Biomedical subjects

C Cioffi

Publications and source records attributed to C Cioffi.

5 recordsLinked to original sources

PubMed1998

Identification of a novel stress activated kinase in kidney and heart.

We have previously described the patterns of stress kinase activation in rat kidney and heart in response to ischemia/reperfusion (Yin et al., 1997, J. Biol. Chem. 272, 19943-19950). During the course of these studies, we observed the activation of a novel kinase capable of phosphorylating c-Jun on serines 63 and 73. The molecular weight of this kinase is approximately 37 kD, significantly below the molecular weight of all previously identified Jun N-terminal kinase (JNK) isoforms. The pattern of activation of this 37 kD kinase in response to ischemia/reperfusion in both kidney and heart is distinct from that of known JNK isoforms. Western analysis of human renal proximal tubular epithelial (RPTE) cells, using a non-isoform specific phospho-JNK antibody, revealed the phosphorylation (activation) of a 37 kD protein in response to hypoxia. The 37 kD protein in RPTE cells is phosphorylated by other stress stimuli capable of activating JNK. Western analysis of tissues, using a non-isoform specific JNK antibody, identifies a cross-reactive 37 kD protein expressed in the liver, thymus and lymph node which is likely to correspond to the 37 kDa stress-activated kinase. The results of this study have led to the identification of a potentially novel kinase closely related to JNK but showing a distinct pattern of activation.

Animals↗

PubMed1997

Molecular and cellular characterization of baboon C-Raf as a target for antiproliferative effects of antisense oligonucleotides.

C-Raf is a an essential member of the growth factor-ras pathway and a target for intervention strategies aimed at blocking cell proliferative responses. Excessive smooth muscle proliferation is considered one cause of the arterial closure in restenosis. Because of the similarity to the human cardiovascular system, a useful current animal model of the disease is a baboon model. As a foundation for animal studies employing antisense oligonucleotides, efforts were made to characterize the molecular and cellular biology of the baboon system. The nucleotide sequence of baboon c-raf cDNA was determined. Antisense phosphorothioate oligonucleotides specific to the 3'-UTR of c-raf mRNA from human and baboon were compared using primary baboon smooth muscle cells in culture. A particular human antisense oligonucleotide, referred to as ISIS 5132, was different by only 2 of 20 bases from the baboon sequence. The corresponding baboon antisense oligonucleotide ISIS 12959, however, was markedly more effective to inhibit c-raf mRNA, protein production, and DNA synthesis, and the results attest to the species specificity of the approach. After antisense treatment, c-raf mRNA levels dropped rapidly, whereas protein levels decreased with a half-life of roughly 24-48 hours, consistent with the antiproliferative effects. The data are discussed with regard to the profile of protein-protein interactions made by C-Raf and with the view that the baboon system closely parallels the human one at the signal transduction level. As this work progressed, a baboon cDNA homolog of a human c-raf-2 pseudogene was isolated, sequenced, and shown to be transcribed into mRNA.

Animals↗

PubMed1997

Phenotypic variability in the chromosome 9 ring.

The syndrome associated to the 9 ring is not commonly observed. The first remark was by Kistenmacher (1970) who examined a male. Later observation of other cases has allowed the syndrome to be described, so that it can be said to be characterized by constant signs, such as microcephaly, psychomotor retardation of varying entity and facial dysmorphism corresponding to that observed in 9 p monosomy. The variability of the phenotype has to be compared with the entity of the telomeric deletion, since the clinical outlook, especially the entity of retardation, could be less serious in case of small deletions.

Abnormalities, Multiple↗

PubMed1997

Novel qualitative structure-activity relationships for the antinociceptive actions of H2 antagonists, H3 antagonists and derivatives.

Recent studies have shown that cimetidine, burimamide and improgan (also known as SKF92374, a cimetidine congener lacking H2 antagonist activity) induce antinociception after intracerebroventricular administration in rodents. Because these substances closely resemble the structure of histamine (a known mediator of some endogenous analgesic responses), yet no role for known histamine receptors has been found in the analgesic actions of these agents, the structure-activity relationships for the antinociceptive effects of 21 compounds chemically related to H2 and H3 antagonists were investigated in this study. Antinociceptive activity was assessed on the hot-plate and tail-flick tests after intracerebroventricular administration in rats. Eleven compounds induced time-dependent (10-min peak) and dose-dependent antinociceptive activity with no observable behavioral impairment. ED50 values, estimated by nonlinear regression, were highly correlated across nociceptive assays (r2 = 0.98, n = 11). Antinociceptive potencies varied more than 6-fold (80-464 nmol), but were not correlated with activity on H1, H2 or H3 receptors. Although highly potent H3 antagonists such as thioperamide lacked antinociceptive activity, homologs of burimamide and thioperamide containing N-aromatic substituents retained H3 antagonist activity and also showed potent, effective analgesia. A literature review of the pharmacology of these agents did not find a basis for their antinociceptive effects. Taken with previous findings, the present results suggest: 1) these compounds act on the brain to activate powerful analgesic responses that are independent of known histamine receptors, 2) the structure-activity profile of these agents is novel and 3) brain-penetrating derivatives of these compounds could be clinically useful analgesics.

Analgesics, Non-Narcotic↗

PubMed1994

Stabilization of C5a receptor--G-protein interactions through ligand binding.

Binding of biotin-C5a to the C5a receptor in membrane fragments followed by detergent solubilization and purification with streptavidin-agarose affinity chromatography resulted in the isolation of a receptor complex with associated G-proteins. In contrast, when receptor was detergent-solubilized in the absence of C5a and purified by affinity chromatography with Affigel-C5a, G-proteins did not copurify. Since the results indicate that receptor ligation stabilized the receptor--G-protein interaction to allow purification of the complex, the findings emphasize the dynamic nature of the C5a receptor-effector interactions. When biotin-C5a-ligated receptor was purified from a mouse cell line overexpressing recombinant human receptor, both Gialpha2 and Gialpha3 subunits copurified, confirming that multiple transducing systems are linked to the C5a receptor. The method of stabilization of receptor-transducer complexes offers the opportunity to further elaborate the interactions of the C5a receptor with diverse transducing elements and second messenger systems.

Animals↗