CN109820849A - Wedelolactone is preparing the application in the drug for treating fungal keratitis - Google Patents
Wedelolactone is preparing the application in the drug for treating fungal keratitis Download PDFInfo
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Abstract
The invention belongs to pharmaceutical technology fields, disclose wedelolactone and are preparing the application in the drug for treating fungal keratitis.Present invention firstly provides have the therapeutic effect to fungal keratitis with wedelolactone under conditions in vitro in vivo.Under in vitro conditions, the influence that wedelolactone secretes IL-1 β is had studied using the human macrophage model that aspergillus fumigatus stimulates；Under the conditions of in vivo, using C57BL/6 mouse fungal keratitis model, the influence that wedelolactone secretes model mice cornea clinical score, pathological change, Caspase-1 signal path, interleukin-1 beta is had studied.In addition, the invention also provides wedelolactone joint Natamycins to prepare the application in the drug for treating fungal keratitis.
Description
Technical field
The invention belongs to pharmaceutical field, in particular to wedelolactone is preparing the drug for treating fungal keratitis
In application.
Background technique
Fungal keratitis (fungal keratitis, FK) is a kind of infectivity high by fungus-caused blind rate
Keratonosus, patient are mainly the peasant of developing country.In recent years, due to hormone and the excessive application of antibiotic, extended wear
Contact lens and ocular surface burns chance increase, and China some areas fungal keratitis disease incidence has been raised to infectivity
The first place of keratonosus, patient are mostly the between twenty and fifty labours in field work.The principle of reatment of fungal keratitis is early stage medicine
Object treatment, drug, which not can control state of an illness person finally, needs row operative treatment.Due to the subjective symptoms of fungal keratitis early stage
It is unobvious, cause patient that more serious ulcer of the cornea has usually occurred when going to a doctor for the first time, common antifungal drug is not in addition
With the disadvantages of that there are anti-fungus spectras in degree is relatively narrow, water-soluble bad, cornea penetrability is poor, whole body toxic side effect is larger, curative effect
It is often bad.Invalid for drug therapy, ulcer, which expands, deepens and has the possible patient of perforation to need row therapeutic keratoplasty.
The operation category high-risk keratoplasty art, limited using immunosuppressor, the postoperative probability that rejection occurs is much higher than common angle
Film transfer operation, donor's cornea lacks in addition, many patients blinding due to no operative chance.Therefore the drug of fungal keratitis
It is not very ideal with surgical result.
As important proinflammatory inflammation factor, IL-1 β participates in the immune defense process of cornea anti-fungal infection.IL-1 β is main
It is generated, can also be generated by each confluent monolayer cells of cornea by the monocyte that activates, participate in mediating acute phase inflammatory reaction, inflammatory cell
Chemotactic and the antigen of activation, Langhans giant cell and macrophage are offered, and new vessels can be stimulated to be formed, expression
It is related with the severity of infectious diseases.There are research (Karmakar M, Sun Y, Hise AG, Rietsch A, Pearlman
E.Cutting edge:IL-1βprocessing during Pseudomonas aeruginosa infection is
mediated by neutrophil serine proteases and is independent of NLRC4and
caspase-1.J Immunol,2012；189 (9): 4231-4235.) discovery, in pseudomonas aeruginosa keratitis pathogenic process,
Neutrophil leucocyte is to be raised inflammatory cell to corneal infection region first, while neutrophil leucocyte is pyocyanic corneal
The main source of IL-1 β when scorching.When pseudomonas aeruginosa keratitis occurs for IL-1 β knock out mice, the infiltration of corneal infection region
Inflammatory cell significantly reduce, the bacterium Scavenging activity of body is decreased obviously (Pearlman E, Sun Y, Roy S, Karmakar
M,Hise AG,Szczotka-Flynn L,Ghannoum M,Chinnery HR,McMenamin PG,Rietsch A.Host
defense at the ocular surface.Int Rev Immunol,2013；32(1):4-18.).The synthesis of IL-1 β,
The strict control of modification and release by body, existing research (Hise AG, Tomalka J, Ganesan S, Patel K,
Hall BA,Brown GD,Fitzgerald KA.An essential role for the NLRP3inflammasome in
host defense against the human fungal pathogen Candida albicans.Cell Host
Microbe,2009；5 (5): 487-497.) show that this process at least needs to pass through two warps by the different stimulant of two classes
Allusion quotation signal path is completed.Classical 1 access of Signal is pre- sharp access, can be passed through by microbes or endogenous molecule all
Such as Toll receptor participates in the pattern recognition receptors starting of innate immune response, it is therefore an objective to activate NF- κ b and induce precursor I L-1 β
Synthesis.Classical 2 access of Signal is activation pathway, can be started by ATP, certain bacteriotoxins and microparticle, it is therefore an objective to
Activation includes the polyprotein inflammatory complex of one or more Nod sample receptor structure, then will be inactive by caspase-1
The precursor I L-1 β-cleavage that size is 31kD is the active body IL-1 β that biologically active size is 17kD, to participate in body
Immune response.
Summary of the invention
The purpose of the present invention is to provide application of the wedelolactone in treatment fungal keratitis.
In order to solve the above technical problems, embodiments of the present invention provide wedelolactone in preparation for treating fungi
Application in the drug of property keratitis.In above-mentioned pharmaceutical applications proposed by the invention, wedelolactone is for inhibiting fungi
1 β of human macrophage secreting leukocytes mesonium of stimulation, wherein the fungi is aspergillus fumigatus；The human macrophage is PMA
The THP-1 cell of induction.More specifically, wedelolactone can inhibit cornea in above-mentioned pharmaceutical applications proposed by the invention
Caspase-1 signal path in tissue.
According to above-mentioned pharmaceutical applications, embodiments of the present invention provide a kind of for treating the medicine of fungal keratitis
Object, it includes wedelolactones and pharmaceutically acceptable auxiliary material.
Present invention firstly provides have the treatment to fungal keratitis with wedelolactone under conditions in vitro in vivo
Effect.Under in vitro conditions, wedelolactone is had studied using the human macrophage model that aspergillus fumigatus stimulates to secrete IL-1 β
Influence.Under the conditions of in vivo, using C57BL/6 mouse fungal keratitis model, it is small to model to have studied wedelolactone
The influence that mouse cornea clinical score, pathological change, Caspase-1 signal path, interleukin-1 beta (IL-1 β) are secreted.
The prepared experimental program of embodiments of the present invention and result are as follows:
Wedelolactone pre-processes human macrophage 2 hours, and cell culture fluid is added in aspergillus fumigatus conidium later
In, infection multiplicity 1.After fungi stimulates 4 hours, collects cell and tested for polymerase chain reaction, detect the mRNA of IL-1 β
Expression.After fungi stimulates 16 hours, collects cell and tested for protein immunoblotting, detect the expression of IL-1 β maturation body.Knot
Fruit shows the processing of wedelolactone pre-administration, can obviously reduce mRNA expression and the IL-1 β of inflammatory factor IL-1 β in cell model
The expression of mature body.
Wedelolactone passes through subconjunctival injection pretreated model mouse in 24 hours and 30 minutes before modeling, uses later
Animalmodel method establishes mouse fungal keratitis animal model, the aspergillus fumigatus point that 2 μ L concentration of injection are 0.5 × 105/ μ L
Raw spore.After modeling 1 day, mouse cornea photo is shot using slit-lamp microscope, collects mouse cornea later, it is glimmering for being immunized
Light experiment and myeloperoxidase (MPO) detection, detect the recruitment situation of neutrophil leucocyte in cornea；For polymerase chain reaction
It should test, the mRNA expression of detection IL-1 β；It is tested for protein immunoblotting, detects IL-1 β and Caspase-1 maturation body
The expression of albumen.Wedelolactone pre-administration is handled as the result is shown, be can obviously reduce mouse fungal keratitis ulcer level, is subtracted
The recruitment quantity and activation degree of neutrophil leucocyte, reduce inflammatory factor IL-1 in model mice cornea in few model mice cornea
The mRNA of β is expressed, and reduces the expression of IL-1 β and Caspase-1 maturation body protein.
Further, embodiments of the present invention additionally provide wedelolactone joint Natamycin in preparation for treating
Application in the drug of fungal keratitis, wherein wedelolactone joint Natamycin can reduce fungal keratitis model
The cornea tissue of mouse destroys.Wedelolactone handles model mice by subconjunctival injection after modeling 24 hours, and uses
The 4 times/day of combination therapies of Natamycin eye drops.After modeling 3 days, mouse cornea photo is shot using slit-lamp microscope.As a result
It shows wedelolactone drug treatment, can obviously improve mouse fungal keratitis ulcer level, can preferably protect cornea
The transparency.
According to the pharmaceutical applications of above-mentioned drug combination, embodiments of the present invention additionally provide a kind of for treating fungoid
The pharmaceutical composition of keratitis, it includes wedelolactone, Natamycin and pharmaceutically acceptable auxiliary materials.
Detailed description of the invention
Fig. 1 is the human macrophage stimulated using polymerase chain reaction detection wedelolactone fungi in embodiment 1
The result figure of the influence of middle IL-1 β mRNA expression；
Fig. 2 is the human macrophage stimulated using protein immunoblotting detection wedelolactone fungi in embodiment 1
The result figure of the influence of middle IL-1 β protein secretion；
Fig. 3 is that the fungal keratitis model mice of simple infection group and wedelolactone pretreated group is built in embodiment 2
The comparison diagram of cornea under the microscope after 1 day vertical；
Fig. 4 is that the fungal keratitis model mice of simple infection group and wedelolactone pretreated group is built in embodiment 2
Clinical score result figure after 1 day vertical；
Fig. 5 is that the fungal keratitis model mice of simple infection group and wedelolactone pretreated group is built in embodiment 2
Using the electron microscope of immunofluorescence technique detection neutrophil recruitment situation after 1 day vertical；
Fig. 6 is that the fungal keratitis model mice of simple infection group and wedelolactone pretreated group is built in embodiment 2
Activity of myeloperoxidase appraisal result after 1 day vertical；
Fig. 7 is using polymerase chain reaction detection wedelolactone in embodiment 2 to fungal keratitis model mice
The result figure for the influence that IL-1 β mRNA is expressed in cornea；
Fig. 8 is using protein immunoblotting detection wedelolactone in embodiment 2 to fungal keratitis model mice
The result figure of the influence of IL-1 β protein secretion in cornea；
Fig. 9 is using protein immunoblotting detection wedelolactone in embodiment 2 to fungal keratitis model mice
The result figure for the influence that Caspase-1 is activated in cornea；
Figure 10 is the model of simple Natamycin treatment group and wedelolactone joint Natamycin treatment group in embodiment 2
The comparison diagram of cornea under the microscope after mouse treatment 2 days；
Figure 11 is the model of simple Natamycin treatment group and wedelolactone joint Natamycin treatment group in embodiment 2
Clinical score result figure after mouse treatment 2 days.
Specific embodiment
To make the object, technical solutions and advantages of the present invention clearer, below in conjunction with attached drawing to each reality of the invention
The mode of applying is explained in detail.However, it will be understood by those skilled in the art that in each embodiment of the present invention,
In order to make the reader understand this application better, many technical details are proposed.But even if without these technical details and base
In the various changes and modifications of following embodiment, each claim of the application technical side claimed also may be implemented
Case.
Wedelolactone is a kind of furocoumarin compound, platymiscium estrogens flavones.It reports for the first time within 1956
It extracts and obtains from plant wedelia chinensis and ecliptae herba, have certain pharmaceutical potential.It is mainly visited in a specific embodiment of the invention
It begs for: under in vitro conditions, the shadow for 1 β of human macrophage secreting leukocytes mesonium (IL-1 β) that wedelolactone stimulates fungi
It rings；Under the conditions of in vivo, wedelolactone to fungal keratitis model mice cornea clinical score, pathological change,
The influence that Caspase-1 signal path, interleukin-1 beta (IL-1 β) are secreted inquires into wedelolactone joint Natamycin and exists
Treat the effect in fungal keratitis model mice.
1 wedelolactone of embodiment inhibits the human macrophage of fungi stimulation to secrete IL-1 β
1. experimental material
1.1 experimental drugs: wedelolactone (is purchased from selleck company)
1.2 experimental cells: Human THP-1 cells (China typical culture collection center)
1.3 experiment fungies: 3.0772 plants of aspergillus fumigatus (China General Microbiological culture presevation administrative center)
2. experimental method
The preparation of 2.1 fungies
Using scarification by aspergillus fumigatus strain inoculated on sabouraud culture medium, 28 DEG C constant incubator culture 2-3 days.It takes
The sterile PBS of 5ml is put into culture dish, with microorganism scraping ring scraping mycelia and conidium, collects mixed liquor, sterile gauze mistake
Filter out mycelia.4 DEG C, 4500rpm centrifugation 10 minutes, discard supernatant, wash, and the sterile PBS of 5ml is added into precipitating and is resuspended, shape
At conidial suspension.It is counted with blood cell counting plate, and conidial concentration is adjusted to 5 × 10 with sterile PBS4
A conidium/μ l.
The experiment of 2.2 cell models
100 μ g/ml are added into culture solution in the RPMI 1640 culture medium containing 10%FBS for THP-1 cell culture
Streptomysin and 100U/ml penicillin.37 DEG C are placed in, 5%CO2It is cultivated in incubator.Use phorbol 12-nutmeg
Acid esters 13- acetic acid esters (PMA) stimulates 48 hours in advance, and THP-1 cell is induced as THP-1 macrophage.Cell is divided into control
Fungi stimulation group after group, fungi stimulation group, wedelolactone pretreated group and wedelolactone pretreatment.By dimethyl sulfoxide
(1.1 μ g/mL of final concentration) is added in control group and fungi stimulation group cell culture fluid, and wedelolactone (10 μM of final concentration) is added
Enter after wedelolactone pretreated group and wedelolactone pretreatment in fungi stimulation group cell culture fluid, it, will after being incubated for 4 hours
After aspergillus fumigatus conidium addition fungi stimulation group and wedelolactone pretreatment in fungi stimulation group cell culture fluid, infection
Plural number is 1.After fungi stimulates 4 hours, collects cell and tested for polymerase chain reaction, the mRNA expression of detection IL-1 β.Very
After bacteria thorn swashs 16 hours, collects cell and tested for protein immunoblotting, detect the expression of IL-1 β maturation body protein.
3. experimental result
Fig. 1 is IL-1 β in the human macrophage stimulated using polymerase chain reaction detection wedelolactone fungi
The result figure of the influence of mRNA expression；Fig. 2 is huge using the people that stimulates fungi of protein immunoblotting detection wedelolactone
The result figure of the influence of IL-1 β protein secretion in phagocyte.
As shown in Figure 1, polymerase chain reaction experiment shows that the stimulation of row fungi, people are huge again after wedelolactone pretreatment
The mRNA of IL-1 β, which is expressed, in phagocyte significantly reduces；As shown in Fig. 2, protein immunoblotting experiment shows that wedelolactone is pre-
Row fungi stimulates again after processing, and the expression of IL-1 β maturation body protein is significantly reduced in human macrophage.
2 wedelolactone of embodiment is to fungal keratitis model mice cornea clinical score, pathological change, Caspase-
The influence that 1 signal path, interleukin-1 beta (IL-1 β) are secreted inquires into wedelolactone joint Natamycin in treatment fungi
Effect in property Keratitis Model mouse.
1. experimental material
1.1 experimental drugs: wedelolactone (is purchased from selleck company), and Natamycin eye drops (is purchased from Alcon company)
1.2 experimental animals: C57BL/6 mouse (this experimental animal Co., Ltd of changzhou Cavan)
1.3 experiment fungies: 3.0772 plants of aspergillus fumigatus (China General Microbiological culture presevation administrative center)
2. experimental method
2.1 model mice
8 week old health cleaning grade female C57BL/6 mouse systemics in order, test the examination with slitlamp microscope row that moves ahead
Except eye disease, random selection is experimental eye at a glance.All animals use the people for meeting Chinese science technology department experimental animal
(vgkfcz-2006-398) is instructed in road treatment, and meets U.S.'s ophthalmology and vision research association (the Association for
Research in Vision and Ophthalmology, ARVO) about the original that animal uses in ophthalmology and vision research
Then and standard.
2.2 wedelolactones pretreatment to fungal keratitis model mice cornea clinical score, pathological change,
The influence that Caspase-1 signal path, IL-1 β secrete
C57BL/6 mouse 72, it is randomly divided into control group, fungal infection group, wedelolactone pretreated group and wedelia chinensis
Fungal infection group after lactone pretreatment, every group 18.24 hours and modeling first 30 minutes before modeling, by 5 μ L dimethyl sulfoxides
(11 μ g/mL) injects under control group and fungal infection group mouse bulbar conjunctiva, will be in (30 μM) injection wedelia chinensis of 5 μ L wedelolactone
After ester pretreated group and wedelolactone pretreatment under fungal infection group mouse bulbar conjunctiva.Mouse is established using animalmodel method
Fungal keratitis animal model injects the 2 sterile phosphorus of μ L in control group and wedelolactone pretreated group mouse cornea Medium Culture
Phthalate buffer (phosphate buffered solution, PBS), after fungal infection group and wedelolactone pretreatment
It is 0.5 × 10 that fungal infection group mouse cornea Medium Culture, which injects 2 μ L concentration,5The aspergillus fumigatus conidium of/μ L.After modeling 1 day,
6 mouse corneas of random selection are taken pictures with slit-lamp microscope in each group carries out clinical observation, and records clinical score, Zhi Houzhai
Take cornea half for immunofluorescence experiment, half is detected for MPO；6 mouse corneas are randomly choosed in each group for polymerizeing
Enzyme chain reaction experiment, the mRNA expression of detection IL-1 β；Other 6 mouse corneas are tested for protein immunoblotting, detection
The expression of IL-1 β and Caspase-1 maturation body protein.
2.3 wedelolactones combine effect of the Natamycin in treatment fungal keratitis model mice
C57BL/6 mouse 12, it is randomly divided into Natamycin treatment group and wedelolactone joint Natamycin treatment group,
Every group 6.Mouse fungal keratitis animal model is established using animalmodel method, is injected in two groups of mouse cornea Medium Cultures
2 μ L concentration are 0.5 × 105The aspergillus fumigatus conidium of/μ L.After modeling 1 day, by (30 μM) injection Peng of 5 μ L wedelolactone
Qi chrysanthemum lactone is combined under Natamycin treatment group mouse bulbar conjunctiva.Two groups of mouse give Natamycin eye drops electrophoresis, and 4 times/day.It controls
After treating 2 days, each group mouse cornea is taken pictures with slit-lamp microscope and carries out clinical observation, and records clinical score.
3. experimental result:
3.1 wedelolactones pre-process the influence to fungal keratitis model mice cornea clinical score
Fig. 3 is after the fungal keratitis model mice of simple infection group and wedelolactone pretreated group establishes 1 day
The comparison diagram of cornea under the microscope；Fig. 4 is the fungal keratitis model of simple infection group and wedelolactone pretreated group
Mouse establish 1 day after clinical score result figure.
As shown in Figure 3,4, when wedelolactone pretreatment can be with the infection of substantially reduced fungal keratitis model mice 1 day
The degree of injury of cornea, the clinical score of fungal infection group is lower than fungal infection group after wedelolactone pretreatment.
3.2 wedelolactones pre-process the influence to fungal keratitis model mice cornea pathological change
Fig. 5 is adopted after the fungal keratitis model mice of simple infection group and wedelolactone pretreated group establishes 1 day
With the electron microscope of immunofluorescence technique detection neutrophil recruitment situation (under 400 × microscope)；Fig. 6 be simple infection group and
The fungal keratitis model mice of wedelolactone pretreated group establish 1 day after activity of myeloperoxidase appraisal result.
As shown in Figure 5,6, when wedelolactone pretreatment can significantly reduce the infection of fungal keratitis model mice 1 day
The recruitment quantity of neutrophil leucocyte in cornea, the MPO scoring of fungal infection group is lower than fungal infection after wedelolactone pretreatment
Group.
3.3 wedelolactones pre-process the influence secreted to fungal keratitis model mice cornea IL-1 β
Fig. 7 is using polymerase chain reaction detection wedelolactone to IL-1 in fungal keratitis model mice cornea
The result figure of the influence of β mRNA expression；Fig. 8 is using protein immunoblotting detection wedelolactone to fungal keratitis mould
The result figure of the influence of IL-1 β protein secretion in type mouse cornea.
As shown in Figure 7,8, polymerase chain reaction experiment shows that wedelolactone pretreatment can significantly reduce fungoid
The mRNA of IL-1 β is expressed in cornea at Keratitis Model mouse infection 1 day；Protein immunoblotting experiment shows in wedelia chinensis
Ester pretreatment can significantly reduce the expression of IL-1 β maturation body protein in cornea when fungal keratitis model mice infects 1 day.
3.4 wedelolactones pre-process the influence to fungal keratitis model mice cornea C aspase-1 signal path
Fig. 9 is using protein immunoblotting detection wedelolactone in fungal keratitis model mice cornea
The result figure of the influence of Caspase-1 activation.
As shown in figure 9, protein immunoblotting experiment shows that wedelolactone pretreatment can significantly reduce fungoid angle
Film inflammation model mice infect 1 day when cornea in Caspase-1 maturation body protein expression.
3.5 wedelolactones combine effect of the Natamycin in treatment fungal keratitis model mice
Figure 10 is the model mice treatment 2 of simple Natamycin treatment group and wedelolactone joint Natamycin treatment group
Corneal infection comparison diagram after it；Figure 11 is simple Natamycin treatment group and wedelolactone joint Natamycin treatment group
Clinical score result figure after model mice treatment 2 days.
As shown in Figure 10,11, compared with simple Natamycin treatment group, wedelolactone combines Natamycin treatment group mould
Corneal injury degree is substantially reduced after type mouse is treated 2 days；The clinical score that wedelolactone combines Natamycin treatment group is low
In simple Natamycin treatment group.
It will be understood by those skilled in the art that the respective embodiments described above are to realize specific embodiments of the present invention,
And in practical applications, can to it, various changes can be made in the form and details, without departing from the spirit and scope of the present invention.
Claims (7)
1. wedelolactone is preparing the application in the drug for treating fungal keratitis.
2. application according to claim 1, which is characterized in that the wedelolactone inhibits people's macrophage of fungi stimulation thin
Intracrine interleukin-1 beta.
3. application according to claim 2, which is characterized in that the fungi is aspergillus fumigatus；The human macrophage is
The THP-1 cell of PMA induction.
4. application according to claim 1, which is characterized in that the wedelolactone inhibits Caspase- in cornea tissue
1 signal path.
5. a kind of for treating the drug of fungal keratitis, which is characterized in that comprising wedelolactone and pharmaceutically acceptable
Auxiliary material.
6. wedelolactone, which combines Natamycin, is preparing the application in the drug for treating fungal keratitis.
7. the pharmaceutical composition for treating fungal keratitis, which is characterized in that include wedelolactone, Natamycin and medicine
Acceptable auxiliary material on.
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