A New RL Constant for the Calculation of log P and n Values in Congeneric Compounds

Retention volumes of iodinated diethylstilbestrols and estradiols measured by high-pressure liquid chromatography on a silica column were found to be linearly related to their experimental partition coefficients (log P). The log P values calculated from the new RL parameter correlate well with experimental values and with those calculated by Hansch :n:-constants. The magnitudes of it-values for iodine in monosubstituted estradiols are discussed in terms of the contribution of steric and »proximity« effects to these constants. The reported technique may be a significant addition to the methodology of obtaining lipophylic-hydrophylic constants in structure- activity relationship studies

A New RL Constant for the Calculation of log P and n Values in Congeneric Compounds

Retention volumes of iodinated diethylstilbestrols and estradiols measured by high-pressure liquid chromatography on a silica column were found to be linearly related to their experimental partition coefficients (log P). The log P values calculated from the new RL parameter correlate well with experimental values and with those calculated by Hansch :n:-constants. The magnitudes of it-values for iodine in monosubstituted estradiols are discussed in terms of the contribution of steric and »proximity« effects to these constants. The reported technique may be a significant addition to the methodology of obtaining lipophylic-hydrophylic constants in structure- activity relationship studies

Aromatic Iodination of Diethylstilbestrol Diphosphate

Sterically crowded estrogenic compound diethylstilbestrol diphosphate was successfully polyiodinated on the aromatic rings applying an electrochemical procedure. The reported synthesis also opens the way for the preparation of potentially useful radiolabelled cancer chemotherapeutics

Proinflammatory Cytokines Activate the Intrinsic Apoptotic Pathway in β-Cells

OBJECTIVE:Proinflammatory cytokines are cytotoxic to beta-cells and have been implicated in the pathogenesis of type 1 diabetes and islet graft failure. The importance of the intrinsic mitochondrial apoptotic pathway in cytokine-induced beta-cell death is unclear. Here, cytokine activation of the intrinsic apoptotic pathway and the role of the two proapoptotic Bcl-2 proteins, Bad and Bax, were examined in beta-cells.RESEARCH DESIGN AND METHODS:Human and rat islets and INS-1 cells were exposed to a combination of proinflammatory cytokines (interleukin-1beta, interferon-gamma, and/or tumor necrosis factor-alpha). Activation of Bad was determined by Ser136 dephosphorylation, mitochondrial stress by changes in mitochondrial metabolic activity and cytochrome c release, downstream apoptotic signaling by activation of caspase-9 and -3, and DNA fragmentation. The inhibitors FK506 and V5 were used to investigate the role of Bad and Bax activation, respectively. [...

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Ecotoxicity of a potential drug nano-formulation: PAMAM-dendrimer and minocycline

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