CN1183960C - Use of bifidobacterium cell wall and bifidobacterium cell wall protein in pharmacy - Google Patents
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- CN1183960C CN1183960C CN 03117357 CN03117357A CN1183960C CN 1183960 C CN1183960 C CN 1183960C CN 03117357 CN03117357 CN 03117357 CN 03117357 A CN03117357 A CN 03117357A CN 1183960 C CN1183960 C CN 1183960C
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Abstract
In the present invention, an experiment verifies that a bacillus bifidus cell wall and cell wall albumen are effective factors for activating phylaxin genes and enhancing the expression of phylaxin, and therefore, the bacillus bifidus cell wall and the cell wall albumen can be used for preparing a medicine for activating mammal phylaxin genes. Medication methods comprise oral taking, venous injection, inhalation or suppository, and enema or oral irrigation. The medicine is mainly used for immunization therapy on infectious diseases of the digestive canal, the respiratory tract, the genitourinary tract, etc. according to the characteristics of phylaxin in a human body.
Description
One, technical field
The present invention relates to the purposes of bifidobacterium cells wall and bifidobacterium cells wall-held protein, particularly the purposes in pharmaceutical field.
Two, background technology
Bacillus bifidus is to find one of physiological antibacterial the earliest, has now obtained clinical practice at the aspects such as treatment of the control of intestinal tract disease, hepatopathy and (has seen " bacillus bifidus " P
131-139, Kang Bai chief editor, publishing house of the Maritime Affairs University Of Dalian, in May, 1998).Studies show that, it is to the body immune system important influence, especially can activate body immune system, for example, activating macrophage, bone-marrow-derived lymphocyte, NK cell ... (see " the immune activation effect and the biological significance thereof of bacillus bifidus ", the Wang Lisheng summary, Pan makes good Zhou Dianyuan examine and revise, foreign medical science physiology, pathology science and clinical fascicle, 1998.18 (4), P
320-322), but Shang Weijian activates the report of alexin (defensins) aspect about bifidobacterium cells wall and cell wall protein.
Three, summary of the invention
The objective of the invention is to prove that bifidobacterium cells wall and cell wall protein have the effect that activates the phylaxin gene expression, so that develop the new medicine of a class.
Alexin is that a class is rich in cysteine and arginic low molecular polypeptide, is distributed widely in animal, plant and the insect bodies.Compare with other antimicrobial peptides, alexin has special resistance mechanism, and it mainly acts on the cell membrane of pathogenic microorganism, makes pathogenic microorganism be difficult for it is produced resistance.And other antimicrobial peptides mainly act on the enzyme of microorganism, and the sudden change of enzyme gene will make target cell that it is produced resistance, so alexin has other antimicrobial peptide incomparable advantage.Alexin also has antimicrobial spectrum very widely in addition, external bacteriostatic experiment show alexin can antibacterium, multiple microorganism such as fungus, tunicle virus, especially the mammal alexin is except having the toxic action antibacterial, fungus, tunicle virus, also mycoplasma, chlamydia, spirillum and some malignant cells (as tumor cell) and HIV (human immunodeficiency virus) there are lethal effect, have antimicrobial spectrum more widely.Except the direct killing pathogenic microorganism, also stimulation effect of function to the natural immunity and acquired immune system, therefore the using value of application prospect and Geng Gao is widely pharmaceutically being arranged, but it is high to separate the alexin cost from host's organism, make alexinic utilization be restricted and (see " alexinic progress of mammal and application prospect thereof " Chen Ying, Ge Yiqiang etc., biochemistry and biophysics progress, 2001; 28 (1), P
17-21).Studies show that recently, alexin (endogenous antibacterial peptide) has the characteristics of abduction delivering, infect, but wound and inflammation signal chafe and mucomembranous epithelial cell are synthetic and secretion endogenous antibacterial peptide (is seen DiamandG, Bevins CL. β-defensins:Endogenous antilcuotics of the innate host defense response.Clin Immunol Immunopathol, 1998,88:221-225), card vaccine protein in cell wall can strengthen expression and the antibacterial activity thereof of people's lung glandular epithelium alexin hBD-1 mRNA and (see " enhancing that card vaccine protein in cell wall is induced people's lung glandular epithelium hBD-1 mRNA expression and antibacterial activity thereof ", Feng Yun etc., China's microbiology and Journal of Immunology the 21st the 4th phase of volume of July calendar year 2001, P
400-403).As seen, stimulating alexin to express by activation factor is to utilize an alexinic more real approach.
The present invention has proved that by experiment bifidobacterium cells wall and cell wall protein are effective activation factors to phylaxin gene, and alexinic expression is obviously increased.Activated mammal alexin is beta-alexin-1, beta-alexin-2, beta-alexin-3, beta-alexin-4, LL-37/CAP18.Therefore, bifidobacterium cells wall and cell wall protein can be prepared into the medicine that activates the mammal phylaxin gene, administrated method can be by oral, intravenous injection, suction or suppository, coloclysis or dentilave.According to alexinic characteristics in the human body, this type of medicine is mainly used in the immunization therapy of infectious disease such as digestive tract, respiratory tract, urogenital tract.
The bifidobacterium cells wall among the present invention and the preparation method of cell wall protein are as follows:
1, the preparation of bifidobacterium cells wall
With freeze dried bacillus bifidus be dissolved in lysate (0.02mol/L phosphate buffer pH7.4,0.025%PMSF) in, under the ice bath, 20,000 hertz of ultrasonic intermittent processing 10～15 times, each processing time is 2 minutes, be 1～3 minute each blanking time, centrifugal 5 minutes of 2000xg gets supernatant, and then 55, centrifugal 30 minutes of 000xg, get precipitation, be dissolved in the phosphate buffer of 0.02mol/L, obtain cell-wall component.
2, the preparation of bifidobacterium cells wall-held protein
The bifidobacterium cells wall is dissolved in the phosphate buffer that contains 1～2%SDS, hatched under the room temperature 30～45 minutes, 55,000～75, centrifugal 30～45 minutes of 000xg gets supernatant, dialysed 3 days, operation sequence by the sedimentation method is removed SDS, then-70 ℃ freezing, concentrate through the freeze dryer lyophilizing at-112 ℃, the storage temperature of the bifidobacterium cells wall-held protein after the lyophilization is-20 ℃.
The present invention has the following advantages and good effect:
1, the medicine of bifidobacterium cells wall and bifidobacterium cells wall-held protein preparation reaches the purpose of disease preventing and treating by the intravital phylaxin gene of activation machine, has opened up a kind of new immunotherapy.
2, alexin can be at mammiferous a lot of tissue expressions, brain for example, kidney, heart, spleen, the cheek mucosa, nasal mucosa, the eye conjunctiva, the tongue choroid plexus, trachea, bronchus, wash bronchus, fallopian tube, the uterus, cervix uteri, vagina, testis, bladder, urethra, esophagus, duodenum, jejunum, ileum, caecum, ascending colon, second is strengthened colon, caecum, descending colon and rectum, ear, pancreas, liver, ovary etc., thereby the medicine of bifidobacterium cells wall and the preparation of bifidobacterium cells wall-held protein can be used to treat the disease that mammal comprises that a plurality of tissue of human and animal is suffered from.
3, bacillus bifidus is useful for the host, be in commensalism between them, thereby the medicine of bifidobacterium cells wall and the preparation of bifidobacterium cells wall-held protein only kills the non-probiotic bacteria of the sensitivity that comprises pathogen when the expression of induced defence element, and do not have direct effect for probiotic bacteria, and can make probiotic bacteria obtain more nutrition, this for probiotic bacteria in vivo microecological environment very effective growth vigor is provided.
4, the source of bacillus bifidus is wide, and the preparation method of bifidobacterium cells wall and bifidobacterium cells wall-held protein is simple, is convenient to realize suitability for industrialized production.
Four, description of drawings
Fig. 1 is the detection figure of bifidobacterium cells wall-held protein, and among the figure, A is the bifidobacterium cells wall-held protein of removing before the SDS, and B is the bifidobacterium cells wall-held protein of removing behind the SDS, and M is a protein molecular marker;
Fig. 2 is total RNA detection figure of people's enteraden epithelial cell HT-29 of each experimental group;
Fig. 3 utilizes RT-PCR detection bacillus bifidus, bifidobacterium cells wall, bifidobacterium cells wall-held protein to induce the experimental result picture of people's enteraden epithelial cell people's beta-alexin-1 (hBD-1) gene expression, among the figure, A is the basal expression that the hBD-1mRNA of HT-29 cell own has low amount, B is the expression that bacillus bifidus stimulates back hBD-1mRNA, C stimulates the expression of back hBD-1mRNA for the bifidobacterium cells wall, the expression that D stimulates back hBD-1mRNA for the bifidobacterium cells wall-held protein, M is a dna molecular amount labelling;
Fig. 4 is the experimental result picture that utilizes Northern technology for detection bacillus bifidus, bifidobacterium cells wall, bifidobacterium cells wall-held protein to induce people's enteraden epithelial cell people's beta-alexin-1 (hBD-1) mRNA to express, among the figure, the negative contrast of A HT-29 cell total rna, B is the post-stimulatory HT-29 cell total rna of bacillus bifidus, C is the post-stimulatory HT-29 cell total rna of bifidobacterium cells wall, and D is the post-stimulatory HT-29 cell total rna of bifidobacterium cells wall-held protein;
Fig. 5 utilizes RT-PCR detection bacillus bifidus, bifidobacterium cells wall, bifidobacterium cells wall-held protein to induce the experimental result picture of people's enteraden epithelial cell people's beta-alexin-2 (hBD-2) gene expression, among the figure, the expression of the negative contrast of A hBD-2mRNA, B is the expression that bacillus bifidus stimulates back hBD-2mRNA, C stimulates the expression of back hBD-2mRNA for the bifidobacterium cells wall, the expression that D stimulates back hBD-2mRNA for the bifidobacterium cells wall-held protein, the expression that the positive contrast of E IL-1 β stimulating group is induced hBD-2mRNA;
Fig. 6 utilizes Northern technology for detection bacillus bifidus, bifidobacterium cells wall, bifidobacterium cells wall-held protein to induce the experimental result picture of people's enteraden epithelial cell people's beta-alexin-2 (hBD-2) mRNA, among the figure, the negative contrast of A HT-29 cell total rna, B is the post-stimulatory HT-29 cell total rna of bacillus bifidus, C is the post-stimulatory HT-29 cell total rna of bifidobacterium cells wall, D is the post-stimulatory HT-29 cell total rna of bifidobacterium cells wall-held protein, the HT-29 cell total rna behind the positive contrast of the E IL-1 β;
Fig. 7 utilizes RT-PCR detection bacillus bifidus, bifidobacterium cells wall, bifidobacterium cells wall-held protein to induce the experimental result picture of people's enteraden epithelial cell LL-37/CAP18 gene expression, among the figure, the negative contrast of A does not have the expression of LL-37/CAP18mRNA, B is the expression that bacillus bifidus stimulates back LL-37/CAP18mRNA, the expression that C stimulates back LL-37/CAP18mRNA for the bifidobacterium cells wall, D stimulates the expression of back LL-37/CAP18AmRNA for the bifidobacterium cells wall-held protein.
Five, the specific embodiment
1, cell strain and bacterial strain
People's enteraden epithelial cell strain HT-29 derives from ATCC, infection immunity research department by the applicant preserves, bacillus bifidus (long bifid B.longum NQ-1501) is cultivated in School of Stomatology microbial room of West China Center of Medical Sciences of Sichuan University by the applicant, and identifies that through Chinese pharmaceutical biological product China's prevention academy of science Institute of Epidemiology and Microbiology identifies in one's power.Be inoculated in the MRS culture medium, 37 ℃ of anaerobism were cultivated 48 hours.
Preparation MRS culture medium (1 liter):
Many peptones of albumen 10g, yeast powder 5g, tryptone 3g, glucose 10g, soluble starch 0.5g, ferrous sulfate 100mg, manganese sulfate 6.74mg, magnesium sulfate 200mg, cysteine 0.5g, potassium dihydrogen phosphate 1g, dipotassium hydrogen phosphate 1g, sodium chloride 100mg, sodium acetate 5g, trisodium citrate 2g, tween 80 1.0g, adding distil water to 1 liter, regulating pH is 7.2, high temperature, high pressure, sterilization.
2. reagent
Agarose, two step method RT-PCR test kit, dna molecular amount reference material are Takara company product.PCR product purification test kit, digoxigenin labeled and detection kit etc. are Boehringer Mannheim company product.It is Invitrogen company product that RNA extracts reagent (TRIZOL).SDS-Out
TMSodium Dodecyl SulfatePrecipitation Kit Reagent and BCA Protein Assay Kit test kit are PIERCE company, and reorganization IL-1 β is available from PeproTech EC.Ltd. company.All the other are homemade analytical pure.
3, primer
According to gene bank people beta-alexin-1 cDNA sequential design special primer, NM_005218.R1:ACT TCCTAC CTT CTG CTG TT R2:CTG CGT CAT TTC TTC TGG, expanding fragment length is 230 bases.Beta-alexin-2 cDNA sequential design special primer, accession number is (NM_004942.2).R1:5 ' TGA TGCCTC TTC CAG GTG TT 3 ', R2:5 ' GAT GAG GGA GCC CTT TCT GA 3 ', expanding fragment length is 205 bases.LL-37/CAP18 cDNA sequence (accession number is X96735) design special primer, F1 5 '-3 ' AAC GGA TCC TTT GCC CTG CTG; F2 5 '-3 ' CCA GGA TCC GGC ACA CAC TAG.Expanding fragment length is 114 bases.β-the actin primer is an internal reference to the while designer, R1:5 ' GCG GGA AATCGT GCG TGA CATT 3 ', and R2:5 ' GAT GGA GTT GAA GGT AGT TTC GTG 3 ', expanding fragment length is 231 bases.
4, the preparation of bacillus bifidus effective ingredient:
(1) preparation of antibacterial stimulus object
Cultivate bacillus bifidus, 8000xg, centrifugation in 10 minutes is collected, 0.02mol/L phosphate buffer (pH7.4) washing 3 times.Take by weighing 10mg after the lyophilizing, be suspended in the 1ml phosphate buffer, reach 10
9Individual/ml bacterium number, boiling water boils bathed 5 minutes.
(2) preparation of bifidobacterium cells wall fraction
Take by weighing freeze dried bacillus bifidus 500mg, be dissolved in the 5ml lysate (0.02mol/L phosphate buffer pH7.4,0.025%PMSF) in, 20,000 hertz of supersound process 2 minutes, 15 times, each 1 minute at interval.Centrifugal 5 minutes of 2000xg gets supernatant, and then 55, centrifugal 30 minutes of 000xg gets precipitation, is dissolved in the phosphate buffer of 0.02mol/L, obtains cell-wall component.
(3) preparation of bifidobacterium cells wall-held protein component
Cell-wall component is dissolved in the PBS buffer that contains 2%SDS, hatched under the room temperature 30 minutes, 55, centrifugal 30 minutes of 000xg gets supernatant, dialyses 3 days, presses SDS-Out
TMThe operation sequence of Sodium Dodecyl Sulfate Precipitation Kit is removed SDS, the cell wall protein of removing the SDS front and back is carried out the discontinuous gel electrophoresis of degeneration (SDS), detect protein band, show that cell wall protein is the mixed protein molecule of the about 15kDa～100kDa of molecular weight, carrying out protein quantification with BCA Protein Assay Kit test kit simultaneously measures, and soluble protein after vacuum lyophilization ,-20 ℃ of preservations.As can be seen from Figure 1, the no significant difference of cell wall protein (B) after removing the preceding cell wall protein (A) of SDS and removing SDS shows that protein extracting method is feasible.
5, people's enteraden epithelial cell HT-29 cell culture stimulation test
Do the stimulation test of adhere-wall culture cell with reference to methods such as Ming Zhang.Get 3 * 10
5The HT-29 cell inoculation is in six orifice plates, 37 ℃, 5%CO
2Cultivated 2-3 days under the condition, when cell length to 10
6, be used for stimulation test.Abandon culture fluid,, add cold PBS with RPMI1640 flush away attached cell not, 4 ℃ hatch the 20min washing after, adding 2ml serum-free RPMI1640 culture medium and bacillus bifidus, bifidobacterium cells wall, bifidobacterium cells wall-held protein carry out stimulation test.Bacillus bifidus is 10
6Individual/ml, the bifidobacterium cells wall is 100 μ g/ml, and bacillus bifidus protein in cell wall matter irritaiting concentration is 50 μ g/ml.If the positive contrast of IL-1 β of 20ng/ml, the negative contrast of unprovoked cell.Continue to cultivate 8 hours.Stimulation test repeats 3 times.
6, total RNA of cultured cell extracts and RT-PCR
The extraction of the total RNA of attached cell is undertaken by TRIZOL RNA purification kit operating instruction.Quality through ultraviolet spectrometry degree meter and agarose gel electrophoresis detection RNA reaches quantitatively no significant difference (see figure 2) between each group.The RT-PCR condition is: first step reverse transcription reaction, and the total RAN of 1 μ l cell, reaction final volume 20 μ l, 55 ℃ of 30min, it is cDNA that 95 ℃ of 5min make the mRNA reverse transcription.The second step PCR reaction, 50 μ l reaction volumes, each reactant final concentration is MgCl
22.5mM, Taq
TMEnzyme 2units, primer 0.2 μ M, the cDNA product of 5 μ l reverse transcriptions, the buffer of 1x and water, 94 ℃ of pre-degeneration 3min, carry out 30 PCR circulations then: 94 ℃ of 30s, 58 ℃ of 35s, 72 ℃ of 45s, 72 ℃ are continued to extend 8min.
7, Northern hybridization
Press " Dig DNA labeling and Detecting Kit " description operation of Boehringer Mannheim company, respectively labelling hBD-1, hBD-2 and β-actin cDNA probe.With the not negative contrast of stimulating group, carry out formaldehyde-sepharose electrophoresis simultaneously with bacillus bifidus, bifidobacterium cells wall, bifidobacterium cells wall-held protein stimulating group and positive control IL-1 β stimulating group RNA, change film, fixing, prehybridization, hybridization is after the NBT/BCIP colour developing.
8, experimental result
(1) about inducing people's enteraden epithelial cell people's beta-alexin-1 (hBD-1) mRNA to strengthen the experimental result of expressing
People's beta-alexin-1 (hBD-1) has strong bactericidal activity to gram-negative bacteria, the intrinsic expression of low amount is generally arranged in tissue, can express enhancing when being subjected to exogenous stimulation, its wide expression is in epithelial cell and alveolar cells such as kidney, female genital tract, oral mucosa, trachea, bronchus, intestinal, salivary gland pancreas, lung submucosal glands.Above-mentioned RT-PCR and the experiment of Northern hybridization technique show: bacillus bifidus can induce beta-alexin-1 gene expression to increase a little, and bifidobacterium cells wall, bifidobacterium cells wall-held protein induce beta-alexin-1 expression obviously to increase, and see Fig. 3, Fig. 4.
(2) experimental result about inducing people's enteraden epithelial cell people's beta-alexin-2 (hBD-2) mRNA to express
People's beta-alexin-2 (hBD-2) has the feature of abduction delivering, mainly is expressed in the epidermis of tissues such as skin, lung, kidney, liver, small intestinal, salivary gland, trachea, uterus, can kill gram-negative bacteria, gram-positive bacteria, fungus effectively.Above-mentioned RT-PCR and the experiment of Northern hybridization technique show: bacillus bifidus can be induced the hBD-2 expression of gene, and is less but the amount of abduction delivering compares; The bifidobacterium cells wall can obviously be induced the expression of hBD-2, and inductive expression is increased obviously; The bifidobacterium cells wall-held protein can obviously be induced the expression of hBD-2, sees Fig. 5, Fig. 6.
(3) induce the experimental result of people's enteraden epithelial cell people LL-37/CAP18 about bacillus bifidus
LL-37/CAP18 is the intravital antibacterial peptide of unique people of existence in the Cathelicidine family, have broad spectrum antibiotic activity and cytotoxicity, it is a linear peptides, in mucosal immunity, has important effect, the natural immunity and acquired immunity are all played a role, therefore come into one's own day by day at the antibiotic peptide development field.The LL-37/CAP18 expression way is intrinsic expression and abduction delivering, is intrinsic expression at bone marrow and epididymal, then shows as abduction delivering at the horn cell and the enterocyte of application on human skin.Above-mentioned RT-PCR experiment shows: bacillus bifidus itself can be induced the expression of LL-37/CAP18, and is less but the amount of abduction delivering compares; The bifidobacterium cells wall can obviously be induced the expression of LL-37/CAP18, and inductive expression is increased obviously; Bifidobacterium cells wall-held protein composition, Fig. 7 is seen in the expression that can obviously induce LL-37/CAP18.
The Sequence Identification of hBD-1, hBD-2, LL-37/CAP18 encoding gene:
The total RNA of special primer personnel selection enteraden epithelial cell (HT-29) cell among the present invention is the resulting hBD-1 of template, hBD-2, LL-37/CAP18 RT-PCR product, obtain the band of 1 treaty 230bp, 200bp, 110bp respectively through 1.5% agarose gel electrophoresis inspection, conform to estimating the amplified fragments size, sequencing result conforms to hBD-2, hBD-1, the LL-37/CAP18 gene cDNA sequence of Genbank login.
Claims (1)
1, the application of bifidobacterium cells wall-held protein in the medicine of preparation activation HEP's beta-alexin-1 and beta-alexin-2 gene.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012526752A (en) * | 2009-05-11 | 2012-11-01 | ネステク ソシエテ アノニム | Bifidobacterium longum NCC2705 (CNCMI-2618) and immune disorders |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7862808B2 (en) * | 2004-07-01 | 2011-01-04 | Mead Johnson Nutrition Company | Method for preventing or treating respiratory infections and acute otitis media in infants using Lactobacillus rhamnosus LGG and Bifidobacterium lactis Bb-12 |
| DE102012203547A1 (en) * | 2012-03-07 | 2013-09-12 | Robert Bosch Gesellschaft Für Medizinische Forschung Mbh | Antimicrobial peptides |
| BR112019017940A2 (en) | 2017-02-28 | 2020-05-19 | Alimentary Health Ltd | bifidobacterium longum capable of beneficially modulating immune response to respiratory virus infection |
| CN110392734A (en) * | 2017-02-28 | 2019-10-29 | 营养健康有限公司 | It can valuably bifidobacterium longum of the metering needle to the immune response of respiratory virus infection |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2012526752A (en) * | 2009-05-11 | 2012-11-01 | ネステク ソシエテ アノニム | Bifidobacterium longum NCC2705 (CNCMI-2618) and immune disorders |
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