Antiplasmodial activity of the natural product compounds alstonine and himbeline.

Malaria, caused by Plasmodium parasites, continues to be a devastating global health issue. Despite a decline in malaria related deaths over the last decade, overall progress has plateaued. Key challenges to malaria prevention and control include the lack of a broadly effective vaccine and parasite drug resistance, including to the current gold standard artemisinin combination therapies (ACTs). New drugs with unique modes of action are therefore a priority for both the treatment and prevention of malaria. Unlike treatment drugs which need to kill parasites quickly to reduce or prevent clinical symptoms, compounds that kill parasites more slowly may be an option for malaria prevention. Natural products and natural product derived compounds have historically been an excellent source of antimalarial drugs, including the artemisinin component of ACTs. In this study, 424 natural product derived compounds were screened for in vitro activity against P. falciparum in assays designed to detect slow action activity, with 46 hit compounds identified as having >50% inhibition at 10 µM. Dose response assays revealed nine compounds with submicromolar activity, with slow action activity confirmed for two compounds, alstonine and himbeline (50% inhibitory concentration (IC50) 0.17 and 0.58 µM, respectively). Both compounds displayed >140-fold better activity against P. falciparum versus two human cell lines (Selectivity Index (SI) >1,111 and > 144, respectively). Importantly, P. falciparum multi-drug resistant lines showed no cross-resistance to alstonine or himbeline, with some resistant lines being more sensitive to these two compounds compared to the drug sensitive line. In addition, alstonine displayed cross-species activity against the zoonotic species, P. knowelsi (IC50 ~1 µM). Outcomes of this study provide a starting point for further investigations into these compounds as antiplasmodial drug candidates and the investigation of their molecular targets.

Gene expression during differentiation of human dendritic cells from cord blood cd34 stem cells.

Human cord blood CD34(+)stem cells were allowed to differentiate in the presence of cytokines stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor alpha (TNF-alpha) into functional CD1a+dendritic cells (DC). A maximum of 1.9 x 10(6) CD1a+ cells were separated from the cells generated from 1.2 x 10(6) CD34(+) stem cells from an individual donor. The percentage of CD1a+cells separated rose to a maximum of 27% at day 11 and fell to 8% at 21 days. Reverse transcription-polymerase chain reaction analysis showed that interleukin 2 receptor, interleukin 3 receptor, interleukin 6 receptor, interleukin 12 receptor (IL-12R) and signal transducer and activator of transcription (STAT) 3, STAT 4 mRNA was expressed in all CD1a+cell populations throughout and appears to be constitutive. Expression of IL-12RmRNA was unexpected in CD1a+DC normally considered to be of myeloid lineage. Expression of interleukin 12 (IL-12) p40 subunit mRNA was not detected. Intermittent expression of the IL-12p35 subunit and IL-4R mRNA suggested that gene expression is inducible, but not obviously correlated with progressive DC development. Expression of mRNA for a spectrum of cytokine receptors indicates that CD1a+DC have the potential to respond to a variety of maturational signals.

Arterial wall changes in type 2 diabetic subjects.

Arterial ultrasonic appearances using high resolution ultrasound were studied in 97 subjects with Type 2 diabetes and age- and sex-matched controls. The intima-media thickness of both common carotid arteries was measured 2 cm proximal to the bifurcation and the presence or absence of plaque on both common and femoral bifurcations was recorded. The mean intima-media thickness in subjects with diabetes was 0.82 +/- 0.22 mm while in the controls 0.66 +/- 0.13 mm (p < 0.001). Multiple regression in diabetic subjects only showed no correlation between age, sex, body mass index, smoking, duration of diabetes, systolic or diastolic blood pressure, cholesterol, HDL, LDL, triglycerides, HbA1 and the common carotid artery intima-media thickness. Type 2 diabetes is associated with increased intima-media thickness which has been found to be a marker of cardiovascular events in the general population.