pI3K、p-Akt和PTEN在鼻咽癌中的表达及意义

目的观察鼻咽癌（NPC）组织中pI3K、p-Akt和PIEN表达,探讨它们在鼻咽癌发生中的作用。方法应用免疫组化方法检测60例NPC组织和23例鼻咽部慢性炎症组织中pI3K、p-Akt和PTEN的表达。结果NPC与慢性炎症组pI3K的表达率分别为86．7％（52160）和60．9％（14／23）（P〈0．05）;p-Akt表达率分别为76．7％（46／60）和47．8％（11／23）（P〈0．05）;PIEN的表达率分别为41．7％（25160）和65．2％（15／23）（P〈0．01）。pI3K／p-Akt表达率NPC组明显高于慢性炎症组;PTEN表达率NPC组明显低于慢性炎症组,二组表达均与PTEN表达呈负相关。结论pI3K／Akt信号通路的激活、PrEN的抑制,可能在鼻咽癌的发生中起重要作用。     

Cripto-1、PI3K、AKT及mTOR在宫颈癌组织中的表达及其意义

[目的]探讨畸胎癌衍生生长因子-1(Cripto-1)、磷脂酰肌醇-3-激酶(PI3K)、丝苏氨酸蛋白激酶(AKT)、雷帕霉素靶体蛋白(mTOR)在宫颈癌组织中的表达及其意义.[方法]选择2016年4月至2017年12月在本院诊治的宫颈癌患者41例及宫颈上皮内瘤变患者37例.收集其宫颈癌组织、癌旁正常宫颈组织及宫颈上皮瘤变组织,采用免疫组化检测Cripto-1、PI3K、AKT及mTOR阳性率,Western blot法检测各组组织中Cripto-1、PI3K、AKT及mTOR蛋白表达水平,分析各蛋白与患者临床特征间的关系及Cripto-1与PI3K/AKT/mTOR通路相关蛋白的相关性.[结果]宫颈癌中Cripto-1、PI3K、AKT与mTOR蛋白表达水平均明显高于正常宫颈组织及宫颈上皮瘤变组织(P<0.05);TNM分期、分化程度及淋巴结转移情况不同的宫颈癌患者癌组织中Cripto-1、PI3K、AKT及mTOR蛋白表达水平比较差异有统计学意义(P<0.05);宫颈癌组织中Cripto-1蛋白表达水平与PI3K、AKT和mTOR蛋白呈明显正相关(P<0.05).[结论]宫颈癌组织中Cripto-1、PI3K、AKT及mTOR蛋白呈高表达,其表达与宫颈癌患者TNM分期、组织分化程度及淋巴结转移情况有关,且Cripto-1表达与PI3K、AKT及mTOR蛋白表达均呈正相关.     

IGF-1/PI3K/Akt/mTOR信号通路失衡与孤独症关系研究进展

IGF-1/PI3K/Akt/mTOR信号通路在调节细胞生长、增殖、分化、能动性、生存、代谢和蛋白质合成过程中起重要作用。孤独症是广泛性发育障碍疾病,病因机制复杂,其发展与其分子机制改变是近年研究的热点。IGF-1/PI3K/Akt/mTOR信号通路失调与孤独症发生有关,该信号通路在孤独症的诊断、治疗中可能有重要作用。本文就IGF-1/PI3K/Akt/mTOR信号通路失衡与孤独症关系的研究进展作一综述。     

PI3K/AKT信号通路与鼻咽癌的预后关系

目的对PI3K/AKT信号通路与鼻咽癌的预后关系进行研究分析。方法选取2011年1月～11月在院治疗的48例鼻咽癌患者,另选取15例鼻咽黏膜慢性炎症患者作为对照组,共63例患者作为研究对象。48例鼻咽癌患者中已发生转移19例,未发现浸润或转移性29例。将所有患者的活检标本进行HE染色和免疫组化检测,对PI3K、AKT、pAKT的阳性表达进行数据统计和分析。结果鼻咽黏膜慢性炎与鼻咽癌组织中PI3K、AKT、pAKT阳性表达有显著差异（P〈0.05）,具有统计学意义;转移组与非转移组中PI3K、pAKT阳性表达有显著差异（P〈0.01）,具有显著统计学意义。结论鼻咽癌的发生、发展与PI3K/AKT信号传导通路有密切的关系,其中PI3K、AKT、pAKT对鼻咽癌的转移和预后有关。     

PI3K/AKT信号通路在急性白血病中调控机制的初步研究

本研究探讨PI3K/AKT通路中的PTEN、CCND1、mTOR、RICTOR、FOXO1基因在急性髓系白血病(AML)、急性淋巴细胞白血病(ALL)患者中与正常人中表达的差异,以期查明PI3K/AKT通路在白血病中是否存在通路失调。随机收集16例骨髓标本,其中白血病12例(AML 6例,ALL 6例),正常骨髓标本4例。用实时定量RT-PCR方法检测PI3K/AKT通路中的PTEN、CCND1、mTOR、RICTOR、FOXO1基因的表达变化;以管家基因GAPDH为内参,按2-△△Ct法计算目的基因相对表达量。结果表明:PTEN、mTOR、RICTOR在AML、ALL中总体呈低表达趋势,PTEN在12例标本中有10例低表达,mTOR在12例标本中9例低表达,RICTOR在12例标本中7例低表达;FOXO1,CCND1在AML、ALL中则呈高表达趋势,FOXO1在12例标本中有9例高表达,CCND1在12例标本中7例高表达。结论:PI3K/AKT信号通路基因在白血病细胞中被激活。     

食管鳞癌组织中 PI3K 和 caspase-3的表达及其临床意义

目的：研究 PI3K 和 caspase-3在食管鳞癌组织(esophageal squamous cell carcinoma,ESCC)中的表达及其与食管肿瘤发生、发展与转移的关系。方法应用免疫组织化学链霉菌抗生物素蛋白过氧化物酶链结(SP)法检测24例正常食管黏膜、94例食管鳞癌组织中 PI3K 和 caspase-3的表达情况,并分析其与临床病理特征之间的关系。结果 PI3K 在食管鳞癌中的表达高于正常食管黏膜(P <0.01);PI3K 蛋白在高中分化鳞癌中表达低于低分化鳞癌,随着浸润深度和临床分期的增加,其表达阳性率增高,在淋巴结转移阳性组的表达高于阴性组(92.0% vs 47.7%, P <0.01);而 caspase-3阳性表达与 PI3K 相反,高中分化鳞癌中表达高于低分化鳞癌,随着浸润深度和临床分期的增加,其表达阳性率降低,在淋巴结转移阳性组的表达低于阴性组(38.0% vs 68.2%,P <0.01);PI3K 与 caspase-3表达有关联(r =-0.230,P <0.05)。结论 PI3K 高表达和 caspase-3低表达与食管鳞癌发生发展及侵袭转移存在协同作用,是反映食管鳞癌生物学行为的重要指标。     

HL-60细胞Nucleostemin表达下调对PI3K/AKT/mTOR信号通路相关蛋白的影响

目的:探讨HL-60白血病细胞中核干细胞因子Nucleostemin(NS)表达下调对其非依赖P53通路的候选途径PI3K/AKT/mTOR中相关蛋白表达是否有影响。方法:采用重组慢病毒表达载体NS-RNAi-GV248转染至P53缺失型HL-60细胞中干扰NS的表达。用Western blot技术评价转染后HL-60细胞NS蛋白的表达水平并检测干扰前后PI3K/AKT/mTOR信号通路中相关蛋白水平的表达变化。结果:重组慢病毒载体NS-RNAi-GV248成功感染了HL-60细胞,在荧光显微镜下可见到GFP荧光表达较强(80%)。Western blot结果显示,NS蛋白表达明显下调,干扰表达有效;干扰HL-60细胞中NS的表达后AKT、p-AKT、p70s6k、p-p70s6k蛋白变化不明显(t_1=2.31,P=0.074;t_2=3.62,P=0.069;t_3=1.60,P=0.251;t_4=2.72,P=0.113),而mTOR复合物中的GβL蛋白表达明显下调(t=15.01,P=0.002)。结论:HL-60细胞中NS蛋白可影响mTOR复合物中GβL蛋白的表达,PI3K/AKT/mTOR通路可能为NS非依赖P53作用途径之一。     

ICAM-1、Bcl-2在鼻咽癌中的表达及意义

【目的】探讨细胞间粘附分子 1(ICAM 1)和细胞凋亡抑制基因Bcl 2在鼻咽癌组织中的表达及意义。【方法】应用免疫组化S P法 ,对 37例鼻咽低分化鳞癌和 30例鼻咽慢性炎性黏膜活检组织进行ICAM 1、Bcl 2表达蛋白产物检测。【结果】①ICAM 1在鼻咽癌组织阳性表达率 6 7.6 % ,明显高于鼻咽慢性炎性黏膜组织 6 .7% (P <0 .0 1)。②Bcl 2在鼻咽癌组织阳性表达率 83.8% ,明显高于鼻咽慢性炎性黏膜组织 10 .0 %(P<0 .0 1)。③ICAM 1、Bcl 2在鼻咽癌中的表达呈正相关。【结论】ICAM 1、Bcl 2在鼻咽癌组织中表达可能在鼻咽癌细胞的凋亡、侵袭和转移过程中起重要作用 ,两者同时高表达可能协同促进鼻咽癌的侵袭和转移。     

mTOR抑制剂在去势抵抗性前列腺癌中的研究进展

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是磷脂酰肌醇-3羟基激酶/蛋白激酶B/mTOR(PI3K/Akt/mTOR)信号通路中的关键蛋白,与肿瘤细胞的发生发展存在密切联系,参与肿瘤细胞的侵袭与转移。在去势抵抗性前列腺癌(castration resistant prostate cancer,CRPC)中,约有50%的病例的PI3K/Akt/mTOR信号通路过度激活,且PI3K/Akt/mTOR信号通路的异常活化通常是诱导前列腺癌向CRPC进展的原因。这表明靶向针对该途径的治疗方法可能在提高患者生存率方面具备显著疗效。本文以期通过总结CRPC中PI3K/Akt/mTOR通路的生物学特点、功能、治疗及联合用药,为CRPC寻找新的分子治疗靶点提供参考。     

垂体瘤患者血清IGF-1、IGFBP-3水平表达及其临床意义

目的分析垂体瘤患者血清胰岛素样生长因子-1(IGF-1)和胰岛素样生长因子结合蛋白(IGFBP-3)水平表达及其临床意义。方法将本院自2014年1月至2018年7月收治的60例垂体瘤患者纳入研究范围,选取同期于本院行体检的健康志愿者60例设为对照组;放射免疫法检测垂体瘤患者及对照组血清IGF-1、IGFBP-3水平表达水平,并计算IGF-1/IGFBP-3比值,比较2组血清IGF-1、IGFBP-3及IGF-1/IGFBP-3比值水平,并将垂体瘤患者按不同临床特征分组,比较不同临床特征患者血清IGF-1、IGFBP-3及IGF-1/IGFBP-3比值。结果垂体瘤IGF-1表达水平及IGF-1/IGFBP-3比值均显著高于对照组,差异有统计学意义(P<0.05),IGFBP-3表达水平比较差异无统计学意义(P>0.05);不同性别、不同肿瘤直径及病理类型的垂体瘤患者IGF-1、IGFBP-3表达水平及IGF-1/IGFBP-3比值比较差异无统计学意义(P>0.05);侵袭性垂体瘤患者IGF-1表达水平及IGF-1/IGFBP-3比值显著高于非侵袭性垂体瘤患者差异有统计学意义(P<0.05);进一步经ROC曲线分析,IGF-1表达水平及IGF-1/IGFBP-3比值对垂体瘤侵袭性有优势明显预测价值(AUC=0.974、0.936),IGF-1、IGF-1/IGFBP-3比值预测垂体瘤侵袭性的敏感度分别100.00%、86.20%,特异度分别为93.50%、87.10%。结论 IGF-1、IGF-1/IGFBP-3比值或对垂体瘤侵袭性发挥有一定预测价值,值得临床重视。     

Antiviral Activity of 3-Deazaguanine, 3-Deazaguanosine, and 3-Deazaguanylic Acid

3-Deazaguanine (ICN 4221), 3-deazaguanosine (ICN 4793), and 3-deazaguanylic acid (ICN 5412) represent a new class of synthetic guanine analogs having antiviral activity. In vitro, nine ribonucleic acid and seven deoxyribonucleic acid viruses were inhibited, including influenza, parainfluenza, rhino-, vesicular stomatitis, adeno-, herpes-, cytomegalo-, vaccinia, pseudorabies, and myxoma viruses. They were effective orally against influenza types A and B and parainfluenza type 1 (Sendai) virus infections in mice, with a therapeutic index of 16 against the latter two viruses. The course of herpes encephalitis was altered only when the drugs were applied directly into the brain. In addition, these drugs were effective inhibitors of Friend leukemia virus-induced splenomegaly in mice; treatment also produced extensions of life in these animals.     

3'-Carbon-substituted pyrimidine nucleosides having a 2',3'-dideoxy and 2',3'-didehydro-2',3'-dideoxy structure: synthesis and antiviral evaluation

The bis(tributylstannyl) derivative of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) underwent an anionic 5'-O-->3'-C stannyl migration to yield the 3'-tributylstannyl-d4U. This compound, with its vinylstannane structure, allowed ready access to the preparation of 3'-carbon-substituted analogues through the Stille reaction. A conventional transformation of the uracil moiety of these d4U analogues led to the corresponding 2',3'-didehydro-2',3'-dideoxycytidine (d4C) counterparts. Some 2',3'-dideoxycytidine (ddC) analogues were also synthesized. Antiviral evaluation revealed that none of these analogues showed activity against HIV, hepatitis B virus, herpes simplex virus-1 (HSV-1) and HSV-2.     

Comparisons of anti-human immunodeficiency virus activities, cellular transport, and plasma and intracellular pharmacokinetics of 3''-fluoro-3''-deoxythymidine and 3''-azido-3''-deoxythymidine.

3'-Fluoro-3'-deoxythymidine (FLT), a candidate anti-AIDS compound in clinical trials, showed anti-human immunodeficiency virus type 1 (HIV-1) potency (50% effective concentration, 0.0052 microM) slightly better than or equal to that of 3'-azido-3'-deoxythymidine (AZT) in MT4 cells and was threefold more potent in H9 cells. There was no FLT resistance demonstrable in the AZT-resistant HIV-1 strains. Both FLT and AZT showed low cytotoxicity for MT4 cells, with selectivity indices (efficacy/toxicity ratio) of greater than 47,000 and greater than 33,000, respectively. Cellular permeation of FLT and thymidine (dThd) was greater than that of AZT, and FLT and dThd permeated the cell membranes by a carrier-mediated mechanism as well as by simple diffusion, as indicated by the existence of nitrobenzylthioinosine-5'-monophosphate-sensitive and -insensitive components. By contrast, transport of AZT into cells was by simple diffusion. The intracellular level of the triphosphate of FLT (FLTTP) in MT4 cells was two- to threefold higher than that of AZT (AZTTP) after exposure to 1.8 microM each compound for 12 h. The elimination kinetics of FLTTP and AZTTP in HIV-1-infected MT4 cells in fresh medium showed biphasic patterns, with initial half-lives of 1.03 and 1.09 h, respectively. In phytohemagglutinin-stimulated human peripheral blood lymphocytes, the FLTTP level was increased 59-fold compared with that in unstimulated cells at 12 h, was four- to sixfold higher than the level of AZTTP in stimulated cells at 12 h, and remained four- to fivefold higher during a 4-h elimination period in fresh medium and twofold higher at the end of a 12-h elimination period. Two- to eightfold more [3H]AZT than [3H]FLT was incorporated into the host cell DNA, and both [3H]AZT and [3H]FLT remained persistently incorporated for over 24 h. The incorporated [3H]AZT and [3H]FLT were alkali labile, whereas incorporated [3H]dThd was alkali stable. Pharmacokinetics of FLT in plasma of monkeys after intravenous (i.v.) administration showed that the FLT concentration in plasma declined, with a half-life of 1.19 +/- 0.1 h; the steady-state volume of distribution was 0.93 +/- 0.2 liter/kg of body weight, and total clearance was 0.56 +/- 0.15 liter/kg. Oral bioavailability of FLT was excellent and comparable to i.v. bioavailability in terms of areas under the concentration-time curves for three monkeys. Of the total dose, 41 to 61% was excreted in urine as unchanged FLT, and only 3.2 to 7.4% of the total dose was identified as glucuronide-conjugated FLT in urine 48 h after i.v. administration to monkeys. We conclude that FLT exhibits an anti-HIV-1 potency similar to that of AZT but with slightly better selectivity of effects and with higher intracellular active metabolite levels.     

Rapid, long-range molecular haplotyping of thiopurine S-methyltransferase (TPMT) *3A, *3B, and *3C

BACKGROUND: Haplotyping is an important technique in molecular diagnostics because haplotypes are often more predictive for individual phenotypes than are the underlying single-nucleotide polymorphisms (SNPs). Until recently, methods for haplotyping SNPs separated by kilobase distances were laborious and not applicable to high-throughput screening. In the case of thiopurine S-methyltransferase (TPMT*), differentiating among TPMT*3A, *3B, and *3C alleles is sometimes necessary for predictive genotyping. METHODS: The genomic region including the two SNPs that define TPMT*3A, *3B, and *3C alleles was amplified by long-range PCR. The resulting PCR product was circularized by ligation and haplotyped by allele-specific amplification PCR followed by product identification with hybridization probes. RESULTS: Critical points were the long-range PCR conditions, including choice of buffer and primers, optimization of the ligation reaction, and selection of primers that allowed for strict allele-specific amplification in the second-round PCR. Different underlying TPMT haplotypes could then be differentiated. Results from the haplotyping method were in full agreement with those from our standard real-time PCR method: TPMT*1/*3A (n = 20); TPMT*1/*3C (n = 4); TPMT*1/*1 (n = 6); and TPMT*3A/*3A (n = 6). One TPMT*1/*3A sample failed to amplify, and no whole blood was available for repeat DNA isolation. CONCLUSIONS: This method for rapid-cycle real-time, allele-specific amplification PCR-assisted long-range haplotyping has general application for the haplotyping of distant SNPs. The procedure is simpler and more rapid than previous methods. With respect to TPMT, haplotyping has the potential to discriminate the genotypes TPMT*1/*3A (intermediate metabolizer) and TPMT*3B/*3C (poor metabolizer).     

Areas 3a, 3b, and 1 of human primary somatosensory cortex.

This study defines cytoarchitectonic areas 3a, 3b, and 1 of the human primary somatosensory cortex by objective delineation of cytoarchitectonic borders and ensuing cytoarchitectonic classification. This avoids subjective evaluation of microstructural differences which has so far been the only way to structurally define cortical areas. Ten brains were fixed in formalin or Bodian's fixative, embedded in paraffin, sectioned as a whole in the coronal plane at 20 microm, and cell stained. Cell bodies were segmented from the background by adaptive thresholding. Equidistant density profiles (125 microm wide, spacing 300 or 150 microm) were extracted perpendicularly to the pial surface across cortical layers II-VI and processed with multivariate statistical procedures. Positions of significant differences in shape between adjacent groups of profiles were correlated with the cytoarchitectonic pattern. Statistically significant borders can be reproduced at corresponding positions across a series of nearby sections. They match visible changes in cytoarchitecture in the cell-stained sections. Area 3a lies in the fundus of the central sulcus, and area 3b in the rostral bank of the postcentral gyrus. Area 1 lies on its crown and reaches down into the postcentral sulcus. Interareal borders, however, do not match macrostructural landmarks of the postcentral gyrus, and they considerably vary in their positions relative to these landmarks across different brains. Hence, only genuine microstructural analysis can define the borders between these cortical areas. Additional significant borders which do not correlate with visible changes in cytoarchitecture can be found within areas 3b and 1. They may represent somatotopy and/or cortical representations of different somatosensory receptors.     

Pharmacokinetics of 3''-fluoro-3''-deoxythymidine and 3''-deoxy-2'',3''-didehydrothymidine in rats.

Concentrations of 3'-fluoro-3'-deoxythymidine (FDT) and 3'-deoxy-2',3'-didehydrothymidine (D4T) in plasma declined in a biexponential fashion. Total clearance of D4T (1.75 +/- 0.22 liters/h/kg; mean +/- standard deviation) was significantly greater than that of FDT (1.19 +/- 0.19 liters/h/kg) owing to greater renal and nonrenal clearances of the former. Steady-state volumes of distribution of FDT (1.20 +/- 0.12 liters/kg) and D4T (1.07 +/- 0.15 liters/kg) were similar.     

Ce3+ and Tb3+ doped Ca3Gd(AlO)3(BO3)4 phosphors: synthesis,tunable photoluminescence,thermal stability,and potential application in white LEDs

Novel blue-green-emitting Ca₃Gd(AlO)₃(BO₃)₄:Ce³⁺,Tb³⁺ phosphors were successfully synthesized via traditional high temperature solid reaction method. X-ray diffraction, luminescence spectroscopy, fluorescence decay time and fluorescent thermal stability tests have been used to characterize the as-prepared samples. The energy transfer from Ce³⁺ to Tb³⁺ ions in the Ca₃Gd(AlO)₃(BO₃)₄ host has been demonstrated to be by dipole–dipole interaction, and the energy transfer efficiency reached as high as 83.6% for Ca₃Gd_0.39(AlO)₃(BO₃)₄:0.01Ce³⁺,0.6Tb³⁺. The critical distance was calculated to be 9.44 Å according to the concentration quenching method. The emission colour of the obtained phosphors can be tuned appropriately from deep blue (0.169, 0.067) to green (0.347, 0.494) through increasing the doping concentrations of Tb³⁺. Moreover, the Ca₃Gd_0.39(AlO)₃(BO₃)₄:0.01Ce³⁺,0.6Tb³⁺ phosphor possessed excellent thermal stability at high temperature, and the emission intensity at 423 K was about 87% of that at 303 K. Finally, the fabricated prototype LED device with a BaMgAl₁₀O₇:Eu²⁺ blue phosphor, CaAlSiN₃:Eu²⁺ red phosphor, Ca₃Gd_0.39(AlO)₃(BO₃)₄:0.01Ce³⁺,0.6Tb³⁺ green phosphor and 365 nm-emitting InGaN chip exhibited bright warm white light. The current study shows that Ca₃Gd_0.39(AlO)₃(BO₃)₄:0.01Ce³⁺,0.6Tb³⁺ can be used as a potential green phosphor for white LEDs.

Novel thermal-stable blue-green-emitting Ca₃Gd(AlO)₃(BO₃)₄:Ce³⁺,Tb³⁺ phosphors were developed for near-ultraviolet-excited white LEDs.     

Pharmacokinetics of 3''-fluoro-3''-deoxythymidine and 3''-deoxy-2'',3''-didehydrothymidine in rhesus monkeys.

3'-Fluoro-3'-deoxythymidine and 3'-deoxy-2',3'-didehydrothymidine are nucleoside analogs which inhibit human and simian immunodeficiency virus in vitro. The pharmacokinetic properties of these compounds in rhesus monkeys after intravenous, oral, and subcutaneous administration of the drug were compared. Half-lives, total clearances, and steady-state volumes of distribution of the two drugs were determined. The half-lives for the drugs by the different routes were between 0.58 and 1.4 h. Oral bioavailability of 3'-deoxy-2',3'-didehydrothymidine was incomplete, with an average of 42% +/- 15% of the dose reaching the systemic circulation. Absorption of 3'-fluoro-3'-deoxythymidine after oral administration was variable, with bioavailability ranging from 21 to 95%. Bioavailability after subcutaneous administration ranged from 59 to 77% for 3'-deoxy-2',3'-didehydrothymidine and from 52 to 59% for 3'-fluoro-3'-deoxythymidine. The ratio of concentrations in cerebrospinal fluid and serum for the drugs was about 0.15 at 1 h after drug administration and was independent of the route of administration, suggesting that a nucleoside carrier-mediated process is involved in the transport of these compounds to the central nervous system. Because of the similar metabolism of nucleoside analogs in monkeys and humans, the potential glucuronide formation was assessed. Whereas the glucuronide of 3'-fluoro-3'-deoxythymidine was readily detected in urine, the amount of 3'-deoxy-2',3'-didehydrothymidine glucuronidated was small or not detectable in one-half of the urine samples. Pharmacokinetic parameters for the two drugs were similar to each other and analogous to those for 3'-azido-3'-deoxythymidine in monkeys, suggesting that the same dose and scheduling of the drug can be used for all three compounds in prophylactic and therapeutic efficacy drug studies in rhesus monkeys.     

Atmospheric oxidation of Folpet initiated by OH radicals,NO3 radicals,and O3

Folpet, a nonspecific sulfenimide fungicide, is widely used to protect crops against mildew. It can be dispersed and transported over long distances. The residence time of Folpet in the atmosphere depends on the oxidation processes initiated by atmospheric oxidants such as O₃, OH and NO₃ radicals. In this study, the reactions of Folpet with gas-phase O₃, OH and NO₃ radicals were investigated via quantum chemical calculation methods, which can effectively provide information about the reaction intermediates and pathways. The obtained results show that the room-temperature rate constants of the reactions between Folpet and OH radicals, NO₃ radicals and O₃ are about 3.69 × 10⁻¹⁴, 5.40 × 10⁻¹⁵, and 1.73 × 10⁻²² cm³ per molecule per s at 298 K, respectively. Considering the oxidant concentration in the atmosphere, Folpet seems to be mainly scavenged by NO₃ radicals, especially at night. This study can contribute to a better understanding of the atmospheric fate of Folpet, elucidating a significant impact of NO₃ radicals on its degradation process in comparison with other oxidants such as O₃ and OH radicals.

The fate of Folpet is dictated by oxidation initiated by atmospheric oxidants such as O₃, OH, and NO₃ radicals. Considering the oxidant concentration in the atmosphere, Folpet seems to be mainly scavenged by NO₃ radicals, especially at night.     

Pharmacological properties of a new antimalarial bisthiazolium salt, T3, and a corresponding prodrug, TE3

A new approach to malarial chemotherapy based on quaternary ammonium that targets membrane biogenesis during intraerythrocytic Plasmodium falciparum development has recently been developed. To increase the bioavailability, nonionic chemically modified prodrugs were synthesized. In this paper, the pharmacological properties of a bisthiazolium salt (T3) and its bioprecursor (TE3) were studied. Their antimalarial activities were determined in vitro against the growth of P. falciparum and in vivo against the growth of P. vinckei in mice. Pharmacokinetic evaluations were performed after T3 (1.3 and 3 mg/kg of body weight administered intravenously; 6.4 mg/kg administered intraperitoneally) and TE3 (1.5 and 3 mg/kg administered intravenously; 12 mg/kg administered orally) administrations to rats. After intraperitoneal administration, very low doses offer protection in a murine model of malaria (50% efficient dose [ED50] of 0.2 to 0.25 mg/kg). After oral administration, the ED50 values were 13 and 5 mg/kg for T3 and TE3, respectively. Both compounds exerted antimalarial activity in the low nanomolar range. After TE3 administration, rapid prodrug-drug conversion occurred; the mean values of the pharmacokinetic parameters for T3 were as follows: total clearance, 1 liter/h/kg; steady-state volume of distribution, 14.8 liters/kg; and elimination half-life, 12 h. After intravenous administration, T3 plasma concentrations increased in proportion to the dose. The absolute bioavailability was 72% after intraperitoneal administration (T3); it was 15% after oral administration (TE3). T3 plasma concentrations (8 nM) 24 h following oral administration of TE3 were higher than the 50% inhibitory concentrations for the most chloroquine-resistant strains of P. falciparum (6.3 nM).