Modulation of host HIF-1α activity and the tryptophan pathway contributes to the anti-Toxoplasma gondii potential of nanoparticles

BackgroundToxoplasmosis constitutes a large global burden that is further exacerbated by the shortcomings of available therapeutic options, thus underscoring the urgent need for better anti-Toxoplasma gondii therapy or strategies. Recently, we showed that the anti-parasitic action of inorganic nanoparticles (NPs) could, in part, be due to changes in redox status as well as in the parasite mitochondrial membrane potential.MethodsIn the present study, we explored the in vitro mode of action of the anti-T. gondii effect of NPs by evaluating the contributions of host cellular processes, including the tryptophan pathway and hypoxia-inducing factor activity. NPs, at concentrations ranging from 0.01 to 200 µg/ml were screened for anti-parasitic activity. Sulfadiazine and/or pyrimethamine served as positive controls.ResultsWe found that interplay among multiple host cellular processes, including HIF-1α activity, indoleamine 2,3-dioxygenase activity, and to a larger extent the tryptophan pathway, contribute to the anti-parasitic action of NPs.ConclusionTo our knowledge, this is the first study to demonstrate an effect of NPs on the tryptophan and/or kynurenine pathway.General significanceOur findings deepen our understanding of the mechanism of action of NPs and suggest that modulation of the host nutrient pool may represent a viable approach to the development of new and effective anti-parasitic agents.     

Direct evidence of Toxoplasma-induced changes in serum testosterone in mice

Latent toxoplasmosis is known to influence the morphology of infected persons and also increases the probability of the birth of male offspring in both humans and mice. All these traits can be related to the observed differences in the concentration of testosterone between Toxoplasma-infected and Toxoplasma-free subjects. However, it is not possible to decide, using the Toxoplasma-human model, whether toxoplasmosis influences the level of testosterone in the infected host or whether individuals with different levels of testosterone vary in the probability of toxoplasma infection. Here we studied changes in the testosterone levels in the latent phase of toxoplasmosis in laboratory mice artificially infected with cystogenic but relatively virulent strain T38 of T. gondii. We observed decreased testosterone levels in both female and male mice with latent toxoplasmosis in comparison to uninfected controls (P = 0.001). The present results indicate that Toxoplasma infection changes the concentration of serum testosterone in mice and human rather than changed concentration of testosterone influences the probability of the Toxoplasma infection. It is possible that the decrease of testosterone is an adaptive mechanism of infected mice aimed to compensate toxoplasmosis-induced immunosuppression observed during latent Toxoplasma infection.     

ABCA2基因mRNA在结核分枝杆菌不同感染阶段的表达及其作为诊断标志物的研究

摘要 目的：比较ATP结合转运蛋白A2（ATP-binding cassette transporterA2,ABCA2）基因mRNA在活动性结核病和结核分枝杆菌潜伏感染状态下的表达差异及其作为诊断标志物的能力。方法：收集活动性结核病患者、结核分枝杆菌潜伏感染者和健康人外周血,荧光定量PCR检测受试者外周血单个核细胞中ABCA2的mRNA水平,统计学分析各组ABCA2基因表达差异,及其鉴别活动性结核和潜伏感染的能力。结果：活动性结核病患者外周血单个核细胞中ABCA2的mRNA表达显著低于潜伏感染者和健康人（（H=83.38,P＜0.0001）。ABCA2鉴别诊断活动性结核和潜伏感染的曲线下面积为0.9235,灵敏度为73.53%（95%的置信区间为63.87%~81.78%）,特异性为93.55%（95%的置信区间为78.58%~99.21%）。结论：外周血单个核细胞中ABCA2基因mRNA是鉴别活动性结核病和潜伏感染者的潜在标志物,有助于活动性结核病的辅助诊断。     

Toxoplasmosis snapshots: Global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis

Toxoplasma gondii’s importance for humans refers mainly to primary infection during pregnancy, resulting in abortion/stillbirth or congenital toxoplasmosis. The authors sought to evaluate the current global status of T. gondii seroprevalence and its correlations with risk factors, environmental and socioeconomic parameters. Literature published during the last decade on toxoplasmosis seroprevalence, in women who were pregnant or of childbearing age, was retrieved. A total of 99 studies were eligible; a further 36 studies offered seroprevalence data from regions/countries for which no data on pregnancy/childbearing age were available. Foci of high prevalence exist in Latin America, parts of Eastern/Central Europe, the Middle East, parts of south-east Asia and Africa. Regional seroprevalence variations relate to individual subpopulations’ religious and socioeconomic practices. A trend towards lower seroprevalence is observed in many European countries and the United States of America (USA). There is no obvious climate-related gradient, excluding North and Latin America. Immigration has affected local prevalence in certain countries. We further sought to recognise specific risk factors related to seropositivity; however, such risk factors are not reported systematically. Population awareness may affect recognition of said risks. Global toxoplasmosis seroprevalence is continuingly evolving, subject to regional socioeconomic parameters and population habits. Awareness of these seroprevalence trends, particularly in the case of women of childbearing age, may allow proper public health policies to be enforced, targeting in particular seronegative women of childbearing age in high seroprevalence areas.     

快速老化鼠脑MT1和MT3 cDNA克隆及mRNA定量条件的建立

金属硫蛋白 (Metallothionein ,MT)基因家族的三种亚型MT1、MT2和MT3在脑组织中均有表达 ,它们在脑组织中具有重要的神经生理和神经调节功能 ,其中MT3可能是老年性痴呆 (Alzheimer′sdisease ,AD)潜在的病因学因子。本研究以快速老化鼠SAMP10脑组织总RNA为模板 ,通过RT PCR扩增出MT1的编码区序列和MT33′非翻译区序列的cDNA片段。将两个片段克隆到pGEM○R TEasy载体上 ,经测序分析确定两个cDNA片段分别为MT1编码区序列和MT33′非翻译区序列。Northern杂交结果表明 ,MT1和MT3mRNA在 2、4、6、8四个月龄的SAMP10和SAMR1脑组织中均有表达。同时建立了MTmRNA的定量条件 ,为进一步研究MTmRNA增龄性变化规律及与老年性痴呆病因学的关系奠定了基础。     

One-pot,multicomponent synthesis of 2,3-disubstituted quinazolin-ones with potent and selective activity against Toxoplasma gondii

The discovery of two quinazolinones with selective, single-digit micromolar activity (IC₅₀?=?6–7?µM) against the tachyzoites of the apicomplexan parasite Toxoplasma gondii is reported. These potent and selective third generation derivatives contain a benzyloxybenzyl substituent at C2 and a bulky aliphatic moiety at N3. Here we show that these quinazolinones inhibit T. gondii tachyzoite replication in an established infection, but do not significantly affect host cell invasion by the tachyzoites.     

纳米医药学基本原理

纳米技术在医药学中的应用,已逐渐成为医药学的一个新的分枝。这一新的分枝称之为纳米医药学。纳米医药学中主要应用纳米粒子的三种基本功能:靶向作用、缓控释作用和跨生物屏障作用。目前对纳米技术应用研究较多的医药学领域包括用纳米材料制备人工生物结构、重大疾病的治疗及诊断。本文就有关方面进行最简要的讨论。     

Refinement of the mouse model of congenital toxoplasmosis

The goals of the present investigation, focusing on the BALB/c mouse model of congenital toxoplasmosis, were: (1) to find a method to determine pregnancy in the mouse. The method has 100% sensitivity and 72% specificity; (2) to test congenital transmission during the chronic stage of toxoplasmosis. This occurred in 2 of 10 mice tested; (3) to investigate the relationship between the infective dose and the rate of congenital transmission. This was not demonstrated for doses of 10(2) to 10(3) bradyzoites and oocysts of Prugniaud, M3 and M7741 strains, with transmission rates of 3 of 8 to 6 of 10 mice inoculated; (4) to determine homologous and heterologous protection. Homologous protection was demonstrated with Prugniaud cysts, and heterologous protection was found between ME-49 and M3 cysts. This finding is consistent with the uniform natural protection against congenital toxoplasmosis seen in immune women and ewes.     

Toxoplasma gondii: protective immunity against experimental toxoplasmosis induced by a DNA vaccine encoding the perforin-like protein 1

Toxoplasma gondii is an important zoonotic parasite infecting about one third of the world population, causing congenital infections and eye disease. T. gondii perforin-like protein 1 (TgPLP1) is believed to be involved in the acute virulence of T. gondii in mice, and is therefore of interest as a vaccine candidate. In this study, we constructed a DNA vaccine expressing TgPLP1, and evaluated the immune response in Kunming mice. The gene sequence encoding TgPLP1 was inserted into the eukaryotic expression vector pVAX I, and Kunming mice were immunized intramuscularly with the plasmid. After immunization, we evaluated the immune response using lymphoproliferative assay, cytokine and antibody measurements, and the survival times of mice challenged lethally with 1 × 10³ tachyzoites of the virulent T. gondii RH strain. The results showed that pVAX/TgPLP1 alone or with pVAX/IL-18 developed specific anti-TLA (T. gondii lysate antigen) antibodies and specific lymphocyte proliferative responses. Co-injection of pVAX/IL-18 significantly increased the production of IFN-γ and IL-2. Further, challenge experiments showed that co-immunization of pVAX/TgPLP1 with pVAX/IL-18 significantly (P < 0.05) increased survival time (12.7 ± 1.2 days) of immunized mice, compared with pVAX/TgPLP1 alone (11.3 ± 0.9 days). These results demonstrate that TgPLP1 is a potential vaccine candidate against toxoplasmosis, worth further evaluation in other animal hosts. IL-18 could enhance the immune effect of TgPLP1, prolonging the survival time of immunized mice.     

纳米技术在生物医学领域的研究现状

纳米生物医学是纳米技术与现代生物医学技术结合的产物,近年来这一领域逐渐受到科学界和企业界的重视,得到了许多振奋人心的进展,具有广泛的应用前景。作者从纳米生物材料、纳米载体、医学诊断和纳米治疗技术四个方面讨论了纳米技术在医学领域的研究现状,希望为读者展现这一新生领域的巨大潜力。     

Fluorescent quantum dots: An insight on synthesis and potential biological application as drug carrier in cancer

Quantum dots (QDs) are nanocrystals of semiconducting material possessing quantum mechanical characteristics with capability to get conjugated with drug moieties. The particle size of QDs varies from 2 to 10 nm and can radiate a wide range of colours depending upon their size. Their wide and diverse usage of QDs across the world is due to their adaptable properties like large quantum yield, photostability, and adjustable emission spectrum. QDs are nanomaterials with inherent electrical characteristics that can be used as drug carrier vehicle and as a diagnostic in the field of nanomedicine. Scientists from various fields are aggressively working for the development of single platform that can sense, can produce a microscopic image and even be used to deliver a therapeutic agent. QDs are the fluorescent nano dots with which the possibilities of the drug delivery to a targeted site and its biomedical imaging can be explored. This review is mainly focused on the different process of synthesis of QDs, their application especially in the areas of malignancies and as a theranostic tool. The attempt is to consolidate the data available for the use of QDs in the biomedical applications.     

Passive immunization protects guinea pigs from lethal toxoplasma infection

Abstract The cellular and humoral interactions that contribute to protective immunity in toxoplasmosis were studied by adoptive transfer of selective cell populations or immune serum and its fractions into normal syngeneic strain 2 guinea pigs. The results of this study with the RH strain of Toxoplasma gondii confirm and extend the findings of previous studies by showing that the passive transfer of parasite-sensitized T cells or of immune serum from previously infected donors protected recipient guinea pigs against lethal toxoplasmosis. An additional key finding was that similar levels of complete protection against lethal infection occurred in guinea pigs receiving partially purified anti- Toxoplasma immunoglobulins or immune cells that had been enriched for B cells prior to transfer. Cells residing in the spleen, lymph nodes and peritoneal cavity, but not the thymus, were equally effective in conferring immunity to challenged recipients. In addition, cell titration experiments revealed that guinea pigs could survive T. gondii infection by infusing them with as little as 2 × 10⁷ sensitized T cells or B cells. Unlike protection mediated by T cells, protection against lethal disease occurring in the B cell recipients was associated with the formation of Toxoplasma antibodies. These findings illustrate the major role of both humoral and cell-mediated immunity in affording protection against toxoplasmosis based on a guinea pig model of the human disease.