CN104023546A - Prophylactic agent for squamous carcinoma, squamous carcinoma model anima, and method for producing said model animal - Google Patents
Prophylactic agent for squamous carcinoma, squamous carcinoma model anima, and method for producing said model animal Download PDFInfo
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- CN104023546A CN104023546A CN201280064271.2A CN201280064271A CN104023546A CN 104023546 A CN104023546 A CN 104023546A CN 201280064271 A CN201280064271 A CN 201280064271A CN 104023546 A CN104023546 A CN 104023546A
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Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
- A23C9/123—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt
- A23C9/1238—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt using specific L. bulgaricus or S. thermophilus microorganisms; using entrapped or encapsulated yoghurt bacteria; Physical or chemical treatment of L. bulgaricus or S. thermophilus cultures; Fermentation only with L. bulgaricus or only with S. thermophilus
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
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- A—HUMAN NECESSITIES
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/11—Lactobacillus
- A23V2400/123—Bulgaricus
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/11—Lactobacillus
- A23V2400/145—Gasseri
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/21—Streptococcus, lactococcus
- A23V2400/249—Thermophilus
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Abstract
Provided are: a fermented material which is effective for the prevention of squamous carcinoma that is developed by Candida infection; a model animal for squamous carcinoma that is developed by Candida infection, in which the difference among individuals is smaller than those in conventional model animals and pharmacological efficacy can be evaluated more properly; and a method for producing the model animal. A prophylactic agent for squamous carcinoma that is developed by Candida infection, which comprises a fermented material produced by fermenting milk with L. bulgaricus, S. thermophilus and L. gasseri as an active ingredient.
Description
Technical field
The preparation method of the prophylactic of the squamous cell carcinoma that the present invention relates to be caused by monilial infection and squamous cell carcinoma animal pattern, this squamous cell carcinoma animal pattern and utilize the screening technique of this animal pattern.
Background technology
Carcinoma of mouth, cancer of the esophagus are the cancers that is derived from stratified squamous epithelium, and cancer of the esophagus is intractable cancer especially, and its death rate is high.On the other hand; known person Candida albicans (C.albicans) is the common bacteria being detected in the oral cavity of Healthy People; but in the patient of the immunity function decline that its patient, cirrhosis disease or diabetic after organ transplantation or major operation is such, usually can cause serious thrush, esophagus candidiasis.In addition, follow bedfast the elderly to increase, sink into low nutritional status, increasing appears in the chance infecting when immunity function reduces also becomes problem.Therefore, in the patient who reduces, the elderly, owing to being easy to infect people's Candida albicans, can cause deep fungal disease, and then develop into the serious result of malignant tumour at immunity function, it becomes great problem.
Therefore, expectation provides the development suppressing from candidiasis to squamous cell carcinoma, pharmaceuticals, the food of the morbidity of prevention squamous cell carcinoma.
On the other hand, the known acidified milk that contains lactobacillus gasseri (Lactobacillus gasseri) has the bacteria-eliminating efficacy to helicobacter pylori, has the gastritis based on this, the preventive effect (patent documentation 2 and 3) of gastric ulcer.But, about the effect to monilial infection, do not know completely.
In addition, conventionally in the screening of effective pharmaceuticals, food to disease, it is effective making disease model, about the animal pattern of squamous cell carcinoma, reported the intracutaneous of Aldh2 disappearance mammal (except people) or the subcutaneous squamous cell carcinoma animal pattern (patent documentation 1) that gives ethanol and/or acetaldehyde and make.But, this squamous cell carcinoma animal pattern, squamous cell carcinoma pathogenetic that is people's high frequency morbidity that to take at the ALDH2 gene relevant to alcohol metabolism be nonactive type illustrated, the animal model that is developed as object of methods for the treatment of, and it is different animal model from the morbidity of following the squamous cell carcinoma of monilial infection.
By having there is to follow the squamous cell carcinoma (non-patent literature 1) of severe infection chronic inflammation in giving the glandular stomach of WBN/Kob rat of alloxan induced Diabetic in the discoveries such as the inventor.But in this model, for the degree of the glandular stomach proliferative lesion of alloxan induced Diabetic rat, the incidence of disease, individual difference is large, in order suitably to suppress the pharmaceuticals of the development from candidiasis to squamous cell carcinoma, the screening of food, need to establish fluctuation disease model still less.
Prior art document
Patent documentation
Patent documentation 1: TOHKEMY 2005-110601 communique
Patent documentation 2: No. 4509250th, Japan Patent
Patent documentation 3: No. 3046303rd, Japan Patent
Non-patent literature
Non-patent literature 1:Sano T, Ozaki K, Kodama Y, Matsuura T, Narama I., Toxicol.Pathol., vol.37, p.790-798 (2009).
Summary of the invention
Problem of the present invention is to provide the effective fermentate of prevention of the squamous cell carcinoma developing being caused by monilial infection.And then problem of the present invention is to provide squamous cell carcinoma animal pattern being caused by monilial infection and preparation method thereof, comparing fluctuation with animal pattern in the past few, can more suitably carry out evaluating drug effect.
The inventor etc. have carried out conscientiously further investigation in order to solve above-mentioned problem, found that, after giving alloxan induced Diabetic to rat, force immediately per os to give people Candida albicans, thereby in the glandular stomach of rat, can bring out in early days the proliferative lesion of following chronic inflammation being caused by monilial infection, make the little squamous cell carcinoma animal pattern of individual difference of this pathology.In addition, find that fermentate milk being fermented with lactobacillus bulgaricus (L.bulgaricus), streptococcus thermophilus (S.thermophilus) and lactobacillus gasseri (L.gasseri) is when suppressing the inflammation being caused by people's candida albicans infection, suppressing the development of proliferative lesion, is useful for the prevention of the squamous cell carcinoma being caused by monilial infection.
That is, the present invention comprises following content.
[1] prophylactic for the squamous cell carcinoma being caused by monilial infection, is characterized in that, using with lactobacillus bulgaricus, streptococcus thermophilus and lactobacillus gasseri, milk is fermented and fermentate as active ingredient.
The prophylactic of the squamous cell carcinoma being caused by monilial infection of [2] recording according to above-mentioned [1], wherein, fermentate is that lactobacillus bulgaricus and streptococcus thermophilus are coordinated to the acidified milk that ferments and coordinate lactobacillus gasseri afterwards and obtain with milk.
The prophylactic of the squamous cell carcinoma being caused by monilial infection of [3] recording according to above-mentioned [1] or [2], wherein, lactobacillus gasseri is lactobacillus gasseri OLL2716 strain (FERM BP-6999).
The prophylactic of the squamous cell carcinoma being caused by monilial infection of [4] recording according to any one in above-mentioned [1]～[3], wherein, squamous epithelium is the squamous epithelium of oral cavity and/or esophagus.
[5] with lactobacillus bulgaricus, streptococcus thermophilus and lactobacillus gasseri, milk is fermented and the application in the prophylactic of manufacturing the squamous cell carcinoma being caused by monilial infection of the fermentate that obtains.
[6] fermentate, its squamous cell carcinoma for preventing to be caused by monilial infection, ferments milk with lactobacillus bulgaricus, streptococcus thermophilus and lactobacillus gasseri and obtains.
[7] prevention method for the squamous cell carcinoma being caused by monilial infection, is characterized in that, gives or absorb the fermentate that with lactobacillus bulgaricus, streptococcus thermophilus and lactobacillus gasseri, milk is fermented and obtain.
[8] preparation method of a kind of squamous cell carcinoma animal pattern, it is characterized in that, comprise and force per os to give the operation of people's Candida albicans to onset diabetes animal pattern, described onset diabetes animal pattern is induced Diabetic by giving diabetes-induced material.
[9] preparation method of recording according to above-mentioned [8], wherein, animal is rat.
[10] the squamous cell carcinoma animal pattern that the method for recording by above-mentioned [8] or [9] is made.
[11] prophylactic of squamous cell carcinoma and/or a screening technique for therapeutic agent, is characterized in that, comprises the squamous cell carcinoma animal pattern that above-mentioned [10] are recorded and give analyte, observes the operation of the variation of squamous cell carcinoma diseased region.
According to the prophylactic of the squamous cell carcinoma being caused by monilial infection of the present invention, can effectively suppress candidiasis and the development from candidiasis to squamous cell carcinoma.In addition, according to the present invention, can make squamous cell carcinoma animal pattern, this animal pattern can individual difference aspect the degree of pathology, incidence little reproduce to the development of the squamous cell carcinoma being caused by monilial infection, by using this model, can screen the prophylactic to the useful material of the treatment of squamous cell carcinoma, the squamous cell carcinoma that caused by monilial infection, in addition, can be used in that the squamous cell carcinoma being caused by people's candida albicans infection is pathogeneticly illustrated, the new treatment of squamous cell carcinoma and the research of prevention method.
Accompanying drawing explanation
Fig. 1 (a) is the glandular stomach of C group (to the group without disposing rat and give people's Candida albicans), and (b) is the glandular stomach of AC group (alloxan induced Diabetic rat being given to the group of people's Candida albicans).For squamous epithelium hyperplasia, AC group is higher than C group.In the epithelium skin section of AC group, the purulent inflammation of the height of people's candida albicans infection is followed in discovery.
Fig. 2 is the diseased region of body one by one of having confirmed the squamous cell carcinoma of initial stage.Figure top is hyperplasia portion, starts irregular flat epithelial cell rope expand downwards from the bottom of this part.By dotted line, having the position of arrow is to infiltrate to present part (Xian Jin part to the cancer cell of muscular layer of mucosa).
Fig. 3 (a) is the glandular stomach diseased region of DC group (alloxan induced Diabetic rat being given to the group of people's Candida albicans), and (b) is the glandular stomach diseased region of DC+LG21 group (alloxan induced Diabetic rat being given to the group of people's Candida albicans and LG21).For squamous epithelium hyperplasia, DC+LG21 group is lighter than DC group.The purulent inflammation of the height of people's candida albicans infection is followed in epithelium skin section discovery in DC group, and is slight in DC+LG21 group.
Fig. 4 (a) is the immunostaining image of the cell proliferation label Ki-67 of DC group, and (b) is the immunostaining image of the cell proliferation label Ki-67 of DC+LG21 group.Ki-67 is positive in the core of the flat epithelial cell of propagation, and the positive rate of comparing DC+LG21 group with DC group is low.
The specific embodiment
Below, illustrate the present invention, but the present invention is not limited to each mode of following narration.
(prophylactic of the squamous cell carcinoma being caused by monilial infection)
As the fermentate of the active ingredient of the prophylactic of the squamous cell carcinoma being caused by monilial infection of the present invention be with lactobacillus bulgaricus, streptococcus thermophilus and lactobacillus gasseri, milk is fermented and fermentate.
This fermentate is except coordinating lactobacillus bulgaricus, streptococcus thermophilus and lactobacillus gasseri (interpolations) ferment to milk, can be also after milk ferments, coordinate (interpolation) lactobacillus gasseri further to ferment lactobacillus bulgaricus and streptococcus thermophilus cooperation (interpolation) and must fermentate.
Wherein, the milk as fermentation raw material, is not particularly limited, and conventionally can use animal milk (being derived from the mammiferous milk such as milk, goat milk, Goat Milk, buffalo milk) etc.Should illustrate, this milk not only consists of raw milk, sterilization milk, in not hindering the scope of fermentation, other food, the food additives that also can coordinate (interpolation) recombined milk raw material (butter, cream, defatted milk, full-cream concentrated milk, degreasing concentrated milk, whole milk powder, skimmed milk power, condensed milk etc.), use as required.
As lactobacillus bulgaricus and streptococcus thermophilus, can preferably use normally used in acidified milk manufacture, to take by CODEX standard be basic leavening by the mixed culture fermentation agent of the standardized lactobacillus bulgaricus of ferment agent for sour milk and streptococcus thermophilus.For example, can enumerate Lactobacillus delbrueckii Bulgaria and plant (L.delbrueckii subsp.Bulgaricus) JCM1002
twith streptococcus thermophilus ATCC19258 etc.In addition, also can add lactic acid bacteria, Bifidobacterium, the yeast etc. such as streptococcus (Streptococcus), Leuconostoc (Leuconostoc), Pediococcus (Pediococcus).
In addition, as lactobacillus gasseri, be not particularly limited, for example, can enumerate lactobacillus gasseri OLL2716 strain.Should illustrate, lactobacillus gasseri OLL2716 strain, as shown in recording in above-mentioned patent documentation 3, on May 24th, 1999 (former preservation day), with deposit number FERM BP-6999, based on the budapest treaty world, be preserved in the biological preservation of Independent Administrative Leged Industrial Technology Complex Inst's patent center (east, Zhu Bo city, Hitachinaka County, Japan 1-1-1 Zhu Bo center central authorities the 6th).This preservation strain is ground bacterium by micro-work on May 24th, 1999 and is posted the domestic preservation of No. P-17399 (former preservation), on January 14th, 2000, moves pipe for the international preservation based on budapest treaty.
Fermentate of the present invention, as shown in hereinafter embodiment, the inflammation that inhibition is caused by people's candida albicans infection, free burial ground for the destitute suppresses the cancerization of flat epithelial cell intentionally.Therefore, fermentate of the present invention can be used as the prophylactic of the squamous cell carcinoma being caused by monilial infection.
Should illustrate, this use is the use in people or non-human animal, can be that therapeutic use can be also that non-therapeutic is used in addition.Wherein, " non-therapeutic " refers to the concept that does not comprise medical act, do not comprise the concept of the method that people is performed the operation, treated or diagnoses, more specifically, refer to that the Human To Human who does not comprise doctor or accept doctor indication implements the concept of the method for operation, treatment or diagnosis.
In the present invention, " prevention of the squamous cell carcinoma being caused by monilial infection " refers to, the cancerization of the tissue that inhibition consists of the flat epithelial cell that infects the preferred people's Candida albicans of candida albicans and prevent the morbidity of squamous cell carcinoma, suppress the development from candidiasis to squamous cell carcinoma, and refer to the inflammation (candidiasis) that the front carninomatosis before inhibition (prevention) or treatment flat epithelial cell cancerization becomes, caused by monilial infection.Wherein, the tissue consisting of flat epithelial cell can be enumerated oral cavity, esophagus, throat, larynx, anus, skin etc., preferably enumerates as gastral oral cavity, top, esophagus, throat, larynx in the present invention.
Should illustrate, the typical squamous cell carcinoma that in the present invention, " squamous cell carcinoma " can be identified on morphology, also comprise the preneoplastic lesions of squamous epithelium.
Therefore, in the prevention of the squamous cell carcinoma being caused by monilial infection of the present invention, for example, except the prevention of carcinoma of mouth, throat cancer, larynx cancer, cancer of the esophagus, also comprise inhibition (prevention) or the treatment of oral cavity endomycosis, the esophagus candidiasis etc. such as acute thrush, thrush, thrush, acute atrophy candidiasis, chronic thrush, the interior inflammation of atrophic mouth, chronic plumpness candidiasis, chronic mucocutaneous candidiasis, median rhomboid glossitis.
The prophylactic of the squamous cell carcinoma being caused by monilial infection of the present invention, can be himself to be suppressed to infect the cancerization of flat epithelial cell of candida albicans to comprise that people's animal absorbs or gives time performance, the people of effect who suppresses the development from candidiasis to squamous cell carcinoma or pharmaceuticals, the food that animal is used, or can be also to coordinate with these pharmaceuticals or food and the material or the preparation that use.Wherein, in this food, comprise take prevention, oidiomycotic prevention or the treatment of the squamous cell carcinoma that caused by monilial infection as aim, represent as required food, the specific food for health care for functional food, patient of its purport.
The form that gives as the above-mentioned pharmaceuticals that contain fermentate of the present invention, can be according to preventing object, improve object, giving the selection formulations such as approach, such as enumerating tablet, coated tablet, pill, capsule, granule, powder, liquor, supensoid agent, emulsion, syrup, injection, suppository, extract, decoction, tincture etc.These various preparations, can be used the normally used known auxiliary materials in pharmaceutical preparations technology field such as filler, extender, excipient, adhesive, NMF, disintegrant, surfactant, lubricant, colouring agent, drug flavoring, dissolving assistant, supensoid agent, coating agent to carry out preparation according to conventional method as required to main ingredient.In addition, in this pharmaceutical preparation, also can contain colouring agent, preserving agent, spices, flavouring agent, sweetener etc., other pharmaceuticals.
As the form of the above-mentioned food that contains fermentate of the present invention can be the food such as milk powder for food for milk, cold drink, acidified milk, Yoghourt, cheese, bread, biscuit, crispbread, Pizza, modified milk powder, liquid food, patient, child, arbitrary form such as the food such as milk powder, nutraceutical for lactating female, about its proterties, can be state any of solid shape (powder, graininess or other), pasty state, aqueous or suspendible shape for example of normally used beverage/food.
Above-mentioned food, can directly be used fermentate of the present invention, or mixes with other food or food composition etc. according to the conventional method manufacture of common beverage/food composition.
As other food composition, not particularly restriction, such as enumerating water, protein, saccharic, lipid, vitamins, mineral matter class, organic acid, organic base, fruit juice, flavor enhancement class etc.Wherein, as protein, such as enumerating of animal or plant nature protein, their hydrolysates such as whole milk powder, skimmed milk power, partially skimmed milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein sepd, alpha-casein, beta-casein, κ-casein, beta lactoglobulin, alpha lactalbumin, lactoferrin, soybean protein, egg protein, meat protein; The various one-tenth that are derived from milk such as butter, whey mineral, cream, whey, amino acids, sialic acid, phospholipid, lactose grade.As saccharic, can enumerate carbohydrate, producing starch (except dextrin, soluble starch, Britain's starch, oxidized starch, starch ester, starch ether etc.), food fiber etc.As lipid, such as can enumerate lard, fish oil etc., they minute carry oil, hydrogenated oil and fat, ester exchange wet goods animal raw fat; Palm oil, safflower oil, corn oil, rapeseed oil, coconut oil, dividing of they are carried oil, hydrogenated oil and fat, ester exchange wet goods vegetative grease etc.As vitamins, such as listing vitamin A, carotenoid, Cobastab group, vitamin C, vitamin D group, vitamin E, vitamin K group, citrin, CoenzymeQ10, nicotinic acid (niacin), nicotinic acid (nicotinic acid), pantothenic acid, biotin, inositol, choline, folic acid etc., as mineral matter class, such as enumerating calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium, whey mineral etc.As organic acid, such as enumerating malic acid, citric acid, lactic acid, tartaric acid etc.These compositions can be combined to two or more and use, also can use composite and/or contain in a large number their food.
The content of fermentate of the present invention in above-mentioned pharmaceuticals or food, can determine arbitrarily according to its object, purposes.For example, with dry product, convert, with respect to total amount, conventionally with the content of 0.001～100 % by weight, coordinate, preferably with 0.01～100 % by weight, the further preferred cooperation of the content with 0.1～100 % by weight.In addition,, as the bacterium number of the lactobacillus bulgaricus in fermentate and streptococcus thermophilus, preferably to add up to every 1mL be 1,000 ten thousand (1 * 10 to the lactic acid bacteria number of the two
7individual) more than.In addition, preferably lactobacillus gasseri is that every 1mL is 1,000,000 (1 * 10
6individual) more than, more preferably lactobacillus gasseri is that every 1mL is 1,000 ten thousand (1 * 10
7individual) more than.
Above-mentioned pharmaceuticals or food give or intake because of biological species, age, the body weight of tested sample, give or to absorb number of times etc. different, the tailoring by those skilled in the art is changed in can be on a large scale.For example, as fermentate of the present invention (dry thing converts), can be 0.01～10000mg/kg body weight/day, be preferably 0.05～6000mg/kg body weight/day, more preferably 0.3～5000mg/kg body weight/day.In addition, giving or absorb number of times can be that single can be repeatedly also, preferably repeatedly gives or absorbs.
In addition, as giving or absorb object, so long as need its people, be not particularly limited, such as enumerating the patients such as thrush, esophagus candidiasis or its reserves etc.
(squamous cell carcinoma animal pattern)
" animal " of in the making of squamous cell carcinoma animal pattern of the present invention, using refer to, for example mouse, rat, and zoologic sex, age in week, body weight etc., can be not particularly limited as the screening of object as long as can be applied to.The oral cavity of known person, tongue, esophagus are covered by stratified squamous epithelium, and in people monkey dog, only keratinization occurs for some, but in mouse rat until keratinization (day pharmacology will, 131,373-377,2008) completely in the Zone Full of glandular stomach.The invention is characterized in that the glandular stomach mouse, rat forms pathology.As this " animal ", such as enumerating WBN/Kob rat, F344 rat etc.
The making of squamous cell carcinoma animal pattern of the present invention, is characterized in that diabetic animal to force per os to give people Candida albicans.As diabetic animal, such as except rat (normal rat), mouse (normal mouse) being given to the animal of the drug-induced diabetes such as alloxan, Streptozotocin, also can use heredity diabetic animal, but can be by occurrent time, the homogenization of severe degree due to what give that diabetes-induced material falls ill, therefore preferably, because the diabetes rat that uses utilization to fall ill as the alloxan of diabetes-induced material is not genotoxic carcinogens matter, therefore preferably.The confirmation whether diabetes fall ill, the usual ways such as the blood sugar of available mensuration animal, glucose in urine are confirmed.
The present invention is characterized in that, after induced Diabetic, forces per os to give people Candida albicans.Preferably the sample of people's Candida albicans being suspended in to normal saline solution carries out per os and gives.In the present invention for the bacterium number of people's Candida albicans of forcing per os to give, give frequency, give for interval so long as people's Candida albicans is fixed on the flat epithelial cell of animal, because of biological species, age, the body weight of the animal of using, give approach, to give number of times etc. different, by those skilled in the art's tailoring, can change on a large scale.For example, when the WBN/Kob rat in 10 week age is given, can enumerate 1 * 10
6individual/mL is above, preferably 1 * 10
7individual/more than mL bacterium number with 1 time weekly～frequency of 4 times forces that per os gives etc. weekly.
In the making of squamous cell carcinoma animal pattern of the present invention, from starting 3 months conventionally, preferably about 6 months, form the squamous epithelium hyperplasia of rat glandular stomach.In the present invention, " squamous cell carcinoma " this term also comprises the preneoplastic lesions of squamous epithelium on morphology discernible typical squamous cell carcinoma.
After animal pattern generation pathology of the present invention, can take a part for this diseased region to judge that the front carninomatosis in Histopathology becomes.For example, if being carried out to hematoxylin eosin staining (HE dyeing), tissue finds that squamous epithelium has the performance of mamillary propagation, can prove at diseased region and form hyperplasia.In addition, find to infiltrate from hyperplasia to continuity the pathology of propagation, certification structure atypia or nuclear atypia also can be confirmed the existence of cancer cell.
The animal pattern that is loaded with squamous cell carcinoma of making by method of the present invention can be used for the screening of the curative of squamous cell carcinoma.Animal pattern per os is given or non-per os gives analyte, such as by observing the results for the treatment of such as development inhibition of the dwindling of cancer diseased region, cancer, can screen the material useful to the treatment of squamous cell carcinoma.When animal pattern is made, can give in advance analyte, then force per os to give people Candida albicans, also can carry out the screening of the preventive medicine of squamous cell carcinoma.
In addition, animal pattern of the present invention, the squamous cell carcinoma causing for the infection by people's Candida albicans morbidity machine-processed illustrated, the methods for the treatment of of squamous cell carcinoma and the research of prevention method are also useful.
Embodiment
Below, enumerate embodiment and illustrate in greater detail the present invention, but the present invention is not limited thereto.Should illustrate, in embodiment, the expression of " % " represents % by weight except the situation of special provision.
The establishment of [embodiment 1] disease model
With experimental immediately after alloxan induced Diabetic, give people Candida albicans, attempt bringing out of Earlier period of inflammation and proliferative lesion.
Female WBN/Kob rat to 10 week age, carries out single with the administered dose of 40mg/kg by tail vein by alloxan (Sigma company) and gives, and confirms the state of diabetes through 2 time-of-weeks.To there is no the animal of onset diabetes, again give alloxan, make onset diabetes.Grouping forms as shown in table 1, uses following grouping: after induced Diabetic, force per os to give people's Candida albicans (6 * 10
7individual/mL) group (AC group, 15), do not force after induced Diabetic per os to give the group (A group, 14) of people's Candida albicans, and do not give the group that pressure per os that alloxan only carries out people's Candida albicans gives (C group, 10).In AC group, giving after alloxan in 2 weeks, will be 6 * 10 by the dilution of people's Candida albicans with physiological saline
7individual/mL and detected material with every 1mL, force per os to give 3 times weekly.Then, with the frequency of 1 time weekly, give 8 weeks, amount to 10 weeks, force per os to give 14 times.All groups are all implemented to cut open inspection for 25 weeks after people's Candida albicans gives, and top alimentary canal are carried out to the observation of Histopathology.Should illustrate, people's Candida albicans has been used the viable bacteria of taking the cultivation keeping of Bing Shenan university Pharmaceutical Department pathological research chamber the stomach with proliferative lesion of the F344 alloxan hero 1896 from dissecting in February, 2008.
[table 1]
The result of the pathological manifestations of AC group, A group and C group is as shown in table 2.In C group (Fig. 1), do not find the hyperplasia of glandular stomach squamous epithelium, infection and the inflammation of people's Candida albicans.In A group, in 14 examples, 4 examples (28.6%) find that glandular stomach flat epithelial cell has from light to moderate hyperplasia (hyperplasia of squamous epithelium, Squamous cell hyperplasia), in 14 examples, 7 examples (50%) neutrophil cell gathers (gathering of neutrophil leucocyte, Accumulation of neutrophils) and in 14 examples 9 examples (64.3%) follow from proper mucous membrane to submucosal by lymphocyte plasmocyte infiltrating (in submucosa lymphocyte and plasmocyte infiltrating, Lymphocytic and plasmacytic infiltration in submucosa) chronic inflammation forming but the degree of pathology is slight～moderate, incidence is also low.On the other hand, in AC group, 15 merely hit 14 routine glandular stomach squamous epitheliums become from moderate to height hyperplasia, at infection and the purulent inflammation of mucous membrane skin section finder Candida albicans, from proper mucous membrane to submucosa, find the chronic inflammation (Fig. 1) being formed by lymphocyte plasmocyte infiltrating.Wherein, there is 1 example to develop into the squamous cell carcinoma (Fig. 2) of initial stage.
Above result shows, in the glandular stomach of alloxan induced Diabetic rat, people's candida albicans infection brings out the proliferative lesion of following chronic inflammation in early days.In addition we know the fluctuation of this disease model is very little, is the model useful to evaluating drug effect.
[table 2]
Hyp: hyperplasia (hyperplasia)
b*from AC significant different (Significantly different from AC) P < 0.01
bfrom AC significant different (Significantly different from AC) P < 0.05
[embodiment 2]
According to the result of embodiment 1, show by giving people Candida albicans to alloxan induced Diabetic rat, can bring out proliferative and Lymph nodes and cancerization at glandular stomach.
Use will be usingd CODEX standard as ferment agent for sour milk and after the mixed culture fermentation agent of standardized lactobacillus bulgaricus and streptococcus thermophilus ferments as basic leavening, adding lactobacillus gasseri OLL2716 ferments, utilize fermentate of the present invention obtained above, investigation people candida albicans infection brings out glandular stomach proliferative and whether inflammatory disorders is suppressed.
Fermentate of the present invention is prepared in such a way.First, by lactobacillus gasseri OLL2716 strain, lactobacillus delbruockii subspecies bulgaricus (L.delbrueckii subsp.Bulgaricus) JCM1002
t, streptococcus thermophilus ATCC19258 is inoculated in 10% skimmed milk power culture medium with 1% respectively, at 37 ℃, cultivate preparation in 15 hours and produce leavening.Then, to inoculating lactobacillus delbruockii subspecies bulgaricus JCM1002 at 95 ℃ of heat treated yogurt mixt of 5 minutes (SNF:9.5%, FAT:3.0%)
t, streptococcus thermophilus ATCC19258 leavening each 1%, the leavening 5% of lactobacillus gasseri OLL2716 strain, 43 ℃ of fermentations 4 hours.Fermentation is cooling lactobacillus gasseri OLL2716 strain, lactobacillus delbruockii subspecies bulgaricus JCM1002 afterwards just
t, streptococcus thermophilus ATCC19258 viable count is separately 9.0 * 10
7cFU/mL, 6.4 * 10
7cFU/mL, 11.0 * 10
8cFU/mL.Below fermentate of the present invention is called to LG21.
After giving alloxan (Sigma company product) induced Diabetic to WBN/Kob rat, with the grouping shown in table 3, form and test.Particularly, the DC+LG21 group that per os gives people's Candida albicans and fermentate of the present invention (LG21) is set, only per os gives the DC group of people's Candida albicans.In DC group, giving after alloxan in 3 weeks, at initial 2 weeks, will be 6 * 10 by the dilution of people's Candida albicans with physiological saline
7individual/mL and detected material with the administered dose of every 1mL, force per os to give 3 times weekly.Then, with the frequency of 1 time weekly until force per os to give people Candida albicans in after giving alloxan 27 weeks.In DC+LG21 group, from giving alloxan 2 thoughtful give alloxan after 27 weeks during, with the administered dose of 5mL/kg body weight, with the frequency of 1 time on the 1st, start to force per os to give fermentate LG21 of the present invention, give after alloxan in 3 weeks, at initial 2 weeks, will by the dilution of people's Candida albicans, be 6 * 10 with physiological saline
7individual/mL and detected material with the administered dose of every 1mL, force per os to give 3 times weekly.Then, with the frequency of 1 time weekly until force per os to give people Candida albicans in after giving alloxan 27 weeks.DC+LG21 group, DC organize these two groups, are giving alloxan and cut open 27 weeks (35 week age) inspection, relatively proliferative lesion, people's candida albicans infection and the Lymph nodes of glandular stomach.
[table 3]
The result of the pathological manifestations of DC+LG21 group and DC group is as shown in table 4.For glandular stomach squamous epithelium hyperplasia and inflammation, two groups is all strong at lesser curvature side, a little less than large curved side.In large curved side, the hyperplasia of DC+LG21 group is compared with DC group free burial ground for the destitute weak (Fig. 3) intentionally, as the Ki-67 positive rate of the propagation label of cell, at DC+LG21, organizes and also shows significant low value (Fig. 4).In addition, the purulent inflammation of people's candida albicans infection and mucous membrane is also slightly slight in DC+LG21 group in large curved side.Above result shows that fermentate of the present invention can have a mind to free burial ground for the destitute and suppress the cancerization of flat epithelial cell.
[table 4]
[table 4]
Curved greatly
Table 3. is found in the Histopathology of the glandular stomach of diabetes rat
Hyp: hyperplasia (hyperplasia)
bsignificant different from LG21+DC
(Significantly?different?from?LG21+DC)P＜0.05
Industrial utilizability
According to the present invention, can provide a kind of and be caused and the prophylactic of the squamous cell carcinoma that develops by monilial infection.In addition, the invention provides a kind of compare with animal pattern in the past its fluctuation less, can more suitably carry out squamous cell carcinoma animal pattern being caused by monilial infection of evaluating drug effect and preparation method thereof, and the screening technique that utilizes this animal pattern.
PCT/RO/134 table
Claims (11)
1. a prophylactic for the squamous cell carcinoma being caused by monilial infection, is characterized in that, using with lactobacillus bulgaricus, streptococcus thermophilus and lactobacillus gasseri, milk is fermented and fermentate as active ingredient.
2. the prophylactic of the squamous cell carcinoma being caused by monilial infection according to claim 1, wherein, fermentate be by lactobacillus bulgaricus and streptococcus thermophilus coordinate with milk coordinate lactobacillus gasseri after fermenting and acidified milk.
3. the prophylactic of the squamous cell carcinoma being caused by monilial infection according to claim 1 and 2, wherein, lactobacillus gasseri is lactobacillus gasseri OLL2716 strain, preserving number is FERM BP-6999.
4. according to the prophylactic of the squamous cell carcinoma being caused by monilial infection described in any one in claim 1～3, wherein, squamous epithelium is the squamous epithelium of oral cavity and/or esophagus.
5. the application of the fermentate that with lactobacillus bulgaricus, streptococcus thermophilus and lactobacillus gasseri, milk is fermented and obtain in the prophylactic of manufacturing the squamous cell carcinoma being caused by monilial infection.
6. a fermentate, its squamous cell carcinoma for preventing to be caused by monilial infection, ferments milk with lactobacillus bulgaricus, streptococcus thermophilus and lactobacillus gasseri and obtains.
7. a prevention method for the squamous cell carcinoma being caused by monilial infection, is characterized in that, gives or absorb fermentate, this for fermentate lactobacillus bulgaricus, streptococcus thermophilus and lactobacillus gasseri milk is fermented and obtains.
8. the preparation method of a squamous cell carcinoma animal pattern, it is characterized in that, comprise and force per os to give the operation of people's Candida albicans to onset diabetes animal pattern, described onset diabetes animal pattern is induced Diabetic by giving diabetes-induced material.
9. preparation method according to claim 8, wherein, animal is rat.
10. a squamous cell carcinoma animal pattern, utilizes the method described in claim 8 or 9 to make.
The prophylactic of 11. 1 kinds of squamous cell carcinomas and/or the screening technique of therapeutic agent, is characterized in that, comprises and give analyte to squamous cell carcinoma animal pattern claimed in claim 10, observes the operation of the variation of squamous cell carcinoma diseased region.
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| JP2011-284133 | 2011-12-26 | ||
| PCT/JP2012/083643 WO2013099939A1 (en) | 2011-12-26 | 2012-12-26 | Prophylactic agent for squamous carcinoma, squamous carcinoma model animal, and method for producing said model animal |
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| CN108094541A (en) * | 2018-01-11 | 2018-06-01 | 黑龙江完达山林海液奶有限公司 | A kind of flavored fermented milk for having the function of that health care is prebiotic and preparation method thereof |
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Non-Patent Citations (4)
| Title |
|---|
| AWAISHEH S.S.等: "Incorporation of selected nutraceuticals and probiotic bacteria into a fermented milk", 《INTERNATIONAL DAIRY JOURNAL》, vol. 15, no. 11, 30 November 2005 (2005-11-30), XP004970567, DOI: doi:10.1016/j.idairyj.2004.11.003 * |
| AWAISHEH S.S.等: "Incorporation of selected nutraceuticals and probiotic bacteria into a fermented milk", 《INTERNATIONAL DAIRY JOURNAL》, vol. 15, no. 11, 30 November 2005 (2005-11-30), XP027677244 * |
| SANO T.等: "Effects of the Antifungal Agent Itraconazole on Proliferative Changes of the Forestomach Mucosa in Alloxan-induced Diabetic Rats", 《TOXICILOGIC PATHOLOGY》, vol. 37, no. 6, 31 October 2009 (2009-10-31), pages 790 - 1, XP055076851, DOI: doi:10.1177/0192623309344204 * |
| WILLIAMS T.等: "Strain persistence of invasive Candida albicans in chronic hyperplastic candidosis that underwent malignant change", 《GERODONTOLOGY》, vol. 18, no. 2, 31 December 2001 (2001-12-31), pages 73 - 78, XP055076860, DOI: doi:10.1111/j.1741-2358.2001.00073.x * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108094541A (en) * | 2018-01-11 | 2018-06-01 | 黑龙江完达山林海液奶有限公司 | A kind of flavored fermented milk for having the function of that health care is prebiotic and preparation method thereof |
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| JP6153114B2 (en) | 2017-06-28 |
| SG10201605249SA (en) | 2016-08-30 |
| SG11201402662SA (en) | 2014-10-30 |
| CN104023546B (en) | 2016-06-15 |
| JPWO2013099939A1 (en) | 2015-05-11 |
| HK1200282A1 (en) | 2015-08-07 |
| WO2013099939A1 (en) | 2013-07-04 |
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