Institute for Health Transformation

Intracellular accumulation of protein-bound uremic toxins in the setting of cardiorenal syndrome leads to adverse effects on cardiorenal cellular functions, where cardiac hypertrophy and cardiorenal fibrosis are the hallmarks. In this study, we sought to determine if Apoptosis Signal-Regulated Kinase 1 (ASK1), an upstream regulator of cellular stress response, mediates cardiac hypertrophy and cardiorenal fibrosis induced by indoxyl sulfate (IS) and p-cre-sol sulfate (PCS) in vitro, and whether ASK1 inhibition is beneficial to ameliorate these cellular effects. PCS augmented cardiac myocyte hypertrophy and fibroblast collagen synthesis (as determined by 3H-leucine and 3H-proline incorporation, respectively), similar to our previous finding with IS. IS and PCS also increased collagen synthesis of proximal tubular cells and renal mesangial cells. Pro-hypertrophic (α-skeletal muscle actin and β-MHC) and pro-fibrotic genes (TGF-β1 and ctgf) were induced by both IS and PCS. Western blot analyses revealed the activation of ASK1 and downstream mitogen activated protein kinases (MAPKs) (p38MAPK and ERK1/2) as well as nuclear factor-kappa B (NF-κB) by IS and PCS. ASK1, OAT1/3, ERK1/2 and p38MAPK inhibitors suppressed all these effects. In summary, IS and PCS exhibit pro-hypertrophic and pro-fibrotic properties, at least in part, via the activation of ASK1 and its downstream pathways. ASK1 inhibitor is an effective therapeutic agent to alleviate protein-bound uremic toxin-induced cardiac hypertrophy and cardiorenal fibrosis in vitro, and may be translated further for cardiorenal syndrome therapy.

Cardiorenal syndrome (CRS) is a multi-organ disease, encompassing heart, kidney and vascular system dysfunction. CRS remains a worldwide problem, with high morbidity and mortality, and inflicts a significant burden on the healthcare system. The pathophysiology is complex, involving interactions between neurohormones, inflammatory processes, oxidative stress and metabolic derangements. Therapies remain inadequate, mainly comprising symptomatic care with minimal prospect of full recovery. Challenges include limiting the contradictory effects of multi-organ targeted drug prescriptions and continuous monitoring of volume overload. Novel strategies such as multi-organ transplantation and innovative dialysis modalities have been considered, but lack evidence in the CRS context. The adjunct use of pharmaceuticals targeting alternative pathways showing positive results in preclinical models also warrant further validation in the clinic. In recent years, studies have identified the involvement of gut dysbiosis, uremic toxin accumulation, sphingolipid imbalance and other unconventional contributors, which has encouraged a shift in the paradigm of CRS therapy.

Ribonucleic acid (RNA) is a thermodynamically unstable molecule. The way RNA samples are preserved is critical to maintain maximum yield and quality, therefore it is useful for molecular analysis such as real time-PCR. There are many contradictions and variations regarding the temperature for RNA storage. The aim of this study is to find the ideal temperature to store RNA among-80 o C,-20 o C and 4 o C by determining changes in RNA concentration over two weeks of storage time. The liver of eight rats was divided into three groups, weighing from 25-26 μg. Samples were homogenized, isolated and stored in-80 o C,-20 o C and 4 o C freezers. Absorbance was measured with spectrophotometry at 260 and 280 nm to determine the concentration of RNA. There was no significant difference in the concentration of RNA samples stored in all temperatures after two weeks, both experimentally and statistically (Kruskal-Wallis,-80 o C p=0.949;-20 o C p=0.885; 4 o C p=0.935). In conclusion, RNA can be stored in-80 o C,-20 o C and 4 o C for two weeks without quantity reduction. Longer duration of study and RNA quality analysis is recommended to check for RNA degradation.

Background Coronary heart disease (CHD) is the highest individual disease burden in Australia and associated with productivity losses through unplanned absence from work, reduced output while at work and early labour force withdrawal. Approximately eighty per cent of CHD cases in Australia are preventable, suggesting the potential benefit of employing preventive strategies addressing populations at risk of CHD. Purpose To determine the preventable productivity burden attributable to CHD over the next ten years, using the novel productivity measure: the “productivity-adjusted life year” (PALY). Methods A dynamic life table model was constructed for the total Australian population, separated by CHD status. Analysis was limited to the Australian working-age population (15–69 years) over ten years (2020–2029). Australian age- and sex-specific prevalence, incidence, migration and mortality data was employed, and productivity estimates were sourced from the literature. The PALY was ascrib...