Development of a SPE/HPLC/DAD method for the determination of antileishmanial 2-substituted quinolines and metabolites in rat plasma

A SPE/HPLC/DAD method was developed for the in vivo monitoring of three new antileishmanial 2-substituted quinolines under study in our laboratory for the development of an oral treatment. Three phase I metabolites were included in this work for the optimization of the method. Trifunctional tC(18) cartridges (resulting from the reaction of trifunctional silanes with silica surface) were selected among four sorbents tested. Two linear gradients were developed to ensure resolution of metabolites. Recovery of quinolines from rat plasma was comprised between 80.6 and 88.2%. In a drug development perspective, apparent pK(a), lipophilicity and solubility were determined, as well as the extent of plasma protein or albumin binding.     

A randomized open-label trial of artesunate- sulfadoxine-pyrimethamine with or without primaquine for elimination of sub-microscopic P. falciparum parasitaemia and gametocyte carriage in eastern Sudan

Background

In areas of seasonal malaria transmission, treatment of asymptomatic carriers of malaria parasites, whose parasitaemia persists at low densities throughout the dry season, could be a useful strategy for malaria control. We carried out a randomized trial to compare two drug regimens for clearance of parasitaemia in order to identify the optimum regimen for use in mass drug administration in the dry season.

Methodology and Principal Findings

A two-arm open-label randomized controlled trial was conducted during the dry season in an area of distinct seasonal malaria in two villages in Gedarif State in eastern Sudan. Participants were asymptomatic adults and children aged over 6 months, with low-density P. falciparum infection detected by PCR. Participants were randomized to receive artesunate/sulfadoxine-pyrimethamine (AS+SP) combination for three days with or without a dose of primaquine (PQ) on the fourth day. Parasitaemia detected by PCR on days 3, 7 and 14 after the start of treatment and gametocytes detected by RT-PCR on days 7 and 14 were then recorded. 104 individuals who had low density parasitaemia at screening were randomized and treated during the dry season. On day 7, 8.3% were positive by PCR in the AS+SP+PQ group and 6.5% in the AS+SP group (risk difference 1.8%, 95%CI −10.3% to +13.8%). At enrolment, 12% (12/100) were carrying gametocytes. This was reduced to 6.4% and 4.4% by day 14 (Risk difference 1.9% (95%CI −9.3% to +13.2%) in AS+SP+PQ and AS+SP groups, respectively.

Conclusion

Addition of primaquine to artemisinin combination treatment did not improve elimination of parasitaemia and prevention of gametocyte carriage in carriers with low-density parasitaemia in the dry season.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00330902","term_id":"NCT00330902"}}NCT00330902     

Performance of Cryptolaemus montrouzieri feeding on Pulvinaria aurantii ovisacs on citrus plants

We studied the performance of the coccinellid Cryptolaemus montrouzieri on citrus plant species infested with orange pulvinaria scale, Pulvinaria aurantii, under controlled conditions in the laboratory. The experimental host plants were blood orange, grapefruit, lemon, pummelo and kumquat. All life history parameters indicated best performance of C. montrouzieri, when reared on P. aurantii ovisacs on the leaves of grapefruit. Pummelo, blood orange, lemon or kumquat were less suitable.     

Rn7SK small nuclear RNA is involved in cellular senescence

Rn7SK is a conserved small nuclear noncoding RNA which its function in aging has not been studied. Recently, we have demonstrated that Rn7SK overexpression reduces cell viability and is significantly downregulated in stem cells, human tumor tissues, and cell lines. In this study, we analyzed the role of Rn7SK on senescence in adipose tissue-derived mesenchymal stem cells (AD-MSCs). For this purpose, Rn7SK expression was downregulated and upregulated via transfection and transduction, respectively, in AD-MSCs and subsequently, various distinct characteristics of senescence including cell viability, proliferation, colony formation, senescence-associated β galactosidase activity, and differentiation potency was analyzed. Our results demonstrated the transient knockdown of Rn7SK in MSCs leads to delayed senescence, while its overexpressions shows opposite effects. When osteogenic differentiation was started, however, they exhibited a greater differentiation potential than the original MSCs, suggesting a potential tool for stem cell-based regenerative medicine.     

Effect of curcumin on glioblastoma cells

Curcumin is a polyphenolic compound derived from Curcumin longa L. There are growing bodies of evidence revealing the antitumor effect of curcumin in different tumors; although the molecular mechanism behind this inhibition in glioblastoma multiform (GBM) still remains unclear. Here we investigated the antitumor activity of nano micelles curcumin compared with erlotinib in U-373 cells in monolayer cell cultures and spheroids models. Furthermore, we characterized affecting cell cycle perturbation, as well as apoptosis induction in GBM cells. The antiproliferative activity of nano micelles curcumin and erlotinib were assessed in monolayer and spheroid models. The influence of the cell cycle and expression levels of nuclear factor κB (NF-κB) and Wnt/β-catenin pathway was checked. Nano micelles curcumin suppressed cell growth in U-373 cells via modulation of Wnt and NF-κB pathways. Moreover, cells developed an early G2/M cell cycle arrest followed by sub-G1 apoptosis and apoptotic bodies formation posttreatment with nano micelles curcumin and erlotinib. In the core signaling pathways of GBM, nano micelles curcumin either significantly influences the NF-κB pathway by decreasing p-65 expression or significantly inhibits the Wnt/β-catenin pathway by declining cyclin D1 expression. In conclusion, we have shown that nano micelles curcumin effectively prevent proliferation, and invasion of GBM cells through perturbation of Wnt/β-catenin and NF-κB pathways, suggesting further investigations on the therapeutic application of this novel anticancer drug in in vivo models.     

The Ameliorative Role of 5-Aminolevulinic Acid (ALA) Under Cr Stress in Two Maize Cultivars Showing Differential Sensitivity to Cr Stress Tolerance

Heavy metal (HM) contamination of the environment is a serious threat to sustainable crop production. Among the HMs, chromium (Cr) is one of the most toxic HMs that is known to negatively affect growth and metabolic activities of diverse crop plants. The present study was designed to investigate the ameliorative role of 5-aminolevulinic acid (ALA) under Cr stress in two maize (Zea mays L.) cultivars showing differential sensitivity to Cr tolerance. ALA is a biosynthesis precursor and it has a dominant regulatory effect related to physiological, respiratory, and photosynthesis processes in various plant species. Three concentrations of Cr (0, 5, and 10 mg kg⁻¹) were tested under the graded levels of ALA application (0, 12.5, and 25 mg L⁻¹). The results indicated that Cr stress differentially reduced plant growth attributes, gas exchange characteristics, photosynthetic pigments, and biomass in both the cultivars. Oxidative stress increased as evidenced in the form of electrolyte leakage, malondialdehyde, and hydrogen peroxide (H₂O₂) accumulation in plants. The anti-oxidative enzyme activities, that is, catalase (CAT), superoxide dismutase (SOD), and peroxidase (POD) both in the leaves and roots of maize cultivars decreased due to Cr stress. The concentration of Cr increased in roots and shoots of maize under Cr levels without ALA. Under Cr stress, ALA exogenous application markedly enhanced plant growth, photosynthetic pigments, gas exchange capacity, and biomass. Furthermore, ALA application decreased the Cr-induced oxidative stress in maize cultivars by improving the activities of CAT, POD, and SOD in plants. After ALA application, the Cr concentrations and total Cr uptake by plants differently decreased in both cultivars. The 6103 cultivar of maize was found to be a tolerant cultivar against Cr stress due to its strong defensive system with a higher rate of antioxidant enzyme activities. On the other hand, the other maize cultivar (9108) was found to be a sensitive cultivar against Cr stress due to its weak defense system with higher contents of reactive oxygen species. These findings suggest that ALA can play a regulatory role in maintaining optimum plant growth and efficient photosynthetic processes under Cr-challenged habitats in maize. Thus, ALA application may be used as a sustainable remedial strategy to alleviate Cr-induced stress in maize cultivars.

     

Study of β-lactam-based drug interaction with albumin protein using optical,sensing, and docking methods

Journal of Biological Physics - The quality and strength of drug and albumin interaction affecting the drug-free concentration and physiological activity are important issues in pharmacokinetic...     

A targeted metabolomics approach toward understanding metabolic variations in rice under pesticide stress

Diazinon insecticide is widely applied throughout rice (Oryza sativa L.) fields in Iran. However, concerns are now being raised about its potential adverse impacts on rice fields. In this study, a time-course metabolic change in rice plants was investigated after diazinon treatment using gas chromatography–mass spectrometry (GC–MS), and subsequently the statistical strategy of random forest (RF) was performed in order to find the stress-associated effects. According to the results, a wide range of metabolites were dynamically varied as a result of the plant response to diazinon such as biosynthesis and metabolism of sugars, amino acids, organic acids, and phenylpropanoids, all correlating with the exposure time. Plant response was involved in multiple metabolic pathways, most of which were correlated with the exposure time. In this study, RF was explored as a potential multivariate method for GC–MS analysis of metabolomics data of rice (O. sativa L.) plants under diazinon stress; more than 31 metabolites were quantitatively determined, and time-course metabolic response of the plant during different days after treatment was measured. Results demonstrated RF as a potential multivariate method for GC–MS analysis of changes in plant metabolome under insecticide stress.     

Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity

Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 K(i)=3.7nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models.     

A comparative study on the efficacy of artesunate plus sulphadoxine/pyrimethamine versus artemether-lumefantrine in eastern Sudan

Background

The most important factor for effective zooprophylaxis in reducing malaria transmission is a predominant population of a strongly zoophilic mosquito, Anopheles arabiensis. The feeding preference behaviour of Anopheline mosquitoes was evaluated in odour-baited entry trap (OBET).

Methods

Mosquitoes were captured daily using odour-baited entry traps, light traps and hand catch both indoor and in pit traps. Experimental huts were used for release and recapture experiment. The mosquitoes collected were compared in species abundances.

Results

Anopheles arabiensis was found to account for over 99% of Anopheles species collected in the study area in Lower Moshi, Northern Tanzania. In experimental release/capture trials conducted at the Mabogini verandah huts, An. arabiensis was found to have higher exophilic tendency (80.7%) compared to Anopheles gambiae (59.7%) and Culex spp. (60.8%). OBET experiments conducted at Mabogini collected a total of 506 An. arabiensis in four different trials involving human, cattle, sheep, goat and pig. Odours from the cattle attracted 90.3% (243) compared to odours from human, which attracted 9.7% (26) with a significant difference at P = 0.005. Odours from sheep, goat and pig attracted 9.7%, 7.2% and 7.3%, respectively. Estimation of HBI in An. arabiensis collected from houses in three lower Moshi villages indicated lower ratios for mosquitoes collected from houses with cattle compared to those without cattles. HBI was also lower in mosquitoes collected outdoors (0.1–0.3) compared to indoor (0.4–0.9).

Conclusion

In discussing the results, reference has been made to observation of exophilic, zoophilic and feeding tendencies of An. arabiensis, which are conducive for zooprophylaxis. It is recommended that in areas with a predominant An. arabiensis population, cattle should be placed close to dwelling houses in order to maximize the effects of zooprophylaxis. Protective effects of human from malaria can further be enhanced by keeping cattle in surroundings of residences.