CN111035632A - Activator of Nrf2 and application of activator in preparation of drugs for preventing and treating environmental toxic substances - Google Patents
Activator of Nrf2 and application of activator in preparation of drugs for preventing and treating environmental toxic substancesDownload PDFInfo
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Abstract
Description
Technical Field
The invention belongs to the technical field of medical application, and relates to a method for preparing an Nrf2 activator by using ferulic acid as an active ingredient, which can be used for preparing a medicine for preventing and treating the damage of environmental toxic substances to organism tissues and organs.
Background
The Keap1-Nrf2 signal path is the most important antioxidant defense response (anti-oxidant response) system of higher organisms, the activation of the Keap1-Nrf2 signal path can cause the expression of hundreds of genes at the downstream of a promoter containing an antioxidant response element (antioxidant response element), the expression products of the genes can eliminate active oxygen species, chemical carcinogen and other toxic substances in organisms and maintain the redox balance in the organisms[1]. The disorder of the Keap1-Nrf2 signal channel can cause the accumulation of Reactive Oxygen Species (ROS) in vivo, namely oxidative stress (oxidative stress), damages biological macromolecules such as nucleic acid, protein, lipid and the like, and seriously influences the physiological function of cellsCan be used. A large number of researches show that cancers, inflammations, neurodegenerative diseases, cardiovascular diseases, diabetes, aging and the like are not related to oxidative stress and are associated with the antioxidant defense reaction capability of organism disorder[1, 2]. The targeted therapy of the Keap1-Nrf2 signal channel has very important application prospect in preventing, delaying and treating the diseases[3]. With the increasing environmental pollution, the research of the Nrf2, which is a main regulator of the antioxidant defense reaction system for eliminating free radicals and toxic carcinogens in vivo, becomes more and more important, and the research and development of small molecule drugs for activating or inhibiting Nrf2 become very important and urgent.
Meanwhile, in recent years, a plurality of cancer counties appear in some places of China, which may be closely related to environmental pollution, such as arsenic pollution of underground water, pollution of chemical waste (such as formaldehyde and the like) and the like. Nrf2 is the most important regulator of human body against environmental pollution. Therefore, the chemical inducer of the Nrf2 can effectively reduce the harm of the environmental toxic substances and the like to human bodies. A large number of epidemiological and laboratory-based research results have shown that some phytochemicals can induce activation of Nrf2, thereby preventing cancer development[4]。
Chinese medicine always plays a significant role in China. In recent years, related experts and scholars continuously separate and extract a series of related active ingredients from Chinese herbal medicines, and the related active ingredients provide wide application prospects for future research. Ferulic Acid (FA) is a phenolic acid derived from plants[5]It is also one of the main components of Chinese medicinal materials of asafetida, Chinese angelica root, cimicifuga root and ligusticum root, etc[6,7]Is represented by phenolic acid component with cinnamic acid as mother nucleus[8]. A series of related studies in recent years have shown that: ferulic acid has wide pharmacological effects, such as removing blood stasis, removing toxic substance, protecting liver, etc., and has stable property and low toxicity[9]. However, ferulic acid is used as an activator of Nrf2, and the application of ferulic acid in preparation of a medicament for preventing and treating the damage of environmental toxic substances to tissues and organs of a body is not reported at present.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a new application of ferulic acid, which is mainly characterized in that ferulic acid is used as an activator ofNrf 2.
The second purpose of the invention is to provide the application of ferulic acid in preparing a medicament for preventing and treating the damage of toxic substances to tissues and organs of a body.
The technical scheme of the invention is summarized as follows:
the ferulic acid is used as an activator of Nrf2 in the preparation of medicines for preventing and treating the damage of environmental toxicants to tissues and organs of organisms. SD rat experiment shows that ferulic acid can prevent and treat the damage of toxic matter to body obviously.
The invention also discloses a composition with treatment or health care function, which is characterized in that: the effective component in the composition is ferulic acid or an active derivative thereof.
The present invention is described in more detail as follows
An activator of Nrf2, mainly comprises ferulic acid.
The molecular formula of ferulic acid is C10H10O4(ii) a The structural formula is shown as the formula (I):
(I)。
the inventors first demonstrated that ferulic acid indeed activates intracellular Nrf2 and its downstream effects, as exemplified by GES-1 and 293T cell lines. Ferulic acid can induce the protein level of Nrf2 in the above two cells to increase, and can enhance the expression of downstream genes such as NQO1 and Mrp2 dependent onNrf 2.
Next, the inventors integrated the ARE-luciferase reporter gene into the genome of GES-1 cells, established a stably expressed cell line, and found that ferulic acid can activate the expression of the luciferase gene to a greater extent. Are (antioxidant responsive element) is an english abbreviation of antioxidant response element, and is a thirty-more base nucleotide sequence specifically bound by antioxidantmajor regulator Nrf 2. Therefore, ferulic acid can remarkably activate the expression of luciferase genes. This result suggests that ferulic acid is a chemoinducer (otherwise known as activator) of Nrf2 and has never been reported before.
Therefore, the inventor discovers for the first time in the world that ferulic acid is a new chemoactivator of Nrf2 and can be used as a new activator thereof. At the cellular level, ferulic acid can activate Nrf2 and its downstream antioxidant protective effects. As a chemical activator of Nrf2, ferulic acid has a very wide application prospect, can be used as a related functional medicine or food adjuvant, and is used for preventing and treating the damage of environmental toxicants to tissues and organs of a body. Related experiments also prove that the ferulic acid can obviously prevent and treat the damage of toxic and harmful substances to organisms.
The Nrf2 activator disclosed by the invention comprises a pharmaceutical composition consisting of ferulic acid and one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical composition can be made into solid oral preparation, liquid oral preparation, injection, etc.
Nrf2 activators of the invention may also be administered parenterally. The preferred form of parenteral administration is injection. The solid and liquid oral formulations comprise: tablets, enteric tablets, capsules, syrups, oral solutions, injections, and the like.
The Nrf2 activator-related pharmaceutical composition of the present invention was prepared as follows: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare microparticles or microspheres. Solid dosage forms include tablets, capsules, sustained release tablets, sustained release pellets and the like. A solid carrier can be at least one substance that can act as a diluent, flavoring agent, solubilizing agent, lubricant, suspending agent, binder, disintegrant, and encapsulating agent. Inert solid carriers include magnesium phosphate, magnesium stearate, powdered sugar, lactose, pectin, propylene glycol, polysorbate 80, dextrin, starch, gelatin, cellulosic materials such as methyl cellulose, microcrystalline cellulose, low melting paraffin, polyethylene glycol, mannitol, cocoa butter, and the like. Liquid dosage forms include solvents, suspensions such as injections, powders, and the like.
Drawings
FIG. 1 shows the experimental results of ferulic acid-activated Nrf 2-dependent antioxidant defense reaction (western-blot validation);
FIG. 2 is the results of ferulic acid-activated Nrf 2-dependent antioxidant defense reaction experiments (q-PCR validation);
FIGS. 3 and 4 are graphs showing the induction effect of ferulic acid antioxidant response elements;
figure 5 is a graph comparing the effect of different treatment groups on GSH content and GSH-PX viability in SD rat brain tissue under formaldehyde exposure.
Detailed Description
The invention is described below by means of specific embodiments. Unless otherwise specified, the technical means used in the present invention are well known to those skilled in the art. In addition, the embodiments should be considered illustrative, and not restrictive, of the scope of the invention, which is defined solely by the claims. It will be apparent to those skilled in the art that various changes or modifications in the components and amounts of the materials used in these embodiments can be made without departing from the spirit and scope of the invention. The raw materials and reagents used in the present invention are commercially available. Wherein the ferulic acid standard is commercially available:
human-derived experimental cell models GES-1 and 293T were purchased from the american ATCC cell collection.
The present invention will be further described with reference to specific examples.
Example 1
The molecular formula of ferulic acid is C10H10O4(ii) a The structural formula is shown as the formula (I):
(I)。
ferulic acid is used as an active ingredient, pharmaceutically acceptable auxiliary materials are added, and the liquid injection with various specifications can be prepared by a conventional method.
The administration routes of ferulic acid include various routes, such as injection administration, intracavity administration and the like.
(1) Preparation of injection:
200 mg of ferulic acid sodium salt, 700 mg of mannitol, PEG 300010 mg and 100 ml of distilled water, wherein the pH value is 7.0-7.5, the concentration of the filtered filtrate is 3mg/ml, the filtrate is subpackaged by 2 ml per ampoule, and the injection is obtained after freeze drying.
(2) Preparation of tablets:
10mg of ferulic acid hydrate, 35 mg of microcrystalline cellulose, 45 mg of starch, 4 mg of polyvinylpyrrolidone, 4.5 mg of sodium carboxymethyl starch, 0.5mg of magnesium stearate and 1 mg of talcum powder; sieving ferulic acid hydrate active ingredient, starch and cellulose, mixing thoroughly, mixing polyvinylpyrrolidone solution with the above powder, sieving to obtain wet granule, drying at 50 deg.C, sieving carboxymethyl starch sodium salt, magnesium stearate and pulvis Talci in advance, adding into the above granule, and tabletting.
(3) Preparation of capsules
10mg of ferulic acid cinnamon crystal form, respectively sieving active ingredient and auxiliary materials with a 100-mesh sieve, weighing the main medicine and the auxiliary materials according to the prescription amount, fully mixing, adding a proper amount of hydroxypropyl methylcellulose solution to prepare soft materials, sieving with a 24-mesh sieve to prepare wet granules, drying in an oven at 50-60 ℃ for about 2-3 hours, uniformly mixing magnesium stearate and talcum powder with the granules, grading, measuring the content of an intermediate, and filling with No. 2 capsules.
Example 2
Discovery and verification of ferulic acid as a new activator ofNrf 2.
The inventor uses ferulic acid (2.5; 5 mu g/ml) with different concentrations and blank groups to respectively treat GES-1 and 293T cell lines, and after the GES-1 and 293T cell lines are acted for 12 hours, the cells are harvested and lysed, and further uses Nrf2 and beta-actin antibodies to carry out Western-blot immunoblotting experiments to detect the corresponding protein expression levels. At the same time, 20. mu.g/mltBHQ was treated as a positive control. Meanwhile, GES-1 and 293T cells are treated by ferulic acid with the concentration of 5 mu g/ml for 12h, the harvested cells are subjected to intracellular total RNA extraction by using a Trizol method, and the mRNA levels of Nrf2, Mrp2 and NQO1 are detected by a real-time fluorescent quantitative q-PCR method. A control was made with 20. mu.g/mltBHQ treatment.
The experimental results show that: expression of the ARE-associated antioxidant gene is correlated to Nrf2 protein expression levels. Ferulic acid, acting on both cell lines for a period of time, did not affect the transcriptional level of Nrf2, but induced an increase in the protein level ofintracellular Nrf 2. At the same time, the expression of target genes NQO1 and Mrp2 downstream of Nrf2 are correspondingly increased. The detailed results are shown in fig. 1 and fig. 2.
Example 3
Ferulic acid activates Nrf 2-dependent antioxidant defense reaction
The inventors inoculated GES-1 cells stably incorporating ARE-Firefly luciferase into a 96-well plate, treated it at a concentration of 5. mu.g/ml for 24 hours when the cell density reached 70% to 80%, and then carried out luciferase activity analysis. A positive control was treated with 20. mu.g/mltBHQ. Next, GES-1 cells were co-transfected with NQO1-ARE-Firefly luciferase and TK-Rellina luciferase. The Firefly luciferase and the Rellina luciferase activities were detected 24 hours after the transfected cells were treated with different concentrations of ferulic acid (1.25; 2.5; 5. mu.g/ml). The ARE-Firefly luciferase expression can be corrected for by Rellina luciferase expression. 2 μ g/ml SF was used as a positive control. The experiment was repeated three times, expressed as standard deviation.
The experimental results show that: in the GES-1 cell model with stably integrated ARE-luciferase, ferulic acid can induce the expression of luciferase genes downstream of ARE. Meanwhile, to further confirm the activating effect of ferulic acid on Nrf2, the inventors used a luciferase dual reporter system with the Rellina luciferase as an internal control, and as a result, confirmed that ferulic acid can indeed activate the expression of ARE-dependent downstream luciferase genes in a dose-dependent manner. The results all show that ferulic acid is a new activator of Nrf2 and has new characteristics. The detailed results are shown in fig. 3 and 4.
Example 4
Ferulic acid can prevent and treat damage of toxic substances to organism tissues and organs.
Plywood and adhesive widely applied in selected decoration materialsThe mixture is made from a contamination room and simulates the living environment after decoration (the concentration of formaldehyde is controlled to be 1.10 +/-0.5 mg/m)3). The experimental SD rats were then randomly divided into three groups, i.e., a negative control group, a model group (infected group), and a dosing group. Placing the rats of the infected group in a virus infection chamber for 6h/d, and carrying out continuous virus infection for 15 days; control rats were placed in a control room (formaldehyde concentration was strictly controlled at the maximum allowable concentration of 0.08mg/m as specified by national sanitation standards)3Within). After formaldehyde contamination is finished every day, the rats in the administration group are injected with ferulic acid drug solution (300 mg/kg) in theabdominal cavity 1 time every day for 15 days. After the experiment is completed, taking brain tissues of each group of rats, and detecting Glutathione (GSH) and glutathione peroxidase (GSH-PX) by a biochemical method. And (4) prompting by a result: the formaldehyde exposure can obviously reduce the GSH content of rat brain tissue and the GSH-PX enzyme activity (p)<0.05), while ferulic acid (300 mg/kg) can obviously improve the content of GSH (glutathione) in the brain tissue of a rat exposed to formaldehyde and the activity of GSH-PX enzyme, and has obvious difference (p) compared with a toxicant exposure group<0.05), thereby prompting that the ferulic acid has obvious prevention and treatment effects on the damage of environmental toxicants to tissues and organs of a body.
Note: at present, most of related medicines capable of preventing and treating the damage of environmental toxic substances to tissues and organs of organisms are chemically synthesized medicines, and have large side effects. Therefore, the low-toxicity and cheap traditional Chinese medicine components representing ferulic acid are expected to be used as active ingredients to develop the medicine aiming at preventing and treating the diseases.
The main references:
1.Villeneuve NF et al. Regulation of the Nrf2-Keap1 Antioxidant responseby the ubiquitin proteasome system: an insight into Cullin-Ring ubiquitinligases. Antioxid Redox Signal 2010, 13:1699-1712.
2. Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway.Drug Metab Rev 2006, 38:769-89.
3. Zhang DD. The Nrf2-Keap1-ARE signaling pathway: the regulation anddual function of Nrf2 in cancer. Antioxid Redox Signal 2010, 13:1623-1626.
4. Zhang DD, Hannik M. Distinct cysteine residues are required for keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 bychemopreventive agents and oxidative stress. Mol Cell Biol 2003, 23: 8137-8151.
5. Sung J, Gim S, Koh P. Ferulic acid attenuates the cerebral ischemicinjury-induced decrease in peroxiredoxin-2 and thioredoxin expression[J].Neurosci Lett, 2014, 26(2):62-67.
6. the development of chemical and pharmacological research on ferulaic acid [ J ]. Chinese patent medicine, 2006, 28(2):253-255.
7. Measuring ferulic acid and ligustilide [ J ] in ligusticum wallichii by an HPLC method, 2010, 33(3) 210-212.
8. Study of permeability of ferulic acid in a Caco-2 cell model and its absorption characteristics in rats [ J ] Chinese herbal medicine, 2012, 43(5): 947 + 951.
9. Yin Hua Fang, Qian Xiao Lian, Liu Bao Rui, etc. the research progress of the anti-tumor action mechanism of ferulic acid [ J ] the modern journal of integration of Chinese and Western medicine, 2010, 19(32): 4238-.
Claims (2)
1. The ferulic acid is used as an activator of Nrf2 in the preparation of medicines for preventing and treating the damage of environmental toxicants to tissues and organs of organisms.
2. A therapeutic or health-promoting composition characterized by: the effective component in the composition is ferulic acid or an active derivative thereof.
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