In particular we focus on assessing the impact of the dissociation constants, K(p), K(L) and K(R) of the drug with, respectively, the proteins, the lipids and the receptors, the permeability and the surface area of the membrane between compartments, and the rate the drug is eliminated from the system. (C) 2010 Elsevier Ltd. All rights reserved.”
“Mitochondrial permeability transition (MPT) is a highly regulated complex phenomenon that is a type of ischemia/reperfusion injury that can lead to cell death and ultimately organ dysfunction. A novel population transition and detailed permeability transition pore regulation model were integrated with an existing
bioenergetics model AZD3965 to describe MPT induction under a variety of conditions. The framework of the MPT induction model includes Tubastatin A solubility dmso the potential states of the mitochondria (aggregated, orthodox and post-transition), their transitions from one state to another as well as their interaction with the extra-mitochondrial environment. The model encodes the three basic necessary conditions for MPT: a high calcium load, alkaline matrix pH and circumstances which favor de-energization.
The MPT induction model was able to reproduce the expected bioenergetic trends observed in a population of mitochondria subjected to conditions that favor MPT. The model was corroborated and used to predict that MPT in an acidic environment is mitigated by an increase in activity of the mitochondrial potassium/hydrogen exchanger. The model was also used to present the beneficial impact of reducing the duration mitochondria spend in the orthodox state on preserving the extra-mitochondrial ATP levels. The model serves HAS1 as a tool for investigators to use to understand the MPT induction phenomenon, explore alternative hypotheses for PTP regulation, as well as identify endogenous pharmacological targets and evaluate
potential therapeutics for MPT mitigation. (C) 2010 Elsevier Ltd. All rights reserved.”
“The Numb and Numb-like are evolutionarily conserved cell fate-determining factors in mammals. For the first time, we investigate the involvement of the Numb and Numb-like in the developing auditory sensory epithelium. We show that both of them are expressed in the rat auditory sensory epithelium, and the four isoforms of the Numb have dynamic expression patterns during cochlear development. At the early stage of the auditory epithelium development, they occur in all progenitor cells. At the late stage of cell differentiation, they are expressed mainly in the cytoplasm of apical cells and their locations are different. Furthermore, we find overexpression of the Numb or Numb-like, in cochlear whole mount cultures, can upregulate mRNA level of Rath1, which is important in the hair-cell development.