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Normal Cellular Functions (normal + cellular_function)
Selected AbstractsAcute effect of antidiabetic 1,4-dihydropyridine compound cerebrocrast on cardiac function and glucose metabolism in the isolated, perfused normal rat heartCELL BIOCHEMISTRY AND FUNCTION, Issue 2 2008Janina Briede Abstract Diabetes mellitus (DM) is an important cardiovascular risk factor and is associated with abnormalities in endothelial and vascular smooth muscle cell function, evoked by chronic hyperglycemia and hyperlipidemia. Chronic insulin deficiency or resistance is marked by decreases in the intensity of glucose transport, glucose phosphorylation, and glucose oxidation, plus decreases in ATP levels in cardiac myocytes. It is important to search for new agents that promote glucose consumption in the heart and partially inhibit extensive fatty acid beta-oxidation observed in diabetic, ischemia. When the oxygen supply for myocardium is decreased, the heart accumulates potentially toxic intermediates of fatty acid beta-oxidation, that is, long-chain acylcarnitine and long-chain acyl-CoA metabolites. Exogenous glucose and heart glycogen become an important compensatory source of energy. Therefore we studied the effect of the antidiabetic 1,4-dihydropyridine compound cerebrocrast at concentrations from 10,10,M to 10,7,M on isolated rat hearts using the method of Langendorff, on physiological parameters and energy metabolism. Cerebrocrast at concentrations from 10,10,M to 10,7,M has a negative inotropic effect on the rat heart. It inhibits L -type Ca2+channels thereby diminishing the cellular Ca2+ supply, reducing contractile activity, and oxygen consumption, that normally favors enhanced glucose uptake, metabolism, and production of high-energy phosphates (ATP content) in myocardium. Cerebrocrast decreases heart rate and left ventricular (LV) systolic pressure; at concentrations of 10,10,M and 10,9,M it evokes short-term vasodilatation of coronary arteries. Increase of ATP content in the myocytes induced by cerebrocrast has a ubiquitous role. It can preserve the integrity of the cell plasma membranes, maintain normal cellular function, and inhibit release of lactate dehydrogenase (LDH) from cells that is associated with diabetes and heart ischemia. Administration of cerebrocrast together with insulin shows that both compounds only slightly enhance glucose uptake in myocardium, but significantly normalize the rate of contraction and relaxation (,±,dp/dt). The effect of insulin on coronary flow is more pronounced by administration of insulin together with cerebrocrast at a concentration of 10,7,M. Cerebrocrast may promote a shift of glucose consumption from aerobic to anerobic conditions (through the negative inotropic properties), and may be very significant in prevention of cardiac ischemic episodes. Copyright © 2007 John Wiley & Sons, Ltd. [source] Identification of a novel and myeloid specific role of the leukemia-associated fusion protein DEK-NUP214 leading to increased protein synthesisGENES, CHROMOSOMES AND CANCER, Issue 4 2008Malin Ageberg The t(6;9)(p22;q34) chromosomal translocation is found in a subset of patients with acute myeloid leukemia (AML). The translocation results in a fusion between the nuclear phosphoprotein DEK and the nucleoporin NUP214 (previously CAN). The mechanism by which the fusion protein DEK-NUP214 contributes to leukemia development has not been identified, and disruptions of normal cellular functions by DEK-NUP214 have previously not been described. In the present study, a novel effect of the DEK-NUP214 fusion protein is demonstrated. Our findings reveal a substantial increase in global protein synthesis in DEK-NUP214 expressing cells. Furthermore, we conclude that this effect is not the result of dysregulated transcription but merely due to increased translation. Consistent with the association with AML, the increased protein synthesis mediated by DEK-NUP214 is restricted to cells of the myeloid lineage. Analysis of potential mechanisms for regulating protein synthesis shows that expression of DEK-NUP214 correlates to the phosphorylation of the translation initiation protein, EIF4E. The present data provide evidence that increase of translational activity constitutes a mechanism by which the leukemogenic effect of DEK-NUP124 may be mediated. © 2008 Wiley-Liss, Inc. [source] Gap junction-mediated intercellular communication in a long-term primary mouse hepatocyte culture systemHEPATOLOGY, Issue 5 2003Stephanie A. Stoehr Gap junction-mediated intercellular communication (GJIC) is critical for maintaining integral cellular processes including differentiation and growth control. The disruption of GJIC has been correlated with aberrant function in many cell types, including hepatocytes in vivo; therefore it is imperative that cellular model systems support intercellular communication to simulate normal cellular functions. Functional GJIC has been shown in long-term primary rat hepatocyte cultures, which have been implemented widely to study various aspects of hepatocellular function; however, the onset of transgenic technology in murine species has necessitated the development of a primary mouse hepatocyte system. In this report, we analyze GJIC in a dimethylsulfoxide (DMSO)-containing long-term primary mouse hepatocyte culture system. The cells retain morphologic and biochemical characteristics of differentiated hepatocytes through day 30 post plating, including liver-specific gene expression. We further show that connexin32 and connexin26 expression and gap junction plaque formation increase over time in culture concomitant with an increase in GJIC between adjoining primary mouse hepatocytes. In conclusion, the findings described in this study make it possible to maintain differentiated primary mouse hepatocytes that also show GJIC in long-term culture for 30 days. In addition, this system has the potential to be extended to study primary mouse hepatocytes isolated from genetically engineered mice. [source] MutationView/KMcancerDB: A database for cancer gene mutationsCANCER SCIENCE, Issue 3 2007Nobuyoshi Shimizu It is known that cancers are caused by accumulated mutations in various genes and consequent functional alterations of proteins that are important for maintenance of normal cellular functions. The changes in nucleotide sequences and expression patterns of cancer-related genes are being extensively studied to better understand the mechanisms of tumorigenesis and to develop methods for DNA protein diagnosis and drug discovery. At present, a number of computer databases for molecular information on cancer-related genes are available publicly through the internet. These databases deal with familial cancer and sporadic cancer at the levels of germline mutation or somatic mutation, genomic or chromosomal abnormalities, and changes in the expression levels of relevant genes. Previously, we constructed a human gene mutation database named MutationView (http://mutview.dmb.med.keio.ac.jp/) and have accumulated mutation data for ,300 genes that are involved mainly in monogenic diseases. Forty-two genes are cancer-related and therefore a separate cancer database named KMcancerDB was constructed. MutationView/KMcancerDB utilizes a graphic display function for both queries and search results much more often than other existing databases, making the system quite user friendly. MutationView/KMcancerDB provides a highly sophisticated search function for all genes through a single internet URL. In the present paper, we briefly review various useful databases for cancer-related genes, and describe MutationView/KMcancerDB in more detail. (Cancer Sci 2007; 98: 259,267) [source] New perspectives in retinal imaging: fundus autofluorescence and age-related macular degenerationACTA OPHTHALMOLOGICA, Issue 2007F HOLZ Fundus Autofluorescence (FAF) imaging using confocal scanning laser ophthalmoscopy is a non-invasive method to to accurately record the topographic distribution of RPE lipofuscin in the human eye in vivo. Excessive lipofuscin accumkulation in the RPE is a common downstream pathogenetic pathway in various complex and monogenetic retinal diseases. Toxic compounds and molecular mechanisms of interference with normal cellular functions have been identified including the dominant fluorophore A2-E. Alterations in fundus autofluorescence (FAF) appearance in eyes with early and late age-related macular degeneration (AMD) can be striking. FAF patterns and distribution do not necessarily correlate with the features of interest in color or angiographic images of eyes with early or late AMD. In the prospective, multicenter FAM study distinct patterns of abnormal FAF were identified and classified in the junctional zone of geographic atrophy (GA). Areas of increased FAF outside GA were associated with variable degrees of loss of retinal sensitivity when tested with microperimetry which suggests a functional correlate of lipofuscin accumulation. Increased FAF preceded the development and enlargement of outer retinal atrophy associated with spread of absolute scotoma in eyes with AMD. Longitudinal examinations showed that the abnormal phenotypic FAF patterns serve as novel prognostic determinants which allows to distinguish fast vs. slow progressors. These findings are relevant and now used to design and carry out interventional trials with agents aimed at slowing down spread of atrophy, e.g. using visual cycle modulators to influence lipofuscinogenesis. Hereby FAF imaging also serves as a mean to accurately delineate and measure areas of GA over time in an automated fashion. A phenotype-genotype correlation was identified for a distinct FAF phenotype subset which was found to represent late-onset Stargardt macular dystrophy mimicking late-stage atrophic AMD. New imaging technologies were recently applied including simultaneous recordings of FAF images and high-resolution, spectral-domain optical coherence tomography (OCT) which allows to identify morphological correlates of abnormal FAF signals in optical biopsies. [source] Conquering the complex world of human septins: implications for health and diseaseCLINICAL GENETICS, Issue 6 2010EA Peterson Peterson EA and Petty EM. Conquering the complex world of human septins: implications for health and disease. Septins are highly conserved filamentous proteins first characterized in budding yeast and subsequently identified in must eukaryotes. Septins can bind and hydrolyze GTP, which is intrinsically related to their formation of septin hexamers and functional protein interactions. The human septin family is composed of 14 loci, SEPT1-SEPT14, which encode dozens of different septin proteins. Their central GTPase and polybasic domain regions are highly conserved but they diverge in their N-terminus and/or C-terminus. The mechanism by which the different isoforms are generated is not yet well understood, but one can hypothesize that the use of different promoters and/or alternative splicing could give rise to these variants. Septins perform diverse cellular functions according to tissue expression and their interacting partners. Functions identified to date include cell division, chromosome segregation, protein scaffolding, cellular polarity, motility, membrane dynamics, vesicle trafficking, exocytosis, apoptosis, and DNA damage response. Their expression is tightly regulated to maintain proper filament assembly and normal cellular functions. Alterations of these proteins, by mutation or expression changes, have been associated with a variety of cancers and neurological diseases. The association of septins with cancer results from alterations of expression in solid tumors or translocations in leukemias [mixed lineage leukemia (MLL)]. Expression changes in septins have also been associated with neurological conditions such as Alzheimer's and Parkinson's disease, as well as retinopathies, hepatitis C, spermatogenesis and Listeria infection. Pathogenic mutations of SEPT9 were identified in the autosomal dominant neurological disorder hereditary neuralgic amyotrophy (HNA). Human septin research over the past decade has established their importance in cell biology and human disease. Further functional characterization of septins is crucial to our understanding of their possible diagnostic, prognostic, and therapeutic applications. [source] | |||||||||||||