Investigating the Contribution of Major Drug-Metabolising Enzymes to Possum-Specific Fertility Control.

The potential to improve the effectiveness and efficiency of potential oestrogen-based oral contraceptives (fertility control) for possums was investigated by comparing the inhibitory potential of hepatic CYP3A and UGT2B catalytic activity using a selected compound library (CYP450 inhibitor-based compounds) in possums to that of three other species (mouse, avian, and human). The results showed higher CYP3A protein levels in possum liver microsomes compared to other test species (up to a 4-fold difference). Moreover, possum liver microsomes had significantly higher basal p-nitrophenol glucuronidation activity than other test species (up to an 8-fold difference). However, no CYP450 inhibitor-based compounds significantly decreased the catalytic activity of possum CYP3A and UGT2B below the estimated IC50 and 2-fold IC50 values and were therefore not considered to be potent inhibitors of these enzymes. However, compounds such as isosilybin (65%), ketoconazole (72%), and fluconazole (74%) showed reduced UGT2B glucuronidation activity in possums, mainly at 2-fold IC50 values compared to the control (p < 0.05). Given the structural features of these compounds, these results could provide opportunities for future compound screening. More importantly, however, this study provided preliminary evidence that the basal activity and protein content of two major drug-metabolising enzymes differ in possums compared to other test species, suggesting that this could be further exploited to reach the ultimate goal: a potential target-specific fertility control for possums in New Zealand.

Psychoactive Substances Bill and Act of New Zealand: A Chance to Engage Undergraduate Scientists with Society using a Transfer Learning Paradigm.

Our aim was to develop a teaching paradigm that connected undergraduate's neuropharmacological/toxicological knowledge to that of government policy. One goal of undergraduate education should be to help develop scientists that can use their scientific knowledge to critique government policy. There is little research, however, on whether democratization of science occurs: nor how to achieve this. Our work focused on a semi-structured workshop designed around the Psychoactive Substances Bill (PSB). Third year science students were given a questionnaire that was designed to address whether participating in the workshop enhanced their understanding of the PSB and its relationship to their established knowledge (i.e., transfer learning). Furthermore, whether they felt that they had enough expertise to consider making a submission (i.e., societal engagement). Results showed that the students appreciated the opportunity to explore potential application of their knowledge and delve into a socio-scientific issue. However, our findings suggested they felt uncomfortable discussing their ideas outside the classroom: nor, did they identify themselves as having sufficient knowledge to contribute to a submission. In conclusion, this study highlights two points. First, that discussion based transfer learning can be used in the tertiary sector and students value the opportunity to apply their knowledge to socio-scientific issue. Second, if social participation and democratization of science is a goal, then more emphasis should be placed on how students can realistically and confidently apply their learning to change social policy. In order to achieve this, education programs need to focus on legitimate real-life processes such as the PSB for engagement.

Exposure to nitrate from food and drinking-water in New Zealand. Can these be considered separately?

Recent epidemiological studies have reported associations between colorectal cancer incidence and nitrates in drinking-water, but not from the diet. The toxicokinetics of nitrates were reviewed and exposure data from New Zealand were analysed. Dietary (including drinking-water) exposure of New Zealanders to nitrates was found to be very similar to most other countries and within internationally-established acceptable daily intakes. Less than 10% of nitrate exposure was from drinking-water, with little difference between adults and children. Approximately half of the total water-based exposure is through water alone, the remainder was consumed as tea and coffee (adults), or water-based fruit drinks (children). For children, drinking-water as a beverage is generally consumed close to a meal time, with 83% of servings consumed within an hour of eating. For adults, this is reduced to 51% of servings consumed within an hour of a meal. Only 2.6% of nitrate exposure for adults and 0.7% of nitrate exposure for children is from drinking-water consumed on its own and not in close temporal association to food consumption. It was concluded from the combination of the biology and the exposure assessment that there is little reason to differentiate between drinking-water and food nitrate exposure.

In Vitro Hepatic Assessment of Cineole and Its Derivatives in Common Brushtail Possums (Trichosurus vulpecula) and Rodents.

Folivore marsupials, such as brushtail possum (Trichosurus Vulpecula) and koala (Phascolarctos cinereus), can metabolise higher levels of dietary terpenes, such as cineole, that are toxic to eutherian mammals. While the highly efficient drug metabolising enzymes, cytochrome P450 3A (CYP3A) and phase II conjugating enzymes (UDP-glucuronosyltransferase, UGT), are involved in the metabolism of high levels of dietary terpenes, evidence for inhibitory actions on these enzymes by these terpenes is scant. Thus, this study investigated the effect of cineole and its derivatives on catalytic activities of hepatic CYP3A and UGT in mice, rats, and possums. Results showed that cineole (up to 50 µM) and its derivatives (up to 25 µM) did not significantly inhibit CYP3A and UGT activities in mice, rats, and possums (both in silico and in vitro). Interestingly, basal hepatic CYP3A catalytic activity in the possums was ~20% lower than that in rats and mice. In contrast, possums had ~2-fold higher UGT catalytic activity when compared to mice and rats. Thus, these basal enzymatic differences may be further exploited in future pest management strategies.

In-vitro degradation and toxicological assessment of pulsed electric fields crosslinked zein-chitosan-poly(vinyl alcohol) biopolymeric films.

We investigated the in vitro degradation and cytotoxic effects of edible films developed from pulsed electric fields (PEF) treated zein-chitosan-poly(vinyl alcohol) dispersions at specific energy 60-70, 385-400, and 620-650 kJ/kg. The degradation was evaluated using both simulated gastro-intestinal electrolyte solutions (SGES) and enzyme hydrolysis. The results of ortho-phthaldialdehyde (OPA) test indicated that the chemical breakdown of the films in SGES and enzyme increased with degradation time, but the product's features were unmodified. The Fourier Transform Infrared spectroscopy (FTIR) data showed enhancement of zein and chitosan transformation from ordered helices to ß-sheet conformation. Relative cell survival rates of Hepa-1c1c7 cells investigated using 3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) showed that the survival remained higher than 70% in both the supernatant and the residue of the SGES degraded samples and the supernatant from enzyme hydrolysis, which suggested that there was no significant toxicity of the films in the tested system. Although the residue from pancreatic digestion (240 min) (i.e. undigested films and a cocktail of digestion enzymes) expressed cytotoxicity activity, there was limited evidence of direct toxicity of the films. The findings of the study demonstrate the potential for PEF modified zein-chitosan-poly(vinyl alcohol) films as value-added biomaterials for the application in edible food packaging.

Critical appraisal of the potential use of cannabinoids in cancer management.

Cannabinoids have been attracting a great deal of interest as potential anticancer agents. Originally derived from the plant Cannabis sativa, there are now a number of endo-, phyto- and synthetic cannabinoids available. This review summarizes the key literature to date around the actions, antitumor activity, and mechanisms of action for this broad range of compounds. Cannabinoids are largely defined by an ability to activate the cannabinoid receptors - CB1 or CB2. The action of the cannabinoids is very dependent on the exact ligand tested, the dose, and the duration of exposure. Some cannabinoids, synthetic or plant-derived, show potential as therapeutic agents, and evidence across a range of cancers and evidence in vitro and in vivo is starting to be accumulated. Studies have now been conducted in a wide range of cell lines, including glioma, breast, prostate, endothelial, liver, and lung. This work is complemented by an increasing body of evidence from in vivo models. However, many of these results remain contradictory, an issue that is not currently able to be resolved through current knowledge of mechanisms of action. While there is a developing understanding of potential mechanisms of action, with the extracellular signal-regulated kinase pathway emerging as a critical signaling juncture in combination with an important role for ceramide and lipid signaling, the relative importance of each pathway is yet to be determined. The interplay between the intracellular pathways of autophagy versus apoptosis is a recent development that is discussed. Overall, there is still a great deal of conflicting evidence around the future utility of the cannabinoids, natural or synthetic, as therapeutic agents.