Novel endoperoxide antimalarials: synthesis, heme binding, and antimalarial activity

We report the synthesis of a series of novel epoxy endoperoxide compounds that can be prepared in high yields in one to three steps from simple starting materials. Some of these compounds inhibit the growth of Plasmodium falciparum in vitro. Structure-activity studies indicate that an endoperoxide ring bisubstituted with saturated cyclic moieties is the pharmacophore. To study the molecular basis of the action of these novel antimalarial compounds, we examined their ability to interact with oxidized and reduced forms of heme. Some of the compounds interact with oxidized heme in a fashion similar to chloroquine and other 4-aminoquinolines, while some of the compounds interact with reduced heme. However, the level of antimalarial potency is not well correlated with these activities, suggesting that some of the endoperoxides may exert their antimalarial activities by a novel mechanism of action.

Don't eat that, you'll get fat! Exploring how parents and children conceptualise and frame messages about the causes and consequences of obesity

Family interactions about weight and health take place against the backdrop of the wider social discourse relating to the obesity epidemic. Parents (and children) negotiate complex and often contradictory messages in constructing a set of beliefs and practices around obesity and weight management. Despite this, very little research attention has been given to the nature of family-unit discourse on the subject of body weight and it's potential influence on the weight-related behaviours of family members. This includes the broad influence that dominant socio-cultural discourses have on family conceptualisations of weight and health. Using in-depth qualitative interviews with 150 family 'groups' comprised of at least one parent and one child in Victoria and South Australia, we explored how parents and children conceptualise and discuss issues of weight- and health-related lifestyle behaviours. Data were analysed using Attride-Stirling's (2001) thematic network approach. Three thematic clusters emerged from the analysis. First, both parents and children perceived that weight was the primary indicator of health. However, parents focused on the negative physical implications of overweight while children focused on the negative social implications. Second, weight and lifestyle choices were highly moralised. Parents saw it as their responsibility to communicate to children the 'dangers' of fatness. Children reported that parents typically used negatively-framed messages and scare tactics rather than positively-framed messages to encourage healthy behaviours. Third was the perception among parents and children that if you were thin, then eating habits and exercise were less important, and that activity could provide an antidote to food choices. Results suggest that both parents and children are internalising messages relating to obesity and weight management that focus on personal responsibility and blame attribution. These views reflect the broader societal discourse, and their consolidation at the family level is likely to increase their potency and make them resistant to change.

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP-4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucose-lowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP-4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half-life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. The off-target inhibition of selective DPP-4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP-4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once-daily dosing. It is unknown if DPP-4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP-4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.

A comparison of novel organoiridium(III) complexes and their ligands as a potential treatment for prostate cancer

A range of 1,4-substituted 2-pyridyl-N-phenyl triazoles were synthesised and evaluated for their antiproliferative properties against lymph node cancer of the prostate (LNCaP) and bone metastasis of prostate cancer (PC-3) cells. Excellent-to-low IC50 values were determined (5.6-250 μM), and a representative group of 4 ligands were then complexed to iridium(III) giving highly luminescent species. Re-evaluation of these compounds against both cell lines was then undertaken and improved potency (up to 72-fold) was observed, giving IC50 values of 0.36-11 μM for LNCaP and 0.85-5.9 μM for PC-3. Preliminary screens for in vivo toxicity were conducted using a zebrafish model showing a wide range of induced toxicity depending of the compound evaluated. Apoptosis and Caspase-3 levels were also determined and showed no statistical difference between some of the treated specimens and the controls. This study may identify novel therapeutic agents for advanced stage of prostate cancer in humans.

Schizophrenia, psychotropic medication, and cataract

OBJECTIVE: To compare the distribution of cataract types between psychiatric patients diagnosed with schizophrenia and the general population not exposed to psychotropic medication, and to compare cataract prevalence between users and nonusers of various psychotropic medications in the general community. DESIGN: Case-control. PARTICIPANTS: A total of 151 (93%) eligible patients from a community mental health service and 3271 (83%) eligible residents from the Melbourne Visual Impairment Project (VIP) were examined. MAIN OUTCOME MEASURES: All patients 40 years of age and older from a community mental health service and residents of nine randomly selected areas of Melbourne were eligible. Best-corrected distance visual acuity was determined using a 4-m logarithm of the minimum angle of resolution (LogMAR) chart. The presence of cataract was determined by photographs or slit-lamp examination using direct and indirect retroillumination. Anterior, cortical, nuclear, and posterior subcapsular cataracts were measured. Participants from the Melbourne VIP were classified as to whether they had taken benzodiazepams, phenothiazines, thioxanthenes, butyrophenols, tricyclic antidepressants, or monoamine oxidase inhibitors for at least 12 months during their lifetime. RESULTS: The distribution of cataract type varied between persons with and without schizophrenia. Anterior subcapsular (ASC) cataract was significantly more prevalent (26%) in participants with schizophrenia from the community mental health service than Melbourne VIP participants (0.2%) not exposed to psychotropic medication (chi-square, 1 degree of freedom = 605.5, P = 0.001). This remained significant after controlling for age (odds ratios = 250, 95% confidence interval = 83.3, 1000). The distribution of the age-related cataract was similar across all groups of psychotropic medication users with the exception of the phenothiazine users. They had less of all types of the age-related cataracts, despite being slightly older than the control group (mean age, 60.0 vs. 58.4, t test = 0.85, P = 0.40). However, only cortical cataract in the phenothiazine group was statistically lower (chi-square, 1 degree of freedom = 3.96, P = 0.047). CONCLUSION: This study has identified the need to investigate whether other newer agents, especially high-potency medications, cause ASC opacities if a certain threshold of exposure to psychotropic medications must be attained to develop cataract, or if schizophrenia itself is associated with cataract formation.

Bioprocess challenges to the isolation and purification of bioactive peptides

Food protein-derived bioactive peptides (BPs) have been reported to trigger certain physiological responses in the body, thereby influencing health positively. These peptides have attracted high research and consumer interests due to their huge potential of use in functional foods and other dietary interventions of disease control and health promotion. However, successful product development is limited by the fact that current manufacturing processes are either difficult to scale up, high in cost, or have the potential to affect the structure-activity properties of these peptides. To overcome these challenges, we have proposed in this review, the use of an integrated ‘-omics’ approach comprising in silico analysis and ‘-omics’ techniques (such as peptidomics) to respectively forecast and validate the biological and physico-chemical properties of the peptides. This information is then used for the rational design of suitable purification steps for peptides of interest. Downstream purification could also be undertaken by liquid chromatography using monolithic adsorbents physico-chemically engineered (using results of in silico analysis) for rapid isolation of peptides. By coupling the high throughput and predictive capability of ‘-omics’ to the enhanced convective hydrodynamics of monolithic columns, it becomes feasible, even at preparative scale, to produce BPs that meet the requirements of high purity, potency, and cost-effectiveness.

Site and mechanism of the colokinetic action of the ghrelin receptor agonist, HM01

Background It has been recently demonstrated that the ghrelin receptor agonist, HM01, caused defecation in rats that were treated to provide a model for the constipation of Parkinson's disease. HM01 significantly increased fecal output and increased Fos activity in neurons of the hypothalamus and hindbrain, but not in the spinal defecation center. Other ghrelin agonists act on the defecation center. Methods Receptor pharmacology was examined in ghrelin receptor (GHSR1a) transfected cells. Anesthetized rats were used to investigate sites and mechanisms of action. Key Results HM01 activated rat GHSR1a at nanomolar concentrations and was antagonized by the GHSR1a antagonist, YIL781. HM01, intravenous, was potent to activate propulsive colorectal contractions. This was prevented by pelvic nerve section and by intravenous YIL781, but not by spinal cord section rostral to the defecation centers. Direct intrathecal application of HM01 to the defecation center at spinal level L6-S1 initiated propulsive contractions of the colorectum. Conclusions & Inferences HM01 stimulates GHSR1a receptors on neurons in the lumbosacral defecation centers to cause propulsive contractions and emptying of the colorectum. It has greater potency when given systemically, compared with other GHSR1a agonists.

Food-derived multifunctional bioactive proteins and peptides: sources and production

Multifunctional proteins and peptides from food proteins have been studied over the past few decades to elucidate their biological potency and the beneficial roles they play in human health. Owing to their multiple biological activities, these peptides have a wider role in modulating physiological functions such as antioxidative, antimicrobial, antihypertensive, cytomodulatory, anxiolytic, anorexic, and immunomodulatory activities in living body systems. Highlighted in this chapter is the biological role of some multifunctional peptides as well as the food proteins and enzyme(s) that are responsible for their release. Other challenges to the bioprocessing of multifunctional peptides and the need for research to address them are also discussed.

Food-derived multifunctional bioactive proteins and peptides: applications and recent advances

Owing to their biological roles, multifunctional peptides constitute a new generation of biologically active molecules whose potential can be exploited in several industrial applications such as functional food, pharmaceutical, and cosmeceutical industries. With the required combination and balance of research and commercial operations, major corporations can effectively harness the diverse functionalities of these peptides for enhanced nutrition and the treatment and mitigation of ill health. However, further insightful research in vivo and clinical studies are needed to unravel the mechanism and fate of these peptides en route to the body systems. This is needed to firmly establish the therapeutic potency of these peptides.

New dibutyltin(IV) ladders: syntheses, structures and, optimization and evaluation of cytotoxic potential employing A375 (melanoma) and HCT116 (colon carcinoma) cell lines in vitro

Synthesis and spectroscopic properties of seven new dibutyltin(IV) compounds of 2-{(E)-4-hydroxy-3-[(E)-4-(aryl)iminomethyl]phenyldiazenyl}benzoic acids (L(n)HH'; n=2-8) with general formula {[Bu2Sn(L(n)H)]2O}2 (1-7) are reported. The compounds were characterized by elemental analysis and by UV-Visible, fluorescence, IR, (1)H, (13)C and (119)Sn NMR spectroscopies. Solid state structures of dibutyltin(IV) compounds 1-3, 6 and 7 were accomplished from single crystal X-ray crystallography which reveal the common ladder-type structure with two endo- and two exo-Sn atoms. The redox properties of L(n)HH' (n=2-4, 7 and 8) and their diorganotin(IV) compounds 1-3, 6 and 7 were also investigated by cyclic voltammetry. In general, the dibutyltin(IV) derivatives exhibited significant in vitro cytotoxic potency towards A375 (melanoma) and HCT116 (colon carcinoma) cell lines as determined by several experiments, like Live and Dead assay, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell viability assay, LDH (lactate dehydrogenase), cleavage of caspases and PARP (poly(ADP-ribose)polymerase), and DNA fragmentation. Dibutyltin(IV) compounds increase cell death without cytolysis and decreases membrane fluidity, without interfering with p53. Among the dibutyltin(IV) compounds, compound 6 was found to be the most potent, with an IC50 value of 78nM. A mechanism of action for tumor cell death is proposed.

Difference-form persuasion contests

We explore the equilibrium properties of two types of "difference-form" persuasion contest functions derived in Skaperdas and Vaidya in which contestants spend resources to persuade an audience. We find that both types of functions generate interior pure strategy Nash equilibria unlike Baik and Che and Gale with characteristics different to existing literature. For one type of function, we find that the reaction function of each player is "flat" and nonresponsive to the level of resources devoted by the rival so that the "preemption effect" as defined by Che and Gale is absent. Further, the equilibrium is invariant to the sequencing of moves. For the second type of function, which applies when there is asymmetry among contestants with regard to the quality of evidence, we find that the reaction functions of the stronger and weaker players have gradients with opposite signs relative to Dixit and therefore their incentive to precommit expenditures in a sequential move game is also different. For both types of functions, the extent of rent dissipation is partial. From the equilibrium analysis, we are also able to establish the potential effects of some specific factors affecting persuasion such as evidence potency, the degree of truth, and bias on aggregate resource expenditures and welfare.