. The back of the mice was perforated using a 6mm bore biopsy punch, and the wounds were continuously recorded with a digital camera using a 10mm bore silicon wafer as a reference. Mice were randomized into 5 groups, physiological saline (Vehicle), PDM high dose (PDM 250 nM), PDM low dose (PDM 125 nM), human recombinant EGF (Epidermal Growth Factor) (EGF 250 nM) and rehabilitation new stock (KFX) respectively. Once every two days, 7 consecutive doses of 20 μl each were administered, and wounds were recorded using a digital camera each time with a 10mm pore size silicone wafer as reference. After administration, the wound is stuck on the whole back by using a 3M medical transparent patch, so that the shrinkage of the wound skin and the overflow of the medicine are prevented. Wound and silica gel pore areas were measured using Image J and wound relative area and wound area relative values were calculated. Wound relative area = wound area/silica gel aperture area 100%; wound area relative value (relative area of wound) =n day wound relative area/0 day wound relative area 100%.
The results are shown in FIG. 3: polydecalinmycin (PDM) can significantly promote skin wound healing and is dose dependent. EGF showed remarkable effect on days 6-8 of wound healing, KFX could remarkably promote wound healing on days 2-8, and the later-period curative effect was not remarkable. Polydecalinmycin (PDM) has remarkable effect on the 6 th to 14 th days of wound healing, and the curative effect is better than that of EGF and rehabilitation new stock solution with the same concentration.
Example 3 Polydecalinmycin (PDM) vs BSK-Lepr em2Cd479 Repair of skin injury model in mice/Gpt
Obesity diabetes model mice BSK-Lepr em2Cd479 After anesthesia, the backs of the mice were shaved and the mice were cleaned with a depilatory cream, per Gpt (female, 6-8 weeks old, weight 40-55 g). The wounds were recorded on the backs of the mice using a 6mm bore biopsy punch using a digital camera with a 10mm bore silicon wafer as reference. The mice were randomized into 4 groups, physiological saline (Vehicle), PDM high dose (PDM 250 nM), PDM low dose (PDM 125 nM) and EGF (EGF 250 nM), respectively. The administration was once every 4 days, 7 times in succession, 20. Mu.L each time, and the wound was photographed and recorded. After administration, the wound is stuck with a 3M medical transparent patchAnd the back is used for preventing wound skin from shrinking and preventing medicine from overflowing. Wound and silica gel pore areas were measured using Image J and wound relative area and wound area relative values were calculated. Wound relative area = wound area/silica gel aperture area 100%; wound area relative value (relative area of wound) =n day wound relative area/0 day wound relative area 100%.
The results are shown in FIG. 4, and from day 16 onwards, PDM significantly promoted BSK-Lepr em2Cd479 Skin wound healing was dose dependent in mice/Gpt. EGF showed significant effects on days 16-28 of wound healing. The PDM curative effect is better than that of EGF with the same concentration.
Reference to the literature
1.Gonzales K A U,Fuchs E.Skin and Its Regenerative Powers:An Alliance between Stem Cells and Their Niche[J].Developmental Cell,2017,43(4):387-401.
2.Geoffrey C.Gurtner,Sabine Werner,Yann Barrandon,et al.Wound repair and regeneration.Nature,2008,453(7193):314-321.
3.Sun B K,Siprashvili Z,Khavari P A.Advances in skin grafting and treatment of cutaneous wounds[J].Science,2014,346(6212):941-945.
Claims (22)
1. Use of a compound polydecalinmycin, or a pharmaceutically acceptable salt thereof, as sole active ingredient in the manufacture of a medicament for promoting epithelial tissue repair and/or regeneration, including promoting repair and/or regeneration of skin wounds or scars, said compound polydecalinmycin having the structure of formula I:
2. the use according to claim 1, wherein the compound polydecalinmycin is synthetic or obtained from a microbial fermentation culture.
3. The use according to claim 1, wherein the compound polydecalinmycin is obtained from a microbial fermentation culture.
4. The use according to claim 3, wherein the microorganism is selected from the group consisting of StreptomycesStreptomycessp, SCSIO 03032spmOA gene deletion mutant.
5. The use according to claim 3, wherein the microorganism is selected from the mutant SPM257.
6. The use according to claim 1, wherein the compound polydecalinmycin, or a pharmaceutically acceptable salt thereof, is used in a concentration of between 10 and 1000 and nM.
7. The use according to claim 1, wherein the skin wound is selected from wounds.
8. The use according to claim 1, wherein the skin wound is selected from burns and scalds.
9. The use according to claim 1, wherein the skin wound is selected from ulcers.
10. The use according to claim 7, wherein the wound is selected from an excisional wound or a puncture wound.
11. The use of claim 7, wherein the wound is selected from a cut or puncture wound.
12. The use of claim 1, wherein the medicament is formulated for topical administration.
13. The use according to claim 1, wherein the medicament is formulated for oral administration, intravenous injection or intramuscular injection.
14. The use according to claim 1, wherein the medicament is formulated as a spray, lotion, patch, bandage or reservoir.
15. The use according to claim 1, wherein the medicament is formulated as a gel.
16. The use according to claim 1, wherein the medicament is formulated as a paste.
17. The use according to claim 1, wherein the medicament is formulated as a paste.
18. The use according to claim 1, wherein the medicament is formulated as a cream.
19. The use according to claim 1, wherein the medicament is formulated as an aqueous solution.
20. The use of claim 1, wherein the medicament is formulated as a depot.
21. The use according to claim 1, wherein the medicament is formulated as an oil.
22. The use according to claim 3, wherein the method for preparing the compound polydecalinmycin comprises the steps of:
s1, preparationspmOA fermentation culture of the gene deletion mutant SPM 257;
s2, adding macroporous resin into the fermentation culture prepared in the step S1, and continuing fermentation;
s3, filtering the prepared mixture after the fermentation in the step S2 is finished to obtain macroporous resin adsorbed with fermentation metabolites;
s4, eluting the macroporous resin prepared in the step S3, concentrating the eluent to obtain a water mixed solution, and extracting the water mixed solution, wherein an extraction layer is the total extract;
s5, performing silica gel column chromatography on the total extract prepared in the step S4, using chloroform/methanol as an eluent, collecting a fraction Fr.1 eluted by a gradient of 92:8 of chloroform/methanol volume ratio, passing through a column, eluting by using chloroform/methanol volume ratio of 1:1 as a mobile phase, concentrating to obtain a fraction Fr.1-1 containing polydecamycin, separating and purifying the fraction Fr.1-1 by the column, and eluting to obtain the compound polydecamycin.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10120575A (en) * | 1996-08-27 | 1998-05-12 | Sekisui Chem Co Ltd | Therapeutic agent for wound |
| CN107951882A (en) * | 2016-10-17 | 2018-04-24 | 内蒙古京新药业有限公司 | The pharmaceutical use of the isocoumarin class compound obtained is separated from American-cockroach-extract |
| CN111732579A (en) * | 2020-06-04 | 2020-10-02 | 中国科学院南海海洋研究所 | Polyether polyketone compound polydecaminmycin and preparation method and application thereof |
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| WO2015118069A1 (en) * | 2014-02-05 | 2015-08-13 | Reponex Pharmaceuticals Aps | Compositions to promote the healing of skin ulcers and wounds |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10120575A (en) * | 1996-08-27 | 1998-05-12 | Sekisui Chem Co Ltd | Therapeutic agent for wound |
| CN107951882A (en) * | 2016-10-17 | 2018-04-24 | 内蒙古京新药业有限公司 | The pharmaceutical use of the isocoumarin class compound obtained is separated from American-cockroach-extract |
| CN111732579A (en) * | 2020-06-04 | 2020-10-02 | 中国科学院南海海洋研究所 | Polyether polyketone compound polydecaminmycin and preparation method and application thereof |
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