CN115003268A

CN115003268A - Angiogenesis inhibitor

Info

Publication number: CN115003268A
Application number: CN202180011051.2A
Authority: CN
Inventors: 宫泽和之; R·吉莱; B·麦卡锡; 金丸哲也
Original assignee: Shiseido Co Ltd
Current assignee: Shiseido Co Ltd
Priority date: 2020-01-31
Filing date: 2021-01-29
Publication date: 2022-09-02
Also published as: JPWO2021153776A1; WO2021153776A1

Abstract

Novel angiogenesis inhibitors are provided. Provided are an angiogenesis inhibitor containing a wavelength converting substance as an active ingredient, a composition and a product containing the angiogenesis inhibitor, and a method for inhibiting angiogenesis in the skin using the same. According to the present invention, the angiogenesis caused by ultraviolet rays is suppressed, thereby exerting an advantageous effect on the skin.

Description

Angiogenesis inhibitor

Technical Field

The present invention relates to an angiogenesis inhibitor containing a wavelength converting substance, a composition and a product containing the angiogenesis inhibitor, and a method for inhibiting angiogenesis in the skin using the same.

Background

The harmful effects on the skin caused by ultraviolet rays include, for example, skin cancer, photoaging, spots, wrinkles, and inflammation, which are not preferable from the viewpoint of health and beauty. In the case of the skin vascular system, angiogenesis is induced by ultraviolet rays. The skin vascular system has functions of supplying oxygen and nutrients and discharging waste products. However, it has been reported that blood vessels induced by ultraviolet rays cause infiltration of inflammatory cells, production of matrix degrading enzymes, damage of dermal matrix components such as elastin fibers, disturbance of skin repair mechanism, structural change of skin, and the like, and participate in skin aging processes typified by wrinkle formation.

Therefore, a large number of countermeasures have been taken to protect the skin from ultraviolet rays. Examples thereof include the use of a sunscreen agent, indoor activities such as the prevention of sunlight exposure, and the use of a cap, clothing, and ultraviolet-resistant film subjected to UV-resistant processing.

Documents of the prior art

Patent document

Patent document 1: japanese patent No. 6424656

Patent document 2: japanese patent No. 6361416

Patent document 3: international publication No. 2018/004006

Patent document 4: japanese patent laid-open publication No. 2018-131422

Patent document 5: japanese laid-open patent publication No. 5-117127

Patent document 6: japanese patent No. 4048420

Patent document 7: japanese patent No. 4677250

Patent document 8: japanese patent No. 3303942

Patent document 9: japanese patent laid-open publication No. 2017-88719

Patent document 10: international publication No. 2018/117117

Disclosure of Invention

Problems to be solved by the invention

The present invention addresses the problem of providing a novel angiogenesis inhibitor for inhibiting angiogenesis caused by ultraviolet light.

Means for solving the problems

As a result of intensive studies, the present inventors have found that when ultraviolet rays are irradiated to skin cells via a wavelength converting substance that converts the wavelength of ultraviolet rays, the expression of angiogenesis-inducing factors is reduced, and have come to think of an angiogenesis inhibitor containing the wavelength converting substance.

The present application provides the following inventions.

(1) An angiogenesis inhibitor contains a wavelength conversion substance as an active ingredient, and inhibits angiogenesis caused by exposure of the skin to light containing ultraviolet rays,

the wavelength conversion substance converts the wavelength of ultraviolet rays included in incident light to emit light having a wavelength longer than the wavelength of the ultraviolet rays.

(2) The angiogenesis inhibitor according to (1), wherein the ultraviolet ray has a peak wavelength of 200nm to 400 nm.

(3) The angiogenesis inhibitor according to (1) or (2), wherein the emitted light has a peak wavelength of 450 to 700 nm.

(4) The angiogenesis inhibitor according to any one of (1) to (3), wherein the wavelength-converting substance comprises 1 or more phycobiliproteins selected from allophycocyanin, C-phycocyanin, R-phycocyanin, phycoerythrocyanin, B-phycoerythrin, B-phycoerythrin, C-phycoerythrin, and R-phycoerythrin; 1 or more inorganic phosphors selected from the group consisting of a zinc oxide phosphor, a magnesium titanate phosphor, and a calcium phosphate phosphor; 1 or more components selected from the group consisting of vitamin a, beta carotene, vitamin K, vitamin B1, vitamin B2, vitamin B6, vitamin B12, folic acid, niacin, lycopene, gardenia (クチナシ), safflower (ベニバナ), turmeric (ウコン), cochineal carmine (コチニール), perilla (シソ), red cabbage (キャベツ), flavonoids (flavanoid), carotenoids, quinoid, porphyrins, anthocyanins, and polyphenols; and/or 1 or more pigments selected from red No. 401, red No. 227, red No. 504, red No. 218, orange No. 205P, yellow No. 4, yellow No. 5, green No. 201, green No. 204 (Pyranine Conc), blue No. 1, 2, 4-diaminophenoxyethanol hydrochloride, violet No. 201 (alizurin pure SS), violet No. 401, black No. 401, red No. 226 (helone indpink), yellow No. 401, yellow No. 205, blue No. 404, red No. 104, and m-aminophenol.

(5) The angiogenesis inhibitor according to (4), wherein the wavelength converting substance comprises 1 or more phycobiliproteins selected from allophycocyanin, C-phycocyanin, R-phycocyanin, phycoerythrin, B-phycoerythrin, B-phycoerythrin, C-phycoerythrin and R-phycoerythrin; 1 or more inorganic phosphors selected from the group consisting of a zinc oxide phosphor, a magnesium titanate phosphor, and a calcium phosphate phosphor; and/or 1 or more vitamin B selected from vitamin B1, vitamin B2, vitamin B6, and vitamin B12.

(6) A composition comprising the angiogenesis inhibitor according to any one of (1) to (5).

(7) The composition according to (6), which is a composition for external application to the skin, for inhibiting angiogenesis caused by exposure of the skin to light comprising ultraviolet rays.

(8) A cosmetic method for inhibiting angiogenesis caused by exposure of the skin of a subject to light comprising ultraviolet light, comprising: applying the composition of (6) or (7) to the skin of a subject.

(9) A product comprising the angiogenesis inhibitor according to any one of (1) to (5).

(10) The article of (9), which is used for inhibiting angiogenesis caused by exposure of the skin to light comprising ultraviolet rays.

(11) A cosmetic method for inhibiting angiogenesis caused by exposure of the skin of a subject to ultraviolet light, comprising: passing light containing ultraviolet light through the article of (9) or (10).

ADVANTAGEOUS EFFECTS OF INVENTION

The present invention is based on the recognition that it is possible to exhibit an effect on the skin which is advantageous by suppressing the angiogenesis of the skin caused by ultraviolet rays. The present invention also provides a novel use of the above-mentioned compounds, which have been mainly used as pigments, ultraviolet scattering agents, ultraviolet absorbers, nutrients, antioxidants, and the like. Further, the present invention may improve the quality of life by feeling that people who have been kept away from ultraviolet rays for beauty and health reasons as much as possible want to go out actively.

Drawings

FIG. 1 is a schematic diagram of experiment 1.

Fig. 2 shows changes in the expression level of VEGFA in cultured cells when UV irradiation was performed using the wavelength converting substance in experiment 2. The vertical axis represents the average of Δ Ct values.

Fig. 3 shows the change in the expression level of ANGPT1 in cultured cells when UV irradiation was performed using the wavelength converting substance in experiment 3. The vertical axis represents the average of Δ Ct values.

Detailed Description

The angiogenesis inhibitor of the present invention contains a wavelength converting substance as an active ingredient. The wavelength conversion substance is a substance that converts the wavelength of ultraviolet rays included in incident light and emits outgoing light having a wavelength longer than the wavelength of the ultraviolet rays.

The ultraviolet rays may include UVA, UVB, UVC, and the like. In one embodiment, the ultraviolet light has a peak wavelength of 200nm to 400 nm. Further, for example, ultraviolet rays may be included in incident light such as sunlight. Alternatively, the incident light may be ultraviolet light, or artificially generated ultraviolet light may be used. Ultraviolet rays can bring various effects to the skin. For example, it is known that ultraviolet rays cause sunburn such as sunburn and suntan, and damage to DNA on cells. For cells exposed to ultraviolet radiation, the activity of the cells changes, and the expression of the gene changes. For example, the expression of angiogenesis-inducing factors is enhanced and the expression of angiogenesis-inhibiting factors is reduced by ultraviolet irradiation. In addition, ultraviolet light, particularly UV-B, is known to cause angiogenesis. Adverse effects such as facial flushing, rosacea, inflammation, infiltration of inflammatory cells, damage to dermal matrix components such as elastin fibers, disturbance of the skin repair mechanism, structural changes in the skin, and skin aging including wrinkles and sagging, which are caused by angiogenesis induced by ultraviolet rays, have also been reported. It is expected to suppress adverse effects such as prevention and improvement of angiogenesis by ultraviolet rays.

The wavelength of the emitted light emitted by the wavelength converting substance is preferably 450 to 700nm, more preferably 500 to 700nm, as long as the wavelength of the ultraviolet light has a peak wavelength. The emitted light may have 1 or more peaks at 450nm, 460nm, 470nm, 480nm, 490nm, 500nm, 510nm, 520nm, 530nm, 540nm, 550nm, 560nm, 570nm, 580nm, 590nm, 600nm, 610nm, 620nm, 630nm, 640nm, 650nm, 660nm, 670nm, 680nm, 690nm, 700nm, or any range of these values, or may be red light, orange light, green light, blue light, or the like, for example, although not limited thereto. In one embodiment, the wavelength converting substance emits light having a dominant wavelength of 450 to 700nm, more preferably 500 to 700nm, when excited with excitation light of 200 to 400 nm.

Examples of wavelength converting substances include the following: phycobiliproteins such as allophycocyanin, C-phycocyanin, R-phycocyanin, phycoerythrocyanin, B-phycoerythrin, B-phycoerythrin, C-phycoerythrin, R-phycoerythrin, etc.; vitamin A, beta carotene, vitamin K, vitamin B1, vitamin B2, vitamin B6, vitamin B12, folic acid, nicotinic acid, lycopene, gardenia, safflower, turmeric, cochineal, perilla, red cabbage, flavonoid, carotenoid, quinoid, porphyrin, anthocyanin, polyphenol and other natural sources or synthetic components; pigments such as red 401, red 227, red 504, red 218, orange 205P, yellow 4, yellow 5, green 201, green 204, blue 1, 2, 4-diaminophenoxyethanol hydrochloride, violet 201, violet 401, black 401, red 226, yellow 401, yellow 205, blue 404, red 104, and m-aminophenol; phosphors doped with an inorganic compound to provide fluorescence, for example, a blue phosphor containing amorphous silica particles, cerium, and phosphorus and/or magnesium as described in japanese patent No. 6424656, a red phosphor containing a compound obtained by europium-activating a mixed crystal of an alkaline earth metal sulfide and a gallium compound as described in japanese patent No. 6361416, a zinc oxide phosphor as described in international publication No. 2018/004006, and a zinc oxide phosphor as described in japanese patent laid-open No. 2018-131422; an inorganic phosphor described in Japanese patent laid-open No. 5-117127; and the like. In one embodiment, the inorganic phosphor is 1 or more phosphors selected from the group consisting of: may be as ZnO: zn, Zn _1+z 、ZnO _1-x The zinc oxide thus represented is doped with a sulfur-containing compound such as a sulfide salt and/or a sulfate salt of zinc sulfide, zinc sulfate or the like described in International publication No. 2018/004006, and M is added to the doped phosphorgTiO ₃ 、Mg ₂ TiO ₄ A magnesium titanate phosphor obtained by doping such magnesium titanate with manganese, and Ca (H) ₂ PO ₄ ) ₂ 、CaHPO ₄ 、Ca ₃ (PO ₄ ) ₂ Such a calcium phosphate phosphor is obtained by doping calcium phosphate with cerium.

The wavelength converting substance may be obtained by a method such as extraction from natural products such as animals, plants, and algae, or may be obtained by an artificial method such as chemical synthesis. For example, phycobiliproteins can be prepared by extracting algae such as blue algae such as Spirulina (Spirulina platensis) and red algae such as Porphyridium purpureum (Porphyridium purpureum) by the methods described in, for example, japanese patent No. 4048420, japanese patent No. 4677250, and japanese patent No. 3303942. The zinc oxide phosphor can be produced by, for example, the methods described in International publication No. 2018/004006, Japanese patent application laid-open Nos. 2018 and 131422, and Japanese patent application laid-open No. 5-117127. The magnesium titanate phosphor can be produced by the method described in Japanese patent laid-open publication No. 2017-88719. The calcium phosphate phosphor can be produced by the method described in international publication No. 2018/117117.

These wavelength converting substances may be composed of the components exemplified above, may contain the components exemplified above, and may be used alone or in combination of two or more kinds thereof, as long as the wavelength converting effect of the present invention is not impaired. For example, the phycobiliproteins and inorganic phosphors may be mixed with other wavelength conversion substances such as vitamin B (vitamin B1, vitamin B2, vitamin B6, vitamin B12, and the like) to achieve a synergistic effect. However, these components are examples, and any substance that exerts the wavelength conversion effect of the present invention may be used.

The content of the wavelength converting substance in the angiogenesis inhibitor, the composition or the product of the present invention is not particularly limited as long as the wavelength converting effect of the present invention is not impaired, and may be appropriately determined depending on the kind of the wavelength converting substance and the use of the angiogenesis inhibitor or the composition. For example, the amount of the surfactant is arbitrarily selected from the range of 0.01 to 99.99 wt%, 0.1 to 999 wt%, and the like.

When ultraviolet rays are irradiated to the angiogenesis inhibitor of the present invention, light is generated, and the emitted light changes the expression of angiogenesis-related proteins in skin cells. Examples of the change in the expression of the angiogenesis-related protein include inhibition of the expression of an angiogenesis-inducing factor and enhancement of the expression of an angiogenesis-inhibiting factor. Examples of the angiogenesis-inducing factor include VEGF family such as VEGFA, angiogenin family such as ANGPT 1), and the like. Examples of the angiogenesis inhibitor include thrombospondin family such as THBS 1. The angiogenesis inhibitor of the present invention can inhibit angiogenesis caused by ultraviolet rays by absorbing ultraviolet rays and emitting emitted light. The angiogenesis inhibitor of the present invention can be used for any subject, and can be applied to a subject exposed to ultraviolet rays outdoors or the like.

VEGFA is a kind of Vascular Endothelial Growth Factor (VEGF), and acts by binding to VEGFR-1 and VEGFR-2, thereby promoting angiogenesis.

ANGPT1 is a glycoprotein of angiogenin, and is involved in angiogenesis, maturation and stabilization of vascular structures, and the like, and binds to Tie2 expressed in vascular endothelium to promote angiogenesis.

The angiogenesis inhibitory effect can be measured, for example, by measuring the inhibition of expression of an angiogenesis-inducing factor such as VEGFA or ANGPT1, or by measuring the enhancement of expression of an angiogenesis inhibitor such as thrombospondin (THBS 1), as in the examples, or by other methods. For example, when the expression level of the angiogenesis inducing factor is decreased by, for example, a statistically significant difference (for example, Dunnett's test or the like) in which the significant level is set to 5% as compared with the state in which the angiogenesis inducing factor is not inhibited, or when the expression level is decreased by, for example, 5% or more, 10% or more, 20% or more, 30% or more, it can be judged that the angiogenesis is inhibited.

The angiogenesis inhibitor and the composition of the present invention may be applied in any form, but in order to inhibit angiogenesis caused by exposure of the skin to light including ultraviolet rays, skin external preparations such as medicines, quasi-medicines, and cosmetics are sometimes preferable. In the case of using the angiogenesis inhibitor or the composition of the present invention as an external preparation for skin, the formulation, application method, number of applications, and the like can be arbitrarily determined. For example, the skin can be applied to the skin in the form of a lotion, a spray, an oil, a cream, a lotion, a gel, a sunscreen agent, or a tanning agent, periodically or aperiodically, for example, 1 to several times in the morning, daytime, evening, or the like, or every time before the skin is expected to be exposed to sunlight, such as during an outdoor trip, a field activity, ocean sports, skiing, or the like.

The angiogenesis inhibitor and the composition of the present invention may be used in combination with additives such as an excipient, a preservative, a thickener, a binder, a disintegrating agent, a dispersant, a stabilizer, a gelling agent, an antioxidant, a surfactant, a preservative, an oil component, a powder, water, an alcohol, a thickener, a chelating agent, a silicone, an antioxidant, a humectant, a perfume, various pharmaceutically effective components, a preservative, a pH adjuster, and a neutralizer, which are optionally selected as needed. Further, in order to enhance the effect of the present invention, other angiogenesis inhibitors and the like may be used in combination.

In addition, the present invention also provides an article such as a sun visor, a hat, clothing, gloves, a screen film, a window spray, a window cream, a window material, a wall material, which comprises the angiogenesis inhibitor of the present invention, for inhibiting angiogenesis caused by exposure of the skin to light including ultraviolet rays. As described above, the use of additives and the like in the product of the present invention, the form of the product, and the like are arbitrary.

In addition, the present invention also provides a method for producing the angiogenesis inhibitor, the composition or the product of the present invention. Also, a method for suppressing angiogenesis caused by exposure of the skin of a subject to light containing ultraviolet rays is provided, wherein the method comprises applying the angiogenesis inhibitor or the composition of the present invention to the skin of the subject, or passing light containing ultraviolet rays through the product of the present invention, and the angiogenesis inhibitor, the composition, and the product convert the wavelength of ultraviolet rays contained in incident light to emit outgoing light having a wavelength longer than the wavelength of the ultraviolet rays, and preferably pass ultraviolet rays having a peak wavelength of 200nm to 400nm to light having a peak wavelength of preferably 450nm to 700nm, and more preferably 500nm to 700 nm. Methods for inhibiting angiogenesis caused by exposure of the skin of a subject to light including ultraviolet rays are sometimes aimed at cosmetology, rather than therapeutic methods used by doctors, medical practitioners. The present invention also provides a cosmetic counseling method for supporting cosmetic behavior of a subject, comprising presenting the cosmetic method, angiogenesis inhibitor, composition or product of the present invention to the subject.

Examples

The present invention will be described in further detail by examples. The present invention is not limited to this.

Experiment 1: changes in gene expression brought about by the use of various wavelength converting substances

Experiment 1-1: modulation of wavelength converting substances

As the wavelength converting substance, a 5% dispersion was prepared by using a zinc oxide phosphor and dispersing it in an alcohol. As the zinc oxide phosphor, Lumate G made by sakai chemical industry co. Lumate G is a zinc oxide phosphor obtained by doping ZnO with a sulfur-containing compound as described in International publication No. 2018/004006, and has an absorption spectrum having a peak wavelength at 365nm and an emission spectrum having a peak wavelength at 510 nm.

Experiments 1-2: preparation of cell sample

A cell sample was prepared as follows.

1. As Human skin Keratinocytes, Normal Human Epidermal Keratinocytes manufactured by Promocell corporation were used. The cell suspension (1mL) preserved with liquid nitrogen was thawed by a hot water bath (37 ℃) to the extent that small ice particles remained, and then diluted with 9mL of warm KGM medium.

2. The dilutions were gently mixed and transferred to a T75 flask and incubated overnight at 37 ℃.

3. The following day, the medium was changed to 10mL of fresh medium.

4. The medium was periodically (2 to 3 days and 1 time) replaced to continue cell proliferation. Meanwhile, the cells were observed under a microscope, and it was confirmed that the cells grew in an accurate form.

5. After the cells reached about 80% confluence (confluent), the cells were passaged.

6. The passage of the cells was performed by washing the cells 1 time with 10mL of warm PBS and then aspirating.

7. 5mL of warm trypsin was added to a T75 flask, and the bottom of the flask was covered with a trypsin solution and left at room temperature for 1 minute, followed by aspiration.

8. For keratinocytes, the flasks were left to stand in an oven at 37 ℃ (max) for 5 minutes. When the cells were observed with a microscope, it was confirmed that the cells were small and oval.

9. The side of the T75 flask was then gently tapped to free the cells. The cells were observed with a microscope, and it was confirmed that the cells were freely moved.

10. For keratinocytes, resuspended in 5mL of warm trypsin neutralizing solution and transferred to a sterilized 50mL Falcon tube. The flask was further rinsed with 5mL of warm FGM and added to a Falcon tube to positively move the whole cell.

11. The cells were centrifuged at 10,000rpm for 5 minutes (4 ℃), and the supernatant was removed while paying attention to the cell particles.

12. The keratinocyte has a size of 4 × 10 ⁴ The cells/well (500. mu.L) were resuspended in KGM and plated onto 4-well slides of collagen envelope glass bottom.

13. The medium was changed every 2 to 3 days to proliferate the cells until 60 to 70% confluence (depending on the type of experiment) was reached.

14. Medium was changed to medium without supplements 24 hours prior to irradiation.

Experiments 1-3: irradiation of ultraviolet rays

1. The lamp was warmed up by switching on the power supply of the solar simulator at least 30 minutes before irradiation. The solar simulator is set using UG11 filters. The UG11 filter is a filter that passes only UVB while cutting off other wavelengths of light. The UV light passing through the UG11 filter has a peak wavelength of 300-385 nm.

2. The temperature control plate was turned on and set to 33 ℃.

3. Cells prepared in experiment 1-2 were washed 1 time with warm PBS.

4. 0.5mL of warmed Martinez solution (145mM NaCl, 5.5mM KCl, 1.2mM MgCl) was added to each well ₂ .6H ₂ O，1.2mM NaH ₂ PO ₄ .2H ₂ O，7.5mM HEPES，1mM CaCl ₂ 10mM D-glucose).

5. As shown in fig. 1, the cell wells were placed on the plate, 0.4ml of the solution containing the wavelength converting substance prepared in experiment 1-1 was injected into each well of the 24-well plate, and was placed so as to cover the wells to which the cells were added, and the solution of the wavelength converting substance was irradiated with UV light through the solution of the wavelength converting substance without being in direct contact with the cell solution.

6. To total 100mJ/cm ² The irradiation is performed in a dose manner. As a control, a sample in which cells were directly irradiated with UV light without placing a wavelength conversion substance on a plate having a cell well and a sample in which cells were cultured in a dark place without irradiating UV light were prepared.

7. After irradiation, the Martinez solution was replaced with warmed KGM (without supplements), and the plates were returned to the 37 ℃ incubator and incubated for 24 hours.

Experiment 2: RT-PCR of VEGFA

Experiment 2-1: RNA extraction

1. RNA was extracted from the cell samples incubated for 24 hours after UV irradiation in experiments 1 to 3 using RNeasy kit (Qiagen) according to the preparation instructions.

2. Concentrations and A260/280 values were recorded for each sample.

Experiment 2-2: reverse transcription

The SuperScript VILO cDNA synthesis kit was used according to the product instructions, 1pg to 2.5. mu.g of RNA was added to 1 container, and the PCR system was operated at the setting of 25 ℃ for 10 minutes, 42 ℃ for 60 minutes, 85 ℃ for 5 minutes, and 4 ℃ for storage.

Experiment 2-3: RT-PCR

The reverse-transcribed sample was diluted 50-fold with RNase-free water and further 5-fold diluted 5-fold to prepare the following reaction system, and the reaction system was measured by a real-time PCR apparatus (Applied Biosystems) (FIG. 2).

[ Table 1]

Reaction system	μ l/well
		Unamplified diluted cDNA	5
Platinum Sybr green qPCR Super Mix-UDG	12.5
		Primer mixture (F/R) (5. mu.M)	1
ROX reference dyes	0.5
		RNase-free water	6
Total up to	25

[ Table 2]

Name of the lead	Sequence of	Serial number
			VEGFA forward direction	GCAGCTTGAGTTAAACGAACG	1
VEGFA reversal	GGTTCCCGAAACCCTGAG	2

Experiment 3: RT-PCR of ANGPT1

The cell samples incubated for 24 hours after the UV irradiation in experiments 1 to 3 were measured using TaqMan (registered trademark) Gene expression Assay (FAM) (product No. 4331182, Assay ID Hs00919202_ m1, https:// www.thermofisher.com/TaqMan-gene-expression/product/Hs00919202_ m1CID & ICID & subtype) by Thermo Fisher Scientific. Specifically, RNA was extracted using an Ambion (registered trademark) RNA isolation kit (Applied Biosystems) according to the protocol of the product described above, reverse transcription was performed using a high-capacity RNA-to-cDNA kit (product No. 4387406) or a high-capacity cDNA reverse transcription kit (product No. 4368813, 4374966) available from Applied Biosystems, the following reaction system was prepared using the reverse-transcribed sample, and the measurement was performed using a real-time PCR apparatus (Applied Biosystems) (FIG. 3).

[ Table 3]

From these results, it was found that the wavelength converting substance exerts an effect of suppressing angiogenesis caused by UV irradiation. Prevention/improvement of facial flushing, rosacea, inflammation, wrinkles, sagging, skin aging, and the like is expected if angiogenesis is inhibited in skin cells.

The embodiments of the present invention have been described above. However, the present invention is not limited to these examples, and the cosmetic, pharmaceutical composition, and the like can be modified as appropriate without departing from the spirit of the invention.

Sequence listing

Kyoho 110 Kyoho Seisakusho

<120> angiogenesis inhibitor

<130> P200730WO

<140> JP 2020-015610

<150> 2020-01-31

<160> 2

<170> PatentIn version 3.5

<210> 1

<211> 21

<212> DNA

<213> Artificial sequence

<220> forward direction of VEGFA

<223> primer

<400> 1

gcagcttgag ttaaacgaac g 21

<210> 2

<211> 18

<212> DNA

<213> Artificial sequence

<220> VEGFA reversal

<223> primer

<400> 2

ggttcccgaa accctgag 18

Claims

1. An angiogenesis inhibitor contains a wavelength conversion substance as an active ingredient, and inhibits angiogenesis caused by exposure of the skin to light containing ultraviolet rays,

the wavelength conversion substance converts the wavelength of ultraviolet rays included in incident light and emits emission light having a wavelength longer than the wavelength of the ultraviolet rays.

2. The angiogenesis inhibitor according to claim 1, wherein the ultraviolet ray has a peak wavelength of 200nm to 400 nm.

3. The angiogenesis inhibitor according to claim 1 or 2, wherein the emitted light has a peak wavelength of 450 to 700 nm.

4. The angiogenesis inhibitor according to any one of claims 1 to 3, wherein the wavelength converting substance comprises 1 or more phycobiliproteins selected from allophycocyanin, C-phycocyanin, R-phycocyanin, phycoerythrocyanin, B-phycoerythrin, B-phycoerythrin, C-phycoerythrin, and R-phycoerythrin; 1 or more inorganic phosphors selected from the group consisting of a zinc oxide phosphor, a magnesium titanate phosphor, and a calcium phosphate phosphor; 1 or more components selected from vitamin a, beta carotene, vitamin K, vitamin B1, vitamin B2, vitamin B6, vitamin B12, folic acid, nicotinic acid, lycopene, gardenia, safflower, turmeric, cochineal, perilla, red cabbage, flavonoids, carotenoids, quinoid compounds, porphyrins, anthocyanins, and polyphenols; and/or 1 or more pigments selected from red No. 401, red No. 227, red No. 504, red No. 218, orange No. 205P, yellow No. 4, yellow No. 5, green No. 201, green No. 204, blue No. 1, 2, 4-diaminophenoxyethanol hydrochloride, violet No. 201, violet No. 401, black No. 401, red No. 226, yellow No. 401, yellow No. 205, blue No. 404, red No. 104, and m-aminophenol.

5. The angiogenesis inhibitor according to claim 4, wherein the wavelength converting substance comprises 1 or more phycobiliproteins selected from the group consisting of allophycocyanin, C-phycocyanin, R-phycocyanin, phycoerythrocyanin, B-phycoerythrin, B-phycoerythrin, C-phycoerythrin, and R-phycoerythrin; 1 or more inorganic phosphors selected from the group consisting of a zinc oxide phosphor, a magnesium titanate phosphor, and a calcium phosphate phosphor; and/or 1 or more vitamin B selected from vitamin B1, vitamin B2, vitamin B6, and vitamin B12.

6. A composition comprising the angiogenesis inhibitor according to any one of claims 1 to 5.

7. The composition according to claim 6, which is a skin external composition for inhibiting angiogenesis caused by exposure of the skin to light comprising ultraviolet rays.

8. A cosmetic method for inhibiting angiogenesis caused by exposure of the skin of a subject to light comprising ultraviolet light, comprising: applying the composition of claim 6 or 7 to the skin of a subject.

9. An article of manufacture comprising the angiogenesis inhibitor of any one of claims 1-5.

10. The article of claim 9, for inhibiting angiogenesis caused by exposure of skin to light comprising ultraviolet light.

11. A cosmetic method for inhibiting angiogenesis caused by exposure of the skin of a subject to ultraviolet light, comprising: passing light comprising ultraviolet light through the article of claim 9 or 10.