The standard Michaelis-Menten model equation must be extended to describe the kinetics of enzyme-catalyzed reactions that exhibit also spontaneous substrate depletion. Hence, its use is limited because the integrated form cannot be expressed in an explicit closed-form reformulation of the time-dependent solution. Thus, we construct explicit approximations to the solution of the extended Michaelis-Menten equation using the Adomian decomposition method, and this report presents its use to an illustrative problem that has been considered solvable only by numerical methods. We demonstrate here that the algebraic nature of these approximations to the solution of the extended Michaelis-Menten equation makes progress-curve analysis an attractive and useful alternative that can be simply performed using a standard nonlinear regression curve-fitting computer program.
COBISS.SI-ID: 32324825
Four ruthenium complexes of clinically used zinc ionophore pyrithione and its oxygen analog 2-hydroxypyridine N-oxide were prepared and evaluated as inhibitors of enzymes of the aldo-keto reductase subfamily 1C (AKR1C). A kinetic study assisted with docking simulations showed a mixed type of inhibition consisting of a fast reversible and a slow irreversible step in the case of both organometallic compounds 1A and 1B. Both compounds also showed a remarkable selectivity towards AKR1C1 and AKR1C3 which are targets for breast cancer drug design. The organoruthenium complex of ligand pyrithione as well as pyrithione itself also displayed toxicity on the hormone-dependent MCF-7 breast cancer cell line with EC50 values in the low micromolar range.
COBISS.SI-ID: 32724441
Wallemia comprises air- and food-borne, mycotoxigenic contaminants including the halophilic W. ichthyophaga, xerotolerant W. sebi and xerophilic W. muriae. Wallemia isolates are easily overlooked and only a comparably small number of strains have been deposited in culture collections so far. In order to better understand the natural distribution of Wallemia spp. and to encounter their natural habitats, we tested more than 300 low-water-activity substrates and 30 air samples from a wide geographical coverage. We isolated more than 150 new Wallemia strains. Wallemia sebi and W. muriae were isolated mostly from hypersaline water, low-water-activity foods, plant materials and indoor. Wallemia muriae is the dominant Wallemia species in the air of natural and human influenced environments in Europe. New isolates of W. ichthyophaga were obtained from hypersaline environments such as brine, salt crystals, salty foods and MgCl2-rich bitterns, and from the air of hay barns in Denmark. Five halotolerant strains were recognised as a hitherto undescribed species Wallemia hederae, the phylogenetic sister of the halophilic W. ichthyophaga. Wallemia spp. show in-vitro growth on media that contain the chaotropic salt MgCl2. Wallemia ichthyophaga can grow in liquid medium enriched with 2 M MgCl2. Never before has a microorganism been grown on comparably high MgCl2 concentrations. Tests of the activity of a wide range of extracellular enzymes in the presence of NaCl also suggested that Wallemia is well-adapted to substrates with a reduced water activity.
COBISS.SI-ID: 3436111
Endometriosis is a complex, polygenic, and estrogen-dependent disease that affects 6% to 10% of women of reproductive age, and 30% to 50% of women with infertility and/or pelvic pain. Surgical diagnosis of endometriosis is still the gold standard, as there are currently no diagnostic biomarkers available. Due to the invasive diagnostics, it can take up to 11 years before affected women are diagnosed and receive the appropriate treatment. We performed a targeted metabolomics study to search for potential semi-invasive biomarkers in peritoneal fluid from endometriosis patients. Our case-control study comprised 29 ovarian endometriosis patients and 36 healthy control women. The 148 metabolites included acylcarnitines, glycerophospholipids, and sphingolipids, which were quantified by electrospray ionization tandem mass spectrometry. The strength of association between the metabolites and the metabolite ratios and disease was assessed using crude and adjusted odds ratios. The best combination of biomarkers was then selected by performing step-wise logistic regression. Our analysis reveals significantly decreased concentrations of 10 metabolites, of carnitine and acylcarnitines (C0, C8:1, C6C4:1 DC, C10:1), phosphatidylcholines (PC aa C38:3, PC aa C38:4, PC aa C40:4, PC aa C40:5), and sphingomyelins (SM C16:1, SM C18:1), and 125 significantly altered metabolite ratios in patients versus control women. The best model includes two ratios: a carnitine to a phosphatidylcholine (C0/PC ae C36:0); and between two phosphatidylcholines (PC aa C30:0/PC ae C32:2). When adjusted for age, this provides sensitivity of 82.8% and specificity of 94.4%, with AUC of 0.944. Our study supports the importance of carnitine, phosphatidylcholine, and sphingomyelin metabolites in the pathophysiolo- gy of endometriosis, and confirms the potential for the combination of individual metabolite ratios to provide biomarkers for semi-invasive diagnostics.
COBISS.SI-ID: 32502745
We describe a novel approach to investigate and evaluate combined effect of a large number of clinical and pharmacogenetic factors on treatment outcome. We have used this approach to investigate predictors of methotrexate (MTX)-induced adverse events (AEs) leading to treatment discontinuation in rheumatoid arthritis (RA) patients. In total, 333 RA patients were genotyped for 34 polymorphisms in MTX transporters, folate and adenosine pathways. The effect of clinical and pharmacogenetic factors was assessed with penalized regression in the cause-specific Cox proportional hazards model. The predictive capacity was evaluated with the area under time-dependent receiver operating characteristic curve where cross-validation was applied. SLC19A1, ABCG2, ADORA3 and TYMS were associated with discontinuation because of AEs in clinical-pharmacogenetic model. Cross-validation showed that both clinical-pharmacogenetic model and nongenetic model had worthless predictive ability for MTX discontinuation because of AEs. These models could be further improved, either with additional polymorphisms or with epigenetic predictors.
COBISS.SI-ID: 32687833