CN107669665B - Application of 5-amyl-3-methoxy-phenol in preparation of products for preventing and treating diseases induced by oxidative stress or inflammatory reaction - Google Patents

Application of 5-amyl-3-methoxy-phenol in preparation of products for preventing and treating diseases induced by oxidative stress or inflammatory reaction Download PDF

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CN107669665B
CN107669665B CN201711167223.7A CN201711167223A CN107669665B CN 107669665 B CN107669665 B CN 107669665B CN 201711167223 A CN201711167223 A CN 201711167223A CN 107669665 B CN107669665 B CN 107669665B
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CN107669665A (en
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沈涛
李妍茹
王小宁
任冬梅
娄红祥
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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Abstract

The invention discloses application of 5-amyl-3-methoxyl-phenol in preparing products for preventing and treating diseases induced by oxidative stress or inflammatory reaction. The chemical formula of the 5-pentyl-3-methoxy-phenol is as follows:
Figure DDA0001476523120000011
5-pentyl-3-methoxy-phenol is an Nrf2 signaling pathway agonist and an NF- κ B signaling pathway inhibitor. The 5-amyl-3-methoxyl-phenol can up-regulate Nrf2 and the level of II-phase detoxification enzyme NQO1 and antioxidant enzyme GCLM regulated by the Nrf2, increase the level of endogenous antioxidant glutathione, inhibit the generation of active oxygen induced by exogenous toxicants, and protect lung bronchial epithelial cells, glomerular membrane system cells, human nerve cells and human breast cancer cells induced by exogenous toxicants. The 5-amyl-3-methoxyl-phenol can inhibit the activation of NF-kB signal channels, can reduce the expression of inflammatory genes, and has an inhibiting effect on mouse macrophage RAW264.7 inflammatory reaction induced by LPS.

Description

Application of 5-amyl-3-methoxy-phenol in preparation of products for preventing and treating diseases induced by oxidative stress or inflammatory reaction
Technical Field
The invention belongs to the field of medicines, relates to an application of an oxidized phenolic compound, and particularly relates to an application of 5-pentyl-3-methoxy-phenol in preparation of medicines, health-care products or cosmetics for preventing or treating diseases induced by oxidative stress or inflammatory reaction.
Background
The rapid development of society leads to the increasing environmental pollution. Various environmental pollutants, such as carbon-sulfur-nitrogen oxides (CO, SO) 2 、NO 2 Etc.), heavy metals (lead, chromium, arsenic, etc.), haze formed by building mineral dust; the exogenous pollutants slowly invade human tissues and organs to cause oxidative stress, wherein the water source pollution and the soil pollution caused by industrial and domestic sewage, the grain pollution and the like are further caused. Subsequently, body tissues produce large amounts of lipid peroxidation products and excess endogenous reactive oxygen species, both of which cause cellular damage by acting on the cell membrane, proteins and DNA. Excessive endogenous reactive oxygen species will also induce Nuclear Factor (NF) - κ B activation, leading to the abundant production of the downstream inflammatory factors TNF- α, IL-6 and IL-1 β. Increasing released inflammatory factor positive feedback to regulate endogenous active oxygen and further activating NF-kappa B to make oxidative stress and inflammatory reaction form spiral ascending type vicious circle, thereby inducing a series of serious diseases, such as cancer, neurodegenerative diseases, cardiovascular diseases, diabetes, chronic obstructive pulmonary disease and the like. Therefore, the antioxidant and anti-inflammatory capability of the body is enhanced, and the method has important significance for preventing and treating related diseases caused by oxidative stress and chronic inflammation.
The Nuclear transcription factor Nrf2(Nuclear factor-erythroid 2-related factor 2) signal pathway is a key pathway for regulating and controlling human body oxidative stress and is a target of the action of chemopreventive agents (medicines). Nrf2 is an important transcription factor for regulating cell redox balance, and regulates cell redox balance by combining with antioxidant enzyme and II phase detoxification enzyme promoter region Antioxidant Reaction Element (ARE), and its target gene includes II phase detoxification enzyme coding GST, UGT, NQO1, and endogenous antioxidant protein such as GCLM, HO-1, etc. The NF-kB signal channel is a key channel for regulating and controlling human inflammatory reaction and is an effective action target point for inhibiting the inflammatory reaction. NF-kB is an important transcription factor for regulating cell inflammatory response, and regulates the expression of inflammation-related genes by combining with a kB sequence. These inflammatory genes include inflammatory factors (tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta)), chemokines, adhesion molecules (e.g., E-selectin) and inflammation-related proteins (cyclooxygenase-2 (COX-2), Inducible Nitric Oxide Synthase (iNOS)). Therefore, activation of the Nrf 2-mediated defense mechanism and inhibition of NF- κ B-regulated inflammatory response are effective strategies against oxidative stress and inflammatory responses.
In response to oxidative stress and inflammatory injury states caused by pollutants, the exogenous Nrf2 agonist is utilized to up-regulate the Nrf2 level of human organs and tissues, so that the self defense capability of the body can be enhanced, the activation of NF-kB signal channels is inhibited, and the method has important significance for preventing chronic obstructive pulmonary diseases, chronic kidney diseases, respiratory inflammation, diabetes, neurodegenerative diseases and tumor diseases. Activating Nrf2 signal channel, regulating II phase detoxifying enzyme level, eliminating carcinogen in pollutant or reducing toxicity, and inhibiting DNA damage and gene mutation induced by carcinogen, thereby preventing tumor. The expression of Nrf2 is up-regulated, so that the glutathione level in cells can be increased, the activity of antioxidant enzyme is enhanced, the peroxidation of cell lipid is inhibited, the active oxygen in cells is eliminated, the activation of NF-kB and the secretion of downstream inflammatory factors are down-regulated, the organism is protected from the harm of environmental pollutants, and the morbidity of diseases such as chronic obstructive pulmonary diseases, chronic kidney diseases, respiratory inflammation, diabetes, neurodegenerative diseases and the like is reduced.
The natural product is an important source of a medicine lead compound and makes an important contribution to the development history of human medicines. At present, many clinical medicines are natural products or are derived from natural products, such as artemisinin, paclitaxel, ET743 and the like, and searching for lead compounds with prevention and treatment effects from the natural products is an important way for drug development. The inventor of the invention discovers for the first time that the litsea martabanica extract has the Nrf2 agonism and NF-kB inhibition effects and has the potential of becoming a drug for preventing and treating diseases induced by oxidative stress. The research on the chemical components of the litsea martabanica is less, and no literature exists for evaluating the biological activity of the chemical components in the litsea martabanica.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide the application of 5-pentyl-3-methoxy-phenol in preparing products for preventing and treating oxidative stress or inflammatory response induced diseases, and the products can be used for preventing or treating chronic obstructive pulmonary diseases, chronic kidney diseases, respiratory inflammation, diabetes, neurodegenerative diseases and tumor diseases.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the application of 5-amyl-3-methoxy-phenol in preparing products for preventing and treating diseases induced by oxidative stress or inflammatory reaction, wherein the chemical formula of the 5-amyl-3-methoxy-phenol is as follows:
Figure BDA0001476523100000021
the inventor discovers through research that 5-amyl-3-methoxy-phenol inhibits the degradation of Nrf2 protein by increasing the stability of the Nrf2 protein, and inhibits the generation of excessive cell endogenous active oxygen induced by arsenic by up-regulating the Nrf2 and the levels of II-phase detoxification enzyme NQO1 and antioxidant enzyme GCLM; can inhibit NF-kB activation, reduce inflammatory gene expression and protect organisms from being damaged by environmental pollutants. In order to confirm the antioxidant and anti-inflammatory capacity of the 5-pentyl-3-methoxy-phenol, firstly, an arsenic-induced lung bronchial epithelium Beas-2B cell damage model is adopted to evaluate the capacity of the 5-pentyl-3-methoxy-phenol for resisting oxidative damage, and the result shows that the compound can increase the level of a cell endogenous antioxidant GSH and inhibit arsenic-induced Beas-2B cell damage and apoptosis; in addition, 5-pentyl-3-methoxy-phenol also showed protective effects on mesangial cell SV40MES13 cells, human neural SHSY5Y cells and human breast cancer MDA-MB-231 cells. Subsequently, an LPS-induced mouse macrophage RAW264.7 inflammation model is adopted to evaluate the anti-inflammatory effect of the 5-amyl-3-methoxy-phenol, and the result shows that the compound can inhibit the activation of NF-kB subunit p65 by up-regulating the level of NF-kB inhibitor protein IkB alpha, reduce the levels of inflammatory mediators TNF-alpha, IL-1 beta and inflammation-related proteins iNOS, COX-2 and down-regulate the cell inflammatory response. Therefore, the 5-amyl-3-methoxyl-phenol provided by the invention can resist oxidative stress and inflammatory reaction, and has the potential of preventing and treating chronic obstructive pulmonary diseases, respiratory inflammation, skin lesions, diabetes, neurodegenerative diseases and tumors.
The invention also aims to provide a pharmaceutical composition for realizing the application, and the effective component comprises 5-amyl-3-methoxy-phenol.
The invention also aims to provide a medicament for realizing the application, which comprises 5-amyl-3-methoxy-phenol and auxiliary materials.
The fourth purpose of the invention is to provide a preparation method of the medicament, 5-amyl-3-methoxy-phenol, starch and dextrin are mixed and sieved, sodium carboxymethylcellulose is added for granulation, magnesium stearate is added for mixing and tabletting to obtain tablets; or adding carbomer and polysorbate into water, mixing, adding 5-amyl-3-methoxyl-phenol, and mixing to obtain gel.
The fifth purpose of the invention is to provide a cosmetic for realizing the application, which comprises the 5-amyl-3-methoxyl-phenol and cosmetic raw materials.
The invention has the beneficial effects that:
the inventor of the invention discovers through research that 5-pentyl-3-methoxy-phenol can up-regulate the protein levels of Nrf2 and II-phase detoxification enzyme NQO1 and antioxidant enzyme GCLM regulated by the Nrf2, and inhibit the generation of excessive endogenous active oxygen induced by arsenic, wherein the activation mechanism is realized by increasing the stability of Nrf2 protein and inhibiting the degradation of Nrf2 protein; meanwhile, excessive endogenous active oxygen induced by arsenic is reduced, NF-kB signal path activation can be weakened, inflammatory gene expression is reduced, and an organism is protected from being damaged by environmental pollutants. In order to confirm the antioxidant and anti-inflammatory capacity of the 5-pentyl-3-methoxy-phenol, firstly, an arsenic-induced lung bronchial epithelium Beas-2B cell damage model is adopted to evaluate the capacity of the 5-pentyl-3-methoxy-phenol for resisting oxidative damage, and the result shows that the compound can increase the level of a cell endogenous antioxidant GSH and inhibit arsenic-induced Beas-2B cell damage and apoptosis; in addition, 5-pentyl-3-methoxy-phenol also showed protective effects on mesangial cell SV40MES13 cells, human neural SHSY5Y cells and human breast cancer MDA-MB-231 cells. Subsequently, an LPS-induced mouse macrophage RAW264.7 inflammation model is adopted to evaluate the anti-inflammatory effect of 5-amyl-3-methoxy-phenol, and the result shows that the compound can inhibit the activation of NF-kB subunit p65 by up-regulating the level of NF-kB inhibitory protein IkB alpha, reduce the levels of inflammatory mediators TNF-alpha and IL-1 beta and inflammation-related proteins iNOS and COX-2, down-regulate the cellular inflammatory response and has the anti-inflammatory effect.
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The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the application and, together with the description, serve to explain the application and are not intended to limit the application.
FIG. 1: is a bar graph of an induction activity assay of NQO1 showing that 5-pentyl-3-methoxy-phenol is capable of inducing the expression and enhancing the activity of the hepa 1c1c7 cell phase II detoxification enzyme NQO1, with the unit of 5-pentyl-3-methoxy-phenol concentration being μ M and sulforaphane 2.0 μ M being a positive control;
FIG. 2 is a graph of immunoblot analysis of various concentrations of 5-pentyl-3-methoxy-phenol, showing that 5-pentyl-3-methoxy-phenol is able to up-regulate the level of Nrf2 and its downstream antioxidant GCLM and phase II detoxification enzyme protein NQO1, the concentration of 5-pentyl-3-methoxy-phenol in the graph being in μ M;
FIG. 3 is a fluorescent micrograph of cellular immunity showing that 5-pentyl-3-methoxy-phenol is able to promote translocation of Nrf2 into the nucleus 5-pentyl-3-methoxy-phenol at a concentration of 25 μ M;
FIG. 4 is a graph of an immunoblot analysis of 5-pentyl-3-methoxy-phenol at various times, showing that 5-pentyl-3-methoxy-phenol is able to extend the half-life of Nrf2 protein, where the concentration of 5-pentyl-3-methoxy-phenol is 25 μ M;
FIG. 5 is a bar graph of the effect of different substances on glutathione, showing that 5-pentyl-3-methoxy-phenol is able to increase the endogenous antioxidant glutathione level in human bronchial epithelial Beas-2B cells, with sulforaphane 2.5. mu.M as a positive control and 5-pentyl-3-methoxy-phenol concentration in. mu.M;
FIG. 6 is a fluorescent photograph of endogenous reactive oxygen species in cells, showing that 5-pentyl-3-methoxy-phenol is able to inhibit the production of excess endogenous reactive oxygen species, and that didox 100. mu.M is a positive control 5-pentyl-3-methoxy-phenol concentration in. mu.M;
FIG. 7 is a bar graph of the amount of cell survival in a cytotoxicity assay showing that 5-pentyl-3-methoxy-phenol is able to inhibit arsenic induced cytotoxicity, as a protective effect of different concentrations of 5-pentyl-3-methoxy-phenol on 6 μ M arsenic induced cytotoxicity.
FIG. 8 is a fluorescent micrograph of apoptosis showing that AO/EB staining indicates that 5-pentyl-3-methoxy-phenol is able to inhibit arsenic-induced apoptosis, with a concentration of 12.5. mu.M 5-pentyl-3-methoxy-phenol and 6. mu.M arsenic.
FIG. 9 is a graph of an NO production inhibition assay showing that 5-pentyl-3-methoxy-phenol is able to inhibit LPS-induced NO production in RAW264.7 cells at a non-toxic dose. The 5-pentyl-3-methoxy-phenol concentration in the figure is given in μ M and the LPS concentration is 1 μ g/mL;
FIG. 10 is a graph of an immunoblot analysis of 5-pentyl-3-methoxy-phenol at various concentrations, showing that 5-pentyl-3-methoxy-phenol is capable of up-regulating the expression of the NF-. kappa.B inhibitor protein IkB α, reducing the levels of NF-. kappa.B subunit p65 and its downstream inflammation-related proteins iNOS, COX-2 protein, in which the concentration of 5-pentyl-3-methoxy-phenol is expressed in μ M; LPS concentration is 1 mug/ml; didox100 μ M is a positive control;
FIG. 11 is a fluorescent micrograph of cellular immunity showing that 5-pentyl-3-methoxy-phenol is able to inhibit LPS-induced translocation of NF-. kappa.B subunit p65 into the nucleus; the concentration of 5-pentyl-3-methoxy-phenol was 25 μ M; the concentration of LPS is 1 mug/mL; didox100 μ M is a positive control;
FIG. 12 is an ELISA graph of various concentrations of 5-pentyl-3-methoxy-phenol, showing that 5-pentyl-3-methoxy-phenol is able to down-regulate the level of TNF- α, IL-1 β, an inflammatory mediator induced by LPS, and the concentration of 5-pentyl-3-methoxy-phenol in the graph is in μ M; the concentration of LPS is 1 mug/mL; didox 100. mu.M is a positive control.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As introduced by the background technology, the research on chemical components of litsea martabanica is less in the prior art, no document exists for carrying out activity detection on the chemical components in litsea martabanica, and in order to solve the technical problems, the application provides the application of 5-pentyl-3-methoxy-phenol in preparing products for preventing and treating diseases induced by oxidative stress or inflammatory reaction.
In one exemplary embodiment of the present application, there is provided a use of 5-pentyl-3-methoxy-phenol for the manufacture of a product for the prevention and treatment of diseases induced by oxidative stress or inflammatory response, wherein the 5-pentyl-3-methoxy-phenol has the formula:
Figure BDA0001476523100000051
according to the application, the research finds that 5-pentyl-3-methoxy-phenol can up-regulate the protein levels of Nrf2 and II-phase detoxification enzyme NQO1 and antioxidant enzyme GCLM regulated by the Nrf2, and inhibit the generation of excessive endogenous active oxygen induced by arsenic, and the activation mechanism is realized by increasing the stability of Nrf2 protein and inhibiting the degradation of Nrf2 protein; meanwhile, excessive endogenous active oxygen induced by arsenic is reduced, NF-kB signal path activation can be weakened, inflammatory gene expression is reduced, and an organism is protected from being damaged by environmental pollutants. In order to confirm the antioxidant and anti-inflammatory capacity of the 5-pentyl-3-methoxy-phenol, firstly, an arsenic-induced lung bronchial epithelium Beas-2B cell damage model is adopted to evaluate the capacity of the 5-pentyl-3-methoxy-phenol for resisting oxidative damage, and the result shows that the compound can increase the level of a cell endogenous antioxidant GSH and inhibit arsenic-induced Beas-2B cell damage and apoptosis; in addition, 5-pentyl-3-methoxy-phenol also showed protective effects on mesangial cell SV40MES13 cells, human neural SHSY5Y cells and human breast cancer MDA-MB-231 cells. Subsequently, an LPS-induced mouse macrophage RAW264.7 inflammation model is adopted to evaluate the anti-inflammatory effect of the 5-pentyl-3-methoxy-phenol, and the result shows that the compound can inhibit the activation of NF-kappa B subunit p65 by up-regulating the level of NF-kappa B inhibitor Ikappa B alpha, reduce the levels of inflammatory mediators TNF-alpha, IL-1 beta and inflammation-related proteins iNOS and COX-2 and down-regulate the cellular inflammatory response, so that the conclusion is drawn that the 5-pentyl-3-methoxy-phenol related to the invention can resist oxidative stress and inflammatory response and has the potential of preventing and treating chronic obstructive pulmonary diseases, respiratory inflammation, skin lesion, diabetes, neurodegenerative diseases and tumors.
The products described in the present application include pharmaceuticals, nutraceuticals, cosmetics, and the like.
Preferably, the oxidative stress-induced disease is chronic obstructive pulmonary disease, respiratory inflammation, skin lesions, diabetes, neurodegenerative disease or tumor disease.
Preferably, the concentration of the 5-amyl-3-methoxy-phenol is 6.25-25 mu M. The concentration has better protection effect on cells. Further preferably, the concentration of said 5-pentyl-3-methoxy-phenol is 12.5 μ M. This concentration gives the best protection of the cells.
The 5-pentyl-3-methoxy-phenol can be synthesized by a chemical method and can also be extracted from plants. The application preferably provides a method for extracting 5-pentyl-3-methoxy-phenol from litsea yunnanensis, which comprises the steps of extracting an ethanol extract of litsea yunnanensis with petroleum ether, carrying out gradient elution on a petroleum ether-ethyl acetate system, separating an 8 th part of the gradient elution of the petroleum ether-ethyl acetate system by a sephadex LH-20 chromatographic column, and separating a 5 th part obtained by separating the sephadex LH-20 chromatographic column by a semi-prepared high performance liquid chromatographic column to obtain the 5-pentyl-3-methoxy-phenol.
Research on activation of Nrf2 signal path effect by 5-amyl-3-methoxy-phenol and pollutant-induced cell damage protection effect
The induction of phase II detoxification enzyme NQO1 by 5-pentyl-3-methoxy-phenol was evaluated using mouse hepa 1c1c7 hepatoma cell line, and the results indicate that 5-pentyl-3-methoxy-phenol can enhance NQO1 activity, i.e. 5-pentyl-3-methoxy-phenol has the effect of inhibiting oxidative stress (fig. 1).
The effect of 5-pentyl-3-methoxy-phenol on the cellular Nrf2 signaling pathway was evaluated using human normal lung epithelial cells, Beas-2B cells. The western blot analysis result shows that 5-pentyl-3-methoxy-phenol can up-regulate the expression of Nrf2 protein and can promote the expression of downstream antioxidant GCLM and II phase detoxification enzyme protein NQO1 (figure 2). Cell immunofluorescence experiments show that 5-amyl-3-methoxy-phenol can promote translocation of Nrf2 into nucleus (figure 3), prolong the half-life of Nrf2 protein, inhibit degradation of Nrf2 protein and increase stability of the Nrf 3556 protein (figure 4).
The effect of 5-pentyl-3-methoxy-phenol on excess endogenous active oxygen in arsenic-induced cells was evaluated using an arsenic-induced lung bronchial epithelial cytotoxicity model, and the results indicate that 5-pentyl-3-methoxy-phenol can inhibit the production of excess endogenous active oxygen in arsenic-induced cells, i.e., 5-pentyl-3-methoxy-phenol can inhibit oxidative stress (fig. 6).
An arsenic-induced lung bronchial epithelial cytotoxicity model is selected, and the protective effect of 5-amyl-3-methoxy-phenol on human normal lung epithelial cells Beas-2B is evaluated. Research has demonstrated that arsenic can increase intracellular reactive oxygen levels, induce cellular oxidative stress, lead to cell damage and death. The results show that treatment of cells with 5-pentyl-3-methoxy-phenol gave the best protection at 12.5 μ M (FIG. 7); in addition, 5-pentyl-3-methoxy-phenol was able to inhibit arsenic-induced apoptosis (fig. 8).
The inhibition of the generation of NO, an inflammatory mediator, by 5-pentyl-3-methoxy-phenol was evaluated using a mouse macrophage RAW264.7 cell line, and the results indicate that 5-pentyl-3-methoxy-phenol can inhibit the NO activity at a non-toxic dose, i.e. 5-pentyl-3-methoxy-phenol has an inhibitory effect on an inflammatory mediator (fig. 9).
The effect of 5-pentyl-3-methoxy-phenol on the NF- κ B signaling pathway in cells was evaluated using the mouse macrophage RAW264.7 cell line. The results of Western blot analysis showed that 5-pentyl-3-methoxy-phenol was able to up-regulate the level of NF-. kappa.B inhibitor protein IkB α, down-regulate the expression of NF-. kappa.B subunit p65 protein, and inhibit the expression of downstream inflammation-associated proteins iNOS and COX-2 (FIG. 10). Cellular immunofluorescence experiments showed that 5-pentyl-3-methoxy-phenol was able to inhibit LPS-induced translocation of NF- κ B subunit p65 into the nucleus (fig. 11). Enzyme-linked immunosorbent assay shows that 5-amyl-3-methoxy-phenol can reduce the levels of inflammatory factors TNF-alpha and IL-1 beta induced by LPS (figure 12) and reduce the cell inflammatory response.
In another embodiment of the present application, there is provided a pharmaceutical composition for achieving the above-mentioned use, wherein the effective ingredient comprises 5-pentyl-3-methoxy-phenol.
In a third embodiment of the present invention, a medicament for achieving the above-mentioned application is provided, which comprises 5-pentyl-3-methoxy-phenol and an adjuvant.
Preferably, the medicament is a capsule, a tablet, powder, a granule, an injection, an oral liquid, a wine, a pill, a mixture or a tincture.
In a fourth embodiment of the present application, a process for preparing the above medicament is provided, wherein 5-pentyl-3-methoxy-phenol, starch and dextrin are mixed and sieved, sodium carboxymethylcellulose is added for granulation, magnesium stearate is added for mixing and tabletting to obtain tablets; or adding carbomer and polysorbate into water, mixing, adding 5-amyl-3-methoxyl-phenol, and mixing to obtain gel.
Preferably, the mass ratio of the 5-amyl-3-methoxy-phenol to the starch to the dextrin is 1-2: 2-3; or the mass ratio of the 5-amyl-3-methoxyl-phenol to the carbomer to the polysorbate is 2-3: 3-4: 1-2.
In a fifth embodiment of the present application, there is provided a cosmetic for realizing the above application, comprising the above 5-pentyl-3-methoxy-phenol and a cosmetic raw material.
Preferably, the cosmetic is a facial mask, a skin cream, a skin lotion, a skin powder or a skin gel.
In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described in detail below with reference to specific embodiments.
Example 1: structure confirmation of 5-amyl-3-methoxy-phenol
The overground part of the litsea yunnanensis is extracted by 95 percent ethanol to obtain an ethanol extract, and then petroleum ether, ethyl acetate and n-butanol are sequentially adopted for extraction. The petroleum ether part is subjected to gradient elution by adopting a petroleum ether-ethyl acetate system, and the concentration of the petroleum ether part is respectively 95: 5 (volume ratio), petroleum ether-ethyl acetate 90: 10 (volume ratio), petroleum ether-ethyl acetate 85: 15 (volume ratio), petroleum ether-ethyl acetate 80: 20 (volume ratio), petroleum ether-ethyl acetate 75: 25 (volume ratio), 70 of petroleum ether-ethyl acetate: 30 (volume ratio), 60 of petroleum ether-ethyl acetate: 40 (volume ratio), 50 of petroleum ether-ethyl acetate: 50 (volume ratio), petroleum ether-ethyl acetate 40: 60 (by volume) and 100% ethyl acetate, 14 fractions (Frs. 1-14). The Fr.8 fraction (petroleum ether-ethyl acetate 90: 10 elution) was separated by sephadex LH-20 column chromatography to obtain six fractions (Frs.8A-F), and Fr.8E was separated by semi-preparative HPLC to obtain 5-pentyl-3-methoxy-phenol.
The method comprises the following steps: and measuring a hydrogen spectrum and a carbon spectrum by using a nuclear magnetic resonance spectrometer and analyzing the structure by using DMSO-d6 as a solvent and TMS as an internal standard.
As a result: the 1H-NMR signals of the compounds are δ H6.32 (1H, s, H-),6.27(1H, s, H-6),6.24(1H, t, J ═ 2.4 Hz, H-2),3.76(3H, s, -OCH3),2.51(2H, t, J ═ 8Hz, H-1 '), 1.55 to 1.62(2H, m, H-2 '), 1.26 to 1.35 (4H, m, H-3 ', 4 '), 0.89(3H, t, J ═ 6.8Hz, H-5 ') the 13C NMR signals of the compounds are δ 160.8(C-3),156.6 (C-1),145.7(C-5),107.9(C-4),106.7(C-6),98.7(C-2),55.2(3-OMe),36.0 (C-1.5) (C-3 '),31, C-3 '), 22.5(C-4 '), 14.0 (C-5'). The structure is confirmed to be 5-amyl-3-methoxy-phenol.
Example 2: evaluation of NQO 1-inducing Activity of 5-pentyl-3-methoxy-phenol
(1) Culture of mouse liver cancer cell hepa 1c1c cell line
Mouse hepatoma cell hepa 1c1c cell line was purchased from American Type Culture Collection (ATCC) and cultured in MEM medium containing 10% Fetal Bovine Serum (FBS) at 37 ℃ in 5% CO 2 Culturing in an incubator.
(2) NQO1 Induction Activity assay
Hepa 1c1c cells were plated on 96-well plates and after cell attachment, 5-pentyl-3-methoxy-phenol (example 1 confirmed) was added at various concentrations for 24 hours, cells were lysed with 0.8% digitonin solution, assay solutions (1.0mL 0.5M Tris-HCl, 15mg bovine serum albumin, 6mg MTT, 150. mu.L Tween-20, 150. mu.L 150mM D-glucose-6-phosphate, 15. mu.L 7.5mM flavin adenine dinucleotide, 27. mu.L 50mM nicotinamide adenine dinucleotide phosphate, 20. mu.L 50mM menadione) were added, left for 3 minutes, and luminescence intensity was measured at 630 nm.
As a result: as shown in FIG. 1, 5-pentyl-3-methoxy-phenol was able to activate NQO1 activity in hpa 1c1c7 cells with a maximum induction activity of 3.83 times (100. mu.M) and a positive control drug sulforaphane (2.0. mu.M) of 2.98 times that of the blank control. The results show that 5-amyl-3-methoxyl-phenol can activate II-phase detoxification enzyme and has protective effect on human cells.
Example 3: 5-pentyl-3-methoxy-phenol is able to upregulate Nrf2, GCLM and NQO1 protein levels
The method comprises the following steps: western blot analysis (Western blot) to detect changes in protein levels in cells
Beas-2B cells are inoculated into a culture dish with the diameter of 35mM, after the cells are cultured until the density reaches 70% -80%, the cells are added with compounds to be tested with different concentrations for treatment for 16h, washed for 2 times by PBS, cell lysate (50 mu g/mL aprotinin, 0.5mM phenylmethylsulfonyl fluoride, 1mM sodium orthovanadate, 10mM sodium fluoride and 10mM beta-glycerophosphate) is added, proteins are collected, and the protein concentration is determined by the Bradford method. Each sample was loaded with protein (100. mu.g), and the protein fractions were separated by SDS-PAGE and the protein bands were transferred to nitrocellulose membranes by electrotransfer. The membrane is sealed for 1h at room temperature by 5 percent skimmed milk powder solution prepared by TBS, and then incubated with each protein antibody to be detected overnight at 4 ℃. After washing with TBS, horseradish peroxidase-conjugated secondary antibodies were added to incubate for 1h, and protein analysis was performed using enhanced ECL chemiluminescence.
As a result: as shown in fig. 2, after the cells were treated with 5-pentyl-3-methoxy-phenol for 16h, Nrf2 and its downstream antioxidant and phase II detoxification enzyme proteins NQO1 and GCLM protein levels exhibited dose-dependent increases with no change in Keap1 protein levels, confirming that the compound is capable of activating the Nrf2 signaling pathway at the protein level.
Example 4: 5-pentyl-3-methoxy-phenol facilitates translocation of Nrf2 protein into nucleus
The method comprises the following steps: immunofluorescence method for detecting intracellular position of Nrf2
Placing the cell slide in a 24-well plate, inoculating Beas-2B cells, adding 5-pentyl-3-methoxy-phenol to treat for 8 hours after the cells are attached to the wall, washing with PBS for 2 times, adding methanol to fix for 4 hours, washing with PBS for 2 times, adding Nrf2 antibody to incubate for 1 hour, washing with PBS for 3 times, adding DAPI and fluorescent secondary antibody to incubate for 50 minutes, observing by using a fluorescent microscope and taking pictures.
As a result: immunofluorescence results (fig. 3) showed that under normal cell conditions, Nrf2 was localized in the cytoplasm and Nrf2 translocated into the nucleus after 8 hours of treatment with 5-pentyl-3-methoxy-phenol and the positive control sulforaphane.
Example 5: 5-pentyl-3-methoxy-phenol increases Nrf2 protein stability
The method comprises the following steps: western blot analysis for detecting protein half-life of Nrf2
Inoculating the Beas-2B cells into a culture dish with the diameter of 35mm, culturing until the density reaches 70% -80%, adding 5-pentyl-3-methoxy-phenol for 8h, then adding cycloheximide, timing, collecting protein respectively in 0, 10, 20, 30 and 40 minutes, carrying out Western blot analysis and detection, and quantifying by adopting Image J software.
As a result: as shown in fig. 4, the half-life of the berf 2 protein in the blank group of Beas-2B cells was 19.23 minutes, and after 8h treatment with 5-pentyl-3-methoxy-phenol, the half-life of the Nrf2 protein was extended to 38.84 minutes, indicating that 5-pentyl-3-methoxy-phenol was able to extend the half-life of the Nrf2 protein.
Example 6: 5-pentyl-3-methoxy-phenol is capable of increasing the level of glutathione, an endogenous antioxidant, in cells
(1) Culture of human normal epidermal Beas-2B cells
Human normal lung bronchial epithelium Beas-2B cells were purchased from American Type Culture Collection (ATCC) using 1640 medium to which 10% Fetal Bovine Serum (FBS), 5% glutamine (Glutamine) were added and placed at 37 ℃ in 5% CO 2 Culturing in an incubator.
(2) Determination of intracellular glutathione content
Beas-2B cells are inoculated in a culture dish with the diameter of 35mM, after the culture is carried out until the density reaches 70% -80%, 5-amyl-3-methoxy-phenol (confirmed in example 1) with different concentrations is added for processing for 24 hours, PBS is used for washing for 2 times, 0.5mL of 50mM sodium phosphate and 1mM EDTA buffer solution are added for collecting the cells, ultrasonic treatment is carried out for 1min, centrifugation is carried out for 15 minutes at 10000g, supernatant fluid is taken, the operation is carried out according to the specification of a glutathione measuring kit, and the absorbance is measured at 412nm and the content of glutathione is calculated.
As a result: as shown in fig. 5, 5-pentyl-3-methoxy-phenol was able to significantly increase intracellular glutathione levels, enhancing intracellular reducing capacity.
Example 7: 5-pentyl-3-methoxy-phenol reduces arsenic-induced levels of excess endogenous reactive oxygen species in human bronchial epithelial Beas-2B cells
The Beas-2B cells are inoculated in a culture dish with the diameter of 35mm, after the culture is carried out until the density reaches 30-40%, 5-amyl-3-methoxy-phenol is added for treating for 8h, then the culture solution is reacted with 5 mu M As for 10h, DCFH-DA (10 mu M) is added for incubation for 30min after the culture solution is discarded, PBS is washed for 3 times, and the observation and the picture taking are carried out by adopting a fluorescence microscope.
As a result: as shown in fig. 6, 5-pentyl-3-methoxy-phenol was able to significantly reduce arsenic-induced levels of excess endogenous reactive oxygen species, inhibiting cellular oxidative stress.
Example 8: protection of arsenic-induced human bronchial epithelial Beas-2B cell damage by 5-pentyl-3-methoxy-phenol
The method comprises the following steps: determination of protective effect of traditional Chinese medicine composition on arsenic-induced cytotoxicity by MTT method
Beas-2B cells are inoculated on a 96-well plate, after the cells are attached to the wall, the cells are pretreated for 8 hours by using 5-amyl-3-methoxy-phenol with the concentration to be measured, arsenic with different concentrations and the 5-amyl-3-methoxy-phenol with the concentration to be measured (example 1 is confirmed) are added for treatment for 48 hours, or after MTT is added for 3 hours, the absorbance is measured at 590nm, and the cell survival rate is calculated.
As a result: as shown in fig. 7, pretreatment of cells with 5-pentyl-3-methoxy-phenol for 8 hours significantly inhibited arsenic-induced cytotoxicity at 10 μ M, and increased cell survival, with 5-pentyl-3-methoxy-phenol at 12.5 μ M concentration being the most active. As shown in fig. 7, 5-pentyl-3-methoxy-phenol at a concentration of 25 μ M was used as a protective drug, which significantly inhibited arsenic-induced cytotoxicity at 5, 10, and 20 μ M, and increased cell survival. The results demonstrate that 5-pentyl-3-methoxy-phenol is able to inhibit carcinogen arsenic induced toxicity.
Example 9: 5-pentyl-3-methoxy-phenol is capable of inhibiting arsenic-induced apoptosis
Beas-2B cells are inoculated on a 35mm culture dish, after adherence, 5 mu M arsenic or 25 mu M5-amyl-3-methoxy-phenol is added for treatment for 12h, Acridine Orange (AO)/Ethidium Bromide (EB) is respectively added for staining, and the cell state is observed by adopting a fluorescence microscope.
As a result: as shown in fig. 8, co-treatment with arsenic and/or 5-pentyl-3-methoxy-phenol for 12 hours significantly inhibited arsenic-induced apoptosis.
Example 10: 5-pentyl-3-methoxy-phenol is able to inhibit LPS-induced NO production in RAW264.7 cells at non-toxic doses.
(1) Culture of mouse macrophage RAW264.7
Mouse macrophage RAW264.7 was purchased from American Type Culture Collection (ATCC) in DMEM medium, and 10% Fetal Bovine Serum (FBS), 5% glutamine was added thereto, and the mixture was incubated at 37 ℃ and 5% CO 2 Culturing in an incubator.
(2) NO production inhibition experiment
Inoculating RAW264.7 cells into a 96-well plate, culturing until the density reaches 70-80%, adding LPS (1 mu g/mL) and co-processing the cells with compounds to be detected with different concentrationsCells were incubated for 18 hours, then 100. mu.L of culture supernatant was taken and mixed with an equal volume of Griess reagent (0.1% naphthyl-ethylenediamine and 1% sulfanilamide at 5% H) 3 PO 4 In solution). After incubation for 15 min at room temperature, the absorbance at 570nm was measured and measured by NaNO 2 The standard curve evaluates the NO content.
After the determination of the NO content, the MTT method was used to determine the cytotoxic effect of the extract on Raw264.7 cells. After removing 100. mu.L of the supernatant, 100. mu.L of 1640 medium containing 0.4% MTT was added to each well, and the cells were incubated at 37 ℃ for 3 hours. Then, the medium was carefully removed and 100 μ L DMSO was added to each well. After the dye crystals dissolved, the absorbance of the solution was measured at 570 nm.
Example 11: the 5-amyl-3-methoxyl-phenol can up-regulate the level of NF-kB inhibitory protein IkB alpha, down-regulate the expression of NF-kB subunit p65 protein, and can inhibit the expression of downstream inflammation-related proteins iNOS and COX-2
The method comprises the following steps: western blot analysis (Western blot) to detect changes in protein levels in cells
RAW264.7 cells were seeded in a 35mM diameter petri dish and cultured to a density of 70% -80%, then test compounds at different concentrations were added for different times, washed 2 times with PBS, cell lysate (50. mu.g/ml aprotinin, 0.5mM phenylmethylsulfonyl fluoride, 1mM sodium orthovanadate, 10mM sodium fluoride, 10 mM. beta. -glycerophosphate) was added, proteins were collected and protein concentration was determined by the Bradford method. Each sample was loaded with protein (100. mu.g), and the protein fractions were separated by SDS-PAGE and the protein bands were transferred to nitrocellulose membranes by electrotransfer. The membrane is sealed for 1h at room temperature by 5 percent skimmed milk powder solution prepared by TBS, and then incubated with each protein antibody to be detected overnight at 4 ℃. After washing with TBS, horseradish peroxidase-conjugated secondary antibodies were added to incubate for 1h, and protein analysis was performed using enhanced ECL chemiluminescence.
As a result: as shown in figure 10, after the cells are treated by 5-pentyl-3-methoxy-phenol for 1h and are incubated with LPS for 1h, the level of NF-kappa B inhibitor Ikappa B alpha is increased, the expression level of NF-kappa B subunit p65 protein is reduced, and after the cells are treated by 5-pentyl-3-methoxy-phenol and LPS for 18h, the level of NF-kappa B downstream inflammation-related protein is reduced in a dose-dependent manner, so that the compound can inhibit NF-kappa B signal pathways on the protein level.
Example 12: 5-pentyl-3-methoxy-phenol inhibits LPS-induced translocation of NF- κ B subunit p65 protein into nucleus
The method comprises the following steps: immunofluorescence method for detecting intracellular position of NF-kB subunit p65
Placing the cell slide in a 24-well plate, inoculating RAW264.7 cells, adding 5-pentyl-3-methoxy-phenol to treat for 1 hour after the cells are attached to the wall, incubating with LPS for 1 hour, washing with PBS for 2 times, adding methanol to fix for 4 hours, washing with PBS for 2 times, adding p65 antibody to incubate for 1 hour, washing with PBS for 3 times, adding DAPI and fluorescent secondary antibody to incubate for 50 minutes, observing by using a fluorescent microscope, and taking a picture.
As a result: immunofluorescence results showed (fig. 11) that under normal cell conditions, NF- κ B subunit p65 is located in the cytoplasm, under LPS-induced conditions p65 enters the nucleus, and after treatment with 5-pentyl-3-methoxy-phenol and the positive control didox100(μ M), p65 returns to the cytoplasm.
Example 13: 5-amyl-3-methoxy-phenol can inhibit inflammatory factor expression induced by LPS
The method comprises the following steps: enzyme linked immunosorbent assay for detecting concentration of inflammatory factors
Inoculating RAW264.7 cells into a 24-well plate, culturing until the density reaches 70% -80%, adding compounds to be detected with different concentrations for pretreatment for 1h, co-treating with LPS for 18h, sucking cell culture fluid, centrifuging, taking supernatant, operating according to the instruction of an enzyme-linked immunoassay kit, and measuring the luminous intensity at 450 nm. The inflammatory factor concentration was calculated from the standard curve.
As a result: the results of ELISA showed (FIG. 12) a dose-dependent increase in the inhibitory potency of 5-pentyl-3-methoxy-phenol against LPS-induced inflammatory factors.
Example 14: preparation of tablets
1g of 5-amyl-3-methoxy-phenol, 1.5g of starch and 1.5g of dextrin are added, sieved, added with a proper amount of sodium carboxymethylcellulose, and granulated. Adding magnesium stearate, mixing, and tabletting.
Example 15: preparation of gel
And 3 g of carbomer, 1g of polysorbate and 100mL of water are uniformly mixed, 2g of 5-amyl-3-methoxy-phenol is added, and the mixture is fully and uniformly mixed and subpackaged to obtain the compound carbomer.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims (6)

  1. The application of 5-amyl-3-methoxy-phenol as the only active component in preparing products for preventing and treating diseases induced by oxidative stress or inflammatory reaction is characterized in that the chemical formula of the 5-amyl-3-methoxy-phenol is as follows:
    Figure FDF0000017637260000011
    the oxidative stress or inflammatory response-induced disease is chronic obstructive pulmonary disease, respiratory inflammation, diabetes or tumor disease.
  2. 2. Use according to claim 1, wherein the concentration of 5-pentyl-3-methoxy-phenol is 6.25 to 25 μ M.
  3. 3. Use according to claim 2, wherein the concentration of 5-pentyl-3-methoxy-phenol is 12.5 μ M.
  4. 4. The use according to claim 1, wherein 5-pentyl-3-methoxy-phenol is prepared by a process comprising: the ethanol extract of the litsea martabanica is extracted by adopting petroleum ether, the petroleum ether extracted part is subjected to gradient elution by adopting a petroleum ether-ethyl acetate system, the 8 th part subjected to gradient elution by the petroleum ether-ethyl acetate system is separated by a sephadex LH-20 chromatographic column, and the 5 th part obtained by separation of the sephadex LH-20 chromatographic column is separated by a semi-prepared high performance liquid chromatographic column to obtain the 5-amyl-3-methoxy-phenol.
  5. 5. Use according to claim 1, characterized in that the product is a capsule, tablet, powder, granule, injection, oral liquid, wine, pill, mixture or tincture.
  6. 6. The use according to claim 1, wherein 5-pentyl-3-methoxy-phenol, starch and dextrin are mixed and sieved, then sodium carboxymethyl cellulose is added for granulation, then magnesium stearate is added for mixing and tabletting to obtain tablets; or adding carbomer and polysorbate into water, mixing, adding 5-amyl-3-methoxyl-phenol, and mixing to obtain gel.
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