CN102408998A - Salt-tolerant marine mangrove endophytic fungi with neurodegenerative disease control activity - Google Patents
Salt-tolerant marine mangrove endophytic fungi with neurodegenerative disease control activity Download PDFInfo
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Abstract
The invention relates to the technical field of microorganisms and discloses salt-tolerant marine mangrove endophytic fungi with neurodegenerative disease control activity. The endophytic fungi are separated from the mangrove barks, and the collection number of the endophytic fungi is CCTCC (China Center for Type Culture Collection) M2011044. The secondary metabolites and extracts of the salt-tolerant marine mangrove endophytic fungi SN3-2 have obvious activity against AD (Alzheimer's disease). The extracts of the endophytic fungi have strong A-beta aggregation inhibiting effect when the E.coli cell model is used for screening and studying the activity against A-beta aggregation, and the extracts of the endophytic fungi have stronger activity against aggregation when the in-vitro A-beta aggregation model is used for testing the activity against A-beta aggregation.
Description
Technical field
The present invention relates to the research of application and the nerve degenerative diseases control activeconstituents of marine microorganism, a kind of specifically have nerve degenerative diseases and prevent and treat active ocean mangrove salt tolerance endogenetic fungus.
Background technology
Nerve degenerative diseases is a kind of frequently-occurring disease and common disease clinically; Comprise A Ercicaimo sick (Alzheimer ' s disease; AD), Parkinson's disease (Parkinson ' s disease; PD), HD (Huntington ' s disease, HD) etc., cardinal symptom comprises the memory of carrying out property and cognition dysfunction, dyspraxia or the like.Along with the aging of human society age structure, the nerve degenerative diseases sickness rate raises day by day, has become the third-largest worldwide health problem that is only second to cardiovascular and cerebrovascular diseases and tumour.
People have carried out big quantity research to the pathogeny of nerve degenerative diseases in recent years, and pathogeny has been proposed some different hypothesis, like entanglement and gathering, the oxidative stress of key protein, biological metal ion stable state is unbalance, mitochondrial function depletion etc.Yet the pathogenic factor of nerve degenerative diseases and mechanism are still very not clear and definite at present.Existing result of study shows; As a big proteinoid false folding sick (molecular conformation is sick); The aggregate and precipitate of the relevant key protein of nerve degenerative diseases has important regulating effect in pathogenic process; Morbidity like AD is promptly directly related with the cytotoxicity that gathering, deposition and the oligomer of A-beta key proteins such as (beta-amyloid) produce; Proteic overexpression of A-beta and gathering, deposition can cause directly that mitochondrial disorders, oxidative stress, nerve synapse transmission interruption, aixs cylinder transportation are interrupted, the impaired multiple AD related pathologies such as break of film integrality changes, and the morbidity of HD is directly related with the gathering of Poly Q etc.Therefore, the aggregate and precipitate of nerve degenerative diseases GAP-associated protein GAP has become research nerve degenerative diseases pathogeny and one of nerve degenerative diseases medicine and the most important target of method.
Though the nerve degenerative diseases GAP-associated protein GAP forms insoluble fibre through the folding crosslinked gathering of β sheet, the death of neurocyte finally appears and causes with block high polymer form.But result of study proves recently, and the soluble proteins oligomer that in forming the insoluble fibre process, produces is only its neurovirulent material of real embodiment.Therefore; Compare with the aggregation inhibitor of research fiber or block high polymer, research has prior theory significance and value for nerve degenerative diseases control activeconstituents to inquire into the aggregation inhibitor of screening study nerve degenerative diseases GAP-associated protein GAP oligomer how.
With nerve degenerative diseases deeply the comparing gradually of mechanism research of curing the disease, nerve degenerative diseases control medicine correlative study and using then obviously lags behind, and does not still have etiotropic specific treatment medicine up to now clinically.Existing medicine has only certain auxiliaring effect to the state of an illness of nerve degenerative diseases; Can delay the deterioration of the state of an illness to a certain extent; But all can not reverse disease; Like anti-AD medicine is example; Existing acetylcholinesterase depressant (IChEIs) is like tacrine, donepezil, huperzine, ENA-713, fuperdin A etc. and be used for clinical uncompetitive nmda receptor antagonist hydrochloric acid memantine (memantine) medicine of etc.ing in recent years certain adjuvant treatment effect is all only arranged, and much also can cause the vagusstoff related reactions under the situation.Therefore; Discovering new, special habitats nerve degenerative diseases control medicine resource and find that therefrom the unique novel active composition of novel structure, effect is very important for the research of nerve degenerative diseases lead drug, is one of core means that solve the nerve degenerative diseases new drug development.
Mangrove forest is a kind of very special ecological zone between marine ecology and land ecology.The influence that receives mangrove forest height salt dutyization, the anoxic of soil, high optical radiation and periodic seawater to soak unique growing environments such as flooding, the very abundant mangrove forest Microbial resources that have characteristic have again become one of unique ocean medicine resource.After separation obtained producing the endogenetic fungus Taxamyces andrenae of novel active from Pacific yew (yewtree) in 1993, the research of mangrove plant endogenetic fungus active substance had caused people's very big interest.At present, both at home and abroad in mangrove endogenetic fungus secondary metabolite isolation identification unique, the novel compounds of a plurality of structures, have antitumor, antiviral, antibiotic isoreactivity.Wherein the sporothrins A of isolation identification and Xylaria sp. meta-bolites Xyloketal A-D have stronger restraining effect to E.C. 3.1.1.7 from Kandelia candel bark endogenetic fungus thalline.This just further proves: mangrove endogenetic fungus and metabolite thereof have great DEVELOPMENT PROSPECT as the resource of nerve degenerative diseases control new drug research.
Summary of the invention
Main purpose of the present invention be to provide a kind of from mangrove yellow water skin rhizome portion bark isolating ocean mangrove salt tolerance endogenetic fungus; It is active that this mangrove endogenetic fungus thalline extract has the nerve degenerative diseases control, and it is active in the E.coli of A-beta protein aggregation cell model, to demonstrate good anti-A-beta protein aggregation.
Ocean of the present invention mangrove salt tolerance endogenetic fungus is identified through Institute of Microorganism, Academia Sinica; Called after: Phomopsis occulta; Hide the little mirror word of Phomopsis (2011) No. 019); It is preserved in Luojiashan, Wuchang, Wuhan City, Hubei Province Wuhan University preservation center on February 23rd, 2011, promptly Chinese typical culture collection center (CCTCC), and deposit number is CCTCCM2011044.The application is to its called after SN3-2.
The solid culture of ocean of the present invention mangrove salt tolerance endogenetic fungus is characterized as:
The PDA solid medium, cultivated 6 days in 25 ℃ of darkrooms, and bacterium colony is a white hair shape, and neat in edge has the Steel Gray point when ripe; Crawl shape growth of mycelia is separated, and gives birth in the spore.
This bacterium has stronger salt tolerance: not containing well-grown on the PDA substratum of NaCl, on the high salinity PDA substratum that contains 1M, 2M, 3M NaCl, all grow fine, explain that this bacterium has very strong salt tolerance; But this bacterium does not have halophilism, because grow fine not containing on the NaCl PDA substratum.This bacterium also has stronger anti-oozing property: it is all very good that ocean of the present invention mangrove salt tolerance endogenetic fungus oozes on the substratum growing way at the PDA solid height that contains 2M, 3M Sorbitol Powder (sorbitol); And to the growing way basically identical of different concns Sorbitol Powder PDA substratum, this this bacterium of explanation has anti-the oozing property of stronger Sorbitol Powder.
Ocean mangrove salt tolerance endogenetic fungus SN3-2 of the present invention well-grown in the fungi basic culture solution: grow fine not containing NaCl and contain respectively in the liquid nutrient medium of 1M, 2M, 3M NaCl; The speed that this bacterium grows in the substratum that contains different N aCl concentration is different, and along with the increase of NaCl concentration, the speed of growth of bacterium continues to reduce, but colonial morphology, mycelia and conidium etc. are consistent.
The base sequence of the 18srDNA of ocean of the present invention mangrove salt tolerance endogenetic fungus is shown in SEQ ID NO:1.
The method of separating marine mangrove salt tolerance endogenetic fungus from the bark of mangrove rhizome portion:
1, the mangrove branch surface that collects is cleaned, brought into sterilisable chamber.Branch is surperficial with flame sterilization 10s～15s.With aseptic cutter it is cut into the segment of 3cm～4cm, 75% alcohol disinfecting 10min, 0.1% mercuric chloride soaks 3min.With sterilized water washing 5 times.Other establishes control group (with the sterilized water of last washing as contrast).The branch segment is inoculated in respectively on the PDA solid medium plate of the NaCl that contains concentration 1M and 3M (every kind of material 3 wares, 3 sections branches of every ware), is positioned in 25 ℃ of thermostat containers and cultivates;
2, wait to grow bacterium colony after, choose the tip of mycelia by the aseptic technique program, be inoculated on the PDA solid medium plate, carry out the separation and purification of bacterial classification, obtain the mangrove endogenetic fungus.
3, purebred bacterial strain being inserted the Sha Shi test tube slant preserves.Switching in per 3 months～4 months once.
The method of isolation of genomic DNA from the mangrove salt tolerance endogenetic fungus of ocean according to the invention:
It is active that ocean of the present invention mangrove salt tolerance endogenetic fungus SN3-2 secondary metabolite and thalline extract have significant nerve degenerative diseases control.Carrying out the nerve degenerative diseases key protein with external A-beta 42 Aggregation Model, Poly Q model etc. assemble to suppress screening active ingredients and discovers; This bacterium thalline extract has very strong A-beta, Poly Q assembles restraining effect, and it is active to demonstrate stronger nerve degenerative diseases control.
Anti-A-beta in the mangrove salt tolerance endogenetic fungus SN3-2 thalline extract of ocean of the present invention assembles effective constituent and has better water solubility; All more stable under the aqueous solution, organic solution, neutrallty condition, weak acid alkali condition, handle 120min successor at 70 ℃ and so keep the activity more than 95%.
It is active that ocean mangrove salt tolerance endogenetic fungus SN3-2 of the present invention has stronger anti-AD; Contain in its secondary metabolite is the anti-gathering type anti-AD active substance of target spot in a large number with the A-beta gathering; Possess the great potential of therefrom finding novel anti AD lead drug, will provide support for the research of novel anti AD medicine.The present invention has very important meaning and value to the research of AD specific medicament and the deep development of China's South Sea mangrove resource.
Description of drawings
Figure 1A and Figure 1B are respectively colonial morphology figure and the micro-structure diagram of ocean mangrove salt tolerance endogenetic fungus SN3-2 according to the invention, and micro-magnification is 1000.
Fig. 2 is the genomic dna nucleic acid agarose electrophoresis figure for ocean mangrove salt tolerance endogenetic fungus SN3-2 according to the invention and part correlation ocean mangrove salt tolerance endogenetic fungus; M: molecular weight is the nucleic acid Marker of 15000bp; 5 is the SN3-2 genomic dna, and 1-4 and 6 is respectively the genomic dna of part correlation ocean mangrove salt tolerance endogenetic fungus.
Fig. 3 is the external A-beta42 Aggregation Model of the thalline extract result of study of ocean mangrove salt tolerance endogenetic fungus SN3-2 according to the invention.
Fig. 4 is the external Poly Q of the thalline extract Aggregation Model result of study of ocean mangrove salt tolerance endogenetic fungus SN3-2 according to the invention.
Embodiment
The whole thinking of the present invention comprise following some: separating marine mangrove salt tolerance endogenetic fungus from the mangrove branch; Isolation of genomic DNA from the mangrove salt tolerance endogenetic fungus of ocean; Clone 18SrDNA sequence from the mangrove salt tolerance endogenetic fungus genome of ocean; The ocean mangrove salt tolerance endogenetic fungus that separation is obtained carries out salt tolerance, halophilism and anti-oozing property and analyzes; Extract ocean mangrove salt tolerance endogenetic fungus secondary metabolite, detect its anti-A-beta aggregation activity; Above each point is all independent embodiment, below will combine specific embodiment to explain further details.
The Pongamia glabra that marine site, Shenzhen mangrove Pongamia glabra is gathered according to following conditional filtering and cultivation, promptly can obtain the described ocean of this patent mangrove salt tolerance endogenetic fungus SN3-2 near root water surface top bark sample in the laboratory.
(1) substratum and preparation:
(1) PDA solid medium: yam 200g cleans peeling, adds water 800ml, boils 30min, six layers of filtered through gauze; Filtrating adds agar 15g, and adding glucose 20g, penicillium mould final concentration are that 80u/ml, Streptomycin sulphate final concentration are 36u/ml.0.1MPa, 121 ℃ of sterilization 30min, glucose, penicillium mould, Streptomycin sulphate are sterilized through filtering mode.
Penicillium mould specification: 1600u/mg, the 5g dress.Compound method: take by weighing 500mg and dissolve in the 10ml water, be mixed with the penicillium mould mother liquor, filter the back and preserve.Add 1ml penicillium mould mother liquor in every liter of substratum during preparing culture medium.The penicillium mould final concentration is 80u/ml.
Sulfuric acid strepto-specification is 720u/mg, the 10g dress.Compound method: take by weighing 500mg and dissolve in the 10ml water, be mixed with the Vetstrep mother liquor, filter the back and preserve.Add 1ml Vetstrep mother liquor in every liter of substratum during preparing culture medium.The Vetstrep final concentration is 36u/ml.
(2) the PDA solid contains salt culture medium: in the PDA solid medium, add NaCl, the PDA solid that obtains containing NaCl concentration and be 1M and 3M contains salt culture medium.
(3) PDA solid height oozes substratum: in the PDA solid medium, add D-sorbitol, obtaining containing sorbitol concentration is 2M, 3M, and the PDA solid height of 4M oozes substratum.
(4) fungi basic culture solution: peptone (peptone) 0.3%, ammonium sulfate 0.2%, yeast extract paste 0.05%; Potassium primary phosphate 0.4%, calcium chloride 0.03%, MAGNESIUM SULPHATE HEPTAHYDRATE 99.5 0.03%; Glucose 10g/L adds the different NaCl that measure respectively, makes its NaCl content be respectively 0-3M.0.1MPa, 121 ℃ of sterilization 30min.
(5) MS substratum:
Macroelement mother liquor (20 * 1L): 33g NH
4NO
3, 38g KNO
3, 8.8g CaCl
22H
2O, 7.4g MgSO
47H
2O, 3.4g KH
2PO
4
Trace element mother liquor (200 * 1L): 4.46g MnSO
4H
2O, 1.72g ZnSO
47H
2O, 0.005g CoCl
26H
2O, 0.005g CuSO
45H
2O, 1.24g H
3BO
3, 0.05g Na
2MO
42H
2O, 0.166g KI.
Mother liquid of iron salt (200 *, 1L): 5.74g FeSO47H2O, 7.46g EDTA.
Organism mother liquor (200 * 1L): 0.2g nicotinic acid, 0.2g pyridoxine hydrochloride (VB
6), 0.04g vitamin, 40g inositol, 0.8g glycocoll.
MS root media (1L): 50ml macroelement (20 *), 5ml trace element (200 *), 5ml organic element (200 *), 5ml molysite (200 *), 30g sucrose, NAA (0.2mg/L), the 10g agar powder, pH 6.0, autoclaving.
(2) concrete separation method
The collection Pongamia glabra, is cleaned the material surface that collects as parting material near root water surface top bark from the mangrove Pongamia glabra of marine site, Shenzhen, brings sterilisable chamber into.Branch is surperficial with flame sterilization 10s～15s.With aseptic cutter it is cut into the segment of 3cm～4cm, 75% alcohol disinfecting 10min, 0.1% mercuric chloride soaks 3min.With sterilized water washing 5 times.Other establishes control group (with the sterilized water of last washing as contrast).The branch segment is inoculated in respectively on the PDA solid medium plate of the NaCl that contains concentration 1M and 3M (every kind of material 3 wares, 3 sections branches of every ware), is positioned in 25 ℃ of thermostat containers and cultivates; After waiting to grow bacterium colony, choose the tip of mycelia, be inoculated on the PDA solid medium plate by the aseptic technique program; Carry out the separation and purification of bacterial classification, obtain ocean mangrove salt tolerance endogenetic fungus, called after Phomopsis occulta; Hide Phomopsis, the application abbreviates SN3-2 as.
Purebred bacterial strain is inserted the Sha Shi test tube slant to be preserved.Switching in per 3 months～4 months once.
SN3-2 is Phomopsis (Phomopsis), and cultivated 7 days in 25 ℃ of darkrooms, observes its morphological specificity and microscopic features, describes to see table 1 and Figure 1A, Figure 1B for details.
The cultural characteristic of table 1 ocean according to the invention mangrove salt tolerance endogenetic fungus SN3-2
The ocean mangrove salt tolerant endogenetic fungus bacterial classification that is separated to is inoculated into respectively to contain NaCl concentration be 1M, 2M, the high salt culture medium of PDA solid of 3M is cultivated in 25 ℃ of darkrooms, and its upgrowth situation of record is seen table 2 after 7 days.
Table 2 ocean mangrove salt tolerance endogenetic fungus is to the tolerance of salinity qualification result of NaCl
Annotate: one "+" expression bacterium colony covers with 1/4 flat board, and "-" expression bacterium colony is not grown.
Ocean mangrove salt tolerant endogenetic fungus bacterial classification behind the purifying is seeded in respectively contains on the salt-free PDA solid medium flat board of 1M NaCl/, cultivate in 25 ℃ of darkrooms, the record growing state, whether detect has halophilic bacterium.The result sees table 3, can know that SN3-2 is non-halophilic bacterium.
Table 3 ocean mangrove salt tolerant endogenetic fungus halophilism detected result
Annotate: "+" expression bacterium colony has growth, and "-" expression bacterium colony is not grown.
The ocean mangrove salt tolerant endogenetic fungus bacterial classification that is separated to is inoculated into respectively to contain Sorbitol concentration be 2M, 3M, the PDA solid height of 4M oozes substratum, cultivates in 25 ℃ of darkrooms, writes down its upgrowth situation, measures its anti-degree of oozing, and the result sees table 4.
Anti-the oozing property qualification result of table 4 ocean mangrove salt tolerance endogenetic fungus
Annotate: "+" expression bacterium colony covers with 1/4 flat board, and "-" expression bacterium colony is not grown.
Isolation of genomic DNA agarose gel electrophoresis result sees Fig. 2 in the mangrove salt tolerance endogenetic fungus of ocean.
From the mangrove salt tolerance endogenetic fungus genomic dna of ocean, separate 18SrDNA, its base sequence is shown in SEQ ID NO:1.
(1) extraction of ocean according to the invention mangrove salt tolerance endogenetic fungus SN3-2 secondary metabolite preparation:
(1) ocean mangrove salt tolerance endogenetic fungus SN3-2 according to the invention at first is seeded to the fungi basic culture solution by the PDA solid medium that contains different concns NaCl; Be transferred to respectively after 2 days and contain 0,1,2, coerce cultivation among each 50L of fungi basic culture solution of 3M NaCl, 25 ℃ leave standstill and cultivated 40 days;
(2) different concns NaCl fungi basic culture solution filters respectively, and the fermented liquid merging is concentrated into 1L, uses the equal-volume ethyl acetate extraction 3 times, and extraction liquid merges, and low temperature (45 ℃) decompression is divided exactly solvent and got SN3-2 fermented liquid extract;
(3) thalline difference low-temperature vacuum drying,, dipping ultrasonic with 3L methyl alcohol extracts 3 times, and extracting solution merges, and low temperature (45 ℃) decompression is divided exactly solvent and is got SN3-2 bacterium thalline extract;
(4) according to the characteristic of different sorts composition, adopt methods such as TLC, SGCC, HPLC, HPCE, FS to crude extract separate repeatedly, purifying, and finally obtain the meta-bolites monomer.
(2) the external A-beta42 Aggregation Model of ocean mangrove salt tolerance endogenetic fungus secondary metabolite according to the invention research:
ThT analyzes and uses synthetic A β 42 polypeptide, and 37 ℃ left standstill 2 hours, added final concentration 100 each sample of μ g/mL, and with the fluorescence intensity of fluorescence microplate reader test reaction system, excitation wavelength is 444nm, and emission wavelength is 485nm.With the negative contrast of DMSO, the positive contrast of EGCG can judge that according to the difference of system fluorescence intensity component suppresses active to the A-beta accumulative.Experimental result is referring to Fig. 3.The experimental result explanation: a plurality of sample relative intensity of fluorescence are lower, A-beta42 assembled have remarkable restraining effect, and the sample segment restraining effect is better than positive control sample EGCG or approaching with it.
(3) the external Poly Q of ocean mangrove salt tolerance endogenetic fungus secondary metabolite according to the invention Aggregation Model research:
ThT analyzes and uses purifying Poly Q albumen, and 37 ℃ left standstill 2 hours, added final concentration 100 each sample of μ g/mL, and with the fluorescence intensity of fluorescence microplate reader test reaction system, excitation wavelength is 444nm, and emission wavelength is 485nm.With the negative contrast of DMSO, the positive contrast of EGCG can judge that according to the difference of system fluorescence intensity component suppresses active to Poly Q accumulative.Experimental result is referring to Fig. 4.The experimental result explanation: a plurality of sample relative intensity of fluorescence are lower, Poly Q assembled have remarkable restraining effect, and sample segment restraining effect and positive control sample EGCG are approaching.
Claims (5)
1. one kind has nerve degenerative diseases and prevents and treats active ocean mangrove salt tolerance endogenetic fungus, and its deposit number is CCTCC M2011044.
2. according to claim 1 a kind ofly have nerve degenerative diseases and prevent and treat active ocean mangrove salt tolerance endogenetic fungus, and it is characterized in that: the base sequence of its 18srDNA is shown in SEQ ID NO:1.
3. the method for separating marine mangrove salt tolerance endogenetic fungus from the mangrove bark may further comprise the steps:
1) gets the mangrove bark, clean, bring the sterilisable chamber sterilization into;
2) the mangrove bark of will sterilizing is inoculated in respectively on the PDA solid medium plate of the NaCl that contains concentration 1M and 3M, is positioned in 25 ℃ of thermostat containers and cultivates;
3) wait to grow bacterium colony after, choose the tip of mycelia by the aseptic technique program, be inoculated on the PDA solid medium plate, carry out the separation and purification of bacterial classification, obtain ocean mangrove salt tolerance endogenetic fungus.
4. according to claim 3 from the mangrove bark method of separating marine mangrove salt tolerance endogenetic fungus, it is characterized in that: said mangrove bark is the bark near root water surface top.
According to claim 3 or 4 described from the mangrove bark method of separating marine mangrove salt tolerance endogenetic fungus; It is characterized in that: said mangrove bark is after using sterilization behind the surface sterilization; Aseptic cutter is cut into the segment of 3cm～4cm with it, soaks sterilization with alcohol and mercuric chloride again.
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| US9114130B2 (en) | 2013-05-06 | 2015-08-25 | University Of South Florida | Compounds and related methods for treatment of neurodegenerative diseases |
| CN111032061A (en) * | 2017-06-14 | 2020-04-17 | 4D制药研究有限公司 | Compositions comprising bacterial strains |
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2011
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