CN106937951B - Application of butylene phthalide - Google Patents
Application of butylene phthalide Download PDFInfo
- Publication number
- CN106937951B CN106937951B CN201610015213.0A CN201610015213A CN106937951B CN 106937951 B CN106937951 B CN 106937951B CN 201610015213 A CN201610015213 A CN 201610015213A CN 106937951 B CN106937951 B CN 106937951B
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- medicament
- oral
- cell
- butylidenephthalide
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- -1 butylene phthalide Chemical compound 0.000 title description 13
- WNZQDUSMALZDQF-UHFFFAOYSA-N isobenzofuranone Natural products C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 46
- 206010016654 Fibrosis Diseases 0.000 claims abstract description 37
- 230000004761 fibrosis Effects 0.000 claims abstract description 37
- 210000004876 tela submucosa Anatomy 0.000 claims abstract description 22
- 238000002347 injection Methods 0.000 claims abstract description 19
- 239000007924 injection Substances 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000000865 liniment Substances 0.000 claims abstract description 7
- 229940040145 liniment Drugs 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- WMBOCUXXNSOQHM-FLIBITNWSA-N (Z)-3-butylidenephthalide Chemical group C1=CC=C2C(=C/CCC)/OC(=O)C2=C1 WMBOCUXXNSOQHM-FLIBITNWSA-N 0.000 claims description 101
- WMBOCUXXNSOQHM-UHFFFAOYSA-N n-butylidenephthalide Natural products C1=CC=C2C(=CCCC)OC(=O)C2=C1 WMBOCUXXNSOQHM-UHFFFAOYSA-N 0.000 claims description 101
- 210000004027 cell Anatomy 0.000 claims description 50
- 210000002200 mouth mucosa Anatomy 0.000 claims description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- 210000000651 myofibroblast Anatomy 0.000 claims description 21
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- 238000011282 treatment Methods 0.000 claims description 11
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- HJXMNVQARNZTEE-UHFFFAOYSA-N Butylphthalide Chemical compound C1=CC=C2C(CCCC)OC(=O)C2=C1 HJXMNVQARNZTEE-UHFFFAOYSA-N 0.000 description 4
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- URVVFIAUKSGYOG-UHFFFAOYSA-N 4-methylpentan-2-one;propan-2-ol Chemical compound CC(C)O.CC(C)CC(C)=O URVVFIAUKSGYOG-UHFFFAOYSA-N 0.000 description 1
- LULPIEVDHWSKDZ-UHFFFAOYSA-N 5-butylidenecyclohexa-1,3-diene Chemical compound CCCC=C1CC=CC=C1 LULPIEVDHWSKDZ-UHFFFAOYSA-N 0.000 description 1
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Use of an active ingredient in the manufacture of a medicament, wherein the active ingredient is selected from the group consisting of: butylenephthalide (BP), a pharmaceutically acceptable salt thereof, and a combination of the foregoing, wherein the medicament is for preventing and/or treating Oral Submucosa Fibrosis (OSF) and can be used in the form of an injection, a tablet, an oral liquid, or a liniment.
Description
Technical field
The present invention relates to use butylidenephthalide to prevent and/or treat oral submucosa fibrosis disease (oral
Submucous fibrosis, OSF) application.
Background technique
Oral submucosa fibrosis disease is a kind of precancerous lesion (pre-cancerous condition) of carcinoma of mouth, but
Not carcinoma of mouth is characterized mainly in that the inflammatory response and fibrosis phenomenon of oral mucosa undertissue and deep layer connective tissue,
If being treated not in time, it is most likely that further evolve into carcinoma of mouth.
The research of epidemiology points out that chewing betel nut is to cause the most important reason of oral submucosa fibrosis disease, lesion
It is common in buccal mucosa, followed by palatine (Palatal portion) and molar back zone, affected part mucous membrane can bleach first, then instead
It appears again existing ulcer or bubble, last mucous membrane can follow the string, cause patient that can not magnify mouth, seriously affect feed, brush teeth, mouth
The common orals function such as chamber inspection and treatment.If lesion betides the soft palate position between oropharynx, it may cause dysphagia, hang
The vertical atrophy of harmony or deformation.Often there are scorching hot, shouting pain, dry and astringent feeling in patient mouthful, to the foods extreme sensitivity such as pungent, hot, but taste
Feel is decline.
The drug of oral submucosa fibrosis disease can not be effectively prevented and/or treat at present, it is solid to rely on class for usually system
Alcohol injection reduces content of the collagen in mucous membrane of mouth undertissue or cuts off lesion via surgical operation or laser
Tissue.However, Steroid injection can only slow down symptom, oral submucosa fibrosis disease can not be cured, and be often accompanied with the moon
Bright face becomes fat, buffalo hump, osteoporosis, thinning of skin, oedema, is easy infection, whelk, long not high, blood glucose rising, infection
The side effects such as rate increase, Fungi Infection of Oral, chaeta increase, wound healing power is deteriorated.In addition, outside via surgical operation or laser
After section's operation and laser cut off biggish pathological tissues, when wound healing, is easy to shrink and form scar, need to consider dehisce by
The problem of limit and beauty, in this, oral surgeon can consider to remedy in a manner of skin-grafting, but the position made skin graft has screening
Cover the secret worry of early stage recurrence lesion.When being treated with surgical operation or the laser patient too big to old patient or lesion,
Even more to consider the problems of nocuity, patient body resistance and the quality of the life of operation.
In view of it is above-mentioned about oral submucosa fibrosis disease treatment the problem of, at present the world of medicine be still dedicated to exploitation can be pre-
Anti- and/or treatment oral submucosa fibrosis disease drug.It is found after inventor's research, butylidenephthalide can be effectively suppressed
Oral mucosa undertissue cell carries out Epithelial and stromal conversion (epithelial-mesenchymal transition, EMT), suppression
Donsole transmucosal undertissue cell differentiation myofibroblast mother cell (myofibroblasts) and the work for inhibiting myofibroblast
Change, therefore can inhibit the collagen accumulation of oral mucosa undertissue, inhibit the contraction in oral mucosa undertissue cytoplasm, uses
In offer prevention and/or the drug for the treatment of oral submucosa fibrosis disease.
Summary of the invention
A purpose of the invention is to provide a kind of purposes for using an active constituent in one medicament of manufacture, the wherein work
Property ingredient be selected from following group: butylidenephthalide (butylidenephthalide, BP), its pharmaceutically acceptable salt and
Combination above-mentioned, and the medicament is for preventing and/or treating oral submucosa fibrosis disease (oral submucous
Fibrosis, OSF).Preferably, the medicament is an injection, pastille, oral solution or liniment.
It is another object of the present invention to provide a kind of using prevention and/or treats oral submucosa fibrosis disease (oral
Submucous fibrosis, OSF) medical composition, it includes an a effective amount of active constituents and one can pharmaceutically connect
The carrier received, wherein the active constituent is selected from following group: butylidenephthalide (butylidenephthalide, BP), its doctor
Acceptable salt and combination above-mentioned on medicine.Preferably, the medical composition is an injection, pastille, oral solution or liniment.
It is still a further object of the present invention is to provide a kind of prevention and/or treatment oral submucosa fibrosis disease (oral
Submucous fibrosis, OSF) method, it includes in it is in need individual in administer a effective amount of active constituent, wherein
The active constituent is selected from following group: butylidenephthalide (BP), its pharmaceutically acceptable salt or combination above-mentioned.Wherein,
The active constituent can be administered to the individual with the pattern of an injection, pastille, oral solution or liniment.
Detailed technology content and part specific implementation aspect of the invention, will be described in the following contents, for the present invention
Fields have usual skill and feature of the invention are illustrated accordingly.
Detailed description of the invention
Fig. 1 is that the fiber primary of the normal oral buccal mucosa of butylidenephthalide (BP) processing of the display through various concentration is female thin
Born of the same parents (buccal mucosal fibroblasts, BMFs；Including " BMF-1 (that is,) " and " BMF-2 (that is, ■) ") and it is fine
Fibroblast primary (fibrotic buccal the mucosal fibroblasts, fBMFs of the oral cavity buccal mucosa of dimensionization；Packet
Include the curve graph of the relative survival rate (%) of " fBMF-1 (that is, ▲) " and " fBMF-2 (that is, ■) "；
Fig. 2A, 2B are display with real-time and quantification Polymerase Chain Reaction (Quanititative real-time
Polymerase chain reaction, Q-PCR) analysis through various concentration butylidenephthalide (BP) processing fBMF-1 or
The relative performance of Twist, Snail and ZEB1 gene of fBMF-2 measures the bar chart of (multiple), and wherein Fig. 2A is the knot of fBMF-1
Fruit, Fig. 2 B are then the results of fBMF-2；
Fig. 3 A is to show that BMFs and the fBMFs of butylidenephthalide (BP) processing through various concentration are migrated to down from upper layer disc
The photo figure of the situation of layer disk, wherein contaminating purpuric part is cell；
Fig. 3 B is to show BMFs (including BMF-1 (blue strip) and BMF-2 (red strip)) and through various concentration
Butylidenephthalide (BP) processing fBMFs (including fBMF-1 (blue strip) and fBMF-2 (red strip)) it is opposite
Migrate the bar chart of ability (%)；
Fig. 4 A, 4B are display with butylidene benzene of real-time and quantification Polymerase Chain Reaction (Q-PCR) analysis through various concentration
α-the SMA of the fBMF-1 or fBMF-2 of phthalein (BP) processing, the relative performance of Col1a1 and S100A4 gene measure the strip of (multiple)
Figure, wherein Fig. 4 A is fBMF-1 as a result, Fig. 4 B is then the result of fBMF-2；
Fig. 5 A is to show that BMFs and the fBMFs of butylidenephthalide (BP) processing through various concentration cause colloid to shrink
The photo figure of situation, wherein the range of green the enclosed choosing of dotted line is the colloid；And
Fig. 5 B is display colloid via BMFs (including BMF-1 (blue strip) and BMF-2 (red strip)) and warp
(including (red is long by fBMF-1 (blue strip) and fBMF-2 by the fBMFs of butylidenephthalide (BP) processing of various concentration
Item)) induction shrink after relative colloid area (%) bar chart.
Specific embodiment
Aspect is embodied in part according to the present invention explained below；But under without departing substantially from spirit of that invention, this hair
Bright still aspect in many different forms is practiced, and the scope of the present invention should not be interpreted as being limited to specification and be stated
Person.In addition, unless in addition Wen Zhongyou illustrates, in this manual (especially in aftermentioned patent claim) used in "
One ", "the" and similar term are interpreted as comprising odd number and plural form.In addition, " about " as used in this specification, " about "
Or the words such as " intimate ", it substantially represents and differs the person within 20% with the numerical value, the person preferably within 10%, and more preferably exist
Person within 5%.
In this manual, so-called " prevention (prevention, prevent, preventing, preventive and
Prophylaxix) ", refer to before disease or illness morbidity, so that it is fallen ill or is deteriorated and be able to avoid, minimize or become
Obtain difficult ability；So-called " treatment " refers to including elimination, removal, reverse, mitigation, improvement or one disease of control or illness；
So-called " effective quantity " or " therapeutically effective amount " when referring to administering to individual, effectively can at least partly improve the state of an illness for suspecting individual
Compound amount；So-called " individual " refers to that mammal, mammal can be the mankind or non-human animal.
Confirm that during oral submucosa fibrosis, the histocyte under oral mucosa will do it epithelium through research
Interstitial converts (epithelial-mesenchymal transition, EMT), and breaks up as myofibroblast
(myofibroblasts).Wherein, when cell carries out Epithelial and stromal conversion (EMT), Twist, Snail in cell and
The genes such as ZEB1 can be showed highly, while the polarity between cell and cell can be lost gradually, and the ability that migrates of cell increases
And be easy to creep and invade, participate in tissue fibrosis.Myofibroblast is a kind of to show α-SMA, Col1a1 and S100A4
Etc. marker gene and have the cell of high mobility, after activation can hypersecretion extracellular matrix (extracellular
Matrix, ECM), such as fibre web albumen (Fibronectin), collagen (Collagen), and in induced tissue cytoplasm
Contraction, thus promote tissue fibrosis.Also verified, excessive extracellular matrix accumulation also with oral submucosa fibrosis disease
Occur closely related.It is aforementioned to can be found in for example: The role of epithelial-mesenchymal transition in
oral squamous cell carcinoma and oral submucous fibrosis.Clin Chim Acta.Aug；
383(1-2):51-56(2007)、Oral submucous fibrosis:An update on etiology and
pathogenesis-A review.Rama Univ J Dent Sci.Mar；2(1):24-33(2015),Oral
submucous fibrosis:Review on aetiology and pathogenesis.Oral Oncol.Jul；42(6):
561-568 (2006) and Molecular pathogenesis of oral submucous fibrosis-a
collagen metabolic disorder.J Oral Pathol Med.Jul；34 (6): 321-328 (2005), the equal texts
The full text offered is simultaneously for reference in herein.
Due to histiocytic Epithelial and stromal conversion (EMT) and activation and the oral submucosa fibrosis of myofibroblast
It is closely related, it is believed that if oral mucosa undertissue cell can be inhibited to carry out Epithelial and stromal conversion (EMT), inhibit oral mucosa the following group
It knits cell differentiation myofibroblast mother cell and/or inhibits the activation of myofibroblast, that is, it is excessive that extracellular matrix can be effectively suppressed
Accumulation, the contraction for inhibiting histocyte interstitial, and can prevent and/or treat oral submucosa fibrosis disease.It is aforementioned to can be found in
Such as: Betal-drived alkaloid up-regulates keratinocyte alphavbeta6 integrin
expression and promotes oral submucous fibrosis.J Pathol.Feb；223(3):366-377
(2011)、Arecoline-induced myofibroblast transdifferentiation from human buccal
mucosal fibroblasts is mediated by ZEB 1.J Cell Mol Med.Apr；18(4):698-708
(2014) and Elevation of S100A4 expression in buccal mucosal fibroblasts by
arecoline:involvement in the pathogenesis of oral submucous fibrosis.PLoS
One.8 (1): e55122 (2013), the full text of the equal documents is simultaneously for reference in herein.
Inventor is the study found that oral mucosa undertissue cell for fibrosis, if with butylidenephthalide (BP)
It is handled, the cell that can be effectively suppressed in the tissue carries out Epithelial and stromal conversion (EMT), especially can inhibit the cells show
The genes such as Twist, Snail and ZEB1 and inhibit creeping and invading for the cell, therefore can reach and inhibit oral mucosa undertissue
The effect of fibrosis.
Inventor separately has found, with butylidenephthalide (BP) to the oral mucosa undertissue cell of fibrosis at
Reason can be effectively suppressed cell differentiation myofibroblast mother cell in the tissue and inhibit myofibroblast activation, especially can inhibit
The histocyte shows the genes such as α-SMA, Col1a1 and S100A4 and inhibits the contraction of histocyte interstitial, and can reach
Inhibit the effect of oral mucosa undertissue fibrosis.
Therefore, the present invention relates to provide medicament, the medicinal combination of prevention and/or treatment oral submucosa fibrosis disease
Object and method.Wherein, the manufacture of the medicament be using an active constituent, the medical composition include one it is a effective amount of activity at
Divide and a pharmaceutically acceptable carrier, this method include to administer a effective amount of active constituent into individual in need.
Medicament, medical composition and method according to the present invention, the active constituent are selected from following group: butylidenephthalide (BP), its
Pharmaceutically acceptable salt or combination above-mentioned.
In medicament of the invention, medical composition and method, the example of the pharmaceutically acceptable salt includes but unlimited
In: alkaline metal salt, such as sodium salt and sylvite；Alkaline-earth metal salt, such as calcium salt, magnesium salts and barium salt；Transition metal salt, such as zinc
Salt, mantoquita, molysite, cobalt salt, titanium salt, vanadic salts；Aluminium salt；Pink salt；Alkanolamine salt such as diethanolamine salt, ethyl -1 2- amido -2-,
3-propanediol salt and triethanolamine salt；Heterocyclic amine salt such as forint salt (morpholine salts), piperazine salt
(piperazine salts) and piperidinium salt (piperidine salts)；And alkali amine salt for example ammonium salt, spermine hydrochlorate, from
Amino acid salt and histamine hydrochlorate etc..Preferably, the active constituent used in medicament of the invention, medical composition and method
It is butylidenephthalide (BP).
It, should when using medicament or medical composition of the invention to prevent and/or treat oral submucosa fibrosis disease
Medicament or medical composition visually desired types of administration and be in corresponding suitable dosage form.For example, but not limited to this, should
Medicament or medical composition can via in intradermal, muscle, peritonaeum, the dosing ways such as vein, subcutaneous, oral, skin and mucous membrane
And it administers to individual in need.
It is suitable for intradermal, muscle, in peritonaeum, for vein, the dosage form of dosing ways such as subcutaneous, medicament of the invention or doctor
Drug composition can be provided with the pattern of injection, and but not limited to this.For example, the example of the injection be include venoclysis
Liquid, emulsion venoclysis liquid, dry powder injection, suspension injection and dry powder suspension injection, but not limited to this.In addition,
The medicament or medical composition can be prepared into solid before an injection, with the dosage form that dissolves in other solution or suspension or
Emulsifiable dosage form provides solid before the injection, and before administering to this individual in need, solid before the injection is dissolved in
It in other solution or suspension or is emulsified, desired injection is provided.
Be suitable for for the dosage form of oral administration medicine supplying, medicament or medical composition provided by the present invention can such as pastille,
The Solid forms such as pill, capsule, granule, powder or such as oral solution, syrup, spirit (spirit), elixir
(elixir), the liquid pattern such as tincture (tincture) provides, and but not limited to this.
It is suitable for for the dosage form of the dosing ways such as skin, mucous membrane, medicament of the present invention or medical composition can be for example newborn
Liniments, collutory, lotion, spray or the patches such as liquid, creams, gel (hydrogel), paste (dispersion cream, ointment)
The pattern of (patch) provides, and but not limited to this.
Preferably, medicament and medical composition of the invention is mentioned with the pattern of injection, pastille, oral solution or liniment
For.
In the present invention, depending on dosing way and/or types of administration, suitable pharmaceutically acceptable carrier can be selected
To provide medicament of the present invention, in addition, also can include a pharmaceutically acceptable carrier in medical composition of the present invention.Citing speech
It, the example of the pharmaceutically acceptable carrier is including but not limited to solvent (buffer, water, saline solution, glucose
(dextrose), glycerol, ethyl alcohol or its analog and combination above-mentioned), oil-based solvent, diluent, stabilization agent, absorption delay
Agent, disintegrating agent, emulsifier, antioxidant, adhesive, bonding agent, tackifier, solubilizer, dispersing agent, suspending agent, lubricant,
Hygroscopic agent, solid carriers (such as starch and bentonite (bentonite)).
Optionally, drug or medical composition of the invention can be packaged in the medicines such as micro- rouge body, particulate or microcapsules
It in object transportation system, then administers to individual in need, to improve the conveying effect of the active constituent in drug or medical composition
Rate, as long as constituting the ingredient of the delivery system to the active constituent (that is, butylidenephthalide (BP), its is pharmaceutically acceptable
Salt or combination above-mentioned) be intended to benefit be not adversely influenced.
Optionally, the addition of suitable dosage also can be separately contained in medicament provided by the present invention or medical composition
Agent, for example, can be improved the suitable sense of the mouth of the medicament or medical composition when taking and visual experience flavoring agent (such as sucrose),
Toner, colorant etc., and can improve the stability of the medicament or medical composition and the buffer of storage characteristics, preservative agent,
Preservative, antibacterial agent, antifungal agent etc..In addition, the medicament or medical composition can be optionally separately containing one or more other activity
Ingredient (such as steroids), or with the drug combination containing one or more other active components, to further strengthen the medicament
The effect of medical composition or increase pharmaceutical formulation use flexibly and allotment degree, as long as the other active components are to this hair
The be intended to benefit of bright active constituent (that is, butylidenephthalide (BP), its pharmaceutically acceptable salt or combination above-mentioned) does not have
Detrimental effect.
Can once a day, one day repeatedly or the inferior different frequency of a few days one applies medicament provided by the present invention or doctor
Drug composition, age, weight and the healthy condition shape of end view administering individual and it is different.For example, when being applied to one with oral way
When individual is to prevent and/or treat oral submucosa fibrosis disease, in terms of butylidenephthalide (BP), dosage is daily about 5 milli
G/kg weight is to about 500 mg kg of body weights, preferably about 10 mg kg of body weights to about 120 mgs/kg bodies daily
Weight, more preferably daily about 20 mg kg of body weights to about 90 mg kg of body weights, wherein the unit " mg kg of body weight "
Refer to the needed dosage of per kilogram of body weight individual.But for acute patient, dosage is visually actually needed and drinks
Increase, such as increases to several times or decades of times.
In addition, also medicament provided by the present invention or medical composition can be used in combination with following one person, with prevention and/or
Treat oral submucosa fibrosis disease: surgical operation therapy and laser treatment.
In the method for prevention and/or treatment oral submucosa fibrosis disease according to the present invention, the related active constituent
The administering approach of (that is, butylidenephthalide (BP), its pharmaceutically acceptable salt or combination above-mentioned), is applicable in agent at administering form
The application of amount and associated treatment, as the above description.
The present invention is hereby illustrated further with the following example.Wherein the embodiments such as this are merely provided as illustrating, rather than
To limit the scope of the invention.The scope of the present invention is as defined in the claims shown in range.
Embodiment
[preparation embodiment]:
A. the culture of cell
Two groups are derived from fibroblast primary (the buccal mucosal fibroblasts of normal oral buccal mucosa；
Hereinafter referred to as " BMF-1 " and " BMF-2 "；Or be referred to as " BMFs ") and two groups of oral cavity buccal mucosas for being derived from fibrosis just
For fibroblast (fibrotic buccal mucosal fibroblasts；Hereinafter referred to as " fBMF-1 " and " fBMF-
2"；Or it is referred to as " fBMFs "), it carries out the following processing respectively: with every hole 2x 104Cell number be inoculated with (seed) respectively in 24 holes
In disk, and cultivate to 8 points full (that is, reaching 80%confluence), then respectively with various concentration (0,12.5,25,50,100,
Or 200 mcg/mls) butylidenephthalide (BP) handled, last 48 hours.
B. the extraction of cell total rna (Total RNA)
After so that group of cells provided by [preparation embodiment] A is suspended with trypsase (trypsin), carry out respectively following
Step: (i) centrifugation (1000rpm, 5 minutes) removes supernatant afterwards；(ii) 1 milliliter of TRIzol reagent is added (to be purchased from
Invitrogen Life Technologies company), after mixing, it is placed in and stands 5 minutes at room temperature；(iii) 100 are added
Microlitre BCP (bromochloropropane) and rock up and down and be mixed evenly it, then be placed in and stand 5 minutes at room temperature；
(iv) supernatant liquid is moved to newly after being centrifuged (Eppendorf centrifuge, F45-30-11 rotor, 4 DEG C, 12000rpm, 15 minutes)
Centrifugation tubule, and in wherein be added isopropyl acetone (isopropanol) be mixed evenly, then be placed at room temperature stand 5 minutes；(v)
Centrifugation (Eppendorf centrifuge, F45-30-11 rotor, 4 DEG C, 12000rpm, 10 minutes) removes supernatant afterwards, then micro- with 500
The 75% alcohol washes Shen Dian risen is in the RNA of tube bottom；(vi) centrifugation (room temperature, 12000rpm, 5 minutes) removes alcohol layer afterwards, and
It is placed in exhausting cabinet and air-dries；And (vii) with 20 microlitres through pyrocarbonic acid diethyl ester (diethyl pyrocarbonate,
DEPC) the water back dissolving RNA precipitate object handled, to measure its light absorption value under 260 nanometer wavelength, and calculates RNA concentration.
Embodiment 1: the cytotoxicity of assessment butylidenephthalide (BP)
[preparation embodiment] group of cells that A is provided is taken, follow the steps below respectively: (i) removes upper in 24 porose discs
500 microlitres of 3- (4,5- dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromide (3- (4,5- is added in clear liquid in each hole
Dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide, abbreviation MTT) buffer is (final dense
Degree is 0.5 mg/ml)；(ii) porose disc is placed in 37 DEG C, 5%CO2Incubator in act on, last 3 hours；(iii)
After removing supernatant, respectively at the isopropanol of 1000 microlitres of addition in each hole, and porose disc is placed on oscillator (shaker)
It rocks, lasts 10 minutes；And (iv) Cong Gekong takes 200 microlitres of mixed solution into 96 porose discs, with spectrophotometric determination
Its light absorption value under 570 nanometer wavelength, and it is converted into the relative survival rate (%) of group of cells, as a result it is shown in Fig. 1.
As shown in Figure 1, concentration is added in culture solution is 50 mcg/mls butylidenephthalide below (BP), to normal
The growth of the fibroblast primary (fBMFs) of the fibroblast primary (BMFs) and fibrosis cheek mucous membrane of cheek mucous membrane is neither
Can have an impact.Therefore, subsequent experiment is carried out with the butylidenephthalide (BP) that concentration is 0 to 50 mcg/ml.
Embodiment 2: analysis butylidenephthalide (BP) carries out Epithelial and stromal conversion in inhibition oral mucosa undertissue cell
The benefit of (epithelial-mesenchymal transition, EMT)
A. the performance amount of the marker gene of Epithelial and stromal conversion (EMT)
Known cell is during carrying out Epithelial and stromal conversion (EMT), the isogenic table of Twist, Snail and ZEB1
Now amount will increase, therefore the grade genes are considered as the marker gene of Epithelial and stromal conversion (EMT).This experiment is poly- by real-time and quantification
Synthase chain reaction (Quanititative real-time polymerase chain reaction, Q-PCR) is inquired into sub-
Whether butylphthalide (BP) will affect performance of the genes such as Twist, Snail and ZEB1 in the buccal mucosa histocyte of oral cavity.
Firstly, taking total serum IgE (each group takes 1 microgram) provided by [preparation embodiment] B, reverse transcription is carried out, to provide
Complementary nuclifort (cDNA).Then, with gene quantification system (PRISM ABI7700Sequence Detecting
System, be purchased from U.S. Applied Biosystems company) collocation specific gene introduction it is (as shown in table 1 below) carry out immediately
Quantitative poly chain reaction (Q-PCR), with analyze the genes such as Twist, Snail and ZEB1 through various concentration (0,25 or
50 mcg/mls) butylidenephthalide (BP) processing fBMFs (including fBMF-1, fBMF-2) in performance.Finally, with not
On the basis of the result of the cell handled through butylidenephthalide (BP), the Relative gene performance amount (multiple) of each group is calculated, is as a result shown
In Fig. 2.
Table 1
By the result of Fig. 2 it is found that the isogenic performance of whether fBMF-1 or fBMF-2, Twist, Snail and ZEB1 all
Obviously decline as the concentration of butylidenephthalide (BP) improves.Aforementioned result shows that butylidenephthalide (BP) can be effectively suppressed
Oral mucosa undertissue cell carries out Epithelial and stromal conversion (EMT), therefore can be used for preventing and/or treating oral mucosa undertissue
Fibrosis.
B. creep ability and the invasive ability of oral mucosa undertissue cell
This research further with penetration cell migration pilot system (System is purchased from Britain
Corning company) collocation pore size be 8 microns polycarbonate leaching film (polycarbonate membrane, be purchased from Britain
Corning company), inquire into whether butylidenephthalide (BP) can inhibit creep ability and the invasion energy of oral mucosa undertissue cell
Power.
Firstly, the culture solution for containing 10%FBS (fetal calf serum) is added in lower layer's disk (lower chamber), and should
Polycarbonate leaching film device is placed in the bottom of a cell culture, referred to herein as upper layer disc (upper chamber).On the other hand,
BMF-1, BMF-2, fBMF-1, fBMF-2 cell in [preparation embodiment] A is taken (respectively to take 2 × 104A cell), respectively with contain
0, it the butylidenephthalide (BP) of 25 or 50 mcg/mls but is uniformly mixed, then will mix without (250 microlitres) of culture solution of serum
It closes in solution injection upper layer disc device.Then, which is placed in incubator and is cultivated, lured into
Cell migration lasts 24 hours.The penetration cell migration pilot system is taken out, will not migrate to lower layer from upper layer disc film surface
After the cell of disk film surface removes, which is fixed with 4% polyformaldehyde (paraformaldehyde),
And it is dyed with 0.1% crystal violet (crystal violet).Load is placed in finally, the polycarbonate leaching film is carefully cut
On slide, (each group all observes 5 different visuals field), record of taking pictures are observed with 100 times of enlargement ratio under microscope, and
On the basis of the result of the BMFs handled without butylidenephthalide (BP), the cell number on the film is converted into cell
It is opposite to migrate ability (%).Previous experiments are to carry out three to repeat, and the result is that being shown in Fig. 3 A, 3B, wherein be infected with purple in Fig. 3 A
Part be the cell that lower layer's disk is migrated to from upper layer disc, Fig. 3 B be then by this three repeat experiment result it is average obtained from
Cell is opposite to migrate ability (%).
By Fig. 3 A, 3B result it is found that compared to " BMFs group ", " fBMFs group " migrates to the thin of lower layer's disk from upper layer disc
Born of the same parents are obviously more.However, if cell is first to handle through butylidenephthalide (BP), being migrated from upper layer disc in " fBMFs group " group
Cell to lower layer's disk is obviously to reduce as the concentration of butylidenephthalide (BP) improves.Aforementioned result is shown, compared to just
Normal oral mucosa undertissue cell, the oral mucosa undertissue cell of fibrosis have the stronger ability of creeping and invasion energy
Power is easy to carry out Epithelial and stromal conversion (EMT), and climbing for oral mucosa undertissue cell can be effectively suppressed in butylidenephthalide (BP)
Row ability and invasive ability.This carries out Epithelial and stromal that is, oral mucosa undertissue cell can be effectively suppressed in butylidenephthalide (BP)
It converts (EMT), therefore can be used for preventing and/or treating the fibrosis of oral mucosa undertissue.
Embodiment 3: analysis butylidenephthalide (BP) is in inhibition oral mucosa undertissue cell differentiation myofibroblast mother cell
Benefit
It is known that the cell in tissue can break up, be transformed into myofibroblast during fibrosis occurs for tissue, and
The marker gene of α-SMA, Col1a1 and S100A4 isogenic line myofibroblast.Therefore, this experiment is to pass through real-time and quantification
Polymerase Chain Reaction (Q-PCR), inquires into whether butylidenephthalide (BP) can inhibit the genes such as α-SMA, Col1a1 and S100A4
Performance in the cell of fibrosis oral cavity buccal mucosa tissue.
Total serum IgE (each group takes 1 microgram) provided by [preparation embodiment] B is taken, reverse transcription is carried out, to provide complementation
Oxygen ribonucleic acid (cDNA).Then, with gene quantification system (PRISM ABI7700Sequence Detecting System,
Purchased from Applied Biosystems company, the U.S.) collocation specific gene introduction progress real-time and quantification (as shown in table 2 below) gather
Synthase chain reaction (Q-PCR), to analyze the genes such as α-SMA, Col1a1 and S100A4 (0,25 or 50 are micro- through various concentration
Grams per milliliter) butylidenephthalide (BP) processing fBMFs (including fBMF-1, fBMF-2) in performance.Finally, with without Asia
On the basis of the result of the cell of butylphthalide (BP) processing, the Relative gene performance amount (multiple) of each group is calculated, figure is as a result shown in
4。
Table 2
By the result of Fig. 4 it is found that whether fBMF-1 or fBMF-2, α-SMA, Col1a1 and the isogenic table of S100A4
Now all obviously decline as the concentration of butylidenephthalide (BP) improves.Aforementioned result shows that butylidenephthalide (BP) has suppression
The benefit of donsole transmucosal undertissue cell differentiation myofibroblast mother cell, therefore can inhibit the collagen of oral mucosa undertissue
Accumulation, the effectively fibrosis of prevention and/or treatment oral mucosa undertissue.
Embodiment 4: analysis butylidenephthalide (BP) is in the benefit for inhibiting mucous membrane of mouth undertissue cytoplasm contract
BMF-1, BMF-2, fBMF-1, fBMF-2 cell in [preparation embodiment] A are taken, is respectively dissolved in aforementioned cells
0.5 milliliter of concentration is in the collagen solution (be purchased from Sigma-Aldrich) of 2 mg/mls, then will each mixed solution
24 porose discs are moved to, 37 DEG C, 5%CO are placed in2Incubator in act on 2 hours, make collagen colloid condense, glue obtained
Body is referred to as " BMFs group " and " fBMFs group ".Then, the colloid of condensation is detached from culture plate, 0.5 milliliter of addition contains
There is the cell culture fluid of the butylidenephthalide (BP) of various concentration (0,25 or 50 mcg/ml) to be cultivated, lasts 48 hours
Afterwards, it observes the situation of each group colloid contraction, photograph to record, and use image analysing computer software ImageJ (U.S., state-run health research
Institute), on the basis of the colloid area of " the BMFs group " that handles without butylidenephthalide (BP), calculate the relative colloid area of each group
(%).As a result Fig. 5 A, 5B are shown in, wherein Fig. 5 A shows the situation that colloid caused by group of cells is shunk, and Fig. 5 B is display
The relative colloid area (%) of each group.
By Fig. 5 A, 5B it is found that compared to " BMFs group ", the colloid area of " fBMF group " is significantly smaller, this is that is, colloid is obvious
There is the phenomenon that contraction.However, in " fBMFs group ", it, should if the cell in colloid is first to handle through butylidenephthalide (BP)
The phenomenon that colloid is shunk can be obviously improved, and improved degree is increased as the concentration of butylidenephthalide (BP) rises.Before
It states the results show that the activation of myofibroblast can be effectively suppressed in butylidenephthalide (BP), and myofibroblast is inhibited to induce
Histocyte interstitial contract.
From the above experimental results, we know that oral mucosa undertissue cell, which can be effectively suppressed, in butylidenephthalide (BP) carries out epithelium
The work that interstitial converts (EMT), inhibits oral mucosa undertissue cell differentiation myofibroblast mother cell, inhibits myofibroblast
Change, therefore can inhibit the collagen accumulation of oral mucosa undertissue, inhibits the contraction in oral mucosa undertissue cytoplasm.
<110>biotech inc Chang Hong
<120>application of butylidenephthalide
<130>nothing
<160> 12
<170> PatentIn version 3.5
<210> 1
<211> 20
<212> DNA
<213>artificial sequence
<220>
<223>Twist introduction-forward sequence
<400> 1
gggagtccgc agtcttacga 20
<210> 2
<211> 20
<212> DNA
<213>artificial sequence
<220>
<223>Twist introduction-reverse sequence
<400> 2
agaccgagaa ggcgtagctg 20
<210> 3
<211> 20
<212> DNA
<213>artificial sequence
<220>
<223>Snail introduction-forward sequence
<400> 3
gcagctattt cagcctcctg 20
<210> 4
<211> 20
<212> DNA
<213>artificial sequence
<220>
<223>Snail introduction-reverse sequence
<400> 4
gttctgggag acacatcggt 20
<210> 5
<211> 23
<212> DNA
<213>artificial sequence
<220>
<223>ZEB1 introduction-forward sequence
<400> 5
agcagtgaaa gagaagggaa tgc 23
<210> 6
<211> 21
<212> DNA
<213>artificial sequence
<220>
<223>ZEB1 introduction-reverse sequence
<400> 6
ggtcctcttc aggtgcctca g 21
<210> 7
<211> 24
<212> DNA
<213>artificial sequence
<220>
<223>α-SMA introduction-forward sequence
<400> 7
agcacatgga aaagatctgg cacc 24
<210> 8
<211> 20
<212> DNA
<213>artificial sequence
<220>
<223>α-SMA introduction-reverse sequence
<400> 8
ttttctcccg gttggccttg 20
<210> 9
<211> 17
<212> DNA
<213>artificial sequence
<220>
<223>Col1a1 introduction-forward sequence
<400> 9
gggtgaccgt ggtgaga 17
<210> 10
<211> 19
<212> DNA
<213>artificial sequence
<220>
<223>Col1a1 introduction-reverse sequence
<400> 10
ccaggagagc cagaggtcc 19
<210> 11
<211> 18
<212> DNA
<213>artificial sequence
<220>
<223>S100A4 introduction-forward sequence
<400> 11
gagctgccca gcttcttg 18
<210> 12
<211> 20
<212> DNA
<213>artificial sequence
<220>
<223>S100A4 introduction-reverse sequence
<400> 12
tgcaggacag gaagacacag 20
Claims (8)
1. a kind of use an active constituent in the purposes for manufacturing a medicament, wherein the active constituent is butylidenephthalide
(butylidenephthalide, BP), its pharmaceutically acceptable salt or combination above-mentioned, and the medicament be for prevent and/
Or treatment oral submucosa fibrosis disease (oral submucous fibrosis, OSF).
2. purposes as described in claim 1, between wherein the medicament is for inhibiting oral mucosa undertissue cell to carry out epithelium
Matter converts (epithelial-mesenchymal transition, EMT).
3. purposes as claimed in claim 2, wherein the medicament is the ability of creeping for inhibiting oral mucosa undertissue cell
With invasive ability.
4. purposes as described in claim 1, wherein the medicament is for inhibiting oral mucosa undertissue cell differentiation at flesh fibre
Tie up mother cell.
5. purposes as described in claim 1, wherein the medicament is the activation for inhibiting myofibroblast.
6. the purposes as described in any one of claims 1 to 5, wherein the medicament is for inhibiting oral mucosa undertissue cell
The contraction of interstitial.
7. purposes as claimed in claim 6, wherein the medicament is an injection, pastille, oral solution or liniment.
8. the purposes as described in any one of claims 1 to 5, wherein the medicament is an injection, pastille, oral solution or smearing
Agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TW105100148A TWI587858B (en) | 2016-01-05 | 2016-01-05 | Uses of butylidenephthalide |
| TW105100148 | 2016-01-05 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106937951A CN106937951A (en) | 2017-07-11 |
| CN106937951B true CN106937951B (en) | 2019-04-30 |
Family
ID=59469072
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610015213.0A Active CN106937951B (en) | 2016-01-05 | 2016-01-11 | Application of butylene phthalide |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN106937951B (en) |
| TW (1) | TWI587858B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI675678B (en) * | 2018-08-23 | 2019-11-01 | 國為生醫科技股份有限公司 | Use of n-butylidenephthalide in dopaminergic progenitor cell transplantation |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201233392A (en) * | 2011-02-15 | 2012-08-16 | Univ China Medical | Pharmaceutical compositions and extracts for inhibiting blood vessel stenosis and uses of the same |
| CN104042606A (en) * | 2013-03-12 | 2014-09-17 | 国钦生物科技股份有限公司 | Application of phthalide compound |
-
2016
- 2016-01-05 TW TW105100148A patent/TWI587858B/en active
- 2016-01-11 CN CN201610015213.0A patent/CN106937951B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201233392A (en) * | 2011-02-15 | 2012-08-16 | Univ China Medical | Pharmaceutical compositions and extracts for inhibiting blood vessel stenosis and uses of the same |
| CN104042606A (en) * | 2013-03-12 | 2014-09-17 | 国钦生物科技股份有限公司 | Application of phthalide compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106937951A (en) | 2017-07-11 |
| TW201725037A (en) | 2017-07-16 |
| TWI587858B (en) | 2017-06-21 |
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