【摘要】：白念珠菌所致的真菌感染發(fā)病率急劇上升,臨床上常用的提高真菌感染的治療效果包括：增大劑量,改變藥物類(lèi)型,兩種藥物或多種藥物組合。兩種藥物聯(lián)合使用有很多優(yōu)勢(shì),如降低毒性較大的藥物的劑量,提高藥物治療的效果,增加抗真菌譜,延緩真菌耐藥性的發(fā)生等等。氨基酸作為臨床目前非常活躍的治療藥物,具有非常重要的作用,如鹽酸賴(lài)氨酸氯化鈉注射液用于腦供血不足、乙酰半胱氨酸用于治療慢性支氣管炎、組氨酸-維生素u-蛋氨酸用于治療潰瘍病等等。因此,氨基酸很有可能作為抗真菌藥物增效劑的來(lái)源之一,我們以賴(lài)氨酸、半胱氨酸為研究對(duì)象,進(jìn)一步深入研究了賴(lài)氨酸、半胱氨酸增強(qiáng)兩性霉素B對(duì)白念珠菌的作用及可能的機(jī)制。本課題主要通過(guò)氨基酸與抗真菌藥物的相互作用研究,以尋找治療真菌感染的一種安全、有效的聯(lián)合用藥方案。 本課題中我們考察外源性氨基酸對(duì)抗真菌藥物的影響的研究表明,半胱氨酸自身能顯著抑制白念珠菌的生長(zhǎng),不同的氨基酸與不同的抗真菌藥物聯(lián)合使用在體外對(duì)白念珠菌的生長(zhǎng)具有不同的影響。①氨基酸與卡泊芬凈(caspofungin, CAS)合用的相互作用結(jié)果：半胱、賴(lài)、蘇、異亮、精、蛋、絲、亮、丙、甘、苯丙、酪、脯氨酸能顯著增強(qiáng)CAS對(duì)白念珠菌的作用,天冬氨酸能拮抗CAS對(duì)白念珠菌的作用；②氨基酸與咪康唑(miconazole, MCZ)合用的相互作用結(jié)果：半胱氨酸能顯著增強(qiáng)MCZ對(duì)白念珠菌的作用,絲氨酸、甲硫氨酸能拮抗MCZ對(duì)白念珠菌的作用；③氨基酸與兩性霉素B (amphotericin B, AmB)合用的相互作用結(jié)果：半胱、賴(lài)、蘇、異亮、精、蛋、亮、組、脯氨酸能顯著增強(qiáng)A『mB對(duì)白念珠菌的作用,鳥(niǎo)氨酸、酪氨酸能拮抗AmmB對(duì)白念珠菌的作用；④氨基酸與5-氟胞嘧啶(5-Flucytosine,5-Fu)合用的相互作用結(jié)果：半胱氨酸、天冬氨酸、谷氨酸能顯著增強(qiáng)5-Fu對(duì)白念珠菌的作用,色氨酸、纈氨酸能拮抗5-Fu對(duì)白念珠菌的作用；⑤氨基酸與特比萘芬(terbinafine, TER)合用的相互作用結(jié)果：半胱、蘇、精氨酸能顯著增強(qiáng)TER對(duì)白念珠菌的作用,甲硫、天冬、谷、苯丙、丙、色氨酸能拮抗TER對(duì)白念珠菌的作用；⑥氨基酸與紫草素(shikonin, SK)合用的相互作用結(jié)果：半胱、賴(lài)、蘇、異亮、精、蛋、苯丙、色、鳥(niǎo)、甘、絲、丙氨酸能顯著增強(qiáng)SK對(duì)白念珠菌的作用,天冬氨酸、亮氨酸能拮抗SK對(duì)白念珠菌的作用。 首先通過(guò)微量液基稀釋法檢測(cè)了20種不同氨基酸對(duì)白念珠菌生長(zhǎng)的影響以及與不同抗真菌藥物相互作用對(duì)白念珠菌生長(zhǎng)的影響。結(jié)果顯示,半胱氨酸能顯著抑制白念珠菌的生長(zhǎng),蘇氨酸對(duì)白念珠菌的生長(zhǎng)抑制作用較弱,其他氨基酸對(duì)白念珠菌的生長(zhǎng)無(wú)抑制作用,不同的氨基酸與不同的抗真菌藥物作用對(duì)白念珠菌的生長(zhǎng)影響不同。 第二部分,考察賴(lài)氨酸、半胱氨酸單用以及與AmB合用對(duì)白念珠菌和其他菌株的作用,通過(guò)spot assay、生長(zhǎng)曲線、生存率實(shí)驗(yàn)進(jìn)一步考察了賴(lài)氨酸對(duì)AmB的抗真菌增效作用以及半胱氨酸的抗真菌作用。實(shí)驗(yàn)選取白念珠菌SC5314為研究對(duì)象,采用微量液基稀釋法測(cè)得0.5mM賴(lài)氨酸就能增強(qiáng)0.25μg/ml的抗白念珠菌作用；0.25mM半胱氨酸能抑制白念珠菌的生長(zhǎng),也能增強(qiáng)0.25μg/ml AmB的抗白念珠菌作用。同樣地,1mM賴(lài)氨酸就能增強(qiáng)0.5μg/ml AmB對(duì)近平滑念珠菌(0401380,392,90018,22090,22019,0201309),新型隱球菌0201309的抗真菌作用；0.25mM半胱氨酸就能影響克柔念珠菌ACCT2159,光滑念珠菌ACCT28226,近平滑念珠菌22090的生長(zhǎng)。Spot aasay實(shí)驗(yàn)結(jié)果顯示,賴(lài)氨酸組與空白組敏感性無(wú)差異,8mM賴(lài)氨酸以上濃度與0.25μg/ml AmB合用能抑制白念珠菌的生長(zhǎng),1mM半胱氨酸就能抑制白念珠菌的生長(zhǎng)。生長(zhǎng)曲線結(jié)果也表明,1mM賴(lài)氨酸與0.25μg/ml AmB合用與0.25μg/ml AmB單用相比能較強(qiáng)地抑制白念珠菌的生長(zhǎng)。我們也通過(guò)XTT還原法考察了AmB與賴(lài)氨酸聯(lián)用對(duì)白念珠菌生物被膜形成的影響,結(jié)果顯示0.5μg/ml AmB與4mM賴(lài)氨酸聯(lián)用對(duì)白念珠菌生物被膜的形成以及生物被膜細(xì)胞代謝活性的抑制作用較強(qiáng)。同時(shí),菌絲生長(zhǎng)實(shí)驗(yàn)證實(shí)賴(lài)氨酸與AmB聯(lián)用對(duì)白念珠菌生物被膜的影響可能是由于對(duì)菌絲形成的抑制作用。 第三部分,賴(lài)氨酸與AmB聯(lián)用的增效作用機(jī)制研究,主要方法有,透射電鏡觀察兩藥合用對(duì)白念珠菌超微結(jié)構(gòu)的影響,流式細(xì)胞儀測(cè)定細(xì)胞周期觀察兩藥合用對(duì)細(xì)胞周期的影響,用多功能微板檢測(cè)儀檢測(cè)兩藥合用細(xì)胞內(nèi)活性氧(ROS)的產(chǎn)生量,JC-1試劑盒測(cè)定兩藥合用后細(xì)胞內(nèi)線粒體膜電位水平等實(shí)驗(yàn)考察AmB與賴(lài)氨酸合用對(duì)白念珠菌的氧化損傷作用。實(shí)驗(yàn)結(jié)果表明,AmB能夠升高白念珠菌的內(nèi)源性活性氧水平,而AmB與賴(lài)氨酸合用白念珠菌細(xì)胞內(nèi)活性氧水平更高,賴(lài)氨酸組與空白組無(wú)明顯差異；同時(shí),我們也應(yīng)用Real-time RT-PCR考察了氧化還原相關(guān)基因的表達(dá),結(jié)果顯示：與AmB單用組相比,AmB與賴(lài)氨酸合用ROS清除相關(guān)基因Sod2表達(dá)水平下降,進(jìn)一步促進(jìn)白念珠菌細(xì)胞內(nèi)源性ROS的堆積：然而,與AmB單用組相比,AmB與賴(lài)氨酸合用氧化應(yīng)激相關(guān)基因(TRR1、CaMCA1、Cap1、GRP2)表達(dá)水平都有不同程度的上調(diào),白念珠菌氧化應(yīng)激能力提高；另外,AmB能夠降低白念珠菌線粒體膜電位水平賴(lài)氨酸,而AmB與賴(lài)氨酸合用白念珠菌線粒體膜電位水平更低,賴(lài)氨酸組與空白組無(wú)明顯差異；與AmB單用組相比,賴(lài)氨酸與AmB合用組細(xì)胞分裂過(guò)程中的隔膜形成不明顯,甚至消失,細(xì)胞周期阻滯于G2/M期,使細(xì)胞有絲分裂受阻,單用組與空白組無(wú)明顯差異。 第四部分,體內(nèi)研究結(jié)果表明,與體外效果不同,半胱氨酸單用對(duì)系統(tǒng)性白念珠菌感染的小鼠沒(méi)有治療效果,但是半胱氨酸合用兩性霉素B治療效果優(yōu)于單用兩性霉素B治療效果,與體外效果一致。 綜上所述,本課題研究發(fā)現(xiàn),多種氨基酸與抗真菌藥物具有體外增效作用；半胱氨酸具有較強(qiáng)的抗真菌活性,在體內(nèi)外都能增強(qiáng)AmB對(duì)白念珠菌的抗真菌活性；賴(lài)氨酸在體外能增強(qiáng)白念珠菌對(duì)AmB的敏感性,其主要作用機(jī)制包括阻止細(xì)胞分裂過(guò)程中隔膜的形成,阻滯細(xì)胞周期中的G2/M期,升高細(xì)胞內(nèi)活性氧,降低線粒體膜電位等；另外賴(lài)氨酸與AmB合用還能引起一些氧化還原相關(guān)基因的表達(dá)發(fā)生改變。
[Abstract]:The incidence of fungal infection caused by Candida albicans has risen sharply. The clinical effects of improving fungal infection include increasing dose, changing drug types, two drugs or combination of various drugs. The combination of two drugs has many advantages, such as reducing the dose of toxic drugs, improving the effect of drug treatment, and increasing resistance. Fungal spectrum, retarding the occurrence of fungal resistance and so on. Amino acids are very active in clinical treatment, such as the use of Lysine Hydrochloride and Sodiun Chloride Injection for cerebral blood supply deficiency, acetylcysteine used in the treatment of chronic bronchitis, and the use of vitamin u- methionine in the treatment of ulcerative diseases, and so on. Therefore, amino acids are likely to be one of the sources of antifungal agents. We use lysine and cysteine as the research object to further study the effect and possible mechanism of lysine and cysteine enhanced amphotericin B on Candida albicans. This topic mainly through the interaction of amino acids and antifungal agents. Objective: to find a safe and effective combination regimen for treating fungal infections.
In this study, we examined the effects of exogenous amino acids on the antifungal agents, which showed that cysteine could significantly inhibit the growth of Candida albicans. The combined use of different amino acids and different antifungal agents had different effects on the growth of Candida albicans in vitro. (1) amino acids and caspofungin (CAS). The results of the combined interaction: cysteine, lyophile, shiny, semen, egg, egg, silk, bright, Gump, Gump, phenylpropyl, cheese, proline can significantly enhance the effect of CAS on Candida albicans, and aspartic acid can antagonize the effect of CAS on Candida albicans; and the results of the interaction between amino acids and miconazole (miconazole, MCZ): cysteine can significantly enhance the MCZ against white The effect of Candida, serine and methionine can antagonize the effect of MCZ on Candida albicans; (3) the interaction results of amino acids and amphotericin B (amphotericin B, AmB): cysteine, Lai, Su, shiny, sperm, eggs, bright, group, and proline can significantly enhance the effect of A "mB on Candida albicans, ornithine, tyrosine can antagonize AmmB against Candida albicans." The interaction between the amino acid and 5- fluorocytosine (5-Flucytosine, 5-Fu): cysteine, aspartic acid, and glutamic acid can significantly enhance the effect of 5-Fu on Candida albicans. Tryptophan and valine can antagonize the effect of 5-Fu on Candida albicans; 5. The interaction of amino acid and terbinafine, TER. Results: cysteine, Su, arginine can significantly enhance the effect of TER on Candida albicans. Methyl sulphur, asparagus, valley, phenylpropyl, C, tryptophan can antagonize the effect of TER on Candida albicans; 6. The interaction results of amino acids and shikonin (SK) combined: cysteine, sou, ISO, semen, eggs, phenylpropyl, color, birds, Gump, silk, and alanine can significantly enhance SK The role of Candida albicans, aspartic acid and leucine, can antagonize the action of SK on Candida albicans.
The effects of 20 different amino acids on the growth of Candida albicans and the effect of interaction with different antifungal agents on the growth of Candida albicans were detected by microdilution method. The results showed that cysteine could significantly inhibit the growth of Candida albicans. The inhibitory effect of threonine on the growth of Candida albicans was weak, and other amino acids were found. The growth of Candida albicans was not inhibited. Different amino acids and antifungal drugs had different effects on the growth of Candida albicans.
In the second part, the effects of lysine, cysteine alone and combined with AmB on Candida albicans and other strains were investigated. The antifungal effect of lysine on AmB and the antifungal effect of cysteine on AmB were further investigated through the experiment of spot assay, growth curve and survival rate. The experiment selected Candida albicans as the object of study, and the use of microsatellite in the experiment. 0.5mM lysine could enhance the anti Candida albicans effect of 0.25 mu g/ml by measuring the solution based lysine; 0.25mM cysteine could inhibit the growth of Candida albicans and enhance the effect of 0.25 mu g/ml AmB on Candida albicans. Similarly, 1mM lysine could enhance 0.5 mu g/ml AmB to nalaciasa (04013803929001822090220190201309). The antifungal effect of Cryptococcus neoformans 0201309, 0.25mM cysteine could affect Candida korubica ACCT2159, Candida smooth ACCT28226, and nearly smooth Candida 22090 growth.Spot aasay experimental results showed that the lysine group had no difference with the blank group, and the consistency of 8mM lysine above and 0.25 mu g/ml AmB could inhibit the growth of Candida albicans. Long, 1mM cysteine could inhibit the growth of Candida albicans. The growth curve also showed that the combination of 1mM lysine and 0.25 mu g/ml AmB could strongly inhibit the growth of Candida albicans compared with 0.25 mu g/ml AmB. We also examined the effect of AmB and lysine on the formation of the biofilm by the XTT reduction method. The results showed that 0. The combination of 5 g/ml AmB with 4mM lysine has strong inhibition on the formation of Candida albicans biofilm and the metabolic activity of biofilm cells. At the same time, mycelium growth proves that the effect of lysine and AmB on Candida albicans biofilm may be due to the inhibition of mycelium formation.
In the third part, the synergistic mechanism of lysine and AmB was studied. The main method was the transmission electron microscope to observe the effect of two drugs on the ultrastructure of Candida albicans. Flow cytometry was used to observe the effect of the combined use of two drugs on the cell cycle, and the production of ROS in the combined cells was detected by the multi-function microplate detector. Measurement of the mitochondrial membrane potential level after the combined use of two drugs by the JC-1 kit, the effects of AmB and lysine on the oxidative damage of Candida albicans were investigated. The results showed that AmB could increase the level of endogenous reactive oxygen species in Candida albicans, while AmB and lysine were used in the combination of lysine and lysine. There was no significant difference from that in the blank group; at the same time, we also used Real-time RT-PCR to investigate the expression of redox related genes. The results showed that compared with the AmB single use group, AmB and lysine combined with ROS scavenging related gene Sod2 expression level decreased, further promoting the accumulation of endogenous ROS in Candida albicans: however, compared with the AmB single use group, The expression levels of AmB and lysine combined with oxidative stress related genes (TRR1, CaMCA1, Cap1, GRP2) were all up regulated in varying degrees, and the oxidative stress of Candida albicans increased. In addition, AmB could reduce the level of lysine in the mitochondrial membrane potential of Candida albicans, while the mitochondrial membrane potential of Candida albicans with AmB and lysine was lower than that of lysine, lysine group and lysine group. There was no obvious difference in the blank group. Compared with the AmB single use group, the membrane in the cell division of lysine and AmB group was not obvious, even disappeared, the cell cycle was blocked in the G2/M phase, and the cell mitosis was blocked. There was no significant difference between the single use group and the blank group.
In the fourth part, the results of the study in vivo showed that cysteine alone had no therapeutic effect on systemic Candida albicans in mice, but cysteine combined with amphotericin B was better than the effect of amphotericin B alone, which was consistent with the effect in vitro.
To sum up, the study found that a variety of amino acids and antifungal agents have synergistic effect in vitro; cysteine has strong antifungal activity and can enhance the antifungal activity of AmB on Candida albicans in vivo and in vitro; lysine can enhance the sensitivity of Candida albicans to AmB in vitro. The main mechanism of which is to prevent cells from the cells. The formation of the septum during the division, the G2/M phase in the cell cycle, the increase of intracellular reactive oxygen species and the decrease of the mitochondrial membrane potential, and the combination of lysine and AmB can cause some changes in the expression of redox related genes.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R96

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3 黃廣華;;白念珠菌有性生殖、形態(tài)發(fā)生及毒性的進(jìn)化[A];中國(guó)菌物學(xué)會(huì)第五屆會(huì)員代表大會(huì)暨2011年學(xué)術(shù)年會(huì)論文摘要集[C];2011年

4 王慧;徐寧;喻其林;程欣欣;邢來(lái)君;李明春;;鈣細(xì)胞存活途徑與白念珠菌的致病性[A];中國(guó)菌物學(xué)會(huì)第五屆會(huì)員代表大會(huì)暨2011年學(xué)術(shù)年會(huì)論文摘要集[C];2011年

5 閻瀾;李妙海;曹永兵;高平揮;王彥;姜遠(yuǎn)英;;白念珠菌耐藥新蛋白——交替氧化酶[A];藥學(xué)發(fā)展前沿論壇及藥理學(xué)博士論壇論文集[C];2008年

6 郭仁勇;;白念珠菌聚苯乙烯黏附增強(qiáng)基因1的研究進(jìn)展[A];2008年浙江省檢驗(yàn)醫(yī)學(xué)學(xué)術(shù)年會(huì)論文匯編[C];2008年

7 ;線粒體功能在不同環(huán)境對(duì)白念珠菌生存及代謝的影響[A];2012年中國(guó)菌物學(xué)會(huì)學(xué)術(shù)年會(huì)會(huì)議摘要[C];2012年

8 曾躍斌;;白念珠菌全基因組表達(dá)譜芯片在抗真菌藥物研究中的應(yīng)用[A];中國(guó)藥理學(xué)會(huì)第十一屆全國(guó)化療藥理學(xué)術(shù)研討會(huì)論文集[C];2012年

9 周萬(wàn)青;沈瀚;張之烽;張葵;;白念珠菌臨床分離調(diào)查及基因分型研究[A];中華醫(yī)學(xué)會(huì)第七次全國(guó)中青年檢驗(yàn)醫(yī)學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2012年

10 景偉芳;王惠平;;白念珠菌對(duì)唑類(lèi)藥物耐藥機(jī)制的研究進(jìn)展[A];中華醫(yī)學(xué)會(huì)第十五次全國(guó)皮膚性病學(xué)術(shù)會(huì)議論文集[C];2009年

相關(guān)重要報(bào)紙文章 前1條

1 國(guó)虹 雨凈;微生物的是是非非[N];中國(guó)教育報(bào);2001年

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2 唐寧楓;白念珠菌烯醇化酶的研究[D];中國(guó)協(xié)和醫(yī)科大學(xué);2000年

3 王平;陰道念珠菌菌種及香蓮方逆轉(zhuǎn)白念珠菌耐藥基因組學(xué)研究[D];廣州中醫(yī)藥大學(xué);2013年

4 許懿;小檗堿與氟康唑協(xié)同抗耐藥白念珠菌的作用機(jī)制研究[D];第二軍醫(yī)大學(xué);2010年

5 李彩霞;陰道細(xì)菌群落多樣性及外陰陰道念珠菌病相關(guān)白念珠菌基因多態(tài)性研究[D];北京協(xié)和醫(yī)學(xué)院;2013年

6 王樂(lè);小鼠口腔陰道雙部位白念珠菌感染模型的構(gòu)建及不同部位來(lái)源白念珠菌的毒力差異研究[D];北京協(xié)和醫(yī)學(xué)院;2014年

7 曾躍斌;特比萘芬對(duì)白念珠菌的藥理作用及誘導(dǎo)耐藥機(jī)制研究[D];汕頭大學(xué);2007年

8 梁曉博;白念珠菌敏感株對(duì)氟康唑產(chǎn)生適應(yīng)性突變耐藥的研究[D];第二軍醫(yī)大學(xué);2000年

9 徐錚;白念珠菌基因芯片的制備和應(yīng)用及兩個(gè)新基因的克隆和功能鑒定[D];第二軍醫(yī)大學(xué);2005年

10 閻瀾;白念珠菌耐藥性產(chǎn)生的“線粒體氧化呼吸抑制”機(jī)制[D];第二軍醫(yī)大學(xué);2009年

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1 劉樂(lè);不同培養(yǎng)條件對(duì)白念珠菌芽管形成的影響[D];蘭州大學(xué);2008年

2 閻瀾;白念珠菌耐藥株的蛋白質(zhì)組與基因表達(dá)譜分析及差異蛋白質(zhì)與差異基因的識(shí)別鑒定[D];第二軍醫(yī)大學(xué);2006年

3 秦曉峰;白念珠菌臨床株耐藥基因表達(dá)與氟康唑耐藥的關(guān)系[D];第二軍醫(yī)大學(xué);2006年

4 許懿;小檗堿與氟康唑協(xié)同抗耐藥白念珠菌作用的蛋白質(zhì)組學(xué)研究[D];第二軍醫(yī)大學(xué);2007年

5 鐘毅;白念珠菌蘋(píng)果酸脫氫酶的結(jié)構(gòu)及功能初步研究[D];中山大學(xué);2012年

6 張蕾;紫外線對(duì)白念珠菌生長(zhǎng)的影響[D];福建醫(yī)科大學(xué);2012年

7 郭雅莉;白念珠菌多位點(diǎn)序列分型研究[D];天津醫(yī)科大學(xué);2012年

8 滿(mǎn)旭;白念珠菌鋅簇轉(zhuǎn)錄因子編碼基因表達(dá)與氟康唑耐藥的關(guān)系[D];天津醫(yī)科大學(xué);2013年

9 吳海棠;整合非靶標(biāo)和靶標(biāo)代謝組學(xué)模式的白念珠菌被膜形成及藥物干預(yù)機(jī)制研究[D];第二軍醫(yī)大學(xué);2013年

10 李蕾;白念珠菌天冬氨酸蛋白酶2真核表達(dá)載體的構(gòu)建及原核表達(dá)[D];中國(guó)人民解放軍軍醫(yī)進(jìn)修學(xué)院;2009年

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