WO2009123211A1 - 血管の成熟化、正常化又は安定化剤及びしわ防止・改善剤 - Google Patents
血管の成熟化、正常化又は安定化剤及びしわ防止・改善剤 Download PDFInfo
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Definitions
- the present invention relates to maturation, normalization or stabilization of blood vessels and Tie2 (Tyrosine Kinase with Ig and EGF Homology Domain 2) comprising an extract derived from a plant of the genus Cinnamomum, in particular, Cinnamomum cassia Blume An activator (Tie2 phosphorylating agent) and a wrinkle prevention / improving agent are provided.
- vascular smooth muscle cells and pericytes collectively called vascular wall cells are adhered to vascular endothelial cells via the extracellular matrix or directly from the outer cavity surface of vascular endothelial cells.
- the ratio of adhesion between endothelial cells and wall cells differs depending on the size of the blood vessel diameter.
- one layer of endothelial cells is lined with multiple layers of wall cells.
- one wall cell is lined with one cell, and in a blood vessel having a smaller diameter, one wall cell adheres to a plurality of endothelial cells.
- the lining of wall cells against vascular endothelial cells is important for the structural “maturation” process of blood vessels.
- adhesion between vascular endothelial cells can form adhesion spots between endothelial cells so that intravascular environmental factors (cells and humoral factors) do not easily leak out of the blood vessel. It is important for the “maturation” process. Furthermore, depending on the demand for oxygen and nutrients in the tissue, especially when they are deficient, the blood vessels increase blood flow by expanding the lumen so that oxygen and nutrients can be adequately distributed to the tissue. Adjust. In other words, the process of controlling the permeability by controlling adhesion by forming adhesion spots between vascular endothelial cells, structurally stabilizing vascular endothelial cells with wall cell lining, and controlling the vascular cavity to large, medium and small , Defined as “blood vessel maturation”.
- blood vessels with disordered blood vessel structures are constructed, and immature blood vessels in which adhesion between endothelial cells is suppressed or adhesion of wall cells to endothelial cells is formed.
- These cause disordered increase in vascular permeability, thereby causing abnormal humoral factors and cellular traffic in the tissues and blood vessels.
- Increased permeability causes tissue edema, causes tissue dysfunction, and causes inflamed inflammatory cell infiltration, resulting in inflammation.
- mural cells suppress sprouting of blood vessels from existing blood vessels, sprouting of blood vessels becomes excessive from blood vessels not accompanied by mural cells, and disordered sprouting of blood vessels is induced, resulting in worsening of the disease state.
- Such a phenomenon is observed in pathological conditions represented by diabetic retinopathy, tumor, and inflammation.
- blood vessels that have broken vascular permeability and abnormal blood vessels that cause disordered growth of blood vessels are promoted by lining the endothelial cells to the endothelial cells by increasing adhesion between the endothelial cells, thereby making the blood vessels normal.
- the state is defined as “normalization of blood vessels”.
- abnormal blood vessels such as those described above may cause changes in the internal and external blood flow factors, such as diabetes, hyperlipidemia, and hypertension, which may cause damage (cell death, etc.) to endothelial cells and mural cells, as well as cancer and inflammation. This triggers an excessive increase in the production of angiogenesis-promoting factors.
- blood vessel stabilization to suppress damage to existing blood vessels, suppress dissociation of endothelial cells, or suppress dissociation of endothelial cells and wall cells.
- This stabilization also includes a mechanism for suppressing cell death of endothelial cells.
- Angiogenesis is a phenomenon in which a new blood vessel network is formed from existing blood vessels, and is deeply related to diseases mainly consisting of vascular lesions such as tumors, rheumatoid arthritis, diabetic retinopathy, hyperlipidemia, and hypertension.
- VEGF vascular endothelial growth factor
- VEGF family and angiopoietin (Angiopoietin; Ang) family molecules have been identified one after another as factors that act specifically on angiogenesis. It was. VEGF and its receptors are involved in a very wide range of angiogenesis, from the initial development of blood vessels called angiogenesis to subsequent angiogenesis.
- Ang functions in luminal formation accompanied by cellular phenomena such as germination, branching, insertion, and retraction by vascular endothelial cells after angiogenesis.
- Ang is a receptor-type tyrosine kinase Tie (tyrosine kinase with Ig and EGF homology domain) -2 expressed in vascular endothelial cells, and vascular endothelial cells and blood vessel walls such as pericytes (pericytes) and vascular smooth muscle cells It controls adhesion to cells and functions to stabilize the structure of blood vessels (Experimental Medicine Vol. 20, No. 8 (2002) pp. 52-57: Non-Patent Document 1).
- Ang-1 and Ang-2 are present in both humans and mice, but Ang-3 is present in mice and Ang-4 is present in humans.
- Ang-1, -4 secreted from mural cells stimulates Tie-2 and induces autophosphorylation of intracellular tyrosine kinase domain, integrin activation, focal adhesion kinase (focal adhesion kinase; FAK) activation
- FAK focal adhesion kinase
- FAK focal adhesion kinase
- PI3K / Akt phosphatidylinositol-3-kinase
- PI3K serine-threonine kinase: Akt
- endothelial cells maintain their adhesion between endothelial cells and mural cells by Ang-1, -4, which is constantly secreted by mural cells, but when hypoxia occurs locally, Ang-1 , -4 antagonist Ang-2, -3 production is increased, Tie2 activation is temporarily suppressed, and adhesion between endothelial cells and wall cells lining it is suppressed. Endothelial cells proliferate by the dissociation of mural cells and initiate sprouting angiogenesis, leading to the formation of new vascular networks. Tie2 activation induces adhesion between endothelial cells and mural cells, thereby contributing to the stabilization of the vascular structure, and promotes adhesion between endothelial cells to control vascular permeability.
- Tie2 activation is also known to suppress endothelial cell death (Cho CH, Kammerer RA, Lee HJ, Yasunaga K, Kim KT, Choi HH, Kim W, Kim SH, Park SK, Lee GM, Koh GY.
- Designedioangiopoietin-1 variant, -COMP-Ang1 protects against radiation-induced endothelial cell apoptosis. Proc Natl Acad Sci U S A. 2004 Apr; 13; 101 (15): 5553-8.
- Patent Document 2 for environmental factors that break down various intracellular and external vascular structures, induces activation of Tie2 and suppresses instability of blood vessels to stabilize and normalize blood vessels Is possible.
- Tie2 activation has been reported to enlarge the vascular cavity, and in ischemic diseases caused by vascular narrowing or suppression of vasodilation The activation of Tie2 can enlarge the vascular space and improve the pathological condition.
- Angptl Angiopoietin-like protein
- hematopoietic stem cells By inducing cell adhesion, hematopoietic stem cells can be induced to maintain anchorage-dependent survival in vivo and externally by activation of Tie2. Furthermore, recent reports have suggested that Tie2 is expressed in cancer stem cells that are considered to be the most malignant in cancer tissues and are involved in cancer recurrence (Lee OH, Xu J, Fueyo J, Fuller GN, Aldape KD, Alonso MM, Piao Y, Liu TJ, Lang FF, Bekele BN, Gomez-Manzano C. Expression of the receptor tyrosine in 1 in 1 in -dependent adhesion the extracellular matrix.trixMol Cancer Res.
- Non-patent document 6 Just as activation of Tie2 can put the cell cycle of hematopoietic stem cells into a dormant state, activation of Tie2 expressed in cancer stem cells can also suppress the growth of cancer stem cells. .
- An object of the present invention is to provide a novel blood vessel maturation, normalization, stabilizer, and Tie2 activation (phosphorylation) agent.
- the inventor has examined in detail the behavior in the skin tissue irradiated with ultraviolet B. Irradiation with ultraviolet B significantly caused thickening of the epidermis and formation of cutaneous blood vessels, causing wrinkle formation. It was found that the expression of Ang-1 was significantly decreased in the skin tissue subjected to such photoaging, and the expression of Ang-2 was increased relative to Ang-1. Furthermore, from the skin tissue section, it was observed that wall cells were detached from vascular endothelial cells by ultraviolet irradiation. From these findings, it was suggested that irradiation of endothelial cells and mural cells was suppressed by ultraviolet irradiation, and Tie2 phosphorylation was suppressed, that is, Tie2 activation was suppressed.
- Tie2 was active in extracts derived from plants belonging to the genus Cinnamomum. It has been found that there is an action to become. In addition, as a result of applying a cinnamon extract to mouse skin that had been photoaged by irradiation with ultraviolet rays B, the improvement effect was specifically shown by applying the extract. Therefore, it can be seen that the extract improves and promotes the adhesion between endothelial cells and mural cells by Tie2 phosphorylation, forms a stable vascular structure, and thus recovers UVB-induced skin damage and wrinkle formation. The present invention has been completed.
- this application includes the following inventions: (1) A vascular maturation, normalization or stabilization agent comprising an extract derived from a genus Nikkei. (2) The vascular maturation, normalization, or stabilization agent according to (1), wherein the extract is derived from a siliceous plant. (3) The blood vessel maturation, normalization or stabilization agent according to (2), wherein the extract is derived from Keishi or Keihi. (4) The blood vessel maturation, normalization or stabilization agent according to any one of (1) to (3), wherein the extract is a water extract. (5) A Tie2 activating (phosphorylating) agent comprising an extract derived from a genus Nikkei.
- the result of Tie2 phosphorylation by Keishi extract and Ang1 in Baf3 cells is shown.
- the result of Tie2 phosphorylation by a cinnamon extract and a cinnamon extract is shown.
- the result of Tie2 phosphorylation by Keishi extract and Ang1 in HUVEC cells is shown.
- a stained image of tube formation is shown.
- the angiogenesis inhibitory effect of the cinnamon extract using the length of the lumen formation as an index is shown.
- the angiogenesis inhibitory effect of the cinnamon extract using the area of lumen formation as an index is shown.
- Nikkei is a plant of the order Lauraceae and Lauraceae, and there are more than 300 species, such as Cinnamomumomcassia Blume, C. camphora, C. daphnoides (C. doederleinii), C. japonicum, Ogasawara bay unic (C. pseudo-pedunculatum), Nikkei (C. sieboldii), Shibaya buns kei Ceylon nicki (C. verum), Cinnamon (C. zeylanicum).
- Cinnamomumomcassia Blume C. camphora, C. daphnoides (C. doederleinii), C. japonicum, Ogasawara bay unic (C. pseudo-pedunculatum), Nikkei (C. sieboldii), Shibaya buns kei Ceylon nicki (C. verum), Cinnamon (C. zeylanicum).
- Tie2 activator (phosphorylating agent) or angiogenesis inhibitor in the present invention preferably Kei (Cinnamomum cassia Blume), in particular Keishi, a young branch of Kei
- an extract derived from Keihi is used.
- an extract derived from keihi which is a bark of kei
- a hair restorer Japanese Patent Laid-Open No. 10-265350
- the above-mentioned extract can be obtained by a conventional method, for example, it can be obtained by soaking or heating and refluxing the plant that is the origin together with the extraction solvent at room temperature or heating, followed by filtration and concentration.
- the extraction solvent can be arbitrarily used as long as it is a solvent that is usually used for extraction.
- an aqueous solvent such as water, physiological saline, phosphate buffer, borate buffer, or an organic solvent such as ethanol, Alcohols such as propylene glycol, 1,3-butylene glycol and glycerin, hydrous alcohols, chloroform, dichloroethane, carbon tetrachloride, acetone, ethyl acetate, hexane and the like can be used alone or in combination.
- water is used as the solvent.
- the extract obtained by extraction with the above solvent can be used as it is or, for example, an extract concentrated by lyophilization or the like, and if necessary, an adsorbent method, for example, an ion exchange resin removed impurities, A polymer (eg, Amberlite XAD-2) adsorbed on a column, eluted with a desired solvent, and further concentrated can be used.
- an adsorbent method for example, an ion exchange resin removed impurities,
- a polymer eg, Amberlite XAD-2
- Activation of Tie2 refers to the ability to convert Tie2 into its active form (phosphorylated Tie2) by phosphorylating it.
- an activator of Tie2 angiopoietin 1 and the like are known to activate Tie2.
- the vascular maturation, normalization or stabilization agent and Tie2 activation (phosphorylation) agent of the present invention is used as a pharmaceutical or cosmetic effective in preventing or improving various diseases and aging caused by changes in the structure of blood vessels. it can.
- the Tie2 phosphorylating agent of the present invention induces normalization and stabilization of blood vessels, thereby causing various inflammatory diseases, immune diseases, adult diseases, etc., for example, various infectious diseases, cancer, rheumatoid arthritis, gout, In high blood pressure, diabetes, arteriosclerosis, atopic dermatitis, etc., it can be used as a medicine for improving the lesion site of the whole body accompanied with neovascularization or vascular breakdown.
- vascular permeability, edema in organs, organs and various tissues including the skin such as inflammatory and immune diseases, vascular edema due to adult diseases, UV exposure, insect bites, allergies, etc.
- Tie2 phosphorylating agent is a cell death of endothelial cells induced by various factors, for example, inflammatory diseases, immune diseases, adult diseases, such as various infectious diseases, cancer, rheumatoid arthritis, gout, hypertension, It can be used as a pharmaceutical or a cosmetic that can suppress the destabilization of blood vessels by suppressing the death of endothelial cells due to diabetes, arteriosclerosis, radiation damage, various drugs or ultraviolet rays.
- Tie2 phosphorylating agent promotes wound healing such as trauma and pruritus by vascular maturation and enlargement of vascular cavity, maturation of blood vessels in revascularization medicine, ischemic disease such as cerebral infarction and myocardial infarction
- ischemic disease such as cerebral infarction and myocardial infarction
- it can be used as a medicine for internal use and external use for low back pain, frostbite, alopecia, etc. by utilizing the effect of improving blood flow.
- application to dementia is also possible.
- It can also be used as a cosmetic for alopecia.
- cancer it can be used as a therapeutic agent for inducing dormancy of cancer cells, and in stem cells as a maintenance agent in vivo and in vivo.
- UVB ultraviolet rays
- UVB intermediate UV
- the amount of UVB exposure necessary to cause photoaging is currently unknown.
- repeated exposure to UVB at levels that cause erythema and sunburn usually leads to photoaging.
- photoaging is rough skin, wrinkle formation, spot coloring, soil coloration, sagging formation, onset of telangiectasia, development of mole, onset of purpura, vulnerable, atrophy, fibrosis It can be specified as the occurrence of a pigment removal region, the development of a pre-malignant tumor, a malignant tumor, and the like.
- Photoaging usually occurs in skin that is habitually exposed to sunlight, such as the face, ears, head, neck, and hands.
- photoaging due to skin damage or exposure to ultraviolet rays is the main cause, but this Tie2 phosphorylating agent can be used to improve photoaging by suppressing vascular damage that causes photoaging.
- the dose, usage, and dosage form of the vascular maturation, normalization or stabilization agent or Tie2 phosphorylating agent of the present invention can be appropriately determined according to the purpose of use.
- the administration form of the angiogenesis inhibitor or Tie2 phosphorylating agent of the present invention may be oral, parenteral, external use and the like.
- the dosage form include oral preparations such as tablets, powders, capsules, granules, extracts, and syrups, or parenteral preparations such as injections, drops, and suppositories, ointments, creams, emulsions, and lotions. And external preparations such as packs and bath preparations.
- the amount of the extract derived from the Nikkei plant that inhibits angiogenesis of the vascular maturation, normalization or stabilization agent or Tie2 activating (phosphorylation) agent of the present invention can be appropriately determined according to the use.
- the total amount of the inhibitor is 0.0001 to 20.0% by mass, preferably 0.0001 to 10.0% by mass as a dry product.
- the vascular maturation, normalization or stabilization agent or Tie2 activation (phosphorylation) agent of the present invention includes, in addition to the above-mentioned Nikkei plant-derived extract, for example, an excipient used for ordinary foods and pharmaceuticals.
- UV absorbers, surfactants, thickeners, alcohols, powder components, colorants, aqueous components, water, various skin nutrients, and the like can be appropriately blended as necessary.
- auxiliary agents commonly used for the skin external preparation such as disodium edetate, edet Metal sequestering agents such as trisodium acid, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, caffeine, tannin, verapamil, tranexamic acid and its derivatives, licorice extract, grabrizine, karin fruit hot water extraction Products, various herbal medicines, drugs such as tocopherol acetate, glycyrrhizic acid and its derivatives or salts thereof, whitening agents such as vitamin C, magnesium ascorbate phosphate, glucoside ascorbate, arbutin, kojic acid, glucose, fructose, mannose, sucrose , Sugars such as trehalose, retinoic acid, retino Vitamin A such as quinol, retinol
- a compounding quantity is the mass%.
- Keishi hot water extract Preparation of dry residue of hot water extract from Keishi 2L of water was added to 400.7g of Keishi ( branch part of Cinnamomum cassia Blume ), followed by heat extraction for 3 hours and filtration. 2 L of water was added to the obtained residue, the same operation was repeated, and the heat extraction was further performed twice. The obtained filtrate was freeze-dried to obtain 39.7 g of a hot water extraction dry residue. This sample was used as Keishi hot water extract.
- Keishi Extract HP-20 Column Treatment Charge 10 g of the hot water extract obtained above to a Diaion HP-20 (Mitsubishi Chemical) column and elute it with a water-containing ethanol system, and use the 50% ethanol elution fraction as the target elution fraction. Obtained.
- Keihi bark part of Cinnamomum cassia Blume
- heat extraction is performed for 3 hours, and 200 ml of water is added to the residue obtained by filtration.
- the operation was repeated, and heat extraction was further performed twice.
- the obtained filtrate was freeze-dried to obtain 1.35 g of a hot water extract dry residue. This sample was used as a Keihi hot water extract.
- FIG. 1 shows the evaluation results of Tie2 phosphorylation of the Keishi hot water extract.
- Keishi extract like Ang-1, was found to cause Tie2 phosphorylation. Therefore, it was suggested that Keishi hot water extract exhibits Tie2 phosphorylation effect and contributes to vascular maturation, normalization, and stabilization, and as a result, angiogenesis can be suppressed.
- FIG. 2 shows the evaluation results of Tie2 phosphorylation of both the cinnamon hot water extract and the cinnamon hot water extract. Like the cinnamon hot water extract, the cinnamon hot water extract was found to result in phosphorylation of Tie2.
- Wrinkle prevention / improvement effect test Photo-aging wrinkle improvement test Hr-1 (Skh-1) hairless mice (Hoshino experimental animals; 6-10 weeks old) and using the method of Schwartz et al. (Haratake A. et al., J. Invest. Dermatol., 108, 769-775, 1997), a method of repeated irradiation with UVB (Naganuma M. et al., J. Dermatol. Sci., 25, 29-35, 2001, Schwartz E., J. Invest ., Dermatol., 91, 158-161, 1988).
- UVB light source; Toshiba FL-20SE fluorescent lamp manufactured by Toshiba Electric
- the total irradiation dose was 4.6 J / cm 2 .
- the amount of ultraviolet rays used was a value measured with UVRADIOMETER (UVR-305 / 365D (II), manufactured by Topcon Corporation). After the UV irradiation was completed, a photo of the back was taken, and the degree of wrinkle formation was changed to the method described below (Bissett DL.
- Example 1 mixed with cinnamon extract and dried hot water extract residue
- Example 2 Cosmetic extract HP-20 column 50% ethanol
- Example 1 The composition of Example 1; (Component) Blending amount (% by mass) Keishi Extract 1.0 Ethanol for cosmetics 30.0 Purified water residue
- Example 2 The composition of Example 2; (Component) Blending amount (% by mass) Keishi Extract HP-20 column 50% ethanol elution fraction 1.0 Ethanol for cosmetics 30.0 Purified water residue
- the hairless mice with a score of 7 or more were divided into 2 groups of 5 each, and the scores of both groups were the same, and the formulations of Example 1 and Example 2 showing the above-described composition on the entire back skin of each group were prepared.
- Each 100 ⁇ l was applied once a day, 5 times a week for 6 weeks. After the application, a photograph of the back was taken, and according to the criteria shown above, three measurers scored the degree of wrinkles individually with the group name of the animal lying down, and the score was determined by discussion.
- the same test was done in the comparative example 1 which extracted the cinnamon extract from the composition of Example 1.
- Comparative Example 1 The composition of Comparative Example 1; (Component) Blending amount (% by mass) Ethanol for cosmetics 30.0 Purified water residue
- the following table shows the degree of wrinkle improvement (wrinkle improvement change amount) obtained according to the above formula as an average value for each group.
- Example 2 the wrinkle reduction was promoted in the control group (containing no drug) applied group in Example 1 (mixed with Kishi extract) application group of the present invention. Similarly, in Example 2, the reduction of wrinkles was promoted predominantly. From the above, it was confirmed that the cinnamon extract solution and the cinnamon extract HP-20 column 50% ethanol elution fraction were effective in improving wrinkles.
- angiogenesis inhibitory effect A test was conducted to confirm the angiogenesis inhibitory effect of Keihi hot water extract.
- an angiogenesis kit manufactured by Kurashiki Boseki
- human normal umbilical vein endothelial cells and human normal dermal fibroblasts were co-cultured at a certain ratio to prepare a proliferative state at the initial stage of tube formation.
- 10 ng / ml vascular endothelial growth factor-A VEGF-A: Kurashiki Boseki
- VEGF-A vascular endothelial growth factor-A
- the medium was replaced with a medium containing a predetermined concentration of cinnamon extract in the presence of VEGF-A. Thereafter, the cell layer of each well was fixed with 70% ethanol and stained with CD31 (PECAM-1). Stained images obtained from each well were photographed (FIG. 4), image formation was performed based on the length and area index of lumen formation, and the angiogenesis inhibitory action was evaluated (FIGS. 5 and 6).
- Angiogenesis quantification software manufactured by Kurashiki Boseki Co., Ltd. was used for image analysis of the length of lumen formation and image analysis of the area. The longer the length of lumen formation and the larger the area of lumen formation, the more angiogenesis was observed.
- a group containing only medium was used as a control
- a group containing only VEGF-A (10 ng / ml) was used as a negative control
- suramin (50 ⁇ M) known as an angiogenesis inhibitor was used as a positive control
- Ang-1 which is known to have an effect of stabilizing blood vessels, was also evaluated for angiogenesis inhibitory activity in the presence of VGF-A.
- FIG. 4 is a stained image obtained by staining the cells with DAB and photographing the lumen formation. Tube formation is observed when cultured in the presence of VEGF-A, whereas in the presence of VEGF-A and suramin or cinnamon extract (especially 300 ppm) known as angiogenesis inhibitors It can be seen that lumen formation is suppressed.
- FIGS. 5 and 6 are quantifications of the observation results of FIG. 4, and it is suggested that the cinnamon extract significantly suppresses angiogenesis induced by VEGF-A in a concentration-dependent manner between 10 ppm and 300 ppm. It was. Interestingly, Ang-1 had no angiogenesis inhibitory effect. Therefore, it is suggested that the hot water extract of Keihi exhibits angiogenesis-inhibiting action by a mechanism different from Ang-1 while it exerts the stabilizing action of blood vessels by Tie2 phosphorylation by Ang-1 like mechanism. It was.
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Abstract
Description
(1)ニッケイ属植物由来の抽出物からなる、血管の成熟化、正常化又は安定化剤。
(2)前記抽出物がケイ種植物由来である、(1)の血管の成熟化、正常化又は安定化剤。
(3)前記抽出物がケイシ又はケイヒ由来である、(2)の血管の成熟化、正常化又は安定化剤。
(4)前記抽出物が水抽出物である、(1)~(3)のいずれかの血管の成熟化、正常化又は安定化剤。
(5)ニッケイ属植物由来の抽出物からなる、Tie2活性化(リン酸化)剤。
(6)前記抽出物がケイ種植物由来である、(5)のTie2活性化(リン酸化)剤。
(7)前記抽出物がケイシ又はケイヒ由来である、(6)のTie2活性化(リン酸化)剤。
(8)前記抽出物が水抽出物である、(5)~(7)のいずれかのTie2活性化(リン酸化)剤。
(9)(1)~(4)のいずれかの血管の成熟化、正常化又は安定化剤を配合するしわ防止・改善剤。
(10)(5)~(8)のいずれかのTie2活性化(リン酸化)剤を配合するしわ防止・改善剤。
本発明の血管の成熟化、正常化又は安定化剤やTie2活性化(リン酸化)剤は血管の構造変化を原因とする、種々の疾患および老化の予防、改善に有効な医薬品または化粧品として利用できる。本発明のTie2リン酸化剤は、血管の正常化、安定化を誘導することにより、種々の炎症性疾患や免疫疾患、成人病など、例えば、種々の感染症、がん、関節リウマチ、痛風、高血圧、糖尿病、動脈硬化症、アトピー性皮膚炎などにおいて、血管新生や血管の破たんを伴う全身の病変部位の改善を図る医薬品として利用できる。また、血管透過性の抑制により、皮膚を含め臓器、器官、各種組織内の浮腫、たとえば炎症性疾患や免疫疾患、成人病による血管浮腫や、紫外線暴露や虫さされ、アレルギーなどによる血管透過性亢進による浮腫やかゆみなどの症状を改善する医薬品または化粧品として利用できる。さらに、Tie2リン酸化剤は、種々の要因によって誘導される内皮細胞の細胞死、たとえば炎症性疾患や免疫疾患、成人病など、例えば、種々の感染症、がん、関節リウマチ、痛風、高血圧、糖尿病、動脈硬化症、または放射線障害、種々の薬剤や紫外線による内皮細胞の細胞死を抑制して、血管の不安定化を抑制できる医薬品または化粧品として利用できる。Tie2リン酸化剤は血管成熟化や血管腔を拡大化することにより、外傷や縟そうなど創傷治癒の促進、血管再生医療における血管の成熟化、虚血性疾患、たとえば脳梗塞や心筋梗塞の改善剤として医薬品に利用でき、また、血流改善効果を利用して、腰痛症、凍傷、脱毛症などに対する内服および外用医薬品としても利用できる。脳血流の増大においては、痴呆症への応用も可能である。脱毛症に対しては、化粧品としての利用も可能である。また、がんにおいては、がん細胞の休眠を誘導する治療薬として、幹細胞においてはその生体内外での維持薬として利用が可能である。
ケイシ(ケイ:Cinnamomum cassia Blumeの枝部分)400.7gに水2Lを加え、3時間加熱抽出を行い、ろ過した。得られた残渣に水2Lを加え、同様の操作を繰り返し、加熱抽出をさらに2回行った。得られたろ液を凍結乾燥し、39.7gの熱水抽出乾燥残分を得た。この試料をケイシ熱水抽出物とした。
上記で得られた熱水抽出物 10gをダイヤイオンHP-20(三菱化学製)カラムにチャージし含水エタノール系で溶出させ、50%エタノール溶出画分を目的溶出画分として得た。
ケイヒ(ケイ:Cinnamomum cassia Blumeの樹皮部分)20.12gに水200mlを加え、3時間加熱抽出を行い、ろ過して得られた残渣に水200mlを加え、同様の操作を繰り返し、加熱抽出をさらに2回行なった。得られたろ液を凍結乾燥し、1.35gの熱水抽出物乾燥残分を得た。この試料をケイヒ熱水抽出物とした。
Wild type Tie2を強制発現した血球系Baf3細胞をRPMI1640培地中、IL-3(BIOSOURCE, PMC0034)、10% FCS存在下にてインキュベーションした。細胞刺激の前日よりFCSを除いた状態で、6ウエルプレートを用いて2X10 6 細胞 /1.5mL/ウエルで播種し一晩インキュベーションした。上記熱水抽出乾燥残分のDMSO溶液、陽性コントロールとしてAngiopoietin-1(R&D system, 923-AN )又は陰性コントロールとしてDMSOをそれぞれ最終濃度が100ppm、0.5ppm、1000ppmとなるようにウエルに添加し、10分間のインキュベーション後、細胞を氷上で冷却し、冷PBSで洗浄した。タンパク質分解酵素阻害剤(Leupeptin, Aprotinin, Pepstatin, PMSF, Na3VO4)を含んだRIPA buffer中、細胞を超音波破砕した。sample buffer ( 0.2 M Tris-HCl (pH 6. 8), 4% SDS, 20 % glycerol, 5 mM EDTA, 0.01% BPB) を加え、SDS-PAGE(7.5%ポリアクリルアミドゲル, 12ウエル, NPU-7.5L, アトー(株))を以下の条件で行った:
ゲル:7.5%アクリルアミドゲル(NPU-7.5L アトー株式会社製)
泳動条件:40mA(75分、ゲル2枚)
Tie2抗体:sc-324(Santa Cruz Biotechnology製)
Phospho-Tie2抗体:#4221(Cell Signaling製)
光老化しわ改善試験
Hr-1(Skh-1)ヘアレスマウス(星野実験動物;6週齢~10週齢)を用い、シュワルツらの方法(Haratake A. et al., J. Invest. Dermatol., 108, 769-775, 1997)を一部変えて、UVBを繰り返し照射する方法(Naganuma M. et al., J. Dermatol. Sci., 25, 29-35, 2001、Schwartz E., J. Invest., Dermatol., 91, 158-161, 1988)に準じてしわを形成させた。すなわち個体背部にUVB(光源;東芝エレクトリック製 東芝 FL-20SE蛍光ランプ)を週3回、10週間照射した。開始後の照射量は36mJ/cm2/回とし、2週目以降は徐々に増加させ、10週目は216mJ/cm2/回とした。総照射量は4.6J/cm2であった。紫外線量はUVRADIOMETER(UVR-305/365D(II)、株式会社トプコン製)にて測定した値を用いた。紫外線照射を終了し、背部の写真を撮影し、ビセットらの方法(Bissett DL. et al., Photochemistry and Photobiology 46, 367-378, 1987)を一部変えた方法でしわの生成度合いを下記に示す判定基準に従ってスコア化し、評点7以上のしわを形成した個体のみを用いて、実施例1(ケイシエキス、前記熱水抽出物乾燥残分配合)又は実施例2(ケイシエキスHP-20カラム50%エタノール溶出画分配合)を塗布した。しわのスコア化作業は、3名の測定者が個別に行い、合議によって評点を決定した。
なお、評価にあたっては、動物愛護管理法他関連法令を遵守し、社内動物実験審議会の承認を得た計画に基づき実施した。
(成分) 配合量(質量%)
ケイシエキス 1.0
化粧品用エタノール 30.0
精製水 残 余
(成分) 配合量(質量%)
ケイシエキスHP-20カラム50%エタノール溶出画分 1.0
化粧品用エタノール 30.0
精製水 残 余
0:しわを認めない。
1:評点2より浅い、短い、または数が少ない。
2:浅いしわを認める。
3:評点2より深い、または長い。評点4より浅い、短い、または数が少ない。
4:浅いしわを全体に認める。
5:評点4より深い、または長い。評点6より浅い、または短い。
6:深く長いしわを認める。
7:評点6よりも深く長いしわが増す。評点8より浅い、または短い。
8:深く、長いしわを全面に認める。
塗布終了後、背部の写真を撮影し、上記に示した判定基準に従って、動物の群名を伏せた状態でしわの度合いを3名の測定者が個別にスコア化し、合議によって評点を決定した。
また、実施例1の組成物中、ケイシエキスを抜去した比較例1にて同様の試験を行った。
(成分) 配合量(質量%)
化粧品用エタノール 30.0
精製水 残 余
「しわの改善度」=「試料溶液塗布前の評点」-「6週間試料溶液塗布後の評点」
の式によって算出した。
下記表に、上記式に従って得たしわ改善度(しわ改善変化量)を各群の平均値として示した。
ケイヒ熱水抽出物の血管新生抑制効果を確認するための試験を行った。
血管新生キット(倉敷紡績製)を用い、ヒト正常さい帯静脈血管内皮細胞とヒト正常真皮繊維芽細胞を一定の比率で共培養させ、管腔形成初期段階の増殖状態に調製した。血管内皮細胞増殖因子-A(VEGF-A:倉敷紡績製)10ng/mlの共存下、ケイヒ熱水抽出物を所定濃度含有した培地を添加後、インキュベーション(37℃・5%CO2条件)した。培養開始から4日後、7日後、9日後各々の時点でVEGF-A共存下、ケイヒ抽出物を所定濃度含有した培地と交換した。その後各ウエルの細胞層を70%エタノールで固定化し、CD31(PECAM-1)で染色した。各ウエルから得られた染色像を撮影し(図4)、管腔形成を長さ、面積指標をもとに画像解析を行い、血管新生抑制作用を評価した(図5,6)。管腔形成の長さの画像解析、面積の画像解析にはそれぞれ血管新生定量ソフトウエア(倉敷紡績株式会社製)を使用した。管腔形成の長さが長いほど、また管腔形成の面積が大きいほど、血管新生が認められたことを意味する。培地のみの添加群をコントロール、VEGF-A(10ng/ml)のみの添加群をネガティブコントロール、また血管新生阻害剤として知られるスラミン(50μM)をポジティブコントロールとした。さらに、血管の安定化を担う作用を有することで知られるAng-1についても、VGF-Aの存在下、血管新生抑制作用を評価した。
図4は細胞をDABで染色し、管腔形成を撮影した染色画像である。VEGF-Aの存在下で培養した場合には管腔形成が認められるのに対し、VEGF-Aと血管新生阻害剤として既知のスラミンやケイヒ抽出物(特に300ppm)との共存下での培養では管腔形成が抑制されていることがわかる。図5及び6は図4の観察結果を数値化したものであり、ケイヒ抽出物は10ppmから300ppmの間において濃度依存的にVEGF-Aにより誘導された血管新生を有意に抑制することが示唆された。興味深いことに、Ang-1は血管新生阻害作用を有しなかった。したがって、ケイヒ熱水抽出物はAng-1様のメカニズムでTie2リン酸化により血管の安定化作用などを発揮する一方で、Ang-1とは異なるメカニズムで血管新生抑制作用を発現することが示唆された。
Claims (10)
- ニッケイ(Cinnamomum)属植物由来の抽出物からなる、血管の成熟化、正常化又は安定化剤。
- 前記抽出物がケイ(Cinnamomum cassia Blume)種植物由来である、請求項1記載の血管の成熟化、正常化又は安定化剤。
- 前記抽出物がケイシ(桂枝)又はケイヒ(桂皮)由来である、請求項2記載の血管の成熟化、正常化又は安定化剤。
- 前記抽出物が水抽出物である、請求項1~3のいずれか1項記載の血管の成熟化、正常化又は安定化剤。
- ニッケイ属植物由来の抽出物からなる、Tie2(Tyrosine Kinase with Ig and EGF Homology Domain 2)活性化剤。
- 前記抽出物がケイ種植物由来である、請求項5記載のTie2活性化剤。
- 前記抽出物がケイシ又はケイヒ由来である、請求項6記載のTie2活性化剤。
- 前記抽出物が水抽出物である、請求項5~7のいずれか1項記載のTie2活性化剤。
- 請求項1~4のいずれか1項記載の血管の成熟化、正常化又は安定化剤を配合するしわ防止・改善剤。
- 請求項5~8のいずれか1項記載のTie2活性化剤を配合するしわ防止・改善剤。
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EP09726820.5A EP2269621B1 (en) | 2008-03-31 | 2009-03-31 | Cinnamonum extract for treating photoaging |
ES09726820.5T ES2655487T3 (es) | 2008-03-31 | 2009-03-31 | Extracto de canela para tratar el fotoenvejecimiento |
CN2009801117518A CN101980716B (zh) | 2008-03-31 | 2009-03-31 | 血管成熟化、正常化或稳定化剂以及皱纹防止和/或改善剂 |
US12/736,316 US9320770B2 (en) | 2008-03-31 | 2009-03-31 | Blood vessel maturation, normalization or stabilization agent and wrinkle preventer/improver |
KR1020107021860A KR101710727B1 (ko) | 2008-03-31 | 2009-03-31 | 혈관의 성숙화, 정상화 또는 안정화제 및 주름 방지·개선제 |
HK11106628.4A HK1152486A1 (en) | 2008-03-31 | 2011-06-28 | Agents for maturing, normalizing or stabilizing blood vessels and wrinkle- preventing and improving agents |
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JP2016094477A (ja) | 2016-05-26 |
TWI491413B (zh) | 2015-07-11 |
TW200948391A (en) | 2009-12-01 |
EP2269621A1 (en) | 2011-01-05 |
US9320770B2 (en) | 2016-04-26 |
KR20100132514A (ko) | 2010-12-17 |
US20110014307A1 (en) | 2011-01-20 |
JP2009263358A (ja) | 2009-11-12 |
EP2269621A4 (en) | 2012-02-22 |
KR101710727B1 (ko) | 2017-02-27 |
EP2269621B1 (en) | 2017-12-27 |
CN101980716B (zh) | 2012-11-21 |
CN101980716A (zh) | 2011-02-23 |
HK1152486A1 (en) | 2012-03-02 |
ES2655487T3 (es) | 2018-02-20 |
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