CN108283632A - Composition containing butyric acid compound and its application - Google Patents
Composition containing butyric acid compound and its application Download PDFInfo
- Publication number
- CN108283632A CN108283632A CN201711217080.6A CN201711217080A CN108283632A CN 108283632 A CN108283632 A CN 108283632A CN 201711217080 A CN201711217080 A CN 201711217080A CN 108283632 A CN108283632 A CN 108283632A
- Authority
- CN
- China
- Prior art keywords
- butyric acid
- acid compound
- liver
- preparation
- formula
- Prior art date
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Links
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 title claims abstract description 134
- -1 butyric acid compound Chemical class 0.000 title claims abstract description 69
- 239000000203 mixture Substances 0.000 title claims abstract description 26
- 206010010317 Congenital absence of bile ducts Diseases 0.000 claims abstract description 51
- 201000005271 biliary atresia Diseases 0.000 claims abstract description 51
- 238000002360 preparation method Methods 0.000 claims abstract description 49
- 235000016709 nutrition Nutrition 0.000 claims abstract description 33
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- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract description 7
- 230000035935 pregnancy Effects 0.000 claims abstract description 6
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 claims description 55
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 42
- 235000013350 formula milk Nutrition 0.000 claims description 40
- 235000013305 food Nutrition 0.000 claims description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
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- PQLMXFQTAMDXIZ-UHFFFAOYSA-N isoamyl butyrate Chemical compound CCCC(=O)OCCC(C)C PQLMXFQTAMDXIZ-UHFFFAOYSA-N 0.000 claims description 4
- JXPHLUCMHXXHEJ-UHFFFAOYSA-N 2-(aminomethyl)-4-bromoaniline Chemical compound NCC1=CC(Br)=CC=C1N JXPHLUCMHXXHEJ-UHFFFAOYSA-N 0.000 claims description 3
- FYPVXEILSNEKOO-UHFFFAOYSA-L calcium;butanoate Chemical compound [Ca+2].CCCC([O-])=O.CCCC([O-])=O FYPVXEILSNEKOO-UHFFFAOYSA-L 0.000 claims description 3
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- RWMKSKOZLCXHOK-UHFFFAOYSA-M potassium;butanoate Chemical compound [K+].CCCC([O-])=O RWMKSKOZLCXHOK-UHFFFAOYSA-M 0.000 claims description 3
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- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 8
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- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 206010056375 Bile duct obstruction Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- BJUFAVXYJRJBLQ-UHFFFAOYSA-N butanoic acid;propane-1,2,3-triol Chemical compound CCCC(O)=O.OCC(O)CO BJUFAVXYJRJBLQ-UHFFFAOYSA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/152—Milk preparations; Milk powder or milk powder preparations containing additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/16—Agglomerating or granulating milk powder; Making instant milk powder; Products obtained thereby
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The present invention provides a kind of composition containing butyric acid compound and its application, the butyric acid compound can be used for preventing Biliary atresia and its complication.The composition containing butyric acid compound, including butyric acid compound and nutritional preparation or excipient substance；A concentration of 5~70mM of the butyric acid compound.Innovative using of the invention is typically applied to the interference method of enteron aisle to prevent Biliary atresia and its complication.Butyric acid compound as a kind of safe and effective control method, be used directly for or be added in nutritional preparation for without any symptom pregnancy and newborn individual, to fundamentally prevent Biliary atresia occurrence and development.And the present invention solves the technical barrier of Biliary atresia complication liver fibrosis prevention simultaneously, and a kind of safe, economic and effective method is provided for the prevention of Biliary atresia liver fibrosis.
Description
Technical field
The present invention relates to food pharmaceutical technology fields, specifically, be related to a kind of composition containing butyric acid compound and
Its application in prevention Biliary atresia and its complication.
Background technology
Biliary atresia (biliary atresia, BA) is a kind of congenital characterized by extrahepatic duct progressive blocks
Sex deviation, incidence 1/5000-1/8000.Most of BA infants usually do not have apparent symptom after life in a couple of days, with
The obstruction of extrahepatic duct progressive, apparent jaundice, clay color stool are gradually shown.Portojejunal anastomosis is Biliary atresia
Preferred therapeutic scheme.However it is unobstructed even if successfully restoring bile duct by portojejunal anastomosis, after bile normal drainage, still
Progressive obstruction of bile duct can occur, liver fibrosis is caused to rapidly develop to hepatic sclerosis.Such as without orthotopic liver transplantation, BA's is long-term
Survival rate is the first cause for leading to Lebertransplantationim im Kindesalter less than 30%.
The cause of disease and pathogenesis of Biliary atresia are still not clear, and are a great problems clinically.Due to the morning of Biliary atresia
Phase diagnosis is extremely difficult, is difficult to and the diseases such as newborn's cholestasis, INFANT HEPATITIS SYNDROME and virus hepatitis in neonatal period
Disease differentiates that infant usually requires, by can just make a definite diagnosis for a long time, it is hard that severe fibrosis even liver have been progressed to when causing to make a definite diagnosis
Change.On the other hand, due to lacking effectively preventing means, without effective remedy measures being diagnosed as Biliary atresia, finally
Still need to Liver Transplantation for Treatment.
Therefore, the control measure of Biliary atresia is the problem of clinically urgent need to resolve.However, the morbidity crowd of Biliary atresia
For newborn, Biliary atresia is early diagnosed without effective method again at present, how in the newborn crowd of non-evident sympton
The safe and effective generation for preventing Biliary atresiaAnd how the infant for being diagnosed as Biliary atresia is safely and effectively inhibited
The liver fibrosis of progressiveThese problems be all presently, there are technical barrier.
Butyric acid is the natural component in mammal milk, and one of the metabolite of intestinal flora in vivo.Butyric acid is made
For one kind of short chain fatty acids, played an important role in terms of maintaining enteron aisle normal physiological function.Currently, grinding about butyric acid
Study carefully and focuses primarily upon intestines problem, and there is not been reported for effect of the butyric acid in preventing Biliary atresia.
On the other hand, the concurrent liver fibrosis progression of Biliary atresia is very rapid, and it is hard that liver is usually developed within some months
Change, and clinically a big difficulty.Liver fibrosis is divided into number of different types, virus hepatitis, alcoholic hepatitis, non-alcoholic fat
The a variety of causes such as fat liver and cholestasis can all lead to liver fibrosis.Different types of liver fibrosis, the cause of disease and pathogenesis
Difference, control measure are also entirely different.The concurrent liver fibrosis of Biliary atresia belongs to one kind of cholestatic liver fibrosis, mesh
Before there is no safely and effectively control measure.
Research confirms that butyric acid has protective effect to some intestines problems such as ulcerative colitis, inflammatory bowel disease, however
The effect of butyric acid is really not so in cholestatic disease.Research finds that the cholestatic disease caused by bile duct ligation is dynamic
In object model, liver declines the metabolic capability of aliphatic acid, and especially short chain fatty acids such as butyric acid etc. can not be decomposed metabolism, cause
Short-chain fat acid concentration increases, and may aggravate cholestatic liver disease (Reichen J, ect.Mechanisms of
impaired hepatic fatty acid metabolism in rats with long-term bile duct
ligation.Hepatology.1994May；19(5):1272-81)(ühl S,ect.Reversibility of
hepatic mitochondrial damage in rats with long-term cholestasis.J
Hepatol.1998Jun；28(6):1000-7).On the other hand, Notch signal paths and bile duct cell hyperplasia are in progressive
It plays an important role in cholestatic liver fibrosis.And the researchs such as Zhang X find butyric acid by promoting Notch signal paths
And hepatic progenitor cell is divided into bile duct epithelial cell, to play the effect (Zhang for promoting cholestatic liver fibrosis
X,et a1.Inhibition of notch signaling pathway prevents cholestatic liver
fibrosis by decreasing the differentiation of hepatic progenitor cells in to
cholangiocytes.Lab Invest.2016Mar；96(3):350-60).Therefore, these results of study, short chain fat are based on
Fat acid such as butyric acid is considered as an important factor for promoting cholestatic liver fibrosis.
Invention content
The technical problem to be solved by the present invention is in view of the shortcomings of the prior art, provide a kind of group containing butyric acid compound
Close object and its application.
The present invention provides a kind of composition can be used in prevention Biliary atresia and its complication.It is especially provided to prevent
With the effect in treatment Biliary atresia and its complication liver fibrosis.
After innovative use butyric acid compound of the invention intervenes pregnant mouse, the very effective hair for preventing Biliary atresia
It is raw.Butyric acid compound is used directly for or is added in nutritional preparation to be used for as a kind of safe and effective control method
The pregnancy of non-evident sympton and newborn individual, to fundamentally prevent the occurrence and development of Biliary atresia.
On the other hand, the complication liver fibrosis of Biliary atresia belongs to cholestatic liver fibrosis, and prevention is also very tired
It is difficult.Even if common anti-inflammatory drug can alleviate liver inflammation reaction, it can not but alleviate the process of liver fibrosis.And it is directed to bile
Effect of the drug of acid synthesis in cholestatic liver fibrosis is also very limited.Because of the cholestatics disease such as Biliary atresia
Sick extrahepatic duct obstruction persistently exists, and the degree of cholestasis is very serious in liver, and the concentration of bile acid is usually above just
Even tens times or more of more than ten times of constant value.It is the enabled synthesis for reducing bile acid, liver that some, which inhibit the drug of bile acid biosynthesis,
In bile acid concentration be still higher than normal value decades of times.And research confirms in the cholestatics diseases such as Biliary atresia, liver is fine
The degree of dimensionization and bile acid levels and non-correlation, thus inhibit bile acid biosynthesis in preventing Biliary atresia liver fibrosis
It acts on very limited.
Research finds that in cholestatic disease animal model, liver declines the metabolic capability of aliphatic acid, causes short
The raising of chain fatty acid concentration may aggravate cholestatic liver disease (Reichen J, ect.Mechanisms of impaired
hepatic fatty acid metabolism in rats with long-term bile duct
ligation.Hepatology.1994 May；19(5):1272-81)( S,ect.Reversibility
of hepatic mitochondrial damage in rats with long-term cholestasis.J
Hepatol.1998 Jun；28(6):1000-7).But we carefully analyze discovery, and positive evidence card is had no in these researchs
Effect of the real butyric acid in progressive cholestatic liver fibrosis.On the other hand, the researchs such as Zhang X find that sodium butyrate passes through
Notch signal paths and hepatic progenitor cell is promoted to be divided into bile duct epithelial cell to play promotion cholestatic liver fiber
Effect (Zhang X, the et a1.Inhibition of notch signaling pathway prevents of change
cholestatic liver fibrosis by decreasing the differentiation of hepatic
progenitor cells in to cholangiocytes.Lab Invest.2016Mar；96(3):350-60).However,
The research confirms the effect of sodium butyrate only with experiment in vitro, and function and effect in vivo are not necessarily so.
Of the invention innovative intervenes the animal model of cholestatic liver fibrosis using butyric acid compound
And treatment, overcome prior art prejudice, can very effective prevention Biliary atresia complication liver fibrosis, solve clinically
Problem.
Research confirms that the degree of the cholestatics disease liver fibrosis such as Biliary atresia is soaked with bile acid levels, inflammatory cell
The indexs such as profit, ALT, AST and non-correlation.Present invention firstly discovers that Th1 types cell proportion and liver in bile duct ligation model liver
Fibrosis is proportionate, and Th1 types cell plays an important role during promoting cholestatic liver fibrosis.It is using
After butyric acid compound is intervened or treated, Th1 type cell proportions are remarkably decreased.Butyric acid compound is inhibited by specificity
The ratio of liver Th1 type cells plays an important role in preventing Biliary atresia progressive liver fibrosis.
The purpose of the present invention is what is be achieved through the following technical solutions：
The present invention provides a kind of butyric acid compounds in preparing the composition of prevention Biliary atresia and its complication
Purposes.
The present invention provides a kind of composition containing butyric acid compound, including butyric acid compound and nutritional preparation or
Excipient substance；A concentration of 5~70mM (mmol/L) of the butyric acid compound.
Preferably, a concentration of 15~45mM of the butyric acid compound.
Preferably, the butyric acid compound is 0.5-7mmol/kg/d as the effective dose of drug.
It is highly preferred that the butyric acid compound is 1.5-4.5mmol/kg/d as the effective dose of drug.
Preferably, the butyric acid compound is selected from sodium butyrate, potassium butyrate, calcium butyrate, magnesium butyrate, butyric acid, butyric acid glycerine
At least one of ester, isoamyl butyrate.
Preferably, the butyric acid compound is selected from least one of sodium butyrate, glycerol monobutyralte, butyric acid.
Preferably, the nutritional preparation is selected from conventional formulation food, special medicine purposes formula food, parenteral nutrition system
At least one of agent, enteral nutrition preparation.
Preferably, the conventional formulation food include in babies ' formula milk powder, pregnancy period and nursing period formula milk at least
It is a kind of；The special medicine purposes formula food includes premature labor/low birth weight baby formula milk, lactose-free formula or low breast
Sugared formula milk, milk protein part hydrolyzed formulas milk powder, lactoprotein depth hydrolysis formula or amino acid formula milk, breast milk and baby
The hardening agent or nutritional supplement of youngster's formula food, be suitable for food intolerance, allergy, hepatopathy special formulation food,
At least one of the formula food of disease or dysfunction；The parenteral nutrition preparation includes fat emulsion injection, All-In-One
At least one of nutrient solution, intravenous fluid；The enteral nutrition preparation includes amino acid pattern enteral nutrition preparation, short peptide type
At least one of enteral nutrition preparation, whole protein type enteral nutrition preparation, assembly type enteral nutrition preparation.
The present invention also provides a kind of preparation methods of the composition containing butyric acid compound, which is characterized in that the system
Preparation Method includes：Butyric acid compound is proportionally added into the nutritional preparation or excipient substance, is uniformly mixed, you can.
Special medicine purposes formula food (Food for Special Medical Purpose, FSMP) is in order to full
Foot feeds the limited, special requirement of Disorder of Digestion and A orption, metabolic disorder or particular disease states crowd to nutrient or diet, specially
The formula food that door processing is formulated.Such product must under doctor or clinical nutrition's teacher guidance, it is individually edible or and its
His food is matched.Special medicine purposes formula food belongs to food for special foods.When target group can not feed commonly
Diet or when can not meet its nutritional need with ordinary meal, special medicine purposes formula food can be used as a kind of nutritional supplementation
Approach plays important nutritional support to treatment, rehabilitation and body function maintenance etc. and acts on.
Preferably, the excipient substance includes pharmaceutically acceptable carrier or excipient, such as lactose hydrous, crystallite
Cellulose, mannitol, sodium citrate, calcium phosphate, glycine, starch；Disintegrant such as crospovidone, copolyvidone, hydroxyl
Amylcose acetate sodium, croscarmellose sodium and specific composition silicate；Binder such as polyvinylpyrrolidone, hydroxypropyl
Ylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and Arabic gum etc..
Preferably, the butyric acid compound be butyric acid when, butyric acid compound by coating or it is coated in the form of add.
It should be noted that the administration form of butyric acid compound is inessential in the present invention, butyric acid compound will be contained and added
It adds to suitable for the formula milk of infant and pregnant and lying-in women, special medicine purposes formula food and other enteral, parenteral nutrition systems
In agent or excipient substance, as long as the effect of prevention Biliary atresia and its complication can be achieved using effective quantity.
As an alternative solution of formula food application, butyric acid compound of the invention can be used as replenishers to apply
Rather than it is integrated into formula food.For example, butyric acid compound can be with pill, tablet, capsule, caplet, powder, liquid or solidifying
Glue form is absorbed.For example, butyric acid compound can be absorbed with other nutritional supplements as breast milk replenishers combine.
Compared with prior art, the present invention has following advantageous effect：
1, innovative the using of the present invention is typically applied to the interference method of enteron aisle to prevent Biliary atresia.Using butyric acid
After class compound intervenes pregnant mouse, the very effective generation for having prevented Biliary atresia.Butyric acid compound as it is a kind of safely, have
The control method of effect, be used directly for or be added in nutritional preparation for without any symptom pregnancy and newborn individual, from
And fundamentally prevent the generation of Biliary atresia.
2, research is thought at present, and in cholestatic disease animal model, liver declines the metabolic capability of aliphatic acid,
Cause the raising of short-chain fat acid concentration that may aggravate cholestatic liver disease；And sodium butyrate is by promoting Notch signals logical
Road and hepatic progenitor cell are divided into bile duct epithelial cell, to play the effect for promoting cholestatic liver fibrosis.This hair
It is bright to overcome prior art prejudice, using butyric acid compound intervention and treatment cholestatic liver fibrosis, as a result show mould
Type group shows as severe liver fibrosis, 3 grades of fibrosis, and intervention group and treatment group have no apparent liver fibrosis.Therefore, originally
Invention solves the technical barrier of Biliary atresia complication liver fibrosis prevention, provides a kind of safe, economical and effectively prevents
Control method.
3, research confirms the degree of hepatic fibrosis and bile acid levels, inflammatory cell of the cholestatics diseases such as Biliary atresia
The indexs such as infiltration, ALT, AST and non-correlation.Present invention firstly discovers that in bile duct ligation model liver, Th1 types cell ratio
Example is proportionate with degree of hepatic fibrosis, and Th1 types cell plays an important role in progressive liver fibrosis process.Using fourth
After acid compounds are intervened or treated, Th1 type cell proportions are remarkably decreased.Butyric acid compound inhibits liver by specificity
The ratio of dirty Th1 types cell plays an important role in preventing Biliary atresia progressive liver fibrosis.
4, the speed being metabolized in vivo due to butyric acid is very fast, and in order to preferably play the function and effect of butyric acid, we will
Butyric acid compound is added to suitable for the nutritional preparation of specific crowd so that butyric acid slowly enters body with nutritional preparation
It digests and assimilates, more efficient plays a role.Butyric acid compound is added to pregnancy and the new life suitable for non-evident sympton
In the nutritional preparation of body, the occurrence and development of Biliary atresia can be fundamentally prevented.
Therefore, add the nutritional preparation of butyric acid compound and drug be it is a kind of safely, effectively, feasible prevention biliary tract closes
Lock disease and its method of complication liver fibrosis.
Description of the drawings
Upon reading the detailed description of non-limiting embodiments with reference to the following drawings, other feature of the invention,
Objects and advantages will become more apparent upon：
Fig. 1 is bile duct ligation (BDL) model liver HE and Masson dyeing；Wherein Fig. 1 a are BDL model group livers HE dyes
Color；Fig. 1 b are the Masson dyeing of BDL model group livers；Fig. 1 c are the HE dyeing of BDL+ sodium butyrates intervention (30mM) liver；Fig. 1 d are
The Masson dyeing of BDL+ sodium butyrates intervention (30mM) liver；Fig. 1 e are that BDL+ sodium butyrates treat the HE dyeing of (45mM) liver；Fig. 1 f
The Masson dyeing of (45mM) liver is treated for BDL+ sodium butyrates；Fig. 1 g are that BDL+ sodium butyrates treat the HE dyeing of (70mM) liver；Figure
1h is that BDL+ sodium butyrates treat the Masson dyeing of (70mM) liver.
Fig. 2 is bile duct ligation (BDL) model liver lymphocyte FCM analysis Th1 type cell proportions；Wherein Fig. 2 a
For BDL model group liver Th1 types cell proportions (black circle)；Fig. 2 b are the intervention of BDL+ sodium butyrates (30mM) liver Th1 type cells
Ratio (black circle)；Fig. 2 c are that BDL+ sodium butyrates treat (45mM) liver Th1 types cell proportion (black circle)；Fig. 2 d are BDL+ fourths
Sour sodium treatment (70mM) liver Th1 types cell proportion (black circle)；Fig. 2 e are the liver of BDL model groups and each sodium butyrate intervention group
Th1 type cell proportions count；Fig. 2 f are that BDL model groups and the liver Th1 type cell proportions of each sodium butyrate treatment group count.
Specific implementation mode
With reference to specific embodiment, the present invention is described in detail.Following embodiment will be helpful to the technology of this field
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill of this field
For personnel, without departing from the inventive concept of the premise, several changes and improvements can also be made.These belong to the present invention
Protection domain.
Embodiment 1
A kind of babies ' formula milk powder of the butyric acid containing coating and preparation method thereof is present embodiments provided, the method is：It will
Food-grade coating butyric acid be added babies ' formula milk powder in, be uniformly mixed to get.Coating butyric acid in the formula milk of the preparation
A concentration of 5mmol/L.
Embodiment 2
A kind of pregnant and lying-in women's formula milk and preparation method thereof containing sodium butyrate is present embodiments provided, the method is：It will
Food-grade sodium butyrate be added pregnant and lying-in women's formula milk in, be uniformly mixed to get.Sodium butyrate is dense in the formula milk of the preparation
Degree is 15mmol/L.
Embodiment 3
Present embodiments provide a kind of preterm formula milk powder and preparation method thereof containing glycerol monobutyralte, the method
For：Will food-grade glycerol monobutyralte be added preterm formula milk powder in, be uniformly mixed to get.In the formula milk of the preparation
A concentration of 20mmol/L of glycerol monobutyralte.
Embodiment 4
A kind of fat emulsion injection and preparation method thereof containing sodium butyrate is present embodiments provided, the method is：It will note
Grade sodium butyrate is penetrated to be added in fat emulsion injection, be uniformly mixed to get.Sodium butyrate is dense in the fat emulsion injection of the preparation
Degree is 30mmol/L.
Embodiment 5
A kind of All-In-One nutrient solution and preparation method thereof containing sodium butyrate is present embodiments provided, the method is：It will note
Grade sodium butyrate is penetrated to be added in All-In-One nutrient solution, be uniformly mixed to get.Sodium butyrate is dense in the All-In-One nutrient solution of the preparation
Degree is 45mmol/L.
Embodiment 6
Present embodiments provide a kind of short peptide type enteral nutrition preparation and preparation method thereof containing glycerol monobutyralte, the side
Method is：Will food-grade glycerol monobutyralte be added short peptide type enteral nutrition preparation in, be uniformly mixed to get.The small peptide of the preparation
A concentration of 55mmol/L of glycerol monobutyralte in type enteral nutrition preparation.
Embodiment 7
A kind of special disease formula food and preparation method thereof containing sodium butyrate is present embodiments provided, the method is：
Will food-grade sodium butyrate be added special disease formula food in, be uniformly mixed to get.The special disease formula food of the preparation
A concentration of 70mmol/L of middle sodium butyrate.
Embodiment 8
Present embodiments provide a kind of pharmaceutical composition containing butyric acid compound and excipient substance.
The butyric acid compound is selected from sodium butyrate, potassium butyrate, calcium butyrate, magnesium butyrate, butyric acid, glycerol monobutyralte, butyric acid
At least one of isopentyl ester.
The effective dose of the butyric acid compound is 0.5~7mmol/kg/d.
Further include other medicine classes compatible with the butyric acid compound in described pharmaceutical composition and pharmaceutically may be used
The carrier and/or auxiliary material of receiving.
Described pharmaceutical composition is pharmaceutically acceptable arbitrary dosage form.
The dosage form is pulvis, injection, capsule, tablet or oral solution.
The butyric acid compound be butyric acid when, butyric acid compound by coating or it is coated in the form of be added into drug.
The composition containing butyric acid compound can effectively prevent Biliary atresia and its complication liver made from above example
Fibrosis.Its optimum effective dose prevented is 15-30mmol/L or 1.5~3mmol/kg/d；The optimum effective dose for the treatment of
For 30-45mmol/L or 3~4.5mmol/kg/d.
Animal experiment compliance test result：
1, Biliary atresia animal model is induced using rotavirus infection newborn mice to be verified
1.1 experimental animals and grouping
The SPF grades of pregnant mouse of pregnant 7 days BALB/C are purchased from Shanghai western Poole-Bi Kai experimental animals Co., Ltd.In Shanghai, traffic is big
The attached Xinhua Hospital animal experimental center of institute of studying medicine is raised, and modeling group, sodium butyrate intervention group and sodium butyrate treatment group are divided into：
Biliary atresia modeling group：In pregnant 24 hours mouse postpartum, using rotation virus intraperitoneal injection newborn rat, carries out biliary tract and close
Modeling is locked, newborn rat uses breast-feeding；14 days after modeling, peripheral blood, bile duct, liver, intestinal tissue is taken to be detected；
Sodium butyrate intervention group (45mM)：Sodium butyrate is added in water and feeds pregnant 7 days pregnant mouse until producing, in pregnant mouse postpartum
In 24 hours, using rotation virus intraperitoneal injection newborn rat, Biliary atresia modeling is carried out, newborn rat uses breast-feeding；Modeling
14 days afterwards, peripheral blood, bile duct, liver, intestinal tissue is taken to be detected；
Sodium butyrate treatment group (45mM)：In pregnant 24 hours mouse postpartum, using rotation virus intraperitoneal injection newborn rat, courage is carried out
Road is latched modeling, and sodium butyrate is added in water and feeds female rat, and newborn rat uses breast-feeding；14 days after modeling, periphery is taken
Blood, bile duct, liver, intestinal tissue are detected.
1.2 result
Biliary atresia modeling group：Extrahepatic bile ducts patency is detected, as a result, it has been found that modeling group mouse extrahepatic bile ducts obstructs
Resistance is infiltrated with serious cholestasis, bile duct paraplasm and liver inflammation；
Sodium butyrate intervention group (45mM)：Extrahepatic bile ducts patency is detected, as a result, it has been found that sodium butyrate intervention group mouse
Extrahepatic bile ducts is unobstructed, it is seen that liver inflammation infiltrates, and has no apparent cholestasis and bile duct proliferation；
Sodium butyrate treatment group (45mM)：Extrahepatic bile ducts patency is detected, as a result, it has been found that sodium butyrate treatment group mouse
Extrahepatic bile ducts is still unobstructed, it is seen that liver inflammation cellular infiltration has no apparent cholestasis and bile duct proliferation.
Therefore, our innovative use butyric acid compounds intervene pregnant mouse, very effective to have prevented newborn rat biliary tract
The occurrence and development of locking are of great significance for the prevention of clinically Biliary atresia.
2, the effect in Biliary atresia liver fibrosis is verified using extrahepatic bile ducts ligation model
Since rotavirus infection model is not suitable for research liver fibrosis, we study biliary tract using bile duct ligation model
It is latched liver fibrosis.
2.1 experimental animal
Cleaning grade three week old Sprague-Dawley (SD) rat, male and female are unlimited, weight about 50g, are purchased from the western Poole-in Shanghai
Bi Kai experimental animals Co., Ltd.It is raised in Xinhua Hospital Attached to Medical School, Shanghai Jiaotong Univ.'s animal experimental center.
2.2 processing method
Bile duct ligation (BDL) model group：Rat is fed using water and normal diet, rat ductus choledochus is carried out after 7 days double
It ligatures and is cut from centre again；Without administration, the 14th day overnight fasting takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, is used
In subsequent experimental.It is fixed with neutral formalin and carries out histotomy, do H-E dyeing, Masson and immunohistochemistry detection respectively.
BDL+ sodium butyrate intervention groups：Sodium butyrate is added to the water and feeds rat, butyric acid na concn is respectively 5mM, 15mM,
30mM, 45mM, dosage are respectively 0.5mmol/kg/d, 1.5mmol/kg/d, 3mmol/kg/d, 4.5mmol/kg/d.Feed 7
After it, dual ligation is carried out to rat ductus choledochus and is cut from centre.Postoperative 14th day overnight fasting takes blood to survey blood biochemistry.It takes
Liver and intestinal tissue are used for subsequent experimental.Fixed with neutral formalin and carry out histotomy, be respectively H-E dyeing,
Masson and immunohistochemistry detection.
BDL+ coating butyric acid intervention groups：Butyric acid is added to the water and feeds rat, butyric acid density is respectively 5mM, 15mM,
30mM, 45mM, dosage are respectively 0.5mmol/kg/d, 1.5mmol/kg/d, 3mmol/kg/d, 4.5mmol/kg/d.Feed 7
After it, dual ligation is carried out to rat ductus choledochus and is cut from centre.Postoperative 14th day overnight fasting takes blood to survey blood biochemistry.It takes
Liver and intestinal tissue are used for subsequent experimental.Fixed with neutral formalin and carry out histotomy, be respectively H-E dyeing,
Masson and immunohistochemistry detection.
BDL+ glycerol monobutyralte intervention groups：Glycerol monobutyralte is added to the water and feeds rat, glycerol monobutyralte concentration difference
For 5mM, 15mM, 30mM, 45mM, dosage is respectively 0.5mmol/kg/d, 1.5mmol/kg/d, 3mmol/kg/d,
4.5mmol/kg/d.After feeding 7 days, dual ligation is carried out to rat ductus choledochus and is cut from centre.Postoperative fasting in 14th day
Night takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, subsequent experimental is used for.It is fixed with neutral formalin and carries out histotomy,
H-E dyeing, Masson and immunohistochemistry detection are done respectively.
BDL+ sodium butyrates treatment group：Dual ligation is carried out to rat ductus choledochus and is cut from centre.It opens within the 7th day after modeling
Beginning, sodium butyrate is added to the water and feeds rat, for successive administration to the 14th day, butyric acid na concn was respectively 15mM, 30mM, 45mM,
70mM, dosage are respectively 1.5mmol/kg/d, 3mmol/kg/d, 4.5mmol/kg/d, 7mmol/kg/d.Fasting in 14th day
Night takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, subsequent experimental is used for.It is fixed with neutral formalin and carries out histotomy,
H-E dyeing, Masson and immunohistochemistry detection are done respectively.
BDL+ clostridium butyricum intervention groups：Clostridium butyricum is added to the water and feeds rat, the viable count of clostridium butyricum is 1 ×
107-4×107CFU/mL, dosage are 1 × 109-4×109CFU/kg/d.After feeding 7 days, rat ductus choledochus is carried out dual
It ligatures and is cut from centre.Postoperative 14th day overnight fasting takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, for follow-up real
It tests.It is fixed with neutral formalin and carries out histotomy, do H-E dyeing, Masson and immunohistochemistry detection respectively.
BDL+ clostridium butyricums treatment group：Dual ligation is carried out to rat ductus choledochus and is cut from centre.The 7th day after modeling
Start, clostridium butyricum is added to the water and feeds rat, for successive administration to the 14th day, the viable count of clostridium butyricum was 5 × 107-9×
107CFU/mL, dosage are 5 × 109-9×109CFU/kg/d.14th day overnight fasting takes blood to survey blood biochemistry.Take liver and intestines
Road tissue is used for subsequent experimental.It is fixed with neutral formalin and carries out histotomy, be H-E dyeing, Masson respectively and be immunized
Groupization detects.
2.3 result
Bile duct ligation (BDL) model group：Animal blood serum liver function index ALT, AST, GGT, TBA, TBIL are significantly increased, liver
Dirty color is obviously turned to be yellow, rough, and quality is harder；There is severe liver fibrosis in liver organization, and fibrosis reaches 3 grades
(Fig. 1 a, Fig. 1 b).The Th1 type cell proportions for promoting progression of fibrosis in BDL model group livers significantly increase, and mean value reaches 21.3%
(Fig. 2 a, Fig. 2 e).
BDL+ sodium butyrate intervention groups:
Sodium butyrate intervention group (5mM)：Liver function index slightly reduces, and liver color is slightly turned to be yellow, and pathological staining result is shown
Liver moderate liver fibrosis, 2 grades of degree of hepatic fibrosis, compared with BDL groups, liver Th1 type cell proportions decline, and mean value is
12.7% (Fig. 2 e)；
Sodium butyrate intervention group (15mM)：Liver function index is substantially reduced, and liver color and luster is red, any surface finish, soft texture, disease
The reason coloration result display slight liver fibrosis of liver, 1 grade of degree of hepatic fibrosis, compared with BDL groups, liver Th1 type cell proportions
It is decreased obviously, mean value is 6.9% (Fig. 2 e)；
Sodium butyrate intervention group (30mM)：Liver function index significantly reduces, and liver color and luster is scarlet, any surface finish, soft texture,
Pathological staining result shows that liver has no obvious fibrosis (Fig. 1 c, Fig. 1 d)；And FCM analysis is the results show that promote fiber
The liver Th1 type cell proportions of change process are remarkably decreased and close to normal values, and mean value is 1.8% (Fig. 2 b, Fig. 2 e)；
Sodium butyrate intervention group (45mM)：Liver function index significantly reduces, and liver color and luster is scarlet, any surface finish, soft texture,
Pathological staining result shows that liver mild fibrosis, 1 grade of degree of hepatic fibrosis, liver Th1 type cell proportion mean values are down to 2.4%
(Fig. 2 e).
The result of coating butyric acid intervention group and glycerol monobutyralte intervention group and the result of sodium butyrate intervention group are almost the same.
BDL+ sodium butyrates treatment group:
Sodium butyrate treatment group (15mM)：Every liver function index reduces, and liver color and luster is slightly yellow, 2 grades of hepatic fibrosis-renal tubular ectasia syndrome degree,
Compared with BDL groups, liver Th1 type cell proportions decline, and mean value is 15.7% (Fig. 2 f)；
Sodium butyrate treatment group (30mM)：Every liver function index is substantially reduced, and liver color and luster is redder, and quality is softer, liver
Slight liver fibrosis, 1 grade of fibrosis, compared with BDL groups, liver Th1 type cell proportions are decreased obviously, mean value 7.6%
(Fig. 2 f)；
Sodium butyrate treatment group (45mM)：Every liver function index significantly reduces, and liver color and luster is scarlet, and surface is smooth, quality
Softness, liver have no apparent liver fibrosis (Fig. 1 e, Fig. 1 f)；Compared with BDL groups, liver Th1 type cell proportions are remarkably decreased,
Value is down to 4.8% (Fig. 2 c, Fig. 2 f)；
Sodium butyrate treatment group (70mM)：Every liver function index significantly reduces, and liver color and luster is scarlet, and surface is smooth, quality
Softness, liver mild fibrosis, 1 grade of degree of hepatic fibrosis (Fig. 1 g, Fig. 1 h), liver Th1 type cell proportions are down to 5.5% (figure
2d, Fig. 2 f).
BDL+ clostridium butyricum groups：
The result of clostridium butyricum intervention group is shown：Give 1 × 107-4×107After CFU/mL clostridium butyricum active bacterias are intervened
Degree of hepatic fibrosis and the reduction of Th1 type cell proportions are not obvious, and fibrosis is 2-3 grades；
The result of clostridium butyricum treatment group is shown：Give 5 × 107-9×107CFU/mL clostridium butyricum active bacterias are treated,
Degree of hepatic fibrosis and Th1 type cell proportions have no and are decreased obviously that fibrosis is still 3 grades.
Therefore, give butyric acid compound to be intervened, the generation of Biliary atresia is not only effectively prevented, for biliary tract
The prevention of blockage complications liver fibrosis also has extraordinary effect；Especially after butyric acid na concn reaches 30mM-45mM, prevention
Effect is especially pronounced.BDL modeling groups show as severe liver fibrosis, and fibrosis is 3 grades, and BDL intervention groups and treatment group
Have no apparent liver fibrosis.Therefore illustrate that butyric acid compound can be used for preventing Biliary atresia and its complication liver fibrosis.And
The function and effect of clostridium butyricum are not obvious, and at present hygiene department regulation only have lactobacillus, Bifidobacterium and streptococcus this
Three kinds of probiotics can be added in food safely, and only Bifidobacterium and lactobacillus can be with security applications in infant formula milk
In powder.What kind of clostridium butyricum can generate in vivo as a kind of active microorganism influences unclear, may there is safety
Hidden danger.
In conclusion butyric acid compound can effectively prevent Biliary atresia and its complication liver fibrosis.Butyric acid is to exist
With a kind of short chain fatty acids in mammal milk, and from the point of view of the result of animal experiment, butyric acid compound is in the concentration
Administration, does not cause any damage and side effect to experimental animal, illustrates that its drug safety is higher in range.Butyric acid compound
There to be very big application prospect for preventing Biliary atresia and its complication liver fibrosis.
Specific embodiments of the present invention are described above.It is to be appreciated that the invention is not limited in above-mentioned
Particular implementation, those skilled in the art can make a variety of changes or change within the scope of the claims, this not shadow
Ring the substantive content of the present invention.In the absence of conflict, the feature in embodiments herein and embodiment can arbitrary phase
Mutually combination.
Claims (10)
1. a kind of purposes of butyric acid compound in preparing the composition of prevention Biliary atresia and its complication.
2. a kind of composition containing butyric acid compound, which is characterized in that including butyric acid compound and nutritional preparation or medicine
Object auxiliary material；A concentration of 5~70mM of the butyric acid compound.
3. the composition according to claim 2 containing butyric acid compound, which is characterized in that the butyric acid compound
A concentration of 15~45mM.
4. the composition according to claim 2 containing butyric acid compound, which is characterized in that the butyric acid compound is made
Effective dose for drug is 0.5-7mmol/kg/d.
5. the composition according to claim 4 containing butyric acid compound, which is characterized in that the butyric acid compound is made
Effective dose for drug is 1.5-4.5mmol/kg/d.
6. according to composition of the claim 1-5 any one of them containing butyric acid compound, which is characterized in that the butyric acid class
Compound is selected from least one of sodium butyrate, potassium butyrate, calcium butyrate, magnesium butyrate, butyric acid, glycerol monobutyralte, isoamyl butyrate.
7. the composition according to claim 6 containing butyric acid compound, which is characterized in that the butyric acid compound choosing
From at least one of sodium butyrate, glycerol monobutyralte, butyric acid.
8. the composition according to claim 2 containing butyric acid compound, which is characterized in that the nutritional preparation is selected from normal
Advise at least one of formula food, special medicine purposes formula food, parenteral nutrition preparation, enteral nutrition preparation.
9. the composition according to claim 8 containing butyric acid compound, which is characterized in that the conventional formulation food packet
Include at least one of babies ' formula milk powder, pregnancy period and nursing period formula milk；The special medicine purposes formula food includes
Premature labor/low birth weight baby formula milk, lactose-free formula or Low lactose milk formula milk, milk protein part hydrolyzed formula
Powder, lactoprotein depth hydrolysis formula or amino acid formula milk, the hardening agent of breast milk and infant formula or nutritional supplement,
Suitable for the formula food of food intolerance, allergy, hepatopathy special formulation food, disease or dysfunction at least
It is a kind of；The parenteral nutrition preparation includes at least one of fat emulsion injection, All-In-One nutrient solution, intravenous fluid；Institute
It includes amino acid pattern enteral nutrition preparation, short peptide type enteral nutrition preparation, whole protein type enteral nutrition system to state enteral nutrition preparation
At least one of agent, assembly type enteral nutrition preparation.
10. a kind of preparation method of the composition according to claim 2 containing butyric acid compound, which is characterized in that institute
Stating preparation method includes：Butyric acid compound is proportionally added into the nutritional preparation or excipient substance, is uniformly mixed, i.e.,
It can.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108208177A (en) * | 2017-11-28 | 2018-06-29 | 上海交通大学医学院附属新华医院 | Composition and its application containing butyric acid compound |
| WO2019169712A1 (en) * | 2018-03-09 | 2019-09-12 | 上海交通大学医学院附属新华医院 | Application of butyric acid compound in promoting tissue endogenous stem cell activation, proliferation and differentiation |
Citations (2)
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|---|---|---|---|---|
| CN107684554A (en) * | 2017-08-29 | 2018-02-13 | 上海市儿科医学研究所 | Butyric acid compound is preparing the application in preventing and treating NEC medicines |
| CN107736614A (en) * | 2017-08-29 | 2018-02-27 | 上海市儿科医学研究所 | Nutritional preparation containing butyric acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107684554A (en) * | 2017-08-29 | 2018-02-13 | 上海市儿科医学研究所 | Butyric acid compound is preparing the application in preventing and treating NEC medicines |
| CN107736614A (en) * | 2017-08-29 | 2018-02-27 | 上海市儿科医学研究所 | Nutritional preparation containing butyric acid |
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| IAC ARNOLDUSSEN ET AL.: "Butyrate restores HFD-induced adaptations in brain function and metabolism in mid-adult obese mice", 《INTERNATIONAL JOURNAL OF OBESITY 》 * |
| JUNBAE JEE ET AL.: "Cxcr2 signaling and the microbiome suppress inflammation, bile duct injury, and the phenotype of experimental biliary atresia", 《PLOS ONE》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108208177A (en) * | 2017-11-28 | 2018-06-29 | 上海交通大学医学院附属新华医院 | Composition and its application containing butyric acid compound |
| WO2019169712A1 (en) * | 2018-03-09 | 2019-09-12 | 上海交通大学医学院附属新华医院 | Application of butyric acid compound in promoting tissue endogenous stem cell activation, proliferation and differentiation |
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