CN109806251A - The application of 3-hydroxybutyrate and its derivative in the product for preparing antiatherosclerosis - Google Patents
The application of 3-hydroxybutyrate and its derivative in the product for preparing antiatherosclerosis Download PDFInfo
- Publication number
- CN109806251A CN109806251A CN201910160173.2A CN201910160173A CN109806251A CN 109806251 A CN109806251 A CN 109806251A CN 201910160173 A CN201910160173 A CN 201910160173A CN 109806251 A CN109806251 A CN 109806251A
- Authority
- CN
- China
- Prior art keywords
- product
- hydroxybutyrate
- derivative
- group
- atherosclerosis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- WHBMMWSBFZVSSR-UHFFFAOYSA-N R3HBA Natural products CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 title claims abstract description 54
- WHBMMWSBFZVSSR-UHFFFAOYSA-M 3-hydroxybutyrate Chemical compound CC(O)CC([O-])=O WHBMMWSBFZVSSR-UHFFFAOYSA-M 0.000 title claims abstract description 49
- 230000000879 anti-atherosclerotic effect Effects 0.000 title abstract description 9
- 210000004369 blood Anatomy 0.000 claims abstract description 18
- 239000008280 blood Substances 0.000 claims abstract description 18
- 150000002632 lipids Chemical class 0.000 claims abstract description 17
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 6
- 230000036541 health Effects 0.000 claims abstract description 5
- 210000002966 serum Anatomy 0.000 claims description 15
- 230000002757 inflammatory effect Effects 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- HPMGFDVTYHWBAG-UHFFFAOYSA-N 3-hydroxyhexanoic acid Chemical compound CCCC(O)CC(O)=O HPMGFDVTYHWBAG-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 239000000470 constituent Substances 0.000 claims description 5
- -1 pulvis Substances 0.000 claims description 5
- 229910021645 metal ion Inorganic materials 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229940100688 oral solution Drugs 0.000 claims description 2
- OMSUIQOIVADKIM-UHFFFAOYSA-N ethyl 3-hydroxybutyrate Chemical compound CCOC(=O)CC(C)O OMSUIQOIVADKIM-UHFFFAOYSA-N 0.000 claims 3
- 150000003839 salts Chemical class 0.000 claims 2
- LDLDJEAVRNAEBW-UHFFFAOYSA-N Methyl 3-hydroxybutyrate Chemical class COC(=O)CC(C)O LDLDJEAVRNAEBW-UHFFFAOYSA-N 0.000 claims 1
- ACCRBMDJCPPJDX-UHFFFAOYSA-N Methyl 3-hydroxyhexanoate Chemical class CCCC(O)CC(=O)OC ACCRBMDJCPPJDX-UHFFFAOYSA-N 0.000 claims 1
- 239000008187 granular material Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- 206010061218 Inflammation Diseases 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 230000004054 inflammatory process Effects 0.000 abstract description 2
- 238000013258 ApoE Receptor knockout mouse model Methods 0.000 description 20
- 239000000047 product Substances 0.000 description 19
- 241000699666 Mus <mouse, genus> Species 0.000 description 14
- 108010023302 HDL Cholesterol Proteins 0.000 description 8
- 108010028554 LDL Cholesterol Proteins 0.000 description 8
- 210000000709 aorta Anatomy 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 210000001367 artery Anatomy 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 150000003626 triacylglycerols Chemical class 0.000 description 6
- 238000004043 dyeing Methods 0.000 description 5
- 229930040373 Paraformaldehyde Natural products 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 229920002866 paraformaldehyde Polymers 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- WZUVPPKBWHMQCE-XJKSGUPXSA-N (+)-haematoxylin Chemical compound C12=CC(O)=C(O)C=C2C[C@]2(O)[C@H]1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-XJKSGUPXSA-N 0.000 description 3
- 101150037123 APOE gene Proteins 0.000 description 3
- 102100029470 Apolipoprotein E Human genes 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Natural products C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 3
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000004434 Calcinosis Diseases 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 239000012224 working solution Substances 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229940126033 PPAR agonist Drugs 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 150000006636 nicotinic acid Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000011022 operating instruction Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000002307 peroxisome proliferator activated receptor agonist Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000004231 tunica media Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008802 xuezhikang Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to field of medicaments, and in particular to the application of 3-hydroxybutyrate and its derivative in the product for preparing antiatherosclerosis.Compared with prior art, the beneficial effects of the present invention are embodied in: (1) 3-hydroxybutyrate and its derivative can be used for prepare the drug or health care product of antiatherosclerosis, blood lipid can not only be reduced but also the inflammatory reaction occurred during incidence of atherosclerosis can be inhibited, to achieve the effect that antiatherosclerosis, there is potential applicability in clinical practice；(2) 3-hydroxybutyrate and its derivative side effect very little, safety is especially high, is suitble to take for a long time, druggability is good.
Description
Technical field
The invention belongs to field of medicaments, and in particular to 3-hydroxybutyrate and its derivative are preparing antiatherosclerosis
Application in product.
Background technique
The generation of atherosclerosis (Atherosclerosis, AS) and the recession for promoting artery plaque are to reduce
The essential measure of cardiovascular and cerebrovascular morbidity and mortality.Atherosclerosis is common in a kind of angiosis of artery sclerosis
And most important one kind, its main feature is that first having lipid and compound carbohydrate accumulation/bleeding and thrombus since artery intimal lesion
It is formed, proliferation of fibrous tissue and calcinosis, and has the gradually transformation and calcification of arterial media, lesion is often involved elastic and big
Medium muscular artery, once developing to obstruction lumen of artery, then the artery is supplied tissue or organ by ischemic or necrosis, by
It is athero- in yellow in the lipid appearance gathered in endarterium, because of referred to herein as atherosclerosis.
Currently, the treatment of atherosclerosis is mainly started in terms of two: first is that reducing blood lipid, but inhibit endangium
Hyperplasia can inhibit the hyperplasia of endangium such as Atorvastatin common on treatment of atherosclerosis, be anti-artery
The key agents of atherosis.
Blood lipid-lowering medicine according to the mechanism of action difference, be broadly divided into 1), HMG-CoA reductase inhibitor (Statins) 2),
PPAR agonist (fibrates) 3), niacin class 4), polyenoid class (fish oil class) 5), Hongqu extract (Effects of Xuezhikang etc.).These
The effect of drug effect for reducing blood fat is clear, but it inhibits artery plaque difference is huge, and it is larger to take side effect for a long time.
Summary of the invention
One of the object of the invention is to provide the new medicinal usage of 3-hydroxybutyrate and its derivative.
The new medicine use of 3-hydroxybutyrate and its derivative provided by the present invention is 3-hydroxybutyrate and its derivative
Preparing the application in following products:
1) delay and/or improve the product of atherosclerosis；
2) product of reducing blood lipid；
3) product of Inflammatory Factors Contents in serum is reduced.
The product concretely drug or health care product.
The 3-hydroxybutyrate and its derivative, structural formula is as shown in following Formulas I or Formula II:
In Formulas I, R1For H, linear or branched alkyl group (such as C1-C20、C1-C10、C1-C6Or C1-C3Linear chain or branched chain alkane
Base), straight or branched alkoxyl (such as C1-C20、C1-C10、C1-C6Or C1-C3Straight or branched alkoxyl), naphthenic base (such as
C3-C6Naphthenic base) or aryl；R2For H, alkyl (such as C of linear chain or branched chain1-C20、C1-C10、C1-C6Or C1-C3Straight chain or
Branched alkyl), naphthenic base (such as C3-C6Naphthenic base) or aryl；
In Formula II, R1For H, linear or branched alkyl group such as C1-C20、C1-C10、C1-C6Or C1-C3Linear chain or branched chain alkane
Base), straight or branched alkoxyl (such as C1-C20、C1-C10、C1-C6Or C1-C3Straight or branched alkoxyl), naphthenic base (such as
C3-C6Naphthenic base) or aryl；R2For metal ion, the n value in Formula II is determined according to the valence state of metal ion.
The 3-hydroxybutyrate and its derivative can be D type or L-type, be also possible to the mixture of D type and L-type.
Concretely: 3-hydroxybutyrate (3-hydroxybutyric acid or 3-HB) methyl esters, 3-hydroxybutyrate (3-HB)
Ethyl ester, 3-hydroxybutyrate (3-HB) (including its sodium salt, sylvite, calcium salt etc.), 3- hydroxycaproic acid (3-hydroxyhexanoic
Acid or 3-HHx) methyl esters, 3- hydroxycaproic acid (3-HHx) ethyl ester, 3- hydroxycaproic acid (3-HHx) (including its sodium salt, sylvite, calcium
Salt etc.).
Heretofore described 3-hydroxybutyrate and its derivative can pass through the hydrolysis and alcoholysis of all kinds of poly-hydroxy fatty acid PHA
It is obtained etc. a variety of methods, by distillation purifying, very high purity is analyzed to identify by GC, endanger cell growth without double bond etc.
By-product (Chen GQ, Wu Q.Microbial Production and Applications of Chiral
Hydroxyalkanoates.Appl Microbiol Biotechnol, 67 (2005) 592-599).
It is also another object of the present invention to provide a kind of products for delaying and/or improving atherosclerosis, reducing blood lipid
Product or the product for reducing Inflammatory Factors Contents in serum.
The product provided by the present invention for delaying and/or improving atherosclerosis, reducing blood lipid product or reduce serum
The product of middle Inflammatory Factors Contents, active constituent are heretofore described 3-hydroxybutyrate and its derivative.
The product can by injection, injection, collunarium, eye drip, infiltration, absorption, physically or chemically the method that mediates imports
Body such as muscle, intradermal, subcutaneous, vein, mucosal tissue；Or body is imported after other material mixings or package.
When needs, one or more pharmaceutically acceptable carriers can also be added in the said goods.The load
Body includes diluent, excipient, filler, adhesive, wetting agent, disintegrating agent, sorbefacient, the table of pharmaceutical field routine
Face activating agent, absorption carrier, lubricant etc..
The production for delaying and/or improving atherosclerosis prepared using 3-hydroxybutyrate and its derivative as active constituent
Injection, tablet, pulvis, particle can be made in the product of Inflammatory Factors Contents in product, the product of reducing blood lipid or reduction serum
The diversified forms such as agent, capsule, oral solution.The drug of above-mentioned various dosage forms can be prepared according to the conventional method of pharmaceutical field.
Compared with prior art, the beneficial effects of the present invention are embodied in: (1) 3-hydroxybutyrate and its derivative can be used for
The drug or health care product of antiatherosclerosis are prepared, blood lipid can be not only reduced but also atherosclerosis can be inhibited
The inflammatory reaction occurred in pathogenic process has potential applicability in clinical practice to achieve the effect that antiatherosclerosis； (2)3-
Hydroxybutyric acid and its derivative side effect very little, safety is especially high, is suitble to take for a long time, druggability is good.
Detailed description of the invention
Fig. 1 is that 3-hydroxybutyrate reduces apoe knock-out mice heart efferent tract plaque area (the mirror following figure).APOE knocks out small
Mouse aortic root patch H&E dyeing example: high in fat group of A., B.+3-HB50mg/kg group high in fat, C.+3-HB100mg/ high in fat
Kg group, D.+3-HB200mg/kg group high in fat.
Fig. 2 is that 3-hydroxybutyrate reduces apoe knock-out mice heart efferent tract plaque area (scatter plot).APOE knocks out small
Mouse aortic root patch area of section statistical analysis :+3-HB50mg/kg high in fat organizes high in fat group of vs, p < 0.05 ,+3- high in fat
High in fat group, p < 0.05 of HB100mg/kg group vs, high in fat group of+3-HB200mg/kg vs high in fat, without significant statistical significance.
Fig. 3 is that 3-hydroxybutyrate reduces apoe knock-out mice Aortic Plaque load (the mirror following figure).A is high in fat group；B is
3-HB50mg/kg group；C is 3-HB100mg/kg group；D is 3-HB200mg/kg group.
Fig. 4 is that 3-hydroxybutyrate can reduce apoe knock-out mice Aortic Plaque load (statistical chart).
Fig. 5 indicates that 3-hydroxybutyrate can reduce apoe knock-out mice blood lipid.Wherein, TC: total cholesterol, TG: total glycerol
Three esters, LDL-C: low density lipoprotein cholesterol, HDL-C: high-density lipoprotein cholesterol, 3-HB 100mg/kg group can drop
The content of low TC, TG, LDL-C, p < 0.05 have significant difference.But to the HDL-C in serum without too big variation.
Fig. 6 indicates that 3-hydroxybutyrate can reduce the inflammatory factor in apoe knock-out mice serum.
Specific embodiment
The present invention will be described below by way of specific embodiments, but the present invention is not limited thereto.
Experimental method used in following embodiments is conventional method unless otherwise specified；Institute in following embodiments
Reagent, biomaterial etc., are commercially available unless otherwise specified.
Experimental material
Mouse: the purchase of apoe knock-out mice is normally to raise mouse in Beijing University's medical board Experimental Animal Center, 5 week old,
One with 60, and mouse growth process is in same environment, and feeds same food.
High lipid food: containing 40% fat, 1.25% cholesterol, 0.5% bile acid is bought from one mouse of Changzhou mouse, two biology
Science and Technology Ltd..
The mouse bought back is placed under same environment, after high lipid food adaptable fed 1 week, is fed 10 weeks, 3- hydroxyl fourth
The daily stomach-filling of acid sodium-salt 200mg/kg, 100mg/kg, 50mg/kg is primary, and after 10 weeks, mouse is put to death after taking blood, sample a part
It is frozen after liquid nitrogen flash freezer in -80 DEG C of refrigerators, a part is placed in 4% paraformaldehyde.
Embodiment 1,3-hydroxybutyrate reduce apoe knock-out mice heart efferent tract plaque area
Mouse aorta root is fixed in 4% paraformaldehyde, is taken out tissue and is made paraffin section, carries out H&E dyeing.
Specific step is as follows: 1) the intact paraffin section of form, microscope under is selected, is first placed in 65 DEG C of baking ovens roasting piece 1-2 hours, 2),
Be put into automatic dehydrator, dewaxing is to water, 3), ColeShi haematoxylin dyeing 2-3 minute, 4), washing removal floating color, microscopic observation
Nucleus coloring case, such as still shallower, can extend ColeShi haematoxylin liquid dyeing time, 5), 1% hydrochloride alcohol breaks up 3-10
Second, microscopic observation nucleus coloring case such as decolourizes overweight, can return to ColeShi haematoxylin dye liquor and redye, 6), flowing water gently
Rinse about 3 minutes, while under the microscope, until nucleus becomes blue, endochylema is not colored, 7), immerse eosin stains moon 3-4
Minute, 8), flowing water wash away the colour of skin, 9), start dehydration procedure, dye piece is taken out from environment friendly transparent agent, microscopic observation nucleus
For blue, cytoplasm is that red waves pink, and room temperature is dried, and soaks environment friendly transparent agent before mounting again, on automatic mounting machine
After mounting, it is placed in dry in draught cupboard and acquires image again.
Fig. 1 is that 3-hydroxybutyrate reduces apoe knock-out mice heart efferent tract plaque area (the mirror following figure).APOE knocks out small
Mouse aortic root patch H&E dyeing example: high in fat group of A., B.+3-HB50mg/kg group high in fat, C.+3-HB100mg/ high in fat
Kg group, D.+3-HB200mg/kg group high in fat.
Fig. 2 is that 3-hydroxybutyrate reduces apoe knock-out mice heart efferent tract plaque area (scatter plot).
APOE knock-out mice aortic root patch area of section statistical analysis :+3-HB50mg/kg group vs high in fat is high in fat
Group, p < 0.05, high in fat group of vs, p < 0.05 of+3-HB100mg/kg group high in fat, high in fat group of+3-HB200mg/kg vs high in fat, nothing
Significant statistical significance.
Embodiment 2,3-hydroxybutyrate reduce apoe knock-out mice Aortic Plaque load
Model group and administration group APOE knock-out mice are rounded a mouse aorta (totally 32), are fixed on 4% paraformaldehyde
In, after aorta cleans twice with PBS, carries out substantially oil red O stain and test, the specific steps are as follows: 1), by aortic tissue
It is taken out from paraformaldehyde fixer, PBS solution washes off formaldehyde；2), aorta is placed under Stereo microscope, is made
With microscissors and microforceps, the two cooperates, and carefully rejects aorta peripheral adipose and its its hetero-organization；3), along actively
Arcus haemalis bending longitudinally splits aorta；4) oil red O working solution (needing Fresh) and with twice of membrane filtration, is prepared, will be indulged
Enter in oil red O working solution to the aorta splitted, room temperature disseminates 2-4 hours；5), with ethanol decolorization 3-5 times of 70%,
15 seconds every time, until being still cerise at no lesion vascular wall bleach patch；6) 3 times are washed, to remove ethyl alcohol
7), aorta is layered on black plate along the place of cutting off, is taken pictures with microscope.
Fig. 3 is that 3-hydroxybutyrate reduces apoe knock-out mice Aortic Plaque load (the mirror following figure).A is high in fat group；B is
3-HB50mg/kg group；C is 3-HB100mg/kg group；D is 3-HB200mg/kg group.
Fig. 4 is that 3-hydroxybutyrate can reduce apoe knock-out mice Aortic Plaque load (statistical chart).
It can thus be appreciated that: 3-hydroxybutyrate has the function of antiatherosclerosis.
Embodiment 3,3-hydroxybutyrate reduce apoe knock-out mice blood lipid
Mouse takes blood before putting to death, and is centrifugated out serum, and serum detects four items of blood lipid tests with automatic clinical chemistry analyzer:
Total cholesterol (TC), total triglycerides (TG), low density lipoprotein cholesterol (HDL-C), high-density lipoprotein cholesterol
(LDL-C)。
Fig. 5 indicates that 3-hydroxybutyrate can reduce apoe knock-out mice blood lipid.Wherein, TC: total cholesterol, TG: total glycerol
Three esters, LDL-C: low density lipoprotein cholesterol, HDL-C: high-density lipoprotein cholesterol, 3-HB 100mg/kg group can drop
The content of low TC, TG, LDL-C, p < 0.05 have significant difference.But to the HDL-C in serum without too big variation.
Embodiment 4,3-hydroxybutyrate can reduce the inflammatory factor in apoe knock-out mice serum
Mouse plucks eyeball before putting to death and takes blood, 4 DEG C standings 2-3 hours, 3000rpm centrifugation 10min is isolated after blood clotting
Supernatant, -80 DEG C save for use, and serum detects inflammatory factor IL-6, TNF-α with ELISA kit, and determination step is according to glad rich
Contain IL-6, the operating instruction of TNF-α enzyme-linked immunosorbent assay (ELISA) reagent box is operated.
Fig. 6 indicates that 3-hydroxybutyrate can reduce the inflammatory factor in apoe knock-out mice serum.
As shown in Figure 6: 3-HB can reduce the content of inflammatory factor in APOE knock-out mice serum: 3-HB 50mg/kg
And 100mg/kg group, p < 0.05 have statistical significance.
Claims (10)
1.3- hydroxybutyric acid and its derivative are preparing the application in following product:
1) delay and/or improve the product of atherosclerosis；
2) product of reducing blood lipid；
3) product of Inflammatory Factors Contents in serum is reduced.
2. application according to claim 1, it is characterised in that: the 3-hydroxybutyrate and its derivative, structural formula is such as
Shown in Formulas I or Formula II:
In Formulas I, R1For H, linear or branched alkyl group, straight or branched alkoxyl, naphthenic base or aryl；R2For H, linear chain or branched chain
Alkyl, naphthenic base or aryl；
In Formula II, R1For H, linear or branched alkyl group, straight or branched alkoxyl, naphthenic base or aryl；R2For metal ion, formula
N value in II is determined according to the valence state of metal ion.
3. application according to claim 1 or 2, it is characterised in that: the 3-hydroxybutyrate and its derivative are D type or L
The mixture of type or D type and L-type.
4. application according to any one of claim 1-3, it is characterised in that: the 3-hydroxybutyrate and its derivative
Are as follows: 3-hydroxybutyrate methyl esters, ethyl 3-hydroxybutanoate, 3-hydroxybutyrate or its salt, 3- hydroxycaproic acid methyl esters, 3- hydroxycaproic acid second
Ester, 3- hydroxycaproic acid or its salt.
5. application according to claim 1, it is characterised in that: the product is drug or health care product.
6. a kind of product for delaying and/or improving atherosclerosis, active constituent is 3-hydroxybutyrate and its derivative.
7. a kind of product of reducing blood lipid, active constituent is 3-hydroxybutyrate and its derivative.
8. a kind of product for reducing Inflammatory Factors Contents in serum, active constituent is 3-hydroxybutyrate and its derivative.
9. according to product described in claim 6,7 or 8, it is characterised in that: the product is drug or health care product.
10. according to product described in claim 6,7 or 8, it is characterised in that: the product can be made into a variety of dosage forms, including note
Penetrate liquid, tablet, pulvis, granule, capsule, oral solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910160173.2A CN109806251A (en) | 2019-03-04 | 2019-03-04 | The application of 3-hydroxybutyrate and its derivative in the product for preparing antiatherosclerosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910160173.2A CN109806251A (en) | 2019-03-04 | 2019-03-04 | The application of 3-hydroxybutyrate and its derivative in the product for preparing antiatherosclerosis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109806251A true CN109806251A (en) | 2019-05-28 |
Family
ID=66608073
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910160173.2A Pending CN109806251A (en) | 2019-03-04 | 2019-03-04 | The application of 3-hydroxybutyrate and its derivative in the product for preparing antiatherosclerosis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109806251A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111304140A (en) * | 2020-03-05 | 2020-06-19 | 清华大学 | Recombinant intestinal bacterium for producing (R) -3-hydroxybutyric acid and construction method thereof |
| WO2022218364A1 (en) * | 2021-04-16 | 2022-10-20 | Nanjing Nutrabuilding Bio-Tech Co., Ltd. | Coated beta hydroxybutyric acid crystal and methods for producing the same |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5880269A (en) * | 1990-11-19 | 1999-03-09 | Board Of Trustees Operating Michigan State University | Antibodies for PHB |
| RU2228746C1 (en) * | 2002-11-25 | 2004-05-20 | Хазанов Вениамин Абрамович | Antihyperlipidemic agent (variants) |
| US20080032982A1 (en) * | 2004-05-03 | 2008-02-07 | Zeiller Jean J | Butanoic Acid Derivatives, Processes For The Preparation Thereof, Pharmaceutical Compositions Comprising Them, And Therapeutic Applications Thereof |
| CN101969769A (en) * | 2008-01-04 | 2011-02-09 | 伊希斯创新有限公司 | Ketone bodies and ketone body esters as blood lipid lowering agents |
| WO2019018683A1 (en) * | 2017-07-21 | 2019-01-24 | Buck Institute For Research On Aging | S-enantiomers of beta-hydroxybutyrate and butanediol and methods for using same |
-
2019
- 2019-03-04 CN CN201910160173.2A patent/CN109806251A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5880269A (en) * | 1990-11-19 | 1999-03-09 | Board Of Trustees Operating Michigan State University | Antibodies for PHB |
| RU2228746C1 (en) * | 2002-11-25 | 2004-05-20 | Хазанов Вениамин Абрамович | Antihyperlipidemic agent (variants) |
| US20080032982A1 (en) * | 2004-05-03 | 2008-02-07 | Zeiller Jean J | Butanoic Acid Derivatives, Processes For The Preparation Thereof, Pharmaceutical Compositions Comprising Them, And Therapeutic Applications Thereof |
| CN101969769A (en) * | 2008-01-04 | 2011-02-09 | 伊希斯创新有限公司 | Ketone bodies and ketone body esters as blood lipid lowering agents |
| WO2019018683A1 (en) * | 2017-07-21 | 2019-01-24 | Buck Institute For Research On Aging | S-enantiomers of beta-hydroxybutyrate and butanediol and methods for using same |
Non-Patent Citations (2)
| Title |
|---|
| RENNAN DE OLIVEIRA CAMINHOTTO等: "Oral β-hydroxybutyrate increases ketonemia, decreases visceral adipocyte volume and improves serum lipid profile in Wistar rats", 《NUTRITION & METABOLISM》 * |
| YOUNG-MIN HAN等: "β-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4", 《MOLECULAR CELL》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111304140A (en) * | 2020-03-05 | 2020-06-19 | 清华大学 | Recombinant intestinal bacterium for producing (R) -3-hydroxybutyric acid and construction method thereof |
| WO2022218364A1 (en) * | 2021-04-16 | 2022-10-20 | Nanjing Nutrabuilding Bio-Tech Co., Ltd. | Coated beta hydroxybutyric acid crystal and methods for producing the same |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Müller et al. | Thioacetamide-induced cirrhosis-like liver lesions in rats usefulness and reliability of this animal model | |
| JP5302856B2 (en) | Lipoxin analogues as novel angiogenesis inhibitors | |
| CN109806251A (en) | The application of 3-hydroxybutyrate and its derivative in the product for preparing antiatherosclerosis | |
| EP2749281B1 (en) | Prophylactic and/or therapeutic agent for cardiovascular complications of diabetes | |
| CN105560390B (en) | A kind of corydalis extract, the medical composition and its use comprising it | |
| NO334606B1 (en) | Compounds, pharmaceutical preparations containing them as well as such compounds and preparations for the treatment of metabolic disorders | |
| CN110075094A (en) | Pterostilbene is preparing the application in drug or health care product | |
| Patelski et al. | The influence of cholinesterase inhibitors on the lipolytic activity of rat aorta | |
| Whittle et al. | The endothelin explosion. A pathophysiological reality or a biological curiosity? | |
| JP2017522386A (en) | Oligomer of 3-hydroxybutyrate | |
| Bodman et al. | The α-glyceryl ethers | |
| CN108421017A (en) | Application of the dragon and tiger jintan in preparing reducing blood lipid and artery plaque drug | |
| CN102271670A (en) | Biological oil composition, formulations comprising the oil composition, and use thereof to prevent or treat cardiovascular disease | |
| FR2614790A1 (en) | NOVEL OPHTHALMIC COMPOSITION BASED ON EICOSAPEUTAENOIC ACID | |
| CN110771694A (en) | Grease composition | |
| EP3834834A1 (en) | Drug used for treating tissue necrosis or for improving cardiac function | |
| CN110169972A (en) | Cucurbatacin E is preparing the application in Antiatherosclerosis medicine | |
| CN109906979A (en) | A kind of method of zebra fish high cholesterol model foundation | |
| CN103616465A (en) | Method for establishing blood correlated fatty acid spectrum | |
| KR20180088146A (en) | Cosmetic composition for antiaging and whitening derived from lipid-extracted microalgae | |
| KR20200039232A (en) | Pharmaceutical composition comprising anchovy work product as an active ingredient | |
| CN106511970B (en) | Application of the rHDL in treatment hypertensive disorder in pregnancy | |
| CN111329854A (en) | Application of natural active substance in relieving benzopyrene-induced RAW264.7 cell lipid metabolism disorder | |
| Islam et al. | Effects of butter and estrogen on lipid profile and histotexure of liver and skin in reference to the development of obesity in Swiss Albino mice | |
| TWI465241B (en) | Use of an extract of juniperus chinensis or lignan for manufacturing a medicament for inhibiting angiogenesis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190528 |