The non-estrogenic 2,5-disubstituted tetrazole core-bearing bisphenol structures (TbB) are being researched as emerging structural congeners of Bisphenol A, an established industrial endocrine ...disruptor. However, there is no understanding of TbB's adverse effects elicited via metabolic activation. Therefore, the current study aimed to investigate the metabolism of TbB ligands, with in silico results serving as a guide for in vitro studies. The Cytochrome P450 enzymes (CYP) inhibitory assay of TbB ligands on the seven human liver CYP isoforms (i.e., 1A2, 2A6, 2D6, 2C9, 2C8, 2C19, and 3A4) using human liver microsomes (HLM) revealed TbB ligand 223-3 to have a 50% inhibitory effect on all the CYP isoforms at a 10 μM concentration, except 1A2. The TbB ligand 223-10 inhibited 2B6 and 2C8, whereas the TbB ligand 223-2 inhibited only 2C9. The first-order inactivity rate constant (Kobs) studies indicated TbB ligands 223-3, 223-10 to be time-dependent (TD) inhibitors, whereas the TbB 223-2 ligand did not show such a significant effect. The 223-3 exhibited a TD inhibition for 2C9, 2C19, and 1A2 with Kobs values of 0.0748, 0.0306, and 0.0333 min-1, respectively. On the other hand, the TbB ligand 223-10 inhibited 2C9 in a TD inhibition manner with Kobs value 0.0748 min-1. However, the TbB ligand 223-2 showed no significant TD inhibition effect on the CYPs. The 223-2 ligand biotransformation pathway by in vitro studies in cryopreserved human hepatocytes suggested the clearance via glucuronidation with the predominant detection of only 223-2 derived mono glucuronide as a potential inactive metabolite. The present study demonstrated that the 223-2 ligand did not elicit any significant adverse effect via metabolic activation, thus paving the way for its in vivo drug-drug interactions (DDI) studies.
Enterococcus is one of the important causes of hospital acquired infections. Drug resistance particularly for High Level Aminoglycosides Resistance is one of the important patterns of resistance ...exhibited by Enterococcus. This study was conducted to determine the high-level aminoglycoside resistance for gentamicin and streptomycin in Enterococcal species isolated from a tertiary care centre. Number of isolates collected were 76 of which 42 (55.2%) from urine 26(34.21%) from exudates, 4(5.26%) from blood and rest from other body fluids. Most of the isolates were Enterococcus faecalis (72%) followed by Enterococcus faecium (28%). All the isolates were subjected to Kirby-Bauer disk diffusion test using high-content gentamicin (120 kg/disk) and streptomycin (300 kg/disk), single concentration agar dilution test with streptomycin 2000 kg/ml, 500 kg/ml and 2000 kg/ml of gentamicin. There were 27 (35.5%) were showed High Level Aminoglycosides Resistance (HLAR), of which 18(23.68%) were High Level Gentamycin Resistance (HLGR), 9(11.84%) were High Level Streptomycin Resistance (HLSR) and 9 (11.84%) isolates showed resistant to both. E.faecalis was the species most frequently exhibited High Level Resistance (HLR) for the drugs tested. Prevalence of HLAR in Enterococci is high and could be a serious problem in a hospital setup, screening for high-level aminoglycoside resistance must be included in routine antibiotic susceptibility reporting for Enterococcal isolates, especially from blood as high-level resistant strains does not show synergism with cell wall acting antibiotics like penicillin group and vancomycin which are the drug of choice.
In recent years, the inclusion of uncertainty analysis in risk assessment has been much debated. One pertinent issue is the translation of the effects observed with a limited number of test species ...to a general protection level for most or all species present in the environment. In a number of cases, toxicity data may consist of data from tests employing only a control and one treatment. Given that more species (or processes) have been tested with the same treatment, the treatment can be considered as fixed, and the effect level of the individual species (or processes) can be considered as variable. The distribution of effects can be viewed as a species effect distribution for that treatment. The distribution will represent all organisms and may be used to predict the maximum impact on any fraction of all organisms (e.g., 95% of all species). Hence, it is possible to predict the maximum effect level, with a selected certainty, for a given fraction of all species.
The isolation of T cells, followed by differentiation into Regulatory T cells (Tregs), and re-transplantation into the body has been proposed as a therapeutic option for inflammatory bowel disease. A ...key requirement for making this a viable therapeutic option is the generation of a large population of Tregs. However, cytokines in the local microenvironment can impact the yield of Tregs during differentiation. As such, experimental design is an essential part of evaluating the importance of different cytokine concentrations for Treg differentiation. However, currently only single, constant concentrations of the cytokines have been investigated. This work addresses this point by performing experimental design in silico which seeks to maximize the predicted induction of Tregs relative to Th17 cells, by selecting an optimal input function for the concentrations of TGF-β, IL-2, IL-6, and IL-23. While this approach sounds promising, the results show that only marginal improvements in the concentration of Tregs can be achieved for dynamic cytokine profiles as compared to optimal constant concentrations. Since constant concentrations are easier to implement in experiments, it is recommended for this particular system to keep the concentrations constant where IL-6 should be kept low and high concentrations of TGF-β, IL-2, and IL-23 should be used.
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