Time and Life: Applications of Modern Chronobiology

Chronobiology is that branch of science which objectively quantifies and explores mechanisms of biological time structure. It is an integrating discipline that impacts on all forms of life. When physiological functions are plotted along a time scale, they appear as regularly repetitive wave forms with means, amplitudes, phasing and periods. In nature these rhythms are found to have many frequencies, from a fraction of a second (ultradian) to a year or more (infradian or circannual); and those with periods of about one day (circadian) have been explored extensively. Examples of several circadian rhythms are given for experimental animals and man. Evidence is presented to show that it is particularly important to consider biological rhythmicity when interpreting experimental results or attempting to extrapolate from one species to another. An organism is indeed a different biochemical and morphological entity at different times, and it may be expected to react differently to a stimulus at different circadian phases. By taking advantage of natural rhythms in the susceptability to drugs, it is possible to optimize chemotherapy and radiotherapy for cancer and other diseases

THE CYCLIC NATURE AND MAGNITUDE OF CELL DIVISION IN GASTRIC MUCOSA OF URODELE LARVAE REARED IN THE POND AND LABORATORY

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Integral role of the EGF receptor in HGF-mediated hepatocyte proliferation

Hepatocyte growth factor (HGF), insulin, and TGF-α stimulate DNA synthesis in cultured hepatocytes. Each ligand activates a distinct tyrosine kinase receptor, although receptor cross-talk modulates signaling. In rat hepatocytes, HGF can stimulate TGF-α production while TGF-α antibodies or antisense oligonucleotides suppress HGF-stimulated DNA synthesis. We report that the epidermal growth factor receptor (EGFR) kinase inhibitor PKI166 blocked both basal and ligand-induced tyrosine phosphorylation of the EGFR (IC50 = 60 nM), but not of the insulin receptor or c-met. Pharmacologic inhibition of the EGFR kinase abolished the proliferative actions of HGF and EGF, but not insulin, whereas PI-3 kinase inhibition blocked both EGF and insulin actions. We conclude that in cultured hepatocytes (i) PI-3 kinase is required for EGF- and insulin-induced proliferation and (ii) EGFR mediates both the basal rate of DNA synthesis and that induced by EGF and HGF, but not insulin. The mitogenic effect of HGF may be secondary to increased synthesis or processing of EGFR ligands such as TGF-α. © 2002 Elsevier Science