CN114984026A - Application of glycyrrhetinic acid monosaccharide glycoside in preparation of medicine for preventing and treating pulmonary fibrosis - Google Patents
Application of glycyrrhetinic acid monosaccharide glycoside in preparation of medicine for preventing and treating pulmonary fibrosis Download PDFInfo
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- CN114984026A CN114984026A CN202210683664.7A CN202210683664A CN114984026A CN 114984026 A CN114984026 A CN 114984026A CN 202210683664 A CN202210683664 A CN 202210683664A CN 114984026 A CN114984026 A CN 114984026A
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- glycyrrhetinic acid
- pulmonary fibrosis
- monoglycoside
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of medicines, and particularly relates to application of glycyrrhetinic acid monosaccharide glycoside in preparation of a medicine for preventing and treating pulmonary fibrosis. The compound glycyrrhetinic acid monoglycoside provided by the invention not only shows a better treatment effect, obviously relieves the inflammatory reaction and collagen deposition of mouse pulmonary fibrosis, inhibits the activation of a PI 3K/AKT/NF-kB signal pathway, and has no side effect, so that the compound Glycyrrhetinic Acid Monoglycoside (GAMG) can be used for preparing anti-pulmonary fibrosis drugs.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of glycyrrhetinic acid monoglycoside in preparation of a medicine for preventing and treating pulmonary fibrosis.
Background
Idiopathic Pulmonary Fibrosis (IPF) is a fatal, progressive fibrotic interstitial disease of the lung, well-developed in the middle-aged and elderly populations. The types of pathological changes characterized are common Interstitial pneumonia (UIP), manifested by mild-to-moderate inflammatory infiltration, alveolar epithelial cell injury and proliferation, excessive deposition of extracellular matrix (ECM), alveolar septal thickening, scarring and formation of fibroblast foci, and temporal heterogeneous fibrotic remodeling of the lung structure. With progressive changes in pulmonary fibrosis, lung tissue loses gas exchange capacity, the mean life span after diagnosis is only 3 years, and the survival rate of patients within 5 years is less than 30%, lower than that of most cancers, so IPF is also often referred to as "cancer that is not cancer". On the other hand, the etiology of Idiopathic Pulmonary Fibrosis (IPF) is unknown, morbidity and mortality are increasing year by year, there are currently few treatment options other than lung transplantation, and there is no effective therapeutic drug, and the FDA has approved only pirfenidone and nintedanib as first-line therapeutic drugs for IPF), however, clinical application thereof is limited due to low patient compliance caused by various side effects. There is therefore an urgent need to find new anti-IPF drugs with improved drug properties and reduced drug side effects.
Disclosure of Invention
In order to solve the problems, the invention provides the application of glycyrrhetinic acid monoglycoside in preparing the medicine for preventing and treating pulmonary fibrosis.
The above object is achieved by the following preparation process:
the invention provides application of glycyrrhetinic acid monoglycoside in preparation of a medicament for preventing and treating pulmonary fibrosis.
As a further optimized scheme of the invention, the glycyrrhetinic acid monoglycoside is added with pharmaceutically acceptable auxiliary materials to prepare clinically usable medicament formulations.
As a further optimization of the invention, the pharmaceutical dosage form is one or more of tablets, capsules, troches, injections, suspensions, suppositories and ointments.
As a further optimization scheme of the invention, the auxiliary material is a carrier or an excipient.
As a further optimization scheme of the invention, the excipient is one or more of carbon microcrystalline cellulose, starch, lactose, crospovidone and hydroxypropyl cellulose.
As a further optimization of the invention, the carrier is one or more of a diluent, a disintegrant, a binder or a lubricant.
As a further optimization scheme of the invention, the dosage of the glycyrrhetinic acid monoglycoside in the medicine is 50-500 mg/kg/d.
As a further optimization scheme of the invention, the dosage of the glycyrrhetinic acid monoglycoside in the medicine is 200 mg/kg/d.
The principle of the invention is as follows:
the liquorice is a common tonifying Chinese herbal medicine, glycyrrhizic acid (GL) is a main bioactive component in the liquorice, has good anti-inflammatory activity, is high in lung tissue distribution concentration, can improve inflammation, oxidative stress, epithelial mesenchymal transition and the like of pulmonary fibrosis, and has good anti-inflammatory effect, and the pulmonary fibrosis is accompanied by inflammatory reaction. Glycyrrhetinic acid monoglycoside (18 β -Glycyrrhetinic acid 3-O- β -D-glu curonide, GAMG) is an active metabolite of pentacyclic triterpene aglycone Glycyrrhetinic acid with one molecule of glucuronic acid removed from GL at the 3-position carbon, and the route is shown in FIG. 9.
Compared with glycyrrhizic acid (GL), Glycyrrhetinic Acid Monoglycoside (GAMG) has the following significant advantages: (1) GAMG is an active metabolite of GL, and has high safety; (2) pharmacokinetics shows that: oral GL C in rats max 346.03 + -145.13 ng/mL, AUC 0-T 459.32 ± 80.81 mg/lh; oral administration of GAMG C to rats max 2377.57 + -547.40 ng/mL, 6625.54 + -1680.70 mg/Lxh; respectively 6.9 times and 14.4 times of GL, and the oral bioavailability of GAMG is significantly higher than that of GL; (3) the GAMG has high distribution concentration in tissues such as lung, kidney, liver, etc., and is more effective for treating pulmonary fibrosis; (4) GAMG has stronger pharmacological activities such as anti-inflammatory and antioxidation than GL: (5) the water solubility of GAMG is obviously better than that of GL, the patent medicine property is good, and the adverse reaction is small. The application of GAMG in preventing and treating pulmonary fibrosis is not reported, and its action mechanism for resisting pulmonary fibrosis is shown in figure 8.
The invention has the beneficial effects that: the invention discloses a new research and development of a medicine for preventing and treating pulmonary fibrosis, and discloses a new application of glycyrrhetinic acid monoglycoside in preparation of a medicine for preventing and treating pulmonary fibrosis or a new application of the compound and pharmaceutically acceptable auxiliary materials in preparation of a medicine for preventing and treating pulmonary fibrosis, wherein the glycyrrhetinic acid monoglycoside can reduce the inflammatory reaction of pulmonary fibrosis and the molecular mechanism of collagen deposition by inhibiting the activation of a PI 3K/AKT/NF-kB signal channel for the first time.
Drawings
FIG. 1 is a graph showing the effect of HE (200X) in lung tissue of each group of mice;
FIG. 2 is a graph showing the comparison of the effects of Masson (200X) on lung tissues of various groups of mice;
FIG. 3 is a graph showing the effect of Sirius red staining (200X) on lung tissue of each group of mice;
FIG. 4 is a graph showing the effect of IHC (200X) in lung tissue of each group of mice;
FIG. 5 is a graph showing that GAMG reduces the secretion of inflammatory cytokines in mice;
FIG. 6 shows that GAMG ameliorates fibrotic conditions by inhibiting PI3K/AKT/P65 NF-kappa B254 signaling pathway: (A) the content of PI3K/AKT/P65 NF-kB protein in lung tissues is detected by an immunoblotting method. (B) P-PI3K/PI3K, P-Akt/Akt and P-P65/P65 relative protein expression levels (upper panel); the relative expression levels of PI3K/β -Actin, Akt/β -Actin and p65/β -Actin in each group (lower panel);
FIG. 7 shows the inhibition of IL-1 β, an inflammatory factor, by GAMG groups at doses of 50-500 mg/kg;
FIG. 8 is a schematic diagram showing the action of glycyrrhetinic acid monoglycoside for resisting pulmonary fibrosis;
FIG. 9 shows the route of obtaining the compound glycyrrhetinic acid monoglycoside.
Detailed Description
The present application will now be described in further detail with reference to the drawings, and it should be noted that the following detailed description is given for purposes of illustration only and should not be construed as limiting the scope of the present application, as these numerous non-limiting modifications and variations will suggest themselves to those skilled in the art in light of the foregoing disclosure.
Detailed description of the preferred embodiments
The preparation method used in this example is a conventional method known to those skilled in the art unless otherwise specified, and for example, the method for preparing tablets, capsules, troches, injections, suspensions, suppositories, ointments and other dosage forms is a conventional method, and the carrier or excipient and other materials are used, wherein the excipient is microcrystalline cellulose, starch, lactose, crospovidone, hydroxypropyl cellulose; the carrier is diluent, disintegrant, binder or lubricant, and is commercially available product unless otherwise specified.
The preparation process of tablets (1000 tablets) each containing 100mg of the active ingredient glycyrrhetinic acid monoglycoside is provided below:
the active ingredient glycyrrhetinic acid monoglycoside is mixed with microcrystalline cellulose, starch and lactose in the amounts indicated in table 1, the mixture is moistened with 75% ethanol and sieved to granulate.
Drying, mixing with crospovidone and magnesium stearate, and tabletting to obtain tablet with weight of 350.0mg and active ingredient content of 100 mg.
TABLE 1 dosage of each ingredient of tablets containing glycyrrhetinic acid monoglycoside
Second, test
1. Material
7-8 week old female C57/BL mice were housed in a purified ventilated (25 + -2) C animal house, provided by the laboratory animal center of the second people hospital, Anhui province, and had free access to food and water.
2. Method of producing a composite material
2.1 preparation of Experimental animal models
Selecting 120 female C57/BL mice 7-8 weeks old, randomly dividing into 4 groups, each group containing 30 mice, experimentally setting blank control group for applying normal saline for trachea instillation, and additionally setting model control group, glycyrrhetinic acid monoglycoside GAMG group (administration concentration 200mg/kg/28d), and glycyrrhizic acid GL group (administration concentration 200mg/kg/28d), and administering to the model control group, glycyrrhetinic acid monoglycoside GAMG group, and glycyrrhizic acid GL group by intraperitoneal injection (preparation method comprises adding active ingredient glycyrrhetinic acid monoglycoside raw material into appropriate amount of water for injection, stirring thoroughly, adding water for injection to reach administration concentration, adding active carbon 2.0g for injection, heating to 60 deg.C, stirring for 30min, filtering with carbon rod, filtering filtrate with 0.25 μm microporous membrane for sterilization, and not only for the preparation process, administering 3 groups of mice with single-wall injection inducer before trachea instillation (carbon nanotube SWCNT) for 30min, the administration was continued for 28 days, and 10 mice in each of the 4 groups were sampled on days 3, 7, and 28 of the administration.
2.2 evaluation index and results
Lung tissue isolation was performed on the mice of different groups on days 3, 7, and 28 to prepare paraffin sections, and the lung tissue injury was observed by paraffin section line HE, Masson, Sirius red, and IHC staining. Pulmonary inflammation and pulmonary fibrosis score criteria reference inflammation scores and Ashcroft scores.
2.2.1HE staining results
As can be seen from the HE staining result in FIG. 1, the inflammatory factors are the most in 3 days, and the HE pathological section of the lung tissue of the mouse in 28 days shows that the inflammatory factors are reduced, the lung tissue of the mouse model control group is disordered and the scar tissues are obviously increased compared with the blank control group, and the lung structure of the GAMG group is relatively better and the scar is reduced compared with the lung structure of the model control group, so that the lung is protected. The histogram in fig. 1 is a statistical depiction of HE staining results on day 3, day 7 and day 28, respectively, with three replicates of data, * p<0.05vs control group; # p<0.05vs SWCNT group; *# p<0.05vs SWCNT + GL group.
2.2.2Masson staining results
As can be seen from the Masson staining result in fig. 2, blue collagen fibers are significantly increased with the increase of time in the model control group compared with the blank control group, and the GAMG group can alleviate the generation of blue collagen fibers, which indicates that pulmonary fibrosis can be alleviated, lung function can be improved, and a protective effect can be achieved.
The bar graph in fig. 2 is a statistical depiction of Masson staining of collagen deposition in lung tissue after SWCNT exposure on days 3, 7 and 28, respectively, with three replicates of data, * p<0.05vs control group; # p<0.05vs SWCNT group; *# p<0.05vs SWCNT + GL group.
2.2.3 results of Sirius red staining
As can be seen from the Sirius red staining result in fig. 3, the collagen fiber deposition is significantly increased with time in the model control group compared to the blank control group, and the GAMG group can alleviate the collagen fiber generation, which also indicates that the pulmonary fibrosis can be alleviated, the lung function can be improved, and the protective effect can be achieved.
2.2.4IHC staining results
As can be seen from the IHC staining results in fig. 4, the collagen fiber deposition is significantly increased with time in the model control group compared to the blank control group, and the GAMG group can relieve the generation of the epithelium to the stroma, which indicates that the lung fibrosis can be relieved, the lung function can be improved, and the protective effect can be achieved.
The histogram in fig. 4 is a statistical depiction of immunohistochemical analysis of lung fibroblast vimentin and alpha-SMA protein levels, respectively, with three replicates of data, * p<0.05vs control group; # p<0.05vs SWCNT group; *# p<0.05vs SWCNT + GL group.
2.2.5GAMG reduction of inflammatory cytokine secretion
As can be seen from FIG. 5, 3-28 days after intratracheal injection of single-walled carbon nanotubes (SWCNT), the levels of IL-1 β, IL-6 and tumor necrosis factor (TNF- α) in alveolar lavage fluid were significantly increased, and collagen deposition was significantly increased at 28 days.
Cytokines IL-1 β, TNF- α and IL-6 are upregulated in inflammatory responses and are involved in the formation of fibroblasts and cell matrices. After 3 days, the ELISA kit is adopted to detect that the expression levels of IL-1 beta, TNF-alpha and IL-6 in lung tissues of each group are obviously increased, and the generation of cytokines is obviously reduced by treating GAMG group and GL group. The GAMG group (200mg/kg/d) was more effective in inhibiting the expression of inflammatory factors in lung tissue than the GL group.
2.2.6Western blotting Experimental results
As can be seen from FIG. 6, the single-walled carbon nanotube stimulates the PI 3K-Akt-NF-kB signal pathway, activates the expression of phosphorylated PI3K (p-PI3K) and AKT (p-AKT) and NF-kB (p-p65), and GAMG is more effective in inhibiting PI3K/AKT phosphorylation and NF-kB activation than GL.
(A) Western Blotting analysis of levels of PI3K/AKT/NF- κ B protein in lung tissue. (B) p-PI3K/PI3K, p-AktRelative expression levels of/Akt, p-p65/p65 protein (see FIG. 6); relative protein expression levels for different groups of PI3K/β -actin, Akt/β -actin, p65/β -actin (FIG. 6 below). Data are presented as mean ± SEM of each independent experiment (n ═ 3). * p<0.05vs control group; (ii) a # p<0.05vs SWCNT group; (ii) a *# p<0.05vs SWCNT + GL group.
2.2.7 inhibition of the inflammatory factor IL-1 beta by GAMG groups at different doses (preliminary experiments)
42 female C57/BL mice of 7-8 weeks old are selected, randomly divided into 7 groups, 6 mice in each group are administered by intraperitoneal injection according to different administration concentrations, a model control group is established, the administration concentrations are respectively 50mg/kg/d, 100mg/kg/d, 200mg/kg/d, 300mg/kg/d, 400mg/kg/d and 500mg/kg/d, 3 groups of mice are administered with the drug by intraperitoneal injection 30min before a trachea instillation inducer (single-walled carbon nanotube SWCNT), the drug administration is carried out for 3 days continuously, and the 7 groups of mice are respectively subjected to material drawing detection on the 3 rd day.
The research shows that the inflammation is gradually reduced and the fibrosis is gradually increased along with the increase of time, and in order to obtain the maximum result with the minimum cost in the preliminary experiment, the release of the inflammatory factor IL-1 beta in 3 days of mice of different groups is mainly observed, the detection result is shown in figure 7, compared with a model control group SWCNT, the detection result can show that the GAMG with the dosage of 50-500mg/kg/d can effectively inhibit the expression of the inflammatory factor of lung tissues, particularly the group with the dosage of 200mg/kg shows the best inhibitory effect of the inflammatory factor IL-1 beta, and therefore, the administration concentration is selected to achieve the best treatment effect.
2.3 conclusion of the experiment
Glycyrrhetinic acid monoglycoside GAMG can relieve pulmonary fibrosis symptoms by blocking PI 3K-AKT-NF-kB signal channel, inhibiting lung fibroblast inflammatory factor expression and HYP and collagen synthesis. Therefore, the compound glycyrrhetinic acid monoglycoside (administration dosage: 50-500mg/kg/d, preferably 200mg/kg/d) can effectively treat pulmonary fibrosis of mice.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
Claims (8)
1. Application of glycyrrhetinic acid monosaccharide glycoside in preparing medicine for preventing and treating pulmonary fibrosis is provided.
2. The use of claim 1, wherein the glycyrrhetinic acid monoglycoside is added to pharmaceutically acceptable excipients to prepare a clinically acceptable pharmaceutical dosage form.
3. The use according to claim 2, wherein the pharmaceutical dosage form is one or more of a tablet, a capsule, a lozenge, an injection, a suspension, a suppository, an ointment.
4. The use according to claim 3, wherein the adjuvant is a carrier or excipient.
5. The use according to claim 4, wherein the excipient is one or more of carbon microcrystalline cellulose, starch, lactose, crospovidone, and hydroxypropyl cellulose.
6. Use according to claim 4, wherein the carrier is one or more of a diluent, a disintegrant, a binder or a lubricant.
7. The use according to any one of claims 1 to 6, wherein the dosage of glycyrrhetinic acid monoglycoside in the medicament is 50 to 500 mg/kg/d.
8. The use according to claim 7, wherein the dosage of glycyrrhetinic acid monoglycoside in the medicament is 200 mg/kg/d.
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| CN101919870A (en) * | 2009-06-12 | 2010-12-22 | 张鲁榕 | Application of glycyrrhetinic acid and glycyrrhizic acid in preparing medicaments for preventing or treating pulmonary fibrosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101919870A (en) * | 2009-06-12 | 2010-12-22 | 张鲁榕 | Application of glycyrrhetinic acid and glycyrrhizic acid in preparing medicaments for preventing or treating pulmonary fibrosis |
Non-Patent Citations (2)
| Title |
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| 姚光弼: "《临床肝脏病学》", 31 July 2011, pages: 648 * |
| 曹梦欣: "甘草次酸单糖苷(GAM)在大鼠体内的药代动力学及组织分布研究", 《中国优秀秀硕士学位论文全文数据库 医药卫生科技辑(月刊)》, no. 1, 15 January 2022 (2022-01-15) * |
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