Peripheral site ligand conjugation to a non-quaternary oxime enhances reactivation of nerve agent-inhibited human acetylcholinesterase

Commonly employed pyridinium-oxime (charged) reactivators of nerve agent inhibited acetylcholinesterase (AChE) do not readily pass the blood brain barrier (BBB) because of the presence of charge(s). Conversely, non-ionic oxime reactivators often suffer from a lack of reactivating potency due to a low affinity for the active site of AChE. It was...

Mannosylated self-peptide inhibits the development of experimental autoimmune encephalomyelitis via expansion of nonencephalitogenic T cells

Tolerance to experimental autoimmune encephalomyelitis (EAE) in SJL mice can be induced by immunization with a mannosylated form of the proteolipid protein (M-PLP139-151), despite the presence of CFA. The state of tolerance is characterized by poor delayed-type hypersensitivity responses and the absence of clinical EAE symptoms. In vivo...

Inhibitors and activation markers of the haemostatic system during hormone therapy: A comparative study of oral estradiol (2 mg)/ dydrogesterone and estradiol (2 mg)/ trimegestone

Epidemiological studies have shown that hormone therapy (HT) increases the risk of venous thromboembolism in post menopausal women. The mechanism of this increased risk is unknown; however, activation of the haemostatic system is known to contribute to the pathogenesis of venous thromboembolism. In post-menopausal women the estrogen /progestogen...

Hepatic glucose production is more sensitive to insulin-mediated inhibition than hepatic VLDL-triglyceride production

Insulin is an important inhibitor of both hepatic glucose output and hepatic VLDL-triglyceride (VLDL-TG) production. We investigated whether both processes are equally sensitive to insulin-mediated inhibition. To test this, we used euglycemic clamp studies with four increasing plasma concentrations of insulin in wild-type C57Bl/6 mice. By...

Minoxidil exerts different inhibitory effects on gene expression of lysyl hydroxylase 1, 2, and 3: Implications for collagen cross-linking and treatment of fibrosis

Collagen deposits in fibrotic lesions often display elevated levels of hydroxyallysine (pyridinoline) cross-links. The relation between the occurrence of pyridinoline cross-links and the irreversibility of fibrosis suggests that these cross-links contribute to the aberrant accumulation of collagen. Based on its inhibitory effect on lysyl...

Quantitative structure activity relationship studies on the flavonoid mediated inhibition of multidrug resistance proteins 1 and 2

In the present study, the effects of a large series of flavonoids on multidrug resistance proteins (MRPs) were studied in MRP1 and MRP2 transfected MDCKII cells. The results were used to define the structural requirements of flavonoids necessary for potent inhibition of MRP1- and MRP2-mediated calcein transport in a cellular model. Several of...

Inhibition of microglial inflammation by the MLK inhibitor CEP-1347

CEP-1347 is a potent inhibitor of the mixed lineage kinases (MLKs), a distinct family of mitogen-activated protein kinase kinase kinases (MAPKKK). It blocks the activation of the c-Jun/JNK apoptotic pathway in neurons exposed to various stressors and attenuates neurodegeneration in animal models of Parkinson's disease (PD). Microglial activation...

Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo

Therapeutic angiogenesis using vascular endothelial growth factor (VEGF) is considered a promising new therapy for patients with arterial obstructive disease. Clinical improvements observed consist of improved muscle function and regression of rest pain or angina. However, direct evidence for improved vascularization, as evaluated by angiography...

The flavones luteolin and apigenin inhibit in vitro antigen-specific proliferation and interferon-gamma production by murine and human autoimmune T cells

Plant-derived flavonoids are inhibitors of various intracellular processes, notably phosphorylation pathways, and potential inhibitors of cellular autoimmunity. In this study, the inhibiting effects of various flavonoids on antigen-specific proliferation and interferon-gamma (IFN-γ) production by human and murine autoreactive T cells were...

Synthesis and antimicrobial evaluation of farnesyl diphosphate mimetics

The synthesis and first antimicrobial evaluation of farnesyl diphosphate mimetics are described. Several analogues (10, 12, 13, and 20) are inhibitors of Candida albicans, Shizosaccharomyces pombe, and Saccharomyces cerevisiae. The activities of analogues 10, 12, and 13, which contain a ω-phenyl moiety and a diphosphate isostere, are not...

Inhibition of zaleplon metabolism by cimetidine in the human liver: In vitro studies with subcellular fractions and precision-cut liver slices

The effect of cimetidine on the metabolism of zaleplon (ZAL) in human liver subcellular fractions and precision-cut liver slices was investigated. 2. ZAL was metabolized to a number of products including 5-oxo-ZAL (M2), which is known to be formed by aldehyde oxidase, N-desethyl-ZAL (DZAL), which is known to be formed by CYP3A forms, and N...

Regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in human hepatoma cell line Hep G2. Effects of inhibitors of cholesterol synthesis on enzyme activity

Incubating Hep G2 cells for 18 h with triparanol, buthiobate and low concentrations (< 0.5 ??M) of U18666A, inhibitors of desmosterol ??24-reductase, of lanosterol 14??-demethylase and of squalene-2,3-epoxide cyclase (EC 5.4.99.7) respectively, resulted in a decrease of the HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase activity....

PAF-acether-induced release of tissue-type plasminogen activator from vessel walls

Platelet-activating factor (PAF-acether; 1-O-octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) induced the release of plasminogen activator in rat, both in vivo and in perfused hind legs. The released plasminogen activator was shown by immunologic and functional criteria to be tissue-type plasminogen activator (t-PA). Release of t-PA by PAF...

Effects of compactin, mevalonate and low-density lipoprotein on 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity and low-density-lipoprotein-receptor activity in the human hepatoma cell line Hep G2

Compactin, an inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase, decreased cholesterol synthesis in intact Hep G2 cells. However, after the inhibitor was washed away, the HMG-CoA-reductase activity determined in the cell homogenate was found to be increased. Also the high-affinity association of LDL (low-density lipoprotein) to Hep...