CN1758917A - Flavanols and procyanidins promote homeostasis - Google Patents
Flavanols and procyanidins promote homeostasis Download PDFInfo
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- CN1758917A CN1758917A CN 200380109418 CN200380109418A CN1758917A CN 1758917 A CN1758917 A CN 1758917A CN 200380109418 CN200380109418 CN 200380109418 CN 200380109418 A CN200380109418 A CN 200380109418A CN 1758917 A CN1758917 A CN 1758917A
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- cytokine
- veterinary animal
- procyanidin
- flavonol
- cytokine levels
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Abstract
The invention encompasses a screening method for identifying cytokine responsiveness of a human or a veterinary animal and products and assays for use therein comprising flavanols, procyanidins and/or derivatives thereof, or mixtures thereof, a method for diagnosing a cytokine phenotype in a human or a veterinary animal; methods for identifying a subject at risk of a condition associated with an inflammatory and/or immunomodulating pathway; methods for identifying a dietary and/or a pharmaceutical intervention to modulate a condition associated with an inflammatory and/or immunomodulating pathway; and the methods of prophylactic or therapeutic treatment of humans or veterinary animals with selected flavanols, procyanidins and/or derivatives thereof, or mixtures thereof.
Description
Invention field
The present invention relates to the reactive screening technique of cytokine of surveyor or veterinary animal and wherein used product and algoscopy, it contains flavonol and procyanidin or their mixture, also relates to the method for cytokine phenotype in diagnosis people and the veterinary animal; Evaluation is in the method for the experimenter in the danger of the disease relevant with inflammation and/or immunomodulatory pathways; Identify diet and/or pharmaceutical intervention method with the adjusting disease relevant with inflammation and/or immunomodulatory pathways; With with selected flavonol and procyanidin or their mixture is preventative or the method for therapeutic treatment people or veterinary animal.
Background
Flavonol has shown the potentiality of regulating the multiple factor relevant with vascular health with procyanidin.Described potentiality comprise antioxidation (people such as Lotito LB, BiochemBioplzys Res Commun 2000; 276:945-951, Arteel and Sies, FEBS Lett 1999; 462:167-170; People such as Sanbongi, Cell Immunol 1997; 177:s 129-136), regulate cytokine and produce (people such as Mao, J Medicinal Foods 2002; 5:17-22; People such as Mao, Life Sciences 2000; 66:1377-1386; People such as Mao, Medicinal Foods 2000; 3:107-114), regulate class dodecylic acid and NO and peroxy-nitrate level and general antiinflammatory feature (people such as Osakabe, Biosci Biotechnol Biochem1998; 62:1535-1538; Arteel and Sies, FEBSLett 1999; 462:167-170).Other beneficial effects of flavonol and procyanidin are also disclosed, for example, as antiplatelet and antimicrobial be used for treatment of cancer (U.S. Patent number 5,554,645 and 6,297,273).
TGF-β 1 is the powerful regulator of cardiovascular system, thus the activity that big quantity research is devoted to handle its generation and is used for the treatment of purpose.The generation that plurality of reagents is used to increase TGF-β 1 has been proposed.People such as Metcalfe propose the formation that zitazonium has reduced the lipid pathological changes, and this part is (people such as Densem, J Heart Lung Trans 2000 due to circulation composition by TGF-β 1 in the mice of taking in food rich in fat rises; 19:551-556); And what coincide therewith is that the plasma concentration that the postmenopausal women of Diurovic report experience Hormone Replacement Therapy demonstrates TGF-β 1 increases, and shows possible method (people such as Grainger, the Nat Med 1995 of the danger that is used to reduce cardiovascular disease; 1:1067-1073).The discovery of the antagonist of TGF-β 1 may be useful in treatment fibroid degeneration disease.Decorin---natural inhibitor of TGF β 1---has been successfully used to suppress the degeneration of tissue fibers sample (people such as Isaka, the Nat Med 1996 of TGF-β 1 mediation in the kidney of rats; 2:418-423).In addition, having reported a kind of food plant polyphenol resveratrol has at parafunctional protective effect in the vascular smooth muscle cell, this part is because resveratrol can suppress TGF-β 1mRNA (people such as Mizutani, Biochem Biophys Res Comm 2000; 274:61-67).Consider the importance of TGF-β 1, need additive method to reply in order to TGF-β 1 in the body of mediator or veterinary animal.
The applicant has been surprisingly found out that now flavonol and procyanidin and their mixture can promote the cytokine homeostasis, comprise TGF-β 1 homeostasis, and can be used as screening implement to identify cytokine reactivity among the experimenter, comprise TGF-β 1 reactive or definite reactive phenotype of described cytokine.This makes internist, clinician and veterinary and nutritionist to identify that experimenter's (people or veterinary animal) is for being in the disease relevant with inflammation or immunomodulatory pathways, in the low or high risk as cardiovascular disease, arthritis and cancer, and can be according to the diet and/or the pharmaceutical intervention of described experimenter's phenotype appropriate design.
Summary of the invention
The present invention relates to screening, diagnosis, prevention, treatment and the nutritional applications of flavonol and/or procyanidin and their mixture, be used to diagnose, prevent and/or treat the disease relevant with inflammation and/or immunomodulatory pathways.The invention still further relates to the design of (that is, intervening) of the customization medicine that is used for people and/or veterinary animal and/or diet program, described scheme is used to handle by screening technique described herein learns the people that identifies or the health tissues of veterinary animal.
On the one hand, reactive screening technique of cytokine and algoscopy in use flavonol and procyanidin and their mixture surveyor or the veterinary animal are provided.The diagnostic assay method that is used for determining external baseline cytokine levels in people or the veterinary animal body sample also within the scope of the invention.
On the other hand, the present invention relates to (promptly according to human or animal's phenotype, the cytokine reactivity) method of the diet of designer or veterinary animal and/or pharmaceutical admixtures (that is, intervening), described scheme can effectively prevent or treat the health status by described screening technique is learned and algoscopy is diagnosed.In certain embodiments, this scheme can comprise and uses flavonol and/or procyanidin or their mixture.
More on the one hand, the prevention of people or veterinary animal or the method for therapeutic treatment are provided, this method comprises the cytokine phenotype based on people or animal, be the diet and/or the pharmaceutical admixtures of reactive described people of design of cytokine or veterinary animal, this scheme can effectively prevent or treat the health status by described screening technique is learned and algoscopy is diagnosed.In certain embodiments, according to this scheme, described preventing/treating comprises uses flavonol and/or procyanidin or their mixture.
The invention still further relates to and determine that the unknown has the method for therapeutic value of the polyphenol of cytokine accommodation property, by producing survivor and at least a high cytokine and produce the described polyphenol of in vitro tests in survivor's the mensuration of body sample containing at least a low cytokine, and body sample and polyphenol hatched to determine that the influence that exists that whether cytokine levels among the low and high cytokine product survivor is subjected to polyphenol realizes the mensuration of described therapeutic value.
The accompanying drawing summary
All individualities (n=13) that Fig. 1 representative is tested and they are to the scatter diagram of the response of every kind of cocoa flavonol/procyanidin (FLO) fraction.On behalf of individual percent, each open circles change the value of (with respect to baseline control) form.
The excretory influence that on behalf of cocoa flavonol/procyanidin (FLO), Fig. 2 low baseline cytokine is produced TGF-β 1 among the survivor.To be used for elisa assay (average ± SEM for the extraction supernatant after in the presence of the independent cocoa fraction (25 μ g/ml) PBMC being hatched 72 hours; N=7).Use has the paired t check of student of two tail p values cocoa is handled inductive value and control value (that is the intermediate value baseline that, does not have cocoa) comparison (* thinks that p＜0.05 is for remarkable).
On behalf of cocoa flavonol and procyanidin (FLO), Fig. 3 high baseline cytokine is produced TGF-β 1 excretory influence among the survivor.To be used for elisa assay (average ± SEM for the extraction supernatant after in the presence of the independent cocoa fraction (25 μ g/ml) PBMC being hatched 72 hours; N=7).Use has the paired t check of student of two tail p values cocoa is handled inductive value and control value (that is the intermediate value baseline that, does not have cocoa) comparison (* thinks that p＜0.05 is for remarkable).
Detailed Description Of The Invention
Incorporate all patents, patent application and the list of references quoted in this application into this paper as a reference. For any inconsistent situation, be as the criterion with the disclosure.
The present invention relates to flavanols and/or procyanidin, or the screening of their mixture, diagnosis, prevention, treatment and nutritional applications, be used as screening implement with cell factor reactivity in surveyor or the veterinary animal, and be used for diagnosing, preventing and/or treating the illness relevant with inflammation and/or immunomodulatory pathways. " pathways of inflammation " used herein is the bio-chemical pathway that mammiferous body alive takes place in replying destructive stimulus and/or tissue damage. " immunomodulatory pathways " is to regulate or to adjust the bio-chemical pathway of immunologic function in the mammiferous body alive. The example of veterinary animal is cat, dog and horse.
The invention still further relates to the design for customization medicine and/or the diet program (that is, intervening) of people or veterinary animal, described scheme is for the treatment of learning the people of evaluation and/or the health tissues of veterinary animal by screening technique described herein. In case identified health tissues or illness, just can use for prevention or sanatory any method. In certain embodiments, this scheme can comprise and uses flavanols and/or procyanidin or their mixture.
Compound and composition
Being used for compound of the present invention is flavanols, such as epicatechin, catechuic acid and their gallic acid form, such as epicatechin gallic acid and catechuic acid gallic acid. Can also use procyanidin, its purpose for the application is defined as the oligomer of flavanols and can contains at least a nutgall acidifying monomer. Procyanidin comprises Type B and A type procyanidin.
Flavonol be monomeric compound and comprise (+) catechuic acid, (-) epicatechin and they separately epimer (for example, (-) catechuic acid and (+) epicatechin) and have structure:
The procyanidin oligomer can have 2 to about 18, preferred 2 to about 12, and most preferably 2 to about 10 monomer unit.At least some monomer unit can the Galla Turcica (Galla Helepensis) acidify.For example, oligomer can be dimer, trimer, the tetramer, pentamer, six aggressiveness, heptamer, eight aggressiveness, nine aggressiveness and ten aggressiveness.In the Type B oligomer, above shown in monomer connect by key between the flavane of (4 → 6) and/or (4 → 8).The oligomer that only has (4 → 8) key is linear; And exist at least one (4 → 6) key to cause having branched oligomer.
Represent linear oligomer by following formula, wherein n is 0 to 16 integer:
Represent the example of branch oligomer with following formula, wherein A and B are 1 to 15 oligomer independently, A and B's and be 3 to 18 in final oligomer:
Can also use A type procyanidin among the present invention, promptly contain the oligomer (containing above-mentioned monomer) of the dual link of C2-O-C7 and C4 → C8 or C4 → C6.
The chemical compound that is used for the present invention can be natural origin or synthetic preparation.The chemical compound of natural generation can for example, separate from cocoa, seed of Fructus Vitis viniferae, Semen arachidis hypogaeae, mossberry, Fructus Mali pumilae and other sources from containing the chemical compound of multiple polyphenol.Those skilled in the art select natural or synthetic compound based on availability and/or cost.
For simplicity, will be from can availablely being used for flavonol of the present invention and procyanidin is called " cocoa polyphenol " (CP) herein.CP can derive from cacao bean, cocoa nib or cocoa composition.Term " cocoa composition " refers to derive from the material that contains cocoa solids of the cocoa nib of no shell, as the cocoa solids (for example, cake or powder) of chocolate liquid and partly or completely defat.CP can be included in the compositions of the present invention with the extraction fraction of cocoa composition, extract, extraction fraction or merging.
By from cacao bean, cocoa nib or cocoa composition, as the cocoa solids of chocolate liquid and partially skimmed, and/or the cocoa solids of defat fully prepares cocoa polyphenol.Preferably, the cocoa powder from defat completely or partially prepares extract.Can use cacao bean from hybrid between any kind of (for example, T.cacao and T.grandiflorum), Herrania or their kind of Theobroma (Theobroma) and in planting.Can be from preparing extract through fermentation, insufficient fermentation or unfermentable bean, the bean that is fermented has minimum cocoa polyphenol, and unfermentable have maximum cocoa polyphenols.The selection of bean can be based on the fermentation factor of bean, for example, can from fermentation factor be 275 or littler bean prepare extract.Can (publish as international patent application no PCT/US97/15893 with WO98/09533, corresponding to U.S. Patent number 6,015,913, quote its relevant portion here as a reference) in the degree of pass through the control fermentation described optimize polyphenol level and its extraction in the cocoa composition.
Can extract cocoa polyphenol from the cocoa composition, wherein used can machinable conventional method (for example, at Industrial Chocolate Manufacture and Use, editor Beckett, S.T., Blackie Acad.﹠amp; Professional, New York, 1997, as describing in 1,5 and 6 chapters) or the U.S. Patent number 6 of Kealey etc., the improvement processing method of describing in 015,913 has been processed described cocoa composition, and described modification method is compared with conventional processing method by preventing that polyphenol from destroying and preserved polyphenol.Described improvement cocoa processing method has been omitted conventional calcination steps.Thereby, can use by (a) cacao bean is heated certain hour and temperature, it enough makes cocoa shell fluff and not roasting cocoa nib; (b) from cocoa shell selecting crude drugs with winnower cocoa nib; (c) screw press cocoa nib and the cocoa solids that (d) reclaims cupu oil and partially skimmed, the cocoa composition that its preservation level of closing cocoa polyphenol obtains.This method keeps much higher procyanidin oligomer than conventional method.The cocoa solids that produces by this method can contain the total procyanidin of every gram nonfatty solid 20,000 μ g; Be preferably greater than 25,000 μ g/g, more preferably greater than 28,000 μ g/g, most preferably greater than 30,000 μ g/g.For the purposes of the present invention, as people such as Hammerstone, definite total procyanidin amount that (J.Agric.Food Chem., 47:2:490-496,1999) are described, this paper quotes the document as a reference.
Can use the solvent extraction cocoa polyphenol of originating from above, wherein polyphenol is dissolved in the described solvent.The suitable solvent comprises water or organic solvent, as methanol, ethanol, acetone, isopropyl alcohol and ethyl acetate.Can use solvent mixture.When water during as solvent, can be with it with for example slight acidify of acetic acid.Preferred solvent is water and organic solvent, for example, and the mixture of aqueous methanol, ethanol or acetone.Aqueous organic solvent can contain, and for example, about 50% to about 95% organic solvent.Thereby, can make 50% in the water, 60%, 70%, 80% and 90% organic solvent.This solution can also contain small amount of acid, as acetic acid, for example, measures and is about 0.5% to about 1.0%.The composition of extract, promptly the expressivity (being oligomer figure) and the amount of procyanidin oligomer will depend on choice of Solvent.For example, water extract mainly contains monomer, and ethyl acetate extract contains monomer and lower oligomers, is mainly dimer and trimer, and aqueous methanol, ethanol or acetone extract contain monomer and a series of senior oligomer.One of preferred solvent that is used to extract monomer and senior procyanidin oligomer is 70% acetone.Yet, can use any extract that contains polyphenol in the present invention.The method that cocoa polyphenol extracts is as known in the art and for example, U.S. Patent number 5, describe among 554,645 people such as () Romanczyk and the international application no PCT/US97/05693 (publishing), quote these two pieces of documents here as a reference with WO97/36497.Thereby, in one embodiment,,, extract cocoa polyphenol, and this extract of purification prepares cocoa extract with its defat by cacao bean is reduced to cocoa powder.With cacao bean and slurry lyophilization, cryodesiccated cacao bean is gone to starch and shell, and the bean that grinding is shelled can prepare cocoa powder.
For example, by decaffeination and/or theobromine, and can purification cocoa polyphenol extract by gel permeation chromatography and/or high pressure liquid chromatography (HPLC) (HPLC).For example, can use the extract of gel permeation chromatography (for example, on Sephadex LH-20) the senior procyanidin oligomer of enrichment.For example, begin just can collect the eluate that contains monomer and lower oligomers up to selected oligomer from the pillar eluting.An example of this extraction is as known in the art and describes in the embodiment 5 of International Patent Application PCT/US97/05693 (publishing with WO97/36497, is U.S. Patent number 6,297,273 now, incorporates its relevant portion into this paper as a reference).By using preparation HPLC, for example, positive HPLC can become the extract fractionated monomer fraction and contain at least 50% monomer by weight or the oligomer fraction of specific oligomer.When fraction contained monomer and lower oligomers (at most and comprise the tetramer), described fraction contained about by weight 90 to 95% specific oligomer fraction.Desirable fraction can be separated the back and merge, for example, obtain oligomer 3-10 or 5-10 to obtain the associating of selected oligomer.Those skilled in the art consider this description guidance, the general knowledge in this area and, for example, U.S. Patent number 5,554, (publishing with 97/36497, is U.S. Patent number 6,297 now for 645 people such as () Romanczyk and international application no PCT/US97/05693,273), WO can handle chromatography condition to realize desirable procyanidin figure.
By containing the cocoa composition of polyphenol, perhaps, can in compositions of the present invention, provide cocoa polyphenol by comprising chocolate, described chocolate can be milk, sweet food and half sweet food, and is preferably dark-coloured chocolate and low fat chocolate.The cocoa composition can prepare by using conventional cocoa processing method, but the method for describing in people's such as the preferred Kealey of use the U.S. Patent number 6,015,913 prepares.Alternatively, in order to improve the level of cocoa polyphenol, can use from fermentation factor is 275 or the cocoa liquid and the cocoa solids of littler cacao bean preparation.The cocoa polyphenol content of these compositions is higher than the cocoa polyphenol content that the cacao bean that uses conventional cocoa processing method (for example, using roasting) and complete fermentation obtains.Use routine techniques can prepare chocolate or use and (publish with WO99/45788 as international application no PCT/US99/05414 from mentioned component, be U.S. Patent number 6 now, 399,139, incorporate its relevant portion into this paper as a reference) describe modification method and also can prepare chocolate during Chocolate Production, to preserve cocoa polyphenol.The chocolate of at least a preparation by following nconventional method preferably is called " chocolate with cocoa polyphenol of reserve capacity " in this article: (i) from insufficient fermentation or the preparation of unfermentable cacao bean; (ii) in cocoa composition production process, preserve cocoa polyphenol; (iii) in the Chocolate Production process, preserve cocoa polyphenol.
Also can use synthetic procyanidin and its by method preparation as known in the art and as for example (publishing with WO99/19319 at international application no PCT/US98/21392, be U.S. Patent number 6 now, 207,842, incorporate its relevant portion into this paper as a reference) describe.
The derivant of flavonol and procyanidin also can be used among the present invention.These derivants comprise Galla Turcica (Galla Helepensis) acidify monomer and oligomer, glycosylation monomer and oligomer and their mixture; The metabolite of monomer and oligomer is as sulphation, glucuronic acidization and the form that methylates; Cut product with the enzyme action of the procyanidin that produces by metabolism of colon microbiologic population or intrinsic mammal metabolism.The example of described derivant and their production method are well known in the art, as for example, describe in international application no PCT/US00/335331 (publish with WO01/41775, incorporate its relevant portion into this paper as a reference).Described derivant can derive from natural origin or synthetic preparation.
Screening and diagnostic assay method
Flavonol of the present invention and procyanidin can be used as screening implement with the cytokine reactivity in evaluation experimenter, people or the veterinary animal, thereby treat with flavonol and procyanidin.The reactive significant advantage of cytokine of determining the experimenter depends on the ability based on individual design medicine and/or diet intervention.
Cytokine comprises interleukin, lymphokine, chemotactic factor, TNF, interferon and TGF.In one embodiment, cytokine is TGF beta[" TGF-β " herein], for example, TGF beta 1[is " TGF-β 1 " herein].The example of cytokine is IL-1, IL-2, IL-4, IL-5 and TNF-α (alpha).With the diagnosis of these cytokine diseases associated or disease and treatment within the scope of the invention.
Being used for the reactive Screening test method of surveyor or veterinary animal cytokine comprises: (i) baseline cytokine levels in the body sample of external definite people or veterinary animal, and wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways; (ii) under the condition that enough inducing cell factor levels change, with described body sample and a series of flavonol and procyanidin, perhaps their mixture is hatched, and measures the gained cytokine levels.This algoscopy can also comprise with baseline cytokine levels and step (ii) in the gained cytokine levels relatively to determine in people or the veterinary animal cytokine reactivity to flavonol and procyanidin.
" baseline cytokine levels " used herein refers to not be subjected to regulating or when causing regulating any diet of this cytokine levels or Drug therapy through being designed for when people or veterinary animal, the cytokine levels in the health of external definite described people or veterinary animal.
Using can identification of cell factor reactivity as the algoscopy of describing among the embodiment 2.Thereby, obtain blood from experimenter, people or veterinary animal; Separating periphery blood monocytic cell (PBMB) is also hatched itself and independent flavonol and procyanidin.Before adding flavonol and procyanidin and measure cytokine secreted in the culture supernatant afterwards, for example, the level of TGF-β 1.Use the individual flavonol and the procyanidin of a series of routine tests, for example, monomer as shown in Example 2, dimer be to ten aggressiveness, perhaps alternatively, uses the mixture of flavonol in the single test specimen and procyanidin can the identification of cell reactivity.Suitable mixture is to contain flavonol and procyanidin oligomer 2-18, for example, and the cocoa extract of monomer and oligomer 2-10.Also can use and be suitable for measuring flavonol and procyanidin other algoscopys the influence of cytokine secretion in the body sample and/or level.
Analysis result is to determine the reactivity of cytokine to flavonol and procyanidin.For example, to the flavonol and the procyanidin of every kind of test, perhaps in alternative approach, flavonol/procyanidin mixture is calculated the percent change of cytokine secretion with respect to experimenter's baseline values.The result is the treble property wanted.
At first, the experimenter can be accredited as low baseline cytokine and produce survivor or high baseline cytokine product survivor.This point is important, because the baseline cytokine levels only by observing this experimenter can not identification of cell factor reactivity; Need to use the incubation step of flavonol and procyanidin.Thereby if flavonol and procyanidin, perhaps their mixture increases the baseline cytokine levels, so the experimenter is accredited as " low baseline produces the survivor ".Compare, if flavonol and procyanidin, perhaps their mixture reduces the baseline cytokine levels, so the experimenter is accredited as " high baseline produces the survivor ".As shown in Example 2, all flavonol and procyanidin all have the cytokine homeostasis or regulate activity, and promptly they increase or reduce (although degree difference) cytokine levels according to experimenter's cytokine phenotype.In other words, identical flavonol or procyanidin can reduce or increase cytokine levels according to experimenter's baseline cytokine levels.For example, as about shown in the TGF-β 1, although some flavonol and procyanidin in a kind of situation than having more activity in the another kind of situation, but the general action of every kind of chemical compound is similar in each individuality, discharge because they stimulate TGF-β 1 to produce the survivor from low baseline, and suppress TGF-β 1 and produce survivor's secretion from high baseline.
Secondly, according to cytokine, identify that the experimenter is a ND health status before low or high cytokine product survivor can diagnose among this experimenter.It also provides the chance for the treatment of according to individuality.Thereby low baseline cytokine is produced the survivor may need to increase cytokine levels, and high baseline cytokine is produced the survivor may need to reduce cytokine levels, and both purposes all are to promote homeostasis.Chemical compound disclosed herein can be used for realizing this effect.Those skilled in the art will understand, and " homeostasis " refers to the tendency of stability in the biological normal body state, and it is realized by the control mechanism system.
Once more, need the most effective flavonol of experimenter of this treatment and/or procyanidin to identify to treatment by flavonol/procyanidin of selecting the most remarkable effect that the baseline cytokine levels is produced.For example, in embodiment 2, it is monomer and dimer that these the most effective flavonol and/or procyanidin produce the survivor for low baseline, and producing the survivor for high baseline is senior oligomer.
Above-described algoscopy can be used for for any cytokine produces one group of standard, and cytokine can be tested their replying flavonol and procyanidin between many experimenters (those experimenters that comprise low, normal and high cytokine levels).These standards help to design diet and/or pharmaceutical admixtures according to experimenter's baseline cytokine levels for this experimenter---experimenter's baseline cytokine levels is compared the also customized solution of appropriate design with described standard, for example, flavonol/procyanidin scheme.When obtaining for a series of cytokines, described standard is particularly useful.According to the baseline cytokine levels, can design diet and/or pharmaceutical admixtures to regulate cytokine levels among the experimenter, promptly promote the homeostasis of cytokine levels in the health of people or veterinary animal.
As mentioned above, screening technique above-mentioned and algoscopy can be further used for the experimenter in the danger that early stage evaluation (diagnosis) is in the disease relevant with inflammation and/or immunomodulatory pathways, also can not identify when even having visible symptom.Those skilled in the art can based on described Screening test in knowledge in the relevant this area of cytokine of testing identify these diseases.
For example, think that TGF-β 1 participates in the multifunctional protein of various physiological processes (Rubanyi and Dzau write (Marcel Dekker Inc, New York) 1997 for Grainger and Metcalfe, The Endothelium in Clinical Practice; 203-243; People such as Kenny, Am Heart J 1994; 127:1456-1461).Especially, TGF-β 1 receives the concern as the potential medium of cardiovascular protection, because Grainger and Metcalfe have proposed their protectiveness cytokine hypothesis (people such as Baxter, J Cardiovasc Phare 2001; 38:930-939, people such as Mao, Int J Immunotherapy 1999; 15:23-29).This hypothesis is based on following evidence: TGF-β 1 keeps the normal physiological phenotype of endotheliocyte and smooth muscle cell in the arterial blood tube wall, thereby suppress the activation of endotheliocyte, and suppress to cause the inductive smooth muscle cell of atherosclerotic agent migration, dedifferente and breed.Research has shown the level of suffering from the activity form of TGF-β 1 among the atherosis experimenter of late arterial descend (people such as Baxter, J Cardiovasc Phare 2001 in the body; 38:930-939), this result supports the inhibitor that TGF-β 1 forms as atherosclerosis.On the other hand, the excessive generation of TGF-β 1 can cause extracellular matrix accumulation, and this is disadvantageous for injured blood vessel wall, therefore causes the degeneration of cardiac fibers sample (people such as Pearson, Methods Enzymol 2001; 335:350-360).The increase of the activity form that studies show that TGF-β 1 to relation between TGF-β 1 and the coronary heart disease (CHD) relevant with seriousness (people such as Grainger, HuMol Gen 1999 with the generation of CHD; 8:93-97).In addition, another studies show that after high TGF-β 1 genotype that produces and the heart transplantation outbreak morning of coronary artery pathological changes relevant (people such as Wang, Cardiovasc Res 1997; 34:404-410).At last, hint TGF-β 1 is the principal element of nephropathy/renal failure.Therefore, determine that in diagnostic assay unusual baseline cytokine levels among the experimenter can help experimenter's early diagnosis and therapy.Thereby, determine that TGF-β 1 level among the experimenter can cause the early diagnosis and therapy of disease above-mentioned (for example, cardiovascular disease, coronary heart disease, the degeneration of cardiac fibers sample, atherosclerosis, nephropathy/renal failure).For example, use screening technique of the present invention to learn, can be (for example with people or veterinary animal, cat, Canis familiaris L.) be diagnosed as and have blood vessel and kidney health problem, as be in cardiovascular disease, coronary heart disease, the degeneration of cardiac fibers sample, atherosclerosis and/or nephropathy or the depleted danger or suffer from cardiovascular disease, coronary heart disease, the degeneration of cardiac fibers sample, atherosclerosis and/or nephropathy or depletion.
Similarly, IL-4 level and allergy, rheumatoid arthritis (people such as Gallagher, Curr.Opin.Rheumatol., 11 (5): 372-6,1999) and asthma (people such as Pauwels, Clin.Exp.Allergy, 28Suppl.3:1-5,1998) relevant with inflammation immunological diseases (people such as Rocken, Immunol Today 17 (5): 225-31,1996).IL-4 also may have effect people such as (, Crit Rev Immunol17 (5-6): 537-44,1997) Cameron in prevention relies on the outbreak of diabetes of insulin.The downward modulation of IL-6 has been used for the treatment of inflammatory bowel (people such as Rogler, World J Surg 22 (4): 382-9,1998).IL-6 plays an important role in the inducing of inflammatory dermatosis, and shows that downward modulation that IL-6 produces can treat this disease people such as (, J Immunol, 161 (10): 5633-9,1998) Sawamura.Hinted that IL-5 is as playing an important role in inflammation with in such as asthma and periodontal disease.And TNF α and inflammatory bowel (people such as Sandborn, Inflamm.Bowel Dis.5 (2), 119-33,1999) are relevant with rheumatoid arthritis (people such as Ohshima, J Clin Immunol, 19 (5): 305-13,1999).Use screening technique of the present invention to learn and to diagnose the disease relevant in early days with these and other cytokines.
The design of diet and pharmaceutical admixtures
The diet of concrete people or veterinary animal and/or pharmaceutical admixtures or intervention can be based on the cytokine phenotypes of this people or animal, that is, cytokine produces carries out custom design, and can advantageously optimize the method that is used for preventative or therapeutic treatment.Use, for example, using of flavonol and/or procyanidin can realize described preventative or therapeutic treatment, yet, can use other preventions or the treatment of the known treatment disease relevant with inflammation and/or immunomodulatory pathways.
The method of design diet and/or pharmaceutical admixtures generally includes: (i) baseline cytokine levels in the body sample of external definite people or veterinary animal, and wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways; (ii) be designed for health status that keeps this experimenter or medicine and/or the diet program (situation that depends on this experimenter) that is used to prevent and/or treat the disease relevant with inflammation and/or immunomodulatory pathways based on the baseline cytokine levels.In one embodiment, described cytokine is TGF β, more specifically, and TGF-β 1.
The scheme of this custom design can keep, increases or reduce the baseline cytokine levels in people or the veterinary animal or prevent and the development of inflammation and/or immunomodulatory pathways associated health situation, perhaps treats this health status.In certain embodiments, described medicine and/or diet program are used flavonol and/or procyanidin oligomer with consideration.Yet, can use the development of the known prevention disease relevant, the described disease of prevention and/or treat any other scheme of described disease with inflammation and/or immunomodulatory pathways.Even therapy as known in the art also can be advantageously and be benefited from the cytokine phenotype of determining described experimenter and reactivity unexpectedly.
This method can also comprise the Screening test method of the reactivity (for example, TGF β, more specifically TGF β 1 reactivity) that is used for identification of cell factor pair flavonol and procyanidin.Can be as this algoscopy of enforcement of describing among previous section and the embodiment 2.
In one embodiment, the method of the diet and/or the pharmaceutical admixtures of designer or veterinary animal is provided, this method comprises: (i) baseline cytokine levels in the body sample of external definite people or veterinary animal, and wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways; (ii) diagnose this people or veterinary animal whether to be in the danger of the disease relevant or suffer from this disease with inflammation and/or immunomodulatory pathways based on the baseline cytokine levels; (iii) design can be effectively preventative or the medicine and/or the diet program of the disease diagnosed in (ii) of therapeutic treatment step.This scheme can comprise uses flavonol, procyanidin or their mixture, but also can use the conspicuous additive method of those skilled in the art.
In other embodiments, the invention provides the method for the diet and/or the pharmaceutical admixtures of designer or veterinary animal, this method comprises: (i) baseline cytokine levels in the body sample of external definite people or veterinary animal, and wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways; (ii) under the condition that enough inducing cell factor levels change, described body sample and a series of flavonol and procyanidin are hatched, and measurement gained cytokine levels; (iii) baseline cytokine levels and the (ii) middle gained cytokine levels of step are compared to determine described people or the veterinary animal cytokine reactivity to flavonol and procyanidin; (iv) based on the cytokine reactivity, design promotes the medicine and/or the diet program of homeostatic cytokine levels in described people or the veterinary animal; Wherein said medicine and/or diet program comprise uses flavonol and/or procyanidin oligomer, perhaps their mixture.
The method that also comprises the diet and/or the pharmaceutical admixtures of designer or veterinary animal in the scope of the present invention, this method comprises: (i) baseline cytokine levels in the body sample of external definite people or veterinary animal, and wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways; (ii) under the condition that enough inducing cell factor levels change, described body sample and a series of flavonol and procyanidin are hatched, and measurement gained cytokine levels; (iii) baseline cytokine levels and the (ii) middle gained cytokine levels of step are compared to determine described people or the veterinary animal cytokine reactivity to flavonol and procyanidin; (iv) whether be in the danger of the disease relevant or suffer from this disease with inflammation and/or immunomodulatory pathways based on cytokine this people of reactive diagnosis or veterinary animal; (v) design can be effectively preventative or the medicine and/or the diet program of the disease diagnosed in (iv) of therapeutic treatment step.This medicine and/or diet program can comprise uses flavonol and/or procyanidin oligomer, but also can use other suitable schemes.The example of the disease that can diagnose is cardiovascular disease, coronary heart disease, the degeneration of cardiac fibers sample, atherosclerosis and/or nephropathy or renal failure.
Whether needs increase, reduce or keep cytokine levels design, this scheme to comprise to use selected flavonol and/or procyanidin according to people or veterinary animal, perhaps their mixture.The present invention also can be used for having the experimenter of normal baseline cytokine levels, can prevent to keep homeostatic cytokine levels because use the mixture of chemical compound described herein.For example, can design diet or pharmaceutical admixtures, and this scheme comprises the mixture that uses rudimentary and senior procyanidin oligomer, described mixture will keep the baseline cytokine levels.
Therapeutic Method
The method of preventative or therapeutic treatment people or veterinary animal also within the scope of the invention.This method comprise based on cytokine phenotype as above-mentioned people or animal be as described in people or veterinary animal design diet and/or pharmaceutical admixtures, and use flavonol and/or procyanidin according to this scheme.
In one embodiment, this method provides the preventative or therapeutic treatment of people or veterinary animal, described method comprises: (i) baseline cytokine levels in the body sample of external definite people or veterinary animal, and wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways; (ii) under the condition that enough inducing cell factor levels change, described body sample and a series of flavonol and procyanidin are hatched, and measurement gained cytokine levels; (iii) baseline cytokine levels and the (ii) middle gained cytokine levels of step are compared to determine described people or the veterinary animal cytokine reactivity to flavonol and procyanidin; (iv) based on the cytokine reactivity, design promotes the medicine and/or the diet program of homeostatic cytokine levels in described people or the veterinary animal; Wherein said medicine and/or diet program comprise uses flavonol and/or procyanidin oligomer; (v) (iv) the medicine and/or the diet program of middle design are used flavonol and/or procyanidin oligomer to described people or veterinary animal according to step; Perhaps their mixture.
The method of the preventative or therapeutic treatment of people or veterinary animal also is provided, described method comprises: (i) baseline cytokine levels in the body sample of external definite people or veterinary animal, and wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways; (ii) diagnose this people or veterinary animal whether to be in the danger of the disease relevant or suffer from this disease with inflammation and/or immunomodulatory pathways based on the baseline cytokine levels; (iii) design can be effectively preventative or the medicine and/or the diet program of the disease diagnosed in (ii) of therapeutic treatment step; (iv) (iii) the medicine and/or the diet program of middle design are treated described people or veterinary animal according to step.In certain embodiments, this medicine and/or diet program can comprise uses flavonol and/or procyanidin oligomer, but also can use additive method.The example of the disease of being diagnosed is cardiovascular disease, coronary heart disease, the degeneration of cardiac fibers sample, atherosclerosis and/or nephropathy or renal failure.
Another embodiment comprises the method for the preventative or therapeutic treatment of people or veterinary animal, described method comprises: (i) baseline cytokine levels in the body sample of external definite people or veterinary animal, and wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways; (ii) under the condition that enough inducing cell factor levels change, described body sample and a series of flavonol and procyanidin are hatched, and measurement gained cytokine levels; (iii) baseline cytokine levels and the (ii) middle gained cytokine levels of step are compared to determine described people or the veterinary animal cytokine reactivity to flavonol and procyanidin; (iv) diagnose described people or veterinary animal whether to be in the danger of the disease relevant or suffer from this disease with inflammation and/or immunomodulatory pathways based on the baseline cytokine levels; (v) design can be effectively preventative or the medicine and/or the diet program of the disease diagnosed in (iv) of therapeutic treatment step; (vi) (medicine and/or the diet program of design are treated described people or veterinary animal v) according to step.This medicine and/or diet program can comprise uses flavonol and/or procyanidin oligomer, but also can use the conspicuous additive method of those skilled in the art.The disease for the treatment of can be cardiovascular disease, coronary heart disease, the degeneration of cardiac fibers sample, atherosclerosis and/or nephropathy or renal failure.
In a more particular embodiment, consider that the low baseline TGF-β 1 of treatment produces survivor and Gao baseline TGF-β 1 product survivor's method.Thereby, below two kinds of methods also within the scope of the invention: (i) treatment experimenter method, described experimenter produces the survivor for low baseline TGF-β, described method comprises uses at least a flavonol and/or procyanidin oligomer to this experimenter, it is selected from monomer, dimer, trimer, the tetramer and pentamer, perhaps their any mixture, but the level of TGF-β among used this experimenter of amount effective stimulus, wherein said experimenter behaves or veterinary animal; (ii) treat experimenter's method, described experimenter is that high baseline TGF-β produces the survivor, described method comprises uses at least a procyanidin oligomer 6-10 to this experimenter, perhaps their any mixture, but the level of TGF-β among used this experimenter of amount effective stimulus, wherein said experimenter behaves or veterinary animal.
Can be as described in this article in the danger that is in the disease relevant with inflammation and/or adjusting approach or the patient who suffers from described disease determine phenotype, diagnosis and/or treatment.The example of these diseases be cardiovascular disease, coronary heart disease, atherosclerosis, the degeneration of cardiac fibers sample, thrombosis (for example, venous thrombosis) and usually other vascular disorder, and asthma, inflammatory bowel, ulcerative colitis, ChronShi disease, gingivitis, periodontitis, acute edema and arthritis (for example, rheumatoid arthritis).
Use flavonol, procyanidin and its derivant with effective dose.Those skilled in the art use general knowledge and the instruction among the application in this area can determine effective dose.For example, can with every day at least about 50mg to every day approximate number gram amount use The compounds of this invention.The highest end eventually amount without limits.In one embodiment, effective dose is about 2 grams for about 100mg arrives, and perhaps about 100mg is to about 1.5g, and perhaps about 200 arrive about 600mg.Consider the half life of described chemical compound in experimenter's health, can use described chemical compound once or for several times (for example, 2 or 3 times) every day.Described chemical compound can with the scheme of those skilled in the art design use or every day, weekly, used in every month, or the like.
Flavonol and/or procyanidin can be with food, food additive, dietary supplements, and perhaps the form of medicine is used.These compositionss can contain carrier, diluent, perhaps excipient.According to the purposes of being planned, can select described carrier, diluent or excipient to be suitable for people or veterinary purpose, food, additive, complementary goods or medicinal usage.
" food " used herein is the material of being made up of protein, carbohydrate and/or fat basically, and it is used for biological body to keep growth, reparation and significant process and energize.Food can also contain supplementation material, as mineral, vitamin and flavoring agent.See Merriam-Webster ' s Collegiate Dictionary, the 10th edition, 1993.Term food comprises the beverage that is suitable for people or animal consumption.Used herein " food additive " defined in 21 C.F.R.170.3 (e) (1) by FDA and comprises direct and indirect additive.Used herein " medicine " is medical medicine.See Merriam-Webster ' s Collegiate Dictionary, the 10th edition, 1993.Medicine can also refer to medicament.Used herein " dietary supplement " is the product (except Nicotiana tabacum L.) that plan replenishes diet, and it has or contains diet composition below one or more: vitamin, mineral, draft or other plant medical material, aminoacid, be used for replenishing the diet material of diet or the combination of concentrate, metabolite, component, extract or these compositions by increasing total daily intake by the people.
The scope of the invention comprises by increasing the improved any conventional food of flavonol/procyanidin level, comprises any beverage.
Situation for cocoa polyphenol, add cocoa polyphenol or its derivant or (ii) contain cocoa polyphenol usually when food to the food that does not contain cocoa polyphenol by (i), as chocolate, improve with realization by strengthening the polyphenol level of in the food of routine preparation, finding.Can pass through to add extra cocoa polyphenol, for example, the cocoa polyphenol of form of extract; Perhaps add cocoa polyphenol with composition (for example, the nut skin) associating that contains another kind of polyphenol; By processing of operation cocoa composition and cacao bean selection, as above-mentioned, the cocoa polyphenol that is used for producing the cocoa composition of food with preservation is realized described enhancing.Thereby these foods (comprising beverage) are compared with conventional food (comprising beverage) and are contained " the polyphenol level of rising " (comprising cocoa procyanidin).Before adding it, cocoa extract that chocolatier will contain cocoa polyphenol by in the available product of commercial sources the time, obtained having the example of chocolate of the elevated levels of polyphenol.Described food can be called " high cocoa polyphenol food ", that is, they contain the polyphenol level higher than their conventional food.
In one embodiment, described food is confection, as identity standard (SOI) or non-SOI chocolate, as milk, sweet and semi sweet chocolate, comprises black chocolate, low fat chocolate and confection, and it can be the confection of chocolate-enrobed.Other examples comprise baked product (for example, brownie, cure snack, cooky, cookies), flavoring agent, granola, too the prince wife chews beverage that sugar, food substitutes bar, daubing product, syrup, powdered beverage mix, cocoa or chocolate flavor, pudding, new year cake, rice mixture, seasoning sauce or the like.If wish that described food can be chocolate or cocoa flavored.Food can also contain L-arginine and/or cholesterol reducing agent.
Described compositions can be applied to healthy mammal for the purpose of preventing or be applied to the mammal that needs treatment or have at least a hazard factor.Any individuality with at least a risk factor relevant with the vascular health problem all is the experimenter that compositions described herein is used.Have the individuality of the family history that cholesterol levels raises, between menopause or women, the old people of the oestrogen deficiencies of damage behind the postmenopausal women, postmenopausal women/myocardial ischemia, operation or chemical induction, to suffer from hyperglycemia, diabetes, hypertension and fat people and smoker all be the sensitive individual that needs treatment described herein.Mammiferous other colonies that the algoscopy that is easy to produce the vascular health problem or use description herein has been accredited as in the danger that is in the generation disease relevant with inflammation and/or immunomodulatory pathways also can accept described compositions according to designed scheme.
The screening of other polyphenol
The invention still further relates to be designed for the assessment other polyphenol whether can promote homeostatic method.
According to mammiferous cell factor produce determine polyphenol regulate the therapeutic value of cytokine levels in this mammal method can by in the determination method that contains low cytokine response person's and at least one high cytokine response person (determining in such as the Screening test method of using flavanols and procyanidin to describe in this article) the body sample from least one the in vitro test polyphenol and with this polyphenol on low cytokine response person's effect with high cytokine response person's effect is compared determine that the impact which kind of mammalian cytokine phenotype (if existence) is subject to the existence of polyphenol implements.
In one embodiment, the present invention relates to determine the method for the therapeutic value of cytokine levels in the polyphenol adjusting mammal, this method comprises: (i) produce survivor from least one low cytokine and obtain body sample with at least one high cytokine product survivor; (ii) determine baseline cytokine levels in this body sample; (iii) under the condition that enough inducing cell factor levels change, described body sample is not hatched with knowing the polyphenol with cytokine accommodation property; (iv) determining step (iii) hatch the back cytokine levels; (v) whether baseline cytokine levels and step cytokine levels comparison (iv) had the cytokine accommodation property with definite described polyphenol.
Further describe the present invention in the following non-limiting Examples.
Embodiment
Embodiment 1-extracts and purification
The procyanidin extraction step
Method 1
Use the modification method of the method for Jalal and Collin (" polyphenol of the maturation plant of cocoa, seedling and tissue culture ", Phytochemistry, 6,1377-1380,1977) description to extract procyanidin from defat, unfermentable lyophilizing cacao bean.With 2 * 400mL, 70% acetone/deionized water, then with the 50 gram batch extracting procyanidins of 400mL 70% methanol/deionized water from the defat cocoa mass.The united extraction thing also removes with rotary evaporator 45 ℃ of evaporations under partial vacuum and desolvates.The gained water is diluted to 1L also with 2 * 400mLCHCl with deionized water
3Extraction.Abandon solvent phase.Use 4 * 500mL ethyl acetate extraction water then.By on Sorvall RC 28S centrifuge, descending centrifugal 30 minutes to destroy any gained emulsion with 10 ℃ of 2,000 * g.In the acetic acid ethyl ester extract that merges, add the 100-200mL deionized water.With the rotary evaporator under the partial vacuum at 45 ℃ of following evaporating solvents.The gained water is freezing in liquid nitrogen, then lyophilizing on the LABCONCO freeze-drying system.List table 1 from the procyanidin crude product productive rate that different cocoa genotype obtain.
Table 1: procyanidin crude product productive rate
| Genotype | Origin | Garden-variety |
| UIT-1 | Malaysia | 3.81 |
| Unknown | West Africa | 2.55 |
| ICS-100 | Brazil | 3.42 |
| ICS-39 | Brazil | 3.45 |
| UF-613 | Brazil | 2.98 |
| EEG-48 | Brazil | 3.15 |
| UF-12 | Brazil | 1.21 |
| NA-33 | Brazil | 2.23 |
Method 2
Alternatively, extract procyanidin with 70% water propanone from defat, unfermentable lyophilizing cacao bean.10 gram fat-free materials are used 100mL solvent homogenate 5-10 minute.With serosity 4 ℃ with 3000 * g centrifugal 15 minutes, and the gained supernatant passed glass cotton.Filtrate is distilled under partial vacuum and the gained water is freezing in liquid nitrogen, lyophilizing on the LABCONCO freeze-drying system then.The productive rate of procyanidin crude product is 15-20%.
Do not wish to be bound by any particular theory, think that the difference of crude product productive rate has reflected the different of different genotype, geographic origin, garden-variety and preparation method.
By gel permeation chromatography partial purification cocoa procyanidin
Method 1
By Sephadex LH-20 (liquid chromatography (LC) partial purification on 28 * 2.5cm) such as the above-mentioned procyanidin that obtains.Help to separate by the stepwise gradient from the deionized water to methanol.Initial gradient is formed and is begun with 15% methanol in the deionized water, progressively uses 25% methanol in the deionized water, 35% methanol in the deionized water, 70% methanol in the deionized water in per then 30 minutes, is 100% methanol at last.Effluent behind the eluting of xanthine alkaloids (caffeine and theobromine) is collected as single fraction.This fraction has produced the subfraction that does not have the xanthine alkaloids, and its further subfractionation to produce 5 kinds of subfractions, is called MM2A to MM2E with them.Evaporate from each subfraction except that desolvating down at 45 ℃ by the rotary evaporator in the partial vacuum.The gained water is the freezing and lyophilizing of spending the night on the LABCONCO freeze-drying system in liquid nitrogen.With this method subfractionation about 100mg material.
Chromatography condition: pillar: 28 * 2.5cm Sephadex LH-20, mobile phase: the methanol stepwise gradient, 15: 85,25: 75,35: 65,70: 30,100: 0, with classification at interval in 1/2 hour, flow velocity: 1.5mL/ minute, detector: lambda
1(λ
1)=254nm, λ
2UV under the=365nm, recorder chart speed: 0.5mm/ minute, column load: 120mg.
Method 2
(72.5 * 2.5cm) go up liquid chromatography (LC) partial purification procyanidin as described above, use 100% methanol as eluting solvent, and flow velocity is 3.5mL/ minute by Sephadex LH 20.Collect the eluent fraction after 1.5 hours, and concentrate fraction, soluble in water again and lyophilizing it by rotary evaporator.These fraction are called the fraction that is rich in pentamer.
Can be as U.S. Patent number 5,554, the use HPLC that 645 and 6,297,273 (their relevant portion is incorporated this paper into as a reference) described separates with procyanidin flavonol in independent fraction.
Embodiment 2-flavonol and procyanidin are to the effect of TGF-β 1
The preparation of cocoa fraction
Cocoa powder (Cocoapro, Mars, Incorporated from high procyanidin content; Hackettstown, NJ) preparation water solublity flavonol and/or procyanidin (FP) fraction.Prepare powder according to the method for describing in people's such as Kealey the U.S. Patent number 6,015,913 (incorporating this paper here into as a reference).Obtain crude extract as what describe among the embodiment 1 with acetone extraction cocoa powder.According to people such as Adamson (J Agric Food Chem 1999; 47:4184-4188.) the use high performance liquid chroma-tography (HPLC) described is from crude extract purification fraction.The purification fraction of research from monomer to ten aggressiveness.Purified FP fraction contains the following total alkaloids class (theobromine and caffeine) of 0.5% (w/w).Be displayed in Table 2 by the monomer of HPLC estimation and the molecular weight of procyanidin composition and these prepared products.With all samples be suspended in the hyclone that contains 10% heat inactivation (Atlanta Biologicals, Noreross, RPMI1640 GA) (Gibco BRL, Gaithersburg, MD) in.They are diluted to final concentration 25 μ g/ml with identical culture medium.
PBMC separates
To collect in the test tube that contains sodium citrate also with the Hanks balanced salt solution (HBSS that does not have calcium chloride, magnesium chloride or magnesium sulfate from healthy volunteer's peripheral blood; Gibco BRL) mixes.Then with the blood of dilution with Histopaque -1077 gradient (Sigma, St.Louis, MO) layering and at room temperature centrifugal 30 minutes with 500 * g.From boundary layer results PBMC, it is used the HBSS washed twice, then counting.Cell is resuspended in contains 10% hyclone and add among the RPMI 1640 of 0.1%50mg/ml gentamycin solution (Gibco BRL).Get rid of to measure estimate after the viability PBMC concentration adjustment to 2 * 10 by trypan blue
6Individual living cells/ml.Viability is always greater than 96%.
Cultivate PBMC with cocoa FP fraction
With 500 μ l 1.0 * 10
6Individual cell suspending liquid uses the multiple cocoa treatment fluid of equal-volume at 37 ℃, 5%CO
248 orifice plates in cultivate.Hatch tranquillization PBMC with the cocoa FP fraction that 25 μ g/ml are independent.All processing are all carried out in duplicate.After hatching 72 hours, results supernatant fraction is used for elisa assay.
TGF-β1(ELISA)
Gather in the crops the culture supernatant fraction after 72 hours and be kept at-20 ℃ up to passing through elisa assay.With 96 hole Costar EIA plates (Cat.#2592) DuoSet people TGF-β 1ELISA colour reagent box (R ﹠amp; D Systems, Minneapolis, the mice anti-TGF-beta 1 bag quilt that provides in MN).The cell culture supernatant of TGF-β 1 that contains the form of hiding is in sour environment (activation and neutralize with 0.1ml 1.2N NaOH/0.5M HEPES among 0.5ml sample+(the 0.1ml 1N HCl).Subsequently, according to TGF-β 1 concentration in the activated supernatant of manufacturer's recommendation measurement.Minimum TGF-β 1 standard of ELISA system is 31.3pg/ml.
Statistics
In the tranquillization PBMC that does not stimulate, checked that different cocoa FP fraction are to TGF-β 1 excretory influence.By the paired t check of the student with two tail p values comparative result (that is, not having the control cells of cocoa flavonoid) to cell with independent FP level divisional processing.Think p＜0.05th, significant.
The result
Tranquillization PBMC that preparation does not stimulate and the cocoa FP fraction that itself and 25 μ g/ml are independent are hatched.Hatch and estimate in the supernatant fraction after 72 hours that TGF-β 1 produces.
Elisa assay shows that interindividual variation is obvious in 13 experimenters that tested.Fig. 1 has described with change form these individualities of expression of the percent with respect to every experimenter's intermediate value baseline the fluctuation of cocoa FP fraction to be replied.Yet, when producing based on the baseline of TGF-β 1 when individuality sorted out, secrete at TGF-β 1 and to observe visible trend aspect the influence that is subjected to cocoa FP fraction.Have 7 low baselines to produce survivors (LBP), their baseline TGF-β 1 concentration is less than 6000pg/ml (3604 ± 568pg/ml), and the remaining high baseline generation group (HBP that is assigned to; 7910 ± 695pg/ml).Independent cocoa FP fraction can stimulate the TGF-β 1 in the low LBP group to discharge (Fig. 2).Usually, low-molecular-weight FP fraction (≤pentamer) bigger oligomer in increase is more effective, inducing from baseline increases by 30% to 68% (table 3), and bigger oligomer (〉=six aggressiveness) only increases TGF-β 1 secretion (15% to 20%, table 3) with respect to the baseline moderate.Monomer and dimer FP fraction have significantly increased TGF-β 1 secretion in the LBP group, produce the concentration of 5981 ± 666 (p=0.0035) and 6062 ± 667 (p=0.0027) pg/ml respectively.Compare with the LBP group, independent cocoa FP fraction suppresses TGF-β 1 secretion (Fig. 3) among the HBP.Trimer significantly suppresses TGF-β 128% to 62% (table 3) to ten aggressiveness FP fraction with respect to baseline, reduces (being respectively 17% and 23%) and monomer and dimer demonstrate moderate.
The result shows that cocoa FP fraction can increase or suppress the homeostasis level of TGF-β 1 release promotion TGF-β 1 by baseline TGF-β 1 level according to individuality.
In this research, excretory assessment shows interindividual variation big among the experimenter who is checked to the baseline of TGF-β 1.People such as Grainger have shown that the circulation composition of TGF-β 1 can be based on very different (the Hu Mol Gen 1999 of this individual genetic background; 8:93-97).Be appreciated that the polymorphism of considering TGF-β 1 gene can influence it and produce, so observe these different baseline values of TGF-β 1.Unfortunately, in current research, the experimenter who is tested is not carried out gene type assay.Yet clearly, cocoa FP fraction can stimulate low (TGF-β 1 protein secreting among 3604 ± 568pg/ml) experimenter's the PBMC of baseline values from TGF-β 1.Compare with low baseline experimenter, (7910 ± 695pg/ml) PBMC demonstrates TGF-β 1 generation and is suppressed after hatching with the FP fraction to produce individuality from high baseline.Carry out gene type assay because low and high TGF-β 1 is not produced individuality, so also may before collecting blood, just be initiated generation TGF-β 1 by HBP from these experimenters.But, cocoa FP fraction still effectively reduces respectively or has increased TGF-β 1 secretion among HBP and the LBP.
Produced the effect that the bigger and less procyanidin fraction with different-effect is observed the effect-two-phase type of cocoa FP pair cell factor generation with showing the pair cell factor in the past.In tranquillization PBMC, bigger FP oligomer (six aggressiveness and more than) significant stimulation IL-1 β and IL-4 discharge, and less fraction suppresses their secretion (people such as Mao, Life Sciences2000; 66:1377-1386; People such as Mao, J Medicinal Foods 2000; 3:107-114).Yet, in this research, be surprisingly found out that FP not only depends on the molecular size of FP fraction to the effect that TGF-β 1 discharges, and depend on the ability of PBMC secretion TGF-β 1.Some fraction has more activity, and the general effect of cocoa fraction in each individuality is similarly, because they stimulate TGF-β 1 to discharge from LBP, and suppresses TGF-β 1 and secretes from HBP.Consider top situation, with cocoa FP platelet response, class dodecylic acid are produced and the influence of vascular reactivity is echoed is that cocoa FP also has the protection effect by the maintenance that promotes homeostatic TFG-β 1 level to cardiovascular system.
The cocoa FLO level component that table 2. is independent
| The fraction title | Molecular weight (Da) | Procyanidin figure | ％ |
| Monomer dimer tripolymer tetramer pentamer six aggressiveness heptamers eight aggressiveness nine aggressiveness ten aggressiveness | 290 578 866 1154 1442 1730 2018 2306 2594 2882 | Monomer dimer tripolymer tetramer pentamer six aggressiveness heptamers six aggressiveness eight aggressiveness heptamers nine aggressiveness ten aggressiveness ten aggressiveness nine aggressiveness eight aggressiveness heptamers | 95 98 93 93 93 89 79 18 76 16 60 28 40 17 22 16 |
Table 3.FLO fraction produces the excretory influence of TGF-β among the survivor to low (n=7) and high (n=6) baseline.The average percentage that value is expressed as with respect to the intermediate value baseline control changes.
Claims (28)
1. the method for the diet of designer or veterinary animal and/or pharmaceutical admixtures, this method comprises:
(i) baseline cytokine levels in the body sample of external definite described people or veterinary animal, wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways; With
(ii) based on the baseline cytokine levels, design promotes the medicine and/or the diet program of homeostatic cytokine levels in described people or the veterinary animal; Wherein said medicine and/or diet program comprise uses flavonol and/or procyanidin oligomer and/or its derivant.
2. the method for the diet of designer or veterinary animal and/or pharmaceutical admixtures, this method comprises:
(i) baseline cytokine levels in the body sample of external definite described people or veterinary animal, wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways;
(ii) diagnose this people or veterinary animal whether to be in the danger of the disease relevant or suffer from this disease with inflammation and/or immunomodulatory pathways based on the baseline cytokine levels; With
(iii) design can be effectively preventative or the medicine and/or the diet program of the disease diagnosed in (ii) of therapeutic treatment step.
3. the method for claim 2, its Chinese medicine and/or diet program comprise uses flavonol and/or procyanidin oligomer and/or its derivant.
4. the method for claim 2, wherein said disease is cardiovascular disease, coronary heart disease, the degeneration of cardiac fibers sample, atherosclerosis and/or nephropathy or renal failure.
5. the method for the diet of designer or veterinary animal and/or pharmaceutical admixtures, this method comprises:
(i) baseline cytokine levels in the body sample of external definite described people or veterinary animal, wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways;
(ii) under the condition that enough inducing cell factor levels change, with described body sample and a series of flavonol and procyanidin and/or its derivant, perhaps their mixture is hatched, and measures the gained cytokine levels;
(iii) baseline cytokine levels and the (ii) middle gained cytokine levels of step are compared to determine described people or the veterinary animal cytokine reactivity to flavonol and procyanidin;
(iv) based on the cytokine reactivity, design promotes the medicine and/or the diet program of homeostatic cytokine levels in described people or the veterinary animal; Wherein said medicine and/or diet program comprise uses flavonol and/or procyanidin oligomer; And/or its derivant, perhaps their mixture.
6. the method for the diet of designer or veterinary animal and/or pharmaceutical admixtures, this method comprises:
(i) baseline cytokine levels in the body sample of external definite described people or veterinary animal, wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways;
(ii) under the condition that enough inducing cell factor levels change with described body sample and a series of flavonol and procyanidin and/or its derivant, perhaps their mixture is hatched, and measurement gained cytokine levels;
(iii) baseline cytokine levels and the (ii) middle gained cytokine levels of step are compared to determine described people or the veterinary animal cytokine reactivity to flavonol and procyanidin;
(iv) based on the cytokine reactivity, diagnose described people or veterinary animal whether to be in the danger of the disease relevant or suffer from this disease with inflammation and/or immunomodulatory pathways; With
(v) design can be effectively preventative or the medicine and/or the diet program of the disease diagnosed in (iv) of therapeutic treatment step.
7. the method for claim 6, wherein said medicine and/or diet program comprise uses flavonol and/or procyanidin oligomer and/or its derivant.
8. the method for claim 6, wherein said disease is cardiovascular disease, coronary heart disease, the degeneration of cardiac fibers sample, atherosclerosis and/or nephropathy or renal failure.
9. the method for preventative or therapeutic treatment people or veterinary animal, this method comprises:
(i) baseline cytokine levels in the body sample of external definite described people or veterinary animal, wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways; With
(ii) based on the baseline cytokine levels, design promotes the medicine and/or the diet program of homeostatic cytokine levels in described people or the veterinary animal; Wherein said medicine and/or diet program comprise uses flavonol and/or procyanidin oligomer; With
(iii) (ii) the medicine and/or the diet program of middle design are used flavonol and/or procyanidin oligomer and/or its derivant to described people or veterinary animal according to step.
10. the method for preventative or therapeutic treatment people or veterinary animal, this method comprises:
(i) baseline cytokine levels in the body sample of external definite described people or veterinary animal, wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways;
(ii) diagnose this people or veterinary animal whether to be in the danger of the disease relevant or suffer from this disease with inflammation and/or immunomodulatory pathways based on the baseline cytokine levels; With
(iii) design can be effectively preventative or the medicine and/or the diet program of the disease diagnosed in (ii) of therapeutic treatment step; With
(iv) (iii) the medicine and/or the diet program of middle design are treated described people or veterinary animal according to step.
11. comprising, the method for claim 10, wherein said medicine and/or diet program use flavonol and/or procyanidin oligomer and/or its derivant.
12. the method for claim 10, wherein said disease are cardiovascular disease, coronary heart disease, the degeneration of cardiac fibers sample, atherosclerosis and/or nephropathy or renal failure.
13. method preventative or therapeutic treatment people or veterinary animal, this method comprises:
(i) baseline cytokine levels in the body sample of external definite described people or veterinary animal, wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways;
(ii) under the condition that enough inducing cell factor levels change with described body sample and a series of flavonol and procyanidin and/or its derivant, perhaps their mixture is hatched, and measurement gained cytokine levels;
(iii) baseline cytokine levels and the (ii) middle gained cytokine levels of step are compared to determine described people or the veterinary animal cytokine reactivity to flavonol and procyanidin and/or its derivant;
(iv) based on the cytokine reactivity, design promotes the medicine and/or the diet program of homeostatic cytokine levels in described people or the veterinary animal; Wherein said medicine and/or diet program comprise uses flavonol and/or procyanidin oligomer and/or its derivant; With
(v) (iv) the medicine and/or the diet program of middle design are used flavonol and/or procyanidin oligomer and/or its derivant, perhaps their mixture to described people or veterinary animal according to step.
14. method preventative or therapeutic treatment people or veterinary animal, this method comprises:
(i) baseline cytokine levels in the body sample of external definite described people or veterinary animal, wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways;
(ii) under the condition that enough inducing cell factor levels change with described body sample and a series of flavonol and procyanidin and/or its derivant, perhaps their mixture is hatched, and measurement gained cytokine levels;
(iii) baseline cytokine levels and the (ii) middle gained cytokine levels of step are compared to determine described people or the veterinary animal cytokine reactivity to flavonol and procyanidin and/or its derivant;
(iv) based on the baseline cytokine levels, diagnose described people or veterinary animal whether to be in the danger of the disease relevant or suffer from this disease with inflammation and/or immunomodulatory pathways; With
(v) design can be effectively preventative or the medicine and/or the diet program of the disease diagnosed in (iv) of therapeutic treatment step; With
(vi) (medicine and/or the diet program of design are treated described people or veterinary animal v) according to step.
15. comprising, the method for claim 14, wherein said medicine and/or diet program use flavonol and/or procyanidin oligomer and/or its derivant.
16. the method for claim 14, wherein said disease are cardiovascular disease, coronary heart disease, the degeneration of cardiac fibers sample, atherosclerosis and/or nephropathy or renal failure.
17. claim 1,2,5,6,9,10,13 or 14 method, wherein said cytokine is TGF-β.
18. claim 1,2,5,6,9,10,13 or 14 method, wherein said cytokine is TGF-β 1.
19. be used for the reactive Screening test method of the cytokine of surveyor or veterinary animal, it comprises: (i) baseline cytokine levels in the body sample of external definite people or veterinary animal, and wherein said cytokine is relevant with inflammation and/or immunomodulatory pathways; (ii) under the condition that enough inducing cell factor levels change, with described body sample and a series of flavonol and procyanidin and/or its derivant, perhaps their mixture is hatched, and measures the gained cytokine levels.
20. the Screening test method of claim 19, it also comprises baseline cytokine levels and the (ii) middle gained cytokine levels of step is compared to determine described people or the veterinary animal cytokine reactivity to flavonol and procyanidin and/or its derivant.
21. the Screening test method of claim 20, it also comprises in the danger of diagnosing described people or veterinary animal whether to be in cardiovascular disease, coronary heart disease, the degeneration of cardiac fibers sample, atherosclerosis or nephropathy or renal failure or suffers from these diseases.
Regulate the method for the therapeutic value of cytokine levels in the mammal 22. determine polyphenol, this method comprises:
(i) produce the survivor from least one low cytokine and obtain body sample with at least one high cytokine product survivor;
(ii) determine baseline cytokine levels in this body sample;
(iii) under the condition that enough inducing cell factor levels change, described body sample is not hatched with knowing the polyphenol with cytokine accommodation property;
(iv) determining step (iii) hatch the back cytokine levels; With
(v) whether baseline cytokine levels and step cytokine levels comparison (iv) had the cytokine accommodation property with definite described polyphenol.
23. the method for claim 22, wherein said mammal is the people.
24. the method for claim 22, wherein said mammal is a veterinary animal.
25. treatment experimenter's method, described experimenter produces the survivor for low baseline TGF-β, described method comprises uses at least a flavonol and/or procyanidin oligomer to this experimenter, described procyanidin oligomer is selected from monomer, dimer, trimer, the tetramer and pentamer, perhaps their any mixture or derivant, but the level of TGF-β among used this experimenter of amount effective stimulus, wherein said experimenter behaves or veterinary animal.
26. the method for claim 25, wherein TGF-β is TGF-β 1.
27. treatment experimenter's method, described experimenter is that high baseline TGF-β produces the survivor, described method comprises uses at least a procyanidin oligomer 6-10 to this experimenter, perhaps their any mixture or derivant, but the level of TGF-β among used this experimenter of amount effective stimulus, wherein said experimenter behaves or veterinary animal.
28. the method for claim 27, wherein TGF-β is TGF-β 1.
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| US60/436,879 | 2002-12-27 |
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| CN102099028B (en) * | 2009-08-11 | 2013-09-25 | 梧桐生物技术私人有限公司 | A novel standardized composition, method of manufacture and use in the resolution of RNA virus infection |
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