Comparison of cytotoxic and genotoxic effects of plutonium-239 alpha particles and mobile phone GSM 900 radiation in the Allium cepa test

The goal of this study was to compare the cytotoxic and genotoxic effects of plutonium-239 alpha particles and GSM 900 modulated mobile phone (model Sony Ericsson K550i) radiation in the Allium cepa test. Three groups of bulbs were exposed to mobile phone radiation during 0 (sham), 3 and 9 h. A positive control group was treated during 20 min with plutonium-239 alpha-radiation. Mitotic abnormalities, chromosome aberrations, micronuclei and mitotic index were analyzed. Exposure to alpha-radiation from plutonium-239 and exposure to modulated radiation from mobile phone during 3 and 9 h significantly increased the mitotic index. GSM 900 mobile phone radiation as well as alpha-radiation from plutonium-239 induced both clastogenic and aneugenic effects. However, the aneugenic activity of mobile phone radiation was more pronounced. After 9 h of exposure to mobile phone radiation, polyploid cells, three-groups metaphases, amitoses and some unspecified abnormalities were detected, which were not registered in the other experimental groups. Importantly, GSM 900 mobile phone radiation increased the mitotic index, the frequency of mitotic and chromosome abnormalities, and the micronucleus frequency in a time-dependent manner. Due to its sensitivity, the A. cepa test can be recommended as a useful cytogenetic assay to assess cytotoxic and genotoxic effects of radiofrequency electromagnetic fields.     

Genotoxicity evaluation of the insecticide imidacloprid on circulating blood cells of Montevideo tree frog Hypsiboas pulchellus tadpoles (Anura,Hylidae) by comet and micronucleus bioassays

Acute toxicity and genotoxicity of imidacloprid (IMI) was evaluated on Hypsiboas pulchellus (Anura: Hylidae) tadpoles exposed under laboratory conditions. A lethal effect was used as the end point for lethality, whereas the frequency of micronuclei (MNs) and DNA single-strand breaks evaluated by the single cell gel electrophoresis assay were employed as end points for genotoxicity. Experiments were performed on tadpoles at stage 36 (range, 35–37) according to the classification proposed by Gosner. Mortality studies revealed an LC₅₀ (96 h) value of 84.91 mg/L IMI (95% confidence limits, 77.20–93.04). While increased frequency of MNs was observed when 15 and 30 mg/L were assayed for 48 h, only 15 mg/L increased the frequency of MNs in tadpoles exposed for 96 h. Furthermore, other nuclear abnormalities, i.e., binucleated cells and blebbed and notched nuclei, were induced in tadpoles exposed for both 48 h when treated with 15 mg/L and 96 h when treated with 15 and 30 mg/L. An increase in the genetic damage index was observed in tadpoles treated with 30 mg/L for 48 and 96 h. This study represents the first evidence of acute lethal and sublethal effects exerted by IMI on tadpoles of an amphibian species native to Argentina. Finally, our findings highlight the hazardous properties of this insecticide for nontarget living species exposed to this agrochemical.     

Genomic damages in peripheral blood lymphocytes and association with polymorphisms of three glutathione S-transferases in workers exposed to formaldehyde

DNA and chromosome damages in peripheral blood lymphocytes were evaluated in 151 workers occupationally exposed to formaldehyde (FA) and 112 non-FA exposed controls. The effects of polymorphisms in three glutathione-S-transferase (GSTs) genes on the DNA and chromosome damages were assessed as well. Alkaline comet assay and cytokinesis-block micronucleus (CBMN) assay were used to determine DNA and chromosome damages, respectively. The genotypes of GSTP1 (Ile105Val), GSTT1, and GSTM1 were assayed. The mean 8-h time-weighted average (TWA) concentrations of FA in two plywood factories were 0.83 ppm (range: 0.08–6.30 ppm). FA-exposed workers had higher olive tail moment (TM) and CBMN frequency compared with controls (Olive TM, 3.54, 95%CI = 3.19–3.93 vs. 0.93, 95%CI = 0.78–1.10, P < 0.01; CBMN frequency, 5.51 ± 3.37 vs. 2.67 ± 1.32, P < 0.01). Olive TM and the CBMN frequency also had a dose-dependent relation with the personal FA exposure. Significant association between FA exposure history and olive TM and CBMN frequency were also identified. The level of olive TM was slightly higher in FA-exposed workers with GSTM1 null genotype than those with non-null genotype (3.86, 95%CI = 3.31–4.50 vs. 3.27, 95%CI = 2.83–3.78, P = 0.07) with adjustment of covariates. We also found that FA-exposed workers carrying GSTP1 Val allele had a slightly higher CBMN frequency compared with workers carrying only the wild-type allele (6.32 ± 3.78 vs. 5.01 ± 2.98, P = 0.05). Our results suggest that the FA exposure in this occupational population increased DNA and chromosome damages and polymorphisms in GSTs genes may modulate the genotoxic effects of FA exposure.     

Evaluation of chemicals requiring metabolic activation in the EpiDerm™ 3D human reconstructed skin micronucleus (RSMN) assay

The in vitro human reconstructed skin micronucleus (RSMN) assay in EpiDerm? is a promising new assay for evaluating genotoxicity of dermally applied chemicals. A global pre-validation project sponsored by the European Cosmetics Association (Cosmetics Europe - formerly known as COLIPA), and the European Center for Validation of Alternative Methods (ECVAM), is underway. Results to date demonstrate international inter-laboratory and inter-experimental reproducibility of the assay for chemicals that do not require metabolism [Aardema et al., Mutat. Res. 701 (2010) 123–131]. We have expanded these studies to investigate chemicals that do require metabolic activation: 4-nitroquinoline-N-oxide (4NQO), cyclophosphamide (CP), dimethylbenzanthracene (DMBA), dimethylnitrosamine (DMN), dibenzanthracene (DBA) and benzo(a)pyrene (BaP). In this study, the standard protocol of two applications over 48 h was compared with an extended protocol involving three applications over 72 h. Extending the treatment period to 72 h changed the result significantly only for 4NQO, which was negative in the standard 48 h dosing regimen, but positive with the 72 h treatment. DMBA and CP were positive in the standard 48 h assay (CP induced a more reproducible response with the 72 h treatment) and BaP gave mixed results; DBA and DMN were negative in both the 48 h and the 72 h dosing regimens. While further work with chemicals that require metabolism is needed, it appears that the RMSN assay detects some chemicals that require metabolic activation (4 out of 6 chemicals were positive in one or both protocols). At this point in time, for general testing, the use of a longer treatment period in situations where the standard 48 h treatment is negative or questionable is recommended.     

In vivo genotoxicity evaluation of a plant based antiarthritic and anticancer therapeutic agent Boswelic acids in rodents

The genotoxic potential of anti-inflammatory/anti-arthritic and anticancer plant based drug molecule Boswelic acids (BA) was studied by in vivo system. Systematic literature survey revealed that studies on the genotoxicity of BA are not available. Although reports on genotoxicity of Boswellia serrata dry extract and modified 3-O-acetyl-11-keto-β-boswelic acid are available and these studies were conducted in in vitro systems. The earlier general toxicity study of BA has been conducted by us, revealed it to be non toxic. The genotoxicity was carried out in Wistar rats using different cytogenetic assay system-abnormalities viz. chromosomal aberrations; sperm morphology, micronuclei and comet assays. Six groups of animals, each comprised of five rats, were taken for each study. Group1-4 received BA at 125, 250, 500 and 1000 mg/kg p.o., respectively prepared as 2% gum acacia suspension, fifth group received a positive control cyclophosphamide (CP) 40 mg/kg p.o. or metronedazole (MTZ) 130 mg/kg p.o. or mercuric chloride (HgCl₂) 0.864 mg/kg p.o. (as per the experiment requirement) whereas the sixth group kept as vehicle control. The results on the bases of the data obtained revealed that BA is quite safe as it did not show any genotoxicity at any dose level up to 1000 mg/kg. The positive controls used in different experiments showed highly significant abnormal cytogenetic changes in comparison to the control group.     

A diazen-1-ium-1,2-diolate analog of 7-azabenzobicyclo[2.2.1]heptane: Synthesis,nitric oxide and nitroxyl release,in vitro hemodynamic,and anti-hypertensive studies

1-(7-Azabenzobicyclo[2.2.1]heptane)diazen-1-ium-1,2-diolate (16) was designed with the expectation that it would act as a dual nitric oxide (NO) and nitroxyl (HNO) donor that is not carcinogenic or genotoxic. Compound 16, with a suitable half-life (17.8 min) in PBS at pH 7, released NO (19%) and HNO (22%) during a 2 h incubation in PBS at pH 7. In addition, compound 16 exhibited a significant in vitro positive inotropic effect, increased the rates of contraction and relaxation, and increased coronary flow rate, but did not induce a chronotropic effect. Furthermore, compound 16 (13.7 mg kg^?1, po dose) provided a significant reduction in the blood pressure of mice up to 3 h post-drug administration. All these data suggest that compound 16 constitutes an attractive ‘lead-compound’ that could have potential applications to treat cardiovascular disease(s) such as congestive heart failure.     

Gene expression of apoptosis-related genes,stress protein and antioxidant enzymes in hemocytes of white shrimp Litopenaeus vannamei under nitrite stress

Apoptotic cell ratio and mRNA expression of caspase-3, cathepsin B (CTSB), heat shock protein 70 (HSP70), manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GPx) and thioredoxin (TRx) in hemocytes of white shrimp Litopenaeus vannamei exposed to nitrite-N (20 mg/L) was investigated at different stress time (0, 4, 8, 12, 24, 48 and 72 h). The apoptotic cell ratio and mRNA expression level of CTSB were significantly increased in shrimp exposed to nitrite-N for 48 and 72 h. Caspase-3 mRNA expression level significantly increased by 766.50% and 1811.16% for 24 and 48 h exposure, respectively. HSP70 expression level significantly increased at 8 and 72 h exposure. MnSOD mRNA expression in hemocytes up-regulated at 8 and 48 h, while CAT mRNA expression level increased at 24 and 48 h. GPx expression showed a trend that increased first and then decreased. Significant increases of GPx expression were observed at 8 and 12 h exposure. Expression level of TRx reached its highest level after 48 h exposure. These results suggest that nitrite exposure induces expression of apoptosis-related genes in hemocytes, and subsequently caused hemocyte apoptosis. Meanwhile, expression levels of HSP70 and antioxidant enzymes up-regulated to protect the hemocyte against nitrite stress.     

Maximizing mouse embryonic stem cell production in a stirred tank reactor by controlling dissolved oxygen concentration and continuous perfusion operation

One of the key challenges in stem cell bioprocessing is the large-scale cultivation of stem cells in order to meet the demanding meaningful cell numbers needed for biomedical applications, especially for clinical settings. Mouse embryonic stem cells [1], used as a model system herein, were cultivated on microcarriers in a fully controlled stirred tank reactor (STR) [2]. The impact of varying the concentration of dissolved oxygen (at 5%, 10%, 20% and 30% DO) and operating under a continuous perfusion mode on cell growth and pluripotency maintenance was investigated. In addition, in order to further optimize the feeding strategy of the STR operating under continuous perfusion toward maximal cell production, the influence of different medium residences times (12 h, 24 h, 32 h, 48 h and 96 h) was evaluated. Overall, the maximal cell concentration of 7.9–9.2 × 10⁶ cells/mL were attained after 11 days, with no passaging required, under a DO of 10–20% in the continuous perfused bioreactor with cell retention and medium residences times of 32–48 h. Importantly, mESC expanded under these conditions, retained the expression of pluripotency markers (Oct4, Nanog and Ssea-1), as well as their differentiation potential into cells of the three embryonic germ layers.The STR-based cultivation platform optimized herein represents a major contribution toward the development of large-volume production systems of differentiated cell derivatives for a wide range of biomedical applications.     

Inhalation of formaldehyde does not induce genotoxic effects in broncho-alveolar lavage (BAL) cells of rats

Male Fischer-344 rats were exposed to formaldehyde (FA) by inhalation for 4 weeks (6 h/day, 5 days/week). Groups of six rats each were exposed to the target concentrations of 0, 0.5, 1, 2, 6, 10 and 15 ppm. Potential genotoxic effects in the lung were investigated as part of a comprehensive study on local and systemic toxic and genotoxic effects. Broncho-alveolar lavage (BAL) cells were obtained by lung lavage with physiological saline and counted. From one half of the cells, slides for the micronucleus test (MNT) were prepared by cytocentrifugation; with the other half, the comet assay was performed. DNA migration in the comet assay was measured both directly and after irradiation of the cells with 2 Gy gamma-radiation. The latter modification of the comet assay was included to increase its sensitivity for the detection of DNA-protein cross-links (DPX). For the comet assay, four slides were analysed from each cell sample, two without and two with irradiation. From each slide, 50 randomly selected cells were measured by image analysis and tail intensity (% tail DNA) and tail moment were evaluated. The frequency of micronucleated BAL cells was determined in acridine orange-stained slides by analysing 2000 cells per animal. FA did not induce any significant effect in any of the genotoxicity tests performed. It can be concluded that inhalation of FA in a 28 days study with FA concentrations up to 15 ppm does not lead to genotoxic effects in BAL cells of rats. Because detection of DPX by the comet assay is a very sensitive biomarker of FA exposure of cells, our results suggest that there is no genetically relevant exposure of the lung after FA inhalation. The results of our inhalation study, which was performed under GLP conditions, call into question the biological significance of previously reported genotoxic effects in the lung of rats after FA inhalation.     

In vivo genotoxicity evaluation of a plant based antiarthritic and anticancer therapeutic agent Boswelic acids in rodents

The genotoxic potential of anti-inflammatory/anti-arthritic and anticancer plant based drug molecule Boswelic acids (BA) was studied by in vivo system. Systematic literature survey revealed that studies on the genotoxicity of BA are not available. Although reports on genotoxicity of Boswellia serrata dry extract and modified 3-O-acetyl-11-keto-β-boswelic acid are available and these studies were conducted in in vitro systems. The earlier general toxicity study of BA has been conducted by us, revealed it to be non toxic. The genotoxicity was carried out in Wistar rats using different cytogenetic assay system-abnormalities viz. chromosomal aberrations; sperm morphology, micronuclei and comet assays. Six groups of animals, each comprised of five rats, were taken for each study. Group1-4 received BA at 125, 250, 500 and 1000 mg/kg p.o., respectively prepared as 2% gum acacia suspension, fifth group received a positive control cyclophosphamide (CP) 40 mg/kg p.o. or metronedazole (MTZ) 130 mg/kg p.o. or mercuric chloride (HgCl₂) 0.864 mg/kg p.o. (as per the experiment requirement) whereas the sixth group kept as vehicle control. The results on the bases of the data obtained revealed that BA is quite safe as it did not show any genotoxicity at any dose level up to 1000 mg/kg. The positive controls used in different experiments showed highly significant abnormal cytogenetic changes in comparison to the control group.     

Effects of pore characters of mesoporous resorcinol–formaldehyde carbon gels on enzyme immobilization

This paper demonstrates, for the first time, the use of resorcinol–formaldehyde carbon gels (RFCs) as enzyme carriers. The immobilization behavior of Bacillus licheniformis serine protease in RFCs of different pore characters was investigated. RFCs derived with (RF1) and without (RF2) cationic surfactant (trimethylstearylammonium chloride; C18) resulted in predominantly microporous, and mesoporous characters, respectively. It was found that support pore size and volume were key parameters in determining immobilized enzyme loading, specific activity, and stability. RF2, with higher mesopore volume (V_mes: RF1 = 0.21 cm³/g; RF2 = 0.81 cm³/g) and mesopore size radius (RF1 = 1.7–3.8 nm; RF2 = 7.01 nm), accommodated approximately fourfold more enzyme than RF1. Serine protease loading in RF2 could reach as high as 21.05 unit/g support. In addition, RF2 was found to be a better support in terms of serine protease operation and storage stability. Suitable mesopore size likely helped preventing immobilized enzyme from structural denaturation due to external forces and heat. However, immobilized enzyme in RF1 gave 12.8-fold higher specific activity than in RF2, and 2.1-fold higher than soluble enzyme. Enzyme leaching was found to be problematic in both supports, nonetheless, higher desorption was observed in RF2. Enhancement of interaction between serine protease and RFCs as well as pore size adjustment will be necessary for repeated use of the enzyme and further process development.     

Toxic and genotoxic effects of potassium dichromate in Pseudokirchneriella subcapitata detected by microscopy and AFLP marker analysis

The effect of chromium on Pseudokirchneriella subcapitata has been assessed using different approaches: growth rate, metabolic activity microscopy analyses, and amplified fragment length polymorphism (AFLP) assessment of DNA damage. Starting from 24 h of treatment all the tested concentrations resulted in consistent algal growth inhibition. The average daily growth rate after 72 h calculated for the control (0.53 ± 0.01) was statistically higher than those estimated for cell treated with 1, 2.5, 5 and 7.5 μg g⁻¹ potassium dichromate (0.46 ± 0.02; 0.32 ± 0.01; 0.25 ± 0.01 and −0.02 ± 0.04, respectively). A reduction of viable cell numbers, estimated with FDA approach, was also observed after 24 h treatment for all the tested chromium concentrations apart from the lowest (1 μg g⁻¹ potassium dichromate). A recovery of esterase activity was detected after 48 and 72 h for all treatments with the except of the 7.5 μg g⁻¹ potassium dichromate treated samples showing a very modest recovery. This data suggests that potassium dichromate is, even from the lowest tested concentration, highly toxic to P. subcapitata, and that this algal strain is a sensitive organism suitable for monitoring chromium in water. Our data also suggest that although algal counting by microscope and the FDA test gave similar indications concerning chromium effect, the FDA test was not completely reliable. In fact, we observed a decrease in the FDA stained cell numbers in control samples after 48 and 72 h of treatment, when most cells were actively proliferating. This lack of fluorescence could be explained by an uncontrolled fluorescein efflux due to the interaction of many experimental factors. The genotoxic effects of the different chromium concentrations were investigated by analyses of the DNA from control and treated algal samples, 72 h after inoculation. AFLP analysis revealed a total of 258 bands, 109 of which were polymorphics. Analysis of the AFLP matrix suggests that potassium dichromate is a powerful genotoxic agent, inducing genetic mutations also at the lowest tested concentration (0.35 μg g⁻¹). Furthermore, we observed a correlation between the polymorphic bands with increasing chromium concentration. Finally, the absence of preferential mutation sites suggests that the chromium induced DNA changes are randomly distributed in the genome.     

Effects of mobile phone radiofrequency on the structure and function of the normal human hemoglobin

Widespread use of mobile phones has increased the human exposure to electromagnetic fields (EMFs). It is required to investigate the effect of EMFs on the biological systems. In this paper the effect of mobile phone RF (910 MHz and 940 MHz) on structure and function of HbA was investigated. Oxygen affinity was measured by sodium dithionite with UV–vis spectrophotometer. Structural changes were studied by circular dichroism and fluorescence spectroscopy. The results indicated that mobile phone EMFs altered oxygen affinity and tertiary structure of HbA. Furthermore, the decrease of oxygen affinity of HbA corresponded to the EMFs intensity and time of exposure.     

Synthesis and antiproliferative activity of two diastereomeric lignan amides serving as dimeric caffeic acid-l-DOPA hybrids

Two new diastereomeric lignan amides (4 and 5) serving as dimeric caffeic acid-l-DOPA hybrids were synthesized. The synthesis involved the FeCl₃-mediated phenol oxidative coupling of methyl caffeate to afford trans-diester 1a as a mixture of enantiomers, protection of the catechol units, regioselective saponification, coupling with a suitably protected l-DOPA derivative, separation of the two diastereomers thus obtained by flash column chromatography and finally global chemoselective deprotection of the catechol units. The effect of hybrids 4 and 5 and related compounds on the proliferation of two breast cancer cell lines with different metastatic potential and estrogen receptor status (MDA-MB-231 and MCF-7) and of one epithelial lung cancer cell line, namely A-549, was evaluated for concentrations ranging from 1 to 256 μM and periods of treatment of 24, 48 and 72 h. Both hybrids showed interesting and almost equipotent antiproliferative activities (IC₅₀ 64–70 μM) for the MDA-MB-231 cell line after 24–48 h of treatment, but they were more selective and much more potent (IC₅₀ 4–16 μM) for the MCF-7 cells after 48 h of treatment. The highest activity for both hybrids and both breast cancer lines was observed after 72 h of treatment (IC₅₀ 1–2 μM), probably as the result of slow hydrolysis of their methyl ester functions.     

Strategies for controlling the ghost ant,Tapinoma melanocephalum (Hymenoptera: Formicidae) with liquid bait

The ghost ant, Tapinoma melanocephalum (F.), is a household pest and a considerable nuisance. The aim of this study is to demonstrate the toxicity and control efficacy of boric acid in liquid bait against queen and worker ghost ants. The LT₅₀ values for workers fed with 0.5%–2.5% boric acid and 2% chicken peptone in 20% sucrose water solutions were 4.3–2.4 days. The lethal times (LT₅₀ = 5.2–7.6 days) for queen ghost ants fed with various concentrations of a boric acid solution depended on the feeding behavior of the queens. The high boric acid (4%) content solutions were not repellent to the ghost ant workers. The liquid bait formulation of 1% boric acid, which caused a 100% worker, brood, and queen population reduction in 4, 4, and 5 weeks, respectively, was significantly more effective than the solid bait formulation containing the same concentration (p ≦ 0.05). The simulation tests involved using chicken peptone and sucrose as the attractant, and colonies were provided an alternate food source (20% sucrose solution and dog food) to achieve a more accurate assessment of bait acceptability in screening for the efficacy of the liquid boric acid bait. The control efficiency attained 99.9% in week 4. The results demonstrated that liquid bait, containing 2% chicken peptone, 20% sucrose as a food attractant, and 1% boric acid as the toxin, is efficient and highly recommended for ghost ant control.     

Effect of storage conditions of blood on radiation-induced chromosomal aberrations and apoptosis in human lymphocytes

To evaluate the effect of storage conditions of blood on the direct relationship between radiation-induced chromosome aberrations and apoptosis in human peripheral blood lymphocytes, whole blood was irradiated with 3 Gy X-rays. Directly after irradiation, a sample of blood was analyzed for chromosome damage and proliferation index, after phytohaemagglutinin stimulation and incubation at 37 °C for 56 h. Blood samples were stored for 48 h at 4 and 20 °C with or without phytohaemagglutinin and analyzed for cell viability and apoptosis at 0, 24 and 48 h storage time. After 48 h of storage, unstimulated cultures were stimulated to proliferate. These samples and cultures stimulated immediately before storage were incubated at 37 °C for 56 h and analyzed for chromosome damage and proliferation index. Metaphases were examined for the presence of dicentrics, excess acentrics, and rings. Storage at 20 °C without phytohaemagglutinin for 48 h increases significantly the yield of apoptosis and decreases significantly the yield of dicentrics. During 48 h of storage time the presence of phytohaemagglutinin and the temperature of 4 °C protected the irradiated lymphocytes from apoptosis allowing accurate estimation of the real yield of radiation-induced chromosome damage. Therefore these blood-storage conditions enable analysis in metaphase and may offer some advantages for biodosimetry of absorbed radiation dose.     

Role of AKAP 149–PKA–PDE4A complex in cell survival and cell differentiation processes

The cellular localization of A-kinase anchoring proteins (AKAPs), protein kinase A (PKAs) and phosphodiesterases (PDEs) is a key step to the spatiotemporal regulation of the second messenger adenosine 3′,5′-cyclic monophosphate (cAMP). In this paper the cellular distribution of the mitochondrial AKAP 149–PKA–PDE4A complex and its implications in the cell death induced by YTX treatment, a known PDE modulator, was studied. K-562 cell line was incubated with YTX for 24 or 48 h. Under these conditions AKAP 149, PKA and type-4A PDE (PDE4A) levels were measured in the cytosol, in the plasma membrane and in the nucleus. Apoptotic hallmarks were also measured after the same conditions. In addition, YTX effect on cell viability was checked after AKAP 149 and PDE4A silencing. The results obtained show a decrease in AKAP 149–PKA–PDE4A levels in cytosol after YTX exposure. 24 h after the toxin addition, the complex expression increased in the plasma membrane and after 48 h in the nucleus domain. Furthermore Bcl-2 levels were decreased and the expression of caspase 3 together with caspase 8 activity were increased after 24 h of toxin incubation but not after 48 h. These results suggest apoptotic cell death at 24 h and a non-apoptotic cell death after 48 h. When AKAP 149 and PDE4A were silenced YTX did not induce cellular death. In summary, AKAP 149–PKA–PDE4A complex localization is related with YTX effect in K-562 cell line. When this complex is mainly located in the plasma membrane apoptosis is activated while when the complex is in the nuclear domain non-apoptotic cellular death or cellular differentiation is activated. Therefore AKAP 149–PKA–PDE4A distribution and integrity have a key role in cellular survival.     

Hypervalent organotellurium compounds as inhibitors of P. falciparum calcium-dependent cysteine proteases

Hypervalent organotellurium compounds (organotelluranes) have shown several promising applications, including their use as potent and selective cysteine protease inhibitors and antiprotozoal agents. Here, we report the antimalarial activities of three organotellurane derivatives (RF05, RF07 and RF19) in two Plasmodium falciparum strains (CQ_S 3D7 and CQ_R W2), which demonstrated significant decreases in parasitemia in vitro. The inhibition of intracellular P. falciparum proteases by RF05, RF07 and RF19 was determined and the IC₅₀ values were 3.7 ± 1.0 μM, 1.1 ± 0.2 μM and 0.2 ± 0.01 μM, respectively. Using an assay performed in the presence of the ER Ca^2 +-ATPase inhibitor we showed that the main enzymatic targets were cysteine proteases stimulated by calcium (calpains). None of the compounds tested caused haemolysis or a significant decrease in endothelial cell viability in the concentration range used for the inhibition assay. Taken together, the results suggest promising compounds for the development of antimalarial drugs.