CN109276564A - Application of butyric acid compounds in promoting the activation, proliferation and differentiation of tissue endogenous stem cells - Google Patents
Application of butyric acid compounds in promoting the activation, proliferation and differentiation of tissue endogenous stem cells Download PDFInfo
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- CN109276564A CN109276564A CN201810195490.3A CN201810195490A CN109276564A CN 109276564 A CN109276564 A CN 109276564A CN 201810195490 A CN201810195490 A CN 201810195490A CN 109276564 A CN109276564 A CN 109276564A
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Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- 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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
-
- 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
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Nutrition Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Emergency Medicine (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Mycology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention provides a kind of butyric acid compounds to promote the application in the activation of tissue endogenous retinal stem cells, proliferation and differentiation, additionally provide a kind of tissue endogenous retinal stem cells activator containing butyric acid compound, the effective concentration of the butyric acid compound is 5-200mM, effective dose 0.5-20mmol/kg/d.Present invention firstly discovers that butyric acid compound can promote the activation of morbid state undertissue organ endogenous retinal stem cells, proliferation and differentiation, in histoorgan reparation, regenerate, prevent from playing a significant role in progression of disease.
Description
Technical field
The present invention relates to food pharmaceutical technology fields, are promoting in tissue specifically, being related to a kind of butyric acid compound
Application in derived stem cells activation, proliferation and differentiation.
Background technique
Stem cell has numerous biomedical applications.With the fast development of stem-cell research basic theory, base at present
It is dry by global concern, including embryonic stem cell technologies (ESC), induced multi-potent in the cell replacement therapy technology of stem cell
Cell technology (iPSC) etc., these technologies are expected to as prevention and treatment tissue organ function's damage/failure important means.However, phase
It is more limited than in the source ESC, and there are problems that trnasplantion immunity repulsion, it is tissue by iPSC technological guide patient's somatic conversion
Specific cell such as liver cell seems with more application advantage.However, iPSC is inefficient, and turn from somatic induction
Become versatile stem cell and be divided into histocyte such as liver cell again, cellular change span is bigger, and step is more complicated, increases
Unstability is added, the safety of the cell generated also needs further to be verified, and implantation technique bottleneck also needs in vivo
It breaks through.In fact, different tissues organ all exist tissue endogenous retinal stem cells for example liver, bile duct, enteron aisle, pancreas islet, kidney, lung,
The histoorgans such as skin, skin accessory organ, heart, blood vessel, brain, research find the histoorgan caused by a variety of causes
After impaired or part is cut off, endogenous retinal stem cells meeting prompt activation is organized to repair damaged tissues.Therefore, each adult tissue is utilized
The self-renewing of organ endogenous retinal stem cells itself and multi-functional differentiation capability, to promote histoorgan caused by a variety of causes
It is repaired after damage, generates histoorgan then transplant in vitro compared to using embryonic stem cell or induction versatile stem cell
It is interior, all there is feasibility from difficulty, the economies of the simplicity of application and cost and safety of technical operation etc..Cause
This, how to effectively facilitate histoorgan endogenous retinal stem cells reparation damage becomes important research direction.
Butyric acid is a kind of short chain fatty acids, although butyric acid is proved to be played in a variety of diseases and histoorgan beneficial to work
With, but research at present thinks that butyric acid has certain inhibition or damaging action to tissue endogenous retinal stem cells.C
The discovery butyric acid such as Verseijden can reduce expression (the Butyrate stimulates of stem cell markers (Lgr5 and Olfm4)
the epithelial potential to produce retinoic acid demonstrated in primary
epithelial enteroid systems)；The discovery butyric acid such as Jones can lower the genetic transcription of colon carcinoma cell line Lgr5
And protein expression (The regulation of the intestinal cancer stem cell marker LGR5by
the dietary fibre derived chemopreventive agent sodium butyrate via an
epigenetic mechanism).A recent studies on Cell magazine shows butyric acid as a kind of potent intestinal stem cell
Inhibitor, limitation intestinal stem cell proliferation, so that enteron aisle potentially be inhibited to meet with by acute injury or because of inflammatory bowel disease
Self-regeneration (The Colonic Crypt Protects Stem Cells from Microbiota- after undermined
Derived Metabolites)。
Summary of the invention
The technical problem to be solved by the present invention is to promote in view of the shortcomings of the prior art, providing a kind of butyric acid compound
Organize the application in endogenous retinal stem cells activation, proliferation and differentiation.
Although research is thought at present, butyric acid has certain inhibition or damaging action for tissue endogenous retinal stem cells.Such as C
The discovery butyric acid such as Verseijden can reduce the expression of stem cell markers (Lgr5, Olfm4)；Jones etc. find butyric acid can under
Adjust genetic transcription and the protein expression of colon carcinoma cell line Lgr5.One on Cell magazine studies have shown that butyric acid as dry thin
A kind of effective inhibitor of born of the same parents' proliferation, prevents enteron aisle to supplement new cell.However, we have found some ask by analysis
Topic.In the research of these inside and outsides experiment, directly act on intestinal stem cell using butyric acid stoste, butyric acid stoste it is direct
Contact may cause physical or chemical lesion to stem cell, rather than generate physiological effect.Another part experiment in vivo
Studies have shown that additionally give the proliferation for not influencing intestinal stem cell after mouse butyric acid even there is certain damage and inhibition
Effect.And in intact animal body, organize the expression of endogenous retinal stem cells very low, only in specific disease or injury
In the case where stem cell just can activation and proliferation, such as research do not take suitable disease model, and giving possibly can not activate after butyric acid
Stem cell.Therefore, the butyric acid of research institute's report is made for tissue endogenous retinal stem cells without effect or with certain damage at present
With, these researchs or using experiment in vitro cannot situation in reactant well, or the experiment in vivo that uses and do not set up
On suitable disease model, or appropriate medication is not used.
In the present invention, we construct a variety of disease models, find that butyric acid compound can promote morbid state for the first time
Undertissue's organ endogenous retinal stem cells activation, proliferation and differentiation, this act on prevention and treatment many reasons caused by histoorgan by
Damage, promote histoorgan itself repair and regeneration, and important work is played during preventing progression of disease, fibrosis, canceration etc.
With.And present invention discover that butyric acid compound has by activation skin and the tissue specifc stem cells of cutaneous appendages
Promote skin scar reparation and hair hyperplasia and regenerated effect.In addition, being expanded on a large scale using butyric acid compound inside and outside
Increase tissue endogenous retinal stem cells, new source can be directly provided for stem cell, provide new hand for the research and treatment of disease
Section.
The present invention is also found surprisingly that butyric acid compound can not only activate tissue endogenous retinal stem cells, promotes organizer
Itself reparation and regeneration of official, it is often more important that, butyric acid compound has the function of promoting histoorgan newborn.Structure of the present invention
Bile duct ligation animal model is built, in the model, we carry out dual ligation to extrahepatic bile ducts and therefrom cut, after bile duct is cut
Bile can not flow into enteric cavity along bile duct, and a large amount of cholestasis cause cholestasis and naked eyes can in liver and remaining bile duct
That sees expands bile duct.And after giving butyric acid compound and being intervened, it has been surprisingly found that department pattern do not occur it is swollen
Big bile duct and cholestasis, but newborn lumen by the biliary drainage in liver into enteric cavity, to fundamentally cure
The disease.Therefore meaning of the present invention is not limited to repair or regenerate after simply promoting injuries of tissues and organs, such as promotes hand
Reparation etc. of histoorgan after the growth of organ length or volume increase, damage after art excision, present invention firstly discovers that butyric acid class
Closing object has the function of promoting histoorgan newborn, can promote generation newly and the functional bile duct of tool or other histoorgans
Deng.
The purpose of the present invention is what is be achieved through the following technical solutions:
In a first aspect, the present invention provides a kind of butyric acid compounds to promote the activation of tissue endogenous retinal stem cells, proliferation
With the application in differentiation.
Second aspect, the present invention provides a kind of butyric acid compounds to promote skin scar reparation and hair hyperplasia and again
Application in life.
The third aspect, the present invention provides a kind of butyric acid compounds in preparing tissue endogenous retinal stem cells activator
Using.
Fourth aspect, the present invention provides a kind of butyric acid compounds to prepare skin scar preparation for repairing or promote hair increasing
Application in raw and devulcanization formulation.
Preferably, the butyric acid compound is selected from least one of butyric acid, butyrate, butanoic acid derivative；The fourth
The effective concentration of acid compounds is 5-200mM, effective dose 0.5-20mmol/kg/d.More preferable butyric acid compound
Effective concentration is 50-150mM, effective dose 5-15mmol/kg/d.
Preferably, the butyrate is selected from least one of sodium butyrate, potassium butyrate, calcium butyrate, magnesium butyrate；The butyric acid
It is multiple that derivative is selected from glycerol monobutyralte, butyric acid list double glyceride, ethyl butyrate, methylbutanoic acid, isoamyl butyrate, butyric acid cyclodextrin
Close at least one of object.
Preferably, the tissue endogenous retinal stem cells include Lgr5 or Olfm4 Positive Stem Cells.The tissue endogenous is dry
Cell is present in body tissue's organ, including liver, bile duct, skin, cutaneous appendages, lung, kidney, pancreas islet, heart, blood
Tissue endogenous retinal stem cells in pipe, brain.
5th aspect, the present invention provides a kind of tissue endogenous retinal stem cells activator containing butyric acid compound are described
Effective concentration of the butyric acid compound in activator is 5-200mM.
Preferably, the activator further includes nutritional preparation, excipient substance.
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 includes formula milk, cereal milk powder, growth cream；The special medicine purposes
Formula food includes respiratory disease nutritional formulas, nephrosis nutritional formulas, tumors of nutrients formula food, liver and gallbladder disease
Sick nutritional formulas, wound, infection, operation, chemicotherapy and other stress situation nutritional formulas, gastrointestinal tract absorb barrier
Hinder, pancreatitis nutritional formulas；The parenteral nutrition preparation includes fat emulsion injection, All-In-One nutrient solution, intravenous injection
Liquid；The enteral nutrition preparation includes amino acid pattern enteral nutrition preparation, short peptide type enteral nutrition preparation, whole protein type enteral battalion
Support preparation, assembly type enteral nutrition preparation.
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 treats it, rehabilitation and body function maintain etc. to play important nutritional support effect.
Preferably, the excipient substance includes pharmaceutically acceptable carrier or excipient, such as lactose hydrous, crystallite
Cellulose, mannitol, sodium citrate, calcium phosphate, glycine, starch；Disintegrating agent 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..
The preparation method of the tissue endogenous retinal stem cells activator containing butyric acid compound includes: by butyric acid class chemical combination
Object is proportionally added into the nutritional preparation, in excipient substance, is uniformly mixed.
6th aspect, the skin scar preparation for repairing or promote hair hyperplasia that the present invention provides a kind of containing butyric acid compound
And devulcanization formulation, the effective concentration of the butyric acid compound are 5-200mM.
Butyric acid compound of the present invention is as stem cell activator, by promoting stem cell activation to can be used for proliferation
It is repaired after promoting injuries of tissues and organs caused by a variety of causes and regeneration, butyric acid compound and combinations thereof swashs as stem cell
Agent living, plays a significant role in the in vivo and in vitro of stem cell and application.
It should be noted that in the present invention, the butyric acid component includes the compound of butyric acid form of ownership, and the present invention is not
It is only applicable to each butyric acid component above-mentioned, applies also for the compound of other butyric acid forms.The butyric acid includes n-butyric acie and different
Butyric acid.
It should be noted that the administration form of butyric acid is inessential in the present invention, by the substance containing butyric acid such as butyric acid and/or fourth
Hydrochlorate and/or butanoic acid derivative are added to nutritional preparation, excipient substance, preparation for external application to skin, promote in hair proliferant agent, only
Applying effective quantity can be achieved to promote the effect of tissue endogenous retinal stem cells activation and proliferation.
As an alternative solution of formula milk application, butyric acid of the invention, butyrate and butanoic acid derivative be can be used as
Replenishers are applied rather than are integrated into formula milk deli.For example, butyric acid, butyrate and butanoic acid derivative can with pill, tablet,
Capsule, caplet, powder, liquid or gel form intake.For example, butyric acid, butyrate and butanoic acid derivative can be with other nutrition
Replenishers are absorbed as breast milk replenishers combine.
Compared with prior art, the present invention have it is following the utility model has the advantages that
1. present invention firstly discovers that butyric acid compound can promote morbid state undertissue organ endogenous retinal stem cells living
Change, proliferation and differentiation, in histoorgan reparation, regenerate, prevent from playing a significant role in progression of disease.Such as prevent and treat various originals
The injuries of tissues and organs because caused by, progressive fibrosis and canceration, and prevent and treat a variety of diseases.
2. present invention firstly discovers that butyric acid compound is dry by the tissue endogenous in activation skin and cutaneous appendages
Cell has and promotes skin scar reparation and hair hyperplasia and regenerated effect.
3. and the present invention is found surprisingly that, butyric acid compound can not only activate tissue endogenous retinal stem cells, promotion group
Knit itself reparation and regeneration of organ, it is often more important that, butyric acid compound has the function of promoting histoorgan newborn.Therefore
Meaning of the present invention is not limited to repair or regenerate after simply promoting injuries of tissues and organs, as promoted organ after operation excision long
Degree increases or volume increases, reparation of histoorgan etc. after damage, present invention firstly discovers that butyric acid compound has promotion group
The effect of organ new life is knitted, can promote to generate new and has functional bile duct or other organizer official ranks.
4. can directly be dry in addition, expanding tissue endogenous retinal stem cells on a large scale using butyric acid compound inside and outside
Cell provides new source, can be used for vitro disease model construction and in vivo transplanting, mentions for the research and stem-cell therapy of disease
New means are supplied.
5. butyric acid compound is added to specific formula food compared with traditional use pharmaceutical intervention and treatment method
The effect of performance disease preventing and treating that can be more long-acting and lasting in product and nutritional preparation.
Detailed description of the invention
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 BDL animal model liver lgr5 Positive Stem Cells ratio；It is divided into control group, BDL model group, BDL+ butyric acid
Sodium intervention group (50mM), BDL+ sodium butyrate intervention group (100mM), BDL+ sodium butyrate intervention group (150mM), BDL+ sodium butyrate intervention
Group (200mM)；
Fig. 2 is the expressing quantity of BDL animal model liver Olfm4；It is divided into control group, BDL model group, BDL+ sodium butyrate
Intervention group；
Fig. 3 is the growth of BDL animal hair and scar reparation；It is divided into control group, BDL+ sodium butyrate intervention group (100mM), BDL
+ sodium butyrate intervention group (150mM)；
Fig. 4 is the mrna expression amount of CCL4 animal model liver lgr5；Wherein CCL4 is modeling group, and CCL4+ intervention is
CCL4+ sodium butyrate intervention group (100mM)；
Fig. 5 is the expressing quantity of CCL4 animal model liver lgr5；Wherein CCL4 is modeling group, and CCL4+ intervention is
CCL4+ sodium butyrate intervention group (100mM).
Specific embodiment
The present invention is described in detail combined with specific embodiments below.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 scope.
Following embodiment provides a kind of butyric acid compound and is promoting the activation of tissue endogenous retinal stem cells, proliferation and differentiation
In application.
It provides a kind of butyric acid compound and is preparing the application in tissue endogenous retinal stem cells activator.
The butyric acid compound is selected from least one of butyric acid, butyrate, butanoic acid derivative；The butyric acid class chemical combination
The effective concentration of object is 5-200mM, effective dose 0.5-20mmol/kg/d.
The butyrate is selected from least one of sodium butyrate, potassium butyrate, calcium butyrate, magnesium butyrate；The butanoic acid derivative
In glycerol monobutyralte, butyric acid list double glyceride, ethyl butyrate, methylbutanoic acid, isoamyl butyrate, butyric acid cyclodextrin complexes
At least one.
The activator further includes nutritional preparation, excipient substance.
The nutritional preparation is selected from conventional formulation food, special medicine purposes formula food, parenteral nutrition preparation, enteral battalion
Support at least one of preparation.
The conventional formulation food includes formula milk, cereal milk powder, growth cream；The special medicine purposes formula food
Match including respiratory disease nutritional formulas, nephrosis nutritional formulas, tumors of nutrients formula food, disease in the liver and gallbladder nutrition
Square food, wound, infection, operation, chemicotherapy and other stress situation nutritional formulas, gastrointestinal tract malabsorption, pancreatitis
Nutritional formulas；The parenteral nutrition preparation includes fat emulsion injection, All-In-One nutrient solution, intravenous fluid；The intestines
Interior nutritional preparation includes amino acid pattern enteral nutrition preparation, short peptide type enteral nutrition preparation, whole protein type enteral nutrition preparation, group
Part type enteral nutrition preparation.
The excipient substance includes pharmaceutically acceptable carrier or excipient, for example, lactose hydrous, microcrystalline cellulose,
Mannitol, sodium citrate, calcium phosphate, glycine, starch；Disintegrating agent such as crospovidone, copolyvidone, starch glycolate NF
Sodium, croscarmellose sodium and specific composition silicate；Binder such as polyvinylpyrrolidone, hydroxypropyl methyl are fine
Tie up element (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and Arabic gum etc..
Embodiment 1
A kind of tissue endogenous retinal stem cells activator and preparation method thereof containing butyric acid compound is present embodiments provided,
The method are as follows: food-grade or injection stage sodium butyrate are added in nutritional preparation, be uniformly mixed to get.The nutrition of the preparation
The concentration of sodium butyrate is 5mM in preparation.
Embodiment 2
Present embodiments provide a kind of stem cell activator and preparation method thereof containing butyric acid compound, the method
Are as follows: food-grade or injection stage sodium butyrate are added in nutritional preparation, be uniformly mixed to get.Fourth in the nutritional preparation of the preparation
The concentration of sour sodium is 50mM.
Embodiment 3
Present embodiments provide a kind of stem cell activator and preparation method thereof containing butyric acid compound, the method
Are as follows: food-grade or injection stage sodium butyrate are added in nutritional preparation, be uniformly mixed to get.Fourth in the nutritional preparation of the preparation
The concentration of sour sodium is 100mM.
Embodiment 4
Present embodiments provide a kind of stem cell activator and preparation method thereof containing butyric acid compound, the method
Are as follows: food-grade or injection stage sodium butyrate are added in nutritional preparation, be uniformly mixed to get.Fourth in the nutritional preparation of the preparation
The concentration of sour sodium is 200mM.
Embodiment 5
It present embodiments provides a kind of skin scar preparation for repairing containing butyric acid compound or promotees hair hyperplasia and regeneration
Preparation and preparation method thereof, the method are as follows: food-grade or injection stage sodium butyrate are added in external preparation, are uniformly mixed, i.e.,
?.The concentration of sodium butyrate is 100mM in the preparation of the preparation.
Embodiment 6
It present embodiments provides a kind of skin scar preparation for repairing containing butyric acid compound or promotees hair hyperplasia and regeneration
Preparation and preparation method thereof, the method are as follows: food-grade or injection stage sodium butyrate are added in external preparation, are uniformly mixed, i.e.,
?.The concentration of sodium butyrate is 200mM in the preparation of the preparation.
Embodiment 7
Present embodiments provide a kind of stem cell activator and preparation method thereof containing butyric acid compound, the method
Are as follows: food-grade or injection stage sodium butyrate are added in excipient substance, be uniformly mixed to get.Sodium butyrate in the drug of the preparation
Effective concentration be 50mM, effective dose 5mmol/kg/d.
Embodiment 8
Present embodiments provide a kind of stem cell activator and preparation method thereof containing butyric acid compound, the method
Are as follows: food-grade or injection stage sodium butyrate are added in excipient substance, be uniformly mixed to get.Sodium butyrate in the drug of the preparation
Effective concentration be 100mM, effective dose 10mmol/kg/d.
Embodiment 9
Present embodiments provide a kind of stem cell activator and preparation method thereof containing butyric acid compound, the method
Are as follows: food-grade or injection stage glycerol monobutyralte are added in excipient substance, be uniformly mixed to get.Fourth in the drug of the preparation
The effective concentration of sour sodium is 200mM, effective dose 20mmol/kg/d.
The stem cell activator that above embodiments are prepared can effectively activate tissue endogenous retinal stem cells, promote organizer
Itself reparation and regeneration of official, and can promote skin scar reparation, hair hyperplasia and regeneration.
Animal experiment compliance test result:
1. the effect using extrahepatic bile ducts ligation model verifying butyric acid compound to tissue endogenous retinal stem cells
1.1 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 animal Co., Ltd.It is raised in Xinhua Hospital Attached to Medical School, Shanghai Jiaotong Univ.'s animal experimental center.
1.2 processing method
NC control group: the rat fed using water and normal diet.14th day overnight fasting takes blood to survey blood biochemistry.Take liver
Dirty and intestinal tissue is used for subsequent experimental.
Bile duct ligation (BDL) model group (modeling group): rat is fed using water and normal diet, operation consent carries out rat
Anesthesia and preserved skin carry out dual ligation to Extrahepatic Bile Duct In Rats and cut from centre；Without being administered, the 14th day overnight fasting,
Blood is taken to survey blood biochemistry.Liver and intestinal tissue are taken, subsequent experimental is used for.
BDL+ sodium butyrate intervention group 1 (2mM): sodium butyrate being added to the water and feeds rat, and butyric acid na concn is 2mM, administration
Amount is 0.2mmol/kg/d.Operation consent carries out anesthesia and preserved skin to rat, to the dual ligation of Extrahepatic Bile Duct In Rats progress and therefrom
Between cut.Postoperative 14th day overnight fasting takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, subsequent experimental is used for.
BDL+ sodium butyrate intervention group 2 (5mM): sodium butyrate being added to the water and feeds rat, and butyric acid na concn is 5mM, administration
Amount is 0.5mmol/kg/d.Operation consent carries out anesthesia and preserved skin to rat, to the dual ligation of Extrahepatic Bile Duct In Rats progress and therefrom
Between cut.Postoperative 14th day overnight fasting takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, subsequent experimental is used for.
BDL+ sodium butyrate intervention group 3 (50mM): sodium butyrate being added to the water and feeds rat, and butyric acid na concn is 50mM, is given
Dose is 5mmol/kg/d.Operation consent carries out anesthesia and preserved skin to rat, to the dual ligation of Extrahepatic Bile Duct In Rats progress and therefrom
Between cut.Postoperative 14th day overnight fasting takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, subsequent experimental is used for.
BDL+ sodium butyrate intervention group 4 (100mM): sodium butyrate being added to the water and feeds rat, and butyric acid na concn is 100mM,
Dosage is 10mmol/kg/d.Operation consent carries out anesthesia and preserved skin to rat, to Extrahepatic Bile Duct In Rats carry out dual ligation and from
It cuts centre.Postoperative 14th day overnight fasting takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, subsequent experimental is used for.
BDL+ sodium butyrate intervention group 5 (150mM): sodium butyrate being added to the water and feeds rat, and butyric acid na concn is 150mM,
Dosage is 15mmol/kg/d.Operation consent carries out anesthesia and preserved skin to rat, to Extrahepatic Bile Duct In Rats carry out dual ligation and from
It cuts centre.Postoperative 14th day overnight fasting takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, subsequent experimental is used for.
BDL+ sodium butyrate intervention group 6 (200mM): sodium butyrate being added to the water and feeds rat, and butyric acid na concn is 200mM,
Dosage is 20mmol/kg/d.Operation consent carries out anesthesia and preserved skin to rat, to Extrahepatic Bile Duct In Rats carry out dual ligation and from
It cuts centre.Postoperative 14th day overnight fasting takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, subsequent experimental is used for.
BDL+ butyric acid intervention group (100mM): sodium butyrate is added to the water and feeds rat, butyric acid density 100mM, dosage
For 10mmol/kg/d.Operation consent carries out anesthesia and preserved skin to rat, carries out dual ligation to Extrahepatic Bile Duct In Rats and cuts from centre
It is disconnected.Postoperative 14th day overnight fasting takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, subsequent experimental is used for.
BDL+ glycerol monobutyralte intervention group (100mM): glycerol monobutyralte being added to the water and feeds rat, and glycerol monobutyralte is dense
Degree is 100mM, dosage 10mmol/kg/d.Operation consent carries out anesthesia and preserved skin to rat, carries out to Extrahepatic Bile Duct In Rats double
It ligatures and is cut from centre again.Postoperative 14th day overnight fasting takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, for subsequent
Experiment.
1.3 results (as shown in Figs. 1-3)
NC control group: liver endogenous retinal stem cells expression quantity is low, FCM analysis liver organization endogenous as the result is shown
Stem cell-lgr5 Positive Stem Cells ratio is only 0.3% or so；Western blot testing result shows liver organization endogenous
The expression quantity of stem cell markers Olfm4 is low；Control group preserved skin area skin tissue endogenous retinal stem cells expression quantity is low, rarely seen few
New piliation is measured, skin scar is obvious.
Bile duct ligation (BDL) model group: liver endogenous retinal stem cells expression quantity slightly increases compared with the control group, with bright
Aobvious hepatic disease；Liver lgr5 Positive Stem Cells ratio is 0.8% or so to FCM analysis as the result is shown；western
Blot testing result shows that the expressing quantity of liver organization endogenous retinal stem cells marker Olfm4 slightly rises compared with the control group
It is high；Model group preserved skin area skin tissue endogenous retinal stem cells expression quantity is low, rarely seen a small amount of new piliation, and skin scar is obvious.
BDL+ sodium butyrate intervention group 1 (2mM): compared with modeling group, hepatic disease has no substantially reduced；FCM analysis
Liver lgr5 Positive Stem Cells ratio is 0.8% or so as the result is shown；Western blot testing result is shown in liver organization
The expressing quantity of derived stem cells marker Olfm4 has no significantly raised compared with modeling group；In preserved skin area skin tissue
Derived stem cells expression quantity is lower, rarely seen a small amount of new piliation, and skin scar is obvious.
BDL+ sodium butyrate intervention group 2 (5mM): compared with modeling group, hepatic disease slightly mitigates, and liver organization endogenous is dry thin
Cellular expression amount is slightly above control group and modeling group；Liver lgr5 Positive Stem Cells ratio is FCM analysis as the result is shown
1.0% or so；Western blot testing result shows the expressing quantity of liver organization endogenous retinal stem cells marker Olfm4
It is slightly increased compared with control group and modeling group；Preserved skin area skin tissue endogenous retinal stem cells expression quantity slightly increases, hair
It does not cover with, skin scar is more apparent.
BDL+ sodium butyrate intervention group 3 (50mM): compared with modeling group, hepatic disease significantly mitigates, liver organization endogenous
Stem cell expression quantity is apparently higher than control group and modeling group；FCM analysis liver lgr5 Positive Stem Cells ratio as the result is shown
It is 1.8% or so；Western blot testing result shows the protein expression of liver organization endogenous retinal stem cells marker Olfm4
Amount is significantly raised compared with control group and modeling group；Preserved skin area skin tissue endogenous retinal stem cells expression quantity is significantly raised, hair
Hair covers with substantially, and skin scar healing is preferable.
BDL+ sodium butyrate intervention group 4 (100mM): compared with modeling group, hepatic disease significantly mitigates, liver organization endogenous
Stem cell expression quantity is significantly higher than control group and modeling group；FCM analysis liver lgr5 Positive Stem Cells ratio as the result is shown
Reach 2.3% or so；Western blot testing result shows the albumen table of liver organization endogenous retinal stem cells marker Olfm4
It is increased up to amount is significant compared with control group and modeling group；Preserved skin area skin tissue endogenous retinal stem cells expression quantity significantly increases,
Hair covers with completely, and skin scar heals.
BDL+ sodium butyrate intervention group 5 (150mM): compared with modeling group, hepatic disease significantly mitigates, liver organization endogenous
Stem cell expression quantity is significantly higher than control group and modeling group；FCM analysis liver lgr5 Positive Stem Cells ratio as the result is shown
Reach 2.7% or so；Western blot testing result shows the albumen table of liver organization endogenous retinal stem cells marker Olfm4
It is increased up to amount is significant compared with control group and modeling group；Preserved skin area skin tissue endogenous retinal stem cells expression quantity significantly increases,
Hair covers with completely, and skin scar heals.
BDL+ sodium butyrate intervention group 6 (200mM): compared with modeling group, hepatic disease significantly mitigates, liver organization endogenous
Stem cell expression quantity is significantly higher than control group and modeling group；FCM analysis liver lgr5 Positive Stem Cells ratio as the result is shown
Reach 2.7% or so；Western blot testing result shows the albumen table of liver organization endogenous retinal stem cells marker Olfm4
It is increased up to amount is significant compared with control group and modeling group；Preserved skin area skin tissue endogenous retinal stem cells expression quantity significantly increases,
Hair covers with completely, and skin scar heals.
BDL+ butyric acid intervention group (100mM): compared with modeling group, hepatic disease significantly mitigates, liver endogenous retinal stem cells
Expression quantity is significantly higher than control group and modeling group；Liver lgr5 Positive Stem Cells ratio is FCM analysis as the result is shown
2.1% or so；Western blot testing result shows the expressing quantity of liver organization endogenous retinal stem cells marker Olfm4
It is significant compared with control group and modeling group to increase；Preserved skin area skin tissue endogenous retinal stem cells expression quantity significantly increases, hair
It covers with substantially, scar healing is preferable.
BDL+ glycerol monobutyralte intervention group (100mM): compared with modeling group, hepatic disease significantly mitigates, liver endogenous
Stem cell expression quantity is significantly higher than control group and modeling group；FCM analysis liver lgr5 Positive Stem Cells ratio as the result is shown
It is 2.5% or so；Western blot testing result shows the protein expression of liver organization endogenous retinal stem cells marker Olfm4
Amount is significant compared with control group and modeling group to be increased；Preserved skin area skin tissue endogenous retinal stem cells expression quantity significantly increases, hair
Hair covers with completely, and scar heals.
Therefore, give butyric acid compound to be intervened, significantly promote tissue endogenous retinal stem cells activation, proliferation with
Differentiation, to repair after the damage of histoorgan and be played an important role in regenerative process.Have simultaneously and promotes skin scar
Trace healing and reparation, hair hyperplasia and regenerated effect.
Also, the present invention is found surprisingly that, after we carry out dual ligation to extrahepatic bile ducts and therefrom cut, bile can not
Enteric cavity is flowed into along bile duct, a large amount of cholestasis cause cholestasis and macroscopic expand in liver and remaining bile duct
Bile duct.And in butyric acid compound intervention group, it has been surprisingly found that there is not the bile duct expanded and bile in department pattern
Siltation, but newborn bile duct by the biliary drainage in liver into enteric cavity, to fundamentally cure the disease.Wherein,
There is the phenomenon (0/20,0%) without an example in BDL group (20), and butyric acid compound intervention group (25) occurs 3 (3/
25,12%).Therefore meaning of the present invention is not limited to repair or regenerate after simply promoting injuries of tissues and organs, such as promotes hand
Reparation etc. of histoorgan after the growth of organ length or volume increase, damage after art excision, present invention firstly discovers that butyric acid class
Closing object has the function of promoting histoorgan newborn, as can promoting to generate the new and functional bile duct of tool or other histoorgans
Deng.
2. the effect using CCL4 animal model verifying butyric acid compound to tissue endogenous retinal stem cells
2.1 experimental animal
6 week old C57 mouse of cleaning grade, male and female are unlimited, weight about 18g, limited purchased from the western Poole-Bi Kai experimental animal in Shanghai
Company.It is raised in Xinhua Hospital Attached to Medical School, Shanghai Jiaotong Univ.'s animal experimental center.
2.2 processing method
CCL4 model group: feeding mouse using water and normal diet, gives CCL4 (2ml/kg)+olive oil intraperitoneal injection and makes
Mould continues two weeks twice a week.It takes blood to survey blood biochemistry after two weeks, takes liver and intestinal tissue, be used for subsequent experimental.
CCL4 modeling+sodium butyrate intervention group (100mM): sodium butyrate being added to the water and feeds mouse, and butyric acid na concn is
100mM, dosage 10mmol/kg/d.Give CCL4 (2ml/kg)+olive oil intraperitoneal injection modeling and continues two twice a week
Week.It takes blood to survey blood biochemistry after two weeks, takes liver and intestinal tissue, be used for subsequent experimental.
2.3 result
CCL4 model group (as shown in Figure 4,5): the horizontal significant raising such as animal blood serum ALT, AST, hepatic disease are obvious；Liver
Dirty tissue endogenous retinal stem cells-lgr5 Positive Stem Cells expression is lower, and the mRNA average value of lgr5 is about 1.5；western
Blot testing result shows that the expressing quantity of liver lgr5 is lower；
CCL4+ sodium butyrate intervention group (100mM) (as shown in Figure 4,5): items are significantly reduced compared with CCL4 model group
Hepar damnification index, hepatic disease are unobvious；Compared with CCL4 model group, liver organization lgr5 Positive Stem Cells expression quantity is significant
Higher than CCL4 model group, the mRNA average value of lgr5 reaches 4.5；Western blot testing result shows the albumen of liver lgr5
Expression quantity is significant compared with modeling group to be increased.
Therefore, give sodium butyrate to be intervened, significantly promote activation, proliferation and the differentiation of tissue endogenous retinal stem cells,
Hepatic injury caused by CCL4 has been prevented and treated to very effective.
3. further verifying effect of the butyric acid compound to tissue endogenous retinal stem cells using hypoxic-ischemic animal model
3.1 experimental animal
Cleaning grade new life Sprague-Dawley (SD) rat is born the 1st day, and male and female are unlimited, weight about 5-6g, purchased from upper
Western Poole-Bi Kai experimental animal the Co., Ltd in sea.It is raised in Xinhua Hospital Attached to Medical School, Shanghai Jiaotong Univ.'s animal experimental center
It supports.
3.2 processing method
NC control group: normal newborn rat；
Hypoxic-ischemic modeling group: neonate rat uses anoxic and cold stimulation twice daily, continues three days；
NEC modeling+sodium butyrate intervention group (100mM): sodium butyrate is added in laboratory milk and feeds neonate rat, sodium butyrate is dense
Degree is 100mM, dosage 10mmol/kg/d, and uses anoxic and cold stimulation twice daily, continues three days；
After establishing model, the feed of close observation neonate rat, defecation, abdomen situation and activity reaction etc..The 4th after modeling
It (96 hours) execution neonate rats observe the general form of rat intestinal tube, collect intestinal tube and blood preparation.
3.3 result
Control group: rat defecation is normal, and in order, body is ruddy, no abdominal distension hematochezia for activity；Intestinal tissue endogenous is dry
The mRNA and protein expression level of cell sign object lgr5 is lower；
Hypoxic-ischemic modeling group: rat gradually appears different degrees of abdominal distension, reduces into milk amount, reacts slow after modeling
Blunt, mobility decline, body cyanosis, and row's kermesinus is just；The mRNA of intestinal tissue endogenous retinal stem cells marker lgr5 and
Expressing quantity has no significant change compared with the control group；
Hypoxic-ischemic modeling+sodium butyrate (100mM) intervention group: rat defecation is normal, and in order, body is ruddy for activity,
Without abdominal distension hematochezia；Compared with modeling group, the mRNA and expressing quantity of intestinal tissue endogenous retinal stem cells marker lgr5 is significant
It increases.
In conclusion the present invention has investigated butyric acid compound to tissue endogenous retinal stem cells using three kinds of animal models
Effect.The results show that butyric acid compound can promote activation, proliferation and the differentiation of tissue endogenous retinal stem cells, it was demonstrated that butyric acid class
Compound can be used as tissue endogenous retinal stem cells activator.It is each to promote with proliferation by promoting the activation of tissue endogenous retinal stem cells
It repairs and regenerates after injuries of tissues and organs caused by kind reason, so as to effectively prevent the damage of histoorgan caused by a variety of causes
Wound, progressive fibrosis, the hardening of tissue, canceration and a variety of diseases.Meanwhile butyric acid compound is attached by activation skin and skin
Belong to the tissue endogenous retinal stem cells of device, has and promote skin scar reparation and hair hyperplasia and regenerated effect.In addition, using fourth
Acid compounds inside and outside expands tissue endogenous retinal stem cells on a large scale, and new source can be directly provided for stem cell, can be used
In vitro disease model construction and transplanting in vivo, new means are provided for the research and treatment of disease.Also, the present invention is for the first time
It was found that butyric acid compound has the function of promoting histoorgan new life, therefore meaning of the present invention is not limited to simply promote
Reparation or regeneration such as promote the growth of organ length or volume increase after operation excision after injuries of tissues and organs, but can promote machine
Body generates new and has functional bile duct or other histoorgans.
Butyric acid is to be present in one of mammal milk short chain fatty acids, and from the point of view of the result of animal experiment, fourth
Acid compounds are administered in the concentration range, do not cause any damage and side effect to experimental animal, illustrate its drug safety
Property is higher.Butyric acid compound and combinations thereof will have very big application prospect.
Specific embodiments of the present invention are described above.It is to be appreciated that the invention is not limited to above-mentioned
Particular implementation, those skilled in the art can make a variety of changes or modify within the scope of the claims, this not shadow
Ring substantive content of the invention.In the absence of conflict, the feature in embodiments herein and embodiment can any phase
Mutually combination.
Claims (11)
1. a kind of butyric acid compound is promoting the application in the activation of tissue endogenous retinal stem cells, proliferation and differentiation.
2. a kind of butyric acid compound is promoting the application in skin scar reparation and hair hyperplasia and regeneration.
3. a kind of butyric acid compound is preparing the application in tissue endogenous retinal stem cells activator.
4. a kind of butyric acid compound is preparing skin scar preparation for repairing or is promoting the application in hair hyperplasia and devulcanization formulation.
5. application according to claim 1-4, which is characterized in that the butyric acid compound is selected from butyric acid, fourth
At least one of hydrochlorate, butanoic acid derivative；The effective concentration of the butyric acid compound is 5-200mM, and effective dose is
0.5-20mmol/kg/d。
6. application according to claim 5, which is characterized in that the butyric acid compound is selected from butyric acid, sodium butyrate, butyric acid
Potassium, calcium butyrate, magnesium butyrate, glycerol monobutyralte, butyric acid list double glyceride, ethyl butyrate, methylbutanoic acid, isoamyl butyrate, butyric acid
At least one of cyclodextrin complexes.
7. a kind of tissue endogenous retinal stem cells activator containing butyric acid compound, which is characterized in that the butyric acid compound
Effective concentration in activator is 5-200mM.
8. the tissue endogenous retinal stem cells activator according to claim 7 containing butyric acid compound, which is characterized in that institute
Stating activator further includes at least one of nutritional preparation, excipient substance.
9. the tissue endogenous retinal stem cells activator according to claim 7 containing butyric acid compound, which is characterized in that institute
Nutritional preparation is stated in conventional formulation food, special medicine purposes formula food, parenteral nutrition preparation, enteral nutrition preparation
It is at least one.
10. the tissue endogenous cell activator according to claim 8 containing butyric acid compound, which is characterized in that institute
Stating conventional formulation food includes formula milk, cereal milk powder, growth cream；The special medicine purposes formula food includes breathing system
System disease nutritional formulas, nephrosis nutritional formulas, tumors of nutrients formula food, disease in the liver and gallbladder nutritional formulas, wound
Wound, infection, operation, chemicotherapy and other stress situation nutritional formulas, gastrointestinal tract malabsorption, pancreatitis nutrient formulation food
Product；The parenteral nutrition preparation includes fat emulsion injection, All-In-One nutrient solution, intravenous fluid；The enteral nutrition preparation
Including amino acid pattern enteral nutrition preparation, short peptide type enteral nutrition preparation, whole protein type enteral nutrition preparation, assembly type enteral battalion
Support preparation.
11. a kind of skin scar preparation for repairing or rush hair hyperplasia and devulcanization formulation containing butyric acid compound, which is characterized in that
The effective concentration of the butyric acid compound is 5-200mM.
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| PCT/CN2018/084670 WO2019169712A1 (en) | 2018-03-09 | 2018-04-26 | Application of butyric acid compound in promoting tissue endogenous stem cell activation, proliferation and differentiation |
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| CN115960830A (en) * | 2022-12-01 | 2023-04-14 | 中国人民解放军军事科学院军事医学研究院 | Application of sodium butyrate in promotion of neural stem cell proliferation |
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