CN109260214A - Application of the paeoniflorin compound in preparation treatment medication for treating pyemia - Google Patents
Application of the paeoniflorin compound in preparation treatment medication for treating pyemia Download PDFInfo
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Abstract
The invention belongs to field of medicaments, are related to paeoniflorin compound and inhibit pyemic occurrence and development to treat pyemic new application；Pass through the expression of reduction late phase inflammation factor high mobility group protein B 1 (HMGB1) more particularly to Paeoniflorin, albiflorin and oxypaeoniflorin, reduce the release of tissue factor (TF), the expression for reducing regulatory T cells (Treg) Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and forked head transcription factor P3 (Foxp3), to treat pyemia.
Description
Technical field:
The invention belongs to field of medicaments, are related to the new therapeutic uses of paeoniflorin compound.
Technical background:
Pyemia is the caused mortality organ dysfunction of host response imbalance for infection, and the state of an illness is dangerous, lethal
Rate height is the main reason for patient with severe symptoms is dead.For many years, antibiotic, antiviral drugs, blood vessel boosting drug etc. are used to
Pyemia traditional treatment, but there has been no enough specific drugs for pathogenesis of sepsis mechanism to put into clinical practice.How
Systemic inflammatory reaction, coagulation disorders and immunologic function disorder during timely correction pyemia occurrence and development, as early as possible
Restore proinflammatory-anti-inflammatory dynamic equilibrium of body, is effectively improved patient's prognosis, becomes urgently to be resolved in treatment of sepsis medicament research and development
Important topic.
'Xuebijing ' injection is the dialectical principle according to " three three methods of card ", under the theoretical direction of " bacterium is scorching and controls ", with
Based on Qing Dynasty's Wang Qingren errors in Medicine Corrected contained " xuefu zhuyu decoction ", a kind of intravenous fluid developed, by safflower, red
The modern crafts such as Chinese herbaceous peony, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Radix Angelicae Sinensis gomi herbs are extracted, refine, is dry, deploying are prepared, and are suitable for septicopyemia
Disease/because of the systemic inflammatory response syndrome of infection-induced；Can also partner treatment multiple organ disorder syndrome organ function
The impaired phase.Related patents have: 1. Chinese patent 03104977.X disclose " a kind of to treat pyemic Chinese materia medica preparation and its preparation
Method ", the i.e. preparation process of 'Xuebijing ' injection, pharmacodynamics prove that it has the function of anti-endotoxin, can be used for treating purulence
Toxication.2. Chinese patent 201611232221.7 discloses " a kind of multicomponent injection ", ingredient is derived from safflower, radix paeoniae rubra, river
Rhizome of chuanxiong, Radix Salviae Miltiorrhizae, Radix Angelicae Sinensis gomi herbs, research confirm that it has treatment to pyemia cell model and septicopyemia disease mouse model and makees
With.
Paeoniflorin (Paeoniflorin, PF), albiflorin (Albiflorin, AL) and oxypaeoniflorin
It (Oxypaeoniflora) is the principle active component of conventional Chinese medicine radix paeoniae rubra and Radix Paeoniae Alba, Paeoniflorin is a kind of monoterpenes glucosides chemical combination
Object, pharmacological action multiplicity have free radical resisting damage, inhibit intracellular calcium overload and anti-neurotoxicity isoreactivity, experiment in vivo
Proving that it has reduces blood viscosity, expansion blood vessel, improves the various biologicals effect such as microcirculation, anti-oxidant, anticonvulsion, and poison
Side effect is smaller.Albiflorin is similar to Paeoniflorin chemical structure, is the isomer of Paeoniflorin, content is compared with Paeoniflorin
Low, albiflorin may act on spleen in immune system, hematopoietic cytokine in thymus gland and hematological system, have specific mend
Blood effect, while may also act to hpa axis and intracerebral monoamine nerve in nervous system and passing, there is apparent antidepressant effect.
Oxypaeoniflorin content is relatively small, and pharmacological research rarely has report.Total glucosides of paeony have analgesic, it is anti-infective, anti-oxidant and
, there is high application value in the effects of anticancer, therefore is worth promoting in clinic.Meanwhile Paeoniflorin, albiflorin and oxygen
Changing Paeoniflorin is the main component in 'Xuebijing ' injection, thus, further investigating its effect in treatment of sepsis has
Important realistic meaning and application value.
The word table of comparisons:
| Chinese name | English name | English abbreviation |
| Paeoniflorin | Paeoniflorin | PF |
| Albiflorin | Albiflorin | AL |
| Endotoxin | Lipopolysaccharide | LPS |
| High mobility group protein B 1 | High Mobility Group Protein B1 | HMGB1 |
| Enzyme linked immunosorbent assay | Enzyme-Linked Immunosorbent Assay | ELISA |
| Tissue factor | Tissue Factor | TF |
| Regulatory T cells | Regulatory T Cell | Treg |
| Cytotoxic T lymphocyte associated antigen-4 | Cytotoxic T Lymphocyte Associated Antigen-4 | CTLA-4 |
| Forked head transcription factor P3 | Forkhead Box P3 | FoxP3 |
| Phycoerythrin | P-phycoerythrin | PE |
| Fluorescein isothiocynate | Fluorescein Isothiocyanate | FITC |
| Allophycocyanin | Allophycocyanin | APC |
| Cecal ligation and perforation art | CecalLigation and Puncture | CLP |
Summary of the invention:
The purpose of the present invention is to provide paeoniflorin compounds to treat the application in pyemic drug in preparation.
Application of the present invention, comprising:
Paeoniflorin compound inhibits the application in pyemia in the drug of HMGB1 expression in preparation.
Paeoniflorin compound inhibits the application in pyemia in the drug of TF release in preparation.
Paeoniflorin compound inhibits the application in pyemia in the drug of CTLA-4 and Foxp3 expression in preparation.
Paeoniflorin compound of the present invention is Paeoniflorin, albiflorin and oxypaeoniflorin.
The chemical structure of paeoniflorin compound of the present invention is as follows:
Compound 1: Paeoniflorin
Molecular formula: C23H28O11 structural formula:
Molecular weight: 480.46
Compound 2: albiflorin
Molecular formula: C23H28O11 structural formula:
Molecular weight: 480.46
Compound 3: oxypaeoniflorin
Molecular formula: C23H28O12 structural formula:
Molecular weight: 496.46
Paeoniflorin compound of the present invention further include its pharmaceutically acceptable salt, solvate, polycrystalline figure,
Enantiomer or raceme mixture.
It is another object of the present invention to provide a kind of using paeoniflorin compound as the pharmaceutical composition of active constituent
The application in pyemic drug is treated in preparation.
In application of the present invention, Paeoniflorin, albiflorin and oxypaeoniflorin can be respectively as pharmaceutical compositions
The sole active agent of object, can also be collectively as the active constituent of pharmaceutical composition；Can also individually or collectively with other medicines
Object is combined as active constituent.
Weight percent shared by paeoniflorin compound of the present invention can be 0.1-99.9%, remaining can for drug
The carrier of receiving.
Pharmaceutical composition of the invention can be prepared into any pharmaceutical dosage form, these dosage forms include: tablet, sugar coated tablet
Agent, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral solution, mouth containing agent, granule, electuary,
Pill, powder, paste, sublimed preparation, suspension, pulvis, solution, injection, suppository, ointment, emplastrum, creme, spray,
Drops, patch.Preparation of the invention, preferably tablet, powder, granule, tincture, pill, capsule, oral solution, atomization
Inhalant, injection.
Pharmaceutical composition of the invention, the preparation of oral administration can contain common excipient, such as adhesive, filling
Agent, diluent, tablet agent, lubricant, disintegrating agent, colorant, flavoring agent and wetting agent when necessary can be coated tablet.
Applicable filler includes cellulose, mannitol, lactose and other similar fillers.Suitable disintegrating agent packet
Include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycollate.Suitable lubricant includes, such as firmly
Fatty acid magnesium.Suitable pharmaceutically acceptable wetting agent includes lauryl sodium sulfate.
Can be by mixing, filling, commonly method prepares solid oral composition for tabletting etc..Carrying out mixing repeatedly can make to live
Property substance be distributed in entirely using in those of a large amount of fillers composition.
The form of oral liquid for example can be aqueous or oily suspensions, solution, emulsion, syrup or elixir,
Or it can be a kind of dry products that can be compounded with water or other suitable carriers before use.This liquid preparation can contain
Conventional additive, such as suspending agent, such as sorbierite, syrup, methylcellulose, gelatin, hydroxyethyl cellulose, carboxymethyl are fine
Dimension element, aluminium stearate gel or hydrogenated edible fats, emulsifier, such as lecithin, anhydro sorbitol monooleate or Arab
Glue；Non-aqueous carrier (they may include edible oil), for example, apricot kernel oil, fractionated coconut oil, such as glycerol ester oily ester,
Propylene glycol or ethyl alcohol；Preservative, such as para hydroxybenzene methyl esters or propylparaben or sorbic acid, and if desired,
Contain conventional flavouring agent or colorant.
For injection, the fluid unit dosage form of preparation contains active material and sterile carrier of the invention.According to carrier
And concentration, this compound can be suspended or be dissolved.The preparation of solution is usually by the way that active material is dissolved in a kind of load
In body, disinfection is filtered before being loaded into a kind of suitable bottle or ampoule, is then sealed.For example a kind of local anaesthesia of auxiliary material
Agent, preservative and buffer are also soluble in this carrier.It, can be after being packed into bottle by this in order to improve its stability
Kind composition frost, and under vacuum remove water.
Suitable pharmaceutically acceptable carrier is optionally added Chinese materia medica preparation of the invention when being prepared into medicament,
The pharmaceutically acceptable carrier is selected from: mannitol, sorbierite, sodium pyrosulfite, sodium hydrogensulfite, sodium thiosulfate, hydrochloric acid
Cysteine, thioacetic acid, methionine, injection Vitamin B_6 DTA disodium, Ethylenediaminetetraacetic Acid Calcium Salt, the carbonate of monovalence alkali metal, acetate,
Phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, malt
Sugar, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose and its spread out
Biology, alginates, gelatin, polyvinylpyrrolidone, glycerol, POLYSORBATE 80, agar, calcium carbonate, calcium bicarbonate, surfactant,
Polyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid material, kaolin, talcum powder, calcium stearate, magnesium stearate etc..
Pharmaceutical preparation of the present invention, preferably injection.
Paeoniflorin compound provided by the invention is for when treating pyemia, administration route to be intravenous injection or vein
Dropleting medicine-feeding, it is 20mg to 2000mg that dosage range, which is used alone, in Paeoniflorin, and it is 5mg that dosage range, which is used alone, in albiflorin
To 2000mg, it is 5mg to 2000mg that dosage range, which is used alone, in oxypaeoniflorin.
Specific embodiment
By following specific embodiments, the present invention is further illustrated, but not as limitation of the invention.
Experiment is all made of paeoniflorin compound respectively on different pyemia cell models and animal model below
Pharmacodynamic study.
Acute toxicity test is administered in 1 paeoniflorin compound mouse vein of embodiment
1. experimental material
Cleaning grade SD rat (half male and half female), 180-220g, Paeoniflorin, albiflorin, oxypaeoniflorin, physiological saline
(0.9% sodium chloride injection).
2. experimental method
80 animals (half male and half female) are screened according to laundering period the weight of animals growth, diet, activity etc. and enter this test, are adopted
It is divided into 4 groups with the weight district's groups method of dividision into groups, every group 20, half male and half female.Experiment uses maximum dosage-feeding method, in Paeoniflorin, Chinese herbaceous peony
Ester glycosides and oxypaeoniflorin maximum concentration are 50mg/mL, and rat intravenous injection limitation is 6mL/kg, to sum up maximum dosage
For 300mg/kg.Experimental group single-dose, 6mL/kg Paeoniflorin, albiflorin and oxypaeoniflorin medical fluid (50mg/mL) are quiet
Arteries and veins is slowly injected；Control group gives the normal saline solution of same dose.
It is at least observed continuously after administration 2 hours, the 1st day morning and afternoon respectively observed and recorded 1 time after administration, later daily observation note
Record 1 time is observed 14 days altogether.In observation period, the death condition of animal toxicity response situation and groups of animals is observed and recorded, to death
Or the timely dissect of moribund animals.14 days after administration, all surviving animals carry out dissect, and visually observing each main organs, whether there is or not obvious
Anomalous variation；When the change such as volume, color, quality occur in internal organs, it should all record and carry out histopathologic examination.
Drug solution preparation method is as follows: weighing 5.0g Paeoniflorin, albiflorin, oxygen respectively in precision balance (1/10000g)
Change Paeoniflorin to be dissolved in appropriate physiological saline (0.9% sodium-chloride water solution), be settled to 100mL filter filtration sterilization,
Concentration is 50mg/mL at this time.
3. experimental result
The slow intravenous injection 300mg/kg Paeoniflorin of rat single, as the result is shown: (1) no abnormality seen disease after animal administration
Shape；(2) there was no significant difference with control group for administration group the weight of animals and body weight growth rate；(3) substantially dissect is shown no obvious abnormalities.
The slow intravenous injection 300mg/kg albiflorin of rat single, as the result is shown: (1) no abnormality seen after animal administration
Symptom；(2) there was no significant difference with control group for administration group the weight of animals and body weight growth rate；(3) substantially dissect has no obvious different
Often.
The slow intravenous injection 300mg/kg oxypaeoniflorin of rat single, as the result is shown: (1) no abnormality seen after animal administration
Symptom；(2) there was no significant difference with control group for administration group the weight of animals and body weight growth rate；(3) substantially dissect has no obvious different
Often.
Embodiment 2, which evaluates paeoniflorin compound, stimulates LPS the influence of lower rat peritoneal macrophages HMGB1 release
1. experimental material
Male cleaning grade SD rat, 180-220g, endotoxin (LPS), Paeoniflorin, albiflorin, oxypaeoniflorin
RPMI-1640 culture medium, 24 orifice plates, HMGB1ELISA kit.
2. experimental method
Separating male SD rat peritoneal macrophage, (male SD rat pre-operative anxiety 12h, opens abdominal cavity after anesthesia, to abdomen
Chamber injection pre-cooling PBS liquid 10mL makes liquid in intraperitoneal flowing with the light kneadding stomach wall of finger.Draw the liquid injection in abdominal cavity
In sterile tube, then it is primary with pre-cooling PBS liquid 10mL lavation, operation is same as above.The irrigating solution 250g being collected into, 4 DEG C of centrifugations will be merged
10min abandons supernatant.2mL erythrocyte cracked liquid lysed erythrocyte is added, twice, each 5s is added after standing 5min for slight concussion
4mL D-Hanks solution terminates reaction.It is centrifuged again according to the method described above, abandons supernatant.Precipitating is washed with culture solution, is then resuspended
Cell) it is made 2 × 106/ mL cell suspension, is inoculated in 24 orifice plates, is placed in 37 DEG C, 5%CO2Cell incubator culture.Experiment point
For control group, model group, Paeoniflorin group 1 (4 μM), Paeoniflorin group 2 (40 μM), Paeoniflorin group 3 (400 μM), albiflorin group 1
(1 μM), albiflorin group 2 (20 μM), albiflorin group 3 (400 μM), oxypaeoniflorin group 1 (1 μM), oxypaeoniflorin
2 (20 μM) of group and oxypaeoniflorin group 3 (400 μM), every group of 6 parallel holes.Supernatant is collected after cultivating 48h and 72h respectively, is used
One step sandwich method enzyme-linked immunosorbent assay (ELISA) of double antibody measures cytokine content.
Packet processing method is as follows: model group: LPS (75ng/mL) thorn is added after cell incubator overnight incubation in cell
Swash.Experimental group: being added corresponding concentration medical fluid and be incubated for 1h, carries out LPS stimulation, after various concentration experimental group intervenes 48,72h, collects
Cell culture supernatant 0.5mL, -20 DEG C of refrigerators save, concentrate and carry out corresponding cytokines measurement.
Drug solution preparing mode is as follows: precision balance (1/10000g) weigh respectively 2.5mg Paeoniflorin, albiflorin,
Oxypaeoniflorin is dissolved in the culture medium (containing 10%FBS) of 1.97mL, and with filter filtration sterilization, packing is saved.It is at this time 2500 μ
The storing liquid of M.In use, being diluted to required concentration according to each experimental group liquor strength needs with culture medium.
3. experimental result
The results showed that compared with model group, Paeoniflorin, albiflorin and the oxypaeoniflorin of each dosage group
The emission levels for significantly reducing 48,72h rat peritoneal macrophages HMGB1, show Paeoniflorin (4-400 μM), albiflorin
(1-400 μM) and oxypaeoniflorin (1-400 μM) have pyemia cell model presses down scorching effect well.
1. Paeoniflorin of table, albiflorin and oxypaeoniflorin stimulate lower rat peritoneal macrophages HMGB1 expression to LPS
Influence (N=6, unit: pg/mL)
Note:#, indicate compared with the control group, P < 0.05；*, indicate P < 0.05 compared with test group
Embodiment 3, which evaluates paeoniflorin compound, stimulates LPS the influence of lower rat aorta endothelial cell TF release
1. experimental material
Male cleaning grade SD rat, 180-220g, LPS, Paeoniflorin, albiflorin, oxypaeoniflorin, ECM culture medium,
24 orifice plates, tissue factor (TF) ELISA kit.
2. experimental method
After putting to death rat with cervical dislocation, it is soaked in 5min in the ethyl alcohol that volume fraction is 75%, successively opens chest, abdomen
Chamber sufficiently exposes chest, abdominal aorta, separates its surrounding tissue, from proximal part separation aorta to arteria iliaca communis bifurcation, is put into
In culture dish containing PBS, the adipose tissue and fibr tissue of sterile removing externa, PBS rinse lumen of vessels.By aorta
It is cut into about 1.5mm × 1.5mm fritter, is placed in the IV Collagenase Type of 6mL 0.25%, 37 DEG C of digestion 15min, every 5min concussion
Once, it carefully siphons away digestive juice, retains tissue block, add the neutral proteinase of 6mL 1.0%, 37 DEG C of digestion 15min, often
5min concussion is primary, siphons away digestive juice, supplements ECM 10mL, blows and beats repeatedly, and 1,000r/min centrifugation 10min discards culture medium
And digestive juice, retain fragment, tissue block is laid in the culture dish bottom of 10cm, put upside down the 2h in 37 DEG C of baking ovens, makes tissue block
It cements, appropriate ECM is added, submerging tissue block is advisable, and puts 37 DEG C, the CO that volume fraction is 5%2Training in saturated humidity incubator
It supports, 3 days one subcultures of replacement.Visible endothelial cell is climbed out of by tissue block edge and is gradually extended outwardly within 7 days or so, in flat
Short shuttle shape or polygonal remove tissue block, at this time with 0.25% trypsin digestion, in the ratio of 1:3 in 25cm2Culture bottle
Middle passage is tested with 3-4 for cell.
According to the cultural method culture cell of rat aorta endothelial cell among the above, cell suspension is prepared, with 1.2 ×
105/ mL inoculating cell, by cell suspension inoculation in 24 orifice plates, 37 DEG C are cultivated, model group and (4 μ of Paeoniflorin group 1 after about 12h
M), Paeoniflorin group 2 (40 μM), Paeoniflorin group 3 (400 μM), albiflorin group 1 (1 μM), albiflorin group 2 (20 μM), Chinese herbaceous peony
Medicine lactone glycoside group 3 (400 μM), oxypaeoniflorin group 1 (1 μM), oxypaeoniflorin group 2 (20 μM) and (400 μ of oxypaeoniflorin group 3
M), give LPS stimulation, experimental group is given different medical fluids respectively and is intervened after 1h, after stimulation for 24 hours, 48h, 72h collect
Supernatant.
Packet processing method and drug solution preparing mode are the same as embodiment 2.
3. experimental result
TF is the important procoagulant Factor of rat aorta endothelial cell, and under pyemia state, hypercoagulative state is shown as
A large amount of releases of TF.Under pharmaceutical intervention the reduction of TF facilitate coagulation factor it is anticoagulant/promote solidifying balance, may advantageously facilitate cell/
Body coagulation function restores toward normal condition.
The results showed that compared with model group, Paeoniflorin, albiflorin and the oxypaeoniflorin of each concentration group
It reduces for 24 hours, the release of 48h and 72h rat aorta endothelial cell procoagulant Factor TF shows Paeoniflorin (4-400 μM), Chinese herbaceous peony
Lactone glycoside (1-400 μM) and oxypaeoniflorin (1-400 μM) have good anticoagulant effect to sepsis model.
2. Paeoniflorin of table, albiflorin and oxypaeoniflorin stimulate lower rat aorta endothelial cell TF to release LPS
Put influence (N=6, unit: pg/mL)
Note:#, indicate compared with the control group, P < 0.05；*, indicate P < 0.05 compared with test group
Embodiment 4, which evaluates paeoniflorin compound, stimulates LPS the shadow of lower Rats Spleen regulatory T cells (Treg) function
It rings
1. experimental material
Male cleaning grade SD rat, 180-220g, LPS, Paeoniflorin, albiflorin, oxypaeoniflorin, ECM culture medium,
24 orifice plates, phycoerythrin (PE)-anti-rat CD25, fluorescein isothiocynate (FITC) mark anti-rat CD4, allophycocyanin
(APC) annexin V apoptosis kit is marked；The anti-PE kit of rat, CD4 magnetic bead, MiniMACS Magnetic Isolation instrument and point
Select column；PE flag F oxp3 kit, PE labeling CT LA-4 kit, anti-rat CD3 monoclonal antibody, anti-rat CD28 Dan Ke
Grand antibody.
2. experimental method
The disconnected neck of male SD rat is put to death, and spleen is taken, and asepsis injector piston grinds spleen, and suction pipe draws suspension to centrifugation
Pipe is centrifuged, abandons supernatant for 1200 turns × 7 minutes, and appropriate MACS Buffer (each spleen of 10mL/) resuspension is added, is added along tube wall
It is centrifuged within 3000 turns × 15 minutes to the upper layer (1:1) of lymphocyte separation medium, draws middle layer liquid with suction pipe, be packed into another centrifuge tube
In, it is added cleaning solution 1200 turns × 7 minutes and is centrifuged, abandon supernatant, it is spare that MACS Buffer resuspension is added.
Every 1 × 107The anti-CD25-APC antibody of 1 μ L, 4 DEG C of incubation 15min, MACS Buffer washings are added in monocyte.Often
1×107The anti-APC magnetic bead of 20 μ L and 80 μ L MACS Buffer is added in cell, and 4 DEG C of incubation 15min, MACS Buffer washings add
Appropriate MACS Buffer is resuspended, and LS column magnetic sorting is to get CD25+Cell.
CD25+After cell count, every 1 × 107Cell is added 20 μ L and dissociates agent, and 4 DEG C of incubation 1min, MACS Buffer are washed
It washs, every 1 × 107The anti-CD4 magnetic bead of 20 μ L and 30 μ L terminators are added in cell, and 4 DEG C of incubation 15min, MACS Buffer washings add
Enter appropriate MACS Buffer to be resuspended, LS column magnetic sorting is to get CD4+CD25+Cell.
The appropriate culture solution of Treg cell is resuspended, adjustment cell number is 2.5 × 106/ mL, 96 orifice plates, every hole access are thin
CD3/CD28 is added in 100 μ L of born of the same parents, model group and experimental group, and (CD3 is 0.5 μ g/106, CD28 is 1 μ g/106)+LPS (1 μ g/mL) thorn
Swash, experiment is divided into control group, model group, Paeoniflorin group 1 (4 μM), Paeoniflorin group 2 (40 μM), Paeoniflorin group 3 (400 μM), Chinese herbaceous peony
Lactone glycoside group 1 (1 μM), albiflorin group 2 (20 μM), albiflorin group 3 (400 μM), oxypaeoniflorin group 1 (1 μM), oxygen
Changing Paeoniflorin group 2 (20 μM) and oxypaeoniflorin group 3 (400 μM), experimental group is given different medical fluids respectively and is intervened after 1h,
CO237 DEG C of culture 72h of incubator.
After cell conditioned medium is collected, cell is cleaned with PBS, removes supernatant, CTLA-4-PE fluorescence antibody is added, 4 DEG C are protected from light incubation
30min is added rupture of membranes agent and stays overnight.Second day, rupture of membranes buffer solution for cleaning is added, removes supernatant, it is anti-that Foxp3-PE-Cy7 fluorescence is added
Body, room temperature, which is protected from light, is incubated for 30min, and rupture of membranes buffer solution for cleaning is added, removes supernatant, and 1% paraformaldehyde is fixed, flow cytometer inspection
It surveys.
Packet processing method and drug solution preparing mode are the same as embodiment 2.
3. experimental result
Foxp3+Treg cell inhibits general T cell by generating immunosuppressive factor such as IL-10, IL-35, TGF-β etc.,
And target cell is killed by granzyme B and perforin -1, to play immunosuppressive action.CTLA-4 also can induce DC dendron shape
Cell generates indoleamine 2,3-dioxygenase, and catalysis tryptophan, which is decomposed into cynruin, causes peripheral cell dead, moreover it is possible to induce DC
Cell secretes other amino acid relevant enzymes, thus the proliferation of depression effect T cell, to play immunosuppressive effect.Therefore,
Treg cell is played a very important role in terms of immunity of organism regulation by Foxp3 and CTLA-4, the expression of Foxp3 and tune
Section property T cell (Treg) function is closely related.
Compared with model group, Paeoniflorin, albiflorin and the oxypaeoniflorin of each dosage group can reduce rat spleen
The expression of dirty regulatory T cells (Treg) 72hCTLA-4 and Foxp3, shows Paeoniflorin (4-400 μM), albiflorin
(1-400 μM) and oxypaeoniflorin (1-400 μM) can lower the depression effect to T lymphocyte proliferation and secreting function.
3. Paeoniflorin of table, albiflorin and oxypaeoniflorin stimulate lower Rats Spleen regulatory T cells CTLA-4 to LPS
Expression influence (N=6, unit: %)
Note:#, indicate compared with the control group, P < 0.05；*, indicate P < 0.05 compared with test group
4. Paeoniflorin of table, albiflorin and oxypaeoniflorin stimulate lower Rats Spleen regulatory T cells Foxp3 to LPS
Expression influence (N=6, unit: %)
Note:#, indicate compared with the control group, P < 0.05；*, indicate P < 0.05 compared with test group
Embodiment 5 evaluates influence of the paeoniflorin compound to the CLP rats with sepsis HMGB1 expression induced
1. experimental material
SD male rat, cleaning grade, weight 180-220g, adaptive feeding 1 week.Paeoniflorin, albiflorin aoxidize Chinese herbaceous peony
Medicine glycosides, HMGB1ELISA detection kit.
2. experimental method
2.1 groupings and intervention
110 rats are randomly divided into control group, model group, Paeoniflorin group 1 (1.8mg/kg), 2 (18.0mg/ of Paeoniflorin group
Kg), Paeoniflorin group 3 (180.0mg/kg), albiflorin group 1 (0.45mg/kg), albiflorin group 2 (9.0mg/kg), Chinese herbaceous peony
Medicine lactone glycoside group 3 (180.0mg/kg), oxypaeoniflorin group 1 (0.45mg/kg), oxypaeoniflorin group 2 (9.0mg/kg) and oxygen
Change Paeoniflorin group 3 (180.0mg/kg), every group each 10.12h fasting before testing, weighs and is divided according to random digits table
Group.Control group only opens skin suture after abdomen exposure caecum, subcutaneous injection 10mL physiological saline recovery；Sepsis model group carries out blind
Intestines ligation and perforation art (CLP) modeling；Experimental group is after CLP modeling, subcutaneous injection 10mL physiological saline recovery.CLP modeling process
It is as follows: to use ketamine injection+Su Mian Xin II injection 2:1 mixed liquor intramuscular anesthesia rat, pyemia is prepared using CLP
Animal model.Cecal ligation and ileum junction penetrate through 2 formation intestinal fistula of caecum, and 2 drainage strips of indwelling with No. 18 syringe needles
(0.5cm × 2.0cm) prevents pin hole from healing, rear layer-by-layer suture skin, and art finishes subcutaneous injection 10mL physiological saline recovery immediately.Greatly
After mouse row CLP operation, experimental group 2h, 12h after surgery, for 24 hours, 36h, 48h and 60h inject injection respectively containing upper through vena dorsalis penis
State different medical fluids；Model group and control group are in the corresponding time through vena dorsalis penis injecting normal saline.
Drug solution preparing mode and experiment injection volume it is as follows: precision balance (1/10000g) weigh respectively 4.5g Paeoniflorin,
Albiflorin and oxypaeoniflorin are dissolved in appropriate physiological saline (0.9% sodium-chloride water solution), are settled to 100mL use
Filter filtration sterilization, concentration is 45mg/mL at this time, is used as high dose group injection and uses, and experiment injection volume is 0.8mL/ times.Root
It is needed according to each experimental group liquor strength, required concentration is diluted to physiological saline constant gradient, experiment injection volume is 0.8mL/ times.
2.2 blood samplings and detection
8h after CLP, for 24 hours, 48h and 72h, abdominal aorta sterile blood sampling 3mL after groups of animals is anaesthetized, using ELISA method,
Detect blood plasma HMGB1 content.
3. experimental result
The results showed that containing a small amount of HMGB1 in control group blood plasma；CLP early postoperative period, model group HMGB1 content
It obviously increases, 8h HMGB1 level further increases, and is gradually reduced in for 24 hours, but postoperative 72h is still higher than control group, difference is equal
Statistically significant (p < 0.05).And the postoperative 8h of experimental group, for 24 hours, the HMGB1 plasma content of 48h and 72h are significantly lower than model
Group (p < 0.05), close to control group level.Above-mentioned discovery shows compared with model group, Paeoniflorin, the peony lactone of each dosage group
Glycosides and oxypaeoniflorin can significantly reduce the expression of CLP rats with sepsis HMGB1, prompt Paeoniflorin (1.8-180.0mg/
Kg), albiflorin (0.45-180.0mg/kg) and oxypaeoniflorin (0.45-180.0mg/kg) are to rats with sepsis model
The scorching effect of apparent suppression is all had, is converted to human dose about are as follows: Paeoniflorin 20mg to 2000mg, albiflorin 5mg are extremely
2000mg, oxypaeoniflorin 5mg to 2000mg.It [is pressed between humans and animals in " pharmacological experimental methodology " edited according to Xu Shuyun
Body surface area Commutation Law calculates, human dose=rat dosage/0.018 (in terms of adult weight 70kg, rat body weight 0.2kg)]
The influence of 5. Paeoniflorin of table, albiflorin and oxypaeoniflorin to the CLP rats with sepsis HMGB1 expression induced
(N=10, unit: pg/mL)
Note:#, indicate compared with the control group, P < 0.05；*, indicate P < 0.05 compared with test group
Embodiment 6 evaluates influence of the paeoniflorin compound to the CLP rats with sepsis TF release induced
1. experimental material
SD male rat, cleaning grade, weight 180-220g, adaptive feeding 1 week.Paeoniflorin, albiflorin aoxidize Chinese herbaceous peony
Medicine glycosides, TFELISA kit.
2. experimental method
2.1 groupings and intervention
110 rats are randomly divided into control group, model group, Paeoniflorin group 1 (1.8mg/kg), 2 (18.0mg/ of Paeoniflorin group
Kg), Paeoniflorin group 3 (180.0mg/kg), albiflorin group 1 (0.45mg/kg), albiflorin group 2 (9.0mg/kg), Chinese herbaceous peony
Medicine lactone glycoside group 3 (180.0mg/kg), oxypaeoniflorin group 1 (0.45mg/kg), oxypaeoniflorin group 2 (9.0mg/kg) and oxygen
Change Paeoniflorin group 3 (180.0mg/kg), every group each 10.12h fasting before testing, weighs and is divided according to random digits table
Group.Control group only opens skin suture after abdomen exposure caecum, subcutaneous injection 10mL physiological saline recovery；Sepsis model group carries out blind
Intestines ligation and perforation art (CLP) modeling, subcutaneous injection 10mL physiological saline recovery.CLP modeling process is as follows: using ketamine injection
+ Su Mian Xin II injection 2:1 mixed liquor intramuscular anesthesia rat prepares pyemia animal model using CLP.Cecal ligation with
Ileum junction penetrates through 2 formation intestinal fistula of caecum with No. 18 syringe needles, and 2 drainage strips (0.5cm × 2.0cm) of indwelling prevent needle
Hole healing, rear layer-by-layer suture skin, art finish subcutaneous injection 10mL physiological saline recovery immediately.After rats underwent CLP operation, experimental group
2h, 12h after surgery, for 24 hours, 36h, 48h and 60h are injected through vena dorsalis penis and are injected above-mentioned different medical fluids respectively；Model group and right
According to group in the corresponding time through vena dorsalis penis injecting normal saline.
Drug solution preparing mode and experiment injection volume are shown in embodiment 5.
2.2 blood samplings and detection
6h, 12h after CLP, for 24 hours, 48h and 72h, abdominal aorta sterile blood sampling 5mL after groups of animals is anaesthetized.Using enzyme-linked
Immunoabsorption (ELISA) detects TF content.
3. experimental result
The results showed that there is certain expression in control group monocyte TF；Model group TF (postoperative 12h, for 24 hours, 48h and
72h) expression is all remarkably higher than control group (p < 0.05), and gradually increases with the extension of Post surgery duration.The TF of experimental group is (postoperative
12h, for 24 hours, 48h and 72h) appearance significantly reduces (p < 0.05) compared with model group for expression.Above-mentioned discovery prompt, with model group
It compares, Paeoniflorin, albiflorin and the oxypaeoniflorin of each dosage group can significantly reduce releasing for CLP rats with sepsis TF
It puts, shows Paeoniflorin (1.8-180.0mg/kg), albiflorin (0.45-180.0mg/kg) and oxypaeoniflorin (0.45-
180.0mg/kg) have the function of significantly inhibiting coagulation factor release to rats with sepsis model, improve hypercoagulative state, conversion
Adult body dosage is about are as follows: Paeoniflorin 20mg to 2000mg, albiflorin 5mg to 2000mg, oxypaeoniflorin 5mg are extremely
2000mg.[translation method is shown in embodiment 5]
The rats with sepsis TF release that 6. Paeoniflorin of table, albiflorin and oxypaeoniflorin induce CLP influence (N=10, unit: pg/mL)
Note:#, indicate compared with the control group, P < 0.05；*, indicate P < 0.05 compared with test group
Embodiment 7 evaluates influence of the paeoniflorin compound to the CLP pyemia regulatory T cells function of inducing
1. experimental material
SD male rat, cleaning grade, weight 180-220g, adaptive feeding 1 week.Anti- rat CD25, FITC label of PE- is anti-
Rat CD4, APC mark annexin V apoptosis kit；The anti-PE kit of rat, CD4 magnetic bead, MiniMACS Magnetic Isolation instrument
And sorting column；PE flag F oxp3 detection kit, PE labeling CT LA-4 detection kit, anti-rat CD3 monoclonal antibody,
Anti- rat CD28 monoclonal antibody.
2. experimental method
2.1 groupings and intervention
110 rats are randomly divided into control group, model group, Paeoniflorin group 1 (1.8mg/kg), 2 (18.0mg/ of Paeoniflorin group
Kg), Paeoniflorin group 3 (180.0mg/kg), albiflorin group 1 (0.45mg/kg), albiflorin group 2 (9.0mg/kg), Chinese herbaceous peony
Medicine lactone glycoside group 3 (180.0mg/kg), oxypaeoniflorin group 1 (0.45mg/kg), oxypaeoniflorin group 2 (9.0mg/kg) and oxygen
Change Paeoniflorin group 3 (180.0mg/kg), every group each 10.12h fasting before testing, weighs and is divided according to random digits table
Group.Control group only opens skin suture after abdomen exposure caecum, subcutaneous injection 10mL physiological saline recovery；Model group and experimental group carry out
Cecal ligation and perforation art (CLP) modeling.CLP modeling process is as follows: with ketamine injection+Su Mian Xin II injection 2:1 mixing
Liquid intramuscular anesthesia rat prepares pyemia animal model using CLP.Cecal ligation and ileum junction, with No. 18 syringe needles
2 formation intestinal fistula of caecum are penetrated through, and 2 drainage strips (0.5cm × 2.0cm) of indwelling prevent pin hole from healing, rear layer-by-layer suture skin,
Art finishes subcutaneous injection 10mL physiological saline recovery immediately.Experimental group injects different medicines through vena dorsalis penis respectively after CLP modeling
Liquid, model group and control group are in the corresponding time through vena dorsalis penis injecting normal saline.
The manner of formulation and experiment injection volume of medical fluid are shown in embodiment 5.
2.2 isolation and culture of cell
Each group rat is sterile after disconnected neck is put to death respectively to take spleen, and 400 mesh filter screens are crossed after grinding, are added after cell suspension centrifugation
Enter lymphocyte separation medium centrifuging and taking middle layer white cell.The anti-CD25 and PE magnetic bead of PE- is added, positive selection (sun choosing) obtains
CD25+T cell, Solid phase (yin choosing) obtain CD25-T cell.Use CD25+T cell dissociate reagent dissociation after, yin select cell with
The anti-CD4 and CD4 magnetic bead sun of FITC- selects up to CD4+CD25+Treg；CD25-T cell is selected with the anti-CD4 and CD4 magnetic bead sun of FITC-
Obtain CD4+CD25-T cell.The purity of flow cytomery double positive cells.With 0.4% trypan blue of mass fraction to CD4+
CD25+Treg is dyed, and cell survival rate is observed.With the RPMll640 culture solution of 20% calf serum containing volume fraction in 48
In well culture plate, in CO2It is cultivated in incubator.Each group was in separation CD4 on the 3rd+CD25+Treg cultivates 12h, then with culture solution tune
Whole CD4+CD25+Treg and CD4+CD25-T cell concentration is 1:1 culture, and concanavalin A (Con A, 5mg/L) is stimulated, 37 DEG C
CO2Centrifuging and taking supernatant after culture 68h, to be checked in -70 DEG C of frosts in incubator.
2.3 detections and analysis
The detection of Treg apoptosis rate: 12h, suspension CD4 are cultivated after separation cell+CD25+Treg(1×109/ L) it is slow with phosphate
Fliud flushing (PBS) is washed 2 times, and 100 μ L combination buffers are added and APC marks annexin V (20mg/L) 10 μ L, room temperature is protected from light
30min adds 10 μ L of actinomycin D (7-AAD), and after being protected from light 5min, 400 μ L combination buffers, fluidic cell is added
Instrument selects 7-AAD feminine gender annexin V positive cells for apoptotic cell, detects apoptosis rate.
Foxp3 and CTLA-4 detection of expression: the CD4 that 100 μ L are prepared.CD25+Treg(1×109/ L) add 1mL newly to prepare
Rupture of membranes liquid, 4 DEG C are protected from light and are incubated for 2h, then are washed with 2mL rupture of membranes buffer；Add the anti-Foxp3 of PE-, after the incubation 30min of 4 DEG C of dark place
It is washed with 2mL rupture of membranes buffer, supernatant is abandoned in centrifugation, and 0.5mL PBS, the mean fluorecence of flow cytomery Foxp3 is added
Intensity.Cell (1 × 10 is resuspended9/ L) in directly plus PE-CTLA-4,4 DEG C are protected from light and are incubated for 30min, detect CTLA-4 mean fluorecence
Intensity.
3. experimental result
Influence of 3.1 paeoniflorin compounds to the CLP pyemia regulatory T cells function of inducing
The results showed that model group Treg apoptosis rate is significantly lower than control group (p < 0.05), experimental group is all remarkably higher than
Model group (p < 0.05).The expression of model group Foxp3, CTLA-4 is apparently higher than control group (p < 0.05), and experimental group is substantially less than
Model group (p < 0.05).Above-mentioned discovery prompt, compared with model group, Paeoniflorin, albiflorin and the oxidation Chinese herbaceous peony of each dosage group
Medicine glycosides can promote pyemia Treg apoptosis, lowers the depression effect to T lymphocyte proliferation and secreting function, shows Paeoniflorin
(1.8-180.0mg/kg), albiflorin (0.45-180.0mg/kg) and oxypaeoniflorin (0.45-180.0mg/kg) are to purulence
Toxication rat model has the function of significantly correcting body cell immunosuppressive condition, is converted to human dose about are as follows: Chinese herbaceous peony
Glycosides 20mg to 2000mg, albiflorin 5mg to 2000mg, oxypaeoniflorin 5mg to 2000mg.[translation method is shown in embodiment
5]
7. Paeoniflorin of table, albiflorin and oxypaeoniflorin to rats with sepsis regulatory T cells apoptosis rate and
Foxp3, CTLA-4 expression influence (N=10, unit: %)
Note:#, indicate compared with the control group, P < 0.05；*, indicate P < 0.05 compared with test group.
Claims (10)
1. paeoniflorin compound treats the application in pyemic drug in preparation.
2. application according to claim 1, which is characterized in that paeoniflorin compound inhibits in pyemia in preparation
Application in the drug of HMGB1 expression.
3. application according to claim 1, which is characterized in that paeoniflorin compound inhibits TF in pyemia to release in preparation
The application in drug put.
4. application according to claim 1, which is characterized in that paeoniflorin compound inhibits in pyemia in preparation
Application in the drug of CTLA-4 and Foxp3 expression.
5. application according to claim 1, which is characterized in that paeoniflorin compound is Paeoniflorin, albiflorin or
Oxypaeoniflorin.
6. application according to claim 1, which is characterized in that paeoniflorin compound further includes that its is pharmaceutically acceptable
Salt, solvate, polycrystalline figure, enantiomer or raceme mixture.
7. the pharmaceutical composition containing paeoniflorin compound is treating the application in pyemic drug.
8. application according to claim 7, which is characterized in that Paeoniflorin, albiflorin and oxypaeoniflorin can divide
It, can also be collectively as the active constituent of pharmaceutical composition not as the sole active agent of pharmaceutical composition；It can also distinguish
Or it is combined jointly with other medicines as active constituent.
9. application according to claim 7, which is characterized in that pharmaceutical composition is prepared into any pharmaceutical dosage form, excellent
It is selected as injection.
10. application according to claim 7, which is characterized in that paeoniflorin compound is for giving when treating pyemia
Medicine approach is intravenous injection or intravenous drip administration, and it is 20mg to 2000mg, peony lactone that dosage range, which is used alone, in Paeoniflorin
It is 5mg to 2000mg that dosage range, which is used alone, in glycosides, and it is 5mg to 2000mg that dosage range, which is used alone, in oxypaeoniflorin.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021169273A1 (en) * | 2020-02-27 | 2021-09-02 | 张作光 | Use of albiflorin in treatment of coronavirus pneumonia |
| WO2022183539A1 (en) * | 2021-03-01 | 2022-09-09 | 天津红日药业股份有限公司 | Pharmaceutical composition for treating sepsis, and use thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106727649A (en) * | 2016-12-28 | 2017-05-31 | 天津红日药业股份有限公司 | A kind of multicomponent parenteral solution |
-
2018
- 2018-10-19 CN CN201811222826.7A patent/CN109260214A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106727649A (en) * | 2016-12-28 | 2017-05-31 | 天津红日药业股份有限公司 | A kind of multicomponent parenteral solution |
Non-Patent Citations (5)
| Title |
|---|
| GAO LI等: "Protective Constituents Against Sepsis in Mice from the Root Cortex of Paeonia suffruticosa", 《ARCH PHARM RES》 * |
| MIN JIANG等: "Identification of NF-κB Inhibitors in Xuebijing injection for sepsis treatment based on bioactivity-integrated UPLC-Q/TOF", 《JOURNAL OF ETHNOPHARMACOLOGY》 * |
| 吴修红等: "赤芍功效物质基础研究进展", 《中医药信息》 * |
| 常蕴青等: "芍药苷对LPS诱导的RAW264.7细胞HMGB1表达的影响", 《长治医学院学报》 * |
| 张倩等: "芍药苷对细菌脂蛋白诱导的THP-1细胞炎症因子表达的影响", 《江苏医药》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021169273A1 (en) * | 2020-02-27 | 2021-09-02 | 张作光 | Use of albiflorin in treatment of coronavirus pneumonia |
| CN115003310A (en) * | 2020-02-27 | 2022-09-02 | 张作光 | Application of albiflorin in treatment of coronavirus pneumonia |
| WO2022183539A1 (en) * | 2021-03-01 | 2022-09-09 | 天津红日药业股份有限公司 | Pharmaceutical composition for treating sepsis, and use thereof |
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