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At least 1,225 records · Page 68Linked to original sources
PubMed2006

Hedgehog signalling: how to get from Smo to Ci and Gli.

The secreted morphogens of the Hedgehog family have important roles in normal development as well as in associated pathologies, including cancer. The Hedgehog signalling pathway has been studied in Drosophila and is thought to be conserved in vertebrates. Hedgehog elicits a signalling response that activates Smoothened (Smo). There is evidence of differences between Drosophila and vertebrates concerning signalling downstream of Smo, as well as in Smo itself. Here, we discuss this evidence and its importance for investigations of the pathway and related biology, as well as for the development of drugs targeting components of the pathway for treatment of associated pathologies.

Animals↗
PubMed2004

Biology of chronic myelogenous leukemia--signaling pathways of initiation and transformation.

Chronic myeloid leukemia (CML) is caused by the Bcr-Abl oncoprotein,the product of the t(9;22) chromosomal translocation that generates the Philadelphia chromosome. Different disease phenotypes are associated with each of the three Bcr-Abl isoforms: p190Bcr-Abl, p210Bcr-Abl, and p230Bcr-Abl all of which have a constitutively activated tyrosine kinase. Mechanisms associated with malignant transformation include altered cellular adhesion, activation of mitogenic signaling pathways, inhibition of apoptosis, and proteasomal degradation of physiologically important cellular proteins.CML is subject to an inexorable progression from an "indolent" chronic phase to a terminal blast crisis. Disease progression is presumed to be associated with the phenomenon of genomic instability.

Cell Transformation, Neoplastic↗
PubMed2001

MAP-kinase signaling pathways in T cells.

The family of MAP-kinases include ERKs, p38 MAP-kinases and JNKs. Recently, the role of MAP-kinases in T lymphocytes has attracted particular interest. Genetically modified mouse models have brought insight into the specific function of each MAP-kinase pathway in T lymphocyte biology. Studies clearly show that these pathways are not redundant and that the role of each pathway depends on the T cell type and differentiation stage.

Animals↗
PubMed2005

Probucol protects against hypochlorite-induced endothelial dysfunction: identification of a novel pathway of probucol oxidation to a biologically active intermediate.

Atherosclerosis is associated with endothelial dysfunction and a heightened state of inflammation characterized, in part, by an increase in vascular myeloperoxidase and proteins modified by its principal oxidant, hypochlorous acid (HOCl). Here we examined whether probucol could protect against endothelial dysfunction induced by the two-electron oxidant HOCl. Hypochlorous acid eliminated endothelium-dependent relaxation of rabbit aorta, whereas endothelial function and tissue cGMP was preserved and elevated, respectively, in animals pretreated with probucol. Exogenously added probucol also protected against HOCl-induced endothelial dysfunction. In vitro, HOCl oxidized probucol in a two-phase process with rate constants k(1) = 2.7 +/- 0.3 x 10(2) and k(2) = 0.7 +/- 0.2 x 10(2) m(-1) s(-1) that resulted in a dose- and time-dependent accumulation of probucol-derived disulfoxide, 4,4'-dithiobis(2,6-di-tert-butyl-phenol) (DTBP), DTBP-derived thiosulfonate, disulfone, and sulfonic acid, together with 3,3',5,5'-tetra-tert-butyl-4,4'-diphenoquinone (DPQ) as determined by high performance liquid chromatography and mass spectrometry. Like HOCl, selected one-electron oxidants converted probucol into DTBP and DPQ. Also, dietary and in vitro added DTBP protected aortic rings from HOCl-induced endothelial dysfunction and in vitro oxidation by HOCl gave rise to the thiosulfonate, disulfone, and sulfonic acid intermediates and DPQ. However, the product profiles of the in vitro oxidation systems were different from those in aortas of rabbits receiving dietary probucol or DTBP +/- HOCl treatment. Together, the results show that both probucol and DTBP react with HOCl and protect against HOCl-induced endothelial dysfunction, although direct scavenging of HOCl is unlikely to be responsible for the vascular protection by the two compounds.

Animals↗
PubMed1990

Neuronal influence on intestinal transport.

Reflex activation of the enteric nervous system (ENS) from the intestinal lumen and also from the serosa induces intestinal secretion. Thus mechanical distention, cholera toxin, heat-stable enterotoxin from E. coli, bile acids, mucosal inflammation and chemical peritonitis all induce an intestinal secretion that is inhibited by 60-100% by nerve-blocking agents. As a result of a large number of in vitro and in vivo studies, a picture of the organization of the secretory enteric nervous reflexes is now emerging. In secretory states with preserved intact intestinal epithelium, it is proposed that the reflex activation occurs via stimulation of receptor cells, i.e. epithelial endocrine cells such as EC and N-cells, which release peptides/amines into the interstitial space and thereby activate nerves close to the epithelium. The afferent neurones appear to transfer the reflex to the myenteric plexus, probably by using tachykinins as transmitters. This is in agreement with a superior and co-ordinating role for the myenteric plexus in the control of intestinal function by the ENS. Interneurones in turn mediate the transmission of the nerve signal to the submucosal plexus and the efferent neurones via cholinergic, nicotinic postganglionic receptors. The transmitters at the effector cells are acetylcholine and probably VIP.

Afferent Pathways↗
PubMed2002

Dissecting the circuitry of protein kinase A and cAMP signaling in cancer genesis: antisense, microarray, gene overexpression, and transcription factor decoy.

Expression of the RI alpha subunit of the cAMP-dependent protein kinase type I (PKA-I) is enhanced in human cancer cell lines, in primary tumors, in transformed cells, and in cells upon stimulation of growth. Signaling via the cAMP pathway may be complex, and the biological effects of the pathway in normal cells may depend upon the physiological state of the cells. However, results of different experimental approaches such as antisense exposure, 8-Cl-cAMP treatment, and gene overexpression have shown that the inhibition of RI alpha/PKA-I exerts antitumor activity in a wide variety of tumor-derived cell lines examined in vitro and in vivo. cDNA microarrays have further shown that in a sequence-specific manner, RI alpha antisense induces alterations in the gene expression profile of cancer cells and tumors. The cluster of genes that define the "proliferation-transformation" signature are down-regulated, and those that define the "differentiation-reverse transformation" signature are up-regulated in antisense-treated cancer cells and tumors, but not in host livers, exhibiting the molecular portrait of the reverted (flat) phenotype of tumor cells. These results reveal a remarkable cellular regulation, elicited by the antisense RI alpha, superimposed on the regulation arising from the Watson-Crick base-pairing mechanism of action. Importantly, the blockade of both the PKA and PKC signaling pathways achieved with the CRE-transcription factor decoy inhibits tumor cell growth without harming normal cell growth. Thus, a complex circuitry of cAMP signaling comprises cAMP growth regulatory function, and deregulation of the effector molecule by this circuitry may underlie cancer genesis and tumor progression.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1997

The vitamin D analog, KH1060, is rapidly degraded both in vivo and in vitro via several pathways: principal metabolites generated retain significant biological activity.

Vitamin D analogs are valuable drugs with established and potential uses in hyperproliferative disorders. Lexacalcitol (KH1060) is over 100 times more active than 1alpha,25-dihydroxyvitamin D3 [1alpha,25-(OH)2D3], as judged by in vitro antiproliferative and cell differentiating assays. The underlying biochemical reasons for the increased biological activity of KH1060 are unknown, but are thought to include 1) metabolic considerations in addition to explanations based upon 2) enhanced stability of KH1060-liganded transcriptional complexes. In this study we explored the in vivo and in vitro metabolism of KH1060. We established by physicochemical techniques the existence of multiple side-chain hydroxylated metabolites of KH1060, including 24-, 24a-, 26-, and 26a-hydroxylated derivatives as well as side-chain truncated forms. KH1060 metabolism could be blocked by the cytochrome P450 inhibitor, ketoconazole. KH1060 was not an effective competitor of C24 oxidation of 1alpha,25-(OH)2D3. Certain hydroxylated metabolites of KH1060 retained significant biological activity in vitamin D-dependent reporter gene systems (chloramphenicol acetyltransferase). Likewise, those metabolites accumulating in the target cell culture models in metabolism studies, particularly 24a-hydroxy-KH1060 and 26-hydroxy-KH1060, retained biological activities superior to those of 1alpha,25-(OH)2D3 in native gene expression systems in vitamin D target cells (osteopontin and P450cc24). We conclude that KH1060 is rapidly metabolized by a variety of cytochrome P450-mediated enzyme systems to products, many of which retain significant biological activity in vitamin D-dependent assay systems. These results provide an explanation for the considerable biological activity advantage displayed by KH1060 compared with 1alpha,25-(OH)2D3 in various in vitro assay systems.

Animals↗
PubMed2002

Emerging targets in the AKT pathway for treatment of androgen-independent prostatic adenocarcinoma.

Prostatic adenocarcinoma (CaP) is the most common, non-cutaneous malignancy and the second-leading cause of cancer death in men. The disease has two distinct phases: the androgen-dependent phase, which can be treated effectively with androgen ablation therapies, and the androgen-independent phase, for which there is no effective life-prolonging therapy. An estimated 32,000 men will die this year from androgen-independent, metastatic CaP. Efforts to understand the metastatic progression of CaP and the emergence of androgen-independent disease have begun to illuminate the molecular events involved. Recent work suggests that CaP progression to androgen-independent, metastatic disease involves a dampened apoptotic response, a release from the cell cycle block that initially follows androgen withdrawal and a shift from dependence on paracrine-derived growth and survival factors to autonomous production of these key proteins. Functional loss of the tumour suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) and subsequent activation of the AKT pathway, have been prominently implicated in the progression of CaP to androgen-independence. Activation of the AKT pathway can suppress the apoptotic response, undermine cell cycle control and selectively enhance the production of key growth and survival factors. Though many proteins and intracellular signalling pathways can influence these biological processes, activation of the AKT pathway may be a particularly potent signal involved in CaP progression to androgen-independence and therefore presents a series of potential targets for therapy of advanced androgen-independent CaP.

Adenocarcinoma↗
PubMed2005

[Family of multiple peptide fragments derived from angiotensin and their interaction].

It is well established that renin-angiotensin system (RAS) is the major regulatory network that maintains blood pressure, fluid and electrolyte balance and the homeostasis of cardiovascular system. Most studies in the last decades centered on the pivotal members of RAS, that is, angiotensin II (Ang II ) and angiotensin converting enzyme (ACE). Recent identification of ACE-2, the homology of ACE, and the identification of the multiple products degraded from angiotensin I, including Ang III, Ang IV, Ang(1-9), Ang(1-7), Des-Asp-angiotensin I(DAA I), etc, have proved that Ang II is not the only biological active compound of RAS. Peptides derived from angiotensinogen,that is, family of angiotensins,display independent and pleiotropic biological activities in vivo, and interact with each other both in metabolism pathway and the biologic effects. The imbalance of the network of angiotensin metabolites exhibits significant pathophysiological role in cardiovascular disease.

Angiotensin-Converting Enzyme 2↗