COS Cells

Publication Title: 
The Journal of Biological Chemistry

The life span of model organisms can be modulated by environmental conditions that influence cellular metabolism, oxidation, or DNA integrity. The yeast nicotinamidase gene pnc1 was identified as a key transcriptional target and mediator of calorie restriction and stress-induced life span extension. PNC1 is thought to exert its effect on yeast life span by modulating cellular nicotinamide and NAD levels, resulting in increased activity of Sir2 family class III histone deacetylases.

Author(s): 
Balan, Vitaly
Miller, Gregory S.
Kaplun, Ludmila
Balan, Karina
Chong, Zhao-Zhong
Li, Faqi
Kaplun, Alexander
VanBerkum, Mark F. A.
Arking, Robert
Freeman, D. Carl
Maiese, Kenneth
Tzivion, Guri
Publication Title: 
Molecular Pharmacology

Artemisinin drugs are of utmost importance in the treatment of malaria, because they represent the sole class of therapeutically used antimalarial drugs to which malaria parasites have not yet developed resistance. The major disadvantage of these medicines is the comparatively high recrudescence rate, which has been attributed to the remarkable decrease of artemisinin plasma concentrations during multiple dosing. Autoinduction of CYP2B6-mediated metabolism has been implicated as the underlying mechanism. So far, the molecular mechanism of induction by artemisinin has not been resolved.

Author(s): 
Burk, Oliver
Arnold, Katja A.
Nüssler, Andreas K.
Schaeffeler, Elke
Efimova, Ekaterina
Avery, Bonnie A.
Avery, Mitchell A.
Fromm, Martin F.
Eichelbaum, Michel
Publication Title: 
The Journal of Biological Chemistry

The antimalarial drugs artemisinins have been described as inhibiting Ca(2+)-ATPase activity of PfATP6 (Plasmodium falciparum ATP6) after expression in Xenopus oocytes. Mutation of an amino acid residue in mammalian SERCA1 (Glu(255)) to the equivalent one predicted in PfATP6 (Leu) was reported to induce sensitivity to artemisinin in the oocyte system. However, in the present experiments, we found that artemisinin did not inhibit mammalian SERCA1a E255L either when expressed in COS cells or after purification of the mutant expressed in Saccharomyces cerevisiae.

Author(s): 
Cardi, Delphine
Pozza, Alexandre
Arnou, Bertrand
Marchal, Estelle
Clausen, Johannes D.
Andersen, Jens Peter
Krishna, Sanjeev
Møller, Jesper V.
le Maire, Marc
Jaxel, Christine
Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals

Artemether (AM) is one of the most effective antimalarial drugs. The elimination half-life of AM is very short, and it shows large interindividual variability in pharmacokinetic parameters. The aim of this study was to identify cytochrome P450 (P450) isozymes responsible for the demethylation of AM and to evaluate functional differences between 26 CYP2B6 allelic variants in vitro. Of 14 recombinant P450s examined in this study, CYP2B6 and CYP3A4 were primarily responsible for production of the desmethyl metabolite dihydroartemisinin.

Author(s): 
Honda, Masashi
Muroi, Yuka
Tamaki, Yuichiro
Saigusa, Daisuke
Suzuki, Naoto
Tomioka, Yoshihisa
Matsubara, Yoichi
Oda, Akifumi
Hirasawa, Noriyasu
Hiratsuka, Masahiro
Publication Title: 
British Journal of Pharmacology

BACKGROUND AND PURPOSE: Widespread resistance to antimalarial drugs requires combination therapies with increasing risk of pharmacokinetic drug-drug interactions. Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding. EXPERIMENTAL APPROACH: A total of 21 selected antimalarials and 11 major metabolites were screened for binding to CAR isoforms using cellular and in vitro CAR-coactivator interaction assays, combined with in silico molecular docking.

Author(s): 
Burk, O.
Piedade, R.
Ghebreghiorghis, L.
Fait, J. T.
Nussler, A. K.
Gil, J. P.
Windshügel, B.
Schwab, M.
Publication Title: 
PloS One

LEDGF/p75 interacts with DNA/protein to regulate gene expression and function. Despite the recognized diversity of function of LEDGF/p75, knowledge of its transregulation is in its infancy. Here we report that LEDGF/p75 gene is TATA-less, contains GC-rich cis elements and is transcriptionally regulated by Sp1 involving small ubiquitin-like modifier (Sumo1). Using different cell lines, we showed that Sp1 overexpression increased the level of LEDGF/p75 protein and mRNA expression in a concentration-dependent fashion.

Author(s): 
Singh, Dhirendra P.
Bhargavan, Biju
Chhunchha, Bhavana
Kubo, Eri
Kumar, Anil
Fatma, Nigar
Publication Title: 
Antimicrobial Agents and Chemotherapy

The human JC polyomavirus (JCPyV) causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). A growing number of patients with induced or acquired immunosuppression are at risk for infection, and no effective antiviral therapy is presently available. The widely used antimalarial drug artesunate has shown broad antiviral activity in vitro but limited clinical success. The aim of this study was to investigate the effect of artesunate on JCPyV replication in vitro.

Author(s): 
Sharma, Biswa Nath
Marschall, Manfred
Rinaldo, Christine Hanssen
Publication Title: 
Antimicrobial Agents and Chemotherapy

Malaria patients are frequently coinfected with HIV and mycobacteria causing tuberculosis, which increases the use of coadministered drugs and thereby enhances the risk of pharmacokinetic drug-drug interactions. Activation of the pregnane X receptor (PXR) by xenobiotics, which include many drugs, induces drug metabolism and transport, thereby resulting in possible attenuation or loss of the therapeutic responses to the drugs being coadministered. While several artemisinin-type antimalarial drugs have been shown to activate PXR, data on nonartemisinin-type antimalarials are still missing.

Author(s): 
Piedade, Rita
Traub, Stefanie
Bitter, Andreas
Nüssler, Andreas K.
Gil, José P.
Schwab, Matthias
Burk, Oliver
Publication Title: 
The EMBO journal

Keap1 is a BTB-Kelch substrate adaptor protein that regulates steady-state levels of Nrf2, a bZIP transcription factor, in response to oxidative stress. We have determined the structure of the Kelch domain of Keap1 bound to a 16-mer peptide from Nrf2 containing a highly conserved DxETGE motif. The Nrf2 peptide contains two short antiparallel beta-strands connected by two overlapping type I beta-turns stabilized by the aspartate and threonine residues.

Author(s): 
Lo, Shih-Ching
Li, Xuchu
Henzl, Michael T.
Beamer, Lesa J.
Hannink, Mark
Publication Title: 
The Journal of Biological Chemistry

Keap1 is a BTB-Kelch substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex that functions as a sensor for thiol-reactive chemopreventive compounds and oxidative stress. Inhibition of Keap1-dependent ubiquitination of the bZIP transcription factor Nrf2 enables Nrf2 to activate a cyto-protective transcriptional program that counters the damaging effects of oxidative stress. In this report we have identified a member of the phosphoglycerate mutase family, PGAM5, as a novel substrate for Keap1.

Author(s): 
Lo, Shih-Ching
Hannink, Mark

Pages

Subscribe to RSS - COS Cells