CN110025785A - Hypocrellin A is preparing the application in optical dynamic therapy skin candida albicans infection disease medicament - Google Patents
Hypocrellin A is preparing the application in optical dynamic therapy skin candida albicans infection disease medicament Download PDFInfo
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Abstract
The invention discloses a kind of hypocrellin As to prepare the application in optical dynamic therapy skin candida albicans infection disease medicament.The invention discloses hypocrellin As by inducing albicans cell apoptosis preparing the application in optical dynamic therapy skin candida albicans infection disease.Hypocrellin A significantly reduces the survival rate of Candida albicans under illumination, and it is horizontal to significantly improve ROS in albicans cell；Hypocrellin A in conjunction with illumination after cause Candida albicans cell membrane potential depolarising and cell membrane integrity damage；Fragmentation occurs for the mitochondrial membrane potential decline of Candida albicans, metacaspse increased activity, DNA after being handled with hypocrellin A, and karyopycnosis, cytoplasm and mitochondrial calcium raise.And the light treatment therapy that hypocrellin A mediates is low toxicity and can effectively treat skin candida albicans infection disease.
Description
Technical field
The invention belongs to field of biotechnology, and in particular to a kind of hypocrellin A is preparing optical dynamic therapy skin white
Application in monilial infection disease.
Background technique
Candida albicans can cause table with the host of immunocompromised as a kind of main opportunistic fungi
The infection of face and threat to life.Although the case where threat to life is seldom, the Fungal Skin Infection on these surfaces can be to people
Quality of life cause adverse effect, and become to have in some cases invasive.Topical anti-fungal drug, for example, it is gram mould
Azoles is the most frequently used selection for treating skin candida albicans infection.However, Candida albicans has reported the drug resistance of clotrimazole
Road may also increase the drug resistance of other antifungal drugs.Therefore, it explores and effectively antagonizes skin candida albicans infection
It substitutes antifungal agent or strategy is vital.
Photodynamic therapy (PDT) is the therapeutic choice having recently been developed, it is based on utilizing nontoxic photosensitizer (PS) and nothing
Evil visible light carrys out the generation of induced activity oxygen (ROS), it can kill the microbial pathogens in conjunction with PS.A large number of studies show that
PDT is highly effective in the in vitro and in vivo inactivation of fungi, and fungi cannot generate the resistance to PDT, because this strategy is situated between
The killing led is the process of a non-specificity and multiple target point, this is also advantage of the PDT relative to traditional antifungal agent.In view of working as
The trend that lower Antifungal resistance continues to increase, antimycotic PDT can provide new thinking for the clinical treatment in future.Hypocrellin A
It (HA), is the fat-soluble ester compounds pigment extracted from the fungi of dictyophora phalloidea and bamboo as one kind of PS.This compound,
It is civil common oral drugs, is used to treat stomach trouble and rheumatoid arthritis very early.The red bacterium of bamboo is reported in some researchs
A prime has effective anticancer, antiviral, antibacterial activity.
The research of the existing photodynamics antifungal activity about hypocrellin A is seldom.Chinese patent CN108785291
Application of the hypocrellin in the product for preparing anti-candida albicans is disclosed, which disclose hypocrellins to Candida albicans
The adhesiveness of bacterium, mycelia formed, biofilm formation and it is pathogenic there is good inhibiting effect, also disclose hypocrellin dialogue
The growth of color candida albicans does not influence, and the effect to Candida albicans is not to kill Candida albicans, and mainly pass through suppression
The adhesiveness of Candida albicans processed, mycelia formation, biofilm formation.The antimycotic application of light power about hypocrellin A is also
It has not been reported.
Summary of the invention
In order to solve deficiency in the prior art, the present invention provides a kind of hypocrellin As to prepare optical dynamic therapy skin
Application in skin candida albicans infection disease medicament.
Technical scheme is as follows:
The present invention provides hypocrellin As in preparing optical dynamic therapy skin candida albicans infection disease medicament
Application.
The present invention significantly reduces the survival rate of Candida albicans by hypocrellin A under the illumination of test valid certificates,
It is horizontal to significantly improve ROS in albicans cell；Hypocrellin A in conjunction with illumination after lead to the cell of Candida albicans
Film potential depolarising and cell membrane integrity damage；After being handled with hypocrellin A under the mitochondrial membrane potential of Candida albicans
Fragmentation, karyopycnosis occur for drop, metacaspse increased activity, DNA, and cytoplasm and mitochondrial calcium raise, and the above results show
Hypocrellin A can induce albicans cell apoptosis.
Wherein, the effective concentration of hypocrellin A is 0.5~1.0 μ g/ml.
Wherein, when optical dynamic therapy, light application time is 30~60min.
Wherein, hypocrellin A treats skin infection Candida albicans disease by induction albicans cell apoptosis
Disease.It is in dose dependent that hypocrellin A, which induces albicans cell apoptosis,.
The present invention also provides a kind for the treatment of or the drug of adjuvant treatment skin candida albicans infection disease, the medicines
It include hypocrellin A in object.
Wherein, the effective concentration of hypocrellin A is 0.5~1.0 μ g/ml.
Further, the drug also contains one or more pharmaceutically acceptable carriers or auxiliary material.
Beneficial effects of the present invention: present invention firstly provides hypocrellin As to pass through induction albicans cell apoptosis
Preparing the application in optical dynamic therapy skin candida albicans infection disease medicament.Hypocrellin A significantly reduces under illumination
It is horizontal to significantly improve ROS in albicans cell for the survival rate of Candida albicans；After hypocrellin A is in conjunction with illumination
Lead to the cell membrane potential depolarising and cell membrane integrity damage of Candida albicans；Candida albicans after being handled with hypocrellin A
The mitochondrial membrane potential of bacterium declines, metacaspse increased activity, and fragmentation occurs for DNA, and karyopycnosis, cytoplasm and mitochondrial calcium are equal
Up-regulation.And the light treatment therapy that hypocrellin A mediates is low toxicity and can effectively treat skin candida albicans infection disease
Disease.
Detailed description of the invention
Fig. 1 is the influence that the hypocrellin A of various concentration grows Candida albicans SC5314；
Fig. 2 is shadow of the hypocrellin A to Candida albicans SC5314 cell survival rate of the various concentration under lighting process
It rings；
Fig. 3 is the hypocrellin A of the various concentration under lighting process to Candida albicans ATCC18804 cell survival rate
Influence；
Fig. 4 is shadow of the hypocrellin A to 07318 cell survival rate of Candida albicans of the various concentration under lighting process
It rings；
Fig. 5 is influence of the hypocrellin A to Candida albicans SC5314 intracellular ROS level under lighting process；
Fig. 6 is influence of the hypocrellin A to Candida albicans ATCC18804 intracellular ROS level under lighting process；
Fig. 7 is influence of the hypocrellin A to 07318 intracellular ROS level of Candida albicans under lighting process；
Fig. 8 is influence of the hypocrellin A to Candida albicans SC5314 cell membrane potential under lighting process；
Fig. 9 is influence of the hypocrellin A to Candida albicans SC5314 cell membrane integrity under lighting process；
Figure 10 is influence of the hypocrellin A to Candida albicans ATCC18804 cell membrane potential under lighting process；
Figure 11 is influence of the hypocrellin A to 07318 cell membrane potential of Candida albicans under lighting process；
Figure 12 is influence of the hypocrellin A to Candida albicans ATCC18804 cell membrane integrity under lighting process；
Figure 13 is influence of the hypocrellin A to 07318 cell membrane integrity of Candida albicans under lighting process；
Figure 14 is influence of the hypocrellin A to Candida albicans SC5314 mitochondrial membrane potential under lighting process；
Figure 15 is that hypocrellin A is active to metacaspase in Candida albicans SC5314 cell under lighting process
It influences；
Figure 16 is influence of the hypocrellin A to Candida albicans ATCC18804 mitochondrial membrane potential under lighting process；
Figure 17 is influence of the hypocrellin A to 07318 mitochondrial membrane potential of Candida albicans under lighting process；
Figure 18 is that hypocrellin A is living to metacaspase in Candida albicans ATCC18804 cell under lighting process
The influence of property；
Figure 19 is that hypocrellin A is active to metacaspase in 07318 cell of Candida albicans under lighting process
It influences；
Figure 20 is influence of the hypocrellin A to Candida albicans SC5314 cellular DNA fragments under lighting process；
Figure 21 is influence of the hypocrellin A to Candida albicans SC5314 nuclear condensation under lighting process；
Figure 22 be under lighting process hypocrellin A to the shadow of DNA fragmentation in Candida albicans ATCC18804 cell
It rings；
Figure 23 is influence of the hypocrellin A to DNA fragmentation in 07318 cell of Candida albicans under lighting process；
Figure 24 be under lighting process hypocrellin A to Candida albicans ATCC18804 and 07318 nuclear condensation
It influences；
Figure 25 is influence of the hypocrellin A to Candida albicans SC5314 cytoplasmic calcium levels under lighting process；
Figure 26 is influence of the hypocrellin A to Candida albicans SC5314 mitochondrial calcium level under lighting process；
Figure 27 is influence of the hypocrellin A to Candida albicans ATCC18804 cytoplasmic calcium levels under lighting process；
Figure 28 is influence of the hypocrellin A to 07318 cytoplasmic calcium levels of Candida albicans under lighting process；
Figure 29 is influence of the hypocrellin A to Candida albicans ATCC18804 mitochondrial calcium level under lighting process；
Figure 30 is influence of the hypocrellin A to Candida albicans 07318 mitochondrial calcium level under lighting process；
Figure 31 is therapeutic effect of the hypocrellin A to mouse skin infection Candida albicans under lighting process；
Figure 32 is influence of the hypocrellin A to mouse skin toxicity under lighting process.
Specific embodiment
The present invention is carried out below with reference to embodiment explanation is explained in detail.
The main bacterial strain and reagent used in the present invention:
Three kinds of albicans strains (SC5314, ATCC18804 and 07318) has been used in the present invention.All bacterial strains
At 30 DEG C using shaking table culture case YPD culture medium (1% yeast extract (Oxoid, Basingstoke, England),
Routinely be incubated overnight in 2% peptone (Solarbio, Beijing, China) and 2% glucose (Solarbio) (200 turns/
min)。
Hypocrellin A (HA) is purchased from Tauto Biotech (Chinese Shanghai), is dissolved in 100% dimethyl sulfoxide (DMSO)
In, prepare hypocrellin A (1.0mg/ml) stock solution.It is stored up by filter sterilizing solution and in the dark surrounds at -20 DEG C
It deposits, uses no more than one week.
Statistical analysis:
Each experiment is at least independently done three times in following embodiments, and data are expressed as mean+SD.As a result it uses
SPSS software is analyzed.Using the Dunnett Multiple range test test after one-way analysis of variance.Asterisk indicates statistical significance
(P < 0.001 * P < 0.05, * * P < 0.01, * * *).
Embodiment 1:The antifungal activity of hypocrellin A is tested
By albicans strain SC5314, ATCC18804 and 07318 overnight culture respectively in YPD culture medium
Then activation culture handles 30min with 0.5 and 1.0 μ g/ml hypocrellin As respectively under 50W tungsten halogen lamp to logarithmic phase；Processing
The luminous intensity at position is 30mW/cm2.Continue after culture is cultivated 3h in the dark, collect cell and is layered on YPD Agr
On plate, is incubated at 30 DEG C and count colony forming single-digit (CFU) afterwards for 24 hours, experiment is independent in triplicate.
In order to observe influence of the hypocrellin A to albicans growth, bamboo is used in the case where having illumination and no light
Red fungus beetle element handles SC5314 bacterial strain.As shown in the result of Fig. 1, in the case where illumination, hypocrellin A is to Candida albicans
The growth of bacterium cell has not significant impact.As shown in the result of Fig. 2, upon irradiation between reach 30min, compared with the control group, bamboo
The survival rate of the albicans cell of red fungus beetle element processing is significantly reduced with dosage-dependent manner, shows that hypocrellin A is situated between
The PDT led significantly reduces the survival of Candida albicans.As Fig. 3,4 result shown in, hypocrellin A mediate PDT to two kinds
The survival of clinical strains ATCC18804 and 07318 has apparent inhibiting effect.
Embodiment 2:Intracellular ROS measurement after hypocrellin A processing
Using 2', it is horizontal that 7'- dichlorofluorescein diacetate esters (DCFH-DA) measure the ROS in albicans cell.
DCFH-DA can be converted into the impermeable reagent D CFH of film by intracellular esterase, its fluorescence then can be quickly oxidized to by ROS
Derivative DCF.The fluorescence intensity of DCF can indicate that the generation of ROS is horizontal.Overnight Candida albicans culture is collected, and dilute
It releases to 106cells/ml.It is incubated for logarithmic phase, after handling 30min with hypocrellin A under light illumination, in the dark by cell
It is incubated for 3h.Then, albicans cell is collected, washed once with YPD culture medium, and is contaminated in the dark with 10 μM of DCFH-DA
Color 30min.Finally using the green of FACSCalibur flow cytometer (Becton Dickinson, USA) analysis resuspension cell
Color fluorescence intensity.
As shown in the result of Fig. 5, hypocrellin A treatment significantly improves ROS level in a manner of dose-dependent.Such as figure
6, shown in 7 result, hypocrellin A is also observed in described two clinical strains ATCC18804 and 07318 to ROS level
Influence, it is horizontal that hypocrellin A equally can increase Candida albicans ROS.The above results show that hypocrellin A processing can draw
Play ROS accumulation in albicans cell.
Embodiment 3: plasmalemma potential is assessed after hypocrellin A processing
The present invention is using DiBAC4 (3) staining evaluation cell membrane potential of albicans strain.DiBAC4 (3) is one
Kind plasma membrane potential sensitive fluorescence probe exists only in the perimeter of plasma membrane in normal cell.However, cell membrane
Depolarising can lead to its inflow, and probe is in conjunction with the compound rich in lipid and leads to fluorescence enhancement.As previously described using film electricity
Position molecular probe DiBAC4 (3) assesses the variation of plasmalemma potential, and centrifugation collects processed Candida albicans and washs three with PBS
It is resuspended after secondary, 20 μ g/ml film potential sensitive dye DiBAC4 (3) is added in PBS, and by sample under 37 DEG C of dark condition
Incubate 30min.The percentage of the albicans cell depolarized in suspension is measured by flow cytometer.
The present invention is using the PI staining evaluation cell membrane integrity of albicans strain.PI is that a kind of DNA insertion is glimmering
Photoinitiator dye not can enter complete cell.When damaged membrane, fluorescence probe can enter cytoplasm and in conjunction with DNA.It is glimmering
Light probe is commonly used in the integrality of research cell membrane.Concrete operations are as follows: will collect the Candida albicans of processing, concentration is added
For the propidium iodide (PI) of 10 μ g/ml, 30min is incubated under the dark condition at 4 DEG C.The red bacterium of bamboo is measured by flow cytometer
The integrality of A prime treated albicans cell film.
As shown in the result of Fig. 8, hypocrellin A processing significantly increases the cell percentages dyed by DiBAC4 (3),
Show that the PDT that hypocrellin A mediates leads to the reduction of Candida albicans plasmalemma potential.As shown in the result of Fig. 9, hypocrellin A
The PDT of mediation is to a certain extent induction of the damage of cell membrane.As shown in figures 10-13, hypocrellin A processing results in two
The membrane depolarization and permeability of a clinical strains ATCC18804 and 07318 enhances.The above results show hypocrellin A
Processing influences the cell membrane of Candida albicans.
Embodiment 4:Mitochondrial membrane potential and metacaspase determination of activity after hypocrellin A processing
Mitochondria is not only one of the target of one of prime producer of active oxygen and active oxygen.The exception of ROS level
Increase will lead to mitochondria dysfunction.To evaluate mitochondrial function, the present invention determines mitochondrial transmembrane potentials.And in order to demonstrate,prove
Influence of the PDT that real hypocrellin A mediates to Candida albicans apoptosis determines metacaspase activity.
With 5,5', 6,6'- tetra- chloro- 1,1', 3,3'- tetraethyls-benzimidazolyl carbocyanine iodide (JC-1) measure line
The variation of mitochondrial membrane potential.Specifically, the Candida albicans for collecting hypocrellin A processing, by washing, and with 2.5 μ g/
Ml JC-1 dyes 20min in the dark.It is washed twice later with PBS, finally uses flow cytometry analysis cell.It calculates poly-
The ratio of the fluorescence intensity of collective JC-1 (FL2) and monomer (FL1).
Use CaspACE FITCVAD-FMK labeled in situ object (Promega) detection metacaspase activity.It will processing
Then the Candida albicans centrifugation crossed, washing are dyed under 30 DEG C of dark condition with 10 μM of CaspACEFITC-VAD-FMK
30min.And then secondary washing cell and use flow cytomery.
As shown in the result of Figure 14, mitochondrial membrane potential is significantly reduced after hypocrellin A processing.Such as the result institute of Figure 15
Show, after hypocrellin A processing, metacaspase is significantly activated with concentration dependant manner.As shown in the result of Figure 16-19,
Hypocrellin A also induction of two kinds of clinical strains ATCC18804 and 07318 mitochondrial membrane potential depolarising and
Metacaspase activation tentatively shows the PDT of hypocrellin A mediation induction of Candida albicans apoptosis.
Embodiment 5The measurement of DNA fragmentation and core concentration after hypocrellin A processing
In order to which whether the PDT for further confirming that hypocrellin A mediates can induce albicans cell apoptosis, Wo Menguan
Observe two important apoptosis marks: DNA fragmentation and core concentration.
Use TUNEL chromoscopy DNA fragmentation.It collects processed cell and is washed with PBS, then more than 3.6%
30min is fixed in polyformaldehyde, and permeabilization 2min on ice.After washing cell again with PBS, is detected and tried using cells in situ death
Agent box dyes 1h at 37 DEG C, and is measured with flow cytometer.
Core concentration and apoptosis or necrosis are assessed by Apoptosis and necrosis test kit.It collects, washed cell,
At 4 DEG C, 20-30min is dyed with 5 μ g/mlhoechst33342 and 5 μ g/ml PI.Then, cell is washed again and uses streaming
Cell instrument measurement.
As shown in the result of Figure 20, with the increase of hypocrellin A concentration, fluorescence intensity enhancing shows hypocrellin A
Processing results in DNA break.Core can be caused to be concentrated to study hypocrellin A, we are bis- using Hoechst 33342/PI
To treated, cell has carried out double dyes to decoration method, which can also show Apoptosis.Normal cell in it is weak it is red/
Weak blue-fluorescence, apoptotic cell are in Qiang Hongse/strong blue-fluorescence in weak red/strong blue-fluorescence, non-viable non-apoptotic cell.Strong blue
Fluorescence shows that treated, and nuclear condensation has occurred in cell.As shown in the result of Figure 21, the white of hypocrellin A processing is read
Pearl bacterium cells show goes out three kinds of fluorescence, including weak red/weak blue-fluorescence, weak red/strong blue-fluorescence and Qiang Hongse/strong blue
Fluorescence shows HA processing other than causing necrosis, also induction of core concentration and apoptosis.In order to further confirm the above results, I
Also to above two clinical strains carried out TUNEL and Hoechst 33342/PI dyeing, as shown in the result of Figure 22-24,
Similar to SC5314 bacterial strain, the ATCC18804 of hypocrellin A processing and 07318 strains expressed go out DNA fragmentationization and concentration
Nucleus, these are the result shows that hypocrellin A is handled induction of Candida albicans apoptosis.
Embodiment 6:Cytoplasmic calcium and mitochondria calcium catalyst after hypocrellin A processing
Detect the variation of cytoplasm and mitochondrial calcium level respectively using Fluo-3AM and Rhod-2AM.It collects processed
Candida albicans washes twice, and is resuspended in 500 μ l HBSS buffers.In order to measure the content of calcium in cytoplasm, it is added
For Fluo-3AM to final concentration of 2 μM, 40min is hatched in dark place at 30 DEG C, washs cell again, is resuspended in 600 μ l HBSS buffering
In liquid, hatch 20min at 30 DEG C.In order to measure mitochondrial calcium content, Rhod-2AM is added to final concentration of 4 μM, at 37 DEG C
30min is hatched in lower dark place, immediately using flow cytometer check Fluo-3AM (excitation 3AM=480nm, transmitting=526nm) and
The fluorescence intensity of Rhod-2AM (excitation=550nm, transmitting=580nm).
As shown in the result of Figure 25 and 26, in the albicans cell handled with hypocrellin A, fluorescence intensity is aobvious
It writes and increases.As shown in the result of Figure 27-30, two kinds of clinical strains also show that similar calcium variation.It is all these the result shows that,
Hypocrellin A causes cytoplasm and mitochondrial calcium to accumulate.
Embodiment 7:The mouse model of skin wound infection
With the detection hypocrellin A treatment Candida albicans skin infection of 7~8 week old ICR female mices (25~30g)
Curative effect.Before wound formation, mouse is anaesthetized by the way that yellow Jackets (50mg/kg) is injected intraperitoneally, then in back table
Face shaving.The skin of mouse is cut by scissors causes wound.Each wound measures about 0.8 × 0.8cm.Then with a drop (25 μ l)
Contain 106The culture solution of CFU Candida albicans is inoculated with the surface of each wound, is applied to wound surface with oese.By mouse
Be divided into following four groups: untreated fish group, Candida albicans SC5314 infected group, Candida albicans SC5314 infect+0.5 μ g/ml bamboo
Red fungus beetle element group, Candida albicans SC5314 infect+1.0 μ g/ml hypocrellin A groups.Every group of 6 mouse.After infecting 30min,
The hypocrellin A of shown concentration, illumination 30min, in the 2-7 days superinfection Candida albicans and painting are smeared to each wound
Smear hypocrellin A.8th day observation wound.In order to evaluate hypocrellin A toxicity, with the red bacterium of bamboo of 0.5 and 1.0 μ g/ml concentration
A prime smears mouse skin, irradiates 30min daily, continues 7 days.Every group of 6 mouse.8th day observation skin.
As shown in the result of Figure 31, the PDT that hypocrellin A mediates significantly reduces Candida albicans skin infection.In order to
The toxicity for detecting hypocrellin A smears the normal mouse skin being uninfected by with the hypocrellin A that concentration is 0.5 and 1.0 μ g/ml
Skin, and irradiate 30min.As shown in the result of Figure 32, through being not significantly different between processing and untreated mouse skin, table
It is bright concentration be lower than 1.0 μ g/ml in the case where, hypocrellin A does not have toxicity to mouse skin.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modification, equivalent replacement and simple modifications etc., should all be included in the protection scope of the present invention in content.
Claims (7)
1. hypocrellin A is preparing the application in optical dynamic therapy skin candida albicans infection disease medicament.
2. application according to claim 1, which is characterized in that the effective concentration of hypocrellin A is 0.5~1.0 μ g/ml.
3. application according to claim 1, which is characterized in that when optical dynamic therapy, light application time is 30~60min.
4. application according to claim 1, which is characterized in that hypocrellin A passes through induction albicans cell apoptosis
To treat skin infection Candida albicans bacterial diseases.
5. the drug of a kind for the treatment of or adjuvant treatment skin candida albicans infection disease, which is characterized in that in the drug
Include hypocrellin A.
6. the drug for the treatment of according to claim 5 or adjuvant treatment skin candida albicans infection disease, feature
It is, the effective concentration of hypocrellin A is 0.5~1.0 μ g/ml.
7. the drug for the treatment of according to claim 5 or adjuvant treatment skin candida albicans infection disease, feature
It is, the drug also contains one or more pharmaceutically acceptable carriers or auxiliary material.
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