CN108300686A - For preventing, delaying or micromolecular compound/combination of reverse both, tissue, organ, body aging, product and application thereof - Google Patents
For preventing, delaying or micromolecular compound/combination of reverse both, tissue, organ, body aging, product and application thereof Download PDFInfo
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- CN108300686A CN108300686A CN201710026346.2A CN201710026346A CN108300686A CN 108300686 A CN108300686 A CN 108300686A CN 201710026346 A CN201710026346 A CN 201710026346A CN 108300686 A CN108300686 A CN 108300686A
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- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
The invention discloses a kind of for preventing, delaying or micromolecular compound/combination of reverse both, tissue, organ, body aging, product and application thereof.The micromolecular compound combination includes at least one of DNMT inhibitor, HMT inhibitor, histone demethylase inhibitor, TGF beta inhibitors, WNT/ β catenin agonists, cAMP agonists, lysine deacetylase inhibitors, RAR agonists and ROCK inhibitor.The present invention uses micromolecular compound or combinations thereof to prevent, delay or reverse both, tissue, organ, body aging, extends cell telomere length, action target spot is clear, composition understands, process that is mature and stable, can accurately regulating and controlling anti-aging；And micromolecular compound is easy to Quality Control and large-scale production.It is safe since the body in mechanism or cell do not express dryness gene；And micromolecular compound and combinations thereof is easy to absorb to body, can respectively cell, tissue, organ, body integral level on, prevent, delay and reverse aging, be of great significance to delaying mankind aging's process, improving health status and quality of life.
Description
Technical field
The present invention relates to cell biology, organizational project and medicine, more particularly to it is a kind of thin for preventing, delaying or reversing
Micromolecular compound/combination of born of the same parents, tissue, organ, body aging, product and application thereof.
Background technology
Human body aging is the major health concern of modern society, and the main reason for most of geriatric disease.
Reduction of the aging course with physical function, the decrease to extraneous variation adaptability, compensation it is low, it is final induce it is more
Kind disease.The degenerative disease, diabetes of such as angiocardiopathy, malignant tumour, nerve, internal organ, bone and muscle all with decline
It is old closely related.Age often increases by 10 years old, because the case fatality rate of cardiovascular disease increases by 2~3 times, it is seen that aging is to human lives' matter
Amount influences huge with health status.
In recent decades, with the relevant factor of aging (such as aging related genes) and antiaging agent, method constantly quilt
Report.Such as 2016, the research team of U.S.'s Mayo Clinic makes the service life of mouse extend to be more than by removing senile cell
20%；Different research institutions finds through feeding mouse rapamycin, Coenzyme I, NMN (nicotinamide mononucleotide), spermidine
Etc. the service life that can significantly extend mouse；There is research institution to disclose RNA montages (RNA splicing) work(using nematode model
It can be with being associated between longevity；Ling You research institutions, which report reactivation of the HOXA9 at old age, can limit the regeneration of skeletal muscle,
The activation of NRF2 is conducive to anti-aging；In addition, according to relevant report, removing the DNA being mutated in mitochondria, or adjustment running, diet
Equal living habits also have positive effect with life style to anti-aging.
Although above-mentioned substance or method, which has, improves organ health status, to improve the effect in service life, in view of
The complexity of cell, tissue, organ level ageing process, people are still limited to the understanding of ageing process and its mechanism, above-mentioned
The method of various anti-aging and the function and effect of substance still have uncertainty.In December, 2016, Sol gram research institute grinds
Study carefully side of the personnel by high expression tetra- factors of Yamanaka (four factors for preparing inducing pluripotent stem cells) in intravital mouse
Formula allows many organs of whole body of early ageing disease mouse to be restored to the state of relative healths youth, and extends the service life of mouse 1/3.
Therefore, the method or substance for delaying either to reverse body most cells or histoorgan ageing process, if effect
Clear, process control is expected to the robust techniques basis as mankind's anti-aging.
Although transgenic technology realizes the reversion of senescence of whole body major part internal organs with early ageing disease mouse, in view of peace
Full property considers that the method is infeasible in human body.In addition, the activation of tetra- factors of Yamanaka used has the risk of tumorigenesis.Cause
This, it is necessary to find the safely and effectively mode of action and substance that can be used for human body.Micromolecular compound or small molecule chemical combination
Object combination has following advantage because of it：1. not importing the exogenous transcriptional factor, do not change the gene structure of source cell, has good
Safety and stability；2. action system is relatively stable, it is easy to Quality Control, it is of low cost；3. mechanism is short, efficient, just
In large-scale production；4. it is convenient for absorption of human body and metabolism, it will be as slowing down or reverse the active principle of ageing process.However,
The report and research of micromolecular compound or micromolecular compound combination anti-aging are seldom, on the one hand should due to lacking screening
The method and system of micromolecular compound；On the other hand, even if useful micromolecular compound is attempted on mouse, due to people
There is about 25% gene difference with mouse in class, be applied to the same cells of people, and feasibility is not also high.Therefore, targetedly
Ground, which screens, can delay or reverse the micromolecular compound of mankind aging's process safely and clearly, to delay mankind aging's process,
It improves health status and quality of life is of great significance.
Invention content
The present invention provides a kind of for preventing, delaying or the small molecule chemical combination of reverse both, tissue, organ, body aging
Object/combination, product and application thereof.The micromolecular compound combination is during cell, tissue, organ, body anti-aging
With Modulatory character, globality, reversibility and safety.
First aspect present invention provides a kind of cell, tissue, organ for preventing, delaying or reverse mammal such as people
Or the micromolecular compound combination of body aging process, the micromolecular compound combination include DNMT inhibitor, HMT inhibition
Agent, histone demethylase inhibitor, TGF-β inhibitor, WNT/ β-catenin agonists, cAMP agonists and lysine
At least one of deacetylase inhibitors.
Alternatively, the micromolecular compound is combined as DNMT inhibitor, HMT inhibitor, histone demethylase
At least one of inhibitor and lysine deacetylase inhibitors.
Alternatively, it is sharp to be combined as TGF-β inhibitor, WNT/ β-catenin agonists, cAMP for the micromolecular compound
At least one of dynamic agent, DNMT inhibitor, HMT inhibitor and lysine deacetylase inhibitors.
Further, the micromolecular compound further includes RAR agonists, ascorbate (ascorbic acid) and ROCK suppressions
At least one of preparation.
Further, micromolecular compound combination includes the first stage compound chronologically used stage by stage and the
Two-stage compound, the first stage compound be DNMT inhibitor, HMT inhibitor, histone demethylase inhibitor,
At least one in TGF-β inhibitor, WNT/ β-catenin agonists, cAMP agonists and lysine deacetylase inhibitors
Kind；
The second stage compound is DNMT inhibitor, HMT inhibitor, histone demethylase inhibitor, TGF-β
Inhibitor, WNT/ β-catenin agonists, cAMP agonists, lysine deacetylase inhibitors, RAR agonists,
At least one of ascorbate (ascorbic acid) and ROCK inhibitor.
The TGF-β acceptor inhibitor is I type TGF-β acceptor inhibitors, and the cAMP agonists are EPAC/RAP1 excitements
Agent.
Further, the micromolecular compound combination is applied in combination with PDGF-AB, improves micromolecular compound combination
Functioning efficiency.
Preferably, the lysine deacetylase inhibitors include sodium phenylbutyrate,
Butyrate, sodium butyrate, MC1568, CI994 (Tacedinaline), chidamide, CAY10683
(SantacruzaMate A), CUDC-907, M344 (Histone Deacetylase Inhibitor III), LAQ824
(NVP-LAQ824, Dacinostat), Pracinostat (SB939), VPA (Valproic acid), Valproic acid
Sodium salt, Scriptaid, Apicidin, LBH-589 (Panobinostat), MS-275, SAHA (Vorinostat),
Trichostatin (TSA), Psammaplin A, PCI-24781 (Abexinostat), Rocilinostat (ACY-1215),
Mocetinostat (MGCD0103), 4-Phenylbutyrate (4PB), splitomicin, SRT1720, resveratrol,
Sirtinol, APHA, CI-994, Depudecin, FK-228, HC-Toxin, ITF-2357 (Givinostat),
Chidamide, RGFP 966, PHOB, BG45, Nexturastat A, TMP269, CAY10603, MGCD-0103,
Niltubacin, PXD-101 (Belinostat), Pyroxamide, Tubacin, EX-527, BATCP, Cambinol,
At least one of MOCPAC, PTACH, MC1568, NCH51 and TC-H106；
The TGF-β acceptor inhibitor includes 616452, LY2109761, Pirfenidone, Repsox (E-616452),
SB431542, A77-01, Tranilast, Galunisertib (LY2157299), A8301, GW788388, ITD-1, SD208,
At least one of SB525334, LY364947, ASP3029, D4476 and SB505124；
WNT/ β-catenin the agonists include MAY-262611, CHIR98014, CHIR99021, LiCl, Li2CO3,
TD114-2, AZD2858, AZD1080, BIO, Kenpaullone, TWS119, LY2090314, CBM1078, SB216763 and
At least one of AR-A014418；
The cAMP agonists include EPAC/RAP1 agonists, 8-Bromo-cAMP, Dibutyryl-Camp and Sp-8-
At least one of Br-cAMPs；
The EPAC/RAP1 agonists include Forskolin, IBMX, Prostaglandin E2 (PGE2), NKH477,
8-pCPT-2 '-O-Me-cAMP, GSK256066, Apremilast (CC-10004), Roflumilast, Cilomilast,
At least one of Rolipram and Milrinone；
The RAR agonists include TTNPB, Bexarotene, Ch55, Tamibarotene, Retinol, AM580,
At least one of ATRA, 13-cis RA, Vitamin A and Vitamin A derivatives；
The ROCK inhibitor includes Y-27632, Y-27632 2HCl, Thiazovivin, Ripasudil (K-115),
Fasudil, Fasudil (HA-1077) HCl, GSK429286A, at least one of RKI-1447 and PKI-1313；
The DNMT inhibitor includes RG108, Thioguanine, 5-Aza-2'-deoxycytidine
(Decitabine), at least one of SGI-1027, Zebularine and 5-Azacytidine (AZA)；
The HMT inhibitor includes EPZ004777, EPZ5676, GSK503, BIX 01294, DZNep, DZNep HCL,
At least one of SGC 0946；
The histone demethylase inhibitor includes parnate (tranylcypromine),
Tranylcypromine (2-PCPA) HCl SP2509,4SC-202, ORY-1001 (RG-6016), in GSKJ1 and GSK-LSD1
At least one.
As further preferred, the lysine deacetylase inhibitors be sodium butyrate, VPA and
At least one of Trichostatin (TSA)；
The TGF-β acceptor inhibitor is at least one of Repsox (E-616452) and SB431542；
WNT/ β-catenin the agonists are at least one of CHIR99021 and BIO；
The cAMP agonists are at least one of Forskolin and Rolipram；
The RAR agonists are at least one of TTNPB and AM580；
The ROCK inhibitor includes at least one of Y-27632 and Thiazovivin；
The DNMT inhibitor is RG108,5-Aza-2'-deoxycytidine (Decitabine) and 5-
At least one of Azacytidine (AZA)；
The HMT inhibitor is at least one of EPZ004777, EPZ5676 and SGC 0946；
The inhibitor of the histone demethylase be parnate (tranylcypromine) and
At least one of Tranylcypromine (2-PCPA) HCl.
The telomere length of cell of the micromolecular compound combination for extending mammal such as people, instantaneously stimulates telomere
The expression or up-regulation of GAP-associated protein GAP, the expression such as TERT (telomerase reverse transcriptase) and TPP1 up-regulations；The food in one's mouth will not be stimulated after effect
The cell of newborn animal such as people expresses dryness gene, such as OCT4, Nanog etc..
Some embodiments of the present invention, the effective concentration of specific micromolecular compound is as follows, concentration model given below
It encloses and only refers to, adaptation can be done on this basis, if other small molecules substitute following small molecule, concentration can also be done
It is adaptively adjusted.
A concentration of 2 μM~20 μM of Forskolin；A concentration of 2~15uM of Repsox；A concentration of 1 μM~10 μ of CHIR99021
M；A concentration of 0.5mM~1.5mM of VPA；A concentration of 3 μM~8 μM of TTNPB；A concentration of 0.03~0.08 μM of AM580；EPZ004777
A concentration of 3~8 μM；A concentration of 3~15 μM of Y-27632, L-Ascorbin acid 2-phosphate a concentration of 0.15~
0.25mM；A concentration of 0.5~20 μM of 5-Aza-2'-deoxycytidine.
The present invention prevents, delays or reverse the mechanism of aging as follows：The present invention by the cell to aging or aging into
Adjusting in row epigenetics, or by activating the relevant transcription factor of early development, such as activate WNT/ β-catenin letters
Number access, activation cAMP signal paths, excitement RA signal paths, inhibition TGF-beta signal paths realize the pre- of cell ageing
It is anti-, delay or reverses.The micromolecular compound combination can be used for extending the telomere length of the cell of mammal such as people, wink
When stimulation Telomeric Protein expression/up-regulation will not stimulate mammal such as such as TERT (telomerase reverse transcriptase) and TPP1
The cell expression dryness gene of people, such as OCT4, Nanog etc., safely and effectively.
Second aspect of the present invention, provide it is a kind of comprising the micromolecular compound combination kit, culture solution/base, medicine
Object, health products, food, cosmetics or medical instrument.
Third aspect present invention provides a kind of micromolecular compound combination and is preventing, delays or is reversing lactation to move
Object such as the cell of people, tissue, organ or application in body aging process and relevant disease and improve mammal such as people's tissue,
The application of organ repair ability.
The cell origin is in the body cell of mammal such as people or the cell of in vitro culture.
Fourth aspect present invention provides one kind and is combined prevention by the micromolecular compound, delays or lactation is reversed to move
The cell of object such as people, the method for tissue, organ or body aging process.
Fifth aspect present invention provides a kind of cell of the rejuvenation obtained by the micromolecular compound compound action
And cellular products.
Sixth aspect present invention provides a kind of cell of the rejuvenation and the application of cellular products.
The term " aging " used in this specification is equivalent in meaning with " aging ", before the cell of rejuvenation refers to aging
Cell.But heretofore described " aging " does not include the permanent cell for stopping division.
The invention has the advantages that：The present invention is prevented using micromolecular compound or combinations thereof, delays or reverse
Cell, tissue, organ, body aging extend cell telomere length, action target spot is clear, composition understands, it is mature and stable, can be accurate
The really process of regulation and control anti-aging；And micromolecular compound is easy to Quality Control and large-scale production.Due to the body in mechanism
Or cell does not express dryness gene, it is safe；And micromolecular compound and combinations thereof is easy to absorb to body, can distinguish
Cell, tissue, organ, body integral level on, prevent, delay and reverse aging, to delay mankind aging's process, improve
Health status and quality of life are of great significance.
Description of the drawings
Fig. 1 is that micromolecular compound acts on descendant source skin fibroblasts aspect graph；
Fig. 2 is that micromolecular compound acts on descendant source mesenchymal stem cell aspect graph；
Fig. 3 is the identification that micromolecular compound acts on descendant source skin fibroblasts cell quality；
Fig. 4 is the identification that micromolecular compound acts on descendant source mesenchymal stem cell cell quality；
Fig. 5 is the telomere length variation of human archeocyte after being acted on by micromolecular compound；
Fig. 6 is the expression of the telomere related gene of human archeocyte after being acted on by micromolecular compound；
Fig. 7 is that the expression acted in the skin fibroblasts of descendant source with aging related genes micromolecular compound changes
Figure；
Fig. 8 is the testing result figure that micromolecular compound acts on the external function vigor of descendant's source skin fibroblasts；
Fig. 9 is the testing result figure that micromolecular compound acts on descendant source skin fibroblasts in vivo functionality vigor；
Figure 10 is the detection of the cell dryness of Long Term Passages and Tumor formation testing result figure after acting on micromolecular compound；
Figure 11 is that the micromolecular compound of Long Term Passages acts on the Clone formation and form of descendant source skin fibroblasts
Figure.
Specific implementation mode
Technical scheme of the present invention is described in further details in the following with reference to the drawings and specific embodiments, but the present invention is simultaneously
It is not limited to following technical scheme.
Embodiment 1
1, the separation of skin fibroblasts
1.1 obtain the skin histology block of diameter about 1cm from volunteer, and adherent method detaches skin fibroblasts, point
From cell culture in basic culture solution, the basic culture solution：10% fetal calf serum (Hyclone)+100U/ml penicillin
(Sigma)+100 μ g/ml streptomysins (Sigma)+height sugar DMDM.
1.2 cells pass on large amplification, and in this experiment, cell is the 12nd generation, the previous day (Day- of processing to cell algebraically
1), inoculating cell density 1~2.5 × 104/cm237 DEG C are incubated at, 5%CO2Incubator in.
2, the micromolecular compound processing of skin fibroblasts
Replacement basic culture solution is small molecule treatment fluid, cultivates cell 2-20 days, and small molecule treatment fluid refers to：10% tire ox
+ 100 μ g/ml streptomysins (Sigma) of serum (Hyclone)+100U/ml penicillin (Sigma)+height sugar DMDM culture mediums
(Gibco)+forskolin (2 μM~25 μM)+Repsox (2~15uM)+CHIR99021 (1 μM~10 μM)+VPA (0.5mM~
1.5mM)+5-Aza-2'-deoxycytidine (0.5~20 μM), 10% fetal calf serum can also be by serum in the culture systems
Substitute (invitrogen) is substituted with 10%~20% concentration；100U/ml penicillin (Sigma) and 100 μ g/ml streptomysins
(Sigma) it can not use.At 37 DEG C, 5%CO2Cell is cultivated under environment.
3, the maintenance culture of skin fibroblasts
The after treatment of above-mentioned second step, is changed to basic culture solution completely, normal to maintain culture, at 37 DEG C, 5%
CO2Cell is cultivated under environment.The basic culture solution：10% fetal calf serum (Hyclone)+100U/ml penicillin (Sigma)+
100 μ g/ml streptomysins (Sigma)+height sugar DMDM, in 10% fetal calf serum can also by serum replacement (invitrogen) with
10%~20% concentration substitutes；100U/ml penicillin (Sigma) and 100 μ g/ml streptomysins (Sigma) can not use.
4, the identification of cell quality after handling
When the passage of 4.1 cells is to 14 generation, contaminated using green skies cell ageing beta galactosidase staining kit
Color is identified；
4.2 cells were passed on to the 14th generation, were dyed using the CD29-PE streaming antibody of ebioscience, it is same to compare
The corresponding Isotype control product of one producer, operate according to shop instruction, are analyzed on BD JAZZ streaming instrument；
4.3 cells were passed on to the 14th generation, were cultivated in 24 orifice plates, and cell is fixed after ten minutes using 4% PFA, according to
The operating procedure of immunofluorescence is dyed using the Vimentin antibody of santa cruz；
The detection of 4.4 cell proliferations, with 1.5x105As initial inoculation cell concentration, cell, Mei Geshi are counted within continuous 12 days
Between point repeat 3 groups；
4.5 cells were passed on to the 14th generation, collected DNA sample, and the inspection of telomere length is carried out using Cawthon qPCR methods
It surveys, fluorescent dye uses Takara SYBR Green I,
Telomere amplification primer sequence is
mTel:CGGTTTGTTTGGGTTTGGGTTTGGGTTTGGGTTTGGGTT；
mTel:GGCTTGCCTTACCCTTACCCTTACCCTTACCCTTACCCT；
Single copy gene primers
36B4-S-F：CAGCAAGTGGGAAGGTGTAATCC；
36B4-S-R：CCCATTCTATCATCAACGGGTACAA；
4.6 cells were passed on to the 14th generation, collected RNA samples, and the detection of TERT is carried out using PCR method, people source TERT's
Primer sequence is F：5'-CGGAAGAGTGTCTGGAGCAA-3；R5'-GGATGAAGCGGAGTCTGGA-3'；
4.7 cells were passed on to the 14th generation, collected RNA samples, by the analysis of transcript profile, quantitative gene TPP1, CDKN1A,
The variation of ATF3, GADD45B, BTG2, H2AFX, ITGA6, COL1A1 expression quantity；
4.8 heterogenous skins are transplanted, and detection micromolecular compound treated people source skin fibroblasts culture solution is exempted from
Epidemic disease adjustment effect.Specific method is：Experimental group be micromolecular compound handle groups of cells, untreated cell group, PBS groups, wherein
It passes on to the 14th generation, executes zoopery according to the requirement of animal welfare committee member, by donor C57B/6 mouse anesthesias, dorsal position is solid
Fixed, full back depilation, back takes the skin of the holostrome of 1.5cmx1.5cm, removes subcutaneous fat and blood vessel, mouse skin is cut into
The skin graft of a diameter of 1.0cm sizes is set spare in the plate containing sterile PBS.The skin graft sheared is turned and has been put into life
In the culture dish for managing brine, subcutaneous tissue is lightly cut with knife blade to corium, is then placed on standby in sterile saline
With.
Receptor is BALB/c mouse, and anesthesia back part depilation, iodine disinfection skin of back prepares the skin of a diameter 1.0cm
Skin notch, artery-sparing are elastic in back against cant to transplanting C57B/6 skin grafts, surface mulching Petroleum gauze and adhesive bandage
Appropriateness.After transplanting in 1 hour, from each group liquid in tail vein injection list.
The detection of 4.9 Cell colonies assays：Cell was passed on to the 14th generation, the cell of logarithmic growth phase, thin with 10
Born of the same parents/cm2 bed boards, every group sets 3 multiple holes, and liquid, 1 week~2 weeks or so Giemsa or PI dyeing were changed every 2 days, is counted under microscope
Clone's quantity of formation.
Embodiment 2
1, the culture of mesenchymal stem cell
The people source mesenchymal stem cell or the remaining bone of volunteer's bone chip after bone wound of 1.1 purchase commercializations
Separating mesenchymal stem cell in marrow, cell culture is in basic culture solution, the basic culture solution：8% fetal calf serum
(Hyclone)+100 μ g/ml streptomysins (Sigma) of+100U/ml penicillin (Sigma)+low sugar DMDM.
1.2 cells pass on large amplification, and in this experiment, cell is the 10th generation, the previous day (Day- of processing to cell algebraically
1), inoculating cell density 1~2.5 × 104/cm237 DEG C are incubated at, 5%CO2Incubator in.
2, the micromolecular compound processing of mesenchymal stem cell
Replacement basic culture solution is small molecule treatment fluid, cultivates cell 2-20 days, and small molecule treatment fluid refers to：10% tire ox
+ 100 μ g/ml streptomysins (Sigma) of serum (Hyclone)+100U/ml penicillin (Sigma)+height sugar DMDM culture mediums
(Gibco)+forskolin (2 μM~25 μM)+Repsox (2~15uM)+CHIR99021 (1 μM~10 μM)+VPA (0.5mM~
1.5mM), in the culture systems 10% fetal calf serum can also by serum replacement (invitrogen) with 10%~20% it is dense
Degree substitutes；100U/ml penicillin (Sigma) and 100 μ g/ml streptomysins (Sigma) can not use.At 37 DEG C, 5%CO2Ring
Cell is cultivated under border.
3, the maintenance culture of mesenchymal stem cell
The after treatment of above-mentioned second step, is changed to basic culture solution completely, normal to maintain culture, at 37 DEG C, 5%
CO2Cell is cultivated under environment.The basic culture solution：8% fetal calf serum (Hyclone)+100U/ml penicillin (Sigma)+
100 μ g/ml streptomysins (Sigma)+low sugar DMDM, in 10% fetal calf serum can also by serum replacement (invitrogen) with
10%~20% concentration substitutes；100U/ml penicillin (Sigma) and 100 μ g/ml streptomysins (Sigma) can not use.
4, the identification of cell quality after handling
When the passage of 4.1 cells is to 12 generation, contaminated using green skies cell ageing beta galactosidase staining kit
Color is identified；
4.2 cells were passed on to the 12nd generation, used the CD29-PE of ebioscience, CD90, CD73, CD34, CD45 streamings
Antibody is dyed, and is compareed as the corresponding Isotype control product of same producer, is operated according to shop instruction, in BD JAZZ streamings
It is analyzed on instrument；
The passage of 4.3 cells is carried out to the 12nd generation using the skeletonization of Cyagen Biosciences and at fat induction liquid
Induction, specific steps are according to product description；
The detection of 4.4 cell proliferations, with 1.5x105As initial inoculation cell concentration, cell, Mei Geshi are counted within continuous 12 days
Between point repeat 3 groups；
4.5 cells were passed on to the 14th generation, collected DNA sample, and the inspection of telomere length is carried out using Cawthon qPCR methods
It surveys, fluorescent dye uses Takara SYBR Green I,
Telomere amplification primer sequence is
mTel:CGGTTTGTTTGGGTTTGGGTTTGGGTTTGGGTTTGGGTT；
mTel:GGCTTGCCTTACCCTTACCCTTACCCTTACCCTTACCCT；
Single copy gene primers
36B4-S-F：CAGCAAGTGGGAAGGTGTAATCC；
36B4-S-R：CCCATTCTATCATCAACGGGTACAA；
4.6 cells were passed on to the 14th generation, collected RNA samples, and the detection of TERT is carried out using PCR method, people source TERT's
Primer sequence is F：5'-CGGAAGAGTGTCTGGAGCAA-3；R5'-GGATGAAGCGGAGTCTGGA-3'；
4.7 cells were passed on to the 14th generation, collected RNA samples, by the analysis of transcript profile, quantitative gene TPP1, CDKN1A,
The variation of ATF3, GADD45B, BTG2, H2AFX expression quantity；
4.8 heterogenous skins are transplanted, detection micromolecular compound treated people source mesenchymal stem cell culture solution
Immunoregulation effect.Specific method is：Experimental group be micromolecular compound handle groups of cells, untreated cell group, PBS groups,
Middle passage executes zoopery to the 14th generation, according to the requirement of animal welfare committee member, by donor C57B/6 mouse anesthesias, dorsal position
Fixed, full back depilation, back takes the skin of the holostrome of 1.5cmx1.5cm, removes subcutaneous fat and blood vessel, mouse skin is cut
At the skin graft of a diameter of 1.0cm sizes, set spare in the plate containing sterile PBS.The skin graft sheared is turned and has been put into
In the culture dish of physiological saline, subcutaneous tissue is lightly cut with knife blade to corium, is then placed in sterile saline
It is spare.
Receptor is BALB/c mouse, and anesthesia back part depilation, iodine disinfection skin of back prepares the skin of a diameter 1.0cm
Skin notch, artery-sparing are elastic in back against cant to transplanting C57B/6 skin grafts, surface mulching Petroleum gauze and adhesive bandage
Appropriateness.After transplanting in 1 hour, from each group liquid in tail vein injection list.
The detection of 4.9 Cell colonies assays：Cell was passed on to the 14th generation, the cell of logarithmic growth phase, thin with 10
Born of the same parents/cm2 bed boards, every group sets 3 multiple holes, and liquid, 1 week~2 weeks or so Giemsa or PI dyeing were changed every 2 days, is counted under microscope
Clone's quantity of formation.
Embodiment 3
1, the separation of skin fibroblasts
1.1 obtain the skin histology block of diameter about 1cm from volunteer, and adherent method detaches skin fibroblasts, point
From cell culture in basic culture solution, the basic culture solution：10% fetal calf serum (Hyclone)+100U/ml penicillin
(Sigma)+100 μ g/ml streptomysins (Sigma)+height sugar DMDM.
1.2 cells pass on large amplification, and in this experiment, cell is the 12nd generation, the previous day (Day- of processing to cell algebraically
1), inoculating cell density 1~2.5 × 104/cm237 DEG C are incubated at, 5%CO2Incubator in.
2, the micromolecular compound processing of skin fibroblasts
Replacement basic culture solution is small molecule treatment fluid, cultivates cell 2-20 days, and small molecule treatment fluid refers to：10% tire ox
+ 100 μ g/ml streptomysins (Sigma) of serum (Hyclone)+100U/ml penicillin (Sigma)+height sugar DMDM culture mediums
(Gibco)+forskolin (2 μM~25 μM)+5-Aza-2'-deoxycytidine (0.5~20 μM), in the culture systems
10% fetal calf serum can also be substituted by serum replacement (invitrogen) with 10%~20% concentration；100U/ml moulds
Plain (Sigma) and 100 μ g/ml streptomysins (Sigma) can not use.At 37 DEG C, 5%CO2Cell is cultivated under environment.
3, the maintenance culture of skin fibroblasts
The after treatment of above-mentioned second step, is changed to basic culture solution completely, normal to maintain culture, at 37 DEG C, 5%
CO2Cell is cultivated under environment.The basic culture solution：10% fetal calf serum (Hyclone)+100U/ml penicillin (Sigma)+
100 μ g/ml streptomysins (Sigma)+height sugar DMDM, in 10% fetal calf serum can also by serum replacement (invitrogen) with
10%~20% concentration substitutes；100U/ml penicillin (Sigma) and 100 μ g/ml streptomysins (Sigma) can not use.
4, the identification of cell quality after handling
Detailed step is the same as embodiment 1
Embodiment 4
1, the separation of skin fibroblasts
1.1 obtain the skin histology block of diameter about 1cm from volunteer, and adherent method detaches skin fibroblasts, point
From cell culture in basic culture solution, the basic culture solution：10% fetal calf serum (Hyclone)+100U/ml penicillin
(Sigma)+100 μ g/ml streptomysins (Sigma)+height sugar DMDM.
1.2 cells pass on large amplification, and in this experiment, cell is the 12nd generation, the previous day (Day- of processing to cell algebraically
1), inoculating cell density 1~2.5 × 104/cm237 DEG C are incubated at, 5%CO2Incubator in.
2, the micromolecular compound processing of skin fibroblasts
Replacement basic culture solution is small molecule treatment fluid, cultivates cell 2-20 days, and small molecule treatment fluid refers to：10% tire ox
+ 100 μ g/ml streptomysins (Sigma) of serum (Hyclone)+100U/ml penicillin (Sigma)+height sugar DMDM culture mediums
(Gibco)+VPA (0.5mM~1.5mM)+Repsox (2~15uM), 10% fetal calf serum can also be by blood in the culture systems
Clear substitute (invitrogen) is substituted with 10%~20% concentration；100U/ml penicillin (Sigma) and 100 μ g/ml strepto-s
Plain (Sigma) can not used.At 37 DEG C, 5%CO2Cell is cultivated under environment.
3, the maintenance culture of skin fibroblasts
The after treatment of above-mentioned second step, is changed to basic culture solution completely, normal to maintain culture, at 37 DEG C, 5%
CO2Cell is cultivated under environment.The basic culture solution：10% fetal calf serum (Hyclone)+100U/ml penicillin (Sigma)+
100 μ g/ml streptomysins (Sigma)+height sugar DMDM, in 10% fetal calf serum can also by serum replacement (invitrogen) with
10%~20% concentration substitutes；100U/ml penicillin (Sigma) and 100 μ g/ml streptomysins (Sigma) can not use.
4, the identification of cell quality after handling
Detailed step is the same as embodiment 1.
Embodiment 5
The micromolecular compound of skin fibroblasts, which is handled, in second step is：It is at small molecule to replace basic culture solution
Liquid, culture cell 2-20 days are managed, small molecule treatment fluid refers to：10% fetal calf serum (Hyclone)+100U/ml penicillin
(Sigma)+100 μ g/ml streptomysins (Sigma)+height sugar DMDM culture mediums (Gibco)+VPA (0.5mM~1.5mM)+Repsox
(2~15uM)+5-Aza-2'-deoxycytidine (0.5~20 μM), 10% fetal calf serum can also be by the culture systems
Serum replacement (invitrogen) is substituted with 10%~20% concentration；100U/ml penicillin (Sigma) and 100 μ g/ml chains
Mycin (Sigma) can not use.At 37 DEG C, 5%CO2Cell is cultivated under environment.Remaining step is the same as embodiment 1.
Embodiment 6
The micromolecular compound of skin fibroblasts, which is handled, in second step is：It is at small molecule to replace basic culture solution
Liquid, culture cell 2-20 days are managed, small molecule treatment fluid refers to：10% fetal calf serum (Hyclone)+100U/ml penicillin
(Sigma)+100 μ g/ml streptomysins (Sigma)+height sugar DMDM culture mediums (Gibco)+VPA (0.5mM~3mM), the training system
10% fetal calf serum can also be substituted by serum replacement (invitrogen) with 10%~20% concentration in system；100U/ml
Penicillin (Sigma) and 100 μ g/ml streptomysins (Sigma) can not use.At 37 DEG C, 5%CO2Cell is cultivated under environment.Its
Remaining step is the same as embodiment 1.
Embodiment 7
The micromolecular compound of skin fibroblasts, which is handled, in second step is：It is at small molecule to replace basic culture solution
Liquid, culture cell 2-20 days are managed, small molecule treatment fluid refers to：10% fetal calf serum (Hyclone)+100U/ml penicillin
(Sigma)+100 μ g/ml streptomysins (Sigma)+height sugar DMDM culture mediums (Gibco)+5-Aza-2'-deoxycytidine
(0.2~20 μM), in the culture systems 10% fetal calf serum can also by serum replacement (invitrogen) with 10%~
20% concentration substitutes；100U/ml penicillin (Sigma) and 100 μ g/ml streptomysins (Sigma) can not use.At 37 DEG C,
5%CO2Cell is cultivated under environment.Remaining step is the same as embodiment 1.
Embodiment 8
The micromolecular compound of skin fibroblasts, which is handled, in second step is：It is at small molecule to replace basic culture solution
Liquid, culture cell 2-20 days are managed, small molecule treatment fluid refers to：10% fetal calf serum (Hyclone)+100U/ml penicillin
(Sigma)+100 μ g/ml streptomysins (Sigma)+height sugar DMDM culture mediums (Gibco)+RG108 (0.5~30 μM), the training system
10% fetal calf serum can also be substituted by serum replacement (invitrogen) with 10%~20% concentration in system；100U/ml
Penicillin (Sigma) and 100 μ g/ml streptomysins (Sigma) can not use.At 37 DEG C, 5%CO2Cell is cultivated under environment.Its
Remaining step is the same as embodiment 1.
Embodiment 9
The micromolecular compound of skin fibroblasts, which is handled, in second step is：It is at small molecule to replace basic culture solution
Liquid, culture cell 2-20 days are managed, small molecule treatment fluid refers to：10% fetal calf serum (Hyclone)+100U/ml penicillin
(Sigma)+100 μ g/ml streptomysins (Sigma)+height sugar DMDM culture mediums (Gibco)+Repsox (2~15uM)+CHIR99021
(1 μM~10 μM)+VPA (0.5mM~1.5mM)+TTNPB (3 μM~8 μM)+AM580 (0.03~0.08 μM)+EPZ004777 (3
~8 μM)+Y-27632 (3~15 μM)+L-Ascorbin acid 2-phosphate (0.15~0.25m M), the culture systems
In 10% fetal calf serum can also by serum replacement (invitrogen) with 10%~20% concentration substitute；100U/ml is green
Mycin (Sigma) and 100 μ g/ml streptomysins (Sigma) can not use.At 37 DEG C, 5%CO2Cell is cultivated under environment.Remaining
Step is the same as embodiment 1.
Embodiment 10
The micromolecular compound of skin fibroblasts, which is handled, in second step is：It is at small molecule to replace basic culture solution
Liquid, culture cell 2-20 days are managed, small molecule treatment fluid refers to：10% fetal calf serum (Hyclone)+100U/ml penicillin
(Sigma)+100 μ g/ml streptomysins (Sigma)+height sugar DMDM culture mediums (Gibco)+forskolin (2 μM~25 μM)+
Repsox (2~15uM)+CHIR99021 (1 μM~10 μM)+VPA (0.5mM~1.5mM)+PDGF-AB (100~250ng/
ML), 10% fetal calf serum can also be by serum replacement (invitrogen) with 10%~20% concentration in the culture systems
It substitutes；100U/ml penicillin (Sigma) and 100 μ g/ml streptomysins (Sigma) can not use.At 37 DEG C, 5%CO2Environment
Lower culture cell.
Remaining step is the same as embodiment 1.
Embodiment 11
The micromolecular compound of mesenchymal stem cell, which is handled, in second step is：Replacement basic culture solution is small molecule
Treatment fluid, culture cell 2-20 days, small molecule treatment fluid refer to：10% fetal calf serum (Hyclone)+100U/ml penicillin
(Sigma)+100 μ g/ml streptomysins (Sigma)+height sugar DMDM culture mediums (Gibco)+forskolin (2 μM~25 μM)+5-
Aza-2'-deoxycytidine (0.5~20 μM), 10% fetal calf serum can also be by serum replacement in the culture systems
(invitrogen) it is substituted with 10%~20% concentration；100U/ml penicillin (Sigma) and 100 μ g/ml streptomysins
(Sigma) it can not use.At 37 DEG C, 5%CO2Cell is cultivated under environment.
Remaining step is the same as embodiment 2.
Fig. 1~Figure 11 is shown in the variation of cell in above-described embodiment；Fig. 1 is that micromolecular compound acts on descendant source skin into fibre
It ties up the metamorphosis of cell normally to cultivate skin fibroblasts when A figures are untreated, pass to the 13rd generation, some are original in length
The fibroblast of fusiformis growth, starts cell volume occur to become larger, and the irregular aging conditions of cell shape use β-gala
Glucosides enzyme dyeing, visible senile cell dyes au bleu in B figures；Using in such as embodiment 1 method processing after, the 14th generation it is thin
Born of the same parents, form are in substantially regularly spindle shape, are dyed using beta galactosidase, and result is feminine gender.
Fig. 2 is the variation that micromolecular compound acts on descendant source mesenchymal stem cell form, when A figures are untreated, just
Often culture mescenchymal stem cell, pass to the 10th generation, some originally be in fusiformis growth cell bodies became larger, cell elongate or
Irregular type is grown, and is dyed using beta galactosidase, and visible senile cell dyes au bleu in B figures；Using in such as embodiment 2
Method processing after, the cell in the 12nd generation, form substantially regularly be in fusiformis, dyed using beta galactosidase, result be the moon
Property.
Fig. 3 is the identification that micromolecular compound acts on descendant source skin fibroblasts cell quality, using in embodiment 1
Method processing after, cell and processing it is preceding as, the molecular marker CD29 (A figures) of normal expression skin fibroblasts,
Vimentin (B figures)；C figures compared the increment situation of cell before and after the processing, and the competence for added value ratio of processing group Fib-treated is not
The Fib of processing is apparent.
Fig. 4 is the identification that micromolecular compound acts on descendant source mesenchymal stem cell cell quality, such as embodiment 2
In, A figures are the expression of the molecular marked compound of mescenchymal stem cell before and after the processing, express positive CD29, CD90, CD73 and the moon
Property CD34, CD45 before treatment after cell in express it is consistent；Cell MSC-treated ratios processing that treated in B figures
The competence for added value of preceding MSC is good；C figures are that treated MSC cells, equally normally carry out the differentiation of 3 systems, and as shown this is thin
The skeletonization of born of the same parents and break up at fat.
Fig. 5 is the variation of the telomere length of human archeocyte after being acted on by micromolecular compound, in A figures, before processing
As a contrast, using the method in embodiment 1, embodiment 3~10, telomere length increases and is more than people source skin fibroblasts
1.5 again；People source mesenchymal stem cell has been handled in B figures, using the method for embodiment 2 and embodiment 11, telomere after processing
Length increases.
Fig. 6 is the telomere length of human archeocyte and the comparison at age and telomere phase after being acted on by micromolecular compound
The expression of correlation gene：Compared with the Mean telomere length of about 35 years old healthy population, and compared with self, individual comes within 52 years old
After small molecule combinatorial is handled, telomere length increases obviously, as shown in A figures the skin fibroblasts in source；Prolong with telomere
The long instantaneous high expression of relevant gene TPP1, such as schemes B；Figure C shows that TERT (telomerase reverse transcriptase) is in immortalized cells 293T
(" 1 "), Fib (the people source skin fibroblasts of Day12；" 2 ", embodiment 1), (people source medulla mesenchyma is dry by the MSC of Day12
Cell；" 3 ", embodiment 2) in transient expression.
Fig. 7 is that the expression acted in the skin fibroblasts of descendant source with aging related genes micromolecular compound becomes
Change, in cell after treatment, lowered with the relevant gene of aging, for example, with the relevant gene of P53 tumor suppressor pathways
CDKN1A, ATF3, GADD45B, BTG2, with the relevant H2A histone families member X of aging；
Fig. 8 is the detection that micromolecular compound acts on the external function vigor of descendant's source skin fibroblasts：Such as embodiment
3, the I-type collagen of skin fibroblasts, apparent up-regulation after treatment；The marker ITGA6 of mesoderm growing early stage Skin Cell,
Up-regulation is apparent after treatment.
Fig. 9 is the detection that micromolecular compound acts on descendant source skin fibroblasts in vivo functionality vigor：From skin point
From fibroblast there is weaker immunoregulation capability, after handling cell by the method for embodiment 6, moved in heterogenous skin
In the model of plant, the culture solution after cell culture 48 hours is injected into receptor mouse body, dermatoplasty position is observed after 8 days,
Compared to control group (untreated cell group Fib, PBS group), the immunological rejection that donor graft skin receives is smaller, after processing
Cell have apparent systemic immunity adjustment effect.
Figure 10 is the detection of the cell dryness of Long Term Passages and Tumor formation testing result figure after acting on micromolecular compound：
To the cell handled in embodiment 1, the subcutaneous cell transplanting of Nod-SCID mouse is carried out, tumor formation is had no after 28 days, such as schemes A white circles
Shown in；Scheme the dyeing to this group of cell progress dryness gene OCT4 in B, has no expression.
The Clone formation quantity of (such as embodiment 1) people source skin fibroblasts is higher than after the effect of Figure 11 micromolecular compounds
Before processing, as shown in figure A；Figure B shows the colony morphology to be formed, and the clone of cell (Fib) is smaller before handling, cell dispersion；Place
Cell (Fib-treated) form managed is close, and clone is larger.
Claims (15)
1. the small molecule of a kind of cell for preventing, delaying or reverse mammal such as people, tissue, organ or body aging process
Compound combination, which is characterized in that micromolecular compound combination includes that DNMT inhibitor, HMT inhibitor, histone go first
Base enzyme inhibitor, TGF-β inhibitor, WNT/ β-catenin agonists, cAMP agonists and lysine deacetylase inhibit
At least one of agent.
2. micromolecular compound combination as described in claim 1, which is characterized in that the micromolecular compound is combined as DNMT
At least one of inhibitor, HMT inhibitor, histone demethylase inhibitor and lysine deacetylase inhibitors.
3. micromolecular compound combination as described in claim 1, which is characterized in that the micromolecular compound is combined as TGF-
Beta inhibitor, WNT/ β-catenin agonists, cAMP agonists, DNMT inhibitor, HMT inhibitor and lysine deacetylase
At least one of inhibitor.
4. micromolecular compound combination as described in claim 1, which is characterized in that the micromolecular compound further includes RAR
At least one of agonist, ascorbate (ascorbic acid) and ROCK inhibitor.
5. micromolecular compound combination as described in claim 1, which is characterized in that the micromolecular compound combination includes pressing
The first stage compound and second stage compound that sequential uses stage by stage, the first stage compound inhibit for DNMT
Agent, HMT inhibitor, histone demethylase inhibitor, TGF-β inhibitor, WNT/ β-catenin agonists, cAMP excitements
At least one of agent and lysine deacetylase inhibitors；
The second stage compound is DNMT inhibitor, HMT inhibitor, histone demethylase inhibitor, TGF-β inhibition
Agent, WNT/ β-catenin agonists, cAMP agonists, lysine deacetylase inhibitors, RAR agonists, ascorbate
At least one of (ascorbic acid) and ROCK inhibitor.
6. micromolecular compound combination as described in claim 1, which is characterized in that the TGF-β acceptor inhibitor is I types
TGF-β acceptor inhibitor, the cAMP agonists are EPAC/RAP1 agonists.
7. the micromolecular compound combination as described in claims 1~6 are any, which is characterized in that the micromolecular compound
Combination is applied in combination with PDGF-AB.
8. the micromolecular compound combination as described in claim 1~7 is any, which is characterized in that the lysine deacetylation
Enzyme inhibitor includes sodium phenylbutyrate, butyrate, sodium butyrate, MC1568, CI994
(Tacedinaline), chidamide, CAY10683 (SantacruzaMate A), CUDC-907, M344 (Histone
Deacetylase Inhibitor III), LAQ824 (NVP-LAQ824, Dacinostat), Pracinostat (SB939),
VPA (Valproic acid), Valproic acid sodium salt, Scriptaid, Apicidin, LBH-589
(Panobinostat), MS-275, SAHA (Vorinostat), Trichostatin (TSA), Psammaplin A, PCI-
24781 (Abexinostat), Rocilinostat (ACY-1215), Mocetinostat (MGCD0103), 4-
Phenylbutyrate (4PB), splitomicin, SRT1720, resveratrol, Sirtinol, APHA, CI-994,
Depudecin, FK-228, HC-Toxin, ITF-2357 (Givinostat), Chidamide, RGFP 966, PHOB, BG45,
Nexturastat A, TMP269, CAY10603, MGCD-0103, Niltubacin, PXD-101 (Belinostat),
In Pyroxamide, Tubacin, EX-527, BATCP, Cambinol, MOCPAC, PTACH, MC1568, NCH51 and TC-H106
At least one；
The TGF-β acceptor inhibitor includes 616452, LY2109761, Pirfenidone, Repsox (E-616452),
SB431542, A77-01, Tranilast, Galunisertib (LY2157299), A8301, GW788388, ITD-1, SD208,
At least one of SB525334, LY364947, ASP3029, D4476 and SB505124；
WNT/ β-catenin the agonists include MAY-262611, CHIR98014, CHIR99021, LiCl, Li2CO3,
TD114-2, AZD2858, AZD1080, BIO, Kenpaullone, TWS119, LY2090314, CBM1078, SB216763 and
At least one of AR-A014418；
The cAMP agonists include EPAC/RAP1 agonists, 8-Bromo-cAMP, Dibutyryl-Camp and Sp-8-Br-
At least one of cAMPs；
The EPAC/RAP1 agonists include Forskolin, IBMX, Prostaglandin E2 (PGE2), NKH477,8-
PCPT-2 '-O-Me-cAMP, GSK256066, Apremilast (CC-10004), Roflumilast, Cilomilast,
At least one of Rolipram and Milrinone；
The RAR agonists include TTNPB, Bexarotene, Ch55, Tamibarotene, Retinol, AM580, ATRA,
At least one of 13-cis RA, Vitamin A and Vitamin A derivatives；
The ROCK inhibitor includes Y-27632, Y-27632 2HCl, Thiazovivin, Ripasudil (K-115),
Fasudil, Fasudil (HA-1077) HCl, GSK429286A, at least one of RKI-1447 and PKI-1313；
The DNMT inhibitor includes RG108, Thioguanine, 5-Aza-2'-deoxycytidine (Decitabine),
At least one of SGI-1027, Zebularine and 5-Azacytidine (AZA)；
The HMT inhibitor includes EPZ004777, EPZ5676, GSK503, BIX 01294, DZNep, DZNepHCL, SGC
At least one of 0946；
The histone demethylase inhibitor includes parnate (tranylcypromine), Tranylcypromine (2-
PCPA) HCl SP2509,4SC-202, ORY-1001 (RG-6016), at least one of GSKJ1 and GSK-LSD1.
9. a kind of kit comprising the micromolecular compound combination as described in claim 1~8 is any, culture solution/base, medicine
Object, health products, food, cosmetics or medical instrument.
10. a kind of micromolecular compound combination as described in claim 1~8 is any is preventing, delaying or is reversing lactation dynamic
Object such as the cell of people, tissue, organ or application in body aging process and relevant disease and improve mammal such as people's tissue,
The application of organ damage repair ability.
11. application as claimed in claim 10, which is characterized in that the cell origin is in the body cell of mammal such as people
Or the cell of in vitro culture.
12. a kind of combining prevention by any micromolecular compound of claim 1~8, delaying or reverse mammal
Such as the method for the cell of people, tissue, organ or body aging process.
13. a kind of cell of rejuvenation obtained by any micromolecular compound compound action of claim 1~8 and
Cellular products.
14. a kind of cell of rejuvenation as claimed in claim 13 and the application of cellular products.
15. a kind of combined by any micromolecular compound of claim 1~8, which is characterized in that the small molecule chemical combination
The telomere length of cell of the object combination for extending mammal such as people, the instantaneous expression or up-regulation for stimulating Telomeric Protein；
The cell of mammal such as people will not be stimulated to express dryness gene after effect.
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| PCT/CN2018/072228 WO2018130178A1 (en) | 2017-01-13 | 2018-01-11 | Small molecule compound/combination for preventing, delaying, or reversing aging of cell, tissue, organ, or body, product and use thereof |
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| CN112640887A (en) * | 2020-12-25 | 2021-04-13 | 武汉睿健医药科技有限公司 | Neural stem cell cryopreservation liquid and application thereof |
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