CN107007632A - For improvement or the composition of prophylaxis of herpes viral infections disease - Google Patents
For improvement or the composition of prophylaxis of herpes viral infections disease Download PDFInfo
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- CN107007632A CN107007632A CN201710061490.XA CN201710061490A CN107007632A CN 107007632 A CN107007632 A CN 107007632A CN 201710061490 A CN201710061490 A CN 201710061490A CN 107007632 A CN107007632 A CN 107007632A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
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Abstract
Present invention aims at there is provided the composition for improvement or prophylaxis of herpes viral infections disease, herpesvirus infection model is set to absorb Bifidobacterium.Its result understands that its virus quantity is reduced, and the development of its infection symptoms is suppressed.And it was found that, reduced even if making the immunologic function of herpesvirus infection model, its inhibition is not also influenceed, therefore Bifidobacterium is also effective in terms of the recurrence of the herpesvirus infection disease occurred when preventing the immunologic function reduction of host.
Description
Technical field
The present invention relates to the composition for improvement or prophylaxis of herpes viral infections disease.More specifically, it is related to containing double
Discrimination bacillus as active ingredient, for improve or prophylaxis of herpes viral infections disease composition.
Background technology
Herpesvirus infection disease is the disease as caused by herpesvirus infection, can be enumerated by herpes simplex virus type 1
(HSV-1) herpes labialis, genital herpes etc. caused by herpes simplex virus type 2 (HSV-2) infection caused by infecting.
So, these diseases are fallen ill due to a variety of herpesvirals, but the phase in terms of latent infection and recurrence
Together.I.e., it is known that herpesviral hides in neuromere after the treating initial infection of body surface, in the immunologic function drop because of hosts such as pressure
Recurred when low.
In addition, being directed to herpesvirus infection disease, it is (non-special that the nucleic acid analog such as ACV, Valaciclovir is used for its treatment
Sharp document 1~3), and the infected is continued to grant also accepted to prevent from recurring.But, for these treatment sides
Method, also reports some side effects, in addition, medicine valency is high, turn into problem greatly to patient body aspect and in the burden of economic aspect.
Also, by continue to grant and its treatment is long-term carry out in the case of, herpesviral is likely to obtain drug resistance.Therefore,
Ask the replacement medical treatment for substituting nucleic acid analog.
So, it is desirable to explore, develop it is cheap and safe be used to improve or prophylaxis of herpes viral infections disease material,
But present situation is not yet to obtain such material.
In addition, the preventive effect and/or disease symptomses of disease are demonstrated for enteric bacteria such as Bifidobacteriums in recent years
Improvement etc., has carried out the trial utilized as safe medicine and/or diet product.However, so far, for double
Discrimination bacillus etc. reports the symptom improvement for various disease, but is not yet reported in the treatment of herpesvirus infection disease
The example of middle application.
Prior art literature
Non-patent literature
Non-patent literature 1：S.E Straus, H etc., N.Engl.J.Med., 1984, volume 310, page 1545~1550
Non-patent literature 2：J.M.Douglas etc., N.Engl.J.Med., 1984 year, volume 310, page 1551~1556
Non-patent literature 3：L.G.Kaplowitz etc., JAMA, 1991 year, volume 265, page 747~751
The content of the invention
The present invention be in view of problem present in above-mentioned prior art and complete, it is therefore intended that find to be used to improve or pre-
Anti- herpesvirus infection disease is effective and has the inexpensive substance of high security.And purpose is that there is provided contain the material conduct
Active ingredient, for improve or prophylaxis of herpes viral infections disease composition.
The present inventors have studied Bifidobacterium having in herpesvirus infection animal model to solve above-mentioned problem
Effect property.Specifically, the model mice orally ingestible is made as the bifidobacterium longum of one of Bifidobacterium
(Bifidobacterium longum) (BR-108 plants), evaluate the virus quantity in the mouse and its degree of symptom.Its result
Understand, by absorbing Bifidobacterium, virus quantity is reduced, and the development of its infection symptoms is suppressed.It will also realize that in addition, it is described double
The antiviral activity of discrimination bacillus is lasting.And it was found that, reduced even if making the immunologic function of model mice, to the inhibition
Also without so big influence, therefore, the recurrence of the herpesvirus infection disease occurred when preventing the immunologic function reduction of host
Aspect, Bifidobacterium is also effective, so as to complete the present invention.
More specifically, the present invention provides following invention.
(1) it is used for the composition of improvement or prophylaxis of herpes viral infections disease, contains Bifidobacterium as active ingredient.
(2) composition according to (1), wherein, the Bifidobacterium is bifidobacterium longum.
(3) composition according to (1) or (2), wherein, the herpesvirus infection disease is by herpes simplex virus 2
Infection disease caused by type.
(4) composition according to any one of (1)~(3), is orally ingestible composition.
In addition, the BR-108 strains of Bifidobacterium as be described hereinafter like that, are that advantage is deposited in the flora (excrement etc.) of normal infant
Bacterium, it can be said that its security determine.In addition, its cultural method is also determined, therefore also can inexpensively it provide.
By absorbing the composition of the present invention, improvement or prophylaxis of herpes viral infections disease can be realized.In addition, the present invention
The active ingredient of composition is Bifidobacterium, cheap and safe.Also, the present invention composition can it is daily easily
Intake, and then also can continue to easily absorb for a long time.In addition, Bifidobacterium is to hold to the inhibition of herpesvirus infection disease
Continuous, also, when the immunologic function reduction of host, Bifidobacterium is also tieed up to the inhibition of herpesvirus infection disease
Hold.So, it is also useful in the recurrence for suppressing herpesvirus infection disease.
Brief description of the drawings
Fig. 1 is to represent to be vaccinated with the virus after being inoculated with 3 days in the mouse propagation device of herpes simplex virus type 2 (HSV-2)
The figure of the measurement result of amount." BR4 hundred million ", " BR20 hundred million " and " BR100 hundred million " represents to make the HSV-2 Mice Inoculateds daily
The result of Bifidobacterium (BR-108 plants) 400,000,000,2,000,000,000 and 10,000,000,000 is absorbed respectively.And " control group " represents not absorbing double
The result of the HSV-2 Mice Inoculateds of discrimination bacillus.And then, "+" represents that the HSV-2 after being disposed through immunodepressant is inoculated with
The result of mouse, "-" represents the result for the HSV-2 Mice Inoculateds disposed without immunodepressant.In addition, block diagram and its
Upper appended bar represents mean ± SD (average value ± standard deviation).And " asterisk " is represented and without immunodepressant disposal
Control group is compared to statistical significant difference (P ＜ 0.05) is observed, " No. # " represents and compareing for being disposed through immunodepressant
Group is compared to it was observed that statistical significant difference (P ＜ 0.05).In addition, statistical significant difference is examined by Dunnet
And Mann-Whitney U are examined and evaluated.
Fig. 2 is to represent to be vaccinated with the figure that lesion score (average value) is changed over time in HSV-2 mouse.In addition, in figure
Label it is identical with Fig. 1 label.
Fig. 3 is to represent to absorb the virus quantity being vaccinated with HSV-2 mouse blood after Bifidobacterium or ACV (ACV)
The figure that (antiviral activity) is changed over time.The longitudinal axis is represented using the blood in each mouse when virus quantity is 100% in the blood of check plot
The ratio (%) of middle virus quantity.The time of transverse axis represents to make mouse absorb the time after Bifidobacterium or ACV.In addition, column
Figure and bar appended thereon represent mean ± SD.
Embodiment
The present invention is provided to improve or prophylaxis of herpes viral infections disease composition, contain Bifidobacterium as effectively into
Point.
In the present invention, " herpesvirus infection disease " refers to by belonging to virus infection caused by the virus of herpetoviridae
Disease, as such virus, for example, can enumerate the herpesviral (herpes simplex virus type 1 for belonging to Alphaherpesvirinae
(HSV-1), herpes simplex virus type 2 (HSV-2), nerpes vinrus hominis 3 (HHV-3, varicellazoster virus, VZV)),
Belong to herpesviral (nerpes vinrus hominis 5 (HHV-5, cytomegalovirus, CMV), the human herpes virus 6 of Betaherperesvirinae
(HHV-6), human herpes virus 7 (HHV-7)), belong to the herpesviral ((HHV- of nerpes vinrus hominis 4 of Gammaherpesvirinae
4, Epstein-Barr viral (Epstein-Barr virus), EBV), (HHV-8, Ka Boxi (Kaposi) sarcoma is related for Human herpesvirus 8
Herpesviral)).
In the present invention, " improvement " in addition to including treatment herpesvirus infection disease completely, also including ease symptom and
Suppress its development." prevention " includes suppressing or postponing the morbidity of herpesvirus infection disease and suppresses its recurrence.Also, improve
Or prevention also includes reducing the amount as herpesviral the reason for herpesvirus infection disease.In addition, implementation for example as be described hereinafter
Shown in example, the effect of the improvement of herpesvirus infection disease or prevention can be determined by the virus quantity based on Plaque assays and/or
Evaluated using the quantizing for symptom degree of lesion score.
Can be the bacterium for belonging to Bifidobacterium, example as " Bifidobacterium " of the active ingredient of the composition of the present invention
Bifidobacterium longum (Bifidobacterium longum), bifidobacterium breve (Bifidobacterium can such as be enumerated
Breve), bifidobacterium bifidum (Bifidobacterium bifidum), bifidobacterium infantis (Bifidobacterium
Infantis), bifidobacterium adolescentis (Bifidobacterium adolescentis), bifidobacterium catenulatum
It is (Bifidobacterium catenulatum), bifidobacterium pseudolongum (Bifidobacterium pseudolongum), thermophilic
Bifidobacterium (Bifidobacterium thermophilum), as long as the improvement with herpesvirus infection disease or prevention are made
With being just not particularly limited.
The Bifidobacterium preferably bifidobacterium longum used in the composition of the present invention, particularly preferably bifidobacterium longum
BR-108 plants.In addition, BR-108 plants (BR-108) are the bifidobacterium longums separated from infant faeces, it is on April 13rd, 2012
It is preserved in independent independent administrative institution System product Evaluation value skill Intraoperative base Disk Machine Agencies (the Leaf Ken Mu Geng Jinshi City か ず さ Sickle of NITE, 〒 292-0818 thousand
Sufficient No. 122 room of 2-5-8) bacterium (preserving number：NITE P-1317).In addition, the Bifidobacterium is also with shown in sequence number 1
Nucleotide sequence as the sequence of 16SrRNA genes bacterium.
In addition, above-mentioned Bifidobacterium can only it is a kind of be used for the present invention composition, can also two or more strains match somebody with somebody
Share in the composition of the present invention.Also, in the present compositions, Bifidobacterium can use as viable bacteria and can also make
Used for dead thalline.Dead thalline is used as the combination of the present invention due to excellent heat resistance, stay in grade, tasteless odorlessness
The active ingredient of thing is preferred.As the dead thalline in the composition of the present invention, the thalline after heating sterilization can be used.Plus
Thalline after thermal sterilization can be prepared as follows：From conventionally culture Bifidobacterium obtained by culture, with for example filtering,
Centrifuge etc. method reclaim thalline, be suspended in after washing in water etc., with less than 120 DEG C (preferably 80~120 DEG C), 30 minutes with
Interior (3 seconds~30 minutes) are heated, and then concentrated as needed, dry (freeze-drying etc.) and pulverization process,
So as to prepare.In addition, the attritive powder of the heating sterilization thalline of BR-108 plants of bifidobacterium longum is used as product name " BR-108 (notes
Volume trade mark) " (manufacture of Combi Off ァ Application Network シ ョ Na Le Off ー ズ division departments) commercially available.In addition, making in the present compositions
For the Bifidobacterium that active ingredient contains can be foregoing thalline or material contained by the bacterium, this is thin
The secretory product of bacterium, by the bacteriogenic metabolite.
The composition of the present invention can be pharmaceutical composition, the diet product for improvement or prophylaxis of herpes viral infections disease
The form of the reagent used in (including animal feed) or animal pattern experiment etc..
Composition in the present invention can be carried out formulation by known galenic pharmacy method.Capsule can be for example made
Agent, lozenge, pill, liquor, powder, granule, fine granule, film coating agent, pill, tablet, sublingual dose, masticatory, mouth containing
Agent, paste, syrup, suspending agent, elixir, emulsion, coating agent, ointment, emplastrum, opoultice, percutaneous absorption type preparation, wash
Agent, inhalant, aerosol, injection, suppository etc., are used oral or parenterally.The present invention is to be used as the double of enteric bacteria
Discrimination bacillus is the composition of active ingredient, can be absorbed by oral non-intruding and simply.That is, composition of the invention is preferred
Acquisition method be to be absorbed by orally.
In these are formulation, the carrier that can pharmacologically or as diet product be allowed using proper combination, specifically make a living
Manage salt solution, aqua sterilisa, vegetable oil, solvent, excipient, matrix agent, emulsifying agent, suspending agent, surfactant, stabilizer, fragrance
Agent, aromatic, medium (vehicle), preservative, bonding agent, diluent, isotonic agent, painless agent, extender, disintegrant,
Buffer, smears, lubricant, colouring agent, sweetener, thickener, drug flavoring, dissolving adjuvant or other additives
Deng.
In the case where using the composition of the present invention as pharmaceutical composition, improvement that can be with herpesvirus infection disease
And/or the known material used in prevention is used in combination.As the known material, for example, it can enumerate ACV, cut down former times
Luo Wei, cidofovir, FCV, Fomivirsen, FOSCARNET, GCV, iodoxuridine, Penciclovir, Trifluridine, figured silk fabrics more former times
Nucleic acid analog, DNA synthetic inhibitors etc. as Luo Wei and arabinosy ladenosine.In addition, as shown in embodiment described later,
ACV antiviral activity reduce when, Bifidobacterium antiviral activity enhancing, therefore, by with the bleb
The known material used in the improvement and/or prevention of viral infectious disease is used in combination, in the present invention can more efficiently and effect
Ground improves and prophylaxis of herpes viral infections disease.
In the case where using the composition of the present invention as diet product, the diet product for example can be healthy food, work(
Can property food, specific health food, trophic function food, feature sign food, dietary supplement, patient with food,
Or animal feed.The diet product of the present invention can be absorbed with above-mentioned such composition forms, can also be with various diet products
Form intake.As the concrete example of diet product, the fermented foods such as Yoghourt, lactic acid drink, fermented beverage can be enumerated；It is edible
The product containing oil such as oil, flavoring, mayonnaise, margarine；Soup class, milk beverage, cold drink, tea beverage, alcohol drink
The liquid food such as material, potus, g., jelly-like beverage, functional beverage；The food containing carbohydrate such as meal class, such as noodles, bread；Fire
The livestock and poultry such as leg, sausage are processed food；The aquatic products processing food such as breaded fish stick, dried food and nuts, cured fish；The fruits and vegetables food such as salted vegetables；Jelly etc.
Semi-solid food；The fermented foods such as miso；Western-style pastry class, Japanese snack categories, confectionery, chewing gum class, soft sweets, frozen dessert,
The various snack categories such as the freezing point heart；The foods packed in carton containers products such as curry, gravy, Chinese soup；Instant soup, the instant food such as fast food miso juice
And/or the corresponding food of micro-wave oven etc..Can also further enumerate be prepared into powder, particle, lozenge, capsule, liquid, pasty state or
The health diet product of g., jelly-like.In addition, the manufacture of the diet product in the present invention can be by manufacturing known to the technical field
Technology is implemented.In the diet product, can add the improvement to herpesvirus infection disease or prevention it is effective it is one or two kinds of with
Upper composition (such as nutrient).Alternatively, it is also possible to pass through other compositions or other with playing the function beyond the improvement etc.
Functional food combination is used as multi-functional diet product.
The composition of the present invention can be used using the animal including people as object, as the animal in addition to people, not had
Especially limitation, can be with various domestic animals, poultry, pet, animal for research etc. for object.Specifically, can enumerate pig, ox,
Horse, sheep, goat, chicken, duck (カ モ), ostrich, duck (ア ヒ Le), dog, cat, rabbit, hamster, mouse, rat, monkey etc., but do not limit
It is formed on this.
In addition, the object of the composition as the present invention, can not consider that it enumerates infection herpesviral with how falling ill
Animal, can be to be applied without infection herpesviral or the animal of suspected infection herpesviral in addition from the viewpoint of prevention
With or make its intake the present invention composition.And from the viewpoint of recurrence prevention, for there is not the carrying of its symptom
The animal of herpesviral, can also preferably use the composition of the present invention.
In the case where granting or absorbing the composition of the present invention, age according to object of its amount of granting or intake, body
Weight, the symptom of herpesvirus infection disease, health status, species of composition (medicine, diet product etc.) etc. are suitably selected.For example lead to
The amount of granting or intake of Bifidobacterium are 0.5 × 10 daily for often9Individual/kg body weight~50 × 109/ kg body weight, preferably 2
×109Individual/kg body weight~50 × 109Individual/kg body weight.
In addition, the method that the present invention also provides the herpesvirus infection disease for improvement or object of prevention like this, it is special
Levy and be, object is granted or it is absorbed Bifidobacterium or is contained Bifidobacterium as the composition of active ingredient.
In addition, as Bifidobacterium or containing Bifidobacterium granting or intake as the composition of active ingredient, such as
It is upper described, once a day or (such as 2 times) several times can also be divided into grant or absorb.In addition, can also during granting or absorbing
Stopped according to the improvement degree of herpesvirus infection disease, but as described above, from the viewpoint of recurrence prevention, expect not stop ground
Continue to grant or absorb.In addition, can be the continuation for continuing or vacating interval daily, in effect for " continuation "
From the aspect of, preferably unceasingly grant or absorb Bifidobacterium or contain Bifidobacterium as the composition of active ingredient daily.
The product (medicine, diet product, reagent) or its specification of the composition of the present invention can be enclosed for improvement or pre-
The sign of the purport of anti-herpesvirus infection disease.In addition, on diet product, can be (specific for health care as health functional food
Food, trophic function food, feature sign food) marks of healthy functions is enclosed on product of composition etc. of the present invention
Show, to be differentiated in terms of form and object with normal food.Wherein " sign is enclosed in product or specification " anticipates
Think of be product in itself, container, packaging etc. enclose sign, or in the specification, additional document, publicity of open product information
Thing, other printed articles etc. enclose sign.
Embodiment
Below, based on embodiment, the present invention is more specifically illustrated, but the present invention is not limited to following examples.
In order to understand fully that Bifidobacterium, to herpesviral and the validity for the infection disease being induced by it, carries out following experiment.
(Bifidobacterium)
Wherein, the Bifidobacterium used is BR-108 plants of the bifidobacterium longum separated from human infant excrement
(Bifidobacterium longum BR-108), is to be preserved in independent independent administrative institution System product Evaluation value skills Intraoperative on April 13rd, 2012
Base Disk Machine Agencies (No. 122 room of Leaf Ken Mu Geng Jinshi City か ず さ Sickle foot 2-5-8 of NITE, 〒 292-0818 thousand) bacterium (preserving number：
NITE P-1317).Also, by material (Combi Off ァ Application obtained by bacterium progress heating sterilization, freeze-drying and pulverization process
The manufacture of Network シ ョ Na Le Off ー ズ division departments, product name：BR-108 (registration mark)) absorb mouse as described later.
(herpesviral)
In addition, the herpesviral used is UW268 plants of HSV-2 (Fushan Mountain county health research is provided).Make the Strain with
0.01PFU/ cell infection Vero cells, moved on to -80 DEG C after 20~24 hours, thereafter freeze-thaw repeatedly for three times.Then, will
Culture is added in 50ml centrifuge tube, 1500 revs/min, the centrifugation of 10 minutes is carried out at 4 DEG C, by each 1ml of its supernatant
Dispensing enters in 1.5ml micro-pipes, preserves and maintains at -80 DEG C.Then, wherein 1 is taken out, plaque point is carried out with Vero cells
Analysis, determines virus quantity (PFU), for infection described later.
Then, using these Bifidobacteriums and HSV-2, tested as follows.I.e., first, 7 are inoculated with HSV-2 described later
Before it, BALB/c mouse (6 week old, female) is divided into following group, every group 10, starts the intake of Bifidobacterium (BR-108).
A：Negative control group (physiological saline) (also referred to as " control group ")
B：BR-108(0.42×109Individual/day) intake group (also referred to as " BR4 hundred million ")
C：BR-108(2.1×109Individual/day) intake group (also referred to as " BR20 hundred million ")
D：BR-108(10.5×109Individual/day) intake group (also referred to as " BR100 hundred million ").
In addition, make BR-108 be suspended in physiological saline, be divided into twice a day make (during during at 9 in the morning and afternoon 6) it is oral
Mouse absorbs so that the daily intake in each group is respectively above-mentioned amount.In addition, to these mouse, in order that the oestrous cycle is same
The neurological susceptibility that phase, increase genitals are infected HSV-2, is subcutaneously injected tumer hydroxyl before 6 days that HSV-2 is inoculated with and before 1 day
Progesterone (medroxyprogesterone 17-acetate, 3mg/ individual).
In addition, herpesvirus infection disease due to immunologic function is reduced and be prone to fall ill, recur, worsening, long life.
Therefore, in these each mouse intake groups, before 7 days that HSV-2 is inoculated with~be subcutaneously injected and exempt from every 1 day after 13 days of the inoculation
Epidemic disease inhibitor 5-FU (5 FU 5 fluorouracil, each intake：0.25mg/0.1ml/ individuals), so as to prepare immune drop respectively
Low group (each 5 of each group).
Then, to the genitals topical vaccination HSV-2 (1 × 10 of these mouse4PFU/20 μ l/ individuals).Then, connect at this
Genitals are locally washed with cold PBS (100 μ l) after planting 3 days, its virus quantity is determined by following Plaque assays.By obtained result
It is shown in Fig. 1.
＜ Plaque assays ＞
The local cleaning solution of recovery is first suitably diluted with PBS.It is thin with the Vero of individual layer shape culture in 35mm wares
The dilution that 100 μ l are obtained is added in born of the same parents, is incubated 1 hour at room temperature, infects it.Then, lamination, which is added, 0.8% methyl
The MEM culture mediums (2ml/ wares) of cellulose and 2% hyclone, are cultivated 2 days at 37 DEG C.After the culture, culture medium is removed, is used
Crystal violet implements fixed dyeing.Then, plaque number is determined under the microscope, and plaque forming unit is calculated by the measure number
(plaque-forming unit, PFU).
Evaluation ＞s of the ＜ based on lesion score
In addition, after HSV-2 inoculations, record herpes symptom and death, based on following lesion score (lesion
Score) evaluated.It the obtained results are shown in Fig. 2.
0：It is asymptomatic
1：It is slight rubescent
2：Moderate is rubescent and swelling
3：With the rubescent and swelling of diffusate
4：Hindlimb paralysis
5：It is dead.
Understood as shown in figure 1, determining the virus quantity results of inoculation HSV-2 after tri- days in genitals, by absorbing bifid
Bacillus (BR-108), virus quantity is reduced.Also, on the reduction, also confirm the tendency in display dose-dependent.Separately
Outside, handled by immunodepressant, the reduction also shows that some relax.
Also, as shown in Fig. 2 it will also realize that by making intake Bifidobacterium, 1 week genital herpes symptom after HSV-2 inoculations
Rapidly development be suppressed (delay).Time point particularly after inoculation HSV-2 is six days, although in no intake Bifidobacterium
Control group in lesion score reach more than 2.5, but lesion score is pressed down in the group of 10,000,000,000 Bifidobacteriums of intake daily
Make " zero " (asymptomatic state).In addition, on the dose-dependent, it is thus identified that in high consumption (BR20 hundred million, BR100
Hundred million) compared with low consumption (BR4 hundred million) more strongly suppress symptom development tendency.In addition, on genital herpes symptom
Suppress, do not find by significantly affecting that immunodepressant processing is brought.In addition, last (to after HSV-2 inoculations 9 in control group
My god, by 12 days after HSV-2 inoculations in Bifidobacterium intake group), it is 100% in any group death rate of granting.
Furthermore it is known that the relapsing course of herpesviral, i.e. from latent infection state to return morbidity during, propagation
Virus quantity for whether to fall ill be big determinant.And by granting Bifidobacterium at this moment, make as shown in Figure 1 in vivo
Viral growing amount reduction, so that predicting to fall ill.So, it can also expect prevention recurrence.In addition, in the mould shown in Fig. 2
The dead condition of the full example of mouse of control group is set in type zoopery, is returned it is taken as that carrying with the mankind when falling ill
Virus quantity compares much bigger load.
The detection ＞ of the anti-HSV activity of ＜
As described above can be clear and definite, by orally ingestible Bifidobacterium, it can reduce the amount of herpesviral, and suppress blister sore
The development of malicious infection disease.Then then, in order to which what the virus multiplication inhibition that should be clearly brought by Bifidobacterium made with
Realized with mechanism, carried out following experiment.
That is, the present inventors assume that the antiviral activity composition from Bifidobacterium is absorbed and be transferred in blood and help
The path suppressed in virus multiplication participates in the possibility of the mechanism, under the hypothesis, orally grants after Bifidobacterium by 0.5
Time point to 8 hours takes serum, and evaluating it has nonreactive HSV activity.
More specifically, the detection of anti-HSV activity is carried out with following steps.
1) first, to BALB/c mouse (female, 6 week old) before virus infection 7 days to orally granting BR-108 (1.0 after 3 days
×1010It is individual/0.4ml/ days) or ACV (ACV) (1mg/0.4ml/ days), twice a day (when 9, when 18).In addition, for each
Group is granted, the sampling of n=3 × 7 time is carried out.In addition, being ready for 3 mouse do not disposed as control.
2) to the genitals topical vaccination HSV-2 (2 × 10 of each mouse4PFU/20 μ l/ mouse).
3) morning after infecting 3 days also grants BR-108 or ACV.Then, grant 30 minutes, 1 hour, it is 2 small
When, 3 hours, 4 hours, 6 hours, after 8 hours, blood is taken from each mouse, from these blood separate serum.
4) obtained each serum culture medium then, is diluted 10 times, 100 μ l/ml are made.
5) in addition, in 48- orifice plates Cultivation of Vero, next day add HSV-2 (0.1PFU/ml), 1 is incubated at room temperature
Hour, infect it.
6) after being washed with PBS, above-mentioned serum dilution 1) is added with 200 μ l/ holes, is incubated at 37 DEG C.
7) after the incubation is started 24 hours, culture (cell and culture medium), the freezen protective at -80 DEG C are reclaimed.
8) three freeze-thaws are carried out, 10 are suitably diluted to PBS1~105Times.Then, by the dilution for using
The Plaque assays of Vero cells (35-mm wares).0 time zone use it is above-mentioned 3) in sampling on the day of time point of 30 minutes from nothing
The serum that the mouse of processing is taken.Check plot replaces serum with PBS.
9) the plaque number of each serum during using the plaque number of check plot in the analysis as 100% then, is tried to achieve in % forms,
The anti-HSV-2 activity of the serum separated with temporally evaluating from the mouse for orally having granted BR-108 or ACV.By obtained result
It is shown in table 1 below and Fig. 3.In addition, the numerical value in table 1 represents the average value ± SD (marks of the plaque number (%) in 3 serum of each group
Quasi- deviation).In addition, Fig. 3 is that these numerical value described in table 1 are made obtained by coordinate figure.
Table 1
From the result shown in table 1 and Fig. 3, ACV is orally granted in group (#2), is lived after granting by 2 hours anti-HSV-2
Property enhancing, activity is slow thereafter weakens, and activity disappears after 6 hours.On the other hand, Bifidobacterium is granted in group (#1), grants 6 small
When after antiviral activity increase, after 8 hours after also continue.
From the result, the physiological activator from Bifidobacterium and its metabolite etc. by being transferred in blood and
Play its anti-HSV activity.In addition, will also realize that the anti-HSV activity is lasting activity.Particularly it is being used as herpesvirus infection disease
Existing medicine ACV antiviral activity reduce when, Bifidobacterium antiviral activity enhancing, therefore, it can by with
The existing medicine is used in combination, so as to more efficiently improve and prophylaxis of herpes viral infections disease with effect.
Industry utilizability
As described above, according to the present invention, it by orally ingestible Bifidobacterium, can subtract the amount of herpesviral
It is few, and suppress the development of herpesvirus infection disease.Also, the effect can be reduced less by the immunologic function of host
Influence play, and be lasting effect.Therefore, intake Bifidobacterium is in terms of the recurrence prevention of herpesvirus infection disease
It is also effective.In addition, Bifidobacterium is material that is safe, can inexpensively providing.
So, the improvement or prevention of composition of the invention by active ingredient of Bifidobacterium in herpesvirus infection disease
In be useful.
Sequence table
<110>Konbe K.K
School artificial person Chubu University
<120>For improvement or the composition of prophylaxis of herpes viral infections disease
<130> CJ-P16-07
<150> JP2016-014817
<151> 2016-01-28
<160> 1
<170>PatentIn version 3s .5
<210> 1
<211> 1508
<212> DNA
<213>Bifidobacterium longum (Bifidobacterium longum)
<400> 1
cctggctcag gatgaacgct ggcggcgtgc ttaacacatg caagtcgaac gggatccatc 60
aggctttgct tggtggtgag agtggcgaac gggtgagtaa tgcgtgaccg acctgcccca 120
tacaccggaa tagctcctgg aaacgggtgg taatgccgga tgctccagtt gatcgcatgg 180
tcttctggga aagctttcgc ggtatgggat ggggtcgcgt cctatcagct tgacggcggg 240
gtaacggccc accgtggctt cgacgggtag ccggcctgag agggcgaccg gccacattgg 300
gactgagata cggcccagac tcctacggga ggcagcagtg gggaatattg cacaatgggc 360
gcaagcctga tgcagcgacg ccgcgtgagg gatggaggcc ttcgggttgt aaacctcttt 420
tatcggggag caagcgagag tgagtttacc cgttgaataa gcaccggcta actacgtgcc 480
agcagccgcg gtaatacgta gggtgcaagc gttatccgga attattgggc gtaaagggct 540
cgtaggcggt tcgtcgcgtc cggtgtgaaa gtccatcgct taacggtgga tccgcgccgg 600
gtacgggcgg gcttgagtgc ggtaggggag actggaattc ccggtgtaac ggtggaatgt 660
gtagatatcg ggaagaacac caatggcgaa ggcaggtctc tgggccgtta ctgacgctga 720
ggagcgaaag cgtggggagc gaacaggatt agataccctg gtagtccacg ccgtaaacgg 780
tggatgctgg atgtggggcc cgttccacgg gttccgtgtc ggagctaacg cgttaagcat 840
cccgcctggg gagtacggcc gcaaggctaa aactcaaaga aattgacggg ggcccgcaca 900
agcggcggag catgcggatt aattcgatgc aacgcgaaga accttacctg ggcttgacat 960
gttcccgacg gtcgtagaga tacggcttcc cttcggggcg ggttcacagg tggtgcatgg 1020
tcgtcgtcag ctcgtgtcgt gagatgttgg gttaagtccc gcaacgagcg caaccctcgc 1080
cccgtgttgc cagcggatta tgccgggaac tcacggggga ccgccggggt taactcggag 1140
gaaggtgggg atgacgtcag atcatcatgc cccttacgtc cagggcttca cgcatgctac 1200
aatggccggt acaacgggat gcgacgcggc gacgcggagc ggatccctga aaaccggtct 1260
cagttcggat cgcagtctgc aactcgactg cgtgaaggcg gagtcgctag taatcgcgaa 1320
tcagcaacgt cgcggtgaat gcgttcccgg gccttgtaca caccgcccgt caagtcatga 1380
aagtgggcag cacccgaagc cggtggccta accccttgtg ggatggagcc gtctaaggtg 1440
aggctcgtga ttgggactaa gtcgtaacaa ggtagccgta ccggaaggtg cggctggatc 1500
acctcctt 1508
Claims (5)
1. a kind of be used for the composition of improvement or prophylaxis of herpes viral infections disease, contain Bifidobacterium as active ingredient.
2. composition according to claim 1, wherein, the Bifidobacterium is bifidobacterium longum.
3. composition according to claim 1, wherein, the herpesvirus infection disease is drawn by herpes simplex virus type 2
The infection disease risen.
4. composition according to claim 2, wherein, the herpesvirus infection disease is drawn by herpes simplex virus type 2
The infection disease risen.
5. it is orally ingestible composition according to composition according to any one of claims 1 to 4.
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| JP2016-014817 | 2016-01-28 | ||
| JP2016014817 | 2016-01-28 |
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| CN107007632B CN107007632B (en) | 2022-05-06 |
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| Publication number | Publication date |
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| JP6803247B2 (en) | 2020-12-23 |
| TWI724099B (en) | 2021-04-11 |
| JP2017137303A (en) | 2017-08-10 |
| TW201729823A (en) | 2017-09-01 |
| CN107007632B (en) | 2022-05-06 |
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