CN107019690A - The wound healing Dermatologic preparation composition and its manufacture method of the element amino acid of mycetocyte containing class - Google Patents
The wound healing Dermatologic preparation composition and its manufacture method of the element amino acid of mycetocyte containing class Download PDFInfo
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- CN107019690A CN107019690A CN201610262066.7A CN201610262066A CN107019690A CN 107019690 A CN107019690 A CN 107019690A CN 201610262066 A CN201610262066 A CN 201610262066A CN 107019690 A CN107019690 A CN 107019690A
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- amino acid
- mycosporine
- mycetocyte
- preparation composition
- dermatologic preparation
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Abstract
The present invention relates to a kind of wound healing composition containing the plain amino acid of class mycetocyte and its manufacture method, more particularly, it is related to a kind of wound healing composition for containing the plain amino acid of class mycetocyte as active ingredient and its manufacture method.According to the present invention, class mycetocyte element amino acid does not have toxicity not only to Skin Cell, and has excellent effect to the healing of wound, can be efficiently applied to trauma care, skin regeneration or the recovery of skin injury.
Description
Technical field
Contain the plain amino acid (Mycosporine-like amino acid, MAAs) of class mycetocyte the present invention relates to one kind
Wound healing composition and its manufacture method, more particularly, are related to one kind and regard the plain amino acid of class mycetocyte as active ingredient
The wound healing Dermatologic preparation composition and its manufacture method contained.
Background technology
Inevitably by wound in the life of people, thus it is very active to the research of healing wound fast, once
Calculate that whole wound healing agent market in 2012 is up to 12,500,000,000 dollars, boundless (the The Global of marketability within 2008
Market for Advanced Wound Care Products 2008；Espicom Business Intelligence).
The healing of wound is a kind of reaction organized to damage, is a kind of process of organized renewing, it is to include chemotaxis
(chemotaxis), cell differentiation and duplication (differentiation and replication), stromatin (matrix
Protein synthesis, the new life of blood vessel, the reconstruction of wound) etc. complicated biological process (Steed, et al.,
Clin.Plast.Surg.25:397-405,1998).As the initial stage and regulation for coming across such wound-healing process hereafter
One of representational material of process can enumerate growth factor, and they affect the whole process of wound healing strongly, and regulation is thin
Growth, differentiation, metabolism of born of the same parents etc., and the environment on wound periphery is adjusted, therefore apply the exploitation of growth factor for treating wound always
Carried out constantly, especially, for wound, constantly require that exploitation is non-toxic to skin and effectively facilitate the medicine of skin regeneration
Agent.
On the other hand, on the plain amino acid of class mycetocyte, though there is the document (patent document referred on ultraviolet protection function
1), to not how many research of purposes in addition.
Prior art literature
Patent document 1：Republic of Korea's registered patent the 10-0969325th
The content of the invention
The present invention is the following marine industries technological development cause project by marine fishery portion of Republic of Korea " using from sea
Exploitation of anti-aging materials of the plain amino acid of the class mycetocyte of algae and products thereof is changed " subsidy and make.
The inventors of the present invention have confirmed that class mycetocyte element amino acid does not have cytotoxicity not only, and right by research
Wound healing or improvement, skin regeneration, the recovery of skin trauma have excellent effect, and complete the present invention.
Therefore, it is an object of the present invention to provide a kind of by the plain amino acid of the class mycetocyte with excellent wound healing function
The wound healing contained as active ingredient with, skin regeneration with or recover skin injury Dermatologic preparation composition.
The plain amino acid of above-mentioned class mycetocyte is contained as active ingredient it is another object of the present invention to provide one kind
The manufacture method of some Dermatologic preparation compositions.
The present invention relates to the external preparation for skin containing the plain amino acid of class mycetocyte safe to the human body and that Wound healing function is excellent
Agent composition and its manufacture method, it is characterised in that contain the plain amino acid of class mycetocyte for recovering function with skin wound.
In order to achieve the above object, the present invention provides a kind of manufacture method of Dermatologic preparation composition, it is characterised in that
Manufacture and contain the plain amino acid of class mycetocyte.
It is a feature of the present invention that comprise the steps, the plain amino acid of class mycetocyte directly or is subjected to powdered to it, and
Mixed with Purified Water, thus manufacture composition.
It is a feature of the present invention that directly or the plain amino acid of class mycetocyte is carried out into powdered to it, and enter with Purified Water
Row mixing, is then extracted with ultrasonic wave extraction or hot water, thus manufactures composition.
The method that wound healing, skin regeneration or the skin injury of the plain amino acid of class mycetocyte recover is the present invention relates to the use of,
More specifically, the step of this method includes the plain amino acid of above-mentioned class mycetocyte being administered to object, object here is to include people
Animal, plant, microorganism of class etc., the implementation of administration can be internal (in vivo) or the shape for external (in vitro)
Formula, suitably can also be implemented using known various medications, form of medication.
Use moreover, the present invention provides the wound healing containing the plain amino acid of class mycetocyte, improve wound skin preparations for extenal use group
Compound.
Below, the present invention is more specifically illustrated.
The photosynthetic organisms such as blue algae, mushroom and seaweeds including microalgae are due to short-term or perch for a long time sudden and violent
It is exposed in the environment of ultraviolet, therefore forms diversified overcome ultraviolet to cell and tissue damage during evolution
Mechanism.They by the recovery of UV-induced DNA damage, detoxication enzyme, the accumulation of carotenoid, free radical scavenger,
The various modes such as the synthesis of the compound of antioxidant and absorption and ultraviolet blocking-up, reduce UV-induced damage.It is ultraviolet
MAAs is got most of the attention known to people because of its ultraviolet block function in line absorption and blocking compound.In the present invention, MAAs
For the UV absorbing material being synthesized in most of photosynthetic plant such as blue algae, mushroom, microalgae and seaweeds.Species there are about
More than 20 plant, a length of 310-360nm of maximum absorption wave.
MAAs species can be enumerated：Mycosporine-taurine、Mycosporine-glycine、Palythine、
Palythine-serine-sulfate、Palythine-Serine、Mycosporine-methylamine-serine、
Mycosporine-methylamine-threonine、Asterina-330、Mycosporine-glutamic acid-
glycine、Palythinol、Mycosporine-2-glycine、Shinorine、Porphyra-334、Mycosporine-
Glycine-valine, Palythenic acid, Usujirene, Palythene or Euhalothece-362 etc..
In the present invention, MAAs is typically extracted by above-mentioned algae and used, for example, can be by Korea Ocean Research and Development Insititute (Korea
Institute of Ocean Science and Technology, kiost) provide algae chlamydomonas
(Chlamydomonas hedleyi) and Porphyra yezoensis (Porhyra yezoensis) carry out mass propgation, are extracted and obtained with methanol
.
The viewpoint of the present invention is that the present invention relates to control the plain amino acid of class mycetocyte as the wound that active ingredient contains
More Dermatologic preparation composition and its manufacture method are used.
In the present invention, the plain amino acid of above-mentioned class mycetocyte can account for the 0.1 to 10% of gross weight in the composition, and this ratio is only
Preferential scope, although for example, in following embodiments including 1% weight, 2.5% weight, 5% weight, 10% weight etc. when
Result of the test, but in addition, 1%, less than 0.5%, when 20%, more than 30%, also show excellent healing, improve wound
Wound, skin regeneration, skin injury recovery and other effects, this is self-evident for a person skilled in the art.Also, contain energy
When enough obtaining MAAs microalgae nutrient solution, above-mentioned wound healing effect is also shown, therefore contain the culture of this microalgae
The wound healing of liquid falls within the scope of the present invention with composition.
The manufacture method of the Dermatologic preparation composition containing the plain amino acid of class mycetocyte of the present invention comprises the following steps：
(a) the step of obtaining class mycetocyte element amino acid；And
(b) the step of composition for the class mycetocyte element amino acid that manufacture is obtained containing above-mentioned (a) step.
In the present invention, what above-mentioned (a) step was obtained can be the form of mixtures of the plain amino acid of class mycetocyte, according to circumstances,
Can also be the plain amino acid of certain kinds mycetocyte separated in the plain ispol of above-mentioned class mycetocyte.
In the present invention, the plain amino acid of class mycetocyte that above-mentioned (a) step is obtained can be Shinorine, Porphyra or
Mycosporine-glycine, or be combinations thereof.
In the present invention, above-mentioned (a) step be from microalgae obtain MAAs the step of, specifically, from MAAs can be produced
Microalgae, such as chlamydomonas (Chlamydomonas hedleyi), Porphyra yezoensis (Porhyra yezoensis), roe dish
(Lemanea fluviatilis), witloof seaweed (Porphyra endiviifolium), fork branch algae (Gymnogongrus
Turquetti), navel shape seaweed (Porphyra umbilicalis), pelvetia silquosa (Mastocarpus stellatus), trident
Rosetangle (Ceramium rubrum), corner river hedge (Gracilaria cornea) etc., directly or after culture (cultivate about 3 extremely
After 10 days) MAAs can be obtained.
Above-mentioned algae is being contained into K2HPO4, 0.0972~0.1188；KH2PO4, 0.0504~0.0616；MgSO4·
7H2O, 0.09~0.11；CaCl2·2H2O, 0.045~0.055；C4H11NO3, 2.1798~2.6642；C10H16N2O8, 0.045
~0.055；BO3H3, 0.01026~0.01254；ZnSO4·7H2O, 0.0198~0.0242；MnCl2·4H2O, 0.004554
~0.005566；FeSO4·7H2O, 0.004491~0.005489；CoCl2·6H2O, 0.001449~0.001771；
CuSO4·5H2O, 0.001503~0.001837；Mo7O24(NH4)6·4H2O, 0.00099~0.00121；Glucose 2~25,
Preferably 5~15,2~10, NH4The μ Μ of Cl 50~600, preferably 100~500 μ Μ culture medium, more particularly, contain
K2HPO4、KH2PO4、MgSO4·7H2O、CaCl2·2H2O、CuSO4·5H2O, and containing being used as trace meter (trace
Metals ZnSO)4·7H2O、MnCl2·4H2O, and contain the FeSO as PH buffers4·7H2O(Acidified Iron
Solution obtained after being cultivated in culture medium), and it be dried processing, dry microalgae with alcohols (for example
Methanol) extract obtain extract solution.For example, the algae that 20mg is dried extracts 2 hours with 20% methanol at 45 DEG C, at room temperature from
The heart is separated 10 minutes, removes upper liquid, and the chloroform for adding 100ul stirs, after then addition 500ul Purified Waters are precipitated
It is centrifuged again, the upper liquid so obtained is exactly the plain amino acid (total MAAs) of class mycetocyte.
This upper liquid includes the plain amino acid of number of types of class mycetocyte, is in admixture in the plain amino acid of multiple types mycetocyte
When, can be according to the intrinsic maximum absorption wavelength of the plain amino acid of foregoing all kinds of mycetocytes and retention time, can be temporally
Separated.
In the present invention, including the plain amino acid of the class mycetocyte that above-mentioned (a) step is obtained is affiliated using the present invention in (b) step
Field known method manufactures Dermatologic preparation composition.
Here it may include the plain amino acid dried object of class mycetocyte directly or after powdered being mixed in Purified Water, and carry out cold water
Extract, hot water is extracted or ethanol extracts the process for producing composition.In the present invention, " extract " is referred to above-mentioned class bacterium
Born of the same parents element amino acid be dried or by dried object powder carry out powdered, and with known to Cold water extraction, hot water extraction method or
The extract that the various extracting methods such as ethanol extraction method are obtained.
In the present invention, had no particular limits for extracting method, for example, can use cold soaking extraction method, ultrasonic wave extraction
Method, reflux extraction, hot water extraction method etc..Here, during using hot water extracting mode, with boiling water distiller in 80~100 DEG C of temperature
The lower heating of degree 8~48 hours, so as to obtain hot water extract.
During using cold water extraction, for example, the xeraphium of the plain amino acid of above-mentioned class mycetocyte can be mixed in cold water (15~25 DEG C)
The last extraction process for carrying out 3 days, so as to obtain cold water extract.
Or, the mode that can be extracted by using water, organic solvent or their mixed solvent is manufactured.Extract solution can
Used directly to use, or after concentration and/or drying process.When being extracted using organic solvent, can be used methanol, ethanol,
Isopropanol, butanol, ethene, acetone, hexane, ether, chloroform, ethyl acetate, butyl acetate, dichloromethane, N, N- dimethyl methyls
Acid amides (DMF), dimethyl sulfoxide (DMSO), 1,3-BDO, propane diols or their mixed organic solvents, and do not destroying or most
Under conditions of small chemical drug material effect composition, extracted in room temperature or heating.According to the different organic solvents due to extraction, medicinal material is effective
The extraction degree and the extent of damage of composition have some differences, therefore need to use suitable organic solvent.For example, during ethanol extraction
It is preferred that 20-50% ethanol extracts can be obtained, as a specific embodiment, after being mixed with 50% ethanol, at the stirring for carrying out 3 days
Manage and obtain.
In the present invention, used after said extracted thing being concentrated or diluted, the distillate of extract can also be used.
" contain in the present invention as active ingredient " and refer to, as Dermatologic preparation composition, can show that skin is damaged
Hinder effective amount of the skin improvement effects such as recovery, skin regeneration, wound healing, wound improvement.
In the present invention, above-mentioned Dermatologic preparation composition can be cosmetic composition or medicament composition.
In above-mentioned cosmetic composition, cosmetic formulations may include acceptable carrier.Here, " can in cosmetic formulations
The carrier of receiving " refers to, can be included in it is in cosmetic formulations, well known to a person skilled in the art compound or composition, or
Person is compound or the composition for needing to develop in the future, and these compounds or composition and contact human skin are without suitable more than human body
Answer the toxicity, unstability or excitant of scope.
In the Dermatologic preparation composition of above-mentioned carrier in the present invention, about 1% to 99.99% weight of gross weight can be accounted for
Amount, preferably accounts for 90% to 99.99% weight.But above-mentioned ratio is produced according to aftermentioned Dermatologic preparation composition in the present invention
Formulation and according to it is specific can be different using position (face or neck etc.) or optimum quantum of utilization etc., therefore, above-mentioned ratio
Rate is no matter from the aspect of that, all it is not intended that limitation of the scope of the invention.
As above-mentioned carrier, alcohol, oil, interfacial agent, aliphatic acid, silicone oil, wetting agent, NMF, viscosity can be listed
Modifying agent, emulsion, stabilizer, ultraviolet scattering diluent, ultra-violet absorber, colour coupler, spices etc..As above-mentioned alcohol, oil, boundary
Face activating agent, aliphatic acid, silicone oil, wetting agent, NMF, viscosity modifying agent, emulsion, stabilizer, ultraviolet scattering diluent, ultraviolet
As long as absorbent, colour coupler, spices etc. and compound/composition for using etc. are it is well known in the art that therefore ability
The technical staff in domain can select appropriate substance/group compound to use.
As one embodiment of the present invention, Dermatologic preparation composition of the invention is except the plain amino acid of above-mentioned class mycetocyte
Outside, glycerine, butanediol, propane diols, Crodaret, ethanol, triethanolamine etc. can also be included, can also root
According to needing to include micro preservative, spices, colouring agent, Purified Water etc..
The Dermatologic preparation composition of the present invention can be made into variform, for example, toner, essence can be made, coagulates
Glue, emulsion, skin lotion, frost (oil-in-water type, water-in-oil type, multiphase), solution, suspension (anhydrous and water system), anhydrous product
(oil or alcohol system), gel, facial mask, Pack, powder or gelatin etc. have capsule (soft capsule, hard shell capsules) formulation of epithelium etc.
Form.
The skin of the present invention, conceptive to refer not only to face, also the skin including scalp, whole body, upper as that can be applied to
The Dermatologic preparation composition of scalp is stated, there is shampoo, hair conditioner, treatment waxes, natural on-off cycles of hair growth agent etc., as being applicable to whole body
Shower cream etc. purposes, the composition of variform can be made.
It is not limited to according to the manufacture method of the Dermatologic preparation composition containing the plain amino acid of class mycetocyte of the present invention
Above-mentioned manufacture method, as long as the personnel of the usual knowledge with the technical field of the invention can be by above-mentioned manufacture
Method makes part deformation, produces the Dermatologic preparation composition containing the plain amino acid of class mycetocyte according to the present invention.
Particularly, except specifically disclosed are manufacture method in addition to, above-mentioned Dermatologic preparation composition can be with
The composition of general emulsion-type and solubilized formulation state is produced by conventional manufacture method.
When being manufactured into cosmetic material composition, the nutritious toner of emulsification formulation cosmetics, frost, essence etc. can
Dissolving formulation has skin softening toner.Moreover, the composition of the present invention can be containing the medium and base allowed on Dermatology, thus
Can produce be generally used on Dermatology locally or systemically, the Dermatologic preparation composition of adjuvant form.
Moreover it also provides be suitable for use as the formulation of cosmetics, such as it is anhydrous with solution, gel, solid or batter
Product, the emulsion that oil phase is scattered in aqueous phase and obtained, suspension, microemulsion, microcapsules, particulate or ionic (lipid
Body), the form of non-ionic vesica dispersant, frost, toner, skin lotion, powder, ointment, spraying or the form for hiding flaw rod
There is provided.And the composition of the present invention can be made into foam (foam) form or the gas for adding compressed propellant again is made
The form of mist agent composition.
In addition, the Dermatologic preparation composition of the present invention can also contain such as fatty material, organic solvent, lytic agent, dense
Contracting agent and gelatinizing agent, softening agent, antioxidant, suspending agent, stabilization agent, foaming agent (foaming agent), aromatic, boundary
Face activating agent, water, ionic or non-ionic softening agents, filler, metal ion block agent and chelating agent, preservative agent, dimension
Raw element, blocking agent, wetting agent, essential oil, dyestuff, pigment, hydrophily or lipophile activating agent, lipid vesicles or with it is usual
Be used in that other any conditions of cosmetics are the same, be generally used in cosmeceutical or Dermatology field in adjuvant.And
And, mentioned component can be added according to commonly used amount in cosmeceutical or Dermatology field.
Dermatologic preparation composition as described above includes that based on enhancement collagen synthesis function improvement can be played
The form of the functional cosmetics of the effect such as wrinkle, skin moisture-keeping, skin-whitening, skin sedation, anti-oxidant.
If the composition of the present invention is pharmaceutical compositions, improvement skin can be played for what is provided in following embodiments
The pharmaceutical compositions of skin state.
Above-mentioned pharmaceutical compositions, except the plain combination of amino acids beyond the region of objective existence of above-mentioned class mycetocyte, may also include " pharmaceutically admissible to carry
Body ", this carrier may be selected from the group being made up of diluent, lubricant, bonding agent, disintegrant, sweetener, stabilizer and preservative
In.Above-mentioned pharmaceutical compositions can also include additive.Above-mentioned additive may include spices, vitamin and antioxidant.As
Above-mentioned carrier, as long as pharmaceutically admissible carrier can be used, such as can be lactose, dextrin, cassava as diluent
(tapioca) starch, cornstarch, soybean oil, microcrystalline cellulose or for mannitol, can be magnesium stearate as lubricant
Or talcum, can be polyvinylpyrrolidone or hydroxypropyl cellulose as bonding agent.Moreover, can be carboxylic first as disintegrant
Base cellulose calcium, Explotab, polacrilin potassium or Crospovidone, can be white sugar, fructose, sorb as sweetener
Candy alcohol or Aspartame, can be sodium carboxymethylcellulose, beta-schardinger dextrin or xanthans as stabilizer, can be with as preservative
For methyl p-hydroxybenzoate, propylparaben or potassium sorbate.
Above-mentioned pharmaceutical composition can be formed in the also well known usual pharmaceutical formulation of the art.Above-mentioned pharmacy
The formulation that composition can be formulated to oral Preparation, injection, suppository, Percutaneously administrable preparation and nasal cavity administrated preparation is entered
Row administration.For example, above-mentioned formulation can be such as liquor, suspending agent, powder, granule, tablet, capsule, pill or such as concentrate
The oral administered dosage form of thing.
Toxicity is not had not only to Skin Cell according to the plain amino acid of the class mycetocyte of the present invention, and had to the healing of wound
Excellent effect, can be efficiently applied to control treatment trauma, skin regeneration or the recovery of skin injury.
Brief description of the drawings
Fig. 1 is analysis result (A.SH, P334 and M-Gly HPLC-DAD (330nm) chromatogram of MAAs characteristics；B.SH,
P334 and M-Gly three-phase and quadrupole square (Triplequadruple) ESI-MS/MS spectrum).
Fig. 2 is the result (A.M-Gly that cytotoxicity (stability) is determined by MTT colorimetric methods (MTT assay)；
B.P334；C.SH).
After Fig. 3 and Fig. 4 is artificial damage human keratinized cell, compare the Wound healing effect after being handled through MAAs.Fig. 3 a
Represent that after just damage (t=0), b-f represents the state of wound healing in 24 hours after damage.B is control group (without MAAs processing
), c is positive controls (positive control), is the EGF for having proven to its Wound healing effect
(epidermal growth factor, EGF) treatment group.D, e, f represent M-Gly, P334, SH treatment groups in order.Fig. 4 is
Fig. 3 result and control group (b, t=24) relatively and are made into the chart of (%) of quantizing.
Fig. 5 is to pass through MAAs FAK, ERK, JNK activity result of the test (FAK, ERK, JNK activity that A. passes through MAAs；B.
The normalized (normalization) of each frequency range (band) intensity (intensity) measure and house-keeping gene (GAPDH)；
The effect of C.FAK, ERK inhibitor；The effect of D.JNK inhibitor).
Fig. 6 is to confirm result (A-B.ERK inhibitor pair by the ERK and MAAs of jnk inhibitor Wound healing effect
The reduction of MAAs Wound healing effect；Suppression of the C-D.JNK inhibitor to MAAs Wound healing effects).
Fig. 7 A are the cell state figure that micro- Microscopic observation cures agent effect as MAAs metabolics, and Fig. 7 B are in observation conduct
MAAs metabolics represent the figure of wound healing percentage when curing agent effect.
Embodiment
Below, by embodiment, the present invention will be described in more detail.Following embodiments are only one to the present invention
Individual example, should not be construed as the scope of the present invention and is only defined in these embodiments, this is to one skilled in the art
It is self-evident.
Embodiment 1
MAAs acquisition and specificity analysis
1.1MAAs culture
MAAs (Porphyra-334 (P334), Shinorine (SH), the Mycosporine-glycine of three species
(M-Gly)) be from Korea Ocean Research and Development Insititute provide chlamydomonas (Chlamydomonas) and Porphyra yezoensis (Porhyra
Yezoensis extracted in).Added in 500ml flasks culture medium Guillard's f/2medium (Sigma-Aldrich,
St.Louis, MO, USA) 250ml, initial inoculum is 5X104Cells/mL, chlamydomonas and bar class seaweed is inoculated with respectively, in temperature
Cultivated in control water tank at 23-25 DEG C.The pH value of nutrient solution maintains 8 to 9, CO2Concentration keeps 1%.Cell culture is received after 7 days
Cell is obtained, is dried with freeze drier.MAAs amount and dry weight (DW) are about~3.72g/ in this culture systems
L ,~0.01mg/gDW.
1.2MAAs is analyzed and identified
Dry algae (dry weight 20mg) is extracted 2 hours with 45 DEG C of 20% methanol (v/v).Use at room temperature
5000Xg is centrifuged 10 minutes, takes upper liquid to use vacuum plant (Jouan evaporator centrifuge at 45 DEG C
RC 10.09, Cedex, France) it is dried.Sediment is dissolved with 500 μ l Purified Waters after vacuum drying, 100 μ l are added
Chloroform is stirred, and this solution is centrifuged 5 minutes in 10,000Xg, upper liquid is carefully moved into new Minitype centrifugal device
Dissolved in pipe after evaporation solvent with 50% methanol.
Thus obtained sample is used equipped with diode array (diode array detection (DAD)-SPD M20A inspections
Survey the device (high performance liquid chromatograph (high-pressure of (Quantum Northwest, Seattle, WA, USA)
Reverse-phase liquid chromatography (HPLC) (Shimadzu-LC20A, Seattle, WA, USA) are carried out
Quantitative analysis.It is 30-60 μ l by sample plant division, 0.5ml is reached with 100%HPLC methanol dilutions to ultimate density, and with very
Empty rotary concentrator is dried.Dry sample is redissolved with 600 μ l Purified Waters, with ammonium hydroxide and 0.2% trifluoroacetic acid
(pH3.0) 10 times are diluted.By dilute solution 0.45uM membrane filtrations, insoluble matter and large particulate matter are removed.After filtering
The μ l of solution 10 be injected into flow rate set be 1ml/min HPLC system in, the HPLC result Class-VP softwares drawn
(Quantum Northwest, Seattle, WA, USA) is analyzed.Its result is with Univ Malaga of Spain F.Figueroa
The P334 of offer, SH, M-Gly are as standard items, with liquid chromatograph mass spectrography (high-resolution reverse-
Phase liquid chromatography/mass spectrometry, HPLC/MS) analyzed, according to each of detection
MAAs maximum absorption wavelength and retention time identification MAAs.
Example-application HPLC isolates and purifies SH
Using the type integrated high voltage double pump liquid phase pumping system of water generation 1525 (the μ Binary HPLC pump of Waters 1525),
Water generation liquid chromatogram 996 (Waters 996photodiode array detector), is used to isolate and purify
Gemini 5 μ C18 110A (5 μm, 4.6 × 250nm, Phenomenex) column.Analysis solvent is to contain 0.1% trifluoro second
The water (solvent orange 2 A) and acetonitrile (solvent) of sour (trifluoroacetic acid, TFA), flow velocity is 1ml/min, 332nm
Detected under (being 334nm during Porphyra, be 332nm during M-Gly) wavelength.
1.3MS/MS analysis
Dry extract Purified Water (1mg/ml) is dissolved, is diluted to 50% methanol solution containing 0.1% formic acid
Ultimate density is reached after 100ppm with 0.45- μm of membrane filtration.MAAs is analyzed with AB SCIEX 3200QTRAP MS/MS
(Applied Biosystems, Foster City, CA, USA) and ESI source (TurbolonSpray, Applied
Biosystem/MDS SCIEX, Concord, Canada) constitute ESI-MS/MS systems (Thermo Fisher
Scientific, San Jose, CA, USA) implement.Its result software (AB SCIEX of AB SCIEX Analyst 1.5
Korea Limited Company, Seoul, Korea) analyzed.MAAs is in positive ion mode (positive mode)
Quantified under daughter ion (M52) pattern (Product Ion (MS2) mode).Inject the feature (Tune of pumping method
Control it is) that a diameter of 4.6mm, the flow velocity of syringe is that the optimal values of 10.00 μ l/min, ESI source parameters is set to turbine
300 DEG C of heater atomization temperature (turbo heater temperature, TEM), electron spray voltage 5500V, gas curtain gas
10psi, atomization gas (GS1) 15Psi, auxiliary gas (GS2) 40Psi.Collision energy (Collision energy, CE) and entrance electricity
Position (entrance potential, EP) is respectively 35V and 4.5V, and in MAAs quality conversion, most suitable removes cluster voltage
(declustering potential, DP) be set as 51V, exit potential (collision cell exit potential,
CXP) it is set as 4V.
By above-mentioned experiment, MAAs is carried out based on the UV absorption spectrums and HPLC retention time that are detected by DAD
Classification.SH, M-Gly and P334 retention time are respectively 4.395,5.356,6.252 minutes, although UV-VIS pairs of DAD
The collection of absorption spectrum is very fast, but MAAs maximum absorption wavelength almost only differs several nm, and the difference of each absorption spectrum is very
It is difficult.In order to overcome this problem to use HPLC/MS, with electron spray ionisation (electrospray ionization, ESI)
The fragment pattern of mass spectrogram, distinguishes SH, M-Gly and P334 characteristic (Fig. 1).
Embodiment 2
MAAs cytotoxicity (cell viability) experiment
Before experiment MAAs Wound healing function, first with cell toxicant of the Human keratinocytes (HaCaT) to MAAs
Property is tested.MTT colorimetric methods (3- (4,5- dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromides, Sigma-
Aldrich, St.Louis, MO, USA) it is the method for determining cells survival rate.
The cell used in this experiment is Human keratinocytes (HaCaT), from American Type Culture Collecti (American
Type Culture Collection, ATCC, Manassas, VA, USA) bought.HaCaT cells are seeded in 96 micro-
In orifice plate, with containing 10% hyclone (FBS) and 2Mm Glus, 100Um-1The Dole primary of Pen .- Strep
Section's modified Eagle medium (Dulbecco's modified Eagle's medium, DMEM, Hyclone, Logan, UT,
USA) cultivated under humidified ambient.It is each with M-Gly, SH, the P334 obtained in embodiment 1 respectively after culture 24 hours
Continue to cultivate 24 hours after handling under 0.01,0.05,0.1,0.5,1mg/ml concentration.Then by nutrient solution with 100 μ l MTT
Solution (0.5mg/ml of cell culture medium) processing, is cultivated 4 hours at 37 DEG C, is removed after culture medium, adds 100 μ l dimethyl
Sulfoxide (DMSO) dissolves MTT first a ceremonial jade-ladle, used in libation (formazan), with the absorbance under spectrophotometric determination 540nm.
As a result it observed with meeting cytotoxicity increases under high concentration (0.5~1mg/ml) during M-Gly and P334 processing,
It is conversely stable under 0.01~0.1mg/m low concentration.SH is also identical, observed in low concentration (0.01~0.05mg/
M) cytotoxicity is minimum under.Confirm that M-Gly, P334 and SH do not have HaCaT cytotoxicities (figure at low concentrations by the above results
2)。
Embodiment 3
MAAs Wound healing effect
MAAs UV safeguard functions and ROS eliminates a variety of excellent functions such as function and has been studied, but MAAs wound is controlled
More function there is no report so far.Wound healing process is to include the significant process of inflammation, new organization formation and reconstruction etc., and skin is thin
The movement of born of the same parents is required to Wound healing.In order to test M-Gly, SH and P334 played in the Wound healing of Skin Cell why
The influence of sample, to HaCaT cells with respective MAAs processing, determines the degree of wound healing.As positive controls, use
It is considered as the EGF effective to Wound healing.
Specifically, Human keratinocytes (HaCaT) are seeded in 6 orifice plates, in 37 DEG C, 5%CO2It is lower to cultivate to thin
Born of the same parents cultivate full to 100% over the surface of the panel.Manufacture wound is scraped in cell surface with 100 μ l pipette tip after culture, with new
Nutrient solution rinse once, and be separately added into containing excipient (vehicle), EGF (Sigma-Aldrich, St.Louis, MO,
USA cultivated in the MAAs (M-Gly, P334, SH)), obtained in embodiment 1 nutrient solution (2ml).During processing, in 2ml nutrient solutions
Middle concentration is respectively EGF 100ng/ml, M-Gly 0.1mg/ml, P3340.05mg/ml, SH 0.05mg/ml.By defined
AxioObserver FL microscopes (Advanced Microscopy Group, Bothell, WA, USA) 10 are used after incubation time
Cell state is determined under times.The cell state of wound part is determined more than 3 positions, and the percentage of wound healing degree is used
ImageJ softwares (http://imagej.nih.gov/ij/index.html) calculated.All experiments are to repeat
3 times.
Fig. 3 a represent after just damage (t=0) that b is by 24 hours after being damaged with control group (without MAAs processing)
State afterwards.Results verification MAAs promotes wound healing in Skin Cell moderate stimulation wound healing mechanism.(Fig. 3 and Fig. 4)
Embodiment 4
The Wound healing mechanism of MAAs inductions is confirmed by FAK-MAP kinase activity
For the principle for the Wound healing for being identified through M-Gly, SH and P334 regulation, the protein table to meeting relation mechanism
Up to being confirmed.Multi-signal conductive protein changes during signaling, wherein focal adhesion kinase (focal
Adhesion kinase, FAK) and non-receptor protein tyrosine kinase (non-receptor protein tyrosine
Kinase (PTK)) be considered as signaling decisive regulatory factor.There are reports that FAK activity promote signaling and
Wound healing.Therefore to MAAs Wound healing, whether the activity based on FAK is tested.
To carry out Western blotting (Western blot) analysis, the Human keratinocytes of culture are rinsed with 1XPBS,
With RIPA buffer solutions (150mM NaCl, 50nM Tris, 1%Triton- containing protease and inhibitors of phosphatases (Roche)
X-100,0.5% NaTDC, 0.1%SDS) dissolution cell.This cell solution is centrifuged 1 minute under 12,000Xg
Cell extract is obtained.Using Bio-Rad Protein Assay reagent (Bio-Rad Laboratories,
Hercules, CA, USA) carry out protein quantification.
Same amount of protein is loaded in after SDS- polyacrylamide gels carry out electrophoresis, electrophoresis protein is moved into nitric acid
Cellulose membrane.Then film is dipped into 5% degreasing milk solution (the Tris-buffered saline containing 0.1%Tween 20)
In, (blocking) is closed at room temperature 1 hour, after closing, first antibody is added in film and reacted a whole night at 4 DEG C, Ran Houyong
The secondary antibody of horseradish peroxidase (horseradish peroxidase) mark reacts 1 hour, Ran Houyong at room temperature
Chemiluminescent immunoblot detecting system (Chemiluminescence Western Blot Detection System,
BioSpectrumr 600Imaging System, Upland, CA, USA)) obtain trace figure.
First antibody has used pFAK (pY397, BD biosciences, San Jose, CA, USA), pErk (Cell
Signaling, Danvers, MA, USA), pAkt (Cell Signaling, Danvers, MA, USA), pJNK (Cell
Signaling, Danvers, MA, USA), GAPDH (Santa Cruz Biotechnology, Santa Cruz, CA, USA).
Inhibitor has used PD98059 (ERK inhibitor, Cell signaling, Danvers, MA, USA), FAK14 (FAK
Inhibitor, Santa Cruz Biotechnology, CA, USA), SP600125 (JNK inhibitor, Santa Cruz
Biotechnology, Santa Cruz, CA, USA).
Its result such as Fig. 5 A, it is thus identified that the phosphorylation increase at FAK Y397 positions when being handled with M-Gly, SH and P334, and
And it is sharp to observe the regulatable MAPKs of the FAK being phosphorylated when being handled with MAAs-extracellular signal regulation
The activity of enzyme (MAPKs extracellular signal-regulated kinase (ERK)).For FAK caused by MAAs,
ERK, JNK1/2 activity increase, Fig. 5 A result are made the work that each protein is illustrated after quantizing and as figure B
Property degree.As a result the activity by FAK and ERK caused by MAAs is understood, the healing of Skin Cell wound is realized.Moreover, nearest JNK
It is a kind of protein that activity is shown in signaling to be studied out in drosophila sample and the Skin Cell of fish etc., is represented
JNK1 may include in the mechanism of Wound healing.Thus, influences of the MAAs to JNK activity is tested in this experiment, as a result, with
JKN1 activity is induced during MAAs processing, there is Wound healing effect which show M-Gly, SH and P334.By Fig. 5 C and
Fig. 5 D are tested, respectively with the active inhibitor (DMSO for suppressing FAK, ERK, JNK；Dissolve the solvent of inhibitor, not containing suppression
Control group, the PD98059 of agent；ERK inhibitor, FAK14；Fak inhibitor, SP600125；Jnk inhibitor) processing after use MAAs
Confirm that respective activity is significantly reduced during processing.Moreover, FAK activity suppression can cause ERK and JNK1 active suppression.By
This, can confirm mechanism of the FAK activity for the preceding step of ERK and JNK1 activity.
Embodiment 5
Pass through the activity of ERK and JNK in MAAs Wound healing
In order to test the importance of ERK and JNK activity in the Wound healing by the MAAs Skin Cells induced, use in advance
Implement Wound healing experiment after ERK and JNK inhibitor processing Skin Cell.Human keratinocytes (HaCaT) are seeded in 6
In orifice plate, in 37 DEG C, 5%CO2Lower culture is cultivated full to 100% over the surface of the panel to cell.Rushed after culture with new nutrient solution
Wash once, be separately added into containing PD98059 (ERK inhibitor, Fig. 6 A f-h) or SP600125 (jnk inhibitor, Fig. 6 C f-
H) nutrient solution (2ml) for, not containing (Fig. 6 A and 6C c-e) is pre-processed 30 minutes.Excipient (vehicle) is used after 30 minutes respectively
And MAAs (M-Gly, P334, SH) processing, scrape manufacture wound in cell surface with 100 μ l pipette tip.Cross after the stipulated time
Determined with AxioObserver FL microscopes (Advanced Microscopy Group, Bothell, WA, USA) under 10 times
Cell state.The cell state of wound part is determined more than 3 positions, the percentage ImageJ softwares of wound healing degree
(http://imagej.nih.gov/ij/index.html) calculate.All experiments are to be repeated 3 times.
Fig. 6 A are the wound for comparing group (f-h) and untreated group (DMSO, c-e) with ERK inhibitor (PD98059) processing
The experiment of mouth healing effect.Fig. 6 C are to compare the group (f-h) handled with jnk inhibitor (SP600125) and untreated group
The experiment of the Wound healing effect of (DMSO, c-e).With ERK inhibitor (Fig. 6 A before Human keratinocytes are handled with MAAs
F-h) or with jnk inhibitor (Fig. 6 C f-h) pre-processed, then respectively with M-Gly (Fig. 6 A c and e, Fig. 6 C c and e),
P334 (Fig. 6 A d and g, Fig. 6 C d and g), SH (Fig. 6 A e and h, Fig. 6 C e and h) processing, are artificially damaged with micro-pipe point, than
The degree of wound healing more after a period of time.Fig. 6 A and 6C a are the state after just damage, and 6A and 6C b are above-mentioned experiment
Control group, display damage after cross 24 hours after state.Fig. 6 B are that, by the chart of 6A number of results value (%), 6D is will
6C result is quantized the chart of (%).
As a result, Wound healing degree is reduced to 15% when can confirm to be handled with ERK inhibitor (PD98059), is suppressed with JNK
Agent totally blocks MAAs Wound healing effect when handling.Pass through such result, it is known that ERK and JNK activity promotes MAAs
Wound healing effect, especially JNK plays an important role in the Skin Cell Wound healing that MAAs is induced.(Fig. 6).
By the above results, 3 kinds of MAAs Wound healing effect can be confirmed, and observed induction be primarily involved in cell
Propagation and mobile, FAK, ERK, JNK of wound healing activity.Thus, MAAs not only acts as known UV safeguard functions, also has
There is the effect for promoting wound healing, confirm the possibility of the cosmetics and raw material chemicals for Wound healing.
The MAAs of agent effect is cured as metabolic
By in Human keratinocytes (HaCaT) and the orifice plate of MEC (MEF) 6, in 37 DEG C, 5%CO2
Lower culture is cultivated over the surface of the panel to cell completely reaches 100%.Rinsed once with new PBS after culture.By new common MDEM
(1% is blue or green by 50mM glucose, 10%FBS by (25mM glucose, 10%FBS, 1% Pen .- Strep) and high glucose DMEM
Mycin-streptomysin) handled respectively with excipient (vehicle) and MAAs (M-Gly, P334, SH), existed with 100 μ l pipette tip
HaCaT cell surfaces scrape manufacture wound, MEF cells 1000uL.To reach press strip is permeated with high glucose DMEM identicals
Part, adds 25mM mannitol in common MDEM.Cross and AxioObserver FL microscopes (Advanced is used after the stipulated time
Microscopy Group, Bothell, WA, USA) determine cell state under 10 times.The cell state of wound part determines 3
It is more than individual position, the percentage ImageJ softwares (http of wound healing degree://imagej.nih.gov/ij/
Index.html) calculate.As a result, as shown in Figure 7 A, 7 B.
As a result, MAAs (P334, SH) in addition to M-Gly promotes Human keratinocytes and small under the conditions of high glucose
The wound healing of rat embryo fibroblast cell.Shown by the above results, 3 kinds of MAAs (M-Gly, P334, SH) are to common wound
Cure effective, and can expect that 2 kinds of MAAs (P334, SH) can induce the metabolic disease patients such as diabetes, the obesity of hyperglycaemia
Wound healing and skin regeneration.
Embodiment 6
The manufacture of cosmetic composition
As the cosmetics of the plain amino acid of the class mycetocyte for containing the embodiment of the present invention 1 with active ingredient, nutrition is manufactured that
The cosmetics of the solubilized formulations such as the cosmetics and skin softening toner of the emulsification formulation such as toner, face cream, essence.
Production Example 6-1：Toner
According to formula as below, it is made of common toner manufacture method.
Table 1
| Material name | Weight % (w/w) |
| Glycerine | 5.0 |
| DPG | 3.0 |
| Hyaluronic acid | 0.5 |
| Rilanit special APEO | 0.1 |
| Polyethylene oleyl ether | 0.1 |
| Ethanol | 5.0 |
| Preservative | 0.15 |
| Spices | In right amount |
| Colour drug | In right amount |
| The plain amino acid of the class mycetocyte of embodiment 1 | 2.0 |
| Purified Water | To 100 |
Production Example 6-2：Essence
According to formula as below, it is made of common essence manufacture method.
Table 2
| Material name | Weight % (w/w) |
| Cetostearyl alcohol | 1.0 |
| Self-emulsifying monostearate | 1.0 |
| Beeswax | 0.5 |
| Saualane | 5.0 |
| Isooctyl acid cetyl ester | 3.0 |
| Dimethyl siloxane | 0.3 |
| Sorbitan monostearate | 0.5 |
| Polyethylene glycol mono stearate | 8.0 |
| Glycerine | 4.0 |
| Propane diols | 0.2 |
| Carboxyl polymer | 0.22 |
| Triethanolamine | 0.25 |
| Preservative | In right amount |
| Spices | In right amount |
| Colouring agent | In right amount |
| The plain amino acid of the class mycetocyte of embodiment 1 | 7.0 |
| Purified Water | To 100 |
Production Example 6-3：Emulsion
According to formula as below, it is made of common emulsion making process.
Table 3
Production Example 6-4：Face cream
According to formula as below, it is made of common face cream manufacture method.
Table 4
Production Example 6-5：Gel
According to formula as below, it is made of common gel manufacture method.
Table 5
| Material name | Weight % (w/w) |
| Glycerine | 4.0 |
| Propane diols | 4.0 |
| Ethanol | 10 |
| Rilanit special APEO | 0.1 |
| Carboxyl polymer | 0.30 |
| Triethanolamine | 0.30 |
| Preservative | In right amount |
| Spices | In right amount |
| Colouring agent | In right amount |
| The plain amino acid of the class mycetocyte of embodiment 1 | 1.0 |
| Purified Water | To 100 |
More than, the specific part of present invention is described in detail, the personnel for possessing the usual knowledge in this area should be understood that
Above-mentioned particular technique is preferred implementation, is not meant to that the scope of the present invention is defined in this, therefore, reality of the invention
Matter scope should make definition according to claim and its equivalent.
Claims (10)
1. a kind of Dermatologic preparation composition, for wound healing, wherein, contain the plain amino acid of class mycetocyte as active ingredient.
2. Dermatologic preparation composition as claimed in claim 1, it is characterised in that the plain amino acid of the class mycetocyte is by following
Mycosporine-taurine, Mycosporine-glycine, Palythine, Palythine- that molecular structural formula is represented
serine-sulfate、Palythine-Serine、Mycosporine-methylamine-serine、Mycosporine-
methylamine-threonine、Asterina-330、Mycosporine-glutamic acid-glycine、
Palythinol、Mycosporine-2-glycine、Shinorine、Porphyra-334、Mycosporine-glycine-
Valine, Palythenic acid, Usujirene, Palythene or Euhalothece-362,
3. Dermatologic preparation composition as claimed in claim 1, it is characterised in that the plain amino acid of the class mycetocyte is at described group
The 0.1 to 10% of gross weight is accounted in compound.
4. a kind of Dermatologic preparation composition, recovers for skin regeneration or skin injury, wherein, contain class as active ingredient
Mycetocyte element amino acid.
5. Dermatologic preparation composition as claimed in claim 4, it is characterised in that the plain amino acid of the class mycetocyte is by following
Mycosporine-taurine, Mycosporine-glycine, Palythine, Palythine- that molecular structural formula is represented
serine-sulfate、Palythine-Serine、Mycosporine-methylamine-serine、Mycosporine-
methylamine-threonine、Asterina-330、Mycosporine-glutamic acid-glycine、
Palythinol、Mycosporine-2-glycine、Shinorine、Porphyra-334、Mycosporine-glycine-
Valine, Palythenic acid, Usujirene, Palythene or Euhalothece-362,
6. Dermatologic preparation composition as claimed in claim 4, it is characterised in that the plain amino acid of the class mycetocyte is in the composition
In account for the 0.1 to 10% of gross weight.
7. the Dermatologic preparation composition as described in any one of claim 1 to 6, it is characterised in that as active ingredient, contains
Porphyra-334 or Shinorine, Wound healing, skin regeneration or skin injury for hyperglycaemia metabolic disease patient
Recover.
8. the manufacture method of the Dermatologic preparation composition described in any one of claim 1 to 6, this method comprises the steps:
(a) the step of extracting class mycetocyte element amino acid from microalgae；And
(b) the step of manufacture contains the composition by the plain amino acid of class mycetocyte that (a) step is obtained.
9. the manufacture method of Dermatologic preparation composition as claimed in claim 8, it is characterised in that in (a) step,
From selected from by chlamydomonas (Chlamydomonas hedleyi), Porphyra yezoensis (Porhyra yezoensis), roe dish
(Lemanea fluviatilis), witloof seaweed (Porphyra endiviifolium), fork branch algae (Gymnogongrus
Turquetti), navel shape seaweed (Porphyra umbilicalis), pelvetia silquosa (Mastocarpus stellatus), trident
Rosetangle (Ceramium rubrum), corner river hedge (Gracilaria cornea) composition any of group microalgae directly or
Person extracts the plain amino acid of the class mycetocyte after being cultivated.
10. the manufacture method of Dermatologic preparation composition as claimed in claim 8, it is characterised in that in (a) step
The plain amino acid of the class mycetocyte obtained is in Shinorine, Porphyra-334, Mycosporine-glycine
Two or more combinations.
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| KR10-2016-0011359 | 2016-01-29 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109260045A (en) * | 2018-10-17 | 2019-01-25 | 拉芳家化股份有限公司 | A kind of spore of bacterium containing class element-glycine from anti-corrosion moisturizing essence |
| CN112118860A (en) * | 2018-05-15 | 2020-12-22 | 申涅斯克印有限公司 | Method for producing collagen-laminin matrix for treating skin ulcer, burn and wound surface |
| CN112292452A (en) * | 2018-02-23 | 2021-01-29 | Cj第一制糖株式会社 | Microorganism producing mycosporine-like amino acid and method for producing mycosporine-like amino acid using the same |
| CN113980918A (en) * | 2021-10-18 | 2022-01-28 | 中国海洋大学 | Antarctic ice algae MAAs synthetase and coding gene and application thereof |
| CN116850099A (en) * | 2023-05-19 | 2023-10-10 | 广州美思生物技术有限公司 | Mild and tear-free moisturizing facial cleanser and preparation method thereof |
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| KR101981428B1 (en) * | 2018-04-19 | 2019-05-22 | 재단법인 전남생물산업진흥원 | PHARMACEUTICAL COMPOSITION Porphyra dentata Kjellman EXTRACT FOR SKIN REGENERATION |
| EP3790568A1 (en) * | 2018-05-08 | 2021-03-17 | Gat Biosciences, S.L. | Imac-enriched microalgal culture supernatant and uses thereof |
| KR102021264B1 (en) * | 2019-02-27 | 2019-09-19 | 재단법인 전남생물산업진흥원 | PHARMACEUTICAL COMPOSITION Porphyra dentata Kjellman EXTRACT FOR SKIN REGENERATION |
| KR102021263B1 (en) * | 2019-02-27 | 2019-09-19 | 재단법인 전남생물산업진흥원 | PHARMACEUTICAL COMPOSITION Porphyra dentata Kjellman EXTRACT FOR SKIN REGENERATION. |
| WO2020175754A1 (en) * | 2019-02-27 | 2020-09-03 | 재단법인 전남생물산업진흥원 | Pharmaceutical composition and cosmetic composition for skin regeneration comprising active ingredient extracted and isolated from porphyra dentata |
| KR102348198B1 (en) | 2019-12-06 | 2022-01-10 | 주식회사 바이오에프디엔씨 | Purification method for mass production of Mycosporine-like amino acid porphyra334 |
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| CN112118860A (en) * | 2018-05-15 | 2020-12-22 | 申涅斯克印有限公司 | Method for producing collagen-laminin matrix for treating skin ulcer, burn and wound surface |
| CN109260045A (en) * | 2018-10-17 | 2019-01-25 | 拉芳家化股份有限公司 | A kind of spore of bacterium containing class element-glycine from anti-corrosion moisturizing essence |
| CN113980918A (en) * | 2021-10-18 | 2022-01-28 | 中国海洋大学 | Antarctic ice algae MAAs synthetase and coding gene and application thereof |
| CN113980918B (en) * | 2021-10-18 | 2023-11-24 | 自然资源部第一海洋研究所 | Antarctic ice algae MAAs synthetase, and coding gene and application thereof |
| CN116850099A (en) * | 2023-05-19 | 2023-10-10 | 广州美思生物技术有限公司 | Mild and tear-free moisturizing facial cleanser and preparation method thereof |
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