CN109820849B - Application of wedelolactone in preparation of medicine for treating fungal keratitis - Google Patents
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Abstract
The invention belongs to the technical field of pharmacy, and discloses application of wedelolactone in preparation of a medicine for treating fungal keratitis. The invention firstly provides that wedelolactone has a treatment effect on fungal keratitis under in-vivo and in-vitro conditions. Under the in vitro condition, the influence of wedelolactone on the secretion of IL-1 beta is researched by adopting a human macrophage model stimulated by aspergillus fumigatus; under in vivo conditions, a C57BL/6 mouse fungal keratitis model is adopted to study the influence of wedelolactone on clinical scores, pathological changes, Caspase-1 signal pathways and interleukin 1 beta secretion of model mouse cornea. In addition, the invention also provides application of wedelolactone and natamycin in preparing a medicine for treating fungal keratitis.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to application of wedelolactone in preparation of a medicine for treating fungal keratitis.
Background
Fungal Keratitis (FK) is an infectious keratopathy caused by fungi with a very high blindness rate, the patients being mainly farmers in developing countries. In recent years, due to the excessive application of hormones and antibiotics, the long-term wearing of corneal contact lenses and the increase of the chance of corneal trauma, the incidence rate of fungal keratitis in partial areas of China has increased to the first place of infectious keratopathy, and patients are more young and vigorous labors working at the first line. The treatment principle of the fungal keratitis is early drug treatment, and patients who cannot control the disease condition need to be treated by operation finally. The subjective symptoms at the initial stage of fungal keratitis are not obvious, so that the patients usually suffer from more serious corneal ulcer when seeing a doctor for the first time, and the common antifungal drugs have the defects of narrow antifungal spectrum, poor water solubility, poor corneal penetrability, large systemic toxic and side effects and the like in different degrees, so that the curative effect is often poor. For drug treatment ineffectiveness, patients with ulcerations deepened and possibly perforated require therapeutic keratoplasty. The operation belongs to high-risk corneal transplantation, the application of immunosuppressive agent is limited, the probability of rejection reaction after the operation is far higher than that of the common corneal transplantation operation, in addition, donor cornea is deficient, and many patients are blinded due to no operation chance. Therefore, the curative effect of the fungal keratitis by the medicine and the operation is not very ideal.
As an important proinflammatory factor, IL-1 β is involved in the immune defense process of the cornea against fungal infections. IL-1 beta is mainly produced by activated monocytes and also by cells in the layers of the cornea, participates in mediating the acute phase inflammatory reaction, chemotaxis and activation of inflammatory cells, antigen presentation by giant cells and macrophages of Langhans, and stimulates neovascularization, the expression level of which is related to the severity of infectious diseases. Studies have been made (Karmakar M, Sun Y, Hise AG, Rietsch A, Pearlman E. cutting edge: IL-1. beta. processing during Pseudomonas aeruginosa infection is mediated by neutral serophiles and is independent of NLRC4and caspase-1.J Immunol, 2012; 189(9): 4231. beta. 4235.) it was found that neutrophils are the first inflammatory cells to be recruited to the corneal infection area during the onset of Pseudomonas aeruginosa keratitis, while neutrophils are the main source of IL-1. beta. during Pseudomonas aeruginosa keratitis. When IL-1 beta gene knockout mice develop pseudomonas aeruginosa keratitis, inflammatory cells infiltrated in the cornea-infected area are significantly reduced, and the bacterial clearance of the body is significantly reduced (Pearlman E, Sun Y, Roy S, Karmakar M, Hise AG, Szczotka-Flynn L, Ghannoum M, Chinnery HR, McMenamin PG, Rietsch A. host fed at the ocular surface. int Rev Immunol, 2013; 32(1): 4-18.). The synthesis, modification and release of IL-1 β is strictly controlled by the body and studies have been carried out (Hise AG, Tomalka J, Ganesan S, Patel K, Hall BA, Brown GD, Fitzgerald KA. an addressing roller for the NLRP3in a magnetic in a Host fed approach, 2009; 5(5):487 & 497.) show that this process needs to be accomplished by at least two classical signaling pathways with two different classes of stimuli. The classical Signal 1 pathway is a pre-excitation pathway that can be initiated by microbial or endogenous molecules through pattern recognition receptors such as Toll receptors that are involved in the innate immune response with the aim of activating NF-. kappa.b and inducing the synthesis of the precursor IL-1. beta. The classical Signal 2 pathway is an activation pathway, which can be initiated by ATP, certain bacterial toxins and microparticles, with the aim of activating a multiprotein inflammatory complex containing one or more Nod-like receptor structures, followed by caspase-1 cleavage of the inactive precursor IL-1 β of size 31kD into the biologically active, active IL-1 β of size 17kD, which participates in the body's immune response.
Disclosure of Invention
The invention aims to provide application of wedelolactone in treating fungal keratitis.
In order to solve the technical problems, the embodiment of the invention provides the application of wedelolactone in preparing a medicine for treating fungal keratitis. In the pharmaceutical application provided by the invention, wedelolactone is used for inhibiting human macrophages stimulated by fungi from secreting interleukin 1 beta, wherein the fungi is aspergillus fumigatus; the human macrophage is a PMA-induced THP-1 cell. More specifically, wedelolactone inhibits the Caspase-1 signaling pathway in corneal tissue in the above pharmaceutical applications proposed by the present invention.
According to the pharmaceutical use, the embodiment of the invention provides a medicine for treating fungal keratitis, which comprises wedelolactone and pharmaceutically acceptable auxiliary materials.
The invention firstly provides that wedelolactone has a treatment effect on fungal keratitis under in-vivo and in-vitro conditions. Under the in vitro condition, the influence of wedelolactone on the secretion of IL-1 beta is researched by adopting a human macrophage model stimulated by aspergillus fumigatus. Under in vivo conditions, a C57BL/6 mouse fungal keratitis model is adopted to study the influence of wedelolactone on clinical scores, pathological changes, Caspase-1 signal pathways and interleukin 1 beta (IL-1 beta) secretion of model mouse cornea.
The experimental protocol and results established for the embodiments of the present invention are as follows:
wedellactone pretreats human macrophage for 2 hours, and then adds aspergillus fumigatus conidium into cell culture solution, and the multiplicity of infection is 1. After 4 hours of fungal stimulation, cells were harvested for PCR experiments to detect mRNA expression of IL-1 β. After 16 hours of fungal stimulation, cells were collected for western blot experiments to detect expression of IL-1 β maturates. The result shows that the wedelolactone pre-administration treatment can obviously reduce the mRNA expression of an inflammatory factor IL-1 beta and the expression of an IL-1 beta mature body in a cell model.
Wedelia lactone is injected under the conjunctiva 24 hours and 30 minutes before modeling to pretreat a model mouse, then an intrastromal injection method is used for establishing a mouse fungal keratitis animal model, and 2 muL of conidia of aspergillus fumigatus with the concentration of 0.5 multiplied by 105/muL is injected. After modeling for 1 day, shooting a mouse cornea picture by using a slit lamp microscope, and then collecting the mouse cornea for immunofluorescence experiments and Myeloperoxidase (MPO) detection to detect the recruitment condition of neutrophils in the cornea; used for polymerase chain reaction experiments, and detecting the mRNA expression of IL-1 beta; the protein is used for Western blotting experiments to detect the expression of IL-1 beta and Caspase-1 mature body proteins. The result shows that wedelolactone pre-administration treatment can obviously reduce the ulcer degree of fungal keratitis of a mouse, reduce the recruitment quantity and the activation degree of neutrophils in the cornea of a model mouse, reduce the mRNA expression of an inflammation factor IL-1 beta in the cornea of the model mouse, and reduce the expression of IL-1 beta and Caspase-1 mature body protein.
Furthermore, the embodiment of the invention also provides the application of the wedelolactone and natamycin in preparing the medicine for treating the fungal keratitis, wherein the wedelolactone and natamycin can reduce the damage of corneal tissues of a mouse model of the fungal keratitis. Wedelolactone is modeled for 24 hours and then treated with subconjunctival injection to model mice, and combined treatment is performed with natamycin eye drops 4 times/day. After 3 days of modeling, a picture of the mouse cornea was taken using a slit-lamp microscope. The result shows that wedelolactone administration treatment can obviously improve the ulcer degree of mouse fungal keratitis and can better protect the transparency of the cornea.
According to the pharmaceutical application of the combined medicine, the embodiment of the invention also provides a pharmaceutical composition for treating fungal keratitis, which comprises wedelolactone, natamycin and pharmaceutically acceptable auxiliary materials.
Drawings
FIG. 1 is a graph showing the results of detection of the effect of wedelolactone on the expression of IL-1. beta. mRNA in human macrophages stimulated by fungi using the polymerase chain reaction in example 1;
FIG. 2 is a graph showing the results of detection of the effect of wedelolactone on secretion of IL-1. beta. protein in human macrophages stimulated by fungi using Western blotting as described in example 1;
FIG. 3 is a microscopic comparison of the cornea obtained from the fungal keratitis model mice of the infection only group and the wedelolactone pretreatment group of example 2 after 1 day of establishment;
fig. 4 is a graph showing the results of clinical scores of the fungal keratitis model mice of the simple infection group and the wedelolactone pretreatment group in example 2 after 1 day of establishment;
FIG. 5 is an electron microscope image of a fungal keratitis model mouse of the simple infection group and the wedelolactone pretreatment group in example 2, which is established for 1 day and then used for detecting the recruitment of neutrophils by an immunofluorescence technique;
FIG. 6 is the myeloperoxidase activity scoring results 1 day after the establishment of the fungal keratitis model mice of the infection-only group and the wedelolactone-pretreated group in example 2;
FIG. 7 is a graph showing the results of detection of the effect of wedelolactone on the expression of IL-1. beta. mRNA in the cornea of a mouse model of fungal keratitis using the polymerase chain reaction in example 2;
FIG. 8 is a graph showing the results of detection of the effect of wedelolactone on the secretion of IL-1. beta. protein in the cornea of a mouse model of fungal keratitis using Western blotting in example 2;
FIG. 9 is a graph showing the results of detection of the effect of wedelolactone on Caspase-1 activation in the cornea of a mouse model of fungal keratitis using Western blotting in example 2;
FIG. 10 is a microscopic comparison of the cornea after 2 days of treatment in the model mice of the mono-pure natamycin treatment group and the wedelolactone-combined natamycin treatment group of example 2;
figure 11 is a graph of the clinical scores of model mice treated for 2 days in the monotropenem and wedelolactone-combined natamycin treatment groups of example 2.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in detail below with reference to the accompanying drawings. However, it will be appreciated by those of ordinary skill in the art that numerous technical details are set forth in order to provide a better understanding of the present application in various embodiments of the present invention. However, the technical solutions claimed in the claims of the present application can be implemented without these technical details and with various changes and modifications based on the following embodiments.
Wedelolactone is a furocoumarin compound, and belongs to plant estrogen flavonoid. In 1956, the Chinese medicinal composition is firstly reported to be extracted from plants including wedeloa chinensis and eclipta alba and has certain medicinal potential. The specific implementation mode of the invention mainly discusses: the influence of wedelolactone on secretion of interleukin 1 beta (IL-1 beta) by human macrophages stimulated by fungi under in vitro conditions; under in vivo conditions, the effects of wedelolactone on clinical scores and pathological changes of the cornea of a model mouse with fungal keratitis, Caspase-1 signal pathways and interleukin 1 beta (IL-1 beta) secretion are discussed, and the effect of wedelolactone and natamycin in treating the model mouse with the fungal keratitis is discussed.
Example 1 Wedelia lactone inhibits fungus-stimulated human macrophages from secreting IL-1 β
1. Experimental Material
1.1 Experimental drugs: wedelolactone (from selelck corporation)
1.2 test cells: human THP-1 cell (China center for type culture Collection)
1.3 experimental fungi: aspergillus fumigatus 3.0772 strain (China general microbiological culture collection management center)
2. Experimental methods
2.1 fungal preparation
Inoculating Aspergillus fumigatus strain on Sabouraud's medium by scratching method at 28 deg.CCulturing in constant temperature incubator for 2-3 days. Placing 5ml sterile PBS into a culture dish, scraping hyphae and conidia by using a microorganism scraping ring, collecting a mixed solution, and filtering by using sterile gauze to remove the hyphae. Centrifugation was carried out at 4500rpm for 10 minutes at 4 ℃ to discard the supernatant, washed, and 5ml of sterile PBS was added to the pellet to resuspend it, thereby forming a conidia suspension. The cells were counted on a hemocytometer and the concentration of conidia was adjusted to 5X 10 with sterile PBS4Conidia/. mu.l.
2.2 cell model experiments
THP-1 cells were cultured in RPMI 1640 medium containing 10% FBS, and 100. mu.g/ml of streptomycin and 100U/ml of penicillin were added to the medium. Standing at 37 deg.C for 5% CO2Culturing in an incubator. THP-1 cells were induced to THP-1 macrophages using phorbol 12-myristate 13-acetate (PMA) pre-stimulation for 48 hours. The cells are divided into a control group, a fungus stimulation group, a wedelolactone pretreatment group and a wedelolactone pretreated fungus stimulation group. Adding dimethyl sulfoxide (final concentration is 1.1 mu g/mL) into cell culture solutions of a control group and a fungus stimulation group, adding wedelolactone (final concentration is 10 mu M) into cell culture solutions of a wedelolactone pretreatment group and a wedelolactone pretreated back fungus stimulation group, incubating for 4 hours, adding conidia of aspergillus fumigatus into cell culture solutions of a fungus stimulation group and a wedelolactone pretreated back fungus stimulation group, wherein the infection complex number is 1. After 4 hours of fungal stimulation, cells were harvested for PCR experiments to detect mRNA expression of IL-1 β. After 16 hours of fungal stimulation, cells were collected for western blot experiments to detect expression of IL-1 β mature body protein.
3. Results of the experiment
FIG. 1 is a graph of the results of using the polymerase chain reaction to detect the effect of wedelolactone on the expression of IL-1 β mRNA in human macrophages stimulated by fungi; figure 2 is a graph of the results of using western blotting to detect the effect of wedelolactone on secretion of IL-1 β protein in fungal-stimulated human macrophages.
As shown in figure 1, a polymerase chain reaction experiment shows that wedelolactone is pretreated and then stimulated by fungi, and the mRNA expression of IL-1 beta in human macrophage is remarkably reduced; as shown in figure 2, Western blotting experiments show that the expression of IL-1 beta mature somaprotein in human macrophage is also significantly reduced by fungus stimulation after wedelolactone pretreatment.
Example 2 effects of wedelolactone on clinical corneal scores, pathological changes, Caspase-1 signaling pathway, and interleukin 1 β (IL-1 β) secretion in a fungal keratitis model mouse, the effects of wedelolactone in combination with natamycin in treating a fungal keratitis model mouse were studied.
1. Experimental Material
1.1 Experimental drugs: wedelolactone (from selelck corporation), natamycin eye drops (from Alcon corporation)
1.2 Experimental animals: c57BL/6 mouse (Jiangsu Changzhou Kavens laboratory animals Co., Ltd.)
1.3 experimental fungi: aspergillus fumigatus 3.0772 strain (China general microbiological culture collection management center)
2. Experimental methods
2.1 model mice
The whole body condition of 8-week-old healthy clean-grade female C57BL/6 mice is good, the slit lamp microscopy is performed before the experiment to eliminate eye diseases, and one eye is randomly selected as an experimental eye. All animals were used in compliance with the humanistic treatment guidelines for laboratory animals of the department of scientific technology of China (vgkfcz-2006-.
2.2 effects of Wedelia lactone pretreatment on clinical scores, pathological changes, Caspase-1 signaling pathway and IL-1 beta secretion of mouse cornea as model of fungal keratitis
72C 57BL/6 mice were randomly divided into a control group, a fungal infection group, a wedelolactone pretreatment group and a wedelolactone pretreated fungal infection group, and each group contained 18 mice. Injecting 5 mu L dimethyl sulfoxide (11 mu g/mL) into mouse subconjunctival of a control group and a fungal infection group 24 hours before modeling and 30 minutes before modeling, and injecting 5 mu L wedelolactone (30 mu M) into wedelolactone pretreatment group and wedelolactone pretreated small mouse infection groupUnder the mouse bulbar conjunctiva. Establishing mouse fungal keratitis animal model by intrastromal injection method, injecting 2 μ L sterile Phosphate Buffer Solution (PBS) into mouse corneal stroma of control group and wedelolactone pretreatment group, and injecting 2 μ L with concentration of 0.5 × 10 in mouse corneal stroma of fungus infection group and wedelolactone pretreated mouse5/. mu.L of conidia of A.fumigatus. After modeling for 1 day, randomly selecting 6 mouse corneas from each group, taking a picture by using a slit lamp microscope for clinical observation, recording clinical scores, and then picking up half of the corneas for an immunofluorescence experiment and half of the corneas for MPO detection; randomly selecting 6 mouse corneas in each group for polymerase chain reaction experiment to detect mRNA expression of IL-1 beta; in addition, 6 mouse corneas were used in Western blotting experiments to detect the expression of IL-1. beta. and Caspase-1 mature body proteins.
2.3 Effect of Wedelia lactone in combination with natamycin in treatment of fungal keratitis model mice
12C 57BL/6 mice were randomly divided into a natamycin treatment group and a wedelolactone-combination natamycin treatment group, each group consisting of 6 mice. Establishing mouse model of fungal keratitis by intrastromal injection, injecting 2 μ L of 0.5 × 10 in corneal stroma of two groups of mice5/. mu.L of conidia of A.fumigatus. After modeling for 1 day, 5 μ L of wedelolactone (30 μ M) was injected under the bulbar conjunctiva of mice in the wedelolactone and natamycin combination treatment group. Two groups of mice were subjected to natamycin eye drop electrophoresis for 4 times per day. After 2 days of treatment, the corneas of each group of mice were photographed with a slit lamp microscope for clinical observation and the clinical scores were recorded.
3. The experimental results are as follows:
3.1 Effect of Wedelia lactone pretreatment on the clinical scores of mouse corneas in the model of fungal keratitis
FIG. 3 is a microscopic comparison of the cornea of a mouse model of fungal keratitis in the simple infection group and the wedelolactone pretreatment group after 1 day of establishment; fig. 4 is a graph of the clinical scoring results of the fungal keratitis model mice of the simple infection group and the wedelolactone pretreatment group after 1 day of establishment.
As shown in fig. 3 and 4, the wedelolactone pretreatment can obviously reduce the damage degree of the cornea when the mouse model of fungal keratitis is infected for 1 day, and the clinical score of the fungus infection group after the wedelolactone pretreatment is lower than that of the fungus infection group.
3.2 Effect of Wedelia lactone pretreatment on pathological changes of mouse cornea in model of fungal keratitis
FIG. 5 is an electron micrograph (under a 400X microscope) of a keratitis mycotica model mouse in a simple infection group and a wedelolactone pretreatment group, which is established for 1 day and then used for detecting the recruitment of neutrophils by an immunofluorescence technique; fig. 6 is a myeloperoxidase activity scoring result 1 day after establishment of fungal keratitis model mice of the simple infection group and the wedelolactone pretreatment group.
As shown in fig. 5 and 6, wedelolactone pretreatment can significantly reduce the recruitment amount of neutrophils in the cornea when a mouse model of fungal keratitis is infected for 1 day, and the MPO score of a fungus infection group after wedelolactone pretreatment is lower than that of the fungus infection group.
3.3 Effect of Wedelia lactone pretreatment on corneal IL-1 beta secretion of mouse model of fungal keratitis
FIG. 7 is a graph showing the results of using polymerase chain reaction to detect the effect of wedelolactone on the expression of IL-1 β mRNA in the cornea of a mouse model of fungal keratitis; FIG. 8 is a graph showing the results of detection of the effects of wedelolactone on the secretion of IL-1. beta. protein in the cornea of a model mouse with fungal keratitis using Western blotting.
As shown in fig. 7 and 8, polymerase chain reaction experiments show that wedelolactone pretreatment can obviously reduce the mRNA expression of IL-1 beta in the cornea when a fungal keratitis model mouse is infected for 1 day; protein immunoblotting experiments show that wedelolactone pretreatment can obviously reduce the expression of IL-1 beta mature body protein in the cornea when a fungal keratitis model mouse is infected for 1 day.
3.4 Effect of Wedelia lactone pretreatment on corneal Caspase-1 signal pathway of mouse model of fungal keratitis
Figure 9 is a graph of the results of using western blotting to detect the effect of wedelolactone on Caspase-1 activation in the cornea of a model mouse with fungal keratitis.
As shown in figure 9, western blotting experiments show that wedelolactone pretreatment can significantly reduce the expression of Caspase-1 mature body protein in the cornea when a fungal keratitis model mouse is infected for 1 day.
3.5 Effect of Wedelia lactone in combination with natamycin in the treatment of fungal keratitis model mice
FIG. 10 is a graph comparing corneal infections 2 days after treatment of model mice from the natamycin only treatment group and the wedelolactone in combination with natamycin treatment group; fig. 11 is a graph showing the clinical scoring results of model mice treated for 2 days in the natamycin only treatment group and the wedelolactone-combined natamycin treatment group.
As shown in fig. 10 and 11, compared with the natamycin only treatment group, the degree of corneal injury was significantly reduced after the wedelolactone and natamycin combined treatment group model mice were treated for 2 days; the clinical score of the wedelolactone and natamycin combined treatment group was lower than that of the natamycin only treatment group.
It will be understood by those of ordinary skill in the art that the foregoing embodiments are specific examples for carrying out the invention, and that various changes in form and details may be made therein without departing from the spirit and scope of the invention in practice.
Claims (2)
1. Use of wedelolactone in combination with natamycin in the preparation of a medicament for the treatment of fungal keratitis.
2. The pharmaceutical composition for treating fungal keratitis is characterized by comprising wedelolactone, natamycin and pharmaceutically acceptable auxiliary materials.
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