CN108853082A - Purposes of the hematoxylin in preparation treatment immunity glomerulonephritis drug - Google Patents
Purposes of the hematoxylin in preparation treatment immunity glomerulonephritis drug Download PDFInfo
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- CN108853082A CN108853082A CN201810673027.5A CN201810673027A CN108853082A CN 108853082 A CN108853082 A CN 108853082A CN 201810673027 A CN201810673027 A CN 201810673027A CN 108853082 A CN108853082 A CN 108853082A
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- 239000012188 paraffin wax Substances 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 238000012808 pre-inoculation Methods 0.000 description 1
- 229940096335 prednisone 1 mg Drugs 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 235000012950 rattan cane Nutrition 0.000 description 1
- 235000003499 redwood Nutrition 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- MPGFEHZDABUJFR-JKSUJKDBSA-N sappanol Chemical compound C([C@@]1(O)COC2=CC(O)=CC=C2[C@@H]1O)C1=CC=C(O)C(O)=C1 MPGFEHZDABUJFR-JKSUJKDBSA-N 0.000 description 1
- 230000036301 sexual development Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 235000015398 thunder god vine Nutrition 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 210000003934 vacuole Anatomy 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- Chemical & Material Sciences (AREA)
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- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses purposes of the hematoxylin in preparation treatment immunity glomerulonephritis drug.It is found in the research of the immunity glomerulonephritis to membranous nephropathy animal model, hematoxylin achievees the purpose that treat membranous nephropathy at least through following three aspects：1) hematoxylin, which has, reduces Urine proteins, improves disorders of lipid metabolism, improves the effect of plasma albumin level.2) hematoxylin has the function of improving the damage of renal tissues pathology morphology.3) vascular endothelial growth factor (VEGF) that hematoxylin has the function of reducing in serum is horizontal, by inhibiting VEGF secretion, adjusts glomerular filtration membrane permeability, reduces the excretion rate of Urine proteins, protect renal function.The present invention specifies that hematoxylin has adjustment for the treatment of effect to immunity glomerulonephritis, provides a kind of new technological means for the treatment of immunity glomerulonephritis, will be with a wide range of applications in the therapy field of immunity glomerulonephritis.
Description
Technical field
The present invention relates to hematoxylic new applications, in particular to use of the hematoxylin in treatment immunity glomerulonephritis
On the way, the invention belongs to tcm development technical fields.
Background technique
Immunity glomerulonephritis is the Chronic glomerular disease that kidney is primary in as caused by the various causes of disease.Majority is immune
Property ephritis the cause of disease it is unclear, research has shown that, various microorganisms, including bacterium, virus, rickettsia, protozoon etc. all may be used
To cause this disease by immunopathogenesis.The therapeutic effect of immune nephritis and prognosis have very close with its pathological change type
Immune nephritis is divided by the connection cut by its histopathologic change in the world：1, minute lesion type.2, membranous nephropathy.3, it is
Film productive nephritis (including IgA ephritis).4, endothelium-MsPGN.5, mesangiocapillary ephritis, again
Claim film productive nephritis.6, focal segmental glomerulosclerosis.7, cresentic ephritis etc..
Wherein, membranous nephropathy (membranous nephropathy, MN) is that Adult immunization's property glomerulonephritis is common
One of histological type, is a kind of kidney trouble for seriously endangering human health, and lesion is often shown as in sexual development is slowly carried out
Nephrotic syndrome, is common Clinical Nephropathy syndrome, and main clinical manifestation is：High-grade Proteinuria, hypoalbuminemia, oedema
And hyperlipidemia, pathological change is mainly characterized by glomerular basement membrane thickening under mirror, and the epithelium of glomerular capillary wall is thin
There is deposit under born of the same parents, it is seen that follow closely prominent spline structure, the patient of membranous nephropathy about 25% can gradually appear renal function after the several years of falling ill
Failure, uremia.It clinically applies glucocorticoid and immunosuppressant treatment more at present, can obtain in a short time certain
Curative effect, but prolonged application toxic side effect is big, disease amelioration rate is low, easy to recur after drug withdrawal.With grinding for China's Chinese Traditional Medicine
Study carefully development, a variety of Chinese medicines with immunosuppressive action are widely used in clinical treatment and obtain considerable curative effect, such as Thunder God
The more glucosides of rattan have immunosuppressive action, so that it is widely used in clinical treatment, and a kind of Novel free of the tacrolimus as strength
Epidemic disease inhibitor is also widely used in the clinical treatment of nephrotic syndrome at present, plays positive effect.
Bush is also known as lignum sappan, red wood, red bavin, palm fibre wood, and it is leguminous plant bush that anaesthetic name, which sweeps a hair all,
The dry duramen of (Caesalpinia sappan L.), originates in Burma, Vietnam, India, the Malay Peninsula and Sri Lanka, domestic
It is distributed mainly on Baise of Guangxi, grand, the ground such as Yunnan Jing Dong, Yuanjiang River, Maguan, Lijing and Taiwan, Hainan mainly contain flavonoids
Compound and phytosterin compound, including sappanol, bush chalcone, brazilin, former haematoxylin etc., Chinese medicine thinks it
Nature and flavor are sweet, salty, pungent, flat, converge to heart and liver channels, have promoting blood circulation, dissolving stasis, detumescence, analgesic and other effects.For treating married woman vim and vigour trusted subordinate
Bitterly, amenorrhoea, the asthma of postpartum blood stasis distending pain is anxious, and dysentery, tetanus, carbuncle swells, liver blood is vigorous, flutters and damages the stagnant equal diseases of having a pain of the stasis of blood.Furthermore bush
As a kind of natural pigment, it is widely used in daily use chemicals, food, leather and textile dyeing etc., and the dye as cell tissue slice
Toner is applied in Pathological experiment.From Japanese scholars the 1970s to the research mark of the external tumor-inhibiting action of bush water extract
Will the beginning to bush pharmacological research, by decades both at home and abroad constantly explore and research, discovery bush except tradition
Outside effect, also there is immunological regulation, antitumor, inoxidizability, antibacterial, anti-inflammatory, anticomplement, hypoglycemic and other effects.Clinically have
Bush and other Chinese prescriptions were once carried out the treatment of autoimmune disease (such as chorionitis) by people.Traditional mongolian medicine Gu Gu wood
Zhu Sumu is written, inhibits the cell immune response of body also by it, hepatic injury caused by being reacted with Reduce allergy, to treat
Hepatitis.Yang Feng etc. is the study found that Caesalpinia sappan water extract has apparent inhibiting effect to mouse T cell, B cell function, effect
Enhance with the increasing of dosage, and confirms that the immunosuppressive action of bush is better than tripterygium wilfordii.With compareing for Ciclosporin A (CSA)
Studies have shown that it has the function of that anti-immunity rejection does not find apparent toxic side effect.Although the immunosupress class such as CSA
The clinical application of drug is that organ transplant and the treatment of immunity disease have been started new era, but these drugs lack mostly at present
On the one hand weary selectivity and specificity, prolonged application easily lead to Abwehrkraft des Koepers decline and induce severe infections and malignant tumour
Deng；On the other hand, immunosuppressor itself is big to the toxicity of body, side effect is more, and serious person can cause intracorporeal organ or plant device
The even loss of function of the dysfunction of official.Therefore, researchers are urgently expected to search out from Chinese herbal medicine a kind of high
Neotype immunosuppressant less toxic, that selectivity is strong is imitated, to reach substitution or partially substitute the Western medicine immunosupress applied at present
Agent and preferably be applied to clinic.
Inventor once did Adriamycin Nephrosis In Rats model, cationization with the water extract of bush
Bovine serum albumin(BSA) induces the animal experiment study of membranous nephropathy, at the same also clinical observation its to immunity glomerulonephritis
As a result the treatment of scorching patient further proves that it has immune modulating treatment effect.So the present inventor and team are by refinement point
Analysis has been done relevant zoopery and experiment in vitro, has been visited using possibility effective component hematoxylin most important in bush as breach
Hematoxylin is begged for the mechanism of action of immunity glomerulonephritis, using Membranous Nephritis Rats model as research object, observes hematoxylin
Influence to its biochemical indicator, pathological tissue and cell factor, compares with tacrolimus, immune applied to clinical treatment for it
Property glomerulonephritis provide experimental basis.
Summary of the invention
The purpose of the present invention is to provide a kind of new use of hematoxylin in preparation treatment immunity glomerulonephritis drug
On the way.
Hematoxylic molecular formula：C16H14O6, molecular weight：302.28 molecular structural formula is:
In order to achieve the above object, present invention employs following technological means：
The present invention chooses adult male SD rats 50, is randomly divided into Normal group (group A, N=10), model group (group
B, N=10), hematoxylin group (group C, N=10), tacrolimus group (group D, N=10), prednisone group (group E, N=10), B, C, D,
Component E does not establish Cationic bovine serum albumin (C-BSA) and causes rat membranous nephropathy, i.e. C-BSA 1mg is added
In 0.5ml phosphate buffer (PBS), be mixed into milky suspension with equivalent incomplete Freund's adjuvant, rats with bilateral oxter,
The subcutaneous injection of groin multiple spot, pre- to be immunized after a week, every rat tail vein injection C-BSA2.5mg (is dissolved in 1ml PH7.4PBS
In), three-times-weekly, totally three weeks.C group gives hematoxylin (essence extract, purity 95%), and 0.1mg/d, D group gives tacrolimus
0.1mg/d, E group give prednisone 1mg/d, and continuous gavage is treated 4 weeks.Twenty-four-hour urine is stayed before treatment, chemically examines twenty-four-hour urine albumen
It is quantitative.The dead each group rat in 4th week end after treatment, leaves and takes renal tissue, and it is big to observe each group for the dyeing such as slice row HE, PAS
The pathological change under pathological change and rat kidney Electronic Speculum under mouse kidney light microscopic, parallel rat VEGF
(VEGF) quantitative enzyme detects, and will test resulting related data and is compared and statistical analysis.As a result, it has been found that model group 24 is small
When quantity of proteinuria, blood lipid it is significantly raised, plasma albumin is substantially reduced；Hematoxylin group, tacrolimus group, the phase of prednisone group
Index is closed to take a favorable turn trend.Histological examination can find that light microscopic drag group renal tissue messangial cell and matrix diffusivity increase
Raw, basilar memebrane obviously thickens, it is seen that follows closely prominent spline structure；Visible basilar memebrane and upper subcutaneously there is volume electron dense object heavy under Electronic Speculum
Product；Each treatment group's basement membrane thickened is unobvious, damages opposite mitigation, and visible a small amount of electron dense object deposits or has no true under Electronic Speculum
Cut electron dense object deposition.VEGF is declined in the expression of each treatment group compared with model group.Illustrate hematoxylin be applied to
After the rat membranous nephropathy that C-BSA induces, blood, urine chemically examine the trend that take a favorable turn, and the existence of rat, which shows, to be improved, pathology
And biochemistry detection prompt, hematoxylin have certain therapeutic effect to rat membranous nephropathy.VEGF detection prompt hematoxylin is inhibiting
Vegf expression mitigates renal tissue damage etc. and plays a role.
According to above conclusion, the invention proposes use of the hematoxylin in preparation treatment immunity glomerulonephritis drug
On the way.
Wherein, it is preferred that the immunity glomerulonephritis is membranous nephropathy.
Wherein, hematoxylin has the Urine proteins for reducing membranous nephropathy patient, improves disorders of lipid metabolism, improves the white egg of blood plasma
The effect of white level.
Wherein, hematoxylin has the function of improving the damage of membranous nephropathy kidneys of patients histopathology morphology.
Wherein, the VEGF that hematoxylin has the function of reducing in membranous nephropathy patients serum is horizontal, by inhibiting VEGF points
It secretes, adjusts glomerular filtration membrane permeability, reduce the excretion rate of Urine proteins, protect renal function.
Detailed description of the invention
Fig. 1 is the variation of each group Rat 24 h excretion quantity of urinary protein；
Note：△ indicates the P compared with model group<0.05；☆ indicates the P compared with the 4th week (before treatment)<0.01.
Fig. 2 is the variation of each group rat VEGF level；
Note：△ indicates the P compared with normal group<0.01, ☆ indicates the P compared with normal group<0.05；# is indicated and model group
Compare, P<0.05；
Fig. 3 is that Normal group HE dyes (× 10)；
Fig. 4 is that Normal group PAS dyes (× 40)；
Fig. 5 is that model group HE dyes (× 100)；
Fig. 6 is that model group PAS dyes (× 100)；
Fig. 7 is that hematoxylin group HE dyes (× 100)；
Fig. 8 is that tacrolimus group PAS dyes (× 100)；
Fig. 9 is that hormone group HE dyes (× 100)；
Figure 10 is that model group follows closely prominent spline structure (× 100)；
Figure 11 is to change under Normal group Electronic Speculum；
Figure 12 is to change under model group Electronic Speculum；
Figure 13 is to change under hematoxylin group Electronic Speculum；
Figure 14 is to change under tacrolimus group Electronic Speculum；
Figure 15 is to change under prednisone group Electronic Speculum.
Specific embodiment
The invention will now be further described with reference to specific embodiments, the advantages and features of the present invention will be with description and
It is apparent.But examples are merely exemplary for these, and it is not intended to limit the scope of the present invention in any way.Those skilled in the art
Member, can details and form to technical solution of the present invention it should be understood that without departing from the spirit and scope of the invention
It modifies or replaces, but these modifications and replacement are fallen within the protection scope of the present invention.
The pharmacodynamic test of 1 hematoxylin of embodiment treatment membranous nephropathy
1. materials and methods
1.1 material
1.1.1 experimental animal
Health male cleaning grade SD rat 50 (200-250 grams of weight), purchased from attached second doctor of Harbin Medical University
Institute's animal experimental center, during test, experimental animal is fed in Second Affiliated Hospital of Harbin Medical Univ.'s zoopery
The heart.Animal adaptive feeding one week before experiment, freely ingests during test, drinks water.
1.1.2 major experimental medication
Hematoxylin：Hematoxylin finished product (purity, 95%), is purchased from Harbin Hong Bo Co., Ltd.
Tacrolimus capsules (health is appointed)：Authentication code：National drug standard H20084522.Production unit：The great medicine company of containing in Zhejiang has
Limit company.
Prednisone (prednisone acetate tablets)：Authentication code：H41020283.Production unit：Henan old name for the Arabian countries in the Middle East medicine company share is limited
Company.
1.1.3 major experimental reagent
Natural bovine serum albumin(BSA) (N-BSA), production unit：Win marine growth Engineering Co., Ltd in Hebei.
Carbodiimides (EDC), production unit：Sigma company (U.S.).
Anhydrous ethylenediamine (EDA), production unit：Shanghai Yi Feng chemical reagent factory.
Incomplete Freund's adjuvant, production unit：Sigma company (U.S.).
10% chloraldurate solution：Pharmacy of Second Affiliated Hospital of Harbin Medical Univ..
Rat VEGF quantitative analysis enzyme-linked immunologic detecting kit, production unit：Beijing Bo Ling section is that biotechnology is limited
Company.
1.1.4 major experimental instrument
Electronic analytical balance：Resolution ratio 0.1mg, Sartorius AG's production.
Automatic clinical chemistry analyzer：7600 type automatic clinical chemistry analyzer of Hitachi.
Tungsten filament scanning electron microscope：Resolution ratio 3.0nm@30KV (SE and W)；4.0nm@30KV (VP with BSD),
Amplification factor：5-1000000x, German Carl Zeiss Inc..
OLYMPUS BX51M optical microscopy：Eyepiece amplification factor：10, object lens magnification：5-100, instrument amplification times
Number：50-1000, Olympus (China)Co., Ltd..
1.2 test method
1.2.1 preparing before experiment
(1) preparation of Cationic bovine serum albumin (C-BSA)：Reference literature (Broder WA, Ward HJ, Kamil
ES, et al.Induction of membranous nephropathy inrabbits by administration of
an exogenous cationic antigen[J].J Clin Invest,1982；69：451-461), by bovine serum albumin
It is white to be cationized.EDA67ml is dissolved in 500ml distilled water first, 6mol/L HCl solution 350ml is added, by pH tune
To 4.75, temperature is controlled at 25 DEG C, then 5g BSA and 1.8g EDA uniform stirring 2 hours, then with the acetic acid solution of 4mol/L
PH to 4.75 is adjusted, by these substances in the case where 4 DEG C, is dialysed 48 hours with distilled water, freezes dried, use polyacrylamide
It measures isoelectric point (PI), PI>8.5.
(2) preparation of phosphate buffer (PBS)：
With electronic balance weighing reagent：8.0007 grams of sodium chloride, 0.20015 gram of potassium chloride, 0.2410 gram of carbonic acid potassium dihydrogen,
3.5289 grams of disodium hydrogen phosphate.Distilled water is added to be dissolved to 800ml above four kinds of reagents, adjusting pH value is about 7.4, adds distilled water
To 1000ml.It is sub-packed in 2 500ml rubber plug vials, seals, sterilizing is spare.
(3) pre- immune liquid is prepared
It is weighed in the mortar after C-BSA 50mg is put into sterilizing with electronic balance, a small amount of PBS is added and carefully grinds, until meat
The invisible C-BSA particle of eye, adds PBS, amounts to 25ml, mixes；The incomplete Freund's adjuvant of 25ml and grinding are added, directly
Become milky to solution (solution left standstill is easily layered, so needing agitated rear injection in pre- inoculation).
(4) C-BSA solution is prepared
It is weighed in the mortar after C-BSA1.848g is put into sterilizing, is carefully ground after a small amount of PBS is added, directly with electronic balance
To the invisible C-BSA particle of naked eyes, which is poured into 1000ml graduated cylinder, cleans mortar for several times with PBS and by cleaning solution
Graduated cylinder is poured into, then is supplemented to 1000ml with PBS, is sub-packed in 10 1000ml rubber plug vials, 4 DEG C of preservations are spare (entirely to match
Process sterile working is set, glass wares used is sterilized with 200 DEG C, 4 hours, and rubber plug, which boils 15 minutes, to sterilize).
1.2.2 experimental animal grouping and model copy
50 SD rat adaptive feedings after a week, are randomly divided into Normal group (group A, N=10), model group (group B, N
=10), hematoxylin group (group C, N=10), tacrolimus group (group D, N=10), prednisone group (group E, N=10), B, C, D, E group
C-BSA is established respectively causes rat membranous nephropathy.
When model copy, every rat with C-BSA 1mg, is added in 0.5mlPBS, with equivalent incomplete Freund's adjuvant
It is mixed into milky suspension, is subcutaneously injected in rats with bilateral oxter, groin multiple spot, pre- to be immunized after a week, every big rat-tail is quiet
Arteries and veins injects C-BSA2.5mg (being dissolved in 1ml PH7.4PBS), three-times-weekly, totally three weeks.
1.2.3 experimental animal administration mode
A and B group rat：Physiological saline 1ml stomach-filling is given, it is for 4 weeks.
C group：1mg hematoxylin (purity 95%) is dissolved in 10ml physiological saline, every rat gives stomach-filling 1ml (i.e. every
The daily 0.1mg hematoxylin of rat), it is administered 4 weeks.
D group：1mg tacrolimus is dissolved in 10ml physiological saline, every rat gives stomach-filling 1ml, and (i.e. every rat is daily
0.1mg tacrolimus), it is administered 4 weeks.
E group：10mg prednisone is dissolved in 10ml physiological saline, every rat gives stomach-filling 1ml, and (i.e. every rat is daily
1mg prednisone), it is administered 4 weeks.
1.2.4 materials
Each group rat leaves and takes twenty-four-hour urine liquid before administration, carries out quantity of proteinuria detection, and all rats are controlled in drug
It treated for the 4th weekend, opens abdomen after lower-left intraperitoneal anesthesia is fixed with chloraldurate (300mg/Kg), adopted with ability mass formed by blood stasis through abdominal aorta
Blood, row biochemical indicator and VEGF detection.After execution, through abdominal aortic cannulation, with physiological saline lavation renal tissue repeatedly, cleaning
Vessel inner blood takes out kidney, is divided into several pieces, is respectively placed in 4% paraformaldehyde and 2% glutaraldehyde fixed, progress scene
With the inspection of Electronic Speculum (each group rat leaves and takes twenty-four-hour urine liquid on the day before putting to death).
1.2.5 pathological examination
(1) renal tissue sample Hematoxylin-eosin dyeing (HE dyeing)
Operating procedure：
1) renal tissue is fixed with 4% paraformaldehyde to stay overnight；
2) tissue dewatering：After impregnating dehydration a few hours in 75% alcohol, it is transferred to 80% alcohol and impregnates dehydration a few hours,
Then after impregnating 1 hour and 2 hours in 95% alcohol I and 95% alcohol II respectively, 100% alcohol I and 100% wine are transferred to
It is impregnated 1 hour in smart II, chloroform impregnates a few hours；
3) conventional organization embeds, and with about 5 μm of microtome, piece is dried；
4) paraffin section is dewaxed using dimethylbenzene and uses alcohol at different levels to washing：Successively dimethylbenzene I, dimethylbenzene II,
100% alcohol, 95% alcohol, 80% alcohol and 75% alcohol impregnate 5min, 5min, 2min, 1min and 1min respectively, finally use
Distillation washing 2min；
5) then haematoxylin dyeing 5min is rinsed with tap water, break up 30sec with acidic alcohol, impregnated with tap water
2min is redyed in 15min, Yihong；
6) dehydration, transparent and mounting：Successively it is dehydrated respectively 2 times, each 1min in 95% alcohol, 100% alcohol, dimethylbenzene,
Resinene mounting, takes a picture under the microscope.
(2) renal tissue sample PAS is dyed
Operating procedure：
1) renal tissue 10min is fixed with 4% paraformaldehyde；
2) tissue dewatering：After impregnating dehydration a few hours in 75% alcohol, it is transferred to 80% alcohol and impregnates dehydration a few hours,
Then after impregnating 1 hour and 2 hours in 95% alcohol I and 95% alcohol II respectively, 100% alcohol I and 100% wine are transferred to
It is impregnated 1 hour in smart II, chloroform impregnates a few hours；
3) conventional organization embeds, and with about 5 μm of microtome, piece is dried；
4) after the conventional dewaxing aquation of slice, 10min is restored with 1% periodic acid aqueous solution；
5) tap water rinses 2 times, and distilled water cleans 1 time；
6) schiff reagent is added, greenhouse, which is protected from light, is incubated for 20min；
7) 0.5% Sodium Metabisulfite drop washes 3 times, every time about 5min；
8) distilled water cleans 3 times, each 5min；
9) the light dye 10min of hematoxylin；
10) conventional dehydration, transparent and mounting：2 times are successively dehydrated respectively in 95% alcohol, 100% alcohol, dimethylbenzene, respectively
1min, resinene mounting, takes a picture under the microscope.
(3) it is checked under renal tissue sample Electronic Speculum
Operating procedure：
1) with fixed in 2% glutaraldehyde buffer；
2) it is then placed in l% osmic acid fixer again fixed after carrying out at room temperature；
3) after with graded ethanol (50%-70%-95%-100% ethyl alcohol) dehydration, nephridial tissue propylene oxide is transparent, then
Tissue is put in propylene oxide and the equivalent mixed liquor of EPON812 resin and is impregnated with, with fresh EPON812 resin embedding group
It knits, heats poly- platform：Tissue block can be with long-term preservation after embedding.
4) it is first cut out with half-thickness microtome:1um semithin section；
5) the obvious glomerulus of lesion is found out under light microscopic after the dyeing of methylene blue liquid, find out the position of lesion bead in tissue block
On the ultra-thin section of 50nm is cut out with ultramicrotome, be loaded on copper mesh collodion membrane.With acetic acid uranium and the dual dye of lead citrate
Color.Slice after dyeing is taken a picture under the microscope in electronic display emblem.
1.2.6 rat VEGF quantitative enzyme detects
Principle：This experiment detects the concentration of rat VEGF in sample using double antibody sandwich ELISA.Rat VEGF capture
Antibody is pre-coated on ELISA Plate, when sample or reference material is added, rat VEGF therein can in conjunction with capture antibody,
Its free ingredient is removed by the process washed.After biotinylated anti-rat VEGF antibody is added, anti-rat VEGF
Antibody is engaged with rat VEGF, forms sandwich immune complex, and other free ingredients are removed by the process washed.With
The avidin of horseradish peroxidase-labeled is added afterwards.Biotin and avidin are specifically bound, and the enzyme of avidin connection will
It is connected with sandwich immune complex；Other free ingredients are removed by the process washed.Color developing agent is eventually adding,
If there are VEGF will will form immune complex in sample, horseradish peroxidase can be catalyzed colourless color developing agent oxidation au bleu
Substance is in yellow after terminate liquid is added.Detected by microplate reader, read the OD value at its 450nm, rat VEGF concentration with
It is proportional between OD450 value, standard curve is drawn by reference to product, OD value in unknown sample is compareed, can calculate in sample
VEGF concentration.Operation sequence is as follows：
(1) it should be set after kit takes out from refrigerator equilibrium at room temperature 20 minutes；Every time after detection remaining reagent ask and up to
It is saved in 4 DEG C.
(2) by concentrated cleaning solution distilled water or deionized water dilution (1 part plus 19 parts of water).
(3) standard items:Standard dilutions 0.25ml, which is added, reaches VEGF final concentration into freeze-drying standard items bottle
1000pg/ml is gently suspended after standing 15 minutes to thoroughly solve, with sequentially adding inspection after standard dilutions multiple proportions gradient dilution
In gaging hole (standard curve takes seven points, maximum concentration 1000pg/ml, and standard dilutions are directly added into as 0 concentration).
(4) by lath number needed for disposable experiment is calculated and determined, lath needed for taking out is placed in frame, temporarily
It takes less than lath and puts back to aluminium foil bag sealing, be stored in 4 DEG C.Blank well, sample to be tested hole and standard sample wells is respectively set, label is each
Sample or various concentration standard items (50 hole μ l/) are added in corresponding aperture respectively for hole site, and sample to be tested is added in sample to be tested hole
10 μ l, then plus 40 μ l of Sample dilution (i.e. 5 times of Sample Dilution)；Blank control wells only add TMB developing solution and stop liquid.With envelope
Plate gummed paper seals reacting hole, is incubated at room temperature 120 minutes.
(5) board-washing 5 times, and last time is set and is patted dry on thick blotting paper.
(6) biotinylated antibody working solution (50 hole μ l/) is added.Reacting hole is sealed with sealing plate gummed paper, is incubated at room temperature 60 points
Clock.
(7) board-washing 5 times, and last time is set and is patted dry on thick blotting paper.
(8) enzyme conjugates working solution (50 hole μ l/) is added.Reacting hole is sealed with sealing plate gummed paper, is protected from light 20 points of incubation at room temperature
Clock.
(9) board-washing 5 times, and last time is set and is patted dry on thick blotting paper.
(10) hole color developing agent TMB50 μ l/ is added, is protected from light incubation at room temperature 20 minutes.
(11) 50 hole μ l/ of terminate liquid is added, measures OD450 value after mixing at once.
(12) it calculates：According to the concentration of standard items and corresponding OD value, standard curve is drawn, further according to sample OD value, meter
Corresponding sample concentration is calculated, ultimate density is practical measurement concentration multiplied by diluted multiple.
1.3 statistical method
Obtained data are all made of mean ± standard deviationIt indicates, is analyzed using SPSS13.0 statistical software, group
Between mean compare using variance analysis and t inspection, have significant statistical significance with p < 0.05.
2. result
The general status of 2.1 experimental rats
Normal rats weight gain is obvious, and the state of mind is good, and freely, fur is glossy, is quick on the draw for activity.B,C,
D, the modeling of E group rat 10 days or so, lassitude is gradually appeared, activity is slow, fur yellowing and deficient gloss, slow in reacting, food
It is intended to decline, body weight increase is slow, rolls up, and does not like activity, and phenomena such as hypourocrinia, different degrees of abdomen then occurs in partial rat
It rushes down, loose stools.There is slight foot, abdominal swelling in modeling second week or so, partial rat, and after the 4th week, modeling group rat has
Different degrees of subcutaneous dropsy such as foot, the positions such as scrotum.The 4-6 weeks, B group subcutaneous rat, subcutaneous and edema of scrotum aggravated, and
There is 1 rats death, the 7-8 weeks, C, D, E rat state were improved earlier above, and appetite is restored, and food ration gradually increases,
Subcutaneous dropsy also has obvious recession, and then state is worse for model group, and has 1 rats death again, can after the 8th week execution rat
Seeing model control group rat has different degrees of ascites.Rats death reason considers that its plasma albumin persistently reduces, internal organs
Oedema, resistance decline, causes to infect, final dead.
The variation of 2.2 each group Rat 24 h excretion quantity of urinary protein
There is High-grade Proteinuria in each group rat after modeling, prompts modeling successful, and albuminuria between modeling group (B, C, D, E)
Level is without significant difference；8th Zhou Ge treatment group quantity of proteinuria is substantially reduced (P compared with before treatment in the 4th week<0.01)；8th
Between all model groups and each treatment group two-by-two compared with as can be seen that each treatment group compared with model group urine protein level significantly reduce (P<
0.05), treatment comparison among groups have no notable difference.See Table 1 for details, Fig. 1.
The variation of 1. each group Rat 24 h excretion quantity of urinary protein of table
Note：# indicates the P compared with model group<0.05；* the P compared with the 4th week (before treatment) is indicated<0.01.
The change of 2.3 each group rat biochemical indicators
For table 2 the results show that model group TG, TC more normally organizes equal apparent increase, more normal group of ALB level is decreased obviously (P<
0.05)；After each treatment group treats the 8th week, TG, which is more normally organized, raising, each to treat without significant difference compared with model group
Group is declined through drug therapy TG level；And TC level of each treatment group after treating returns to normal level, and obvious
Lower than model group (P<0.01)；Treatment group's significant raising horizontal compared with the ALB of model group, Hypoproteinemia are improved after the treatment
(P<0.01)；Without significant difference, the indices difference between each treatment group is not statistically significant for Cr, BUN level between 5 groups.
See Table 2 for details.
The change of 2. each group rat biochemical indicator of table
Note：* the P compared with normal group is indicated<0.05；* indicates the P compared with normal group<0.01；# is indicated and model group ratio
Compared with P<0.01.
The variation of 2.4 each group rat VEGF levels
Table 3 is the results show that model group, hematoxylin group, tacrolimus group, rat peripheral blood VEGF is horizontal in prednisone group
Higher than Normal group, P<0.01, there are notable differences；Treatment group's rat peripheral blood VEGF level more has compared with model group
A degree of reduction, there are statistical difference, P<0.05, illustrate that drug has certain reduction to act on VEGF level；Respectively control
It compares between treatment group, statistical difference is not present.See Table 3 for details, Fig. 2.
The variation of 3 each group rat VEGF level of table
Note：* indicates the P compared with normal group<0.01, * indicates the P compared with normal group<0.05；# is indicated and model group ratio
Compared with P<0.05.
The change of 2.5 each group rat kidney tissues
(1) change under light microscopic：
In the renal tissue of the Normal group of light microscopic observation HE dyeing and PAS dyeing, it is seen that nephridial tissue structure is normal,
Cortex renis, medullary substance are clear in structure, and glomerulus has no hardening, enlargement, and capillary clump has no hyperplasia, and petty action astillen, which has no, to be thickened,
Lumen has no narrow, and renal tubule has no expansion, atrophy, and renal interstitial has no obvious lymphocytic infiltration, has no fibrosis lesion.In detail
See Fig. 3-4.
The obvious enlargement of model group glomerulus, mesangial cell and matrix diffusivity hyperplasia, it is seen that follow closely prominent spline structure, base
Counterdie diffusivity thickens, it is seen that renal cells vacuole and granular degeneration, renal interstitial massive inflammatory cells infiltrated, parteriole
Tube wall thickening, luminal stenosis.It is detailed in Fig. 5-6,10.
Treatment group's glomerulus swelling is unobvious, and mesangial cell and the slight hyperplasia of matrix have different degrees of inflammation
Property cell is accordingly reduced, and wherein hematoxylin group and tacrolimus group, basement membrane thickened are unobvious, renal interstitial special mess shape inflammatory cell
Infiltration.It is detailed in Fig. 7-9.
(2) change under Electronic Speculum：
Under Electronic Speculum in the degree of main detection glomerular basement membrane thickening and visceral layer epithelial cell, upper subcutaneous, basilar memebrane
And the deposition of the electron dense object of mesangial region.
Basilar memebrane, which has no, under Normal group Electronic Speculum thickens, and each area has no obvious electron dense object deposition, has no that podocytic process is thin
Born of the same parents' fusion.It is detailed in Figure 11.
Visible basilar memebrane irregular thickening under model group Electronic Speculum, visible volume electron dense object deposition, visceral layer in basilar memebrane
Epithelial cell podocytic process diffuses fusion, upper subcutaneous visible volume electron dense object deposition.It is detailed in Figure 12.
Show similar under hematoxylin group and tacrolimus group Electronic Speculum, basilar memebrane is without obviously thickening, the fusion of podocytic process segmental, on
Subcutaneous and mesangial region has no definite electron dense object deposition.It is detailed in Figure 13,14.
Hormone group then shows as basilar memebrane without obviously thickening under Electronic Speculum, and podocytic process merges extensively, and upper subcutaneous and mesangial region can
See a small amount of electron dense object deposition.It is detailed in Figure 15.
3, conclusion
1) hematoxylin improves disorders of lipid metabolism by the Urine proteins of reduction C-BSA Membranous Nephritis Rats model, improves blood
Starch albumin level.
2) hematoxylin plays the role of improving the damage of C-BSA Membranous Nephritis Rats model renal tissues pathology morphology.
3) by the detection to VEGF, it is found that C-BSA Membranous Nephritis Rats rat model Serum VEGF increases, through reviving
VEGF level after another name for treatment in rat blood serum is declined, and prompts hematoxylin that can adjust kidney by inhibiting VEGF secretion
Bead filters membrane permeability, reduces the excretion rate of Urine proteins, protects renal function.
4) this experimental study is that hematoxylin will be applied to Clinical Nephropathy syndrome as a kind of new medicine immunosupress
Treatment, provide part Experiment foundation.
Claims (5)
1. purposes of the hematoxylin in preparation treatment immunity glomerulonephritis drug, the hematoxylic molecular formula：
C16H14O6, molecular weight：302.28 molecular structural formula is:
2. purposes as described in claim 1, which is characterized in that the immunity glomerulonephritis is membranous nephropathy.
3. purposes as claimed in claim 2, which is characterized in that hematoxylin has the Urine proteins for reducing membranous nephropathy patient, changes
Kind disorders of lipid metabolism, improves the effect of plasma albumin level.
4. purposes as claimed in claim 2, which is characterized in that hematoxylin has improvement membranous nephropathy kidneys of patients histopathology
The effect of morphology damage.
5. purposes as claimed in claim 2, which is characterized in that hematoxylin has the VEGF reduced in membranous nephropathy patients serum
Horizontal effect adjusts glomerular filtration membrane permeability, reduces the excretion rate of Urine proteins, protect kidney by inhibiting VEGF secretion
Dirty function.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2009242247A (en) * | 2008-03-28 | 2009-10-22 | Institute Of Physical & Chemical Research | Human immunodeficiency virus infection inhibitor and aids-treating or preventing drug |
| CN105748461A (en) * | 2016-04-13 | 2016-07-13 | 天津大学 | Application of haematoxylin to inhibition of amyloid beta-protein aggregation and related toxicity |
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| JP2009242247A (en) * | 2008-03-28 | 2009-10-22 | Institute Of Physical & Chemical Research | Human immunodeficiency virus infection inhibitor and aids-treating or preventing drug |
| CN105748461A (en) * | 2016-04-13 | 2016-07-13 | 天津大学 | Application of haematoxylin to inhibition of amyloid beta-protein aggregation and related toxicity |
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| Title |
|---|
| KYE-YOON YOON等: "Brazilin Suppresses Inflammation via the Down-regulation of IRAK4 in LPS-stimulated Raw264.7 Macrophage", 《JOURNAL OF FOOD AND NUTRITION RESEARCH》 * |
| 胡克杰 等: "苏木治疗大鼠膜性肾病的实验研究", 《中医药信息》 * |
| 陈钊 等: "小分子IRAK-4 抑制剂的研究进展", 《中南药学》 * |
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