CN111004296B - Oligomeric agar oligosalts and application thereof in preparation of medicines for treating neurodegenerative diseases and cardiovascular and cerebrovascular diseases - Google Patents
Oligomeric agar oligosalts and application thereof in preparation of medicines for treating neurodegenerative diseases and cardiovascular and cerebrovascular diseases Download PDFInfo
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- CN111004296B CN111004296B CN201911213453.1A CN201911213453A CN111004296B CN 111004296 B CN111004296 B CN 111004296B CN 201911213453 A CN201911213453 A CN 201911213453A CN 111004296 B CN111004296 B CN 111004296B
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- Prior art keywords
- agar
- oligomeric
- oligo
- diacid
- thioagar
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- 208000015122 neurodegenerative disease Diseases 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 title claims abstract description 14
- 208000024172 Cardiovascular disease Diseases 0.000 title claims abstract description 11
- 208000026106 cerebrovascular disease Diseases 0.000 title claims abstract description 11
- 230000002526 effect on cardiovascular system Effects 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims description 5
- 229940079593 drug Drugs 0.000 title abstract description 9
- 230000015556 catabolic process Effects 0.000 claims abstract description 22
- 238000006731 degradation reaction Methods 0.000 claims abstract description 22
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- 229920001542 oligosaccharide Polymers 0.000 claims description 28
- 210000004027 cell Anatomy 0.000 claims description 25
- 108091034117 Oligonucleotide Proteins 0.000 claims description 24
- 150000002482 oligosaccharides Chemical class 0.000 claims description 23
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims description 21
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- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 210000005036 nerve Anatomy 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Inorganic materials Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 claims description 3
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 3
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- FMGYKKMPNATWHP-UHFFFAOYSA-N Cyperquat Chemical compound C1=C[N+](C)=CC=C1C1=CC=CC=C1 FMGYKKMPNATWHP-UHFFFAOYSA-N 0.000 claims description 2
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- 238000000034 method Methods 0.000 abstract description 29
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 abstract description 2
- 159000000000 sodium salts Chemical class 0.000 abstract description 2
- AEMOLEFTQBMNLQ-VANFPWTGSA-N D-mannopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H]1O AEMOLEFTQBMNLQ-VANFPWTGSA-N 0.000 abstract 1
- 230000000593 degrading effect Effects 0.000 abstract 1
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- 229930182830 galactose Natural products 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 241000206613 Pyropia yezoensis Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
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- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
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- 102000013498 tau Proteins Human genes 0.000 description 2
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
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- 208000028698 Cognitive impairment Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
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- 240000003237 Hedychium spicatum Species 0.000 description 1
- 235000015030 Hedychium spicatum Nutrition 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000006302 Usnea Species 0.000 description 1
- 108010045649 agarase Proteins 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
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- BBWBEZAMXFGUGK-UHFFFAOYSA-N bis(dodecylsulfanyl)-methylarsane Chemical compound CCCCCCCCCCCCS[As](C)SCCCCCCCCCCCC BBWBEZAMXFGUGK-UHFFFAOYSA-N 0.000 description 1
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- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
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- CTYRPMDGLDAWRQ-UHFFFAOYSA-N phenyl hydrogen sulfate Chemical compound OS(=O)(=O)OC1=CC=CC=C1 CTYRPMDGLDAWRQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
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- 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
- A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
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- A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/729—Agar; Agarose; Agaropectin
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- A—HUMAN NECESSITIES
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
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Abstract
The invention provides an oligomeric agar oligosalt and application thereof in preparing medicines for treating neurodegenerative diseases and cardiovascular and cerebrovascular diseases. The oligomeric agar oligocarbonate is prepared from red algae serving as a raw material by degrading through a chemical degradation method or a physical degradation method or an enzymatic method or a free radical method or an ozone degradation method or a combination of degradation methods, and then oxidizing with weak acid to prepare the oligomeric oligocarbonate and oligocarbonate with different molecular weights; the oligomeric oligo-diacid and the oligosalt are neutralized to prepare lithium salt, sodium salt, potassium salt, calcium salt or magnesium salt of the oligomeric mannuronate with different molecular weights, and the polymerization degree is 1-50dp. The oligomeric agar oligosalt is derived from marine red algae polysaccharide, has the advantages of rich resources, easy industrialization, safety, effectiveness and the like, and has wide development and application prospects in the treatment of neurodegenerative diseases.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an oligomeric agar oligosalt and application thereof in preparing medicines for treating neurodegenerative diseases and cardiovascular and cerebrovascular diseases.
Background
Neurodegeneration is the gradual loss of neuronal structure and function, including neuronal death and glial cell balance, leading to cognitive impairment such as dementia. Among other causes, age (alzheimer's disease (AD), parkinson's Disease (PD)) or genetic mutations affecting CNS cell function (huntington's disease, early-onset AD or PD, amyotrophic Lateral Sclerosis (ALS)) can cause neurodegenerative diseases.
The pathological hallmarks of AD are plaques and tangles in the brain. Plaques consist of amyloid β protein, among others, whereas tangles consist mainly of hyperphosphorylated tau protein. Detection of proteins responsible for this disease has helped to develop specific antibodies. In the research setting, these products play an important role in assessing the expression and sedimentation of amyloid β and tau and other proteins involved in neurodegenerative disease progression. Parkinson's Disease (PD) is a disease of dyskinesia and eventually progression to cognitive dysfunction, which also has an age and genetic basis, and protein aggregation is more complex than AD. Although most PDs are idiopathic, some have known genetic mutations, which makes new therapies very complex to study. At present, effective therapeutic drugs for neurodegenerative diseases are lacking, and currently marketed sodium mannite can only relieve symptoms of early and middle stages of AD and cannot block and reverse the progress of the diseases.
The agaropectin and the agaropectin have been reported to have various pharmacological activities, but no pharmacological activity report of the oligomeric agaropectin and the oligomeric agaropectin is available at present; on the basis of the previous study, the invention prepares the agar oligosaccharide derivatives, namely the oligomeric agar oligonucleotides and the oligomeric diacid salts, adopts a series of different cells and animal models of neurodegenerative diseases and cardiovascular and cerebrovascular diseases, discovers that the pharmacodynamic effects of the oligomeric agar oligonucleotides and the oligomeric agar diacid salts are obviously superior to those of the raw materials, and shows the application value of the oligomeric agar oligonucleotides and the oligomeric agar diacid salts in preparing the drugs for resisting the neurodegenerative diseases and the cardiovascular and cerebrovascular diseases.
Disclosure of Invention
The invention aims to provide an oligomeric agar oligosalt and application thereof in preparing medicaments and health-care foods for treating neurodegenerative diseases and cardiovascular and cerebrovascular diseases.
The invention adopts an A beta protein induced nerve PC12 cell injury model, a CoCl2 induced myocardial cell and nerve cell hypoxia injury model and MPP + The resulting damage model of SK-N-MC cells explores the protective effect of the oligoagar oligocarbonate and the thioagar oligocarbonate on nerve cells and cardiac muscle cells. Research proves that the oligomeric agar oligosalt and the thioagar oligodiacid salt can effectively inhibit the aggregation of Abeta in cells; obviously inhibit the decrease of the survival rate of cells induced by CoCl 2; and effectively reduce the hypoxia injuryApoptosis of PCl2 nerve cells and H2C9 cardiomyocytes; at the same time can obviously improve MPP + The resulting damage to SK-N-MC cells effectively inhibits aggregation of Synclein protein; can resist neurodegenerative diseases and cardiovascular and cerebrovascular diseases through various ways.
In order to achieve the aim of the invention, the invention is realized by adopting the following technical scheme:
the invention provides an oligomeric agar oligosalt, which has the following structural formula:
further: the oligomeric agar oligosalts are specifically 4 kinds of the following: the structural formulas of the oligomeric agar oligoates, the novel agar oligoates, the thioagar oligodioates and the laver gum oligodioates are as follows:
the invention also provides application of the oligomeric agar oligosalt in preparing medicines for treating neurodegenerative diseases and cardiovascular and cerebrovascular diseases.
Further: the oligomeric agar oligose and the oligomeric agar diacid take red algae as raw materials, and are degraded by an enzymatic degradation method, a chemical degradation method, a physical degradation method, a free radical degradation method, an ozone degradation method or a combination of the degradation methods to prepare oligomeric agar oligose, neoagarase oligose, oligomeric agar oligose and oligomeric agar oligose with different molecular weights; preparing the prepared oligosaccharide into 1-55% aqueous solution, adding oxidant to a final concentration of 1-35%, and reacting at 25-120 ℃ to obtain the oligomeric oligonucleotides with different molecular weights, wherein the C1 position of the reducing end of the oligomeric oligonucleotides is carboxylic acid; the oligosaccharide can be neutralized to prepare the oligomeric agar oligonucleotides, neoagaropectins, thioagaropectins and lithium, sodium, potassium, calcium or magnesium salts of the laver agar oligonucleotides with different molecular weights, the weight average molecular weight is 0.3 kDa-20 kDa, and the polymerization degree is 1-50.
Further: the oxidant is one of hydrogen peroxide, bromine water, hypochlorous acid and hypochlorite.
Further: the red algae comprises thallus Porphyrae, porphyrae haitanensis, hedychium spicatum, and Gloiopeltis furcata.
Further: the agar oligosalt can obviously improve the damage of the aggregated Abeta protein to the nerve PCl2 cells and effectively inhibit the aggregation of Abeta in the cells.
Further: the agar oligosalt can obviously inhibit the reduction of the survival rate of CoCl 2-induced cells, and effectively reduce the apoptosis of PCl2 nerve cells and H2C9 myocardial cells caused by hypoxia injury.
Further: the agar oligosalt can obviously improve the damage of SK-N-MC cells caused by MPP+ and effectively inhibit the aggregation of Abeta protein.
Further: the chemical degradation method is an acid degradation method or a Fenton degradation method, and the physical degradation method is a microwave or ultrasonic degradation method; the enzyme degradation method uses agarase or thioagarase; the free radical degradation method is a degradation method of hydrogen peroxide auxiliary Cu ions; the ozone degradation method is a degradation method that solutes are filled with ozone and assist in a certain temperature; the degradation method is combined and degraded into any 2 or any combination of more than 2 degradation methods.
The invention has the advantages and beneficial effects that:
1. the invention adopts an A beta protein induced nerve PCl2 cell injury model, a CoCl2 induced myocardial cell and nerve cell hypoxia injury model and MPP + The resulting SK-N-MC cell injury model discovers the effective protection effect of the oligoagar oligocarbonate and the thioagar oligocarbonate on nerve cells and cardiac muscle cells. And the effect of the oligomeric agar oligosalt and the thioagar oligodiacid is obviously better than that of the raw material medicines of the agar oligosalt and the thioagar oligosalt.
2. The product is derived from marine natural polysaccharide, has the advantages of rich resources, easy industrialization, safety, effectiveness and the like, and can be developed into medicines and functional foods for resisting neurodegenerative diseases and cardiovascular and cerebrovascular diseases, thereby having better market application prospect.
Detailed Description
The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.
Example 1: preparation of Usnea, hedge, laver extract and its oligosaccharide
Oven drying three kinds of seaweed including Gloiopeltis furcata, herba Origani and thallus Porphyrae at 35deg.C, and pulverizing to 40 mesh. Adding 500ml of 85% ethanol into 100g of crushed seaweed, degreasing and decoloring for 2 hours at 85 ℃, repeating the operation for 1 time, filtering with 100 meshes of bolting silk, drying at 35 ℃, extracting with distilled water under stirring for three times after degreasing, merging the supernatant after each centrifugation, concentrating, dialyzing, precipitating with ethanol, and drying to obtain the extracted polysaccharide. The total sugar content is 30-80% by using phenol sulfate, the D-galactose and the inner ether galactose content is 10-40% by using a calibration method, the sulfate content is 10-40% by using a barium sulfate turbidimetry method, the polysaccharide can be further separated by using a QFF anion exchange chromatographic column to obtain a purified component, the purified component can be degraded for 2 hours by using a 0.1MH2SO460 ℃ or the degraded oligosaccharide can be prepared by one or more methods of an enzymatic method, microwave assistance, free radical and ozone degradation, the molecular weight of the obtained polysaccharide and oligosaccharide is measured by using an HPGPC Agilent1260 Series high performance liquid system, the polysaccharide and oligosaccharide are separated by using different gel chromatographic columns (Shodex Series), the polysaccharide and oligosaccharide molecular weight are analyzed by using an on-line differential detector (RI) and an octadeca laser scattering instrument (MALS) in combination, the Agilent Chemstation control system and GPC data processing software, the mobile phase is 0.1mol/L NaNO3 solution, and the column temperature is 25 ℃ and the flow rate is 0.5mL/min. Polysaccharide samples were prepared at a concentration of 5mg/mL, centrifuged at 12000 rpm for 10min, and the supernatants were collected and fed into an autosampler of 20uL. And separating the obtained polysaccharide and oligosaccharide containing galactose and/or galactose sulfate and/or lacto-oligosaccharide with galactose sulfate and galactose ether.
The structural formula of the oligomeric agar oligosalt is as follows, and the molecular weight of the oligomeric agar oligosalt is between 0.1 and 200 kDa:
the structure is divided into the following 4 structures:
n=0-50, and the corresponding components are agaro-oligosaccharide, neoagaro-oligosaccharide, thioagaro-oligosaccharide and laver-oligosaccharide.
Preparing the prepared oligo-agar oligosaccharides, neoagaropectins, thioagaropectins and laver-agar oligosaccharides into 1-55% aqueous solution, adding oxidizing agents (including but not limited to hydrogen peroxide, bromine water, hypochlorous acid, hypochlorite and the like) to a final concentration of 1-35%, reacting at 25-120 ℃, and checking whether the reaction is complete according to Benedict reagent (prepared from citric acid, copper sulfate and sodium carbonate) until no brick red precipitate appears, namely complete oxidation; separating and purifying the prepared agar oligo-acid and the prepared thioagar oligo-diacid by using a Bio-GelP4 column, and then neutralizing to prepare the oligo-agar oligo-acid, the neoagaro-acid, the thioagar oligo-diacid or the lithium salt, the sodium salt, the potassium salt, the calcium salt or the magnesium salt of the laver oligo-diacid with different molecular weights, wherein the polymerization degree is 1-60; the structure of the prepared oligonucleotide is as follows:
n=0-50, and is corresponding to agar oligo-acid, neoagar oligo-acid, thioagar oligo-diacid and laver oligo-diacid respectively.
EXAMPLE 2 protection of Abeta-aggregate-induced neuronal injury by agar and Thosetron oligonucleotides
Taking cell activity without Abeta 1-42 as negative control, observing the inhibition of the tested compound to the nerve cell toxicity induced by Abeta, and concretely implementing the following steps: PCl2 cells are inoculated into MEM complete culture solution, placed into a 96-well plate for culture, placed into a constant temperature cell culture box for incubation for 24 hours, and then added with Abeta protein oligomer aggregated in advance, 2 hours later, each hole is added with test compound solution, and the incubator continues to incubate for 24 hours. After completion, the cell viability was determined by MTT method. The experiment was repeated three times in triplicate.
The results in Table 1 show that the agar and the thioagar are effective in protecting nerve cells from Abeta-collectin, wherein the protection from 20uM is excellent, and the efficacy increases with the increase of the dosage. Wherein, the effect of the thioagar oligo-diacid is best, and the protection effect reaches 88-90% when 100-500 uM.
TABLE 1 influence of agar and thioagar oligonucleotides on Aβ aggregate-induced neuronal cell injury
Example 3, agar oligo-and thioagar oligo-pair CoCl 2 Protective effect of inducing hypoxia injury of nerve cells and cardiac muscle cells
By not adding CoCl 2 Cell viability of induced nerve cells PCl2 and myocardial cells H9C2 is used as negative control, and the series of compounds are observed to induce CoCl 2 The inhibition of the hypoxia injury of the nerve cells and the myocardial cells is carried out by the following specific steps: inoculating PCl2 and H9C2 cells into MEM or DMEM complete culture solution, culturing in 96-well plate, incubating in constant temperature cell incubator for 24 hr, and adding pre-dissolved CoCl-containing solution 2 After 2 hours, serial compound solutions were added to each well and the incubator was incubated for a further 48 hours. After completion, the cell viability was determined by MTT method. The experiment was repeated three times in triplicate.
The results in tables 2 and 3 show that agar and thioagar oligonucleotides are effective in protecting nerve cells from CoCl 2 Wherein the protection from 20uM is excellent and the efficacy increases with increasing dosage. Wherein, the effect of the thioagar oligo-diacid is best, the protection effect reaches 88% at 100uM, and the protection effect reaches 94% at 100 uM; meanwhile, the agar oligonucleotides and the thioagar oligonucleotides can also effectively protect myocardial cells from being damagedCoCl 2 Wherein the protection effect of the thioagar oligo-diacid reaches 88-92% at 100-500 uM.
TABLE 2 agar oligo-and thioagar oligo-pair CoCl 2 Influence of hypoxia-induced neuronal cell injury
TABLE 3 agar oligo-and thioagar oligo-pair CoCl 2 Effects of hypoxia-induced cardiomyocyte injury
| Sample (uM) | Cell viability |
| Control group | 52±2.1％ |
| Low dose of agar oligo 20 | 67±2.4％ |
| Dose of 100 in agar oligo | 78±2.6％ |
| High dose 500 of agar oligo acid | 86±3.0％ |
| Low dose of thioagar oligo diacid 20 | 72±2.5％ |
| Dosage of 100 of thioagar oligo-diacid | 86±3.9％ |
| High dose of thioagar oligo diacid 500 | 92±3.7％ |
| Low dose of laver glue oligo diacid 20 | 65±1.6％ |
| Porphyra yezoensis oligosaccharide diacid dose 100 | 77±2.5％ |
| Laver gum oligo diacid high dose 500 | 86±1.8％ |
Example 6 agar oligo and thioagar oligo pair MPP + Protective effect of inducing nerve cell injury
The nerve cell SK-N-MC which is not added with hydrogen peroxide is used as a negative control, the inhibition effect of the series of compounds on nerve cell damage induced by hydrogen peroxide is observed, and the specific implementation steps are as follows: inoculating SK-N-MC cells into MEM complete culture solution, culturing in 96-well plate, incubating in constant temperature cell incubator for 24 hr, adding MPP + After 2 hours, serial compound solutions were added to each well and the incubator was incubated for a further 48 hours. After completion, the cell viability was determined by MTT method. The experiment was repeated three times in triplicate.
Table 4 shows that the agar and thioagar oligonucleotides are effective in protecting nerve cells from MPP + Injury, from 20uM, has good protection and increases in efficacy with increasing dose. Wherein, the thioagar oligo-diacid has the best effect and is ensured at the time of 100uM-500uMThe protective effect reaches 85-88%.
TABLE 4 agar and thioagar pair MPP + Influence of induction of SK-N-MC neuronal cell damage
| Sample of | Cell viability |
| Control group | 53±2.1％ |
| Low dosage of agar oligo acid | 67±1.9％ |
| Dosage of agar oligo acid | 83±2.4％ |
| High dosage of agar oligo acid | 86±2.7％ |
| Low dosage of thioagar oligo diacid | 71±3.1％ |
| Dosage of thioagar oligo diacid | 85±3.3％ |
| High dosage of thioagar oligo diacid | 88±2.2％ |
| Low dose of laver glue oligo diacid 20 | 69±2.7％ |
| Porphyra yezoensis oligosaccharide diacid dose 100 | 78±2.5％ |
| Laver gum oligo diacid high dose 500 | 86±1.8％ |
The above embodiments are merely illustrative of the technical solution of the present invention, and are not limiting thereof; although the invention has been described in detail with reference to the foregoing embodiments, it will be apparent to one skilled in the art that modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for some of the technical features thereof; such modifications and substitutions do not depart from the spirit and scope of the corresponding technical solutions.
Claims (4)
1. The application of the oligomeric agar oligonucleotides in preparing medicaments for treating neurodegenerative diseases is characterized in that:
the oligomeric agar oligonucleotides are divided into agar oligonucleotides, thioagar oligonucleotides and laver agar oligonucleotides; the structural formulas of the agar oligo-acid, the thioagar oligo-diacid and the laver oligo-diacid are respectively as follows:
the oligomeric agar oligosaccharides are prepared from red algae by enzymatic degradation, chemical degradation, physical degradation, free radical degradation, ozone degradation, or a combination thereof to obtain agar oligosaccharides, thioagar oligosaccharides and laver oligosaccharides with different molecular weights;
preparing agar oligosaccharide, thioagar oligosaccharide and laver oligosaccharide into 1-55% aqueous solution, adding oxidant to a final concentration of 1-35%, and reacting at 25-120deg.C to obtain agar oligosaccharide, thioagar oligosaccharide diacid and laver oligosaccharide diacid;
the agar oligo-acid, the thioagar oligo-diacid and the laver oligo-diacid can obviously improve the damage of the aggregated Abeta protein to the nerve PC12 cells and effectively inhibit the aggregation of Abeta in the cells.
2. The use of the oligomeric agar oligonucleotides according to claim 1 for the preparation of a medicament for the treatment of neurodegenerative diseases, characterized in that: the oxidant is one of hydrogen peroxide, bromine water, hypochlorous acid and hypochlorite.
3. The use of the oligomeric agar oligonucleotides according to claim 1 for the preparation of a medicament for the treatment of neurodegenerative diseases, characterized in that: the oligomeric agar oligonucleotide can obviously inhibit the decrease of the survival rate of CoCl 2-induced cells and effectively reduce the apoptosis of PC12 nerve cells caused by hypoxia injury.
4. The use of the oligomeric agar oligonucleotides according to claim 1 for preparing a medicament for treating neurodegenerative diseases and cardiovascular and cerebrovascular diseases, characterized in that: the oligomeric agar oligonucleotide can obviously improve the damage of SK-N-MC cells caused by MPP+ and effectively inhibit the aggregation of Abeta protein.
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| CN110669149A (en) * | 2019-09-25 | 2020-01-10 | 中国海洋大学 | Galacto-oligosaccharide and derivative and application thereof in medicines or health products for improving mitochondrial function and preventing and treating insulin resistance related diseases |
| CN110812364A (en) * | 2019-10-22 | 2020-02-21 | 中国海洋大学 | Application of galactooligosaccharide and derivatives thereof as SGLTs inhibitor |
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| CN110669149A (en) * | 2019-09-25 | 2020-01-10 | 中国海洋大学 | Galacto-oligosaccharide and derivative and application thereof in medicines or health products for improving mitochondrial function and preventing and treating insulin resistance related diseases |
| CN110812364A (en) * | 2019-10-22 | 2020-02-21 | 中国海洋大学 | Application of galactooligosaccharide and derivatives thereof as SGLTs inhibitor |
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