CN110292593A - Application of the Cortex Magnoliae Officinalis in preparation Tamiflu - Google Patents
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Abstract
The invention discloses application of the Cortex Magnoliae Officinalis in preparation Tamiflu, it is experimentally confirmed, the expression that the effective component of Cortex Magnoliae Officinalis --- traditional Chinese medicine monomer magnolol and honokiol pass through specifically inhibition influenza m 2 ionophorous protein, influenza virus duplication can be effectively suppressed, and have chemiluminescence with Tamiflu Oseltamivir, amantadine, Rimantadine, Ribavirin, the anti influenza effect of these antiviral drugs can be enhanced.
Description
Technical field
The present invention relates to Tamiflu technical fields, and in particular to application of the Cortex Magnoliae Officinalis in preparation Tamiflu.
Background technique
Influenza virus belongs to orthomyxoviridae family, is in spherical or Filamentous, is a kind of single-chain fragment minus-stranded rna virus.According to stream
The antigenicity of Influenza Virus nucleoprotein and stromatin is different, and influenza virus can be divided into tri- types of A, B, C (or for first, second, third
Three types)[1].Wherein, Type B and c-type influenza mainly cause localized epidemics and distribute.And influenza A is according to hemagglutination
The antigenic specificity of plain (Hemagglutinin, HA) and neuraminidase (Neuraminidase, NA) is divided into several hypotypes, respectively
Genetic recombination can occur between hypotype, easily morph, evolutionary rate is fast, antigen is changeable, infectious and pathogenic strong, propagation speed
Degree is fast, can cause seasonal influenza and break out flu outbreak, is a kind of acute respiratory biography for seriously endangering human health
Metachromia virus[1,2,3].20th century successively repeatedly broke out global big influenza so far, brought very grave disaster to the mankind and were difficult to estimate
The economic loss of amount.And different degrees of Influenza epidemic situation occurs in countries in the world every year, in children, old man and people at highest risk
The death rate it is higher, life or even life to the mankind cause huge harm[3]。
Currently, the prevention and treatment of influenza has the following problems: 1, because the height of influenza virus makes a variation, vaccine also can only portion
The eruption and prevalence of sub-control influenza, it is available without ready-made vaccine when there is new influenza virus eruption and prevalence, develop new vaccine
Need certain time[4].2, Tamiflu such as M2 ion channel blocking agent amantadine, Rimantadine and neuraminidase suppression
Preparation zanamivir and Oseltamivir are restricted its clinical application due to serious drug resistance and side effect[5,6,7,8]；3,
The case of new influenza A Subtypes people continuously emerges in recent years, indication there may be big Influenza epidemic situation, such as high to cause
Characteristic of disease H 5 N 1 avian influenza pathogenicity is strong, and the death rate is high after infection, brings fear to the whole world[2,9].Therefore, explore new safety,
Effective Tamiflu, becomes urgent problem, and research and development can overcome the novel Tamiflu of influenza virus drug resistance
It is still the emphasis in current Tamiflu research and development field.
In recent years, by illustrating influenza virus pathogenesis, the molecular structure of influenza virus critical function albumen is explained, one
A little drugmakers and research institution carry out drug design from molecular level and have made some progress[3].It is a kind of if para rice is big
Novel NA neuraminidase inhibitor, has listed as Tamiflu[9], but face drug resistance problems.In order to overcome
The problem of height variation of influenza virus is also easy to produce drug resistance, one of strategy is exactly cocktail therapy, with existing antiviral drug Internet of Things
Medicine treatment influenza is shared, the generation of multidrug resistant disease strain is reduced or inhibits the duplication of multidrug resistant disease strain[15,16,17,18,19].Strategy
Two, part researcher thinks to start with from host cell, and cell component necessary to influenza virus is replicated is found in host cell,
And as drone design and screening Tamiflu.It is copied that research finds that several hundred kinds of host cell contents participate in influenza virus
The committed step of journey[20,21,22,23].As NF-kappaB signal pathway directly participates in adjusting influenza virus from cRNA synthesis vRNA
Process inhibits NF-kappaB signal pathway that influenza virus duplication can be effectively suppressed[24,25,26].Apoptosis is body to virus
The important defense mechanism of infection, a variety of virus compositions such as NS1 etc. activate PI3K/Akt signal pathway to inhibit Apoptosis, to extend
Influenza virus doubling time[27,28]；And c-FLIP is lowered in influenza infection cell as the amphiregulin of apoptosis,
C-FLIP lowers unknown to the destiny of virus infected cell[27,28].It is anti-that these results of study show that host cell contents can be used as
The target of flu pharmaceutical opens new field for research and development Tamiflu.
Honokiol (honokiol, HNK) and magnolol (magnolol, MGN) are Cortex Magnoliae Officinalis (Magnolia
Officinalis Rehd.et wils) main pharmacodynamics ingredient[29,30].Cortex Magnoliae Officinalis category Magnoliaceae Magnolia arbor, bark are
China's tradition precious Chinese herbal medicine is known as three medicinal materials, be the Moschus of state plan management, Radix Glycyrrhizae, Cortex Eucommiae, 4 kinds of Cortex Magnoliae Officinalis it is important
One of medicinal material is used for a variety of prescriptions and Chinese patent drug, such as anti influenza tea, HuoXiangZhengQiShui.Traditional Chinese Medicine thinks that Cortex Magnoliae Officinalis has and dispels
Except chill, full bored, the alleviation headache of chest and abdomen is eliminated, inhibits anxiety, stomach invigorating, antidiarrheal and activating microcirculation and removing stasis medicinal, dispel the effects of apoplexy.
HNK and MGN is isomer, belongs to biphenyl phenolic compound, molecular formula is shown in Fig. 1[32], there is anti-inflammatory, antibacterial, antioxygen
Change, is antitumor, inhibiting the pharmacological actions such as morphine withdrawal syndrome.Wherein, by the research of HNK and MGN Anticancer Effect and Mechanism,
The molecular mechanism that HNK and MGN play a role in cell is more and more clearer[29,30,31,32,33].JI N etc. thinks that HNK passes through induction
The apoptosis of oral squamous cell carcinoma cell and inhibit tumour growth[34]；Chen L etc. confirms that HNK can be inhibited by blood-brain barrier
The growth of glioma cell[35]；Chen N, JiangQ etc. confirm that HNK can cooperate with the antitumous effect of enhancing cis-platinum[36,37,38]；Hu
X etc. is studies have shown that HNK passes through the non-dependent pathway activation Caspase of P53, the apoptosis of induction colorectal cancer tumour cell RKO[39],
It is withered with HNK is also confirmed that by adjusting the tumour cells such as opening induced breast cancer MCF-7 of mitochondria permeability transition pore
It dies[40].In a word, research think HNK and HNK mainly pass through induce cell apoptosis and break up, inhibits angiogenesis, inhibit cell increasing
It grows, inhibit metastases and reversing tumor drug resistance and is antitumor[32,33].NF-kappaB approach is the most important letter of cell
One of number approach participates in the important life processes such as immune, inflammatory reaction, cell Proliferation, its activation protection cell is from apoptosis.
HNK and MGN prevents I κ B α from phosphorylation and degradation, to inhibit NF-kappaB by the activation of inhibition I κ B alpha kinase and Akt
The activation of approach[32,33,41,42].Therefore, NF-kappaB approach is related to the multiple biological activities of HNK and MGN, be as it is anti-inflammatory,
The key signaling pathways of antitumor action etc..Though having been reported that HNK, MGN and its similar bisphenol compound have AntiHIV1 RT activity disease
The effects of poison, HSV-1, dengue fever virus, but its mechanism of action is unknown[43-46].Some researches show that honokiol spreads out in recent years
Raw compounds, which have, inhibits the active effect of influenza neuraminidase[47,48], but there is no honokiol and magnolol anti influenza
Report.
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Summary of the invention
In view of the deficiencies of the prior art, the present invention is intended to provide application of the Cortex Magnoliae Officinalis in preparation Tamiflu.
To achieve the goals above, the present invention adopts the following technical scheme:
The present invention is intended to provide a kind of application of Cortex Magnoliae Officinalis in preparation Tamiflu.
It include the effective component magnolol of Cortex Magnoliae Officinalis as one of technical solution, in Tamiflu.
It further, also include Oseltamivir, amantadine, Rimantadine, Ribavirin in the Tamiflu
One or more of.
It include the effective component honokiol of Cortex Magnoliae Officinalis as another technical solution, in Tamiflu.
It further, also include Oseltamivir, amantadine, Rimantadine, Ribavirin in the Tamiflu
One or more of.
The present invention also provides a kind of Tamiflu, the Tamiflu include Cortex Magnoliae Officinalis effective component magnolol with and
One or both of magnolol.
Further, which further includes Oseltamivir, amantadine, Rimantadine, one in Ribavirin
Kind is several.
The beneficial effects of the present invention are: the present invention is experimentally confirmed, the effective component of Cortex Magnoliae Officinalis --- and traditional Chinese medicine monomer is thick
It is multiple that influenza virus can be effectively suppressed by the expression of specifically inhibition influenza m 2 ionophorous protein in plain phenol and honokiol
System, and have chemiluminescence with Tamiflu Oseltamivir, amantadine, Rimantadine, Ribavirin, it can be enhanced
The anti influenza of these antiviral drugs acts on.
Detailed description of the invention
Fig. 1 is the schematic arrangement of HNK (Honokiol) and MGN (Magnolol)；
Fig. 2 is that HNK and MGN inhibits influenza virus PR8 duplication to act on schematic diagram；
Fig. 3 is that MGN collaboration enhancing amantadine inhibits influenza virus duplication to act on schematic diagram；
Fig. 4 is that MGN collaboration enhancing Ribavirin inhibits influenza virus duplication to act on schematic diagram；
Fig. 5 is that MGN collaboration enhancing Rimantadine inhibits influenza virus duplication to act on schematic diagram；
Fig. 6 is that MGN collaboration enhancing Oseltamivir inhibits influenza virus duplication to act on schematic diagram；
Fig. 7 is that MGN collaboration enhancing amantadine inhibits influenza virus duplication to act on schematic diagram；
Fig. 8 is that HNK collaboration enhancing amantadine inhibits influenza virus duplication to act on schematic diagram；
Fig. 9 is that HNK collaboration enhancing Ribavirin inhibits influenza virus duplication to act on schematic diagram；
Figure 10 is that HNK collaboration enhancing Oseltamivir inhibits influenza virus duplication to act on schematic diagram；
Figure 11 is that HNK inhibits the duplication of PR8 influenza to act on schematic diagram；
Figure 12 is influence schematic diagram of the HNK and MGN to viral protein expression.
Specific embodiment
Below with reference to attached drawing, the invention will be further described, it should be noted that the present embodiment is with this technology side
Premised on case, the detailed implementation method and specific operation process are given, but protection scope of the present invention is not limited to this reality
Apply example.
The present embodiment screens discovery by establishing Tamiflu screening technique from 500 various plants extract monomers
The duplication of influenza virus can be effectively suppressed in HNK and MGN, and HNK inhibits more efficient, as shown in table 1 and Fig. 2.And this reality
Applying PR8 influenza virus used in example is amantadine multidrug resistant disease strain, and when HNK and MGN and amantadine are combined, inhibitory effect is more
Add significant.
Table 1 HNK and MGN inhibit influenza virus duplication
The corresponding experimental method of table 1 is specific as follows:
PR8 influenza infection mdck cell 2h (96 orifice plate), washes away virus, and the Chinese medical extract list of respective concentration is added
22 kinds of compounds such as body HNK and MGN, four multiple holes of each compound, wherein 2 multiple holes and amantadine are combined, such as 1 institute of table
Show.Measure NA enzymatic activity (substrate MU-NANA) in supernatant afterwards for 24 hours, excitation wavelength 360nm measures wavelength 460nm, NA enzymatic activity
Reflect influenza virus duplication.Monomeric compound concentration is 10 μ g/ml.The monomer added in experimental group C5,6,7,8 is HNK, wherein
C7,8 are combined with amantadine；The monomer added in experimental group D1,2,3,4 is MGN, and wherein D3,4 are combined with amantadine；It is real
It tests a group G9,10 be the control group that compound is not added；Experimental group G11, amantadine is only added in 12；Experimental group H9,10,11,12
Middle addition Ribavirin (50 μm of ol/L), wherein H11,12 are combined with amantadine.
Corresponding experimental method is as follows in Fig. 2:
It after mdck cell infects PR8 influenza virus 2h, removes supernatant and is washed cell 2 times with PBS, it is solidifying to spread 0.6% agarose
Glue, the as shown in Figure 2 compound containing respective concentration (MNG, HNK and amantadine) are fixed with 4% formaldehyde after 48h, anti-with mouse
The anti-mouse antibody of PR8 serum and HRP label combines, and dyes (AEC staining Kit, Sigma, AEC-101), and spot is stream
Influenza Virus plaque, spot size reflect that influenza virus duplication is strong and weak.
Fig. 3 show MGN collaboration enhancing amantadine and inhibits influenza virus print effect schematic diagram, corresponding experimental method
Are as follows:
It after mdck cell infects PR8 influenza virus 2h, removes supernatant and is washed cell 2 times with PBS, it is solidifying to spread 0.6% agarose
Glue is marked by containing the compound of respective concentration, being fixed after 48h with 4% formaldehyde shown in Fig. 3 (a) with the anti-PR8 serum of mouse and HRP
Anti-mouse antibody combine, dye (AEC staining Kit, Sigma, AEC-101), spot is influenza virus plaque, and spot is big
Small reflection influenza virus duplication is strong and weak.
Mdck cell infects PR8 influenza virus, removes supernatant after 37 DEG C of incubation 2h, washes cell 2 times, respective concentration is added
The culture medium of MGN measures the enzymatic activity (MU-NANA, Sigma, M8639) of NA in supernatant cell pyrolysis liquid, as a result such as afterwards for 24 hours
Shown in Fig. 3 (b).
Fig. 4 show MGN collaboration enhancing Ribavirin and inhibits influenza virus print effect schematic diagram, corresponding experimental method
Are as follows:
It after mdck cell infects PR8 influenza virus 2h, removes supernatant and is washed cell 2 times with PBS, it is solidifying to spread 0.6% agarose
Glue is marked by containing the compound of respective concentration, being fixed after 48h with 4% formaldehyde shown in Fig. 4 (a) with the anti-PR8 serum of mouse and HRP
Anti-mouse antibody combine, dye (AEC staining Kit, Sigma, AEC-101), spot is influenza virus plaque, and spot is big
Small reflection influenza virus duplication is strong and weak.
Mdck cell infects PR8 influenza virus, removes supernatant after 37 DEG C of incubation 2h, washes cell 2 times, respective concentration is added
The culture medium of MGN measures the enzymatic activity (MU-NANA, Sigma, M8639) of NA in supernatant cell pyrolysis liquid, as a result such as afterwards for 24 hours
Shown in Fig. 4 (b).
Fig. 5 show MGN collaboration enhancing Rimantadine and inhibits influenza virus print effect schematic diagram, corresponding experimental method
Are as follows:
It after mdck cell infects PR8 influenza virus 2h, removes supernatant and is washed cell 2 times with PBS, it is solidifying to spread 0.6% agarose
Glue is marked by containing the compound of respective concentration, being fixed after 48h with 4% formaldehyde shown in Fig. 5 (a) with the anti-PR8 serum of mouse and HRP
Anti-mouse antibody combine, dye (AEC staining Kit, Sigma, AEC-101), spot is influenza virus plaque, and spot is big
Small reflection influenza virus duplication is strong and weak.
Mdck cell infects PR8 influenza virus, removes supernatant after 37 DEG C of incubation 2h, washes cell 2 times, respective concentration is added
The culture medium of MGN measures the enzymatic activity (MU-NANA, Sigma, M8639) of NA in supernatant cell pyrolysis liquid, as a result such as afterwards for 24 hours
Shown in Fig. 5 (b).
Fig. 6 show MGN collaboration enhancing Oseltamivir and inhibits influenza virus print effect schematic diagram, corresponding experimental method
Are as follows:
It after mdck cell infects PR8 influenza virus 2h, removes supernatant and is washed cell 2 times with PBS, it is solidifying to spread 0.6% agarose
Glue is fixed after 48h with 4% formaldehyde as shown in Figure 6 containing the compound of respective concentration, is marked with the anti-PR8 serum of mouse and HRP
Anti-mouse antibody combines, and dyes (AEC staining Kit, Sigma, AEC-101), and spot is influenza virus plaque, spot size
Reflect that influenza virus duplication is strong and weak.
Fig. 7 show HNK collaboration enhancing amantadine and inhibits influenza virus print effect schematic diagram, corresponding experimental method
Are as follows:
It after mdck cell infects PR8 influenza virus 2h, removes supernatant and is washed cell 2 times with PBS, it is solidifying to spread 0.6% agarose
Glue is marked by containing the compound of respective concentration, being fixed after 48h with 4% formaldehyde shown in Fig. 7 (a) with the anti-PR8 serum of mouse and HRP
Anti-mouse antibody combine, dye (AEC staining Kit, Sigma, AEC-101), spot is influenza virus plaque, and spot is big
Small reflection influenza virus duplication is strong and weak, as a result as shown in Fig. 7 (b).
Mdck cell infects PR8 influenza virus, removes supernatant after 37 DEG C of incubation 2h, washes cell 2 times, respective concentration is added
The culture medium of HNK measures the enzymatic activity (MU-NANA, Sigma, M8639) of NA in supernatant cell pyrolysis liquid afterwards for 24 hours.
Fig. 8 show HNK collaboration enhancing Rimantadine and inhibits influenza virus print effect schematic diagram, corresponding experimental method
Are as follows:
It after mdck cell infects PR8 influenza virus 2h, removes supernatant and is washed cell 2 times with PBS, it is solidifying to spread 0.6% agarose
Glue is marked by containing the compound of respective concentration, being fixed after 48h with 4% formaldehyde shown in Fig. 8 (a) with the anti-PR8 serum of mouse and HRP
Anti-mouse antibody combine, dye (AEC staining Kit, Sigma, AEC-101), spot is influenza virus plaque, and spot is big
Small reflection influenza virus duplication is strong and weak.
Mdck cell infects PR8 influenza virus, removes supernatant after 37 DEG C of incubation 2h, washes cell 2 times, respective concentration is added
The culture medium of HNK measures the enzymatic activity (MU-NANA, Sigma, M8639) of NA in supernatant cell pyrolysis liquid, as a result such as afterwards for 24 hours
Shown in Fig. 8 (b).
Fig. 9 show HNK collaboration enhancing Ribavirin and inhibits influenza virus print effect schematic diagram, corresponding experimental method
Are as follows:
It after mdck cell infects PR8 influenza virus 2h, removes supernatant and is washed cell 2 times with PBS, it is solidifying to spread 0.6% agarose
Glue is marked by containing the compound of respective concentration, being fixed after 48h with 4% formaldehyde shown in Fig. 9 (a) with the anti-PR8 serum of mouse and HRP
Anti-mouse antibody combine, dye (AEC staining Kit, Sigma, AEC-101), spot is influenza virus plaque, and spot is big
Small reflection influenza virus duplication is strong and weak.
Mdck cell infects PR8 influenza virus, removes supernatant after 37 DEG C of incubation 2h, washes cell 2 times, respective concentration is added
The culture medium of HNK measures the enzymatic activity (MU-NANA, Sigma, M8639) of NA in supernatant cell pyrolysis liquid, as a result such as afterwards for 24 hours
Shown in Fig. 9 (b).
Figure 10 show HNK collaboration enhancing Oseltamivir and inhibits influenza virus print effect schematic diagram, corresponding experiment side
Method are as follows:
It after mdck cell infects PR8 influenza virus 2h, removes supernatant and is washed cell 2 times with PBS, it is solidifying to spread 0.6% agarose
Glue is fixed after 48h with 4% formaldehyde as shown in Figure 10 containing the compound of respective concentration, is marked with the anti-PR8 serum of mouse and HRP
Anti-mouse antibody combines, and dyes (AEC staining Kit, Sigma, AEC-101), and spot is influenza virus plaque, spot size
Reflect that influenza virus duplication is strong and weak.
It as shown in figure 11 may be by inhibiting the mechanism of the release of virion to play antivirus action signal for HNK
Figure.
Corresponding experimental method are as follows: mdck cell infects PR8 influenza virus, removes supernatant after 37 DEG C of incubation 2h, washes cell 2
It is secondary, by the culture medium for the HNK that respective concentration is added shown in Figure 11, measure the enzymatic activity of NA in supernatant cell pyrolysis liquid afterwards for 24 hours
(MU-NANA,Sigma,M8639)。
As it can be seen that in 22.2 and 7.4 μm of ol/L, NA enzymatic activity obviously drops HNK in cells and supernatant compared with not dosing
It is low, and NA enzymatic activity does not have notable difference in cell pyrolysis liquid, shows: HNK is likely to inhibit the generation of influenza virus particles.This
A little preliminary result of study prompts, HNK and MGN can be used as potential Tamiflu and researched and developed.Therefore, study HNK and
MGN resisiting influenza virus mechanism of action is of great significance.
As shown in figure 12, HNK and MGN inhibits the expression schematic diagram of M2 ionophorous protein, corresponding experimental method are as follows:
1MOI influenza virus PR8 infects A549 cell 2h, and the compound of prescribed concentration is added, and harvests cell phase afterwards for 24 hours
The antibody western blot detection answered.Compound concentration is followed successively by HNK:50,25,12.5 μM, MGN:50,25,12.5 μM,
BAY11-708:50,25,12.5 μM.
For those skilled in the art, it can be provided various corresponding according to above technical solution and design
Change and modification, and all these change and modification, should be construed as being included within the scope of protection of the claims of the present invention.
Claims (7)
1. application of the Cortex Magnoliae Officinalis in preparation Tamiflu.
2. application according to claim 1, which is characterized in that include the effective component Cortex Magnoliae Officinalis of Cortex Magnoliae Officinalis in Tamiflu
Phenol.
3. application according to claim 2, which is characterized in that also include Oseltamivir, Buddha's warrior attendant in the Tamiflu
One or more of alkanamine, Rimantadine, Ribavirin.
4. application according to claim 1, which is characterized in that include the effective component magnolia obovata of Cortex Magnoliae Officinalis in Tamiflu
Phenol.
5. application according to claim 4, which is characterized in that also include Oseltamivir, Buddha's warrior attendant in the Tamiflu
One or more of alkanamine, Rimantadine, Ribavirin.
6. a kind of Tamiflu, which is characterized in that the Tamiflu includes the effective component magnolol and and thickness of Cortex Magnoliae Officinalis
One or both of plain phenol.
7. Tamiflu according to claim 6, which is characterized in that the Tamiflu further includes Oseltamivir, Buddha's warrior attendant
One or more of alkanamine, Rimantadine, Ribavirin.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103212079A (en) * | 2013-04-26 | 2013-07-24 | 陆媛 | Oral medical composition for preventing and/or treating cold and application thereof |
| CN103585571A (en) * | 2013-10-16 | 2014-02-19 | 青岛众泰禽业专业合作社 | Disease-resistant auxiliary material for chickens |
| CN107073123A (en) * | 2014-05-16 | 2017-08-18 | 归属疗法有限公司 | The novel anti-infection strategy of resisiting influenza virus and staphylococcus aureus concurrent infection |
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|---|---|---|---|---|
| CN103212079A (en) * | 2013-04-26 | 2013-07-24 | 陆媛 | Oral medical composition for preventing and/or treating cold and application thereof |
| CN103585571A (en) * | 2013-10-16 | 2014-02-19 | 青岛众泰禽业专业合作社 | Disease-resistant auxiliary material for chickens |
| CN107073123A (en) * | 2014-05-16 | 2017-08-18 | 归属疗法有限公司 | The novel anti-infection strategy of resisiting influenza virus and staphylococcus aureus concurrent infection |
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