CN110237057A - Application of the inositol in anti-aging - Google Patents
Application of the inositol in anti-aging Download PDFInfo
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- CN110237057A CN110237057A CN201910168215.7A CN201910168215A CN110237057A CN 110237057 A CN110237057 A CN 110237057A CN 201910168215 A CN201910168215 A CN 201910168215A CN 110237057 A CN110237057 A CN 110237057A
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- inositol
- food
- health care
- nematode
- care product
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- UZMPYXSDDZXMAI-OHKKONBVSA-N [(2r)-2-hexadecanoyloxy-3-[hydroxy-[(2r,3r,5s,6r)-2,4,6-trihydroxy-3,5-diphosphonooxycyclohexyl]oxyphosphoryl]oxypropyl] hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC)COP(O)(=O)OC1[C@H](O)[C@@H](OP(O)(O)=O)C(O)[C@@H](OP(O)(O)=O)[C@H]1O UZMPYXSDDZXMAI-OHKKONBVSA-N 0.000 description 1
- ZSZXYWFCIKKZBT-ZVDPZPSOSA-N [(2r)-3-[[(2s,3s,5r,6s)-2,6-dihydroxy-3,4,5-triphosphonooxycyclohexyl]oxy-hydroxyphosphoryl]oxy-2-hexadecanoyloxypropyl] hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC)COP(O)(=O)OC1[C@H](O)[C@H](OP(O)(O)=O)C(OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H]1O ZSZXYWFCIKKZBT-ZVDPZPSOSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
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- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
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- 210000004940 nucleus Anatomy 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- RGCLLPNLLBQHPF-HJWRWDBZSA-N phosphamidon Chemical compound CCN(CC)C(=O)C(\Cl)=C(/C)OP(=O)(OC)OC RGCLLPNLLBQHPF-HJWRWDBZSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- 229920001592 potato starch Polymers 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
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- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
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- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 229940048102 triphosphoric acid Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 235000015099 wheat brans Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Mycology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
The present invention provides application of the isolated inositol shown in following formula in drug, health care product or the food that the adjoint muscle function of preparation anti-aging, delaying senility course is lost and/or locomitivity declines.
Description
Technical field
The application that the present invention relates to inositols in anti-aging.
Background technique
Inositol is a kind of metabolin generally existing in eucaryote.For hexa-atomic cyclic alcohol, there are 9 kinds of isomers, with myo-
Inositol (MI) stablizes common (Michell, R.H., Inositol derivatives:evolution and the most
Functions, Nat Rev Mol Cell Biol, 2008,9 (2): p.151-61).MI can generate phosphatidyl-4 with CDP-DAG
Alcohol (PI, phosphatidylinositol), the 3 of PI, 4,5 hydroxyls can by mono-phosphorylated (generating PI3P, PI4P, PI5P),
Dual phosphorylation (generates PI (3,4) P2, PI (3,5) P2, PI (4,5) P2), and triphosphoric acid (generating PI (3,4,5) P3) generates 7 kinds
Phospholipid molecule.
Inositol can also exist in the form of inositol monophosphate.But it is many biological due to lacking relevant enzyme including the mankind, no
IP3 (inositoltriphosphoric acid) can be obtained by degradation PI directly by inositol monophosphate, IP3 can further be phosphorylated generation
IP4, IP5, IP6 (phytic acid), or even IP7 and IP8 is generated by dual phosphorylation at 1,3,5；IP3 can also be degraded to IP2, IP.
MI and its metabolin participate in numerous cellular physiological processes, comprising: insulin signaling pathway transduction, cytoskeleton group
Dress, Vesicle transport, intracellular calcium ion control, cell membrane potential maintenance, fat acid decomposition, gene expression etc..In mammals, MI
There are many functions for addition, comprising: increases insulin sensitivity；Lower white adipose tissue；Improving lipid ingredients (it is sweet to reduce serum
Oily three esters reduce total cholesterol and low density cholesterol, increase high density cholesterol), suffer from cardiovascular risk to reduce；Separately
Outside, MI has promotion female reproduction；The effect for treating more capsule ovarian follicle syndromes (polycystic ovary syndrome)
(Croze, M.L. and C.O.Soulage, Potential role and therapeutic interests of myo-
Inositol in metabolic diseases.Biochimie, 2013,95 (10): p.1811-1827).
Cell obtains inositol by 3 kinds of modes: from extracellular absorption, degrade molecule and utilization -6 phosphoric acid of glucose containing inositol
(G6P) de novo formation.99.8% inositol is by intestinal absorption.Glucose will affect inositol absorption, it may be possible to because structure is similar,
So hyperglycemia may cause inositol shortage.Blood plasma inositol concentration is about 30uM.There are 3 kinds of dedicated transport proteins of inositol:
SMIT1/2 and HMIT.SMIT1/2 is mainly in kidney, brain.Brain inositol concentration be greater than perienchyma (Schneider S.,
Inositol transport proteins, FEBS Lett, 2015；589:1049-1058).
MI and inositol monophosphate are largely present in many foods, such as orange, "Hami" melon and milk.Mostly with phytic acid in plant
(IP6) or phytate exists, such as wheat bran.Human body cannot digest phytic acid, after phytic acid is degraded to inositol in gastronomical process, can be
Absorption of human body (Holub BJ., Metabolism and function of myo-inositol and inositol
Phospholipids, Annu Rev Nutr, 1986；6:563-597).
Half lethal dose of the MI in mouse is 10,000mg/kg weight.The mankind can be resistant to safely daily 18g and continue 3
Month, or 2g continues 1 year daily.Side effect is mainly enteron aisle discomfort, including nausea, flatulence, diarrhea (Lam, S. etc., A phase I
Study of myo-inositol for lung cancer chemoprevention, Cancer Epidemiol
Biomarkers Prev, 2006,15 (8): p.1526-31；Carlomagno, G. and V.Unfer, Inositol safety:
Clinical evidences, Eur Rev Med Pharmacol Sci, 2011,15 (8): p.931-6).
MI is recombined in rat testicle, brain, kidney and liver.And with the conjunction of same reaction step in various biologies
It is MIOS at, rate-limiting enzyme (1-D-myo-inositol-phosphate synthase, homologous gene is inos-1 in nematode)
(Majumder AL,Chatterjee A,Ghosh Dastidar K,Majee M.Diversification and
Evolution of L-myo-inositol 1-phosphate synthase.FEBS Lett, 2003；553:3-10).People
Class kidney about synthesizes 4 grams of inositols daily, is greater than food source (about 1 gram daily).
Inositol can be degraded to glucuronic acid (D-glucuronic by MIOX (myo-inositol oxygenase)
Acid), inositol can be further degraded to carbon dioxide in rats.People's kidney is the organ of unique degradation inositol, so kidney
It is dirty particularly important during controlling serum inositol concentration.
Of greatest concern with PI (3,4,5) P3 in the metabolin of MI, PI (3,4,5) P3 there's almost no in resting cell,
But after being stimulated, can occur in several minutes.The enzyme of synthesis PI (3,4,5) P3 is that (nematode homologous gene is age- to PI3K
1).PI3K participates in DNA synthesis control, activates AKT, promotes apoptosis, promotes cell growth and differentiation and Vesicle transport, cell bone
Frame tissue is related to cell movement.Oncogene Src and T-antigen can induce PI3K active.In many tumours, AKT is held
Continuous activation.The AKT meeting phosphorylation transcription factor FOXO3A (nematode homologous gene is daf-16) of activation, inhibits FOXO3A to enter thin
Karyon, and accelerate biological decay.PI (3,4,5) P3 can be hydrolyzed to PI (4,5) P2 or PI (3,4) P2 there are many phosphatase,
PTEN is one of them.
PTEN (phosphatase and tensin homolog deleted on chromosome 10) is that lactation is dynamic
One of most important 4 tumor suppressors of object.Participate in physiology courses (the Worby CA, Dixon such as tumor suppression, metabolism, development
JE.Pten.Annu Rev Biochem 2014；83:641-669).As phosphatidase, substrate can be lipositol,
It can be the phosphorylation site of protein.Activity of the PTEN as lipositol enzyme is followed successively by the dephosphorylation efficiency of substrate
PI(3,4)P2>PI(3,4,5)P3>PI(3,5)P2.The N-terminal of PTEN is PI (4,5) p2 binding motif, and 15 arginine are important
Amino acid.After PI (4,5) P2 combination PTEN, its activity of phospholipase to PI (3,4,5) P3 and PI (3,4) P2 is activated, this is one
Kind positive feedback mechanism, so PI (4,5) P2 is both its product and its agonist.
Homologous gene of the PTEN in nematode is daf-18, and the daf-18 of nematode can be substituted by PTEN, illustrate the base
Because guarding (Liu, J. and I.D.Chin-Sang, C-elegans as a model to study PTEN's in people and nematode
Regulation and function, Methods, 2015,77-78:p.180-190).Daf-18 is from mesoderm growing early stage in nematode
(bean stage) starts to express, and is expressed in enteron aisle, nerve, body wall muscle, epidermis thereafter.It is active in many tissues.?
The function of knowing includes: learning and memory, and the service life determines, thermal response, Dauer larvae development, the development of ovary, in negative regulation nerve
Transcription factor, chemotactic adjusting etc..Insulin receptor, FAK, src kinases are also the substrate of PTEN.PTEN is also played in nucleus
The splicing form (PTEN-L) of function, PTEN and its length also functions in mitochondria, and can be secreted into other cells.
PTEN has an apparent dosage effect, and PTEN expression lowers 20%, be just adequate to bring about tumour (Alimonti, A. etc.,
Subtle variations in PTEN dose determine cancer susceptibility, Nat Genet,
2010,42 (5): p.454-458).It is overexpressed daf-18 in nematode and extends service life (Brisbin, S. etc., A role for
C.elegans Eph RTK signaling in PTEN regulation, Dev Cell, 2009,17 (4): p.459-69).
Pten overexpression can also mouse life be made to extend, but influence development, make mouse head become smaller (the reason is that inhibition of cell proliferation and
Non- influence cell size) (Ortega-Molina, A. etc., Pten Positively Regulates Brown Adipose
Function, Energy Expenditure, and Longevity, Cell Metabolism, 2012,15 (3): p.382-
394；Garcia-Cao, I. etc., Systemic elevation of PTEN induces a tumor-suppressive
Metabolic state, Cell, 2012,149 (1): p.49-62).
Summary of the invention
The present invention, which provides inositol and loses and/or enhance in the adjoint muscle function of preparation anti-aging, delaying senility course, to decline
Application in the drug of the locomitivity of old object, health care product or food.
The present invention also provides the muscle function funerals adjoint in preparation anti-aging, delaying senility course of the food naturally containing inositol
The health care product of the locomitivity of mistake and/or enhancing aging object or the application in food.
The present invention also provides promote inositol synthesis expression of enzymes or improve the reagent of its enzyme activity in preparation anti-aging drug, health care
Application in product or food.
The present invention also provides promotion inositol synthesis expression of enzymes or the reagent for improving its enzyme activity to prepare delaying senility course companion
With muscle function lose and/or the drug of locomitivity of enhancing aging object, health care product or food in application.
In certain embodiments, the inositol has the following structure formula:
The present invention also provides a kind of pharmaceutical composition, described pharmaceutical composition contains the inositol and pharmaceutically of therapeutically effective amount
Acceptable carrier.
The present invention also provides a kind of health care product, the health care product contains inositol, wherein shape of the inositol to isolate and purify
Formula is added in the health care product, or is added to the health care in the form of the concentrate of its naturally occurring food or extract
In product.
The present invention also provides a kind of food, are added with inositol, wherein the inositol is added in the form isolated and purified
In the food.
Detailed description of the invention
Fig. 1: MI extends the nematode service life.The molecular structure of a:MI.B:50mM MI addition extends the (average life span of nematode service life
Extend 19%, p < 0.001).C: rate-limiting enzyme (inos-1) the extension nematode service life for being overexpressed MI synthesis in nematode, (average life span was prolonged
Long 19%, p=0.002).D: so that the enzyme (ttx-7) for the another single step reaction for synthesizing MI in nematode is lost partial function and shorten nematode
Service life (8%, p < 0.001 is shortened in average life span).E:50mM MI makes the base that downward is expressed in nematode aging course in mRNA level in-site
Because of up-regulation (p < 0.001).F:50m MI makes the gene deregulation (p=that up-regulation is expressed in nematode aging course in mRNA level in-site
0.0147)。
Fig. 2: MI extends the life-span of nematode.Locomitivity (the n.s. that a:50mM MI delays nematode to decline with aging
To be not significant, * is p < 0.5).B: it is overexpressed the locomitivity that inos-1 delays nematode to decline with aging.C:50mM MI is reduced
Nematode body fat content (* * * is p < 0.001).D, e:50mM MI delay the segment of Muscle Mitochondria in nematode aging course
Change (* * * is p < 0.001).(* is p < 0.05, * * * to the locomitivity that f:50mM MI reverses Parkinson disease model nematode to decline
For p < 0.001).G, h:50mM MI inhibit the aggregation (* of α-SYNUCLEIN::YFP albumen in Parkinson disease model line polypide
For p < 0.05).
Fig. 3: MI delays the aging of mouse.A, mouse experiment design.B, MI table during mRNA level in-site makes mice age
Up to the gene upregulation (p < 0.001) of downward.C, MI expressed during mRNA level in-site makes mice age up-regulation gene deregulation (p <
0.001).D, MI increase the running ability of mouse (* is p < 0.05, and * * * is p < 0.001).The four limbs grip of e:MI increase mouse
(for n.s. to be not significant, * * * is p < 0.001).F:MI addition reduces mouse systemic fat content (n.s. is not significant).
Fig. 4: daf-18 (PTEN) is the target of MI.A:daf-18 (ok480) function loss mutation blocks MI to line completely
The worm service life extends.B:daf-18 (ok480) is blocked completely is overexpressed inos-1 to nematode life-time dilatation.C:daf-18
(ok480) 50mM MI is blocked to make the gene upregulation (p < 0.001) for expressing downward in nematode aging course in mRNA level in-site.D:
Daf-18 (ok480) block 50mM MI mRNA level in-site make to express in nematode aging course up-regulation gene deregulation (p <
0.001).(n.s. is not show to the locomitivity that e:daf-18 (ok480) blocks 50mM MI that nematode is delayed to decline with aging
It writes).F:daf-18 (ok480) blocks 50mM MI to reduce nematode body fat (n.s. is not significant).G, h:MI increase Mouse Bone
The protein level of the intramuscular PTEN of bone (n.s. is not significant).
In each figure, " CTL " refers to control.
Specific embodiment
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to constitute preferred technical solution.
Present invention discover that the nematode service life can be extended by giving inositol, the gene changed during mice age is reversed, mouse is made
The gene deregulation raised in aging course, the gene upregulation lowered in aging course；In addition, inositol can also delaying senility course companion
With muscle function lose and Fat Accumulation, improve aging object locomitivity.Thus the present invention is completed.
Specifically, the present invention relates to anti-ageing out-of-date methods, the method that the adjoint muscle function of delaying senility course is lost, with
And the method for the locomitivity of enhancing aging object.The method includes giving the object of needs a effective amount of inositol.Object can
To be mammal, especially people.Effective quantity can according to the physical conditions of different objects and the effect of desired acquisition etc. because
Element determines.Half lethal dose of the MI in mouse is 10,000mg/kg.The mankind can be resistant to safely daily 18g and continue 3 months, or
Daily 2g continues 1 year.Therefore, a effective amount of inositol for example can be the amount lower than 18g/ days, or the amount lower than 2g/ days.
When daily intaking amount is higher, such as at 18g/ days or so, then it can shorten the time of lasting intake.Under normal conditions, daily to take the photograph
Entering amount can be between 1.0~2.0g, such as daily intaking amount is 0.1~1.0g or 0.1~0.5g.
Inositol can be made into the form of drug, health care product or food.
Pharmaceutically acceptable carrier or excipient can be contained in drug.Suitable pharmaceutically acceptable carrier can make
Various suitable auxiliary materials, especially filler, such as carbohydrate such as lactose or sucrose, mannitol or sorbierite；Cellulose preparation and/or
Calcium phosphate, such as tricalcium phosphate or calcium monohydrogen phosphate；And binder, such as gelatinized corn starch, including cornstarch, wheaten starch,
Rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose,
And/or polyvinylpyrrolidone.If desired, disintegrating agent, such as carboxymethyl starch can be increased, crosslinked polyvinylpyrrolidone,
Agar or alginic acid or its salt, such as sodium alginate.Suitable carrier further includes flowing regulator and lubricant, for example, silica,
Talcum, stearic acid or its salt, such as magnesium stearate or calcium stearate and/or polyethylene glycol etc..
Health care product can be the health care product for anti-aging of this field routine.Food can be involved by various diets
And various food, including but not limited to various drinks, dairy produce, snack food etc..It can be in the health care product and food of daily consumption
Suitable inositol is added in product, and health care product and food of the invention is made.
Therefore, the present invention also provide inositol lose in the adjoint muscle function of preparation anti-aging, delaying senility course and/or
Enhance the application in the drug, health care product or food of the locomitivity of aging object.It should be understood that previously described inositol Ying Zhicong
The inositol separated in its natural existing environment, or the inositol of preparation after purification.It is applied to pure inositol described
In drug, health care product and food.
In certain embodiments, the present invention also provides the naturally food containing inositol and is preparing anti-aging, delaying senescence
The health care product or the application in food that the locomitivity of aging object is lost and/or enhanced to the adjoint muscle function of journey.This field
It is known various naturally containing the food of inositol, including but not limited to animal's liver, brewer's yeast, white flower beans, bovine brain, cattle heart, the U.S.
Muskmelon, grape fruit, raisins, malt, unpurified molasses, peanut, Brussels sprouts and whole wheat grain etc..These foods can be made
Health care product or food form, daily to take, the muscle function adjoint to anti-aging, delaying senility course loses and/or enhancing
The locomitivity of aging object.
In certain embodiments, the present invention also provides the reagents that promotion inositol synthesizes expression of enzymes or improves its enzyme activity to make
Application in standby anti-aging drug, health care product or food, or prepare the adjoint muscle function of delaying senility course lose and/or
Enhance the application in the drug, health care product or food of the locomitivity of aging object.
Inositol synzyme can be the various enzymes on inositol route of synthesis, including its rate-limiting enzyme such as 1-D- Myo-Inositol-phosphorus
Acid enzyme.The reagent of inositol synthesis expression of enzymes is promoted to can be nucleic acid molecules；The reagent for improving inositol synthase activity can be with
It is some small molecule compounds, such as the agonist of inositol synzyme.Nucleic acid molecules can be such as some inositol synzyme such as institute
State the expression vector of rate-limiting enzyme.The yield of object itself inositol is improved by improving the expression of inositol synzyme, to realize
Delay senescence, delay it is described during adjoint muscle function lose or the purpose of locomitivity decline.It is normal that this field can be used
The method building of rule can express the expression vector of inositol synzyme, the skeleton carrier of expression vector can be it is well known in the art can
With carrier for therapeutic purposes.
In certain embodiments of the invention, the present invention also provides a kind of pharmaceutical composition, described pharmaceutical composition contains
There are the inositol and pharmaceutically acceptable carrier of therapeutically effective amount.In general, the inositol in pharmaceutical composition be with pure activity at
The form divided is added in described pharmaceutical composition.
In certain embodiments, the present invention also provides a kind of health care product, the health care product contains inositol.The inositol can
It is added in the health care product in a pure form, or can be added in the form of the concentrate of its naturally occurring food or extract
Into the health care product.For example, animal's liver, brewer's yeast, white flower beans, bovine brain, cattle heart, U.S.'s sweet tea can be contained in health care product
The concentrate of any one of melon, grape fruit, raisins, malt, unpurified molasses, peanut, Brussels sprouts and whole wheat grain and/
Or extract, the concentrate or extract contain inositol.
In certain embodiments, the present invention also provides a kind of food, are added with inositol, wherein the inositol is with pure
Form be added in the food.In other words, at least partly inositol is not that the other ingredients of the food naturally contain in the food
Have and is carried in the food.
In certain embodiments, inositol described herein has the following structure formula:
Have the advantage that MI is existing main inositol form in organism using MI, thus body have to MI it is higher
Tolerable concentration, it means that without deliberately controlling intake；In addition, MI is cheap, the medicine of anti-aging can be greatly reduced
The cost of product, health care product, food additives.
The present invention will be hereafter illustrated in a manner of specific embodiment.It should be understood that these embodiments are only illustrative, and
Not intended to limit protection scope of the present invention.Used method and material in embodiment, unless otherwise stated, being ability
The method and material of domain routine.
One, experimental material and method
1, experimental material
1.1 nematodes and bacterium strain
Nematode strain used and OP50 (Escherichia coli uracil deficiency) are tested from Caenorhabditis
Genetics Center is obtained.Nematode strain includes N2 (Bristol), IK575 [(ttx-7 (nj40)], SJ4103 [ges-
1::GFP (mit)], NL5901 { pkIs2386 [unc-54p::alphasynuclein::YFP+unc-119 (+)] }, RB712
[daf-18(ok480)]。
1.2 inositol suppliers: SIGMA (I5125).PTEN antibody supplier: SANTA CRUZ (sc-7974).
2, experimental method
2.1 nematode culture
Nematode culture according to normal process (Stiernagle, T., Maintenance of C.elegans.WormBook,
2006,1-11), i.e., 20 DEG C of cultures, feeding OP50 on nematode growth media (NGM) agar plate.
The statistical analysis technique of 2.2 nematode viabilities experiment
Nematode is synchronized by way of picking worm's ovum, since adding compound adult in solid medium.OP50
With 520 cross-linker (100mJ/cm of Hoefer UVC2Irradiation 4 minutes) sterilization, it is used after placing 6 hours.It is right daily
Dead insect counts, until all insects are dead.N-th day to (n+1)th day dead insect, service life are denoted as n+1 days.Existence
Curve Log Rank Test comparing difference conspicuousness, each processing statistical average service life and standard deviation, MaLS and standard
Poor (average life span of last 10% insect is as MaLS).
The building of 2.3 nematode transgenosis worm strains
Used carrier is pPD158.87.With restriction enzyme by inos-1 from atg start codon to the last one amino
The codon of acid is connected into carrier, and template is genomic DNA.Picking band fluorescence nematode in 2 days after injection.It does not integrate.Specially
Psur-5::GFP::let858.3-3 ' UT and Psur-5::inos-1::GFP::let858.3-3 ' UTRR.GFP；daf-18
(ok480) and inos-1::GFP；Daf-18 (ok480) is by hybridizing acquisition with both the above worm system for daf-18 (ok480).
The primer are as follows:
Inos-1F:CAGTGCGGCCGCATGAGCTCGGCCCAAGTTAATGGAAT (SEQ ID NO:1),
Inos-1R:TCGAGGTACCGACTGAGATTTCG (SEQ ID NO:2).
2.4RNA sequencing
Nematode processing is same as life tests experiment.The 4th day or the 10th day insect is taken to pass through the worm with old age respectively as year
Son.Nematode MI processing experiment, uses the 10th day nematode as sample.When receiving sample, washed 3 times or more with phosphate buffer (M9),
To remove bacterium.After removing supernatant, adds Trizol, be stored in after quick-frozen in liquid nitrogen in -80 DEG C of refrigerators or liquid nitrogen.RNA is extracted
It is operated by Trizol specification.But cleavage method is slightly different: nematode sample liquid nitrogen, 60 DEG C of Metal constant temperature baths freeze repeatedly
Melt 6~8 cracking.RNA mass is detected with 2100 Bioanalyzer of Agilent, it is desirable that RIN value is greater than 8.Sequencing is used
2000 sequencing system of Illumina HiSeq.RNA-seq sequencing result uses Tophat after checking the quality of data through preliminary treatment
Sequencing result is compared onto genome, then does quality inspection with fastqc software again.Then it will be sequenced with cufflinks software
As a result transcript is connected into, then looks for difference expression gene with cuffdiff software.Gene Set Enrichment GSEA journey
Sequence realizes (Subramanian, A., et al.Gene set enrichment analysis:a knowledge-based
Approach for interpreting genome-wide expression profiles, Proc Natl Acad Sci
USA 2005；102(43):15545-15550).
2.5 nematode movement capacity experimentals
Add 100 milliliters of M9 on 35 millimeters of NGM plates, a nematode is chosen into M9, after adapting to 30 seconds, nematode in record 30 seconds
It wags the tail number.10 nematodes are tested in each processing, and every nematode is tested 4 times.Then test surveys second by each processing 1
Processing is carried out by processing cycle.
2.6 nematode oil red Coloration experiments
The dyeing of nematode oil red, reference standard method (O'Rourke EJ, Soukas AA, Carr CE, Ruvkun
G.C.elegans major fats are stored in vesicles distinct from lysosome-related
Organelles.Cell Metab, 2009,10:430-435).After nematode washes 3 times with PBS, with 2*MRWB (160mM KCl,
40mM NaCl, 14mM Na2EGTA, 1mM R-gene, 0.4mM spermine, 30mM Na-PIPES pH 7.4,0.2% β-mercapto
Base ethyl alcohol) and 2% PFA it is fixed after, washed twice with pH7.4 100mM Tris-Cl.Next with the 100mM of the DTT containing 10mM
Tris-Cl solution reduction 30 minutes.It is washed 15 minutes after removing supernatant with 70% isopropanol.Then oil red (SIGMA 85578) is used
Stained over night.Secondary daily PBS is washed once, is saved.Photo is shot with Nikon inverted microscope, one insect of every picture.With soft
Part analyzes the gray value of every photo.Each processing at least shoots 30 insects and statisticallys analyze.
2.7 nematode mitochondrial assays
SJ4103 [ges-1::GFP (mit)] can show the mitochondria of nematode body wall muscle cell.In this experiment, MI
Processing mode is same as life experiment.Adult the 8th day, insect is layered on 2% agarose with anesthetic, after coverslip, with referring to
Nail polish mounting.It takes pictures under 63 times of Laser Scanning Confocal Microscopes (CONFOCAL).Line taking worm tail region, every nematode clap 1, each
Processing at least claps 30.Mitochondria coverage is analyzed with this laboratory self-compiling program.
2.8 nematode Parkinson disease model experiments
Nematode Parkinson disease model, with NL5901 { pkIs2386 [unc-54p::alphasynuclein::YFP+
Unc-119 (+)] } worm system.MI processing mode is same as life experiment.Nematode movement capacity experimental and CONFOCAL are same as above, but are schemed
2g is shot with 20 times of mirrors.
2.9 mouse experiment
Mouse species are C57BL/6J, and feeding environment is SPF grades, room temperature 22-24 degree, relative humidity 40-70%, 12 hours
Light and shade is alternately raised.Mouse adds MI by stomach-filling every other day.Processing 3 months after, with prologue experimental test mouse movement ability, i.e.,
Compare the distance run in open field test instrument (Shanghai Ren Yi Biotechnology Co., Ltd) in mouse 20 minutes, open field test
System software is Clever System Inc (TopScan Lite).The grip of mouse four limbs is tested with grip sensor
(Bioseb company G3, pulling force: 0-2000g；Precision: 0.1g, error < 0.3).Mouse body fat is tested with borne densitometers
(PLXIMUS)。
Immunoblot experiment weighs the mouse liver of phase homogenous quantities, and lysate, homogenate is added, and boiling water bath boils 5 minutes.With
Glue, 10% separation gel electrophoresis is concentrated in 4% polyacrylamide.Then pvdf membrane is gone to.After 5% skim milk is closed 1 hour,
I antibody is diluted with 5% bovine serum albumin(BSA), 5% skim milk dilutes II antibody.Centre is with Tris buffer solution for cleaning 3 times, every time
5 minutes.Then it is taken pictures with substrate colour developing.
Two, result
1, inositol addition extends the nematode service life
The molecular structure of MI is shown in Fig. 1 (a).The MI that 50mM is added in the culture medium of nematode can significantly extend nematode and be averaged
Service life (Fig. 1, b, average life span+19%, p < 0.001).The rate-limiting enzyme (inos-1) that synthesis MI is overexpressed in nematode can also prolong
Long nematode service life (Fig. 1, c, average life span+19%, p=0.002).And make the part enzyme ttx-7 for synthesizing the another single step reaction of MI
Loss of function shortens the nematode service life, and (I (3) P and intracorporal I (4) P that inos-1 is synthesized is converted to MI, Fig. 1, d by ttx-7, is put down
Equal service life -8%, p < 0.001).
With transcript profile in aging course, the variation including mRNA level in-site, anti-aging usually can reverse this mRNA's
Change (Hou L, Wang D, Chen D et al.A Systems Approach to Reverse Engineer
Lifespan Extension by Dietary Restriction.Cell Metab, 2016,23:529-540).In nematode
In, the MI processing of 50mM can reverse the gene changed in aging course.That is, make to lower in aging course gene upregulation (Fig. 1,
E, p < 0.001).The gene deregulation (Fig. 1, f, p=0.0147) raised in aging course, this extends the result in nematode service life with MI
Unanimously.
2, inositol addition delays muscle function forfeiture and Fat Accumulation adjoint in nematode aging course
MI adds the service life that can not only extend nematode, and delays the aging of its health status.The MI of 50mM, which is added, to be increased
The ability of the movement of nematode has compared with control group nematode stronger in the experiment test of wagging the tail of adult the 4th, 6,8,10 in the past few days
Locomitivity, be significant (Fig. 2, a, n.s. are not significant, * is p < 0.5) at the 10th day.The same inos-1 that is overexpressed can also prolong
The locomitivity of slow nematode was significant (Fig. 2, b) at the 6th and 10 day with the decline of aging.
According to reports, MI addition can reduce biological body fat.The MI addition of 50mM can be substantially reduced the 10th day rouge of adult and contain
Amount (Fig. 2, c, * * * are p < 0.001).
Because MI can obviously increase the locomitivity of nematode, we have detected nematode muscle Mitochondria MI before and after the processing
Variation.In aging course, mitochondria in muscle by year through when network-like structure, gradually fragmentation, may use line grain
Body coverage is quantitative, can slow down this variation after MI processing (Fig. 2, d, e, * * * are p < 0.001).In view of this phenotype, we
MI is added to the nematode as mitochondrial disease model, this nematode strain locomitivity is remarkably decreased compared with wild type, and MI addition can be with
The decline of part counter transport kinetic force (Fig. 2, f, * are p < 0.05, and * * * is p < 0.001).This disease model passes through in wild line
It is overexpressed α-synuclein::YFP building in worm, causes to assemble this albumen in nematode body, be shown as under fluorescence microscope
Yellow patch, MI addition can reduce the quantity of yellow patch (Fig. 2, g, h, * are p < 0.05).
3.MI delays the aging of mouse
In order to verify whether anti-aging effects of the MI in nematode are guarded in mammals, we pass through to female
Fill within C57BL/6 mouse every 3 days the MI, experimental design such as Fig. 3 (a), wherein " CTL " referred to for 12 monthly ages of food 0.58g per kilogram of body weight
Untreated control；" MI " refers to the processing control at 12 monthly ages, wherein starts to give MI when September；" Pre-treatment CTL " refers to 9
The untreated control at monthly age；" Young CTL " refers to the untreated control at 3 monthly ages.
The results show that MI can also reverse the variation of gene expression during mice age, make the base lowered in aging course
Because of up-regulation (Fig. 3, b, p < 0.001), make the gene deregulation (Fig. 3, c, p < 0.001) raised during mice age.
We compare the locomitivity of mouse, and 12 mouse September ages at monthly age were compared, and the distance run in 20 minutes is obvious
Decline, and MI addition can slow down this variation (Fig. 3, d, * are p < 0.05, and * * * is p < 0.001).MI can also slow down mouse four
The decline of limb grip (to be not significant, * * * is p < 0.001 by Fig. 3, e, n.s.).Experiment has also reproduced it has been reported that the MI crossed is reduced
The effect of body fat content, but result not significant (Fig. 3, f, n.s. are not significant) (the Hayashi E, Maeda in this experiment
T,Tomita T.The effect of myo-inositol deficiency on lipid metabolism in
Rats.I.The alteration of lipid metabolism in myo-inositol deficient rats,
Biochim Biophys Acta, 1974；360:134-145).
4, daf-18 function loss mutation body can block MI to nematode life-time dilatation
In order to find the mechanism of MI anti-aging, we have attempted the classical signal path of had an impact aging, and detection is each
Can the key gene mutant of access block the effect of MI, however, it was found which mutation physical efficiency MI to be blocked to imitate completely without
Fruit.It can be combined in view of derivative PI (4,5) P2 of MI and activate PTEN (phosphatase and tensin
Homologue), we have attempted function of the PTEN in nematode and have completely lost mutant daf-18 (ok480).Ok480 can be with
Completely block 50mM MI addition to nematode life-time dilatation (Fig. 4, a), can also block completely be overexpressed inos-1 to nematode
Life-time dilatation (Fig. 4, b).Ok480 can also block 50mM MI add in nematode aging course changes in gene expression it is inverse
Turn, i.e., cannot make the gene upregulation (Fig. 4, c, p < 0.0001) lowered in aging course, can not make to raise in aging course
Gene deregulation (Fig. 4, d, p < 0.0001).And ability (the figure that ok480 blocks 50mM MI that nematode movement is delayed to decline with aging
4, e, n.s. are not significant).MI can not reduce the intracorporal fat of ok480 nematode, and (Fig. 4, f, * * are p < 0.01, and n.s. is not show
It writes).Next we compare mouse respectively organize in pten protein horizontal expression amount MI addition before and after variation, find in the heart
It is changed in dirty and skeletal muscle, variation becomes apparent from skeletal muscle, but significantly (Fig. 4, g, h, n.s. are not show to statistical analysis
It writes).
Sequence table
<110>Shanghai Inst. of Life Science, CAS
<120>application of the inositol in anti-aging
<130> 179570z1
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 38
<212> DNA
<213>artificial sequence (Artificial Sequence)
<400> 1
cagtgcggcc gcatgagctc ggcccaagtt aatggaat 38
<210> 2
<211> 23
<212> DNA
<213>artificial sequence (Artificial Sequence)
<400> 2
tcgaggtacc gactgagatt tcg 23
Claims (10)
1. isolated inositol shown in following formula is lost and/or is transported in the adjoint muscle function of preparation anti-aging, delaying senility course
The application in drug, health care product or food that kinetic force declines:
2. the food naturally containing inositol shown in following formula is lost in the adjoint muscle function of preparation anti-aging, delaying senility course
And/or the application in the health care product or food of locomitivity decline:
3. application as claimed in claim 2, which is characterized in that the naturally food containing inositol includes animal's liver, beer
Yeast, white flower beans, bovine brain, cattle heart, cantaloupe, grape fruit, raisins, malt, unpurified molasses, peanut, Brussels sprouts and
One of whole wheat grain is a variety of.
4. promoting inositol synthesis expression of enzymes or improving reagent the answering in preparation anti-aging drug, health care product or food of its enzyme activity
With, or preparing drug, health care product or the food that the adjoint muscle function of delaying senility course is lost and/or locomitivity declines
In application.
5. application as claimed in claim 4, which is characterized in that the inositol synzyme is the synthesis of inositol shown in following formula
Enzyme:
6. application as described in claim 4 or 5, which is characterized in that the reagent for promoting inositol synthesis expression of enzymes is nucleic acid
Molecule, the reagent for improving inositol synzyme enzyme activity are the agonist of the enzyme.
7. application as described in claim 4 or 5, which is characterized in that the inositol synzyme is the rate-limiting enzyme of inositol synthesis, such as
1-D- Myo-Inositol-phosphate synthase.
8. a kind of pharmaceutical composition, which is characterized in that the inositol and pharmaceutically may be used that described pharmaceutical composition contains therapeutically effective amount
The carrier of receiving.
9. a kind of health care product, which is characterized in that the health care product contains inositol, wherein form of the inositol to isolate and purify
It is added in the health care product, or is added to the health care product in the form of the concentrate of its naturally occurring food or extract
In.
10. a kind of food is added with inositol, wherein the inositol is added in the food in the form isolated and purified.
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|---|---|---|---|---|
| CN1736262A (en) * | 2004-08-18 | 2006-02-22 | 杜士明 | Composition containing flavonoid, jphosphatidyl inositol and/or inosite |
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| WO2016076310A1 (en) * | 2014-11-10 | 2016-05-19 | 昭和電工株式会社 | Moisturizing agent |
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2019
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| CN1736262A (en) * | 2004-08-18 | 2006-02-22 | 杜士明 | Composition containing flavonoid, jphosphatidyl inositol and/or inosite |
| CN101015350A (en) * | 2007-01-12 | 2007-08-15 | 南京大渊美容保健有限公司 | Senescence delaying health care composition |
| WO2016076310A1 (en) * | 2014-11-10 | 2016-05-19 | 昭和電工株式会社 | Moisturizing agent |
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