CN113384575A - Use of diosbulbin in cell proliferation inhibition - Google Patents
Use of diosbulbin in cell proliferation inhibition Download PDFInfo
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- CN113384575A CN113384575A CN202110758729.5A CN202110758729A CN113384575A CN 113384575 A CN113384575 A CN 113384575A CN 202110758729 A CN202110758729 A CN 202110758729A CN 113384575 A CN113384575 A CN 113384575A
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- diosbulbin
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- itraconazole
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
The invention provides application of diosbulbin B and tetrahydrodiosbulbin B in inhibition of HaCaT cell proliferation, and itraconazole has a synergistic effect on inhibition of HaCat cell proliferation by the diosbulbin B and the tetrahydrodiosbulbin B. The invention provides experimental basis for the development of HaCaT cell proliferation inhibition drugs, and opens up a way for the development of new drugs and the utilization of xanthium seed resources.
Description
Technical Field
The invention belongs to the technical field of biological medicines, relates to an inhibition effect of diosbulbin on cell proliferation, and particularly relates to an inhibition activity of diosbulbin B and derivatives (analogues) thereof on HaCaT cells.
Background
The Dioscorea bulbifera is tuber of Dioscorea bulbifera of Dioscorea of Dioscoreaceae, also named Dioscorea bulbifera, Dioscorea bulbifera root, Dioscorea bulbifera, Pseudobulbus Cremastrae seu pleiones, oviductus Ranae, and rhizoma Iridis Tectori. Mainly produced in Hunan, Hubei, Jiangsu, etc., and also planted in Shandong, Henan, Anhui, Zhejiang, Fujian, etc. The airpotato yam rhizome is cool in nature and bitter in taste, has the effects of cooling blood, reducing pathogenic fire, clearing gall and detoxifying, has the pharmacological action and clinical application recorded in ancient books, and is high in medicinal value and wide in application. In modern clinic, the airpotato yam rhizome is mostly used for treating diseases such as goiter, hematemesis and epistaxis, esophagus cancer, gastric cancer, scrofula, breast tumor and the like, but the airpotato yam rhizome is found to have hepatotoxicity, and the toxicity severely restricts the clinical function.
The airpotato yam rhizome contains various compounds such as stilbenes, flavonoids, steroids, diterpene lactones and the like, but at present, research aiming at the pharmacological action and related mechanisms of a specific chemical component in the airpotato yam rhizome is concentrated in a few compounds such as diosgenin, diosgenin and the like, and the pharmacological actions and mechanisms of the other compounds are yet to be further researched (Zhu Da Cheng, the university of traditional Chinese medicine in Jiangxi, 2020,32(02), 117-containing materials 121).
Modern researches show that diterpene lactone compounds are main effective and toxic components of airpotato yam, and found diterpene lactone components mainly comprise diosbulbin A-M, 8-epidiosbulbin acetate (EEA) and the like, wherein diosbulbin B and 8-epidiosbulbin acetate are taken as main components (Lijun and the like, a Chinese medical science journal 2020,38(12), 100-. Diterpene lactone components represented by diosbulbin B are active components of airpotato yam and toxic components thereof (Lijun, et al, J. Others. J., 2019,39(15), 3846-3848).
For toxicological studies on xanthoceras sorbifolia hepatotoxicity, the hepatotoxicity mechanism of xanthoceras sorbifolia is mainly studied from the aspects of metabolic activation, oxidative stress, mitochondrial damage, apoptosis and the like. Parallel in vitro toxicity screening of 6 yellow toxins (Diosbulbins) based on L-02 cells revealed that a variety of yellow toxins, including yellow toxin B, are the material basis for xanthene hepatotoxicity (suyu et al, proceedings of the chinese symposium of pharmacology in 2012 and the twelfth week of chinese pharmacist). Research on the Liangyuqiong and the like shows that the continuous administration of the general saponin (TSRD) of the airpotato yam rhizome has certain toxicity to the liver of a mouse, and the mechanism of the TSRD is probably related to oxidative stress injury and induction of the expression of liver tissue Nrf2 and CYP2E1 (the Chinese medical journal of 2020 and 10).
With the continuous and deep research on toxic components and toxicological mechanisms of xanthate, the understanding of the liver toxicity mechanism of xanthate becomes more objective and clear. However, the inhibitory effect of xanthium and its extracts on cell proliferation still needs to be further investigated.
Disclosure of Invention
The invention aims to provide the inhibitory activity of diosbulbin B and derivatives (analogs) thereof on HaCaT cells. Based on the existing literature and the research and development results disclosed by the existing literature, diterpene lactone compounds represented by diosbulbin B are the main effective components and toxic components of airpotato yam. The invention is obtained through cell culture experiments, and the diosbulbin B and the derivatives (analogues) thereof have different proliferation inhibition effects on HaCaT cells and show inhibition synergistic effect with the existing medicines.
The invention provides application of diosbulbin B (DSB) and tetrahydrodiosbulbin B (4H-DSB) in HaCaT cell proliferation inhibition. Based on the conclusion of the invention, any one of the diosbulbin B and the tetrahydrodiosbulbin B has the proliferation inhibition effect on HaCaT cells; or the combination of the diosbulbin B and the tetrahydrodiosbulbin B has the proliferation inhibition effect on HaCaT cells.
The invention also provides the application of the combination of the diosbulbin B and the tetrahydrodiosbulbin B with itraconazole in HaCaT cell proliferation inhibition. Based on the conclusion of the invention, the combination of the diosbulbin B and the itraconazole has the proliferation inhibition effect on HaCaT cells; alternatively, the combination of tetrahydroxantholone B and itraconazole has proliferation inhibitory effect on HaCaT cells. Furthermore, the itraconazole has a synergistic effect on inhibition of proliferation of HaCat cells by the diosbulbin B and the tetrahydrodiosbulbin B.
Furthermore, the invention provides the application of the itraconazole in enhancing the inhibition of the proliferation of HaCat cells by the diosbulbin B and the tetrahydrodiosbulbin B.
The invention provides a HaCaT cell proliferation inhibition drug, which comprises components including diosbulbin B, tetrahydrodiosbulbin B or a combination thereof.
The invention provides a medicine for inhibiting HaCat cell proliferation, which is prepared by taking diosbulbin B and itraconazole as effective components.
The invention provides a medicine for inhibiting HaCat cell proliferation, which is prepared by taking tetrahydropalmatine B and itraconazole as effective components.
It should be noted that the diosbulbin B of the present invention is isolated from airpotato yam or airpotato yam extract, or obtained from other possible routes (e.g., chemical synthesis, biosynthesis). The present invention is not particularly limited in this regard.
The preparation of the various medicaments of the invention by persons of ordinary skill in the art, including researchers in the field, comprises the effective components and also comprises auxiliary materials, carriers or auxiliary agents and the like which are acceptable in the medical field. The invention is not described in further detail here. Based on the technical teaching of the invention, the medicines of the invention do not exclude other medicine components, and the existence or nonexistence of the medicine components has proliferation inhibition effect on HaCaT cells.
Compared with the prior art, the application of the diosbulbin in the aspect of cell proliferation inhibition has the beneficial effects or advantages that: the main contribution of the invention is to define the application of the diosbulbin B and the tetrahydrodiosbulbin B in the aspect of inhibiting the proliferation of HaCaT cells, and the itraconazole has a synergistic effect on inhibiting the proliferation of HaCat cells by the diosbulbin B and the tetrahydrodiosbulbin B, so that the new application of medicines such as the diosbulbin B, the tetrahydrodiosbulbin B, the itraconazole and the like is expanded. In addition, the invention provides experimental basis for the development of HaCaT cell proliferation inhibition drugs, and opens up a way for the development of new drugs and the utilization of xanthate seed resources.
Drawings
FIG. 1 is a graph of the inhibition of HaCaT cell proliferation by the agents described in the examples. In FIG. 1, "+" below the abscissa represents treatment with LPS (lipopolysaccharide) or Itraconazole (Itraconazole); "-" indicates no treatment with LPS or Itraconazole. Comparing the groups corresponding to the lower parts of the two ends of the horizontal line in fig. 1, it is concluded whether the group on the right side below the horizontal line has significant difference compared with the group on the left side. In the context of figure 1 of the drawings,
denotes: the cell proliferation rate of the LPS-induced group is obviously greater than that of the group without LPS induction, and p is less than 0.01.
Represents: on the basis of LPS induction, the cell proliferation rate of the DSB treatment group is obviously lower than that of the blank solvent DMSO treatment group, and p is less than 0.05.
Denotes: on the basis of LPS induction, the cell proliferation rate of the 4H-DSB treatment group is obviously lower than that of the blank solvent DMSO treatment group, and p is less than 0.01.
n.s. denotes: itraconazole had no significant effect on the proliferation rate of normal HaCat cells.
And # denotes: on the basis of LPS induction, the cell proliferation rate of the itraconazole treatment group is obviously lower than that of the blank solvent DMSO treatment group, and p is less than 0.01.
n.s. denotes: based on LPS induction and DSB treatment, the cell proliferation rate of the itraconazole treatment group is not significantly different from that of the group without itraconazole treatment.
And # # denotes: based on LPS induction and 4H-DSB treatment, the cell proliferation rate of the itraconazole-treated group was significantly lower than that of the group treated without itraconazole, with p <0.001(n ═ 6).
Detailed Description
The following examples are given to illustrate the technical aspects of the present invention, but the present invention is not limited to the following examples.
Diosbulbin b (dsb) solution: weighing 17.0mg DSB, adding 500 μ L DMSO, ultrasonic treating to make it fully suspended and dissolved, and storing at 4 deg.C for use.
Tetrahydroxantholone B (4H-DSB) solution: weighing 17.2mg of 4H-DSB, adding 500 mu L of DMSO, performing ultrasonic treatment to fully suspend and dissolve the mixture, and storing the mixture at 4 ℃ for later use.
Itraconazole (ITC) solution: 7.1mg ITC was weighed, 200. mu.L DMDO was added, and the mixture was sonicated to fully suspend and stored at 4 ℃ for further use.
Recovering HaCaT cells (human immortalized epidermal cells) to 75cm2The culture flask was cultured in MEM medium containing 15% Fetal Bovine Serum (FBS), 1% penicillin and streptomycin, and placed at 37 ℃ under 5% CO2An incubator. After passage HaCaT cells in logarithmic growth phase were taken for experiments.
The HaCaT cells were seeded in 96-well plates at a density of 5000 cells/well, and when the HaCaT cell growth confluence reached 50-60%, the complete medium (MEM medium containing 15% FBS, 1% penicillin-streptomycin) was replaced with MEM medium containing no FBS, and the HaCaT cells were starved for 12 hours. Then the culture broth (without FBS, containing 1%MEM medium with penicillin-streptomycin) was again changed to 0.5 μ g/mL LPS; itraconazole of 20 μm; LPS (lipopolysaccharide) 0.5 μ g/mL and itraconazole 20 μm; 0.5. mu.g/mL LPS and 100. mu.M DSB; 0.5. mu.g/mL LPS and 100. mu.M 4H-DSB; 0.5 μ g/mL LPS, 20 μ M itraconazole and 100 μ M DSB; 0.5. mu.g/mL LPS, 20. mu.M itraconazole and 100. mu.M 4H-DSB in MEM (containing 1% penicillin and streptomycin), and a blank solvent DMSO in MEM as a control. After 24h, 10. mu.l of CCK-8 solution was added to each well, and the incubation was performed in an incubator (37 ℃ C., 5% CO)2) The culture was continued for 1.5h, and then the absorbance was measured at 450 nm. Each group of 6 multiple wells.
The growth inhibition rate was [ (1-experimental OD value/blank OD value) x 100% ].
The results of the effect of the above drugs on the proliferation of HaCaT cells are shown in FIG. 1. As can be seen from figure 1, after 24H of administration, 100 μ M of 4H-DSB and DSB have proliferation inhibition on HaCaT cells, and the inhibition rates are 12.7% and 8.3%, respectively; and the itraconazole has a synergistic effect on the 4H-DSB and the DSB to inhibit the proliferation of HaCat cells.
As described above, the present invention can be preferably implemented, and the above-mentioned embodiments only describe the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various changes and modifications of the technical solution of the present invention made by those skilled in the art without departing from the design spirit of the present invention shall fall within the protection scope defined by the present invention.
Claims (7)
1. Use of diosbulbin B and tetrahydrodiosbulbin B in inhibiting HaCaT cell proliferation is provided.
2. The use of diosbulbin B and tetrahydrodiosbulbin B in combination with itraconazole in HaCaT cell proliferation inhibition is provided.
3. The use according to claim 2, wherein itraconazole has a synergistic effect on the inhibition of proliferation of HaCat cells by diosbulbin B and tetrahydrodiosbulbin B.
4. A HaCaT cell proliferation inhibitor contains xanthomazine B, tetrahydroxanthomazine B or their combination as effective component.
5. A medicine for inhibiting HaCat cell proliferation is prepared from diosbulbin B and itraconazole.
6. A medicine for inhibiting HaCat cell proliferation is prepared from tetrahydroxanthomazone B and itraconazole as effective components.
7. The application of itraconazole in enhancing the inhibition of the proliferation of HaCat cells by using diosbulbin B and tetrahydrodiosbulbin B.
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