CN103462977A - Application of 4', 5, 7-genistein in preparing rotavirus resisting medicine - Google Patents
Application of 4', 5, 7-genistein in preparing rotavirus resisting medicine Download PDFInfo
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Abstract
The invention discloses application of 4', 5, 7-genistein in preparing rotavirus resisting medicine. The genistein can restrain damage of tyrosine protein kinase to cell junction by restraining activation, caused by rotavirus infection, of tyrosine protein kinase of intestinal epithelial cells, so that the intestinal epithelial cells are prevented from being damaged by rotavirus, the completeness of intestinal mucosa is protected, the symptom of rotavirus diarrhea is obviously reduced, and the lethality is reduced. Thus, when the genistein is used as a main active ingredient, high-efficient and low-toxicity specificity rotavirus diarrhea resisting medicine can be researched and developed hopefully.
Description
Technical field
The invention belongs to the new purposes of compound, particularly 4', the application of 5,7-trihydroxy-isoflavone (Genistein) in preparing the medicine of anti-rotavirus.
Background technology
Rotavirus (Rotavirus, RV) belong to arc reovirus virus section, for without after birth double-stranded RNA (dsRNA) virus, article 11, dsRNA respectively is wound around rna dependent rna polymerase (VP1) and the guanyl of 1 molecule and the core that transmethylase (VP3) is positioned at virion of 1 molecule, the 12 kinds of protein of encoding, comprise 6 kinds of structural protein (VP1～4,6～7) and 6 kinds of non-structural proteins (NSP1～6).VP2 forms the internal layer capsid parcel viral genome of rotavirus; The middle level capsid that VP6 forms holds VP2 and forms rotavirus double capsid granule (DLP); The outer capsid that VP4 and VP7 form holds DLP again and forms three layers of capsid particles of complete rotavirus (TLP).Rotavirus enters cell through cell membrane under the mediation of receptor, take off outer capsid formation DLP and start reproduction process, newly-generated viral dsRNA and albumen are assembled the formation virus particle in endochylema, and assembling generates DLP therein, DLP does not have infection ability, it enters endoplasmic reticulum subsequently, with new synthetic VP4 and VP7, is assembled into the TLP with infection ability and secretes host cell, completes viral reproduction process.Rotavirus infection can suppress the expression of host cell proteins, activates multiple protein kinases in host cell and, as the activation of PKA, PKB, PKC, PKG and tyrosine protein kinase, causes that destruction, intestinal mucosal permeability that enterocyte connects increase.Rotavirus infection is the Etiological that causes infantile diarrhea, causes approximately 1.25 hundred million routine gastroenteritis in childrens every year, causes 352,000-592, and 000 example child below 5 years old, because of rotavirus infection death, mainly occurs in developing country.
Up to now, people are also very insufficient to the research of rotavirus infection mechanism of causing a disease, are mainly symptomatic treatment clinically, lack targetedly medicine safely and effectively.Traditional antiviral drugs is mainly IFN-γ or metabolism class antiviral drugs, because these medicines have the shortcomings such as the large and therapeutic effect of toxic and side effects is not good, therefore lessly for anti-rotavirus, infects.For reducing infant infection rate and mortality rate, clinically the high-efficiency low-toxicity medicine of specific treatment rotavirus diarrhea had to very urgent need.
4', 5,7-trihydroxy-isoflavone (Genistein), be the compound extracted from leguminous plant Flos Caraganae Sinicae rhizome, has the effects such as antioxidation, inhibiting tyrosine protein kinase and topoisomerase II, antitumor and inhibition angiogenesis.But up to now, there is not yet Genistein both at home and abroad and there is the relevant report that anti-rotavirus infects the effect of diarrhoea aspect.
Summary of the invention
In view of this, the object of the present invention is to provide the new purposes of Genistein, be the application of Genistein in the medicine for preparing the anti-rotavirus infection, can suppress rotavirus infection and cause that the intestinal epithelial cell tyrosine protein kinase activates, and then the inhibition intestinal epithelial cell comes off, delay the generation of diarrhoea, and reduce fatality rate.
For solving the problems of the technologies described above, provide following technical scheme:
1,4', the application of 5,7-trihydroxy-isoflavone in the medicine for preparing the anti-rotavirus infection.
Further, 4', 5,7-trihydroxy-isoflavone suppresses the application in medicine that rotavirus infection causes that the intestinal epithelial cell tyrosine protein kinase activates in preparation.
Further, 4', 5,7-trihydroxy-isoflavone suppresses the application in medicine that rotavirus infection causes that intestinal epithelial cell comes off in preparation.
Further, 4', 5,7-trihydroxy-isoflavone delays the application in medicine that rotavirus infection causes diarrhoea in preparation.
The present invention use the quantitative proteomics method to human body cell the protein expression profiles after by rotavirus infection analyze, find that rotavirus infection can cause that cell join dependency protein level declines to a great extent, and confirmed the above results by quantitative fluorescent PCR, immunoblotting, then after utilizing the immunofluorescence laser co-focusing to show rotavirus infection, cell junction cell join dependency albumen significantly descends, and illustrates that rotavirus infection has destroyed the cell connection.Because cell connects the adhesive capacity determined between iuntercellular and cell and basement membrane, cell connects damage and directly causes the cell adhesion miopragia and be easy to come off.In body, studies show that, rotavirus infection can cause approximately 50% jejunal epithelium cell and 75% ileal epithelium cell detachment, and epithelial coming off occurs in before symptom of diarrhea occurs.Jejunum and ileal epithelium cell food digest and assimilate process in play topmost effect, and rotavirus diarrhea generally is considered to cause that with viral infection intestinal is directly related to the food digestion malabsorption at present.Therefore, rotavirus infection causes that it is the immediate cause of rotavirus diarrhea that enterocyte cell continuous damage, enterocyte come off in a large number.If the destruction that the cell that can stop rotavirus infection to cause connects, suppress symptom and consequence that enterocyte comes off and just can alleviate rotavirus diarrhea, the medicine thereby the specificity anti-rotavirus of developing high-efficiency low-toxicity is suffered from diarrhoea.In view of cell connects the tight regulation and control that are subject to protein kinase and phosphoprotein phosphatase, the activation of protein kinase causes cell join dependency protein phosphorylation and the connection of rapid damage cell.So, the effect of the cell continuous damage that the present invention causes rotavirus infection by test multiple protein inhibitors of kinases, finding that tyrosine protein kinase inhibitor Genistein is external can significantly suppress destruction and epithelial the coming off that cell that rotavirus infection causes connects.Then issue after examination and approval now in the pilot scale of Balb/c mice rotavirus diarrhea model, thereby Genistein can significantly suppress jejunum and coming off of ileal epithelium cell that rotavirus infection causes, obviously delay the generation of rotavirus diarrhea.In lethal rotavirus diarrhea Balb/c mouse model, Genistein can significantly reduce the mortality rate that rotavirus infection causes filial mice.Above-mentioned experimental result explanation, the destruction that Genistein can connect cell by the activation of inhibiting tyrosine protein kinase, thereby alleviate a large amount of losses of the intestinal epithelial cell that rotavirus infection causes, reach the symptom that obviously alleviates rotavirus diarrhea and the effect of consequence.Take it as active component, be expected to develop the specificity anti-rotavirus medicaments of high-efficiency low-toxicity.
Beneficial effect of the present invention is: the invention provides the application of Genistein in preparing anti-rotavirus medicaments, be expected to develop the specificity anti-rotavirus medicaments of high-efficiency low-toxicity, solve existing antiviral drugs poor effect or the larger problem of toxic and side effects when the treatment rotavirus infection, meet the clinical treatment needs, ensure people's health.
The accompanying drawing explanation
In order to make purpose of the present invention, technical scheme and beneficial effect clearer, the invention provides following accompanying drawing:
Fig. 1 shows and rotavirus infection causes in enterocyte that cell join dependency protein level significantly descends (A is that quantitative proteomics (SILAC technology) is analyzed the variation of enterocyte (Caco-2 cell) in rotavirus infection 24h expression of cellular proteins spectrum, and circle prompting cell join dependency albumen appears at expresses in the albumen significantly descended; B is the quantitative fluorescent PCR analysis result; C is western blot analysis result).
Fig. 2 is cell junction cell join dependency protein expression situation after immunofluorescence laser co-focusing demonstration rotavirus infection.
Fig. 3 is not Babl/c neonatal rat intestinal epithelial cell quantity in the same time of rotavirus infection.
The dropping situations that Fig. 4 is the enterocyte that under in-vitro simulated intestinal luminal digestion environment, different protease inhibitor inhibition rotavirus infections cause.
Fig. 5 is that (A is the intestinal epithelial cell result that comes off for the coming off of Genistein jejunum that rotavirus infection is caused and ileal epithelium cell, diarrhoea and lethal result; B is neonatal rat diarrhoea situation; The lethal situation that C is the rotavirus infection neonatal rat).
The specific embodiment
Hereinafter with reference to accompanying drawing, the preferred embodiments of the present invention are described in detail.The experimental technique of unreceipted actual conditions in preferred embodiment, usually according to normal condition, the molecular cloning experiment guide (third edition for example, J. the work such as Pehanorm Brooker, Huang Peitang Deng Yi， Science Press, 2002) described in condition, or the condition of advising according to manufacturer.
One, the albumen of quantitative proteomics methods analyst host cell after by rotavirus infection changes spectrum
Adopted quantitative proteomics method-cell culture stable isotope aminoacid labelling (SILAC) to analyze the variation that RV infects rear enterocyte Caco-2 protein expression profiles.At first prepare " gently " DMEM culture medium, " in " DMEM culture medium and " weight " DMEM culture medium, wherein " gently " DMEM culture medium be in the DMEM culture medium lysine and arginine replace with respectively L-Lysine-2HCl with and L-Arginine-HCl, " in " the DMEM culture medium is that in the DMEM culture medium, lysine and arginine replace with respectively as L-Lysine-2HCl (4, 4, 5, 5-D4) with L-Arginine-HCl (13C6), " weight " DMEM culture medium is that DMEM culture medium lysine and arginine replace with respectively L-Lysine-2HCl(13C6, 15N2) with L-Arginine-HCl (U-13C6, 15N4), and the dialysis hyclone that volume ratio is 10% in culture medium respectively, penicillin (final concentration 100U) and streptomycin (final concentration 0.1mg/L).Then the Caco-2 cell is at least reached to 6 multiplication cycles with three kinds of culture medium culturing cells respectively, guarantee that arginine on cell protein and lysine can be all by isotope-labeled aminoacid replacement, form respectively " gently " Caco-2 cell, " in " Caco-2 cell and " weight " Caco-2 cell.Will " in " Caco-2 cell and Wa strain rotavirus infection (infection multiplicity MOI=3) for " weight " Caco-2 cell, " gently " Caco-2 cell compares infection with DMEM.After infecting 24h, with the RIPA cell pyrolysis liquid collect " gently " Caco-2 cell and " in " the Caco-2 cell, collect " weight " Caco-2 cell after infection 48h, the extraction total protein of cell, the BCA method is carried out protein quantification.Get equal protein and mixed from 3 groups, get the albumen that 100 μ g mix and carry out the SDS-PAGE electrophoresis with the 10%Bis-Tris pre-prepared colloid, then with the blue dyeing of colloid.The band that will dye is cut into 20 parts to be delivered to new life company of marine section and carries out mass spectral analysis, obtain the initial data that protein diversity is expressed, then these data are carried out to the hierarchical clustering analysis (Gene Ontology Enrichment Analysis-based Hierarchical Clustering) of analyzing based on the gene ontology enrichment.The result demonstration, RV infects the expression (Figure 1A) that has significantly weakened the cell adhesion correlation molecule.The cell join dependency protein gene expression amounts such as tight junction protein ZO-1, desmoplakin 1DSP1 and desmoplakin 2DSP2, epithelium-calcium conglutination element CDH1, PLECTIN1, CTNND1, CGN, JUP1, JUP2 significantly descend (Figure 1B) after qRT-PCR detection display Wa strain rotavirus infects.The analysis showed that the also significantly decline (Fig. 1 C) of expression after Wa strain rotavirus infects of the cell join dependency albumen such as E-caherin, Plakoglobin, Desmoplakin, Laminin B2, Fibronectin1, CGN, Plectin1 and ZO-1 through Western blot.
Two, after the immunofluorescence laser co-focusing shows rotavirus infection, cell junction cell join dependency albumen significantly descends
The rotavirus infection cell, with adopting the laser co-focusing method to observe, is observed to the impact of rotavirus infection cell on cell join dependency protein localization.Found that, after rotavirus infection, cell join dependency albumen join dependency as tight as ZO-1(), E-caherin(adheres to join dependency), Desmoplakin(desmosome join dependency) in the cell junction, significantly descend (Fig. 2), show that rotavirus infection has destroyed various cells and connected.
Three, rotavirus infection intestinal epithelial cell counting in the same time not
Model rotavirus infection Diarrhea Model, utilize 5 age in days Balb/c neonatal rats (body weight 3.0g-4.0g) to infect rotavirus SA11 strain (the 6th generation), and the virus inoculation amount is 2 * 10
6pFU/g.In this model, viral infection 16h part neonatal rat starts to occur obvious symptom of diarrhea (watery stool), and after infection 24h, 100% symptom of diarrhea all occurs.We 8h, 12h, 16h and 24h after viral infection separate respectively Babl/c neonatal rat small intestinal (minute duodenum, jejunum, the ileum) epithelial cell of infection and use the blood cell counting plate counting, and result as shown in Figure 3.Result shows, infects 8h, each Duan Junwei of 12h small intestinal and obvious epithelial cell loss occurs.Yet, to infecting 16h, with the matched group ratio, infected group has reduced 50% jejunal epithelium cell and 75% ileal epithelium cell, infect the 24h result consistent with 16h.Result shows that in this model, rotavirus infection 16h can cause that neonatal rat jejunum and ileal epithelium cell come off in a large number.Jejunum and ileal epithelium cell food digest and assimilate process in play topmost effect.Therefore, rotavirus infection causes that it is the immanent cause of rotavirus diarrhea that intestinal epithelial cell seriously comes off, and directly causes the appearance of symptom of diarrhea subsequently.
Four, Genistein can significantly suppress coming off of enterocyte that rotavirus infection causes
Rotavirus infection causes that it is the immediate cause of rotavirus diarrhea that enterocyte cell continuous damage, enterocyte come off in a large number.If the destruction that the cell that can stop rotavirus infection to cause connects, suppress symptom and consequence that enterocyte comes off and just can alleviate rotavirus diarrhea, the medicine thereby the specificity anti-rotavirus of developing high-efficiency low-toxicity is suffered from diarrhoea.In view of cell connects the tight regulation and control that are subject to protein kinase and phosphoprotein phosphatase, the activation of protein kinase causes cell join dependency protein phosphorylation and the connection of rapid damage cell.So; the present invention is by digestibility environment (adding 100 μ g/ml trypsin in the Caco-2 cell culture fluid) in in-vitro simulated small intestinal enteric cavity; and the protective effect that in the rotavirus infection situation, cell connected of the kinases inhibitor that test concentrations is 1 μ g/mL under this environment, selected following kinases inhibitor: HT-89, Staurosporine, Genistein, SP600125, U0126, SB203580, Wortmannin and DMSO in experiment.Then observation of cell quantity, suppress to obtain kinases inhibitor the epithelial dropping situations that rotavirus infection causes in vitro, and result as shown in Figure 4.Result shows, tyrosine protein kinase inhibitor Genistein is external can significantly suppress epithelial the coming off that rotavirus infection causes.
Destruction and epithelial coming off that the activation of the tyrosine protein kinase caused due to rotavirus infection connects cell play pivotal role.Therefore, the cell detachment by the Genistein inhibiting tyrosine protein kinase, rotavirus infection caused has this significantly to alleviate effect.Accordingly, the cell tyrosine protein kinase can be used as the drug effect target, by its inhibitor, as Genistein, suppresses its activity, thereby is expected to develop the specificity anti-rotavirus medicaments of high-efficiency low-toxicity.
Five, Genistein significantly suppresses coming off of intestinal epithelial cell that rotavirus infection causes, obviously delays the generation of rotavirus diarrhea, reduces the rotavirus infection fatality rate.
When infecting 4h, 8h, 12h, neonatal rat press respectively 1 μ g/g body weight to Genistein.The Genistein preparation becomes the liquid storage of 50mM, and solvent is DMSO.Administering mode, for the Genistein liquid storage of dosage is diluted to 50 μ L with PBS, pours in the neonatal rat stomach by neonatal rat gavage flexible pipe.Contrast administration group gavage equivalent DMSO, and be diluted to 50 μ L with PBS.After infecting 16h, put to death neonatal rat and separate intestinal epithelial cell counting, structure as shown in Figure 5A.Result shows, after infected group gavage Genistein, intestinal epithelial cell is compared without significantly reducing with infected group not, and remarkable minimizing (Fig. 5 A) appears in infected group not gavage group.Result shows in rotavirus infection Balb/c neonatal rat model that gavage Genistein can suppress intestinal epithelial cell and come off.
Simultaneously, the diarrhoea situation of statistical experiment neonatal rat, result is as shown in Figure 5 B.Result shows, the same at rotavirus infection Balb/c neonatal rat model gavage Geinistein(dosage and mode), only have 30% appearance diarrhoea after gavage during 24h, diarrhoea just all occurs to 48h, and diarrhoea just all appears in matched group rotavirus infection 24h.The above results shows that Genistein can obviously delay the generation of rotavirus diarrhea.
Set up the Balb/c neonatal rat model of a lethal rotavirus infection, utilized 5 age in days Balb/c neonatal rats (body weight>4.5g) to infect rotavirus SA11 strain (the 6th generation), the virus inoculation amount is 2 * 10
6pFU/g, then observe neonatal rat diarrhoea and death condition, and result as shown in Figure 5 C.Result shows, in this model, takes turns viral infection 16h rear section neonatal rat and starts to occur obvious symptom of diarrhea (watery stool), and after infection 24h, 100% symptom of diarrhea all occurs, infects the death of 48h part neonatal rat, infects almost all neonatal rat death of 60h.Yet, in this model, gavage Genistein(dosage and mode are the same) after can significantly reduce the fatality rate of rotavirus infection, the neonatal rat of gavage Genistein is showed no death, illustrates that Genistein can obviously reduce the rotavirus infection fatality rate.
By the above results, can be judged; Genistein can pass through inhibiting tyrosine protein kinase; suppress the destruction that rotavirus infection connects cell and the coming off of the intestinal epithelial cell caused; the digestive and absorptive functions of protection small intestine epithelium; thereby delay the generation of rotavirus diarrhea, reduce the rotavirus infection fatality rate.It can be used as active component, apply separately or form compound recipe with other active component, adopt pharmaceutically acceptable adjuvant and preparation conventional method, make the anti-rotavirus medicaments of the various dosage forms such as tablet, capsule, granule, powder, oral liquid or injection, for clinical.
Finally explanation is, above preferred embodiment is only unrestricted in order to technical scheme of the present invention to be described, although the present invention is described in detail by above preferred embodiment, but those skilled in the art are to be understood that, can make various changes to it in the form and details, and not depart from the claims in the present invention book limited range.
Claims (4)
1.4', the application of 5,7-trihydroxy-isoflavone in the medicine for preparing the anti-rotavirus infection.
2. application according to claim 1 is characterized in that: 4', 5,7-trihydroxy-isoflavone suppresses the application in medicine that rotavirus infection causes that the intestinal epithelial cell tyrosine protein kinase activates in preparation.
3. application according to claim 1 is characterized in that: 4', 5,7-trihydroxy-isoflavone suppresses the application in medicine that rotavirus infection causes that intestinal epithelial cell comes off in preparation.
4. application according to claim 1 is characterized in that: 4', 5,7-trihydroxy-isoflavone delays the application in medicine that rotavirus infection causes diarrhoea in preparation.
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| CN2013104622381A CN103462977A (en) | 2013-09-30 | 2013-09-30 | Application of 4', 5, 7-genistein in preparing rotavirus resisting medicine |
| PCT/CN2013/085618 WO2015043024A1 (en) | 2013-09-30 | 2013-10-21 | Use of genistein in preparing rotavirus resisting medicament |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104744448A (en) * | 2015-02-15 | 2015-07-01 | 庄爱华 | Isoflavone compound as well as pharmaceutical composition, preparation method and functions thereof |
| CN104926772A (en) * | 2015-07-02 | 2015-09-23 | 云南中烟工业有限责任公司 | Novel flavonoid compound as well as preparation method and uses thereof |
| CN111110837A (en) * | 2020-01-06 | 2020-05-08 | 中国人民解放军陆军军医大学 | Application of carboxypeptidase inhibitor in preparation of medicine for preventing severe lethal rotavirus infection |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104761526B (en) * | 2015-04-11 | 2017-03-08 | 云南中烟工业有限责任公司 | A kind of isoflavonoid with antiviral activity and its preparation method and application |
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- 2013-10-21 WO PCT/CN2013/085618 patent/WO2015043024A1/en active Application Filing
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744448A (en) * | 2015-02-15 | 2015-07-01 | 庄爱华 | Isoflavone compound as well as pharmaceutical composition, preparation method and functions thereof |
| CN104744448B (en) * | 2015-02-15 | 2016-03-02 | 庄爱华 | Isoflavone compounds, its pharmaceutical composition and its production and use |
| CN104926772A (en) * | 2015-07-02 | 2015-09-23 | 云南中烟工业有限责任公司 | Novel flavonoid compound as well as preparation method and uses thereof |
| CN104926772B (en) * | 2015-07-02 | 2017-05-17 | 云南中烟工业有限责任公司 | Novel flavonoid compound as well as preparation method and uses thereof |
| CN111110837A (en) * | 2020-01-06 | 2020-05-08 | 中国人民解放军陆军军医大学 | Application of carboxypeptidase inhibitor in preparation of medicine for preventing severe lethal rotavirus infection |
| CN111110837B (en) * | 2020-01-06 | 2022-11-25 | 中国人民解放军陆军军医大学 | Application of carboxypeptidase inhibitor in preparation of medicine for preventing severe lethal rotavirus infection |
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Application publication date: 20131225 |