Towards prevention of ischemia-reperfusion kidney injury: Pre-clinical evaluation of 6-chromanol derivatives and the lead compound SUL-138✰.

Acute kidney injury (AKI) is a global healthcare burden attributable to high mortality and staggering costs of dialysis. The underlying causes of AKI include hypothermia and rewarming (H/R), ischemia/reperfusion (I/R), mitochondrial dysfunction and reactive oxygen species production. Inspired by the mechanisms conferring organ protection in hibernating hamster, 6-chromanol derived compounds were developed to address the need of effective prevention and treatment of AKI. Here we report on the pre-clinical screening of 6-chromanol leads that confer protection during I/R to select compounds with favorable profiles for clinical testing in AKI. A library of 6-chromanols (n = 63) was screened in silico for pharmacochemical properties and druggability. Selected compounds (n = 15) were screened for the potency to protect HEK293 cells from H/R cell death and subjected to a panel of in vitro safety assays. Based on these parameters, SUL-138 was selected as the lead compound and was found to safeguard kidney function and decrease renal injury after I/R in rats. The compound was without cardiovascular or respiratory effects in vivo. SUL-138 pharmacokinetics of control animals (mouse, rat) and those undergoing I/R (rat) was identical, showing a two-phase elimination profile with terminal half-life of about 8 h. Collectively, our phenotype-based screening approach led to the identification of 3 candidates for pre-clinical studies (5%, 3/64). SUL-138 emerged from this small-scale library of 6-chromanols as a novel prophylactic for AKI. The presented efficacy and safety data provide a basis for future development and clinical testing. SECTION ASSIGNMENTS: : Drug discovery and translational medicine, renal, metabolism SIGNIFICANCE STATEMENT: : Based on in silico druggability parameters, a 63 compound 6-chromanol library was narrowed down to 15 compounds. These compounds were subjected to phenotypical screening of cell survival following hypothermia damage and hit compounds were identified. After subsequent assessment of in vivo efficacy, toxicity, pharmacokinetics, and cardiovascular and respiratory safety, SUL-138 emerged as a lead compound that prevented kidney injury after ischemia/reperfusion and demonstrated a favorable pharmacokinetic profile unaffected by renal ischemia.

Differential Urinary Proteomic Analysis of Endometrial Cancer.

Endometrial cancer is one of the most frequent gynecological malignancies present in more than 95 % of all uterine cancers. In spite of that, screening of such disease is not commonly performed in clinical practice due to enormous costs and relatively low sensitivity. Therefore, developing an effective screening test to diagnose endometrial cancer at early stages is of great importance for the clinical area of investigation. In this work, we applied urinary proteomics (i.e., bottom-up proteomic approach followed by nano HPLC-ESI-MS/MS) in patients with endometrial cancer, with respect to find proteins aimed for the early diagnostics and screening. According to the results, the significant semi-quantitative changes were observed in urinary proteome of treated patients. The proteins that may be pivotal in pathogenesis of endometrial cancer, like cadherin-1 (CDH1), vitronectin (VTN) and basement membrane specific-heparan sulphate proteoglycan core protein (HSPG2) were down-regulated, when compared to the control group. Ultimately, it can be stated that urinary proteomics has a potential for the searching of cancer protein biomarkers based on their altered concentration.

Detection of maduramycin residues in the tissues of chickens and pheasants by the screening test for antibiotic residues (STAR).

Maduramycin is a coccidiostat authorized as a feed additive in poultry. Council Directive 96/23/EC stipulates that monitoring of foods of animal origin for residues of coccidiostats is mandatory. The aim of the present study was to evaluate the STAR for the screening of maduramycin residues in the tissues of broiler chickens and pheasants. Both animal species were supplied feed medicated with Cygro l% premix according to recommendations for use (5 mg kg(-1) of complete feed). The residues were investigated for a period of 7 days: day 0 (the last day of the administration of maduramycin), days 1-5 (the days of the withdrawal period) and day 6 (the first day after elapse of the withdrawal period). According to STAR the positivity of the sample (the presence of residues of antibacterial substances) is indicated by a zone of inhibition exceeding 2 or 4 mm in width, depending on the test organism. Maduramycin residues were detected only on the plates seeded with the test organism Bacillus stearothermophilus var. calidolactis ATCC 10149. The results showed that there was higher potential for the presence of maduramycin residues in broiler chickens than in pheasants. All chicken tissues (muscle/thigh and breast/gizzard, liver, heart, kidneys, spleen, lungs) were positive for maduramycin (inhibition zones ≥4 mm) not only throughout the withdrawal period, but also even 5 days after elapse of the withdrawal period. In the case of pheasants the positive results were detected in the gizzard, liver, heart, kidneys, spleen and lungs. On day 5 of the withdrawal period no positive results were detected; however, on day 6 the heart and spleen were positive again.