Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations

The widespread introduction of artemisinin-based combination therapy has contributed to recent reductions in malaria mortality. Combination therapies have a range of advantages, including synergism, toxicity reduction, and delaying the onset of resistance acquisition. Unfortunately, antimalarial combination therapy is limited by the depleting repertoire of effective drugs with distinct target pathways. To fast-track antimalarial drug discovery, we have previously employed drug-repositioning to identify the anti-amoebic drug, emetine dihydrochloride hydrate, as a potential candidate for repositioned use against malaria. Despite its 1000-fold increase in in vitro antimalarial potency (ED50 47 nM) compared with its anti-amoebic potency (ED50 26±32 uM), practical use of the compound has been limited by dose-dependent toxicity (emesis and cardiotoxicity). Identification of a synergistic partner drug would present an opportunity for dose-reduction, thus increasing the therapeutic window. The lack of reliable and standardised methodology to enable the in vitro definition of synergistic potential for antimalarials is a major drawback. Here we use isobologram and combination-index data generated by CalcuSyn software analyses (Biosoft v2.1) to define drug interactivity in an objective, automated manner. The method, based on the median effect principle proposed by Chou and Talalay, was initially validated for antimalarial application using the known synergistic combination (atovaquone-proguanil). The combination was used to further understand the relationship between SYBR Green viability and cytocidal versus cytostatic effects of drugs at higher levels of inhibition. We report here the use of the optimised Chou Talalay method to define synergistic antimalarial drug interactivity between emetine dihydrochloride hydrate and atovaquone. The novel findings present a potential route to harness the nanomolar antimalarial efficacy of this affordable natural product

Effects of molecular structure on the physical, chemical, and electrical properties of ester‐based transformer insulating liquids

This article presents the experimental studies carried out on the environmental friendly polyol ester insulating liquids to investigate the effect of molecular structure on the physical, chemical, and electrical properties. Six different polyol esters that can be produced from the transesterification of various methyl esters with neopentylglycol/trimethylolpropane alcohols were synthesized and compared with those of refined, bleached, and deodorized palm oil (RBDPO) and mineral transformer oil. The finding suggests that the physical properties like fire point, pour point, and viscosity are very much affected by the molecular weight and molecular composition of the polyol esters. The electrical properties are also highly influenced by the molecular structure‐related characteristics, such as the polarity, dipole polarization, carbon chain length, and degree of branching. The results confirm the findings of previous studies that the polyol esters and RBDPO have more polarity and dipole polarization compared to mineral oil. The experimental evidence showed that the newly synthesized insulating liquids have favorable thermal and electrical properties, thus suggesting that the insulating liquids have the potential to replace conventional insulating liquids to provide a more sustainable power system in the future

Rigid Tissue Increases Cytoplasmic pYAP Expression in Pre-Malignant Stage of Lung Squamous Cell Carcinoma (SCC) In Vivo

Increased tissue rigidity is able to activate the Hippo signaling pathway, leading to YAP inactivation by phosphorylation and translocation into the cytoplasm. Accumulating evidence suggests that cytoplasmic pYAP serves as a tumor suppressor and could be a prognostic biomarker for several solid cancers. However, the relationship between tissue rigidity and cytoplasmic pYAP expression in the early stage of lung squamous cell carcinoma (SCC) remains elusive; this was determined in this study by using a mouse model. Female BALB/c mice were assigned into two groups (n = 6; the vehicle (VC) and the pre-malignant (PM) group, which received 70% acetone and 0.04 M N-nitroso-tris-chloroethylurea (NTCU) for 15 weeks, respectively. In this study, the formation of hyperplasia and metaplasia lesions was found in the PM group, indicating the pre-malignant stage of lung SCC. The pre-malignant tissue appeared to be more rigid as characterized by significantly higher (p < 0.05) epithelium thickness, proliferative activity, and collagen content than the VC group. The PM group also had a significantly higher (p < 0.05) cytoplasmic pYAP protein expression than the VC group. In conclusion, increased tissue rigidity may contribute to the upregulation of cytoplasmic pYAP expression, which may act as a tumor suppressor in the early stage of lung SCC

Combinatory index values, recommended symbols and descriptions for classifying synergism or antagonism using the Chou-Talalay method.

<p>Combinatory index values, recommended symbols and descriptions for classifying synergism or antagonism using the Chou-Talalay method.</p

CalcuSyn output for the combination between atovaquone and proguanil.

<p>CalcuSyn output for the combination between atovaquone and proguanil.</p

CalcuSyn output for the dihydroartemisin-emetine combination.

<p>CalcuSyn output for the dihydroartemisin-emetine combination.</p

Optimisation of the atovaquone-proguanil treatment regime.

<p>(a) Trophozoite stage parasites (strain K1) were treated with a 2-fold dose series of atovaquone (ATQ), proguanil (PG) or a constant-ratio combination of both drugs (ATQ+PG) for 48 hours. The mid-point was equated to the previously determined ED₅₀ value for each drug. (b) Was a replica of (a) but with an increased atovaquone dose series. (c) Ring stage parasites were treated for 72 hours with a 3-point constant-ratio dose series of atovaquone and proguanil either alone or in combination. SG-FCM method was used to analyse parasite growth. The parasitaemia of drug treated samples was determined relative to untreated controls (100% parasitaemia). Triplicate samples were used to derive error bars based on standard error of the mean (SEM).</p

The dose series used for the combination of existing antimalarials (AM) with emetine (Eme).

<p>The dose series used for the combination of existing antimalarials (AM) with emetine (Eme).</p

Combinatory classification for emetine with existing antimalarials using the CalcuSyn analysis method.

<p>Combinatory classification for emetine with existing antimalarials using the CalcuSyn analysis method.</p

Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin

Gerodermia osteodysplastica is an autosomal recessive disorder characterized by wrinkly skin and osteoporosis. Here we demonstrate that gerodermia osteodysplastica is caused by loss-of-function mutations in SCYL1BP1, which is highly expressed in skin and osteoblasts. The protein localizes to the Golgi apparatus and interacts with Rab6, identifying SCYL1BP1 as a golgin. These results associate abnormalities of the secretory pathway with age-related changes in connective tissues