莳萝子挥发油抗真菌活性及其作用机制研究
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摘要
随着广谱抗生素、糖皮质激素、免疫抑制剂等广泛的应用,念珠菌和皮肤癣菌等真菌引起的真菌感染日益增加,临床真菌感染的发病率和死亡率呈逐年上升趋势。目前,临床常用抗真菌药物主要是唑类药物和两性霉素B,这些抗真菌药物均对人体有不同程度的毒副作用；且随着抗真菌药物的广泛应用,临床上出现越来越严重的真菌耐药现象。因此,临床上迫切需要寻找一种新的抗真菌药物来治疗真菌感染。
挥发油是植物体内次生代谢产物之一。据报道,挥发油具有抗菌驱虫、抗炎、抗病毒、抗氧化、抗肿瘤、解热镇痛、祛痰止咳等多种生物活性。莳萝子是伞形科草本植物莳萝的种子,具有香气。其挥发油具有降血脂、抗氧化、抗菌等多种生物活性。
本研究是以莳萝子挥发油为研究对象,研究其体外体内抗菌活性和抗菌机制。
1.采用水蒸气蒸馏法,提取莳萝子挥发油。并研究莳萝子存储时间对挥发油得率和抗菌活性的影响。实验结果表明,随着储存时间的延长,莳萝子挥发油得率有所降低,储存一年后,莳萝子挥发油得率降低了39.02%。采用GC-MS对莳萝子挥发油进行分析,从莳萝子挥发油中共鉴定出23个化合物,占总含量的99.4%。主要物质有香芹酮(41.5%),柠檬烯(32.6%)及芹菜脑(16.8%)等。采用高效气相色谱法,依据香芹酮和柠檬烯标准曲线测定了不同储存时间莳萝子的挥发油中香芹酮和柠檬烯的含量,分析和评价储存时间对莳萝子挥发油主要成分(香芹酮和柠檬烯)含量的影响。结果表明,储存时间对莳萝子挥发油主成分(香芹酮和柠檬烯)的含量基本上没有影响。
2.采用美国临床实验室标准化委员会(NCCLS)制定的真菌敏感性测定方案(M38-A2)采用微量稀释法测定莳萝子挥发油对皮肤癣菌的最低抑菌浓度(MIC),用带毒平板法测定莳萝子挥发油对皮肤癣菌菌丝抑制作用。研究莳萝子挥发油对皮肤癣菌孢子萌发和生物量的影响。进一步以红色毛癣菌为代表菌株,研究莳萝子挥发油对皮肤癣菌细胞膜中麦角固醇含量、线粒体中苹果酸脱氢酶、琥珀酸脱氢酶、三磷酸腺苷酶活性的影响。结果表明莳萝子挥发油抑制皮肤癣菌MIC为0.156-0.312μL/mL。当莳萝子挥发油浓度为1.25μL/mL时能完全抑制皮肤癣菌菌丝生长。不同浓度莳萝子挥发油对皮肤癣菌孢子萌发和生物量都有抑制作用,与浓度呈正相关。莳萝子挥发油处理红色毛癣菌后能减少细胞膜中麦角固醇的合成,降低线粒体中苹果酸脱氢酶、琥珀酸脱氢酶、三磷酸腺苷酶活性,表明莳萝子挥发油通过破坏细胞膜和线粒体达到抗菌效果。
3.采用美国临床实验室标准化委员会(NCCLS)制定的真菌敏感性测定方案(M27-A3)采用微量稀释法测定莳萝子挥发油对念珠菌(Candida spp.)的最低抑菌浓度(MIC)；在液体培养基中,观察不同浓度莳萝子挥发油对Candida spp生长曲线的影响以及Candida spp经莳萝子挥发油处理后的芽管萌发情况。由实验结果可知莳萝子挥发油对Candida spp具有较强抑制作用,MIC为0.312-0.625μL/mL；莳萝子挥发油在浓度为1.25-2.5μL/mL范围内能完全抑制Candida spp生长；由芽管萌发实验可知,莳萝子挥发油浓度为0.625μL/mL时,白色念珠菌(C.albicans09-1522)、克柔念珠菌(C. krusei09-1681)、热带念珠菌(C. tropicalis032)、近平滑念珠菌(C.parpapsilosis07-305)芽管形成率分别为3.33%、2.33%、1.67%、1.33%,说明莳萝子挥发油能抑制Candida spp芽管萌发。进一步用XTT法测定莳萝子挥发油对Candida spp生物膜形成的抑制作用,结果表明当莳萝子挥发油浓度大于0.312μL/mL能抑制(Candida spp生物膜的形成。用XTT法检测莳萝子挥发油对Candidaspp.成熟生物膜的活性的影响,结果表明,莳萝子挥发油能降低Candida spp生物膜的活性。比较莳萝子挥发油对Candida spp生物膜和悬浮细胞的抑制作用,结果表明挥发油抑制悬浮细胞作用强于生物膜。
4.采用小鼠免疫抑制模型进行体内实验,评价莳萝子挥发油对阴道念珠菌病的预防和治疗作用。结果表明莳萝子挥发油浓度为2%(v／v)能清除小鼠阴道C.albicans,真菌检验和组织病理检查证明了莳萝子挥发油对阴道念珠菌病有较强的防治作用。
5.以细胞膜和线粒体为靶标点研究莳萝子挥发油对C.albicans的抗菌机制,采用碘化吡啶染色法测定莳萝子挥发油对C.albicans细胞膜的损坏,结果表明莳萝子挥发油能严重破坏C.albicans的细胞膜。本实验进一步测定莳萝子挥发油对C.albicans线粒体功能的影响。采用罗丹明染色法测定莳萝子挥发油作用后C.albicans的线粒体膜电势、分光光度法测定线粒体脱氢酶活性、染色法测定线粒体内活性氧含量。结果表明莳萝子挥发油导致C.albicans线粒体膜电势超级化和线粒体内脱氢酶的活性被显著抑制。莳萝子挥发油所致线粒体功能的异常导致线粒体内活性氧累积,抗氧化剂半胱氨酸不但可以抑制莳萝子挥发油诱导的线粒体内活性氧累积,而且可以抑制莳萝子挥发油的抗真菌活性,说明活性氧是莳萝子挥发油发挥抗真菌作用的关键介质。
6.活性氧是真菌凋亡的关键调节因子,因此,本实验进一步研究莳萝子挥发油诱导C.albicans线粒体活性氧累积是否导致真菌凋亡。采用透射电镜观察莳萝子挥发油作用于C.albicans后细胞超微结构的改变,采用共聚焦显微镜观察DAPI染色后细胞核的形态变化,FITC-AnnexinV染色后C.albicans磷脂酰丝氨酸的外翻、FITC-VAD-FMK荧光染色法测定莳萝子挥发油作用后白色念珠菌(C.albicans)的Metacaspase活性,分光光度法测定线粒体内细胞色素C含量。结果表明莳萝子挥发油导致C.albicans出现典型的凋亡特征,如染色质凝集、细胞核浓缩和磷脂酰丝氨酸的外翻,说明莳萝子挥发油导致了C.albicans细胞凋亡。莳萝子挥发油促进C.albicans线粒体内细胞色素C的释放,并激活了Metacaspase。抗氧化剂半胱氨酸抑制挥发油导致的细胞核裂解,磷脂酰丝氨酸的外翻以及Metacaspase的活化,提示活性氧是莳萝子挥发油导致细胞凋亡的重要介质,实验结果表明莳萝子挥发油通过引起C.albicans线粒体活性氧累积,进而激活Metacaspase诱导真菌凋亡,从而发挥其抗真菌作用。
The incidence of fungal infections (such as Candida spp. and Dermatophyte) has increased dramatically, causing high morbidity and mortality. The more the broad-spectrum antibiotics, corticosteroids, immunosuppressive agents are used by humans, the easlier they get fungal infections. Currently, with the large scale application of broad-spectrum antifungal agents and the introduction of protocols for antifungal prophylaxis in patients at risk, there has been a notable increase in drug resistance. The development of more effective antifungal therapies is therefore of paramount importance.
Essential oil is one of secondary metabolites in plants. It is reported that essential oil has antibacterial insecticide, anti-inflammatory, antiviral, antioxidant, antitumor, antipyretic and analgesic, expectorant cough and other biological activity. A. graveolens (dill), one of species of Umbelliferae, is a traditional Chinese herb. Dill seed essential oil have antioxidant, antimicrobial and other biological activity.
In this paper, the activities (in vitro and in vivo) and mechanism of the seed of Anethum graveolens L. against fungal were researched.
1. The dill seed essential oil was obtained by steam distillation. The chemical composition of the DSEO was analyzed by gas chromatography-mass spectral (GC-MS) spectroscopy. Twenty-three compounds, constituting about99.4%of the total essential oil, were identified. The most abundant oil components are carvone (41.5%), limonene (32.6%), apiole (16.8%).We study the storage of dill seeds at different time on the yield and main composition of DSEO. Besides, antifungal activity of DSEO on Candida spp. and dermatophytes when dill seeds storage different time. The results showed that the yield of DSEO was reduced. The yield of DSEO was reduced39.02%after storage one year. The storage time of dill seeds had little effect on the content of carvone and limonene.
2. The microbroth dilution method was used in the minimal inhibitory concentration (MIC), according to M38-A2of the guidelines of the Clinical and Laboratory Standard Institute (CLSI). The effect of DSEO on hyphal growth of dermatophyte by agar dilution method. And then, we study DSEO on spore germination and biomass of dermatophyte. The results showed that DSEO was active in vitro against all tested strains, with MICs ranging from0.156-0.312μL/mL for dermatophyte. All tested stains were completely inhibited by DSEO at1.25μL/mL. The spore germination of dermatophyte were inhibited, and the biomass of dermatophyte were reduced on dose-dependent by DSEO.The further study the effect of DSEO on ergosterol content, and the activity of the Malate Dehydrogenase (MDH), Succinate Dehydrogenase (SDH), T-ATPase of T. rubrum ATCC40051. The results showed that ergosterol biosynthesis were inhibited and the activities of MDH, SDH andT-ATPase of T. rubrum ATCC40051were reduced by DSEO. It means that DSEO antidermatophytic through mitochondrial and membrance dysfunction
3. The microbroth dilution method was used in the minimal inhibitory concentration (MIC), according to M27-A3of the guidelines of the Clinical and Laboratory Standard Institute (CLSI). And then, Growth curves and germ tube formation of Candida spp. inhibited by DSEO. The results showed essential oil was active in vitro against all tested strains, with MICs ranging from0.312-0.625μL/mL for Candida spp. All tested stains were completely inhibited bydill seed essential oil at1.25-2.5μL/mL.The germ tube formation rate were3.33%,2.33%,1.67%,1.33%for C. albicans09-1522、C. krusei09-1681、C. tropicalis032、C. parpapsilosis07-305, respectively, while the dill seed essential oil concentration at0.625μL/mL, it means that the germ tube formation were inhibited by dill seed essential oil. Further,
The biofilm metabolic activity of Candida spp. were measured by XTT reduction assay.The result showed that dill seed essential oil severly inhibited Candida spp.strains from forming biofilms at concentrations>0.312μL/mL. Candida spp. strains biofilms treated with dill seed essential oil showed a significant reduction in metabolic activity when viability was measured by XTT reduction assay.The susceptibility of fungal biofilms to dill seed essential oil was investigated and compared with that of planktonic yeast cells. The result showed Candida spp. biofilms were significantly more resistant to dill seed essential oil than their planktonic counterparts.
4. Efficacy evaluation of essential oil in the prophylaxis and treatment of experimental vaginal candidiasis was performed in immunosuppressed mice. The anti-Candida activity was analyzed by microbiological and histological techniques and was compared with that of fluconazole (FCZ). Essential oil (2%v/v) was highly efficacious in accelerating C. albicans09-1555clearance from experimentally infected mice vagina by prophylaxis and therapeutic treatments. In both therapeutic efficacy and prophylaxis studies, the histological findings confirmed the microbiological results. The experimental results revealed that the tested essential oil is effective against vulvovaginal candidiasis in immunosuppressed mice.
5. Effect of dill seed essential oil on membrane of Candida albicans by pyridine iodine staining and UVspectrophotometry. The result showed that membrane of Candida albican were severly damaged by dill seed essential oil. We assayed the mitochondrial membrane potential (mtAy) using rhodamine123and detected the antivities of mitochondrial dehydrogenases by spectrophotometry. Besides, the mitochondrial dysfunction-induced reactive oxygen species (ROS) production was determined by a fluorometric assay, and the effects of antioxidant L-cysteine on DSEO-induced ROS production and the antifungal effect of DSEO on C.albicans were also investigated. The results showed that exposure to DSEO resulted in an elevation of (mtΔΨ) and inhibition of the mitochondrial dehydrogenases. The dysfuntions of mitochondria caused ROS accumulation in C.albicans, and the increase in the level of ROS production and DESO-induced decrease in cell viability were prevented by addition of L-cysteine, indicating that ROS was an important mediator of the antifungal action of DSEO. In summary, DSEO exert its antifungal activity through mitochondrial dysfunction induced ROS accumulation in C.albicans.
6. The ROS are a key regulator to yeast apoptosis. As a consequence, the further study was designed to investigate whether DSEO induced apoptosis in C.albicans.We observed the ultrastructure by transmission electron microscopy, studied the nuclear fragmentation by DAPI staining, and investigated the expore of phosphatidylserine at the outer layer of the cytoplasmic membrane by the FITC-Annexin V staining. Besides, the activity of metacaspase was detected by FITC-V AD-FMK staining, and the release of cytochrome C from mitochondria was also determined. Furthermore, the effect of antioxidant L-cysteine on DSEO-induced apoptosis in C.albicans was also investigated. The results showed that cells treated with DSEO showed typical markers of apoptosis, such as phosphatidylserine exposure, nuclear fragmentation, chromatin condensation. Besides, DSEO promoted the cytochrome C release and activated the metacaspase, which resulted in the yeast apoptosis. The addition of L-cysteine prevented DSEO-induced nuclear fragmentation, phosphatidylserine exposure, and metacaspase activation, indicating the ROS was an important mediator of DSEO-induced apoptosis. In summary, DSEO induced apoptosis in C.albicans through a metacaspase-dependent apoptotic pathway.
挥发油是植物体内次生代谢产物之一。据报道,挥发油具有抗菌驱虫、抗炎、抗病毒、抗氧化、抗肿瘤、解热镇痛、祛痰止咳等多种生物活性。莳萝子是伞形科草本植物莳萝的种子,具有香气。其挥发油具有降血脂、抗氧化、抗菌等多种生物活性。
本研究是以莳萝子挥发油为研究对象,研究其体外体内抗菌活性和抗菌机制。
1.采用水蒸气蒸馏法,提取莳萝子挥发油。并研究莳萝子存储时间对挥发油得率和抗菌活性的影响。实验结果表明,随着储存时间的延长,莳萝子挥发油得率有所降低,储存一年后,莳萝子挥发油得率降低了39.02%。采用GC-MS对莳萝子挥发油进行分析,从莳萝子挥发油中共鉴定出23个化合物,占总含量的99.4%。主要物质有香芹酮(41.5%),柠檬烯(32.6%)及芹菜脑(16.8%)等。采用高效气相色谱法,依据香芹酮和柠檬烯标准曲线测定了不同储存时间莳萝子的挥发油中香芹酮和柠檬烯的含量,分析和评价储存时间对莳萝子挥发油主要成分(香芹酮和柠檬烯)含量的影响。结果表明,储存时间对莳萝子挥发油主成分(香芹酮和柠檬烯)的含量基本上没有影响。
2.采用美国临床实验室标准化委员会(NCCLS)制定的真菌敏感性测定方案(M38-A2)采用微量稀释法测定莳萝子挥发油对皮肤癣菌的最低抑菌浓度(MIC),用带毒平板法测定莳萝子挥发油对皮肤癣菌菌丝抑制作用。研究莳萝子挥发油对皮肤癣菌孢子萌发和生物量的影响。进一步以红色毛癣菌为代表菌株,研究莳萝子挥发油对皮肤癣菌细胞膜中麦角固醇含量、线粒体中苹果酸脱氢酶、琥珀酸脱氢酶、三磷酸腺苷酶活性的影响。结果表明莳萝子挥发油抑制皮肤癣菌MIC为0.156-0.312μL/mL。当莳萝子挥发油浓度为1.25μL/mL时能完全抑制皮肤癣菌菌丝生长。不同浓度莳萝子挥发油对皮肤癣菌孢子萌发和生物量都有抑制作用,与浓度呈正相关。莳萝子挥发油处理红色毛癣菌后能减少细胞膜中麦角固醇的合成,降低线粒体中苹果酸脱氢酶、琥珀酸脱氢酶、三磷酸腺苷酶活性,表明莳萝子挥发油通过破坏细胞膜和线粒体达到抗菌效果。
3.采用美国临床实验室标准化委员会(NCCLS)制定的真菌敏感性测定方案(M27-A3)采用微量稀释法测定莳萝子挥发油对念珠菌(Candida spp.)的最低抑菌浓度(MIC)；在液体培养基中,观察不同浓度莳萝子挥发油对Candida spp生长曲线的影响以及Candida spp经莳萝子挥发油处理后的芽管萌发情况。由实验结果可知莳萝子挥发油对Candida spp具有较强抑制作用,MIC为0.312-0.625μL/mL；莳萝子挥发油在浓度为1.25-2.5μL/mL范围内能完全抑制Candida spp生长；由芽管萌发实验可知,莳萝子挥发油浓度为0.625μL/mL时,白色念珠菌(C.albicans09-1522)、克柔念珠菌(C. krusei09-1681)、热带念珠菌(C. tropicalis032)、近平滑念珠菌(C.parpapsilosis07-305)芽管形成率分别为3.33%、2.33%、1.67%、1.33%,说明莳萝子挥发油能抑制Candida spp芽管萌发。进一步用XTT法测定莳萝子挥发油对Candida spp生物膜形成的抑制作用,结果表明当莳萝子挥发油浓度大于0.312μL/mL能抑制(Candida spp生物膜的形成。用XTT法检测莳萝子挥发油对Candidaspp.成熟生物膜的活性的影响,结果表明,莳萝子挥发油能降低Candida spp生物膜的活性。比较莳萝子挥发油对Candida spp生物膜和悬浮细胞的抑制作用,结果表明挥发油抑制悬浮细胞作用强于生物膜。
4.采用小鼠免疫抑制模型进行体内实验,评价莳萝子挥发油对阴道念珠菌病的预防和治疗作用。结果表明莳萝子挥发油浓度为2%(v／v)能清除小鼠阴道C.albicans,真菌检验和组织病理检查证明了莳萝子挥发油对阴道念珠菌病有较强的防治作用。
5.以细胞膜和线粒体为靶标点研究莳萝子挥发油对C.albicans的抗菌机制,采用碘化吡啶染色法测定莳萝子挥发油对C.albicans细胞膜的损坏,结果表明莳萝子挥发油能严重破坏C.albicans的细胞膜。本实验进一步测定莳萝子挥发油对C.albicans线粒体功能的影响。采用罗丹明染色法测定莳萝子挥发油作用后C.albicans的线粒体膜电势、分光光度法测定线粒体脱氢酶活性、染色法测定线粒体内活性氧含量。结果表明莳萝子挥发油导致C.albicans线粒体膜电势超级化和线粒体内脱氢酶的活性被显著抑制。莳萝子挥发油所致线粒体功能的异常导致线粒体内活性氧累积,抗氧化剂半胱氨酸不但可以抑制莳萝子挥发油诱导的线粒体内活性氧累积,而且可以抑制莳萝子挥发油的抗真菌活性,说明活性氧是莳萝子挥发油发挥抗真菌作用的关键介质。
6.活性氧是真菌凋亡的关键调节因子,因此,本实验进一步研究莳萝子挥发油诱导C.albicans线粒体活性氧累积是否导致真菌凋亡。采用透射电镜观察莳萝子挥发油作用于C.albicans后细胞超微结构的改变,采用共聚焦显微镜观察DAPI染色后细胞核的形态变化,FITC-AnnexinV染色后C.albicans磷脂酰丝氨酸的外翻、FITC-VAD-FMK荧光染色法测定莳萝子挥发油作用后白色念珠菌(C.albicans)的Metacaspase活性,分光光度法测定线粒体内细胞色素C含量。结果表明莳萝子挥发油导致C.albicans出现典型的凋亡特征,如染色质凝集、细胞核浓缩和磷脂酰丝氨酸的外翻,说明莳萝子挥发油导致了C.albicans细胞凋亡。莳萝子挥发油促进C.albicans线粒体内细胞色素C的释放,并激活了Metacaspase。抗氧化剂半胱氨酸抑制挥发油导致的细胞核裂解,磷脂酰丝氨酸的外翻以及Metacaspase的活化,提示活性氧是莳萝子挥发油导致细胞凋亡的重要介质,实验结果表明莳萝子挥发油通过引起C.albicans线粒体活性氧累积,进而激活Metacaspase诱导真菌凋亡,从而发挥其抗真菌作用。
The incidence of fungal infections (such as Candida spp. and Dermatophyte) has increased dramatically, causing high morbidity and mortality. The more the broad-spectrum antibiotics, corticosteroids, immunosuppressive agents are used by humans, the easlier they get fungal infections. Currently, with the large scale application of broad-spectrum antifungal agents and the introduction of protocols for antifungal prophylaxis in patients at risk, there has been a notable increase in drug resistance. The development of more effective antifungal therapies is therefore of paramount importance.
Essential oil is one of secondary metabolites in plants. It is reported that essential oil has antibacterial insecticide, anti-inflammatory, antiviral, antioxidant, antitumor, antipyretic and analgesic, expectorant cough and other biological activity. A. graveolens (dill), one of species of Umbelliferae, is a traditional Chinese herb. Dill seed essential oil have antioxidant, antimicrobial and other biological activity.
In this paper, the activities (in vitro and in vivo) and mechanism of the seed of Anethum graveolens L. against fungal were researched.
1. The dill seed essential oil was obtained by steam distillation. The chemical composition of the DSEO was analyzed by gas chromatography-mass spectral (GC-MS) spectroscopy. Twenty-three compounds, constituting about99.4%of the total essential oil, were identified. The most abundant oil components are carvone (41.5%), limonene (32.6%), apiole (16.8%).We study the storage of dill seeds at different time on the yield and main composition of DSEO. Besides, antifungal activity of DSEO on Candida spp. and dermatophytes when dill seeds storage different time. The results showed that the yield of DSEO was reduced. The yield of DSEO was reduced39.02%after storage one year. The storage time of dill seeds had little effect on the content of carvone and limonene.
2. The microbroth dilution method was used in the minimal inhibitory concentration (MIC), according to M38-A2of the guidelines of the Clinical and Laboratory Standard Institute (CLSI). The effect of DSEO on hyphal growth of dermatophyte by agar dilution method. And then, we study DSEO on spore germination and biomass of dermatophyte. The results showed that DSEO was active in vitro against all tested strains, with MICs ranging from0.156-0.312μL/mL for dermatophyte. All tested stains were completely inhibited by DSEO at1.25μL/mL. The spore germination of dermatophyte were inhibited, and the biomass of dermatophyte were reduced on dose-dependent by DSEO.The further study the effect of DSEO on ergosterol content, and the activity of the Malate Dehydrogenase (MDH), Succinate Dehydrogenase (SDH), T-ATPase of T. rubrum ATCC40051. The results showed that ergosterol biosynthesis were inhibited and the activities of MDH, SDH andT-ATPase of T. rubrum ATCC40051were reduced by DSEO. It means that DSEO antidermatophytic through mitochondrial and membrance dysfunction
3. The microbroth dilution method was used in the minimal inhibitory concentration (MIC), according to M27-A3of the guidelines of the Clinical and Laboratory Standard Institute (CLSI). And then, Growth curves and germ tube formation of Candida spp. inhibited by DSEO. The results showed essential oil was active in vitro against all tested strains, with MICs ranging from0.312-0.625μL/mL for Candida spp. All tested stains were completely inhibited bydill seed essential oil at1.25-2.5μL/mL.The germ tube formation rate were3.33%,2.33%,1.67%,1.33%for C. albicans09-1522、C. krusei09-1681、C. tropicalis032、C. parpapsilosis07-305, respectively, while the dill seed essential oil concentration at0.625μL/mL, it means that the germ tube formation were inhibited by dill seed essential oil. Further,
The biofilm metabolic activity of Candida spp. were measured by XTT reduction assay.The result showed that dill seed essential oil severly inhibited Candida spp.strains from forming biofilms at concentrations>0.312μL/mL. Candida spp. strains biofilms treated with dill seed essential oil showed a significant reduction in metabolic activity when viability was measured by XTT reduction assay.The susceptibility of fungal biofilms to dill seed essential oil was investigated and compared with that of planktonic yeast cells. The result showed Candida spp. biofilms were significantly more resistant to dill seed essential oil than their planktonic counterparts.
4. Efficacy evaluation of essential oil in the prophylaxis and treatment of experimental vaginal candidiasis was performed in immunosuppressed mice. The anti-Candida activity was analyzed by microbiological and histological techniques and was compared with that of fluconazole (FCZ). Essential oil (2%v/v) was highly efficacious in accelerating C. albicans09-1555clearance from experimentally infected mice vagina by prophylaxis and therapeutic treatments. In both therapeutic efficacy and prophylaxis studies, the histological findings confirmed the microbiological results. The experimental results revealed that the tested essential oil is effective against vulvovaginal candidiasis in immunosuppressed mice.
5. Effect of dill seed essential oil on membrane of Candida albicans by pyridine iodine staining and UVspectrophotometry. The result showed that membrane of Candida albican were severly damaged by dill seed essential oil. We assayed the mitochondrial membrane potential (mtAy) using rhodamine123and detected the antivities of mitochondrial dehydrogenases by spectrophotometry. Besides, the mitochondrial dysfunction-induced reactive oxygen species (ROS) production was determined by a fluorometric assay, and the effects of antioxidant L-cysteine on DSEO-induced ROS production and the antifungal effect of DSEO on C.albicans were also investigated. The results showed that exposure to DSEO resulted in an elevation of (mtΔΨ) and inhibition of the mitochondrial dehydrogenases. The dysfuntions of mitochondria caused ROS accumulation in C.albicans, and the increase in the level of ROS production and DESO-induced decrease in cell viability were prevented by addition of L-cysteine, indicating that ROS was an important mediator of the antifungal action of DSEO. In summary, DSEO exert its antifungal activity through mitochondrial dysfunction induced ROS accumulation in C.albicans.
6. The ROS are a key regulator to yeast apoptosis. As a consequence, the further study was designed to investigate whether DSEO induced apoptosis in C.albicans.We observed the ultrastructure by transmission electron microscopy, studied the nuclear fragmentation by DAPI staining, and investigated the expore of phosphatidylserine at the outer layer of the cytoplasmic membrane by the FITC-Annexin V staining. Besides, the activity of metacaspase was detected by FITC-V AD-FMK staining, and the release of cytochrome C from mitochondria was also determined. Furthermore, the effect of antioxidant L-cysteine on DSEO-induced apoptosis in C.albicans was also investigated. The results showed that cells treated with DSEO showed typical markers of apoptosis, such as phosphatidylserine exposure, nuclear fragmentation, chromatin condensation. Besides, DSEO promoted the cytochrome C release and activated the metacaspase, which resulted in the yeast apoptosis. The addition of L-cysteine prevented DSEO-induced nuclear fragmentation, phosphatidylserine exposure, and metacaspase activation, indicating the ROS was an important mediator of DSEO-induced apoptosis. In summary, DSEO induced apoptosis in C.albicans through a metacaspase-dependent apoptotic pathway.
引文
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