MOG analogues to explore the MCT2 pharmacophore, α-ketoglutarate biology and cellular effects of N-oxalylglycine.

α-ketoglutarate (αKG) is a central metabolic node with a broad influence on cellular physiology. The αKG analogue N-oxalylglycine (NOG) and its membrane-permeable pro-drug derivative dimethyl-oxalylglycine (DMOG) have been extensively used as tools to study prolyl hydroxylases (PHDs) and other αKG-dependent processes. In cell culture media, DMOG is rapidly converted to MOG, which enters cells through monocarboxylate transporter MCT2, leading to intracellular NOG concentrations that are sufficiently high to inhibit glutaminolysis enzymes and cause cytotoxicity.

Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism.

The Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an essential role in the receptor signaling of cytokines that have been implicated in the pathogenesis of severe asthma, and there is emerging interest in the development of small-molecule-inhaled JAK inhibitors as treatments. Here, we describe the optimization of a quinazoline series of JAK inhibitors and the results of mouse lung pharmacokinetic (PK) studies where only low concentrations of parent compound were observed. Subsequent investigations revealed that the low exposure was due to metabolism by aldehyde oxidase (AO), so we sought to identify quinazolines that were not metabolized by AO.

Serial estimation of Th1:th2 cytokines profile in women undergoing in-vitro fertilization-embryo transfer.

Problem: To investigate changes in the ratio of T-cell subpopulations expressing intracellular T helper1 (Th1) and T helper 2 (Th2) cytokines in women with a history of recurrent failed implantation under going in-vitro fertilization (IVF)-embryo transfer.

Method Of Study: Twenty-eight peripheral blood samples were obtained at two time points, from 14 women undergoing IVF treatment; eight women with a history of recurrent failed implantation, who did not get pregnant in the index IVF cycle and six who had one or more previous successful IVF pregnancy and who became pregnant in the index IVF cycle. The proportion of lymphocytes expressing interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), and interleukin 4 (IL-4) and the Th1:Th2 ratios of IFN-gamma:IL-4, and TNF-alpha:IL-4 in T helper cells was measured by flow cytometry, in samples obtained before commencing IVF treatment and in samples obtained after ovarian stimulation (on the day of oocyte retrieval).