48 research outputs found
Short chain acyl-CoA dehydrogenase deficiency and short-term high-fat diet perturb mitochondrial energy metabolism and transcriptional control of lipid-handling in liver
Nucleotide and Glutathione Adducts and DNA Modifications by Cisplatin Analogue [PtCl2(cis-1,4-DACH)].
Cytotoxicity, cellular uptake, glutathione and DNA interactions of an antitumor large-ring PtII chelate complex incorporating the cis-1,4-diaminocyclohexane carrier ligand
International audienceEarlier studies have described promising antitumor activity of a large-ring chelate complex [PtCl(-1,4-DACH)] (DACH = diaminocyclohexane). Encouraging antitumor activity of this analogue of cisplatin prompted us to perform studies focused on the mechanistic basis of pharmacological effects of this complex. Four early steps in the mechanism of biological activity of cisplatin have been delineated: cell entry, reactions with sulfur-containing compounds, platinum–DNA binding along with processing platinated DNA by proteins (enzymes) and DNA repair. Here, we describe comparative experiments (involving also cisplatin) revealing: (i) improved cytotoxicity (3.4 – 5.4-fold) of [PtCl(-1,4-DACH)] in human tumor ovarian cell lines; (ii) enhanced cellular uptake (∼1.5-fold) of [PtCl(-1,4-DACH)]; (iii) somewhat enhanced rate of reactions of [PtCl(-1,4-DACH)] with glutathione (∼1.5-fold), but a similar rate of reactions with metallothionenin-2; (iv) enhanced rate of DNA binding of [PtCl(-1,4-DACH)] in cell-free media (∼2-fold); (v) similar sequence preference of DNA binding of [PtCl(-1,4-DACH)] in cell-free media; (vi) identical DNA interstrand crosslinking efficiency (6%); (vii) similar bending (32 °) and enhanced local unwinding (∼1.5-fold) induced in DNA by the major 1,2-GG-intrastrand crosslink; (viii) markedly enhanced inhibiting effects of DNA adducts of [PtCl(-1,4-DACH)] on processivity of DNA polymerase; and (ix) a slightly lower efficiency of DNA repair systems to remove the adducts of [PtCl(-1,4-DACH)] from DNA
Detection by Elisa Test of Antibodies to Human Papillomavirus (HPV) Type 16 E7 Oncoprotein in Patients with Benign or Malignant Papillomas from Skin or Mucosa
Small-molecule inhibitor sorafenib regulates immunoreactions by inducing survival and differentiation of bone marrow cells
ACC1 (Acetyl Coenzyme A Carboxylase 1) Is a Potential Immune Modulatory Target of Cerebral Ischemic Stroke
An update to the cost-effectiveness of posaconazole vs fluconazole or itraconazole in the prevention of invasive fungal disease among neutropenic patients in the United States
Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression.
The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A1 receptors (A1Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A1R-selective agonist, benzyloxy-cyclopentyladenosine (BnOCPA), is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A1Rs arises from BnOCPA's unique and exquisitely selective activation of Gob among the six Gαi/o subtypes, and in the absence of β-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native A1R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism