Fulltext search in archive

The human circadian system is evidently regulated by components which can be found in the retina (light input), a suprachiasmatic nucleus in the hypothalamus (clock genes) and the pineal gland (melatonin synthesis). Clock genes are interdependent through two intracellular feedback loops. The pineal gland is not the single important producer of melatonin, as immune cells can also produce this hormone. Immune cells contain active clock genes as SCN cells and we can suggest that the regulation of the circadian system is a component of the neuroimmune regulation of the organism. The endogenous character is dominant in SCN, which is modulated by darkness and which synchronizes organisms to the light/dark regime including immunity. The exogenous character seems to be dominant in the immune system which synchronizes the organism including SCN cells to other environmental stimuli. The mathematical theory of chaos shows that the circadian activity of a cell is derived from ultradian metabolic rhythms; these rhythms support the stability of living systems which can be changed by a limited repertoire of interventions. The complexity of neuroimmune interactions perhaps explains why we are far from knowing the mechanism concerning the regulation of biorhythms despite the vast number of related scientific publications.

Our research group has previously studied the role of melatonin in the immune system of birds and mice, finding that incubation with both pharmacological and physiological doses of melatonin augmented the activity of phagocytes from these animals, and that this activity was lowered in pinealectomized animals. Since melatonin is synthesized from the amino acid tryptophan, the aim of the present work was to determine whether the administration of tryptophan might affect the plasma levels of melatonin and the phagocytic activity of peritoneal macrophages over the course of a circadian cycle. The study animals were 14-week-old male Wistar rats. They were administered tryptophan orally in a daily single dose of 125 mg/kg at 19:00 h for 21 days. Prior to beginning this treatment, the circadian rhythms of plasma melatonin and phagocytic activity were evaluated under basal conditions over a 24-h period, taking blood and cell suspension samples each 2 hours during the light period (08:00-20:00) and each hour during the dark period (20:00-08:00), since it is during this latter period that the secretion of melatonin is maximum. The results showed that, under basal conditions, the rats' plasma melatonin levels and phagocytic activity peaked at 02:00. After the tryptophan administration, there were increases in plasma melatonin levels with respect to basal and control-group values, with a peak at 21:00, and in the phagocytic activity of the peritoneal macrophages, which peaked at 02:00. This suggests that the tryptophan administration stimulated melatonin synthesis, leading to increased and earlier peaking plasma levels of this hormone, and augmented the innate immune response carried out by the peritoneal macrophages as a result of the immunoregulatory action of melatonin.

Excitatory amino acids (EAA) represent major brain neurotransmitters. They are present in numerous neuronal systems and thus are involved in almost all aspects of normal and pathological brain activity. Changes in EAA transmission have been associated with the functional impairments characterizing major neurological disorders, including epilepsy and schizophrenia. There is also a suspicion that EAA systems underlie the neuronal death associated not only with acute CNS insults, such as in ischemia or post-traumatic lesions, but also with neurodegenerative diseases such as ALS, Huntington's disease and Parkinson's disease. The neurotoxicity of EAA, referred to as excitotoxicity, is presumably mediated primarily through an excess of EAA synaptic receptor stimulation. Indeed, overstimulation of the ionotropic NMDA or AMPA/kainate receptor subtypes has been shown to produce an intense membrane depolarisation and further a massive increase in intracellular calcium leading to cell damage. The extreme diversity and specific pattern of expression of EAA receptor subunits could account for the differential vulnerability of certain brain areas to such excitotoxic processes. In addition, it is now believed that besides abnormalities in receptor functioning or in release processes, alterations in EAA transmission may result from dysfunction of the EAA uptake system, which represents the mechanism for EAA removal from the synapse. From the five transporter proteins cloned, termed EAAT1-5, the primarily glial transporters EAAT1 and EAAT2 have been shown to mediate the bulk of EAA uptake in the brain and it has then been suggested that they play a major role in the prevention of excitotoxic processes. In this respect, the degeneration of motor neurons in ALS has been associated with altered expression or inactivation of EAAT2. Moreover, recent evidence has been provided that pharmacological alteration of glutamate transport can also induce astrocyte degeneration, as observed in neurodegenerative insults, but through a mechanism independent of stimulation of EAA receptors. Thus, one can obviously consider that these EAATs can represent a key target for further development of new neuroprotective agents.

Circadian biorhythms change with age and such changes are caused by the loss of both the time and the space structure. These alterations of biorhythms are associated with poor health and the end of life but we do not know the extent to which they represent cell clock system injury. It seems that ageing of biorhythms in mammals, i.e. including humans, is caused by the ability of suprachiasmatic nuclei to drive oscillations in other tissues. Social synchronization extending photic stimuli, which diminishes during degeneration of nerve and optic system, enhances the quality of life and therefore further studies of the influence of health and social care systems on circadian rhythms could contribute to the lengthening of life.

This paper concerns the functional architecture of the cell nucleus. Though it is DNA that carries our literal blueprint, our ancestry includes the nucleus itself, passed down through the 2.5 billion year evolutionary history of the Eukarya. Nuclear structure is presented here as two contrasting possibilities. In one case, the nucleus is envisioned as being built upon a backbone of protein filaments, analogous to the cytoskeleton. In this conceptual framework, the chromosomes are considered to passively adopt locations that are dictated by their attachments to the imagined skeleton, and their activity is postulated to be the result of such attachments. In the other case, nothing in the architectural design of the nucleus is more deterministic than the chromosomes themselves, and their activity. Here, gene activity is thought to be based on the binding of DNA sequence-specific activator or silencing proteins that arrive at their target sites by diffusion. Moreover, additional elements of nuclear structure are viewed as arising from the very action of the genes themselves, such as nascent mRNAs packaged into ribonucleoprotein particles as well as large, heterotypic molecular machines involved in RNA processing. In this case, termed the "genome-centric model", the observed structure of the nucleus is not based on some underlying, prefabricated skeleton, but is in fact the actual ongoing cytological manifestation of genes in action. Upon careful analysis of all the evidence, the genome-centric model enjoys favor at the present time. However, we are still in kindergarten days in our understanding of the cell nucleus and, as always, it is wise to keep an open mind. New advances in biophysical, nanotechnology and systems biology approaches to nuclear architecture encourage us to believe that we may soon graduate into the gymnasium - if not university, level of our nuclear education. Viewed metaphorically as art (as in the playful title of this paper), we understand the paint at every atom of pigment on the palette - i.e., the covalent genome, the DNA. It is the final, creative work as applied to the gene expression canvas itself that we must now strive to know.

The liver is the main organ involved in the metabolism of xenobiotic (foreign) compounds. The responsible enzymatic systems are the cytochromes P450 (mixed function oxidases or phase I reactions) and enzymes coupling larger water soluble groups to the substrate (phase II reactions). Especially during phase I reactions, highly reactive metabolites can be formed capable of interacting with DNA and causing mutations. On the other hand reactive xenobiotics may be detoxified. Therefore, the primary parenchymal liver cell (hepatocyte) appears to be the optimal and most reliable in vitro system for the determination of mutagenicity/genotoxicity. Since however, primary hepatocytes are proliferatively quiescent, a culture system had to be developed allowing for proliferation enabling the determination of induced changes at the chromosomal level. This paper summarizes the special features of primary hepatocytes, the findings on in vitro proliferation and the application of hepatocyte cultures for in vitro and ex vivo/in vitro toxicological testing.

Abrin, ricin, viscumin, modeccin, and volkensin are very potent toxins derived from plants. They are glycoproteins composed of two polypeptide chains linked by a disulphide bridge. The A-chain is the enzymatic toxic moiety and B-chain is responsible for bonding to the target cell and internalization of toxin. The toxic part of the toxin molecule removes an adenine from a specific adenosine residue in ribosomal RNA and block proteosynthesis. That is the reason of extreme toxicity of these compounds and their capacity to be used as biological warfare agents or terrorist weapon. Therefore all these compounds are in the schedules of controlled biological agents and toxins. Contrariwise, plant ribosome-inactivating proteins are studied intensive as possible chemotherapeutic agents.