CN105311089A - Use of a fermented soy extract as inhibitor for indoleamine 2,3-dioxygenase - Google Patents
Use of a fermented soy extract as inhibitor for indoleamine 2,3-dioxygenase Download PDFInfo
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- CN105311089A CN105311089A CN201510321283.4A CN201510321283A CN105311089A CN 105311089 A CN105311089 A CN 105311089A CN 201510321283 A CN201510321283 A CN 201510321283A CN 105311089 A CN105311089 A CN 105311089A
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Abstract
The invention discloses use of a fermented soy extract as inhibitor for indoleamine 2,3-dioxygenase. Particularly, the invention discloses use of a fermented soy extract as inhibitor for indoleamine 2,3-dioxygenase.
Description
The mutual reference of related application
The application advocates the in application on June 13rd, 2014 the 62/011st, the priority of No. 856 U.S. Provisional Patent Application cases, and these to be all completely incorporated to as reference at this.
Technical field
The present invention about fermented soybean extract as indoleamine 2, the purposes of 3 dioxygenases (indoleamine2,3-dioxygenase, IDO) inhibitor.
Background technology
Indoleamine 2,3 dioxygenases (IDO1 or IDO) are a kind of containing iron content haemachrome monomeric protein, the degraded of its catalysis essential amino acids tryptophan (Tryp).IDO has been considered to be a kind of ferment giving strong immunomodulatory effect, with the immunoreation in control agent, causes catabolic enzyme activity of essential amino acids tryptophan owing to it.The tryptophan catabolism that IDO regulates has been proved and has produced effect by being transferred by multiple machine to T cell, comprise the T cell hypertrophy of reduction, increase T cell suicide and modulating T cell (Tregulatorycells, bringing out Tregs), it causes the infringement [1-4] of cell immune response jointly.
Summary of the invention
The non-expected discovery of the present invention, fermented soybean extract is effective in suppression indoleamine 2, and the activity of 3 dioxygenases, thus can be used as IDO inhibitor.
Therefore, the invention provides the application of fermented soybean extract as IDO inhibitor.
Specifically, described fermented soybean extract is by with at least one lactobacillus (such as, Lactobacillus (LactobaciIIusspecies) and can at least one yeast (such as, Saccharomycodes (Saccharomycesspecies)) optionally make soluble soybean extract ferment obtain.
In some embodiments, carry out one or more after fermentation and be selected from by the step of the following group formed: sterilizing, filtration, concentrated, lyophilizing and any combination thereof.
In certain specific embodiments, this fermented soybean extract is that the process by comprising following steps obtains: (a) makes soluble soybean extract ferment, to form fermentation liquid with at least one lactobacillus with at least one yeast; B () carries out sterilizing to this fermentation liquid; C () filters through sterilization fermentation liquid; (d) water is removed, to form concentrated fermented soybean extract from fermentation liquid after filtration.
The specification specified of each instantiation of the present invention is as rear.Further feature of the present invention will be known via the detailed description in each instantiation following and claims and presents.
Accompanying drawing explanation
For explaination object of the present invention, show current preferred embodiment in the drawings.However, it should be understood that the present invention is not limited to shown preferred embodiment.In the drawings:
The IDO activity that MS-20 (fermented soybean extract of the present invention) suppresses interferon gamma (IFN γ) to bring out at human peripheral's blood monocyte (PBMCs) is shown in Fig. 1.Result comes from n=6 and tests separately, data present in the mode of average ± standard deviation, wherein (a) show Tryptophan concentration reduce (μM, Tryp), b () kynurenin (kynurenine) concentration increases (μM, and (c) Kyn/Tryp ratio (μm ol/mmol) kyn).
The IDO activity that MS-20 suppresses IFN γ to bring out with dose dependent fashion at human peripheral's blood monocyte (PBMCs) is shown in Fig. 2, wherein (a) is Tryptophan concentration (Tryp), (b) kynurenin concentration (Kyn), and (c) is Kyn/Tryp ratio (* 10
3).These results display MS-20 suppresses IDO active with dose dependent fashion, EC
50be respectively 0.71,0.46 or 0.48% (1%MS-20=4mg/mL) as calculated.
Showing MS-20 in Fig. 3 draws (HeLa) human cervical cancer cell IDO active with the sea that dose dependent fashion suppresses IFN γ to bring out, wherein (a) suppresses percentage ratio (%) for kynurenin concentration (μM, Kyn) and (b).These results represent (n=3 independent experiment) with average ± standard deviation.
Fig. 4 shows the survival rate of human peripheral's blood monocyte (PBMCs).2 days are reached with the MS-20 process mankind PBMCs of 0.125%-1% (0.5-4mg/mL).Analyze with MTT and measure cell survival rate.Result showed cell survival rate increases in the dose-dependent mode of MS-20.These results come from the meansigma methods of 2 independent experiments.
The survival rate of extra large holding class cervical cancer cell is shown in Fig. 5.2 days are reached with (a) of variable concentrations MS-20 or (b) L-1MT process extra large holding class cervical cancer cell.Result showed cell survival rate reduces along with the concentration increase of MS-20.These results represent (n=3 independent experiment) with average ± standard deviation.
Fig. 6 shows MS-20 and suppresses IDO enzyme activity with dose dependent fashion.Data represent to suppress percentage ratio (%).These results represent (n=2 independent experiment) with average ± standard deviation.
Detailed description of the invention
Unless otherwise defined, otherwise all technology used herein and scientific terminology all have and general with those skilled in the art of the invention understand identical implication.Person as used herein, following term has the meaning owing to these terms, unless otherwise defined.
In this article, article " " refer to one or more (that is, at least one) these articles grammatically by word.For example, an assembly refers to an assembly or more than one assembly.
In the present invention, non-expected discovery, fermented soybean extract is effective in suppression indoleamine 2, and the activity of 3 dioxygenases, thus can be used as IDO inhibitor.
Therefore, the invention provides a kind of suppression indoleamine 2, the method for 3 dioxygenases (IDO), comprise and suppress the content of IDO activity to come into operation in individuality in need to be effective in fermented soybean extract.
The present invention also provides fermented soybean extract for the preparation of suppression indoleamine 2, the application of the compositions of 3 dioxygenase activity.The present invention also provides a kind of and suppresses indoleamine 2, and the method for 3 dioxygenase activity, comprises and make indoleamine 2, and 3 dioxygenases contact with the fermented soybean extract being effective in the content suppressing IDO activity.
According to the present invention, fermented soybean extract as used herein refers to by utilizing at least one lactobacillus and can the extract that makes soluble soybean extract fermentation obtain of at least one yeast optionally.In one embodiment, this at least one lactobacillus is Lactobacillus and this at least one yeast is Saccharomycodes.In a particular embodiment, fermentation uses the different types of Lactobacillus culture culture of 30 kind of lactobacillus strains (such as 5,10,15,20,25 or) to implement, and preferably, at least one yeast is added in different types of Lactobacillus culture.The lactobacillus strains that can be used for fermenting comprises, but be not limited to, bacillus acidophilus (Lactobacillusacidophilus) CCRC (Foodstuff Industrial and Development Inst.'s living resources are preserved and research center, Taiwan) 10695,14026,14064,14065 and/or 14079; Lactobacillus delbruockii subspecies bulgaricus (Lactobacillusdelbrueckiibulgaricus) CCRC10696,14007,14009,14010,14069,14071,14098 and/or 16054; Lactobacillus delbrueckii subsp. lactis (LactobacillusIactislactis) CCRC10791,12267,12306,12312,12315,12323,14016,14015 and/or 14117; Lactobacillus kefir (LactobaciIIuskefir) CCRC14011 and/or lactobacillus kefiranofaciens (Lactobacilluskefiranofaciens) CCRC16059.The yeast strain that can be used for fermenting comprises, but be not limited to, saccharomyces cerevisiae (Saccharomycescerevisiae) CCRC20577,20578,20581,21494,21550,21797,21805,22138,22234,22337,22731 and/or 22728 and/or candida kefyr bacterium (Candidakefyr) CCRC21269,21742 and/or 22057.Specifically, carry out one or more steps after fermentation, such as sterilizing, filtration, concentrated, lyophilizing or its any combination.Preferably, carry out sterilizing by such as heating after fermentation, and can optionally carry out filtering and concentrating.More preferably, dry fermented soybean extract can be carried out, to obtain the fermented soybean extract in powder type via such as lyophilizing.In a certain embodiment, fermented soybean extract of the present invention is that the processing procedure by comprising following steps obtains: (a) utilizes at least one lactobacillus soluble soybean extract to be fermented, to form fermentation liquid with at least one yeast; B () carries out sterilizing to this fermentation liquid; C () filters through sterilization fermentation liquid; (d) filtering fermentating liquid of hanging oneself removes water, to form concentrated fermented soybean extract.Fermented soybean extract used herein can as United States Patent (USP) the 6th, 855, No. 350 and the 6th, prepares for 733, No. 801, and each of described patent all in full way of reference is incorporated herein.
As United States Patent (USP) the 6th, described in 733, No. 801, preparation method be by Glycine Organic substance (after degrease) and distilled water according to 1: 10 ratio mix.Mixture is heated to 100 DEG C, and keeps 30 minutes, then filter and obtain Glycine extract.Beef and Sargassum are kept fluidized state 30 minutes, to obtain broth bouillon in distilled water.Add salt, sugar and agar to obtain special agar culture medium.Lactobacillus and yeast strain is added in special agar culture medium.Lactobacillus in culture medium and optional yeast are transferred in Glycine extract, cultivate 45-50 hour at 36-43 DEG C.Due to growth characteristics that different types of microorganism is similar according to it, to form all living creatures long, therefore preferably separately joined in Glycine extract by these micropopulations before cultivation.These growth characteristics are any requirement of (such as) unique Nutrient medium, whether can produce good abnormal smells from the patient and whether this quasi-microorganism can survive under the condition of this uniqueness after microbial strains fermentation.The object done like this reduces the negative effect between bacterial strain not of the same race.Different microbial bacteria group of hills preferably joins in Glycine fermentation, extraction thing with equal proportion before cultivation, and the extract obtained cultivates 45-47 hour at 40 DEG C.After this incubation terminates, then xenogenesis culture is introduced in Glycine extract, at 36-43 DEG C, cultivate 100-150 hour.Final fermentation, extraction thing heat sterilization is filtered.In concentrator, remove the moisture content of 95%, obtain the Glycine extract of the fermentation of concentrated or state of aggregation.The superiors filter through porcelain, divide to put to seal preservation in a reservoir.
Noun as used herein " individuality " or " object " comprise the mankind and non-human animal, such as, companion animals (as, Canis familiaris L., cat and fellow), farm-animals (as, cattle, sheep, pig, horse and fellow) or laboratory animal (e.g., rat, mice, guinea pig and fellow).
Noun as used herein " treatment " refers to the progress in order to cure, healing, alleviate, releive, change, correct, improve, improve or affect this disease, the symptom of this disease, deformity that this disease causes or this disease, and the compositions comprising one or more activating agent is used or administration to the individuality suffering from this disease, the symptom of this disease or the progress of the patient's condition or this disease.
Noun as used herein " effective dose " refers to that each active component can produce the desired content of response to treatment to individuality, can be independent or in conjunction with one or more active component.As intelligible in haveing the knack of the technology person, effective dose will play by ear, and depend on, such as, route of administration, the use of excipient, and with other active ingredients and use.Such as, be effective in and suppress the amount of IDO activity to be reduce or suppress the amount of IDO activity, it can use the known method in this field decide or assess, such as, and the analysis based on cell or enzymatic analysis (see following instance).
In some embodiments, it is active that fermented soybean extract of the present invention is effective in the IDO reducing peripheral blood mononuclear cell (PBMCs).
In some embodiments, fermented soybean extract of the present invention is effective in the survival rate increasing peripheral blood mononuclear cell (PBMCs).
In some embodiments, fermented soybean extract of the present invention is effective in increase immunoreation, the immunoreation of particularly T cell adjustment, via, such as, increase T cell hypertrophy, reduce T cell suicide and reduce regulatory T-cell and reach.
Specifically, fermented soybean extract of the present invention is effective in the immunocompromised regulated at individual treatment IDO in need.Noun as used herein " immunocompromised " can refer to the damage of the arbitrary member of immune system, causes the immunologic function reduced.Immunocompromised may be caused by various factors, such as, pressure, malnutrition, catch, the chemotherapy of cancer, the anti-rejection drugs of organ transplantation, anti-inflammatory drug or cancer or radiation therapy.
In some embodiments, catching is viral infection, is selected from the group that Human Immunodeficiency virus (HIV), hepatitis C virus, Measles virus, dengue virus and lymph corpuscle choriomeningitis virus (LCMV) form.
In some embodiments, chemotherapy is via coming into operation anticancer chemotherapeutic agent and carrying out, and is selected from the group that cisplatin (cisplatin), Docetaxel (docelaxel), general Ehrlichin (epirubicin), Ai boolean (eribulin), Fu Ruisi ingot (fareston), its guest (gemcitabine) of Ji Xi, Paclitaxel (paclitaxel), Tamoxifen (tamoxifen) and vincristine (vincristine) form.
In part instantiation, radiation therapy comprises caesium, iridium, iodine or cobalt.Radiation therapy can be general or the locality for position, such as, for knub position and solid cancer tissue.It can be traditional external exposure and electronic emission therapy, Proton Radiation Therapy, brachytherapy and molecular radiation therapy that width penetrates treatment.
Specifically, field like this well known, the immunosuppressive activity of IDO is confirmed in different physiology and pathologic condition, comprises cancer.Based on the research of serum-concentration measuring tryptophan and kynurenin, IDO is presented at chronic activation in the sufferer suffering from cancer, and IDO activation is with morbid state is relevant widely.IDO excessively shows in many human tumor kinds and the sternzellen (DCs) that is positioned tumor-draining lymphode (TDLNs).It is the independent prognostic variable factor of reduction survival of sufferer for suffering from acute myeloid leukaemia (AML), small cell lung cancer, melanoma, ovarian cancer, colorectal carcinoma, cancer of pancreas and carcinoma of endometrium that the IDO performance increased has shown.Therefore, IDO suppresses the mode likely that can be confirmed to be immunotherapy for cancer.
In some embodiments, cancer comprises gastric cancer, colon cancer, breast carcinoma, hepatocarcinoma, pulmonary carcinoma, cervical cancer, carcinoma of prostate, cancer of pancreas, renal carcinoma, ovarian cancer and leukemia.
Fermented soybean extract of the present invention is sent by any physiologically acceptable approach, such as, and per os, through intestinal outer (such as, intramuscular, intravenous, subcutaneous, intraperitoneal), percutaneous, per rectum, by sucking.In one embodiment, fermented soybean extract of the present invention be oral administration with.
In some embodiments, can come into operation and reach one section of enough time by effective dose according to fermented soybean extract of the present invention, with in sufferer activation in need or to recover T cell active.
For helping to send, fermented soybean extract of the present invention is allocated as compositions by available physiologically acceptable supporting agent.The present composition can be deployed into medicine, food additive or health promoting product.
" physiologically acceptable " used herein second word refers to that active ingredient contained in supporting agent and compositions is compatible, preferably can stablize this active ingredient, and individual harmless to treatment.Supporting agent can be used as the diluent of active ingredient, mediator, excipient or medium.Some examples of proper excipient comprise lactose, dextrose, sucrose, sorbitol, mannitol, starch, arabic gum (gumacacia), calcium phosphate, alginate, Tragacanth, gelatin, calcium silicates, microcrystalline Cellulose, polyvinylpyrrolidone, cellulose, sterilized water, syrup and methylcellulose.Medical composition can comprise lubricant in addition, such as, and Pulvis Talci, magnesium stearate and mineral oil; Wetting agent; Emulsifying agent and suspending agent; Antiseptic, such as, methyl hydroxybenzoate and nipasol; Increase together sweet; And correctives.
Routine techniques can be used optionally to prepare compositions of the present invention in any form according to institute's teachings that provides in description.In some instances, the present composition can be made following form: the powder of lozenge, pill, powder, lozenge, sachet, cachet, elixir, suspending agent, Emulsion, solution, syrup, soft hard gelatin capsule, suppository, aseptic parenteral solution and packaging.
The present composition is sent by any physiologically acceptable approach, such as per os, through intestinal outer (such as intramuscular, intravenous, subcutaneous, intraperitoneal), percutaneous, per rectum, by suck and like this.In one embodiment, compositions of the present invention be oral administration with.
Now more specifically set forth the present invention with reference to following examples, provide described embodiment for illustration of property non-limiting object.
Embodiment
In this research, human peripheral's blood monocyte (PBMCs) that we use IFN γ to stimulate, to study the effect of fermented soybean extract (calling MS-20 in the following text) of the present invention for tryptophan degradation.Stimulate PBMC to bring out significant tryptophan catabolism with IFN γ, it can react on the parallel increase of Tryptophan concentration reduction and kynurenin concentration, compared to the cell without stimulation.Concurrently, the increase of cell survival is also observed.To increase the tryptophan degradation that dosage 0.5-4mg/mL (0.125%-1%) MS-20 process suppresses IFN γ to bring out through the PBMC that IFN γ stimulates significantly.These effects of MS-20 are dose-dependent.This one to analyze based on the IDO of cell and also carries out in the extra large holding class cervical cancer cell with higher interior raw IDO performance, and result also observes the identical suppression phenomenon via MS-20 in HeLa cell, IC
50for 1.8mg/mL.Suppress IDO also to confirm via enzymatic analysis by MS-20, obtain with based on the similar result (IC of cell analysis
50for 1.86mg/mL).These results confirm that the IDO that MS-20 brings out for IFN γ has inhibitory action.
1. MATERIALS METHODS
1.1. reagent
Cell strain purchased from American Type Tissue Culture center (ATCC) and the condition of culture routine maintenance according to suggestion.L-1MT (IDO inhibitor), L-Trp, L-kynurenin are purchased from Sigma-Aldrich.Mankind IFN γ, purchased from R & DSystems, stores according to manufacturer's recommendation and uses.
1.2IDO enzyme activity is analyzed
IDO determination of activity adopts colorimetry.In brief, by 2 × 10
6cell is by freezing and destruction of thawing, solute (250 μ L) is by centrifugal clarification, add equivalent 2 times of IDO buffer (100mM phosphate buffered saline (PBS) (PBS), pH is 6.5, containing 40mM ascorbic acid, the methylene blue of 20 μm, the L-Trp (Sigma-Aldrich of 200mg/ml catalase and 800 μm, St.Louis, MO)).After cultivating 30 minutes at 37 DEG C, 30% trichloroacetic acid adding 100 μ L, with cessation reaction, is cultivated 30 minutes more in addition at 52 DEG C, and centrifugal.By supernatant Ehrlich reagent (the p-dimethylbenzaldehyde of 100mg, 5mL glacial acetic acid) in micro titer plate well (96 hole form) mixed in equal amounts, make Color development 10 minutes, then read suction brightness in point luminance at 490nm.Sample reads at micro-plate analyser (BioTekSystems) with 490nm filter relative to blank reagent.The concentration of kynurenin corresponds to kynurenin standard curve and is calculated.
1.3 IDO based on cell analyze
Inhibitor activity is measured at mankind PBMC
Human peripheral's blood monocyte (PBMCs) is by the leukocyte cell concentrate (from blood bank obtain) of Ficoll-Hypaque density gradient separation from healthy volunteer.This is determined as follows and carries out: mankind PBMCs is with every hole 2 × 10
5density be inoculated in 96 well culture plates containing RPMI culture medium, RPMI contains 10% hyclone, 100 units per ml penicillins and streptomycin (GIBCO).The mankind IFN γ (R & DSystems) of 100ng/mL and MS-20 serial dilution are added into suitable hole, make every Kongzui final volume be 200 μ L culture medium.Containing 5%CO
2humidified incubator in, cultivate after 40-44 hour in 37 DEG C, collect the supernatant in the hole of repeating from three and preserved, for by the tryptophan of HPLC and kynurenin analysis.For remaining cell, carry out MTT cell survival assay, to measure the cell survival rate after various process.
1.4 measure inhibitor activity in the IDO/ kynurenin analysis based on HeLa cell
HeLa cell (#CCL-2) is from American Type Tissue Culture center (ATCC, Manassas, Virginia) obtain, and routine is maintained at DulbeccoShi improvement Eagle culture medium (DMEM), it contains 10% fetal bovine serum, the penicillin containing 100 units per ml and streptomycin (GIBCO).Cell is remained on 37 DEG C, supply 5%CO
2humidified incubator in.This is analyzed as follows and carries out: by HeLa cell with 5 × 10
3the density in every hole is seeded in 96 well culture plates, grow overnight.The next day, by the mankind IFN γ (R & DSystems) of 50ng/mL and the serial dilution of MS-20 or L-1MT, with every hole 200 μ L culture medium cumulative volume, join in cell.After extra 40-44 hour cultivates, collect the supernatant in the hole of repeating from three and preserved, for by the tryptophan of HPLC and kynurenin analysis.For remaining cell, carry out MTT cell survival assay, to measure cell survival rate.
1.5 by the tryptophan in HPLC analysis culture medium and kynurenin.
In order to measure IDO activity, use high-effect liquid chromatography (Highperformanceliquidchromatography) in the anti-phase tryptophan of measurement supernatant and the concentration of kynurenin, and calculating K yn/Tryp [5].
2. result
In the IDO based on cell analyzes, stimulate PBMC with IFN γ, the degraded observing tryptophan has lifting.Compared to undressed cell, the supernatant of the PBMC that IFN γ stimulates contains the concentration (P<0.001, table 1 and Fig. 1) of significantly lower tryptophan.In comparison, in the cell that IFN γ stimulates, kynurenine concentration significantly rises (P<0.001 does not show).Therefore, Kyn/Tryp ratio compares at the PBMC stimulated without IFN γ taller (P<0.001, table 1a and Fig. 1) at the PBMC that IFN γ stimulates.
With the MS-20 process cell of 0.5-4mg/mL (0.125%-1%), do not affect the tryptophan metabolism (data do not show) of resting cell.In comparison, at PBMC, stimulate with IFN γ and improve the degraded of tryptophan, the generation of kynurenine, and Kyn/Tryp ratio is subject to the impact (Fig. 2) of MS-20 with dose dependent fashion.At the extra large holding class cervical cancer cell that IFN γ activates, also observe the similar phenomenon (Fig. 3) suppressed by MS-20.Really, after HeLa cell is subject to the IFN γ of 50ng/mL to stimulate 40-42 hour, Tryptophan concentration in the medium drops to even lower than detection restriction (table 1b).L-1MT, a kind of IDO inhibitor, is tested abreast, to compare IDO inhibit activities.Suppress IDO also can obtain by IDO enzymatic analysis with MS-20 to confirm, result is similar to the analysis (Fig. 6 based on cell; IC50=1.86mg/mL).These results show, and MS-20 suppresses IDO active effectively.
The survival rate of MTT (cell survival rate) analysis result display PBMC increases (table 1a) under MS-20 exists, and the survival rate of HeLa cell is under MS-20 maximum concentration (4mg/mL), only there is slight reduction (20%).These are dose dependent (Fig. 4-5) in the change of the cell survival rate of PBMC and HeLa cell.Comprehensive descision it, to be reduced by MS-20 process viewed IDO activity and caused by unprovoked cell quantity or cell survival rate decline.
Table 1: at the supernatant of (1a) elementary mankind PBMCs or (1b) extra large holding class cervical cancer cell, in the situation of presence or absence MS-20 or L-1MT (IDO inhibitor), without stimulate or the tryptophan that stimulates with IFN γ and kynurenine concentration and kyn/Tryp ratio.
Salty letter those skilled in the art in the invention describing based on this paper, the present invention can be applied to its most extensive scope by illustration that need not be further.Therefore, should be appreciated that mentioned herein to describe and claims are for illustrating object but not limiting the category of the present invention by any way.
List of references:
1.Godin-EthierJ,HanafiLA,PiccirilloCA,etal.Indoleamine2,3-dioxygenaseexpressioninhumancancers:clinicalandimmunologicperspectives.ClinCancerRes.2011Nov15；17(22):6985-91.
2.BeckerJC,AndersenMH,SchramaD,etal.Immune-suppressivepropertiesofthetumormicroenvironment.CancerImmunolImmunother.2013Jul；62(7):1137-48.
3.MurakamiY,HoshiM,ImamuraY,etal.RemarkableRoleofIndoleamine2,3-DioxygenaseandTryptophanMetabolitesinInfectiousDiseases:PotentialRoleinMacrophage-MediatedInflammatoryDiseases.MediatorsInflamm.2013；2013:391984.
4.LiuX,NewtonRC,FriedmanSM,etal.Indoleamine2,3-dioxygenase,anemergingtargetforanti-cancertherapy.CurrCancerDrugTargets.2009Dec；9(8):938-52.
5.WidnerB,WernerER,SchennachH,WachterH,FuchsD.SimultaneousmeasurementofserumtryptophanandkynureninebyHPLC.ClinChem1997；43:2424–6.
Claims (13)
1. fermented soybean extract is for the preparation of a suppression indoleamine 2, the application of the compositions of 3 dioxygenase activity.
2. apply as claimed in claim 1, wherein said compositions is effective in and reduces the monocytic indoleamine 2 of peripheral blood, 3 dioxygenase activity.
3. apply as claimed in claim 1, wherein said compositions is effective in increases the monocytic survival rate of peripheral blood.
4. apply as claimed in claim 1, wherein said compositions is effective in lifting immunoreation.
5. apply as claimed in claim 4, wherein said immunoreation is the immunoreation that T cell regulates.
6. apply as claimed in claim 1, wherein said compositions is effective in treatment indoleamine 2, the immunocompromised that 3 dioxygenases regulate.
7. apply as claimed in claim 1, wherein said compositions comprises another indoleamine 2,3 dioxygenase inhibitors.
8. apply as claimed in claim 1, another wherein said indoleamine 2,3 dioxygenase inhibitors are 1-methyl tryptophans.
9. the application according to any one of claim 1 to 8, wherein said fermented soybean extract be by with at least one lactobacillus and can at least one yeast optionally make soluble soybean extract ferment obtain.
10. apply as claimed in claim 9, wherein this at least one lactobacillus is Lactobacillus (Lactobacillusspecies) and this yeast is Saccharomycodes (Saccharomycesspecies).
11. apply as claimed in claim 9, wherein carry out one or more after fermentation and are selected from by the step of the following group formed: sterilizing, filtration, concentrated, lyophilizing and any combination thereof.
12. apply as claimed in claim 9, and wherein this fermented soybean extract is that process by comprising following steps obtains: a) soluble soybean extract is fermented, to form fermentation liquid with at least one lactobacillus with at least one yeast; B) sterilizing is carried out to this fermentation liquid; C) filter through sterilization fermentation liquid; And d) remove water, to form concentrated fermented soybean extract from fermentation liquid after filtration.
13. 1 kinds are suppressed indoleamine 2, and the method for 3 dioxygenase activity, comprises and make indoleamine 2, and 3 dioxygenases contact with fermented soybean extract, and wherein the amount of this fermented soybean extract is effective in suppression indoleamine 2, the activity of 3 dioxygenases.
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| US201462011856P | 2014-06-13 | 2014-06-13 | |
| US62/011,856 | 2014-06-13 |
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2015
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- 2015-06-12 CN CN201510321283.4A patent/CN105311089A/en active Pending
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2016
- 2016-07-06 HK HK16107872.0A patent/HK1219874A1/en unknown
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| 孙敬岩: "吲哚胺2,3双加氧酶诱导调节T细胞参与肿瘤免疫耐受机制研究", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
| 张文颖: "吲哚胺2,3双加氧酶与肿瘤免疫耐受", 《中国肿瘤生物治疗杂志》 * |
| 王义善 等主编: "《现代肿瘤基础与临床》", 30 September 2012, 河北科学技术出版社 * |
| 王学军: "吲哚胺2,3双加氧酶在肿瘤局部免疫耐受中的作用", 《山东医药》 * |
| 石远凯 主编: "《中国肿瘤内科进展 中国肿瘤医师教育》", 30 June 2013, 中国协和医科大学出版社 * |
| 赵硕 等: "吲哚胺2,3-双加氧酶的研究进展", 《中国医药科学》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| TW201600101A (en) | 2016-01-01 |
| HK1219874A1 (en) | 2017-04-21 |
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