CN108324710A - Contain composition for prevent or treat rotavirus infection caused by disease of the Geniposide as active ingredient - Google Patents
Contain composition for prevent or treat rotavirus infection caused by disease of the Geniposide as active ingredient Download PDFInfo
- Publication number
- CN108324710A CN108324710A CN201810053173.8A CN201810053173A CN108324710A CN 108324710 A CN108324710 A CN 108324710A CN 201810053173 A CN201810053173 A CN 201810053173A CN 108324710 A CN108324710 A CN 108324710A
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- Prior art keywords
- geniposide
- rotavirus
- cells
- infection
- disease
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- 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
-
- 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
-
- 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
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Mycology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
The present invention relates to the new applications of Geniposide (genipin) compound, specifically, the present invention relates to contain the composition for preventing, treating or improving disease caused by rotavirus infection of Geniposide or its pharmaceutically acceptable salt as active ingredient.Geniposide compound in the present invention has the effect of outstanding prevention and treatment rotavirus infection.
Description
Technical field
The present invention relates to the new applications of Geniposide (genipin) compound, specifically, the present invention relates to contain Geniposide
Or its pharmaceutically acceptable salt is used to preventing, treating or improving disease caused by rotavirus infection as active ingredient
Composition.
Background technology
Rotavirus (Rotavirus) belongs to Reoviridae (Reoviridae), it is known that is to induce acute child's intestines
Scorching most important reason.The double capsid (double capsid) of virion looks like a carriage wheel, and title is come
Derived from the wheel (rota, English wheel) of Latin, therefore it is referred to as rotavirus.Nineteen forty-three, Lai Te (Light) and He De
This (Hodes) once reported the phenomenon that infant's severe diarrhea, and the filtering pathogen for causing diarrhea is isolated from excrement, but
Be its morphological feature be in 1973 disclosed in electron microscope.It has been isolated from mammal and birds and has exhaled the lonely disease of intestines
Malicious sample is viral (reovirus-like virus), these viruses are it is verified that be rotavirus, and be classified as in 1978
The rotavirus (Genus Rotaviruses) of arc reovirus virus section (Family Reoviridae).
Rotavirus gene group (genome) is made of 11 segments of double-stranded RNA (double-stranded RNA), wheel
Shape virion is the spherical shape of diameter 70nm, has outer layer capsid (outer capsid) and internal layer capsid (inner capsid)
Two shells (shell).Internal layer capsid (inner capsid) is formed by VP6 protein, includes containing 11 dual segments RNA
Partly the structural protein with VP1, VP2, VP3, outer layer capsid (outer capsid) are made of core (core) VP7 and VP4.
In the VP4 and VP7 for forming outer layer capsid, VP4 is a kind of viral hemagglutinin (virus hemagglutinin), as host
The attachment protein of cell protrudes as sharp shaped material (spike) from virus surface, accounts for the 2.5% of viral entirety.VP7 is a kind of
The glycoprotein (glycoprotein) of 37kDa forms shell (the smooth outer capsid of smooth outer layer capsid
Shell), the 30% of viral entirety is accounted for.Since VP4 albumen resolves into VP5 and VP8 by host protein enzyme, serotype is referred to as P
Type (P type), VP7 albumen is glycosylated (glycosylation), so its serotype is referred to as G types (G type)
(Ciarlet,M.and Ester,M.K.Rotaviruses:basic biology,epidemiology and
methodologies in encyclopedia of envirionmental microbiology.pp.2753-2773,
2002).VP4 and VP7 protein participates in the defence of host by inducing neutralizing antibody.Serotype is according to for middle layer capsid
The serotype of albumen VP6 is divided into totally 7 kinds of A-G.Wherein A types rotavirus is most common virus in human and animal, it is
It is annual that global 1.3 hundred million people is caused to suffer from enteritis, lead to the very important infectant of wherein 870,000 3 thousand people death.
In general, in order to treat this viral disease, it may be considered that inhibition is adsorbed onto epithelial cell, inhibits to invade carefully
Born of the same parents, suppressor transcription and replication inhibit protein synthesis and inhibit the method discharged from cell, these are considered as
A kind of antiviral target, but so far almost without the target of specific rotavirus.
The treatment of recent rotavirus has non-specificity to human rotavirus (HRV, human rotavirus) infection.
Therefore, protection children are infected in vaccine inoculation from HRV and death plays an important role.HRV vaccines, including RotarixTMWith
RotaTeq begins to use in nineteen ninety and 2000 respectively.However, these methods are needed using inactivation HRV or injection dilution HRV
It wants skill and has to change the immune side effect with disease susceptibility of collective, this can induce disease caused by vaccine.
The shortcomings that in order to overcome vaccine, about the research of the natural material of rotavirus can be inhibited in progress.
Invention content
In this regard, the present inventor confirms in studying anti-rotavirus preparation, Geniposide (genipin) inhibits rotavirus
It replicates, thus shows anti-rotavirus infection activity, so as to complete the present invention.
Therefore, the purpose of the present invention is to provide contain Geniposide (genipin) or the conduct of its pharmaceutically acceptable salt to have
The pharmaceutical compositions for preventing or treating disease caused by rotavirus infection of effect ingredient.
Contain Geniposide (genipin) or its pharmaceutically acceptable salt furthermore it is also an object that providing
The food compositions for preventing or improving disease caused by rotavirus infection as active ingredient.
In order to reach the purpose, the present invention is provided to be made containing Geniposide (genipin) or its pharmaceutically acceptable salt
For the pharmaceutical compositions for preventing or treating disease caused by rotavirus infection of active ingredient.
In order to reach another object of the present invention, present invention offer contains Geniposide (genipin) or it pharmaceutically may be used
Food compositions for prevent or improve rotavirus infection caused by disease of the salt of receiving as active ingredient.
The present invention is described in detail below.
The Geniposide (genipin) of the present invention has the structure of following formula 1, and can be purified from natural origin,
Can be by commercially available acquisition, or can be prepared by chemical synthesis process known in the art.
<Chemical formula 1>
The present inventor finds out the purposes of the anti-rotavirus of Geniposide for the first time, this embodiment in the description of the present invention
In be best shown out.
In the implementation profit of the present invention, Geniposide inhibits the generation of nitric oxide (NO, Nitric oxide) and suppression
IL-6 processed, IL-10, IL-1 β, PGE2Deng the secretion for the cell factor (cytokine) for promoting inflammatory reaction, and maintain TNF-α etc.
Inhibit the secretion (embodiment 2) for the cell factor (cytokine) of virus replicated into the cell.
In another embodiment of the present invention, it with rotavirus infection MA104 cells, is infected in virus front and back with capital Buddhist nun
It is flat individually or with various ways such as viral parallel processings to handle, and measure its effect (with reference to embodiment 3).As a result, it was confirmed that capital Buddhist nun
It is flat not only to inhibit the duplication of rotavirus and there is therapeutic effect (with reference to embodiment 3-1) to rotavirus infection, but also prevent
Effect (with reference to embodiment 3-2 and 3-3) is also very outstanding.Specifically, as shown in embodiment 3-2 and 3-3, it was confirmed that utilize capital
Buddhist nun puts down to be used parallel in the prevention and treatment of rotavirus infection, can show better disease inhibition.
Therefore, present invention offer contains Geniposide (genipin) or its pharmaceutically acceptable salt as active ingredient
Pharmaceutical compositions for preventing or treating disease caused by rotavirus infection.
Term " prevention " in the present invention refers to, by putting into composition, inhibiting or postponing rotavirus infection breaking-out
All behaviors.
Term " treatment " in the present invention refers to, by putting into composition, mitigating or improvement being caused by rotavirus infection
Symptom all behaviors.
The rotavirus is not particularly limited its source animal, can be people (Human) rotavirus, pig (Pocine)
Rotavirus, ox (Bovine) rotavirus or goat (Goat) rotavirus, preferably human rotavirus.
The type of disease caused by the rotavirus infection is not particularly limited, if be known in the industry as by
Disease caused by rotavirus, type preferably enterogastritis, enteritis, diarrhea, flu, sphagitis, bronchitis and
It is selected in the group of pneumonia combination.
The pharmaceutical compositions of the present invention are characterized as containing Geniposide or its pharmaceutically acceptable salt.It is described " pharmaceutically
Acceptable salt " refers to being allowed to use according to physiology, when putting into human body, will not be caused allergic reaction or similar reaction,
The salt is preferably the acid-addition salts that pharmaceutically acceptable free acid (free acid) is formed.Free acid can be organic acid
Or inorganic acid.Organic acid includes but not limited to, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid,
Oxalic acid, three sieve acetic acid, benzoic acid, gluconic acid, sulfonic acid, glycolic, succinic acid, 4- toluenesulfonic acids, glutamic acid and asparagus fern ammonia difficult to understand
Acid.In addition, inorganic acid includes but not limited to hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid.
Pharmaceutical compositions according to the present invention can individually contain Geniposide or its pharmaceutically acceptable salt, or further
Contain one or more pharmaceutically acceptable carriers, excipient or diluent.Pharmaceutically acceptable carrier can be further
Include the carrier for oral medication or the carrier etc. for non-oral administration.Oral medication carrier may include lactose, starch,
Cellulose derivative, magnesium stearate, stearic acid etc..In addition, non-oral administration carrier can contain, water, suitably oily, salt is molten
In addition liquid, glucose solution and ethylene glycol can also contain stabilizer and preservative.Suitable stabilizer has bisulfite
The antioxidants such as sodium, sodium sulfite or ascorbic acid.Suitable preservative includes benzalkonium chloride, methyl p-hydroxybenzoate or right
Nipasol and methaform.Other pharmaceutically acceptable carriers can refer to the record in following bibliography
(Remington's Pharmaceutical Sciences,19th ed.,Mack Publishing Company,Easton,
PA,1995)。
The pharmaceutical compositions of the present invention can put into mammal including people by any method.For example, can
With oral or non-oral administration.Non-oral administration method includes but not limited in intravenous, intramuscular, intra-arterial, marrow, endocranium
In interior, intracardiac, transdermal, subcutaneous, intraperitoneal, nasal cavity, enteral, local, sublingual or drop rectum with drug.
As described above, pharmaceutical compositions can be configured to oral or non-oral administration preparation according to administration route.Take orally to
In the case of medicine preparation, composition of the invention can be configured to by methods known in the art pulvis, granule, tablet,
Pill, sugar-tablet agent, capsule, liquid agent, gelling agent, syrup, slurry agent, suspension etc..For example, oral administration preparation can lead to
It crosses and mixes active constituent with solid excipient, then crush, suitable auxiliary agent is added, then mixture is processed into the mixing that granulates
Object obtains tablet or sugar-tablet agent.Suitable excipient includes lactose, dextrose, sucrose, D-sorbite, mannitol, xylose
The starch such as the carbohydrates such as alcohol, antierythrite and maltitol, including cornstarch, wheaten starch, rice starch and potato starch
The celluloses such as class, including cellulose, methylcellulose, sodium carboxymethylcellulose and hydroxypropyl methyl cellulose, including it is gelatin, poly-
The fillers such as vinylpyrrolidone.Alternatively, it is also possible to add crosslinked polyvinylpyrrolidone, agar, alginic acid or sodium alginate
As disintegrant.In addition, the pharmaceutical compositions of the present invention can further include anti-coagulants, lubricant, wetting agent, fragrance, emulsification
Agent and preservative.
In the case of non-oral administration, methods known in the art such as injection, creme, emulsion, external application can be passed through
The form preparation of ointment, finish, moisturizer, gelling agent, aerosol and snuff.These preparations are in all pharmaceutical chemistries
Prescription book document that field has been apprised of (Remington's Pharmaceutical Science, 15th Edition,
1975.Mack Publishing Company,Easton,Pennsylvania 18042,Chapter 87:Blaug,
Seymour described in).
The Geniposide of the present invention or total effective quantity of its pharmaceutically acceptable salt can be according to single dose (single
Dose) the fractionated therapy plan to put into patient or be put into for a long time according to multiple amount (multiple dose)
(fractionated treatment protocol) is put into.Pharmaceutical compositions in the present invention can according to the type of disease
Active ingredient containing different content.The Geniposide of the present invention or total dosage of its pharmaceutically acceptable salt, preferably daily
Every 1 kg patient body weight about 0.01 to 1000mg, more preferably 0.1 to 100mg.But the dosage need to consider pharmaceutical compositions
Input approach and treatment number of times also need to consider age of patient, weight, health status, gender, the severity of disease, diet
It is determined with after many factors such as excretion rate.In view of factors above, fields are those skilled in the art can be according to described
Geniposide or its pharmaceutically acceptable salt are as the prevention of disease caused by rotavirus infection or the specific use for the treatment of preparation
Way determines its effective input amount.As long as the pharmaceutical compositions in the present invention have the effect of the present invention, it is not limited to
Its dosage form, input approach and input method.
In addition, present invention offer contains Geniposide (genipin) or its pharmaceutically acceptable salt as active ingredient
Food compositions for preventing or improving disease caused by rotavirus infection.
The food compositions of the present invention include functional food (functional food), nutritional supplement
(nutritional supplement), healthy food (health food) and food additives (food additives) etc.
Form of ownership.Such food composition can in a variety of manners be prepared according to conventional method known in the art.For example, strong
Health food can liquefy the Geniposide of the present invention or its pharmaceutically acceptable salt, be granulated, encapsulated and powdered
The form of tea, fruit juice or beverage is used to prepare into drink.Furthermore it is also possible to by the present invention Geniposide or its can pharmaceutically connect
The salt received and known antiviral (further including not only inhibitor to other viruses to rotavirus) active principle or it is active at
Mixing is divided to be prepared into composition form.
In addition, functional food includes but not limited in beverage (including alcoholic beverage), fruit and its processed food (such as tank
The jam etc. that dress fruit, bottled fruit, jam, lemon or orange spawn), fish, meat and its processed food (such as ham, perfume (or spice)
Intestines etc.), bread and such as noodles (such as Noodle, buckwheat flour, hand-pulled noodles, pasta, macaroni etc.), fruit juice, various beverages, cake
Dry, sugar, dairy products (such as butter, cheese), edible vegetable oil, margarine, vegetable protein, cooking food, freezing food
Geniposide is added in product, various seasonings (such as thick broad-bean sauce, soy sauce, sauce) to prepare.In order in the form of food additives
Using the Geniposide of the present invention, the form that can be prepared into powder or concentrate uses.
In the food compositions of the present invention, the content of the Geniposide or its pharmaceutically acceptable salt is not limited especially
System, but in the food finally prepared, 0.01~90 weight % is preferably accounted for, more preferably account for 0.5~60 weight %.
The effect of invention：
The present invention relates to the effect of the anti-rotavirus of Geniposide, i.e. prevention and treatment of the Geniposide to rotavirus infection
Effect highly significant.
Description of the drawings
Fig. 1 is the schematic diagram for measuring Geniposide to the toxicity of RAW264.7 cells；
Fig. 2 is the schematic diagram for measuring Geniposide to the toxicity of MA104 cells；
Fig. 3 is the schematic diagram of the ability for inhibiting NO generations of Geniposide in the RAW264.7 cells for induced inflammation by LPS；
Fig. 4 is the signal of the ability for inhibiting IL-6 generations of Geniposide in the RAW264.7 cells for induced inflammation by LPS
Figure；
Fig. 5 is the signal of the ability for inhibiting IL-10 generations of Geniposide in the RAW264.7 cells for induced inflammation by LPS
Figure；
Fig. 6 is the signal of the ability for inhibiting IL-1 β generations of Geniposide in the RAW264.7 cells for induced inflammation by LPS
Figure；
Fig. 7 is the inhibition PGE of Geniposide in the RAW264.7 cells for induced inflammation by LPS2The signal of the ability of generation
Figure；
Fig. 8 is the ability of the maintenance TNF-α secretion level of Geniposide in the RAW264.7 cells for induced inflammation by LPS
Schematic diagram；
Fig. 9 is after infecting MA104 cells with Rotavirus Wa strain strain, with the signal for the therapeutic effect that Geniposide is handled
Figure；
Figure 10 A are by being pre-processed to MA104 cells with the composition of Rotavirus Wa strain strain and Geniposide
Afterwards, it is infected with Wa strain, is reprocessed later according to the Geniposide of various concentration, to confirm prevention rotavirus
Infection and the schematic diagram for inhibiting virus breeding effect (improve and treat)；
Figure 10 B are by being pre-processed to MA104 cells with the composition of Rotavirus Wa strain strain and Geniposide
Afterwards, it is infected with Wa strain, is reprocessed later without Geniposide, to confirm that the Geniposide of the experimental group is located in advance
Manage the schematic diagram of effect (the prevention rotavirus infection effect of Geniposide)；
Figure 11 A be by the way that pretreatment in 24 hours is carried out to MA104 cells with Geniposide after, felt with Wa strain
Dye, is reprocessed according to the Geniposide of various concentration later, prevents rotavirus infection and inhibition virus breeding effect to confirm
The schematic diagram of fruit (improve and treat)；
Figure 11 B be by the way that pretreatment in 24 hours is carried out to MA104 cells with Geniposide after, felt with Wa strain
Dye, is reprocessed later without Geniposide, to confirm Geniposide pretreating effect (the prevention wheel of Geniposide of the experimental group
Shape virus infectious effect) schematic diagram.
Specific implementation mode
The present invention is described in detail below.
But the embodiment is only to be illustrated to the present invention, and present disclosure is not limited to the embodiment.
<Embodiment 1>To the toxicity assessment of Geniposide
Mouse macrophage RAW264.7 cells are passed on 3-4 times weekly, culture medium is to be tried containing 20 μ g/ml gentamicins
The DMEM of agent solution (Gibco BRL, Gentamicine Reagent Solution) and 10%FBS (Gibco BRL)
(Dulbecco's Modified Eagle's Medium) culture medium, in 37 DEG C and 5%CO2It is cultivated under environment.It is thin from South Korea
Born of the same parents (strain) bank obtains MA104 cells.In the minimum minimal medium containing 5%FBS and 20 μ g/ml gentamicin reagent solutions
α(MEM-α；Gibco BRL) in culture.Virus be human rotavirus A group strains G1P1A (hereinafter referred to as ' Wa strain',VR-2018TM)。
By RAW264.7 cells with 2 × 103The concentration of a cells/well is seeded in 96 orifice plates and cultivates 24 hours.Not
In new DMEM culture mediums containing FBS, Geniposide (Genipin powder, Sigma-aldrich) dissolving is made into ultimate density point
Not Wei 10,50,100,150,160,180,200 μM/ml, cultivated 24 hours after handling cell.In order to measure cell strain
Survival rate, use MTT [3- (4,5- dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromides] ([3- (4,5-
Dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide]) it is used as reagent, and pass through microplate reader
(microplate reader：Model Infinite F200, Tecan, Mannedorf, Switzerland), extinction is measured at 590nm
Degree.Also the cytotoxicity of MA104 cells is measured in an identical manner.
As a result, as depicted in figs. 1 and 2, with the cell survival rate of RAW264.7 cells and MA104 cells that Geniposide is handled
The tendency being decreased obviously is shown since the concentration of 160 μM/ml, but survival rate is 95% or more until concentration to 100 μM/ml,
Display cell viability identical with untreated fish group, confirms no cytotoxicity.
<Embodiment 2>Impact analysis of the Geniposide to NO and cell factor
<2-1>NO is detected
By 264.7 cells of RAW of culture with 3 × 105The concentration of a cells/well is seeded in 24 orifice plates and to cultivate 24 small
When.In order to induce inflammation, LPS is added in the new DMEM culture mediums without FBS, so that its concentration is reached 0.1 μ g/ml, uses capital
Buddhist nun, which divides equally, is not handled cell with the ultimate density of 0,10,50,100 and 150 μM/ml, is cultivated 24 hours.After 24 hours,
By Griess reagents according to 1 in cell supernatant：To measure NO generations, reaction after ten minutes, uses microplate reader for 1 mixing
(microplate reader) measures absorbance at 540nm.In addition, measuring Geniposide using the following method to induction type one
Nitric oxide synthase (iNOS：Inducible nitric oxide synthase) expression ability.With same as mentioned above
Mode handles 3 × 10 with LPS5The RAW264.7 cells of a cells/well are used in combination Geniposide to be handled simultaneously according to ultimate density respectively
Culture 24 hours.It after 24 hours, centrifuges and obtains cell, TRIZOL reagents (MRC, Cincinnati, the E Hai of 900 μ l is added
Russia state) and homogenize.100 μ l chloroforms are added thereto, and mixture are placed at room temperature 5 minutes.By the mixture with 13,
000rpm is centrifuged 10 minutes, collects supernatant, the isopropanol (isopropanol) of equivalent is added thereto, at room temperature
It places 5 minutes, centrifuges.It washed once with 70%DEPC- ethyl alcohol, drying at room temperature after centrifugation, 30 μ l be added and contain 70%
The distilled water of DEPC.In order to carry out RT-polymerase chain reaction detection (Reverse transcription-PCR assay),
The DMSO of 1.4 μ l is added in the RNA of 5 μ l, and is denaturalized 5 minutes at 97 DEG C.10x buffer solutions (buffer) containing 1 μ l,
Enzyme AMV (the enzyme of 1x dNTPs of 0.4 μ l, the iNOS specific forward primers of each 0.2 μ l and reverse primer, 0.1 μ l
AMV) the mixture (totally 10 μ l) of (Promega, Medison, USA) and the water (RNase-free water) without RNase carries out
RT-polymerase chain reaction detects (Reverse transcription-PCR assay) analysis (60 minutes, 95 DEG C at 42 DEG C
Lower 5 minutes), cDNA is generated, and result is confirmed by electrophoresis.
Experimental result, as shown in figure 3, compared with the control group only handled with LPS, the experimental group handled with Geniposide is shown
The rejection ability for rejection ability and the iNOS expression that the NO of concentration dependent is generated.In particular, the Geniposide processing group of 100 μM/ml
The NO levels for showing 10%, show that NO similar with LPS untreated fish groups is horizontal.
<2-2>Cytokines measurement
By the RAW264.7 cells of culture with 3 × 105The concentration of a cells/well is seeded in 24 orifice plates and to cultivate 24 small
When.In order to induce inflammation, LPS is added in the new DMEM culture mediums without FBS, so that its concentration is reached 0.1 μ g/ml, uses capital
Buddhist nun, which divides equally, is not handled cell with the ultimate density of 0,10,50,100 and 150 μM/ml, is cultivated 24 hours.After 24 hours,
In order to measure the generation degree of IL-6, IL-10, IL-1 β, TNF-α and PGE-2 from cell supernatant, tried using parametric measurement
Agent box (ParameterTMImmunoassay kit) andImmunity detection reagent (
Immunoassay kit) (R＆D Systems, Minneapolis, MN, USA), it is tested according to handbook.Each cell factor
Albumen quality absorbance is measured at 450nm with microplate reader (microplate reader).
As a result, the bioactie agent IL-6 (Fig. 4), IL-10 (figures for promoting inflammatory reaction in cell
5), IL-1 β (Fig. 6), PGE2(Fig. 7), the experimental group handled with Geniposide are observed compared with the control group only handled with LPS
The cytokine secretion rejection ability of concentration dependent.When especially concentration is respectively 100 and 150 μM/ml, it is shown that with LPS
The similar level of untreated fish group, when a concentration of 150 μM/ml, the cytokine secretion reduces 75% respectively, 83%, 77%,
75%.Fig. 8 confirmed the result of TNF-α secretion, it can be seen that all be maintained under all concentration of 10,50,100 and 150 μM/ml
High level.These results indicate that the Geniposide of the present invention inhibits IL-6, IL-10, IL-1 β and PGE2Deng promotion inflammatory reaction
The secretion of cell factor, while TNF-α is maintained etc. and inhibits the secretion for the cell factor of virus replicated into the cell, show Geniposide
It tells on to rotavirus, can be more broadly used for preventing rotavirus or is used as pharmaceutical compositions.
<Embodiment 3>The inhibition rotavirus replication ability of Geniposide detects
It confirmed the inhibition of the virus replication of Geniposide in the MA104 cells of infection rotavirus below.With
The Rotavirus Wa strain Strain of MOI0.01 infects MA104 cells, and is tested by following 3 kinds of methods.Pass through real-time RT-
Rotavirus quantifies in each experiment of PCR (real-time RT-PCR) confirmations.It is tried specifically, being extracted using viral RNA
Agent box (QIA amp Viral RNA Mini Kit) (Qiagen, Valencia, CA, USA) extracts viral RNA.First, will
The supernatant of 140 μ l is added 560 μ l and contains 5.6 μ g vector rnas (carrier RNA) (Qiagen, Valencia, CA, USA)
In AVL solution and mix 15 seconds.Culture after ten minutes, is added the ethyl alcohol of 560 μ l and mixes 15 seconds.Mixture is transferred to 2ml
It is centrifuged 1 minute in pipe and with 8000rpm.After carrying out 2 washings, the water without RNase of 50 μ l is added them to
In (RNase-free water), and stored for RT-polymerase chain reaction (RT (Reverse at -80 DEG C
transcription)-PCR)。
RT-polymerase chain reaction measurement (Reverse is carried out using 6 gene of rotavirus vp as template
transcription-PCR assay).First, the DMSO of 1.4 μ l is added in the viral RNA (viral RNA) of 5 μ l, so
It is denaturalized 5 minutes at 97 DEG C afterwards.1x dNTPs10, each 0.2 μ l of 10x buffer solutions (buffer), 0.4 μ l containing 1 μ l are just
To primer (SEQ ID No.1:5 '-AATGGAGTAGCGCCACAATC-3 ') and reverse primer (SEQ ID No.2:5’-
TAAGCCACATGGTTCCCATT-3 '), enzyme AMV (enzyme AMV) (Promega, medison, USA), the Yi Jiwu of 0.1 μ l
The mixture (totally 10 μ l) of the water (RNase free water) of RNase carries out RT-polymerase chain reaction measurement (Reverse
Transcription-PCR assay) (at 42 DEG C 5 minutes at 60 minutes, 95 DEG C), generate cDNA.In order to carry out real-time PCR inspections
It surveys (real-time PCR assay), uses reaction mixture (master mix) (Applied of the cDNA of 2 μ l, 5 μ l
Biosystems, USA), the forward and reverse primer (10 μM, sequence same as described above) and 1.5 μ l probes (SEQ of each 0.2 μ l
ID No.3:6FAM-GCACCGGATTTGTTTTTCAT-MGBNFQ) (2pM) and the water (RNase free water) without RNase
The PCR mixtures of 10 μ l of composition.It uses ABI7500 real time thermocyclers (ABI 7500real-time thermocycler)
(Biosystems, Foster City, CA, USA) carries out reverse transcription (at 50 DEG C 10 minutes at 2 minutes, 95 DEG C).Denaturation is 94
It is carried out 15 seconds at DEG C, annealing carries out 40 cycles (at 60 DEG C 1 minute).
It is handled with Geniposide after 3-1. infection rotavirus
By MA104 cells with 3 × 105The concentration of a cells/well is seeded in 24 orifice plates and is cultivated 24 hours at 37 DEG C.With
The Rotavirus Wa strain Strain of MOI0.01 infects MA104 cells, reacts 1 hour.Later, unattached virus is carried out 2 times
Washing.To infecting the cell of Rotavirus Wa strain Strain, respectively with the capital Buddhist nun of 0,10,50,100,130 and 150 μM/ml concentration
It is flat to be handled (24 hours).
The results are shown in Figure 9 for it, and virus replication quantity is reduced according to the concentration of Geniposide, and 150 μM/ml most
62% minimizing effect is shown under high concentration.
After 3-2. rotavirus and Geniposide mixture are pre-processed, rotavirus is infected, is carried out again with Geniposide
Processing
By MA104 cells with 3 × 105The concentration of a cells/well is seeded in 24 orifice plates and is cultivated 24 hours at 37 DEG C.Point
It is not mixed in culture medium with rotavirus with the Geniposide of 0,10,50,100,130 and 150 μM/ml concentration, and cultivates 4 at 37 DEG C
Hour.It after washing MA104 cells, is pre-processed, and is cultivated 1 hour with the virus prepared and Geniposide mixture.1
After hour, MA104 cells are infected with the Rotavirus Wa strain Strain of MOI 0.01, are reacted 1 hour.Later, to unattached disease
Poison carries out 2 washings.To the cell of infection Rotavirus Wa strain Strain prepared by the method, grouping respectively with 0,10,50,
100, the Geniposide of 130 and 150 μM/ml concentration is handled (24 hours) or without processing, measures rotavirus replication journey
Degree.
Figure 10 A be by being pre-processed to MA104 cells with Rotavirus Wa strain strain and Geniposide after, use Wa
Strain is infected, and is reprocessed later according to the Geniposide of various concentration, prevents rotavirus infection and suppression to confirm
The schematic diagram of virus replication effect (improve and treat) processed.Viral load especially exists as the concentration of Geniposide increases and reduces
88% minimizing effect is shown under the concentration of 150 μM/ml.Figure 10 B are the knots for the experimental group that unused Geniposide is reprocessed
Fruit schematic diagram, compared with untreated fish group, viral load is as the concentration of Geniposide increases and reduces, under the concentration of 150 μM/ml
Show 57% minimizing effect.As shown in Figure 10 B, even if after infection rotavirus, unused Geniposide is reprocessed, still
Viral infection can so be inhibited, this shows the outstanding rotavirus infection preventive effect of Geniposide.
After 3-3. is pre-processed with Geniposide, rotavirus is infected, is reprocessed with Geniposide
By MA104 cells with 3 × 105The concentration of a cells/well is seeded in 24 orifice plates and is cultivated 24 hours at 37 DEG C.It will
Geniposide is added to culture medium and MA104 mixing with cells, and it is respectively 0,10,50,100,130 and 150 μM/ml to make its concentration, and
Culture 24 hours.Later, it using method identical with illustrated embodiment 3-2, virus infection and is reprocessed with Geniposide.
Figure 11 A be by with Geniposide to MA104 cells carry out 24 hours pretreatment after, infected with Wa strain,
The result reprocessed later according to the Geniposide of various concentration.Viral load is reduced with the concentration increase of Geniposide,
Viral load is all greatly reduced compared with untreated fish group under all concentration conditions, especially in 130 μM/ml and 150 μM/ml
Concentration under show about 88% minimizing effect.Figure 11 B are the result schematic diagrams that unused Geniposide is reprocessed, and are not located
Reason group compares, and viral load shows that 76% subtracts as the concentration of Geniposide increases and reduces under the concentration of 150 μM/ml
Few effect.In particular, as shown in Figure 11 B, even if after infection rotavirus, unused Geniposide is reprocessed, and remains able to press down
System virus infection, this shows the outstanding rotavirus infection preventive effect of Geniposide.
By the experiment of the embodiment 3, Geniposide inhibits rotavirus replication, not only has to rotavirus infection and controls
Therapeutic effect (with reference to embodiment 3-1), and preventive effect (with reference to embodiment 3-2 and 3-3) is also very outstanding.In particular, as implemented
Shown in example 3-2 and 3-3, it is thus identified that in the prevention and treatment of rotavirus infection, use Geniposide parallel, can show more preferable
Disease inhibition.
As a result, the Geniposide of the present invention has preventive effect and inhibition to rotavirus, and parallel pre-
When anti-and treatment, better effect can be shown.
Industry application possibility
As previously discussed, the present invention relates to the new applications of Geniposide (genipin) compound, specifically, the present invention relates to
And contain Geniposide or its salt pharmaceutically also received as active ingredient for preventing, treating or improving rotavirus infection
The composition of caused disease.
The Geniposide compound of the present invention has outstanding anti-rotavirus effect, can be used for preventing, treating and improve wheel
The pharmacy or food group of disease (such as enteritis, diarrhea, flu, sphagitis, bronchitis and pneumonia) caused by the infection of shape virus
Object is closed, industry is high using possibility.
Sequence table
<110>Univ Chung Ang Ind
<120>Contain combination for prevent or treat rotavirus infection caused by disease of the Geniposide as active ingredient
Object
<130> DAG35590
<160> 3
<170> SIPOSequenceListing 1.0
<210> 1
<211> 20
<212> DNA
<213>Artificial sequence (Artificial Sequence)
<400> 1
aatggagtag cgccacaatc 20
<210> 2
<211> 20
<212> DNA
<213>Artificial sequence (Artificial Sequence)
<400> 2
taagccacat ggttcccatt 20
<210> 3
<211> 20
<212> DNA
<213>Artificial sequence (Artificial Sequence)
<400> 3
gcaccggatt tgtttttcat 20
Claims (4)
1. one kind containing Geniposide (genipin) or its pharmaceutically acceptable salt as active ingredient for preventing, treating
Or improve the pharmaceutical compositions of disease caused by rotavirus infection.
2. according to the 1st composition of entitlement requests, it is characterized in that,
The rotavirus behaviour (Human), pig (Pocine), ox (Bovine) or goat (Goat) rotavirus.
3. according to the 1st composition of entitlement requests, it is characterized in that,
The disease caused by the rotavirus infection is enterogastritis, enteritis, diarrhea, flu, sphagitis, bronchitis and pneumonia
Any type disease selected in the group of combination.
4. a kind of containing Geniposide or its pharmaceutically acceptable salt as active ingredient for preventing or improving rotavirus
The food compositions of disease caused by infection.
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| KR1020170009254A KR101918704B1 (en) | 2017-01-19 | 2017-01-19 | Composition for preventing or treating disease induced by rotavirus infection comprising genipin as an active agent |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104523676A (en) * | 2014-12-16 | 2015-04-22 | 中国中医科学院中药研究所 | Application of genipin in prevention or treatment of ischemic brain injury |
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2017
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104523676A (en) * | 2014-12-16 | 2015-04-22 | 中国中医科学院中药研究所 | Application of genipin in prevention or treatment of ischemic brain injury |
Non-Patent Citations (3)
| Title |
|---|
| JONG-HWA KIM等: "Genipin inhibits rotavirus-induced diarrhea by suppressing viral replication and regulating inflammatory responses", 《SCIENTIFIC REPORTS》 * |
| MIYEON CHO等: "Genipin Enhances Kaposi’s Sarcoma-Associated Herpesvirus Genome Maintenance", 《PLOS ONE》 * |
| 葛雯等: "热毒宁注射液化学成分、药理作用及临床应用研究进展", 《中草药》 * |
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