Search results for "Purines"

The repair of oxidized purines in the DNA of human lymphocytes requires an activation involving NF-YA-mediated upregulation of OGG1.

2014

8-Oxoguanine DNA glycosylase (OGG1), which initiates the repair of DNA purine modifications such as 8-oxo-7,8-dihydroguanine (8-oxoG), is often regarded as a house keeping protein ubiquitously active in mammalian cells. We have analysed the repair rates of oxidized purines generated by photosensitization in peripheral human lymphocytes and observed that the cells were virtually unable to remove these lesions (less than 10% removal within 24h). However, stimulation of the lymphocytes with phytohemagglutinin (PHA) strongly accelerated the repair so that ∼30% of the lesions were repaired within 4h. Within 24h following PHA stimulation and preceding the induction of cell proliferation, Western …

Sildenafil protects epithelial cell through the inhibition of xanthine oxidase and the impairment of ROS production

2009

Recent reports suggest that xanthine oxidase (XO), a modified form of the native xanthine dehydrogenase enzyme, plays an important role in various forms of ischemic and vascular injuries, inflammatory diseases, and chronic heart failure. The XO inhibitors allopurinol and its oxidation product oxypurinol held considerable promises in the treatment of these conditions both in experimental animals and in human clinical trials. More recently, an endothelium-based protective effect of sildenafil, a well-known type-5 phosphodiesterase inhibitor, has been reported in preconditioning prior to ischemia/reperfusion in healthy human subjects. Based on the structural similarities between allopurinol an…

A frozen analogue approach to aminopyridinylimidazoles leading to novel and promising p38 MAP kinase inhibitors.

2012

In this study we report the design, synthesis, and biological evaluation of constrained aminopyridinylimidazoles as p38α MAP kinase inhibitors. The frozen analogue approach focused on the pyridinyl unit, using purine bioisosteres as constrained structure analogues. The identification of the most potent bioisostere was followed by a further derivatization to address hydrophobic region II. In combination with C-2 modifications of the imidazole core, we were able to design highly active inhibitors on the p38α MAP kinase. The inhibitor design presented herein represents a promising and highly efficient advancement of recent stages of development in this class of p38 MAP kinase inhibitors. In co…

Interplay between cannabinoids and purines in the modulation of the spontaneous mechanical activity of mouse ileum.

2008

Modulation of the spontaneous mechanical activity of mouse ileum: interplay between cannabinoids and purines

2008

TREATMENT WITH SILDENAFIL PREVENTS IMPAIRMENT OF LEARNING IN RATS BORN TO PRE-ECLAMPTIC MOTHERS

2010

Pre-eclampsia is an important hypertensive pregnancy disorder and a main cause of maternal and fetal morbidity and mortality Children born from mothers with preeclampsia may present cognitive deficits The mechanisms leading to this cognitive impairment remain unclear and no treatments to improve it have been tested Pre-eclampsia is associated with impaired regulation of the nitric oxide 3 5 guanosine monophosphate cyclic (cGMP) pathway, which modulates some cognitive functions We hypothesized that alterations in the NO-cGMP pathway would be involved in the mechanisms leading to cognitive impairment in rats born to pre-eclamptic mothers and that treatment with sildenafil an inhibitor of the …

cGMP MODULATES STEM CELLS DIFFERENTIATION TO NEURONS IN BRAIN IN VIVO

2010

During brain development neural stem cells may differentiate to neurons or to other cell types. The aim of this work was to assess the role of cGMP (cyclic GMP) in the modulation of differentiation of neural stem cells to neurons or non-neuronal cells. cGMP in brain of fetuses was reduced to 46% of controls by treating pregnant rats with nitroarginine-methylester (L-NAME) and was restored by co-treatment with sildenafil.Reducing cGMP during brain development leads to reduced differentiation of stem cells to neurons and increased differentiation to non-neuronal cells. The number of neurons in the prefrontal cortex originated from stem cells proliferating on gestational day 14 was 715 +/- 14/…

Cigarette smoke-induced pulmonary endothelial dysfunction is partially suppressed by sildenafil.

2009

Abstract Cigarette smoke mediated oxidative stress and endothelial dysfunction are important processes in the pathogenesis of several lung disorders. In this study we evaluated the effect of PDE5 inhibition on pulmonary artery endothelial dysfunction induced by cigarette smoke in vitro . Human pulmonary artery endothelial cells (HPAEC) were incubated in the absence or presence of PDE5 inhibitor sildenafil (10 nM–1 μM), PKG agonist 8-Br-cGMP (1 mM), or the antioxidants dyphenyleneiodonium (DPI 1 μM) and N -acetylcysteine (NAC 1 mM) for 30 min. Then, cigarette smoke extract (CSE) was added for 24 h. CSE (2.5–10%)-induced ROS generation was suppressed by DPI, and partially reversed by sildenaf…

Functional characterization of the human tRNA methyltransferases TRMT10A and TRMT10B

2020

Abstract The TRM10 family of methyltransferases is responsible for the N1-methylation of purines at position 9 of tRNAs in Archaea and Eukarya. The human genome encodes three TRM10-type enzymes, of which only the mitochondrial TRMT10C was previously characterized in detail, whereas the functional significance of the two presumably nuclear enzymes TRMT10A and TRMT10B remained unexplained. Here we show that TRMT10A is m1G9-specific and methylates a subset of nuclear-encoded tRNAs, whilst TRMT10B is the first m1A9-specific tRNA methyltransferase found in eukaryotes and is responsible for the modification of a single nuclear-encoded tRNA. Furthermore, we show that the lack of G9 methylation cau…