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WO2016080449A1 - Inhibiteur du stress du réticulum endoplasmique - Google Patents

Inhibiteur du stress du réticulum endoplasmique Download PDF

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Publication number
WO2016080449A1
WO2016080449A1 PCT/JP2015/082424 JP2015082424W WO2016080449A1 WO 2016080449 A1 WO2016080449 A1 WO 2016080449A1 JP 2015082424 W JP2015082424 W JP 2015082424W WO 2016080449 A1 WO2016080449 A1 WO 2016080449A1
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WIPO (PCT)
Prior art keywords
bifidobacterium
endoplasmic reticulum
ferm
reticulum stress
strain
Prior art date
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Ceased
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PCT/JP2015/082424
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English (en)
Japanese (ja)
Inventor
拓哉 秋山
憲司 大石
アンディ ウラールト
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Yakult Honsha Co Ltd
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Yakult Honsha Co Ltd
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Priority to JP2016560271A priority Critical patent/JP6670251B2/ja
Publication of WO2016080449A1 publication Critical patent/WO2016080449A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria

Definitions

  • the present invention relates to an inhibitor of endoplasmic reticulum stress involved in cardiomyopathy and the like.
  • Patent Document 1 As preventive and therapeutic agents for diseases caused by endoplasmic reticulum stress, ASK1 inhibitors (Patent Document 1), fat-soluble extract components derived from mulberry yellow (Patent Document 2), Yokukansan (Patent Document 3) and the like have been reported. Yes.
  • the subject of this invention is providing the endoplasmic reticulum stress inhibitor which has the safe and outstanding effect.
  • the present inventors searched for endoplasmic reticulum stress inhibitors by paying attention to probiotics, and found that Bifidobacterium bacteria have a strong endoplasmic reticulum stress inhibitory action, thereby completing the present invention.
  • the present invention provides the following [1] to [12].
  • An endoplasmic reticulum stress inhibitor containing a Bifidobacterium genus and / or a treated product thereof as an active ingredient.
  • the genus Bifidobacterium is at least one selected from Bifidobacterium breve, Bifidobacterium adrecentis, Bifidobacterium bifidum and Bifidobacterium longum
  • the endoplasmic reticulum stress inhibitor as described.
  • Bifidobacterium bacteria are Bifidobacterium breve YIT12272 strain (FERM BP-11320), Bifidobacterium breve YIT10001 strain (FERM BP-8205), Bifidobacterium adrecentis YIT4011 strain Endoplasmic reticulum stress according to [1] or [2], which is at least one selected from (ATCC 15703), Bifidobacterium bifidum YIT10347 strain (FERM BP-10613) and Bifidobacterium longum YIT4021 strain (ATCC15707) Inhibitor.
  • the genus Bifidobacterium is one or more selected from Bifidobacterium breve, Bifidobacterium adrecentis, Bifidobacterium bifidum and Bifidobacterium longum [4] Use of description.
  • Bifidobacterium genus bacteria are Bifidobacterium breve YIT12272 strain (FERM BP-11320), Bifidobacterium breve YIT10001 strain (FERM BP-8205), Bifidobacterium adrecentis YIT4011 strain The use according to [4] or [5], which is one or more selected from (ATCC 15703), Bifidobacterium bifidum YIT10347 strain (FERM BP-10613) and Bifidobacterium longum YIT4021 strain (ATCC15707).
  • the genus Bifidobacterium is one or more selected from Bifidobacterium breve, Bifidobacterium adrecentis, Bifidobacterium bifidum and Bifidobacterium longum [7] The bacterium described above and / or a treated product thereof.
  • Bifidobacterium genus bacteria include Bifidobacterium breve YIT12272 strain (FERM BP-11320), Bifidobacterium breve YIT10001 strain (FERM BP-8205), Bifidobacterium adrecentis YIT4011 strain (ATCC15703), Bifidobacterium bifidum YIT10347 strain (FERM BP-10613) and Bifidobacterium longum YIT4021 strain (ATCC15707), which is one or more selected from [7] or [8] Or a treated product thereof.
  • a method for suppressing endoplasmic reticulum stress comprising administering an effective amount of a Bifidobacterium bacterium and / or a treated product thereof.
  • the genus Bifidobacterium is one or more selected from Bifidobacterium breve, Bifidobacterium adrecentis, Bifidobacterium bifidum and Bifidobacterium longum [10] The method described.
  • Bifidobacterium bacteria are Bifidobacterium breve YIT12272 strain (FERM BP-11320), Bifidobacterium breve YIT10001 strain (FERM BP-8205), Bifidobacterium adrecentis YIT4011 strain
  • the endoplasmic reticulum stress inhibitor of the present invention is useful as a preventive and therapeutic agent for cardiomyopathy and the like because of its high safety and strong endoplasmic reticulum stress inhibitory action.
  • FIG. 6 shows Western blotting of Grp78 expression in Caco-2 monolayers after tunicamycin stimulation.
  • the lower row shows Western blotting of ⁇ actin (loading control) expression.
  • 2 shows the effect of Bifidobacterium (YIT10001 strain) on the enhancement of membrane permeability of Caco-2 monolayers caused by endoplasmic reticulum stress (stunicamycin stimulation from the apical side).
  • 2 shows the effect of Bifidobacterium (YIT10001 strain) on the enhancement of membrane permeability of Caco-2 monolayers caused by endoplasmic reticulum stress (stimulated tunicamycin from the basal side).
  • 2 shows the effect of various Bifidobacteria on enhancement of membrane permeability of Caco-2 monolayers caused by endoplasmic reticulum stress (stunicamycin stimulation from the apical side).
  • the effect of Bifidobacterium (YIT4001 strain, YIT10347 strain) on the expression of endoplasmic reticulum stress marker (CHOP) is shown.
  • the lower row shows Western blotting of ⁇ actin (loading control) expression.
  • the effect on the expression of UGGT mRNA in Caco-2 monolayer of various Bifidobacterium is shown.
  • the active ingredient of the endoplasmic reticulum stress inhibitor of the present invention is a bacterium belonging to the genus Bifidobacterium and / or a treated product thereof.
  • the bacteria belonging to the genus Bifidobacterium at least one selected from Bifidobacterium breve, Bifidobacterium adrecentis, Bifidobacterium bifidum and Bifidobacterium longum is preferable.
  • Bifidobacterium breve YIT12272 (FERM BP-11320), Bifidobacterium breve YIT10001 (FERM BP-8205), Bifidobacterium adrecentis YIT4011
  • the method for preparing the genus Bifidobacterium used in the present invention is not particularly limited, and may be performed according to a conventional method.
  • the Bifidobacterium genus bacterium used in the present invention is cultured by inoculating the inoculum of the bacterium into a proliferable medium, and using a means for isolating and purifying the microbial cells such as centrifugation and filtration after the culture.
  • the bacterium can be used as it is, the lyophilized microbial cell, a dead cell obtained by subjecting the microbial cell to heat treatment or alcohol treatment, and a culture containing the microbial cell.
  • the culture containing the bacteria is subjected to a treatment such as heat treatment or the like. May be used as an active ingredient of the endoplasmic reticulum stress inhibitor of the present invention.
  • the medium capable of growing Bifidobacterium is not particularly limited, and is a nutrient medium composed of various organic and inorganic nutrient sources, such as GAM medium, MRS medium, BL medium, and the like. Can be mentioned.
  • animal milk such as cow's milk, goat milk, skim milk, milk powder, skim milk powder, milk products such as fresh cream, soy milk, processed soybean products such as soy flour, etc. can be used as a suitable medium. These may be used as they are or after diluting or concentrating to an appropriate concentration as necessary.
  • the pH of the medium is not particularly limited.
  • Bifidobacterium genus bacteria may not always have good growth depending on the type of medium. Therefore, a known bifido that can be used as a yeast extract, soybean peptide, or other fermentation aid in the medium as necessary. It is preferable to add a growth promoting substance for bacteria belonging to the genus Bacteria and a reducing agent such as vitamin C.
  • the culture of Bifidobacterium using the above-mentioned medium is not particularly limited as long as normal culture conditions are applied as they are. That is, various conditions such as temperature, time, and culture atmosphere suitable for the Bifidobacterium inoculated into the medium may be appropriately set.
  • the culture temperature may be 25 to 46 ° C., preferably 35 to 42 ° C.
  • the culture time may be 6 to 120 hours, preferably 24 to 72 hours.
  • the culture atmosphere is preferably carried out under anaerobic conditions, and the culture method is not particularly limited, such as standing, stirring, shaking, etc., and any of them may be selected.
  • Bifidobacterium genus bacteria used as an active ingredient of the endoplasmic reticulum stress inhibitor of the present invention many of these microorganisms have been conventionally used for the production of various fermented foods such as yogurt, so they are always taken orally. However, it is safe and has an excellent endoplasmic reticulum stress-suppressing action as shown in Examples below, and therefore can be used as a prophylactic and therapeutic drug for diseases caused by endoplasmic reticulum stress, such as cardiomyopathy.
  • the Bifidobacterium bacterium used as an active ingredient of the endoplasmic reticulum stress inhibitor of the present invention has an action of suppressing the expression of various endoplasmic reticulum stress response factors (CHOP, GRP78, ERdj4, XBP1s, etc.), It can be used as an endoplasmic reticulum stress response factor expression inhibitor, or an expression inhibitor of one or more proteins selected from CHOP, GRP78, ERdj4 and XBP1s.
  • Bifidobacterium bacteria also enhance the mRNA expression of UDP-glucose: glycoprotein glucosyltransferase (UGGT), an enzyme that reduces the unfolded glycoprotein in the endoplasmic reticulum back into the folding cycle. Therefore, the mechanism of the endoplasmic reticulum oxidative stress suppression action by Bifidobacterium is considered to be due to the UGGT expression promoting action.
  • Bifidobacterium bacteria are useful as UGGT expression promote
  • the desired effect can be obtained by ingesting the Bifidobacterium genus bacterium used in the present invention orally regardless of the state of live cells and / or dead cells. Therefore, the Bifidobacterium genus bacteria used in the present invention do not necessarily need to be used as viable cells, and the desired cells described above can be used even if cells that have been completely or partially killed due to internal or external factors due to storage or the like are used. Since an effect can be acquired, it can be set as the form for medicine etc. which gave various processing (processing). Moreover, Bifidobacterium genus bacteria can be used also as food-drinks for endoplasmic reticulum stress suppression.
  • the endoplasmic reticulum stress-suppressing agent of the present invention can be made into pharmaceutical compositions of various dosage forms together with a pharmaceutically acceptable carrier according to a conventional method. Moreover, as a form of food / beverage products, functional food, health food, food for specified health, etc. are mentioned.
  • lactose sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and other excipients, water, ethanol, propanol, Glucose solution, starch solution, gelatin solution, binders such as carboxymethylcellulose, methylcellulose, potassium phosphate, polyvinylpyrrolidone, sodium alginate, catechin powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, etc.
  • binders such as carboxymethylcellulose, methylcellulose, potassium phosphate, polyvinylpyrrolidone, sodium alginate, catechin powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, etc.
  • Granules, tablets, capsules and the like can be produced by conventional methods by adding a disintegrant, a humectant such as glycerin and starch, a lubricant such as purified talc, stearate and polyethylene glycol.
  • the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multiple tablets.
  • Specific examples of the food and drink include yogurt and beverages.
  • the endoplasmic reticulum stress inhibitor of the present invention may contain lactic acid bacteria that can be taken orally and give a beneficial function to the living body.
  • the amount of Bifidobacterium genus used per day in the endoplasmic reticulum stress-suppressing agent of the present invention varies depending on the subject's symptoms, age, weight, etc., and thus cannot be generally determined.
  • the number of dead bacteria may be about 10 3 to 10 13 or the amount obtained by treating the number of cells as a treated cell.
  • Example 1 A Materials and Methods (1) Preparation of heat-killed cells Bifidobacterium breve YIT10001 strain, Bifidobacterium breve YIT12272, Bifidobacterium adrecentis YIT4011 T , Bifidobacterium bifidum YIT10347 and Bifidobacterium Each strain of Um longum YIT4021 T was cultured overnight, and the cells were collected by centrifugation and then washed twice with sterile water. The washed cells were suspended in sterilized water and heated in a boiling water bath for 30 minutes to prepare heated dead cells.
  • a part of the suspension containing the dead cells was stained with DAPI (4 ′, 6-diamidino-2-phenylindole), and the number of bacteria was measured using a fluorescence microscope.
  • the heated dead cells were lyophilized, suspended in PBS to a concentration of 5 10 cells / mL, and aliquoted and stored at ⁇ 80 ° C.
  • TEER Cell culture and transepithelial electrical resistance test Human colon cancer-derived epithelial cell line (Caco-2) was cultured in Dulbecco's modified Eagle's medium (DMEM) with 10% (v / v) fetal bovine serum ( FBS), 100 U / mL penicillin, 100 ⁇ g / mL streptomycin, 1% non-essential amino acid, 25 mM Hepes, 1 mM sodium pyruvate, 2 mM L-glutamine at 37 ° C., 5% (v / v) CO 2 Incubated under high humidity.
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • the transmembrane electrical resistance (TEER) test was performed by partially modifying the protocol of the Biocoat HTS Caco-2 assay system (Beckton Dickinson).
  • Caco-2 cells were seeded on a fibrous collagen membrane-treated culture insert (pore 1 ⁇ m, surface area 0.3 cm 2 ) at a cell density of 10 5 or 2 ⁇ 10 5 / insert and suspended in the above medium. did.
  • the apical (corresponding to the luminal side of intestinal epithelial cells) and basal (corresponding to the lamina intestinal epithelial cells) medium was replaced with Entero-Stim differentiation medium supplemented with Mito + Serum Extender.
  • Anti-CHOP antibody (1: 1000, Cell Signaling
  • anti-GRP78 antibody (1: 1000, Cell Signaling
  • anti-XBP1s antibody (1: 1000, BioLegend)
  • Anti- ⁇ -actin antibody (1: 1000, Santa Cruz).
  • Blocked PVDF was incubated with each primary antibody at 4 ° C. overnight, washed, and then incubated with an HRP-conjugated secondary antibody (Abcam) derived from mouse, rabbit or goat. Protein bands were detected with ECL (Enhanced chemiluminescent: Pierce) and ChemiDoc MP system (Biorad).
  • the obtained cDNA was prepared to 5 ng / ⁇ L using nuclease free H 2 O, and 2 ⁇ L (10 ng) was subjected to TaqMan gene expression assay (Applied Biosystems) using a 384-well plate to perform RT-qPCR.
  • the expression level of each mRNA was compared by calculating the relative expression level with respect to Tbp, which is a reference gene, by the ⁇ Ct method.
  • the probes used for the analysis were as follows: Tbp; Hs00427620_mL, GRP78; Hs00607129_gH, CHOP; Hs00358796_gL, ERdj4; Hs01052402_mL.
  • Bifidobacterium genus bacteria other than Bifidobacterium breve YIT10001 Effect of Bifidobacterium genus bacteria other than Bifidobacterium breve YIT10001 on endoplasmic reticulum stress
  • Bifidobacterium breve YIT12272, Bifidobacterium adrecentis YIT4011, Bifidobacterium bifidum YIT10347, and Bifidobacterium longum YIT4021 were examined for their inhibitory effects on the enhancement of membrane permeability caused by endoplasmic reticulum stress.
  • FIG. 5 it was found that the Bifidobacterium genus shows an excellent endoplasmic reticulum stress inhibitory action.
  • CHOP protein a kind of endoplasmic reticulum stress marker
  • Example 2 (UGGT expression promoting action) (1) The Caco-2 monolayer was dissolved in TRIzol (Life technologies) and then subjected to RNeasy kit (Qiagen) to extract RNA. The concentration of the obtained RNA was measured with Nanodrop (Thermo Scientific), and it was confirmed by performing PCR on ⁇ -actin that there was no contamination of gDNA (Genomic DNA). Using 1 ⁇ g of RNA as a template, cDNA was synthesized using iScript cDNA synthesis kit (BioRad).
  • the obtained cDNA was prepared to 5 ng / ⁇ l using nuclease free H 2 O, and 2 ⁇ l (10 ng) was subjected to TaqMan gene expression assay (Applied Biosystems) using a 384-well plate, and RT-qPCR was performed. The expression level of each mRNA was compared by calculating the relative expression level with respect to the reference gene Tbp by the ⁇ Ct method.
  • the probes used for the analysis were as follows: Tbp; Hs00427620_m1, UGGT; Hs00917255_m1.
  • glucose at the oligosaccharide end is removed by an enzyme called Glucosidase II, and the protein dissociates from the molecular chaperone.
  • Glucosidase II an enzyme that dissociates from the molecular chaperone.
  • the protein is excreted from the endoplasmic reticulum, and in some cases after further modification in the Golgi apparatus, it is then extracellularly or onto the cell membrane. And will be transported.
  • the glycoprotein is transported to the degradation mechanism with the help of a defective proteolytic factor (ii) or (iii) by an enzyme called UGGT (UDP-glucose: glycoprotein glucosyltransferase)
  • UGGT UDP-glucose: glycoprotein glucosyltransferase

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Abstract

L'invention concerne un inhibiteur du stress du réticulum endoplasmique qui est stable et particulièrement efficace. Cet inhibiteur du stress du réticulum endoplasmique comprend des bactéries appartenant au genre Bifidobacterium, et/ou des produits traités desdites bactéries, en tant que principe actif.
PCT/JP2015/082424 2014-11-19 2015-11-18 Inhibiteur du stress du réticulum endoplasmique Ceased WO2016080449A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019087280A1 (fr) * 2017-10-31 2019-05-09 森永乳業株式会社 Composition pour augmentation de la masse musculaire
JP2022104253A (ja) * 2020-12-28 2022-07-08 株式会社ヤクルト本社 ビフィドバクテリウム属細菌を有効成分とするｄｎａ損傷修復促進剤
WO2025206186A1 (fr) * 2024-03-27 2025-10-02 雪印メグミルク株式会社 Composition pour soulager le stress, aliment humain et boisson, médicament et aliment animal

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JPH0859492A (ja) * 1994-08-26 1996-03-05 Yakult Honsha Co Ltd 抗糖尿病薬
JPH1132763A (ja) * 1997-07-14 1999-02-09 Yakult Honsha Co Ltd ビフィドバクテリウム・ビフィダム用モノクローナル抗体
JP2009242430A (ja) * 2009-07-17 2009-10-22 Snow Brand Milk Prod Co Ltd 加齢に伴う代謝異常疾患の予防・改善・治療剤
WO2012043532A1 (fr) * 2010-10-01 2012-04-05 株式会社ヤクルト本社 Aliment fermenté et procédé de fabrication associé
WO2013144080A1 (fr) * 2012-03-30 2013-10-03 Nestec S.A. Acide 4-oxo-2-penténoïque et santé cardiovasculaire

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* Cited by examiner, † Cited by third party
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JPH0859492A (ja) * 1994-08-26 1996-03-05 Yakult Honsha Co Ltd 抗糖尿病薬
JPH1132763A (ja) * 1997-07-14 1999-02-09 Yakult Honsha Co Ltd ビフィドバクテリウム・ビフィダム用モノクローナル抗体
JP2009242430A (ja) * 2009-07-17 2009-10-22 Snow Brand Milk Prod Co Ltd 加齢に伴う代謝異常疾患の予防・改善・治療剤
WO2012043532A1 (fr) * 2010-10-01 2012-04-05 株式会社ヤクルト本社 Aliment fermenté et procédé de fabrication associé
WO2013144080A1 (fr) * 2012-03-30 2013-10-03 Nestec S.A. Acide 4-oxo-2-penténoïque et santé cardiovasculaire

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LE, THI KIM CHUNG ET AL.: "Oral administration of Bifidobacterium spp. improves insulin resistance, induces adiponectin, and prevents inflammatory adipokine expressions", BIOMEDICAL RESEARCH, vol. 35, no. 5, October 2014 (2014-10-01), pages 303 - 310 *
NAOHIRO EGAWA ET AL.: "Shohotai Stress to Shikkan Shohotai Stress to Shinkei Shikkan", GEKKAN MEDICAL SCIENCE DIGEST, vol. 33, no. 13, 2007, pages 1217 - 1220 *
NOZOMI KONO ET AL.: "Saturated fatty acid and unfolded protein response", JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE, vol. 248, no. 13, March 2014 (2014-03-01), pages 1178 - 1183 *
TAKANORI KUMAGAI ET AL.: "ER stress and kidney diseases", THE CELL, vol. 45, no. 4, 2013, pages 184 - 188 *
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019087280A1 (fr) * 2017-10-31 2019-05-09 森永乳業株式会社 Composition pour augmentation de la masse musculaire
CN111212575A (zh) * 2017-10-31 2020-05-29 森永乳业株式会社 肌肉增量用组合物
JPWO2019087280A1 (ja) * 2017-10-31 2020-10-22 森永乳業株式会社 筋肉増量用組成物
JP7193469B2 (ja) 2017-10-31 2022-12-20 森永乳業株式会社 筋肉増量用組成物
JP2022104253A (ja) * 2020-12-28 2022-07-08 株式会社ヤクルト本社 ビフィドバクテリウム属細菌を有効成分とするｄｎａ損傷修復促進剤
WO2025206186A1 (fr) * 2024-03-27 2025-10-02 雪印メグミルク株式会社 Composition pour soulager le stress, aliment humain et boisson, médicament et aliment animal

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JPWO2016080449A1 (ja) 2017-08-24

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