本文選題：日本血吸蟲 + PZQ�。� 參考：《蘇州大學(xué)》2014年碩士論文

【摘要】：第一部分吡喹酮衍生物DW-3-15、P96及P96異構(gòu)體體外抗日本血吸蟲蟲期及性別特異性生物學(xué)效應(yīng) 目的：觀察兩種吡喹酮衍生物DW-3-15、P96體外抗日本血吸蟲童蟲及雌、雄成蟲生物學(xué)效應(yīng)，初步探討9種P96異構(gòu)體體外抗日本血吸蟲童蟲和成蟲生物學(xué)效應(yīng)。 方法：于小鼠感染日本血吸蟲尾蚴后第16d及第5w肝門靜脈灌注法分別收集童蟲與（雌、雄）成蟲，加入不同濃度的DW-3-15、P96及其異構(gòu)體、青蒿琥酯（Art）、吡喹酮（PZQ）于DMEM培養(yǎng)液中繼續(xù)培養(yǎng)72h，觀察蟲體死亡率及活力降低情況。 結(jié)果：兩種PZQ衍生物對日本血吸蟲均有較好的殺蟲效應(yīng)。抗童蟲效應(yīng)：DW-3-15和P96作用濃度為50μmol/L時，童蟲的存活率分別為33.3%和25.0%，活力降低率為71.1%和91.7%，50μmol/L的Art作用于童蟲，存活率和活力降低率分別為42.9%和59.5%�？钩上x效應(yīng)：DW-3-15作用濃度為50μmol/L時，雄蟲與雌蟲的存活率分別為20.0%和41.9%，活力降低率為93.3%和82.9%； P96作用濃度為50μmol/L時，雄蟲全部死亡，雌蟲有33.3%的存活率；PZQ15μmol/L作用雄蟲和雌蟲時，存活率分別為11.1%和37.8%。9種P96異構(gòu)體抗成蟲作用濃度為100μmol/L時，只有P96-3作用后，蟲體存活率和活力降低率分別為60.0%和77.8%，抗童蟲作用濃度為50μmol/L，存活率和活力降低率分別為44.1%和66.7%。 結(jié)論：兩種PZQ衍生物體外具有一定的抗日本血吸蟲童蟲效應(yīng)，均優(yōu)于Art，其中以P96抗童蟲效果更好。兩種化合物及PZQ對日本血吸蟲雌、雄成蟲作用后，均顯示雌蟲對藥物耐受性較強(qiáng)，而雄蟲較敏感，殺雄蟲效果優(yōu)于雌蟲。對P96的9種異構(gòu)體抗蟲效果初步篩選結(jié)果表明這些化合物抗蟲效果不明顯，不如P96。 第二部分PZQ衍生物DW-3-15與P96對不同動物模型體內(nèi)抗日本血吸蟲生物學(xué)效應(yīng)的觀察 目的：觀察兩種PZQ衍生物對感染小鼠和家兔體內(nèi)日本血吸蟲童蟲和成蟲的殺蟲效應(yīng)。 方法：小鼠感染日本血吸蟲后，于蟲體不同發(fā)育時期（3d、14d、35d），以200mg/kg劑量經(jīng)灌胃給予DW-3-15、P96、Art和PZQ，連續(xù)5d，停藥后3w解剖小鼠，計算減蟲率。家兔感染日本血吸蟲后，于第2w和第4w給予不同劑量（150mg/kg、300mg/kg）P96，頓服，于1w后各重復(fù)治療一次，于感染后第10w，剖查蟲荷數(shù)，計算減蟲率和減卵率。 結(jié)果：小鼠實驗:童蟲與成蟲經(jīng)DW-3-15、P96和Art作用后平均檢獲蟲數(shù)與對照組相比，均顯著減少（P0.05），DW-3-15和P96對3d、14d童蟲期減蟲率分別為64.0%、56.2%和69.1%、70.4%，Art對3d、14d減蟲率分別為66.5%、67.4%，兩種化合物和Art作用童蟲后減蟲率均顯著高于PZQ組（22.2%、18.0%）(P0.05)；DW-3-15、P96和Art對35d成蟲的減蟲率分別為81.1%、82.8%和51.1%，低于PZQ組（95.7%），DW-3-15、P96組與PZQ組無顯著性差異（P0.05）。9種P96異構(gòu)體抗14d童蟲作用，結(jié)果顯示，給藥劑量為200mg/kg/只時，P96-3的減蟲率達(dá)到60.0%，與P96相似（76.4%），無顯著性差異，具有一定的抗童蟲效應(yīng)。. 家兔實驗:家兔于感染后第2w、第4w分別給予150mg/kg P96頓服，于1w后各重復(fù)治療一次，減蟲率分別為25.3%和65.2%，減卵率為30.5%和84.0%，在相同感染后時間點（2w、4w）以同樣給藥方式將P96劑量增加為300mg/kg，減蟲率分別為62.2%和91.7%，減卵率為86.2%和97.7%，顯著高于150mg/kg P96治療組(P0.05)，與PZQ組相近（減蟲率：95.4%、98.5%；減卵率：94.1%、97.1%）。 結(jié)論：小鼠實驗，DW-3-15、P96對3d、14d的童蟲以及35d成蟲均具有良好的殺蟲作用，抗童蟲效果與Art相似，但顯著高于PZQ組，抗成蟲作用優(yōu)于Art，與PZQ組相近。9種P96異構(gòu)體中發(fā)現(xiàn)P96-3對14d童蟲具有一定的殺滅作用，其構(gòu)效關(guān)系值得進(jìn)一步深入探討。 家兔實驗，高劑量治療效果優(yōu)于低劑量治療效果，增大治療劑量后減蟲率與減卵率均提高并顯示良好的抗蟲效果；尤其P96對28d成蟲的減蟲率達(dá)到91.7%，接近PZQ的殺蟲效應(yīng)。具有發(fā)展為新的抗血吸蟲藥的潛在應(yīng)用價值。 第三部分Real-time PCR檢測日本血吸蟲感染家兔血清DNA水平評價P96體內(nèi)殺蟲效應(yīng) 目的：觀察家兔疾病模型經(jīng)P96和PZQ治療后血清DNA的動態(tài)變化，評價其殺蟲效應(yīng)。 結(jié)果：150mg/kg P96、300mg/kg P96和150mg/kg PZQ于第2w（14d）開始治療日本血吸蟲感染的家兔，家兔血清DNA檢測結(jié)果總體變化趨勢相似，但應(yīng)用兩種治療劑量的P96治療后的DNA最高濃度分別為267.8，299.5（拷貝數(shù)），均高于PZQ組最高濃度DNA249.5（拷貝數(shù)），提示P96的殺童蟲效果優(yōu)于PZQ；而150mg/kg P96、300mg/kg P96和150mg/kgPZQ于第4w（28d）開始治療日本血吸蟲感染的家兔血清DNA變化，結(jié)果顯示，兩種劑量的P96和PZQ均在治療后第3d血清DNA濃度達(dá)到最高值，分別為495.7、1049.5、1222.4（拷貝數(shù)），并顯示當(dāng)P96用藥量為300mg/kg其殺蟲效應(yīng)與PZQ有效劑量相似。 不同劑量P96治療童蟲和成蟲效果，結(jié)果顯示治療成蟲時，大劑量P96組檢測到的高濃度DNA（1049.5拷貝數(shù)）顯著高于小劑量P96組（495.7拷貝數(shù)）（P0.05），治療童蟲時，兩種劑量組檢測結(jié)果雖無顯著性差異，但大劑量P96組檢測到的高濃度DNA（299.5拷貝數(shù)）仍高于小劑量P96組（267.8拷貝數(shù)），提示大劑量P96殺蟲效果優(yōu)于小劑量P96，但其有效劑量仍需探索。 結(jié)論：通過Real-time PCR法檢測血吸蟲感染的家兔動物模型經(jīng)P96治療后血清DNA水平的動態(tài)變化，進(jìn)一步證明了P96體內(nèi)殺蟲效果，結(jié)果表明P96體內(nèi)殺童蟲效果優(yōu)于PZQ，且劑量越高，殺蟲效果越好，當(dāng)用藥劑量達(dá)300mg/kg時其殺成蟲效果與PZQ有效劑量相似，顯示出作為抗血吸蟲候選新藥的潛在價值。 第四部分PZQ壓力下日本血吸蟲耐受性誘導(dǎo)及其差異表達(dá)蛋白的篩選 目的：分析經(jīng)PZQ ED50體內(nèi)誘導(dǎo)日本血吸蟲感染小鼠的耐藥性蟲體與未誘導(dǎo)蟲體之間的差異表達(dá)蛋白，為闡明PZQ的作用機(jī)制，探索候選疫苗靶抗原及藥物治療靶點，提供實驗依據(jù)。 方法：應(yīng)用半數(shù)有效量（ED50）的PZQ，經(jīng)灌胃連續(xù)誘導(dǎo)30天，停藥21d后，給予治療劑量（200mg/kg）連續(xù)灌胃5d，觀察蟲體對PZQ及其衍生物的敏感性。收集誘導(dǎo)蟲體和未誘導(dǎo)蟲體，應(yīng)用2D-DIGE技術(shù)分析篩選差異表達(dá)蛋白，再對候選蛋白點進(jìn)行質(zhì)譜鑒定，結(jié)果通過NCBI數(shù)據(jù)庫檢索，在線uniprot檢索差異蛋白的功能注釋。 結(jié)果：經(jīng)PZQ ED50壓力誘導(dǎo)的蟲體體外分別暴露于14μmol/L、28μmol/L、56μmol/L和112μmol/L的PZQ作用后72h，蟲體存活率分別為87.5%、82.0%、77.3%和75.6%，與對照組（存活率100%）相比無顯著性差異（P0.05）。隨著PZQ臨界致死濃度的倍數(shù)增加，誘導(dǎo)后蟲體的存活率與活力分值雖然有所下降，但變化不明顯，特別是PZQ濃度增至112μmol/L，即8倍的正常血吸蟲臨界致死濃度，仍有75.6%蟲體存活，可見誘導(dǎo)后蟲體對PZQ的敏感性顯著下降，顯示耐藥趨勢。誘導(dǎo)蟲體對不同濃度PZQ衍生物DW-3-15和P96交叉抗性觀察，結(jié)果顯示，DW-3-15和P96作用濃度為正常蟲體臨界致死濃度時（分別為15μmol/L和25μmol/L），存活率分別為95.8%和86.7%，活力降低率分別為26.1%和42.2%。但當(dāng)兩種衍生物DW-3-15和P96的濃度增至臨界致死濃度的4倍時(分別為60μmol/L和100μmol/L)，蟲體存活率僅為10.0%和20.0%，活力降低率達(dá)到96.7%和93.3%，兩組間差異不明顯，與PZQ組相比有顯著性差異（112μmol/L時存活率為75.6%）（P0.05）。提示2種PZQ衍生物的作用靶點與PZQ可能存在差異。 收集誘導(dǎo)蟲體和未誘導(dǎo)蟲體，應(yīng)用2D-DIGE和質(zhì)譜技術(shù)共篩選鑒定出34個差異蛋白點，質(zhì)譜結(jié)果通過MASCOT軟件搜索并通過NCBI數(shù)據(jù)庫Blast比對氨基酸序列與去重復(fù)分析后共確認(rèn)有30個差異表達(dá)蛋白，其中12個蛋白表達(dá)上調(diào)，18個蛋白表達(dá)下調(diào)，主要是細(xì)胞骨架相關(guān)蛋白、細(xì)胞中參與糖代謝和能量代謝的酶類、氧化還原酶類以及應(yīng)激蛋白和參與解毒代謝的蛋白酶等。 結(jié)論：經(jīng)誘導(dǎo)的蟲體對PZQ敏感性下降顯著，顯示出明顯的耐受性，誘導(dǎo)蟲體對DW-3-15和P96的耐受性比PZQ低，提示兩種PZQ衍生物的作用靶點與PZQ可能存在差異。對誘導(dǎo)蟲體和未誘導(dǎo)蟲體差異蛋白分析，部分蛋白分子呈現(xiàn)差異表達(dá)。這些差異蛋白的表達(dá)上調(diào)或下調(diào)，提示PZQ誘導(dǎo)促進(jìn)或抑制了某些特定基因的表達(dá)。對誘導(dǎo)蟲體和未誘導(dǎo)蟲體差異表達(dá)蛋白的篩選與分析，有助于深入闡明PZQ作用機(jī)制，，并為探索新的疫苗候選抗原及藥物治療的靶點，提供科學(xué)依據(jù)，同時為研發(fā)抗血吸蟲新藥開拓新途徑和新思路。
[Abstract]:Part one: in vitro anti Schistosoma japonicum worm stage and sex specific biological effects of praziquantel derivatives DW-3-15, P96 and P96 isoforms.
Objective: To observe the biological effects of two kinds of praziquantel derivatives DW-3-15, P96 in vitro against Schistosoma japonicum and female and male adults, and preliminarily explore the biological effects of 9 P96 isomers against Schistosoma japonicum and adult in vitro.
Methods: in mice infected with Schistosoma japonicum cercariae, 16d and 5W hepatic portal vein perfusion method were used to collect the adult worms and (female and male) adults respectively, adding different concentrations of DW-3-15, P96 and their isomers, artesunate (Art), and praziquantel (PZQ) in DMEM culture, to continue to cultivate 72h, and to observe the mortality and vitality of the insect body.
Results: two PZQ derivatives have good insecticidal effect on Schistosoma japonicum. When the action concentration of DW-3-15 and P96 is 50 mol/L, the survival rate of children is 33.3% and 25%, the decrease of vitality is 71.1% and 91.7%, and 50 mu mol/L Art acts on the worm, and the survival rate and vitality decrease rate are 42.9% and 59.5%. respectively. The survival rate of male and female worms was 20% and 41.9% when the concentration of DW-3-15 was 50 mu mol/L, and the survival rate was 93.3% and 82.9% respectively. When the concentration of P96 was 50 mol/L, the males died and the females had 33.3% survival rate; the survival rates of the males and females with PZQ15 mu mol/L were 11.1% and 37.8%.9 P96 isomers respectively. When the action concentration was 100 mu mol/L, the survival rate and activity reduction rate of the insect body were 60% and 77.8% respectively after the action of P96-3, and the concentration of anti child insect was 50 mu mol/L, and the survival rate and the reduction rate of vitality were 44.1% and 66.7%., respectively.
Conclusion: two kinds of PZQ derivatives have a certain effect on the resistance to Schistosoma japonicum, which are better than Art, and the effect of P96 on children is better. The two compounds and PZQ are more tolerant to the drug after the action of the female and male adults of Schistosoma japonicum, and the male is better than the female. The 9 isomers of P96 are better than those of the female. The preliminary screening results of insect resistance showed that these compounds had no obvious effect on insect resistance than P96..
The second part is the observation of the biological effects of PZQ derivative DW-3-15 and P96 on Schistosoma japonicum in different animal models.
Objective: To observe the insecticidal effects of two PZQ derivatives on Schistosoma japonicum larvae and adults in infected mice and rabbits.
Methods: mice infected with Schistosoma japonicum (3D, 14d, 35d) were given DW-3-15, P96, Art and PZQ at a dose of 200mg/kg at a dose of 200mg/kg, and the mice were dissected to calculate the rate of worm reduction. After infected with Schistosoma japonicum, the rabbits were given different doses in 2W and first 4W. After treatment, the number of worm load was counted at 10W after infection, and worm reduction rate and egg reduction rate were calculated.
Results: the average number of insects detected by DW-3-15, P96 and Art decreased significantly compared with the control group (P0.05). DW-3-15 and P96 were 64%, 56.2% and 69.1%, 70.4%, Art to 3D, and Art were 66.5%, 67.4%, respectively, and two compound and Art action worm reduction rates were both significant. Higher than group PZQ (22.2%, 18%) (P0.05), DW-3-15, P96 and Art were respectively 81.1%, 82.8% and 51.1% of 35d adults, lower than PZQ group (95.7%), DW-3-15, P96 group and PZQ group had no significant difference (P0.05). There is no significant difference, it has certain anti insect effect.
Rabbit experiment: the rabbits were treated with 150mg/kg P96 after infection at 2W and 4W respectively. After 1W, the rate of worm reduction was 25.3% and 65.2% respectively. The rate of egg reduction was 30.5% and 84% respectively. The dosage of P96 increased to 300mg/kg at the same time point (2W, 4W), the rate of worm reduction was 62.2% and 91.7%, the rate of egg reduction was 86.2% and 9, respectively. 7.7%, significantly higher than 150mg/kg P96 treatment group (P0.05), similar to group PZQ (worm reduction rate: 95.4%, 98.5%; egg reduction rate: 94.1%, 97.1%).
Conclusion: the mice experiment, DW-3-15 and P96 have good insecticidal effect on 3D, 14d and 35d adults, and the effect of anti child insect is similar to that of Art, but it is significantly higher than that of the PZQ group. The anti adult effect is superior to Art, and the killing effect of P96-3 to the child is found in the.9 P96 isomers of the PZQ group, and its structure-activity relationship should be further explored. Please.
In the rabbit experiment, the effect of high dose treatment was better than that of low dose treatment. After increasing the treatment dose, the rate of worm reduction and egg reduction increased and the effect of insect resistance showed good resistance. Especially, the reduction rate of P96 to 28d adult was 91.7%, close to the insecticidal effect of PZQ, and it was of potential application value for the development of new anti schistosomiasis medicine.
In the third part, Real-time PCR was used to detect serum DNA level in rabbits infected with Schistosoma japonicum, and to evaluate the killing effect of P96 in vivo.
Objective: To observe the dynamic changes of serum DNA in rabbits with disease models after P96 and PZQ treatment, and to evaluate their insecticidal effects.
Results: 150mg/kg P96300mg/kg P96 and 150mg/kg PZQ began to treat the rabbits infected with Schistosoma japonicum in 2W (14d). The overall change trend of serum DNA detection results of rabbit serum was similar, but the highest concentration of DNA after P96 treatment with two kinds of therapeutic doses was 267.8299.5 (copy number), which was higher than that of the highest concentration of PZQ group (copy number). The effect of P96 was better than that of PZQ, while 150mg/kg P96300mg/kg P96 and 150mg/kgPZQ began to treat the serum DNA changes in rabbits infected with Schistosoma japonicum by 4W (28d). The results showed that the two doses of P96 and PZQ were all at the highest value after the treatment. The insecticidal effect of 300mg/kg was similar to that of PZQ.
The effect of different doses of P96 on children and adults showed that the high concentration of DNA (1049.5 copy number) detected in the large dose P96 group was significantly higher than that of the small dose P96 group (495.7 copies) (P0.05). Although there was no significant difference in the test results of the two dose groups, the high concentration of DNA (299.5 copies) detected by the large dose P96 group (299.5 copies) The number is still higher than the low dose P96 group (267.8 copy number), suggesting that the high dose P96 insecticidal effect is superior to the small dose P96, but its effective dose still needs to be explored.
Conclusion: the dynamic changes of serum DNA level after P96 treatment in rabbit model of Schistosoma infection by Real-time PCR method further proved the killing effect of P96 in the body. The results showed that the effect of P96 in the body was better than that of PZQ, and the higher the dose, the better the effect of insecticidal effect. When the dosage reached 300mg/kg, the effect of the insecticide on the adult was effective and the PZQ was effective. Similar doses showed a potential value as a new candidate for schistosomiasis control.
The fourth part is the induction of tolerance and differentially expressed proteins of Schistosoma japonicum under PZQ stress.
Objective: to analyze the differentially expressed proteins between drug resistant and uninduced bodies induced by PZQ ED50 in mice infected with Schistosoma japonicum, in order to elucidate the mechanism of PZQ, and to explore the candidate vaccine target antigen and the target of drug treatment.
Methods: using PZQ of half effective dose (ED50), after continuous induction of gastric perfusion for 30 days, after stopping drug 21d, the treatment dose (200mg/kg) was given to 5D continuously. The sensitivity of the insect body to PZQ and its derivatives was observed. The insect body and the uninduced body were collected. The differential expression protein was screened by 2D-DIGE technique, and then the candidate protein points were identified by mass spectrometry. Results through NCBI database retrieval, online UniProt retrieved functional annotation of differential proteins.
Results: the strain induced by PZQ ED50 was exposed to 14 mu mol/L, 28 mol/L, 56 mu mol/L and 112 mol/L PZQ, and the survival rate of the insect body was 87.5%, 82%, 77.3% and 75.6%, respectively, compared with the control group (survival rate 100%). Although the ratio and vitality score decreased, the change was not obvious, especially the PZQ concentration increased to 112 mu mol/L, or 8 times the critical lethal concentration of normal Schistosoma, and there were still 75.6% insect bodies, which showed that the sensitivity of the insect body to PZQ decreased significantly and showed the resistance trend. The cross resistance of the insect body to the different concentration of PZQ derivatives DW-3-15 and P96 was induced. The results showed that the concentration of DW-3-15 and P96 was at the critical lethal concentration of the normal insect body (15 mu mol/L and 25 mol/L respectively), the survival rate was 95.8% and 86.7% respectively, and the decrease of vitality was 26.1% and 42.2%., respectively, but when the concentration of two derivatives DW-3-15 and P96 increased to 4 times the critical lethal concentration (60 mu mol/L and 100 u mol/L respectively), the insect body The survival rate was only 10% and 20%, the rate of vitality decreased to 96.7% and 93.3%, the difference between the two groups was not obvious, and there was a significant difference compared with the PZQ group (112 mu mol/L survival rate 75.6%) (P0.05). It suggested that the target of 2 PZQ derivatives may be different from PZQ.
34 differential proteins were screened and identified by 2D-DIGE and mass spectrometry. The results of mass spectrometry were searched by MASCOT software and 30 differentially expressed proteins were confirmed by NCBI database Blast comparison and repeated analysis of amino acid sequences. The expression of 12 proteins was up and 18 proteins were downregulated. Mainly cytoskeleton related proteins, enzymes involved in glycometabolism and energy metabolism, oxidoreductases, stress proteins and proteases involved in detoxification.
Conclusion: the induced susceptibility to PZQ decreased significantly, showing obvious tolerance and the tolerance to DW-3-15 and P96 was lower than that of PZQ, suggesting that the target points of the two PZQ derivatives may be different from PZQ. The expression of protein is up or down, suggesting that PZQ induces or inhibits the expression of certain specific genes. Screening and analysis of differentially expressed proteins in the induced and uninduced bodies can help to elucidate the mechanism of PZQ action, and provide a scientific basis for exploring new vaccine candidate antigens and targets for the treatment of drugs. New ways and new ideas for new drug development of Schistosoma japonicum.
【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R532.21

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