CN106176793A - Catalpol is as the purposes of advanced glycosylation end-products inhibitor - Google Patents
Catalpol is as the purposes of advanced glycosylation end-products inhibitor Download PDFInfo
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- CN106176793A CN106176793A CN201610562834.0A CN201610562834A CN106176793A CN 106176793 A CN106176793 A CN 106176793A CN 201610562834 A CN201610562834 A CN 201610562834A CN 106176793 A CN106176793 A CN 106176793A
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- 230000000630 rising effect Effects 0.000 description 1
- 108010048734 sclerotin Proteins 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229940047183 tribulus Drugs 0.000 description 1
- 230000006492 vascular dysfunction Effects 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
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- 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
- A61K31/70—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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- 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
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- General Health & Medical Sciences (AREA)
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Abstract
The present invention relates to the catalpol purposes as advanced glycosylation end-products inhibitor, catalpol of the present invention is a kind of iridoid glucoside compounds, it is primarily present in the plants such as Radix Rehmanniae, the catalpol of the present invention still prevents NO and activates, can be used for preventing and treating the diabetic complication caused due to AGE imbalance, the relevant disease such as Alzheimer, atherosclerosis, and have certain blood sugar lowering, effect for reducing fat.
Description
Invention field
The present invention relates to catalpol and be effectively prevented advanced glycosylation end-products AGE (advanced glycationend
Products AGE) generate or suppress the activity of AGE, still prevent NO and activate, can be used for preventing and treating owing to AGE lacks of proper care the sugar caused
The sick complication of urine, the relevant disease such as Alzheimer, atherosclerosis.
Background technology
Advanced glycosylation end-products (advanced glycationend products AGE) is sugar and the egg of excess
The product that white matter combines, has two sources in vivo, and one is excessive sugar and protein synthesizes AGE in vivo, and two is by entering
Eat and AGE present in food is taken in internal.The AGE harm to human body: one is the glycosylation that can cause vivo protein matter, makes
Protein on blood vessel changes, and makes blood vessel wall lower toughness, is prone to impaired.Two is to be combined by the receptor on cell,
Promoted the release of inflammatory cytokine by a series of reaction, promote that inflammation is formed and tissue injury.Three is to make blood vessel
The nitric oxide of endotheliocyte release loses activity, and nitric oxide is vasodilatory important molecule, and the tonicity of blood vessel increases
Add, relevant with hypertension or blood vessel injury.Four is the formation that can promote oxygen-derived free radicals, and oxygen-derived free radicals can make tissue injury.Research
Prove: AGE can speed up the aging of human body, it is possible to causes various chronic degenerative disease, such as diabetic complication, A Erci
The diseases such as sea silent disease, atherosclerosis.Defying age can be played so reducing AGE and prevent various chronic degenerative disease.
AGE is with old and feeble: along with being on the rise of world population ages's problem, concerned the asking of the anti-ageing one-tenth of health care
Topic.Nonenzymatic glycosylation aging theory be by numerous scholars generally acknowledge one of old and feeble theoretical.Advanced glycosylation end-products
(advanced glycosylation end products, AGE) is the end-product of non-enzymatic glycation, and it is a hatching egg
White matter, with advancing age, it serum, tissue in generation and accumulation be inevitable.In human body, the albumen of AGE is repaiied
Decorations are the mediating factors of Senile disease, can be as the clock of test ager process.The crosslinking of the protein that glycosylation can cause
Damage, can make normal protein structure be transformed into the structure of old albumen, and AGE gathers the most in vivo and increases, meeting
The hardness causing blood in human body in tube wall increases；The unbalance of bone metabolism can be caused by direct or indirect effect, cause sclerotin to be dredged
Pine；There is the change that also can make the astrocyte of cerebral nerve maincenter that a series of form and functions occur in AGE.
AGE Ahl tribulus sea silent sickness: Advanced glycation end products is the end product of the non-enzymatic saccharification of protein, has irreversible
Property, relevant with chronic complicating diseases of diabetes, normal aging.Advanced glycation end products deposited in the brain is joined by receptor and non-receptor pathway
With the pathogenic process of alzheimer disease, stockpile with protein-crosslinking in abnormal brain, oxidative stress, neuron loss relevant.Anti-sugar
Change dead end product treatment and be likely to become the new way for the treatment of Alzheimer.
AGE atherosclerosis: atherosclerotic generation, development have close with the chronic accumulation of internal AGE
Relation.The research such as Kanauchi M finds that in patients with coronary heart disease blood, AGE concentration more non-coronary heart disease matched group is significantly raised；And it is non-
In diabetic coronary artery disease patient's blood, AGE content is proportionate with coronary arteries vascular lesion number, the most branched hat
In patient's blood of shape arterial disease, AGE content is apparently higher than single coronary artery pathological changes and double coronary artery pathological changes patients.Sugar
Urine patient is when merging coronary heart disease, there is AGE deposition widely in ductus arteriosus wall inside and outside macrophage and smooth muscle cell, and with
The atherosclerotic lesion order of severity is correlated with.Research finds that diabetes merge carotid arterial atherosclerosis and especially have carotid atherosclerotic plaque
Patients serum AGE be significantly higher than without Carotid Artery Atherosclerotic Patients, further illustrate AGE in atherosclerotic progress
Play an important role.
AGE and diabetic complication: chronic complicating diseases of diabetes almost involves each organ-tissue of whole body, onset is hidden, early
Phase is difficult to be found, and in gradual development, after developing into certain phase, therapeutic effect is the best, causes patient to disable lethal
Major reason.Numerous studies evidence shows, persistent high blood sugar causes internal multiple proteins nonenzymatic glycosylation and is consequently formed
Advanced glycosylation end-products (Advanced glycation endproducts, AGE) sending out at chronic complicating diseases of diabetes
Pathogenesis system plays an important role.Advanced glycation end products concentration in serum and tissue and the order of severity of chronic complicating diseases of diabetes
There is concord, and stop glycosylation, reduce its chance formed, can reduce or alleviate complication.AGE is to blood vessel and kidney
Dirty damage is the most serious, the common complication of this diabetics just.The diabetic complication AGE of Clinical practice treatment at present
Inhibitor mainly has:
Aminoguanidine: be a kind of AGE inhibitor, it also can be effectively prevented AGE under the conditions of high sugar and generates or suppress AGE's
Activity.Aminoguanidine is by competing and the combination of macro-molecular protein with glucose, and Selective depression protein non-enzyme glycosylation is early
The formation of phase product.Activate it was found that aminoguanidine still prevents NO, adjust diabetes vascular dysfunctions in early days.
AR enzyme level (spirohydantoin): clinical observation result is to preventing diabetic retinopathy, outer
All neuropathy and nephropathy curative effect are slight, and onset is slow.Because using the time the shortest, using the most extensive, it is objective to need to be made
Evaluate.
Traditional Chinese medical science application Radix Rehmanniae defying age, treatment diabetes, prior cardiovascular history are long, as described in " herbal classic ": Radix Rehmanniae
" clothes are made light of one's life by commiting suicide not old for a long time, and survivor is the best ".Described in " not Lu ": Radix Rehmanniae " main man's five kinds of strain and seven kinds of impairment, woman's damaging the spleen and stomach threatened abortion hematochezia is broken
Stagnant blood, hematuria, profit intestine and small intestine, go dyspepsia in stomach, full power to break off, tonifying five ZANG-organs internal injury is not enough, promoting blood circulation, physical strength profiting, profit knowledge ".
It is loaded in prescription " Radix Rehmanniae is decocted " the treatment diabetes of " Shengji Zonglu "；
Catalpol is a kind of iridoid glucoside compounds, is primarily present in the plants such as Radix Rehmanniae, and structure is as follows:
Catalpol can reduce hyperglycemia mouse blood sugar；Also there is anticancer, neuroprotective, antiinflammatory, diuresis, blood sugar lowering and anti-hepatitis
The effects such as virus.
Owing to catalpol polarity is relatively big, and chemical stability is poor, thus preparation purity monomer more than 90% in a large number
Composition difficulty is bigger.
We's invention is to solve the problem of catalpol process for producing, is found surprisingly that simultaneously, and catalpol can promote AGE
Crack and can reverse the damage of tissue and the organ caused by AGE.Experiment show catalpol can by promote AGE crack and can
Reversing the damage of kidney and other organs caused by AGE, treatment diabetic nephropathy effect substantially and has certain blood sugar lowering, blood fat reducing to make
With.
Summary of the invention
Generate or the activity of suppression AGE it is a discovery of the invention that catalpol can be effectively prevented AGE, still prevent NO and activate, can
The diabetic complication caused due to AGE imbalance for preventing and treating, the relevant disease such as Alzheimer, atherosclerosis.
The present inventor, it has been investigated that the catalpol of following formula I can be effectively prevented the activity that AGE generates or suppresses AGE, also may be used
Prevent NO from activating, can be used for preventing and treating the diabetic complication caused due to AGE imbalance, Alzheimer, atherosclerosis
Deng relevant disease.
First aspect present invention relates to the catalpol of Formulas I to be had and prevents AGE from generating or the activity of suppression AGE.
First purpose for this present invention is that catalpol prevents AGE from generating or the food of activity of suppression AGE, guarantor in preparation
Strong product, the application of pharmaceutical preparations.
Second aspect present invention relates to the glycosuria that the catalpol of Formulas I causes due to AGE imbalance for treatment or prevention in preparation
Sick complication, purposes in the medicine of the relevant disease such as Alzheimer, atherosclerosis.
Third aspect present invention relate to the catalpol of Formulas I for treatment or prevention due to AGE imbalance cause diabetes complicated
Disease, the compositions of the relevant disease such as Alzheimer, atherosclerosis, it catalpol including Formulas I and pharmaceutical carrier or tax
Shape agent.
Fourth aspect present invention relates to the diabetic complication treating or preventing to cause, Alzheimer due to AGE imbalance
The method of the relevant diseases such as disease, atherosclerosis, it includes giving to control by the catalpol for the treatment of or the Formulas I of prevention effective dose
Treat or the patient of prevention.
According to the present invention, the catalpol of the Formulas I of the present invention be may be from natural plants or obtained by synthesis, such as can be from sky
So plant such as Radix Rehmanniae extracts isolated.Preferably, the catalpol of the Formulas I of the present invention can be prepared by the following method: freshly
Huang, by water supersound extraction three times, adds 6 times amount water every time, ultrasonic 1 hour.United extraction liquid, concentrating under reduced pressure.It is concentrated into density
1.10 (60 DEG C) left and right, carries out chromatography with D101 macroporous adsorptive resins, with water-ethanol gradient elution, discards water elution
Liquid, collects 20% ethanol elution, concentrating under reduced pressure, obtains crude product, ethyl alcohol recrystallization and get final product.
According to the present invention, " catalpol is as the purposes of advanced glycosylation end-products inhibitor " refer to the catalpol of Formulas I for
Treat the diabetic complication caused due to AGE imbalance, the relevant disease such as Alzheimer, atherosclerosis.
According to the present invention, in the present invention, term patient used means the mammal such as mankind.
According to the present invention, catalpol can be made into the preparation of intestinal or parenterai administration by known method, as tablet, capsule,
Granule, injection etc..
Below by way of experimental data, beneficial effects of the present invention is described.
1 catalpol biological experiment to AGE effect
The 1.1 enzyme linked immunological experiments cracking external formation AGE cross-linked structure
(1) preparation of AGE-BSA: AGE crosslinking analogies AGE-BSA, bovine serum albumin BSA (V) 50mg/ml and
0.5M glucose is in 0.2MPBS (PH7.4), and under 37 DEG C of aseptic conditions, lucifuge hatches 3-4 month so that it is form glycosylation BSA
I.e. BSA-AGE.Meanwhile, not glycosyafated BSA is prepared with the BSA without glucose.Then in 0.01MPBS (pH7.4) dialysis solution thoroughly
Analysis, removes unreacted glucose, fluorescent scanning (Exi/Em (395/460nm)), and SDS-PAGE and identifies that BSA-AGE is formed,
Use Lowery method to carry out protein quantification simultaneously.
(2) elisa assay step: be coated 96 orifice plates with tail collagen, with in the full hole of pH7.4PBS and acid collagen 1 hour；
SuperBlock (PIERCE) 37 DEG C, closes 1 hour；PBST (PBS-Tween) washes plate 3 times, every time vibration 1 minute；Dilute with PBS
Release AGE-BSA, to obtain in the hole of A, B, C, D row that the AGE-BSA 100 μ l of maximum degree of cross linking concentration adds 96 orifice plates, identical
The BSA of concentration adds in the hole of E, F, G, H row, and 1 arranges PBS in front 3 holes, and as system and reagent blank, 37 DEG C, 4h is allowed to and glue
Former crosslinking；PBST washes plate 4 times, interval vibration 1 minute.
Used pH7.4PBS to dilute by reagent, take 100 μ l/ holes and be added on AGE-BSA crosslinking and each 4 holes, BSA hole respectively, equally
Mode adds PBS 100 μ l/ hole and compares as non-cracking, hatches 16h for 37 DEG C；PBST washes plate 4 times, interval vibration 1min；Add 80 μ
37 DEG C of l/ hole rabbit anti-BSA antibody (1 500), 50min；PBST washes plate 4 times, interval vibration 1min；Add 80 μ l/ hole Radix Cochleariae officinalis peroxides
Compound enzyme labelling goat anti-rabbit igg (1 1000) 37 DEG C, 50min；PBST washes plate 3 times, interval vibration 1min；Add substrate solution TMB (3,
3 ', 5,5 '-tetramethyl benzidine) 100 μ l/ pore chamber temperature, black out 20min；Use 2mol/L H2SO4Terminate reaction；In 10 minutes,
Under BOBRAD Model550 plate reading machine 450nm, OD value is read in the zeroing of plate blank well.The percentage rate table that cleavage rate reduces with OD value
Show:
[the OD meansigma methods in (the OD meansigma methods in PBS hole-by reagent hole OD meansigma methods)/PBS hole] × 100%.
1.2 catalpol crack the enzyme linked immunological experiment of the erythrocyte surface AGE-IgG cross-linked structure of internal formation
(1) preparation of AGE-IgG crosslinking: 3 Wister rats, male, body weight 180-200g, after adaptability is raised 2 days
8 hours pneumoretroperitoneums injection streptozotocin (65mg/Kg) of fasting, after 72 hours, tail venous blood sampling surveys blood glucose, and blood sugar level is higher than
16.7mmol/L rat is continued to employ, and after routine is raised 12 weeks, takes blood, anticoagulant heparin, and PH 7.4PBS washes three times, 1 250 dilutions.
(2) elisa assay step: 96 orifice plates (Millipore, MAIPS4510) are with 300 μ l Superblock
(PIERCE) close 1h for 37 DEG C, wash plate 1 time with the full hole of PBST, then wash plate 2 times with PBS；To dilute with PBS and the RBC 50 of mixing
μ l adds in hand-hole, and every rat RBC sample adds 4 repeating holes, stays 4 holes to add PBS as antibody control hole simultaneously.PBS washes RBC
1 time, add 50 μ l horseradish peroxidase-labeled rabbit anti-rat IgG (1 2000) room temperature interval concussion 2 hours.
Add and put into 37 DEG C of incubators, 1h by reagent；PBS washes 4 times, adds substrate solution OPD (o-phenylenediamine) 100 μ l/ hole, room
Temperature, lucifuge 30min；Use 2mmol/L H2SO450 μ l/ holes terminate reaction；Quickly every hole liquid 120 μ l is proceeded to plain edition 96 hole
ELISA Plate, under BOBRAD Model 550 plate reading machine 490nm, plate blank returns to zero, and reads OD value.Cleavage rate is with RBC-IgG content
The percentage rate reduced represents:
[(control animals RBC-IgG is by reagent process group RBC-IgG)/control animals RBC-IgG] × 100%
1.3 statistical analysis method and experimental result
Quantitative target all withForm represent, the interpretation of result to two groups of quantitative datas, use Student '
S t inspection carries out the significance test of difference of mean between two groups.To single factor test k (k ＞ 2) level design experimental result, use
SPSS10.0 statistical software carries out one factor analysis of variance to data, if it is statistically significant respectively to organize the difference between mean,
Then with bilateral Dunnett t inspection, each process group mean and matched group mean are carried out multiple comparisons.As P ＜ 0.05, difference
Statistically significant.Analysis result shows:
The catalpol splitting action to AGE-BSA-collagen cross-linking structure: under normal condition, internal also have AGE and crosslinking knot thereof
The formation of structure, but especially slowly and accumulation is little to form speed, and under high sugar state, formation and the accumulation of internal AGE can be bright
Aobvious aggravation, the AGE that vascular stroma albumen is formed can cross-link with other histone amino in blood circulation further, accelerates egg
White molecule deposition, in blood vessel wall, makes sclerosis of blood vessels, loss of elasticity, reduces physiological protein enzyme sensitivity.As tested material can have
Effect cracking crosslinking protein, makes aging albumen be able to renaturation or metabolism, to eliminate the pathology effects that these crosslinking proteins are caused, and will
Be conducive to alleviating and prevent and treat old and feeble and diabetic complication.For this this laboratory observation, diabetes rat tail tendon collagen is sent out by catalpol
Whether raw crosslinking has reverse effect.With AGE-BSA be coated on rat tail tendons protein-crosslinking in 96 hole ELISA Plate, external preparation
AGE cross-linked structure, uses ELISA method to evaluate the splitting action that AGE is cross-linked by catalpol.
With AGE-BSA be coated on rat tail collagen protein-crosslinking on 96 hole enzyme plates, external preparation simulation AGE crosslinking knot
Structure, uses the splitting action that AGE is cross-linked by ElISA method evaluation aminoguanidine and catalpol, and result shows, aminoguanidine and catalpol are one
Under fixed concentration, AGE crosslinking is had certain splitting action, and there is dose-dependence.Compare with positive drug aminoguanidine,
Although the cleavage rate of catalpol is slightly lower, but it is not statistically significant (P ＞ 0.05), it may have good lytic activity.Tentatively
One of drug target showing catalpol is probably AGE.
The catalpol reverse effect to internal AGE cross-linked structure: under high sugar state, IgG is repaiied by Advanced Glycation thing at end (AGE)
Decorations gradually form cross-linking agent IgG-AGE, and IgG-AGE is easily combined with erythrocyte (RBC) surface, as tested material can interrupt AGE-IgG
Between crosslinking, then the function that can reduce the binding capacity of IgG and erythrocyte surface, IgG and erythrocyte is reversed.For entering one
Step confirms that catalpol has the effect of the AGE cross-linked structure effectively cracking internal formation, and this laboratory observation catalpol is to aged glycosuria
The unkehr effect of sick Rat Erythrocytes surface A GE-IgG crosslinking.
AGE can cross-link with multiple protein, including cell surface protein.This test is by detection IgG and erythrocyte
The ability that medicine cracks the AGE of internal formation is evaluated in the minimizing of surface binding capacity.Result of study shows: catalpol and aminoguanidine energy
Reduce internal established AGE and cross-linked structure thereof, compare with aminoguanidine, though the lytic effect of catalpol is slightly lower, but also have
There is good lytic effect (being shown in Table 3), also further demonstrate that AGE is one of drug target of catalpol simultaneously.
Table 3 catalpol reverse effect to internal AGE cross-linked structure
Above-mentioned experimental study shows, catalpol can stop the formation of AGE and accumulation and can crack AGE cross-linked structure, its effect
Molecule mechanism be to interrupt AGE distinctive dicarbapentaborane key.Catalpol is by optionally cracking over-deposit AGE in blood vessel wall
Cross-linked structure, improves the hemodynamic index of diabetes rat, improves Arterial compliance, can make blood vessel and tissue
Elastic return, reverses sclerosis of blood vessels.
Traditional blood sugar lowering method can only delay the generation of complication, the most incompetent to established protein aging and sclerosis of blood vessels
For power, and catalpol is with AGE as drug target, to having reverse effect due to high sugar and the old and feeble protein-crosslinking caused,
So that aging albumen is able to renaturation or metabolism, and then eliminate owing to these cross-link the pathology shadow that aging albumen is caused
Ring, thus can prevent and treat or the visceral organ injury such as kidney that diabetes-alleviating is relevant.
2 catalpol improve the biological experiment of type 2 diabetes mellitus Rat Cardiovascular complication
The foundation of 2.1 rat models, it is grouped and is administered
Take 170-210g male Wistar rat 50, random point 5 groups, often group 10, respectively Normal group, model
Matched group, metformin positive drug group (100mg/kg), catalpol low high group (100mg/kg, 300mg/kg).Except Normal group
Outward, other are respectively organized equal tail vein injection STZ (60mg/kg) and measure blood glucose with blood glucose meter after one week and be defined as more than 11.1mmol/L
Diabetes rat model.After 1 week, give high lipid food 8 weeks continuously.Within 4th day, start to be administered from modeling, treatment group mice gavage respectively
Give glibenclamide and catalpol, Normal group and model control group gavage and give equal-volume distilled water, every 0.4ml, every day 1
Secondary, continuous 3 weeks.
2.2 improve type 2 diabetes mellitus Rat Cardiovascular Observations On The Complications index
After blood-sugar level measuring: before starting to be administered, and continuous gavage catalpol treatment surrounding, afterbody takes blood, drops in blood glucose
The reactive end of strip, demonstrates the blood glucose value of animal by blood glucose monitoring system.
Glucose tolerance: Rat Fast 12h, oral 2.5g/kg glucose, tail venous blood sampling measures gavage glucose respectively
Before the blood glucose value of 0.5h, 1h, 2h after (0h), injection, and by trapezoidal faces area method calculating Area under the curve of blood glucose (AUC).
AUC=0.25 × 0h blood glucose value+0.5 × 0.5h blood glucose value+0.75 × 1h blood glucose value+0.5 × 2h blood glucose value
Biochemical Indices In Serum measures: after OGTT 24h, rat eye socket takes blood, centrifugation serum.Use automatic biochemistry analyzer
Measure Triglycerides in Serum (TG), T-CHOL (TC), HDL-C (HDL-C), creatine kinase (CK), breast
Acidohydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and blood urea nitrogen (BUN)
Content.
Hemodynamic Changes: after last is administered, ip.40mg/kg pentobarbital sodium is anaesthetized, and glucose tolerance test terminates
After rat eye socket takes blood, lumbar injection 40mg/kg pentobarbital sodium is anaesthetized, and right common carotid artery intubates to aorta, and connects pressure
Power transducer recording blood pressure and heart rate；Row thoracotomy exposes ascending aorta, and overlaps with suitable Doppler probe mensuration blood stream
Speed.Through Biopac polygraph record the hemodynamics indices that calculates.
The catalpol blood glucose value on type 2 diabetes mellitus rat and the impact of blood fat: use and destroy islets of langerhans with low dose of STZ and continue again
Feed high lipid food and cause type 2 diabetes mellitus rat experiment model.Test result indicate that, after inducing 8 weeks, with the normal rat raised
Comparing, it is significantly raised that remaining respectively organizes blood glucose value, but blood glucose absolute value differences is the most little, model group and the blood glucose value of administration group
Not being the highest, all within normal range, but glucose tolerance is higher than the most far away normal group, and impaired glucose tolerance shows
Write.Modeling success is described, is suitably applied the research of type 2 diabetes mellitus.
2.3 statistical analysis method and experimental results
Quantitative target all withForm represent, the interpretation of result to two groups of quantitative datas, use
Student ' s t inspection carries out the significance test of difference of mean between two groups.To single factor test k (k ＞ 2) level design experiment knot
Really, use SPSS10.0 statistical software that data are carried out one factor analysis of variance, if the difference respectively organized between mean has statistics
Learn meaning, then with bilateral Dunnett t inspection, each process group mean and matched group mean are carried out multiple comparisons.As P ＜ 0.05
Time, difference is statistically significant.Analysis result shows:
Catalpol has reduction effect to the blood glucose of type 2 diabetes mellitus rat, does not has statistical significance, can suppress blood glucose upper of rat
Rising, and model group compares, after being administered surrounding, rat blood sugar value is not in progress and model group rats blood glucose has raised, and is shown in Table 4.
Table 4 catalpol on the impact of type 2 diabetes mellitus rat blood sugar (N=10)
#P < 0.05, # compares with matched group
Catalpol improves the blood lipid level of type 2 diabetes mellitus rat: type 2 diabetes mellitus to be typically characterised by blood glucose value the highest, blood
Fat is abnormal.From table 2-2 it can be seen that the T-CHOL normal rats to be significantly higher than (P 0.01) of rat, blood after modeling 8 weeks
Aloof from politics and material pursuits density lipoprotein normal rats to be significantly lower than (P 0.05), low density lipoprotein, LDL is significantly higher than normal rats. says
Bright long-term impaired glucose tolerance can cause lipometabolic disorder and exception.
After catalpol treatment surrounding, the serum total cholesterol values of high dose group and middle dosage group rat will the lowest and model group
Rat, prompting catalpol can effectively reduce the high smectic state of diabetes rat.HDL has antiatherogenic effect, result
Display catalpol can significantly improve the serum high-density LP content (P 0.01) of diabetes rat, it was demonstrated that high sugar is drawn by catalpol
The cardiovascular function infringement risen has certain protective effect, is shown in Table 5.
Table 5 catalpol on the impact of type 2 diabetes mellitus rat fat (N=10)
# compares with matched group, and #p < 0.05, ##p < 0.01, * compares with model group, * p < 0.05.
Catalpol improves sclerosis of blood vessels rat aorta compliance: internal AGE is too much formed and accumulation, can cause protein molecular
Over-deposit, in blood vessel wall, causes blood vessel hardness to increase, and vascular compliance reduces.Vascular compliance refers to the buffering of blood vessel wall
Ability, is the inherent elastic characteristic of blood vessel.As medicine can stop formation and the accumulation of AGE, or can effectively crack AGE crosslinking knot
Structure, then can make vascular be reversed, and vascular compliance increases.
As shown in table 6 and table 7, model group rats blood pressure, heart rate are apparently higher than Normal group diabetes rat, and glycosuria
Sick every hemodynamic index such as rat cardiac output, systemic arterial compliance (SAC) compare with normal rats all have aobvious
Write to decline, and total peripheral resistance (TPR) significantly raises；The hemodynamic index showing diabetes rat is abnormality.
Comparing with model control group, metformin, catalpol two dosage of height can significantly improve rat cardiac output, reduce the resistance of total periphery
Power (TPR) also significantly improves systemic arterial compliance (SAC).
Table 6 catalpol is on diabetes rat heart rate, the impact of blood pressure
The impact on diabetes rat vascular compliance of table 7 catalpol
* model compares with normal group: * P ＜ 0.05, * * P ＜ 0.01；◆Administration group compares with model group:◆P ＜ 0.05,◆◆P
＜ 0.01
The safety biological experiment of 3 catalpol
This test uses 5g/kg dosage that its acute toxicity has been carried out preliminary observation.Take healthy ICR mice 80, male and female
Half and half, each sex mice is randomly divided into 2 matched groups and 2 catalpol administration groups, after fasting 6 hours, and gavage and abdomen the most respectively
Chamber injection gives catalpol 5g/kg, matched group gavage equal-volume distilled water.
Animal be administered after Continuous Observation 8 hours, after administration 1-14 days, observe 2 every day.Record the general of each treated animal to live
Dynamic state, is distributed with or without dead and dead front performance and dead animal.Dead animal does gross anatomy in time and observes.Live and deposit animal
Put to death after within 14 days after medicine, weighing, carry out gross anatomy observation, if variant, carry out pathological study.
Student ' s t inspection is used to carry out the significance test of difference of mean between two groups.As P ＜ 0.05, difference has
Statistical significance.
Result shows: after gavage of mice gives catalpol, and some animals activity reduces, but quickly recovers normal, without it
Its reaction.Without animal dead within the observation period of 14 days, mice general activity is in good condition, takes food, defecating shows no obvious abnormalities.
Body weight and matched group no significant difference (table 8) before and after experiment.Gross anatomy shows, heart, liver, kidney, lungs etc. are the dirtiest
The change that device is visible by naked eyes.
Catalpol 5g/kg acute toxicity test mice do not occur death, body weight and behavior compared with matched group without significant difference,
Anatomical Observation is the most no abnormal, and this dosage is 500 times of clinical effective dose, accordingly it is believed that catalpol is used for treating sugar
The sick nephropathy dosage range of urine is the widest.
Body weight change (g) after table 8 mouse stomach catalpol
Detailed description of the invention:
Further illustrate the present invention by the following examples, but do not mean that any limitation of the invention.
Embodiment 1: the preparation of catalpol and Structural Identification
The preparation of 1.1 catalpol:
Take Radix Rehmanniae, by water supersound extraction three times, add 6 times amount water every time, ultrasonic 1 hour.United extraction liquid, reduces pressure dense
Contracting.It is concentrated into density 1.10 (60 DEG C) left and right, carries out chromatography with D101 macroporous adsorptive resins, wash with water-ethanol gradient
De-, discard water elution liquid, collect 20% ethanol elution, concentrating under reduced pressure, obtain crude product, ethyl alcohol recrystallization and get final product.
1.2 Structural Identifications:
This own product is white powder (EtOH), is soluble in methanol, ethanol, water equal solvent.Fusing point: 207-209 DEG C (is decomposed
Point).Do not decline with the mixed melting point of catalpol reference substance, can tentatively judge that this compound is catalpol.
Carrying out Structural Identification: ESI-MS spectrum further through following spectrum, UV composes, and IR composes, and 1H-NMR composes, and 13C-NMR composes,
1H-1HCOSY composes, and HMQC composes, and HMBC composes, and DEPT composes..
(1) ESI-MS: molecular ion peak 385.2 (M+Na)+, 360.9 (M-1)-, 190 (M-1-aglycons)-, 181 (M-1-
Aglycon-OH)-, show that this compound molecular weight is 362.It is 49.74% that elementary analysis records Elements C content, and element H content is
6.12%, deduction molecular formula is C15H22O10.
(2)UVλH2Omax:210nm.The end absorption peak of 210nm shows that this structure is without conjugated double bond.
(3) IR υ KBr cm-1:3405 (br. OH), 1672 (C=C).The absworption peak of 3405cm-1 is that the flexible of O H shakes
Dynamic.Absworption peak between 3200～2800cm-1 belongs to the stretching vibration of C H.Relatively strong absorption at 1672cm-1 belongs to C=C's
Stretching vibration.
(4) 1H-NMR combines 1H-1HCOSY spectrum: δ H 4.74 (1H, d, J=7.9Hz) is β-glucose H-1 ' signal；δH
6.34 (dd, J=1.7,5.9Hz), δ H 5.04 (dd, J=4.5,5.8Hz) is respectively the signal of H-3, H-4, mutual for double bond
Coupling；δ H 2.25 (dddd, J=2.0,3.4,5.3,7.8Hz) is 5 H signal, and 2.51 (dd, J=7.6,9.8Hz) are 9 H
Signal；The H signal of 10 CH2 is (4.14d, 3.77d)；The H signal of 6 ' position CH2 is (3.9d, 3.65dd).
(5) 13C-NMR combine DEPT spectrum: 2 secondary C (δ c61.05C-10, δ c 62.38C-6 '), 10 tertiary C, wherein C-5
δ C is 38.53, and C-9 δ C is 43.37.6 C that are connected with-OH (C-2 ', C-3 ', C-4 ', C-5 ', C-6, C-10).Glucose C-1 '
δ C is 99.11, and C-1 δ C is 95.06, shows to be connected with glucose.1 season C is C-8, δ C66.05.
1H and 13C composes: self-control catalpol 1H and 13C modal data list 1 are summarized as follows:
Catalpol made by oneself by table 11H and13C modal data
δ in document (Chen Dechang edits " traditional Chinese chemical contrast service manual ")CC-6 is 77.4, δCC-3 ' is 79.6, root
Infer it should is that chemical shift data overturns according to the two-dimensional map of sample: in HMBC spectrum, δHH and C-4 of 3.875, C-5, C-7
Relevant, and be connected with-OH and press, eliminating H-9, therefore it is judged as the chemical displacement value of H-6.Compose in conjunction with HMQC, H-6 and δCIt is 79.11
C be correlated with, so C should be C-6, i.e. δCC-6 is 79.11.Equally, according to two-dimensional spectrum it can be extrapolated that δCC-3 ' is 77.10.So,
In document, data should be modified to δCC-6 is 79.6, δCC-3 ' is 77.4.
Document (Chen Dechang edits " traditional Chinese chemical contrast service manual ") catalpol13C modal data and this own product13C composes number
It is compared as follows according to list 2:
Table 2 document report catalpol and this product13C data compares
Found out by this table, this product and document report catalpol13C data is basically identical.
Scanning electron microscope, X-powder diffraction and TG/DSC testing result show, the catalpol crystallization that different precipitation conditions obtain is all
For a kind of crystal formation, research not finding, catalpol exists polytropism, do not find that crystal formation can extend with standing time and send out yet
Changing.
According to above spectral data, reporting with reference to relevant document, can confirm this compound is catalpol.
The preparation of embodiment 2 catalpol drop pill
Catalpol 0.5g and the 10.5g PEG-4000 of Example 1 is mixed homogeneously, and adds heat fusing, moves to drip after material
In ball drip irrigation, medicinal liquid drops in 6-8 DEG C of liquid paraffin, oil removing, prepares drop pill 400.
The preparation of embodiment 3 catalpol tablet
The catalpol 0.5g of Example 1, addition starch 10g, after sucrose 4.5g, mix homogeneously, pelletizing press sheet, to obtain final product.
The preparation of embodiment 4 catalpol capsule
The catalpol 0.5g of Example 1, addition starch 10g, after sucrose 4.5g, mix homogeneously, pelletize encapsulated, to obtain final product.
Claims (6)
1. catalpol application in the food that preparation prevents AGE from generating or suppression AGE is active, health product, medicine.
2. the diabetic complication that catalpol causes due to AGE imbalance for treatment or prevention in preparation, Alzheimer, tremulous pulse
The application of atherosis medicine.
Application the most according to claim 2, it is characterised in that described diabetic complication is selected from diabetic nephropathy.
4. according to any application of claim 1 or 2, it is characterised in that described medicine includes catalpol and pharmaceutically acceptable
Carrier.
Application the most according to claim 3, it is characterised in that the medicine agent that described medicine can be taken selected from any one
Type.
Application the most according to claim 5, it is characterised in that described pharmaceutical dosage form is selected from: tablet, capsule, granule,
Injection.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610562834.0A CN106176793A (en) | 2016-07-16 | 2016-07-16 | Catalpol is as the purposes of advanced glycosylation end-products inhibitor |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610562834.0A CN106176793A (en) | 2016-07-16 | 2016-07-16 | Catalpol is as the purposes of advanced glycosylation end-products inhibitor |
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Cited By (3)
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| CN107739398A (en) * | 2017-10-19 | 2018-02-27 | 焦作大学 | A kind of propionating catalpol derivatives and its preparation method and application |
| CN108912183A (en) * | 2018-07-06 | 2018-11-30 | 河南中医药大学 | A kind of catalpol derivatives and its preparation method and application that crotons are acylated |
| CN112336738A (en) * | 2020-12-25 | 2021-02-09 | 孟胜喜 | Traditional Chinese medicine monomer composition for preventing and treating Alzheimer disease and application thereof |
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| CN102824463A (en) * | 2012-09-24 | 2012-12-19 | 南京中医药大学 | Traditional Chinese medicine extract for suppressing generation of in-vitro glycosylation product and extraction method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107739398A (en) * | 2017-10-19 | 2018-02-27 | 焦作大学 | A kind of propionating catalpol derivatives and its preparation method and application |
| CN108912183A (en) * | 2018-07-06 | 2018-11-30 | 河南中医药大学 | A kind of catalpol derivatives and its preparation method and application that crotons are acylated |
| CN108912183B (en) * | 2018-07-06 | 2020-09-18 | 河南中医药大学 | Catalpol derivative acylated with croton and preparation method and application thereof |
| CN112336738A (en) * | 2020-12-25 | 2021-02-09 | 孟胜喜 | Traditional Chinese medicine monomer composition for preventing and treating Alzheimer disease and application thereof |
| CN112336738B (en) * | 2020-12-25 | 2021-11-19 | 孟胜喜 | Traditional Chinese medicine monomer composition for preventing and treating Alzheimer disease and application thereof |
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