Biomedical subjects

C Schmutte

Publications and source records attributed to C Schmutte.

22 records · Page 2Linked to original sources

PubMed1990

[The effect of Ca++ antagonists on cellular lipid metabolism].

The antiatherogenic effects of Ca2(+)-antagonists have been proved in animal studies and in man. It is suggested that drugs of this class--unlike lipid-lowering drugs--do not exert their effects by decreasing lipoprotein plasma levels but by a modulation of signal transducers. Ca2(+)-antagonists inhibit the extracellular matrix synthesis and thereby decrease cell adhesion and the modification of matrix-bound low density lipoproteins (LDL). Thus less modified LDL are produced, which are catabolized by scavenging or by phagocytosis of macrophages, leading to a reduction of foam cell production. Ca2(+)-antagonists also enhance the synthesis of membrane phospholipids, e.g. sphingomyelin (SPM), thereby increasing the membrane turnover and fluidity. In addition they positively influence the formation and catabolism of radicals. The resulting membrane protective effects possibly delay the general ageing process and improve the integrity of the cytoskeleton as well as of the adjacent membranes. In various studies it has been established that the use of Ca2(+)-antagonists leads to a reversal of atherosclerotic processes at the stage of early lesions. The effects of this class of drugs on a molecular level will be a focal point of future research. Of special importance will be the study of the cell specific signal transducing processes in those types of cells involved in atherosclerosis and the understanding of their role in the process as a whole.

Arteriosclerosis↗

PubMedDate not supplied

Growth stimulation of primary rat hepatocytes by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The modulation of liver growth control by the tumor promoter, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), was investigated in primary hepatocytes of adult rats. Under defined conditions in serum-free cultures, the interaction of TCDD with growth-related hormones was studied. TCDD-treatment of the cultured hepatocytes for two days caused a transient stimulation of both DNA synthesis and mitotic activity. This effect was maximal at the very low nontoxic concentration of 10(-12) M TCDD, i.e., two orders of magnitude below the optimal concentrations for induction of drug metabolizing enzymes. Growth stimulation by TCDD was dependent on the presence of growth-related hormones; in primary rat hepatocytes, TCDD acted synergistically with insulin and epidermal growth factor (EGF) and antagonized the growth inhibition by dexamethasone. Under culture conditions allowing high rates of DNA synthesis, e.g., at low concentrations of dexamethasone, in the presence of EGF plus alpha 1-adrenergic agonists or rat serum, no significant effect of TCDD on cellular growth was observed. Furthermore, TCDD failed to stimulate DNA synthesis in a rat hepatoma cell line, H4IIE, which is less sensitive to growth controlling factors than normal hepatocytes. Therefore, the results suggest that the growth modulation of primary rat hepatocytes by TCDD is the most sensitive parameter of the agent thus far observed. This effect may involve both a release from the growth inhibition caused, for instance, by glucocorticoids, as well as a direct growth-stimulating effect, synergistic to the one induced by insulin.

Adrenergic alpha-Agonists↗

PubMedDate not supplied

Involvement of DNA methylation in human carcinogenesis.

It is now generally accepted that the presence of 5-methylcytosine (5mC) in human DNA has both a genetic and an epigenetic effect on cellular development, differentiation and transformation. First, 5mC is more unstable than its unmethylated counterpart cytosine. Hydrolytic deamination of 5mC leads to a G/T mismatch and subsequently, if unrepaired, to a C-->T transition mutation. Sites of DNA methylation are mutational hotspots in many human tumors. Second, DNA methylation of promoter regions is often correlated with the down regulation of the corresponding gene. Both of these effects have fundamental consequences for basic functions of the cell like cellular differentiation, the development of cancer and possibly other diseases, and on the evolutionary process. Recent hypotheses also propose a role for methylation in the process of aging. In this review we will describe recent findings and hypotheses about the function of 5mC in DNA with the focus on its involvement in human carcinogenesis.

Animals↗

PubMedDate not supplied

Genomic instability: first step to carcinogenesis.

Multiple genetic alterations are commonly observed in human cancers. It has been suggested that inactivation of DNA repair pathways, which leads to an increased mutation rate and chromosomal instability, can initiate and accelerate the neoplastic process. Such a causality has been shown for DNA mismatch repair and Hereditary Nonpolyposis Colorectal Cancer (HNPCC), and evidence is accumulating that several other DNA repair pathways are frequently inactivated in different cancer types. In addition to genetic alterations, perturbations in DNA methylation patterns (epigenetic changes), which include both local hypermethylation and genome-wide hypomethylation, are frequently observed early in tumorigenesis. Therefore, genomic instability including genetic and/or epigenetic alterations may be the first step in carcinogenesis. Knowledge of these biochemical mechanisms are likely to lead to more effective cancer diagnosis and therapy.

Cell Transformation, Neoplastic↗