Cyclooxygenases I. Role in Inflammation

Summary:: Cyclooxygenases are enzyme involved in an enzymatic pathway for membrane phospholipid-derivatives, leading to formation of prostanoids i.e. prostaglandins and thromboxanes. Prostaglandins control different physiological processes such as protection of gastrointestinal integrity, renal functions, reproduction, and course of inflammation. Cyclooxygenase exists in at least two isoforms encoded by different genes that are located on different chromosomes. Significant differences between the isoforms are also observed on mRNA level but both enzymes have a similar primary protein structure and carry out an identical catalytic activity. Cyclooxygenase-1 (COX-1) is involved both, in homeostatic control of the body in normal conditions, and in the early stage of inflammation (0-1 hour). On the other hand, cyclooxygenase-2 (COX-2) participates in subsequent stages of inflammation (>1 hour) during the onset of inflammatory reaction. Recent studies, however, reveal that COX-2 is also involved in the resolution of inflammation since its activity produces cyclopentenone prostaglandins of the J-series (PGD₂ metabolites), e.g. 15-deoxy-D^{12, 14}PGJ₂. These prostaglandins possess anti-inflammatory properties as they activate the nuclear receptor PPAR-g and/or inhibit nuclear factor kB (NFkB). In order to explain these contradictory activities of COX-2 a hypothesis was postulated that proinflammatory activity should be attributed to COX-2 but the anti-inflammatory properties to the third isomer of COX (COX-3). Putative COX-3 could be structurally similar to COX-2, maybe even encoded by the same gene since its activity can be blocked by selective COX-2 inhibitors. Implications of this fact for treatment of inflammatory diseases are discussed in part II of this article.

Key words: inflammation, COX, prostaglandin G/H synthase, prostaglandins, animal models

Cyclooxygenases II. Nonsteroidal Anti-inflammatory Drugs as Their Inhibitor

Summary: Since its discovery in 1897 aspirin (acetylsalicylic acid) was the most important and common anti-inflammatory, analgesic and anti-pyretic drug throughout the twentieth century. Aspirin and aspirin-like drugs, named commonly Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), exert their action through inhibition of cyclooxygenase enzymes. Cyclooxygenase exists in at least two isoforms: constitutive COX-1 and inducible COX-2. Aspirin and other classical NSAIDs inhibit both isoforms. As prostaglandins that are produced due to COX-1 activity protect mucosa of gastrointestinal tract, inhibition of this isoform leads to ulceration of stomach and duodenum. In order to prevent ulcer development mucosal coating drugs can be co-administrated, or classical NSAIDs may be substituted by NSAIDs releasing nitric oxide or associated with zwitterionic phospholipids. Recent studies led to development of selective COX-2 inhibitors inhibiting only COX-2 that is involved in inflammation and pain. New generation of NSAIDs is safer but not free of side effects that are due to constitutive expression of COX-2 in kidneys, healing ulcers and reproductive tract. Increasing number of studies, including those on paracetamol, implies existence of the third COX isoform (COX-3). Till now the mechanism of paracetamol action was unknown. The fact that paracetamol reduces pain and fever but not inflammation, while possessing low selectivity for COX-1 and COX-2, seems to confirm this hypothesis. Above discoveries changed the position of aspirin in the twenty-first century. Nowadays, low-dose aspirin is recommended as an anti-thrombotic drug since platelets contain exclusively COX-1.

Key words: COX, NSAID-non-selective COX inhibitors, selective COX-2 inhibitors, COX-3, aspirin, paracetamol
 

Influence of Vanadium on Sugar Metabolism and Other Processes in the Cell

Summary: The potential role of vanadium compounds in human therapy promises an interesting study in the use of this element, in particular as an insulin-mimetic agent. Among many other biological properties, the most important is the capability of vanadium compounds to normalise several parameters disturbed in diabetes mellitus. Vanadium decreases both blood glucose and lipids to normal levels, insulin resistance of target tissues and regulates many processes that are included in sugar and lipids metabolism. Besides insulin-mimetic activities, vanadium compounds are studied from others aspect because they are effective in the regulation of various processes in the cell. Vanadium has been used in several studies as a regulator of apoptosis, proliferation, cancer development or immunological responses. Most of these effects are a direct result of phosphatase inhibition or kinase activation by vanadium. These are key enzymes that control the phosphorylation and dephosphorylation ratio in the cell so vanadium compounds could be useful in the regulation of many important metabolic processes. Regardless of their ultimate success or failure as therapeutic agents, vanadium continues to be a useful probe of enzyme structure and function in a number of biological processes.

Key words: vanadium, diabetes, phosphatases, kinases

Abiotic Stress Signaling Pathways in Plant Cell

Summary: Plants exhibit a variety of responses to abiotic stress that enable them to tolerate and survive adverse conditions. The first step is perceiving the stress as it occurs and to relay information about it through a signal transduction pathway. Signal molecules are recognized by receptors, which are localized on the plasma membrane of the cell. Binding of a ligand can result in the stimulation of an intrinsic enzymatic activity of its receptor or the modulation of transducing protein. Recent studies in plants indicate that mitogen – activated protein kinase (MAPK) cascades have emerged as a universal signal transduction mechanism that connects diverse sensors to cellular and nuclear responses. The signaling pathways constitute a network that is interconnected at many levels, it is called ‘cross-talk’.

Key words: signal transduction, abiotic stresses, receptors, signal transducers, ‘cross-talk’

Nitric Oxide in Plants...

Summary: Nitric oxide, the well-known mammalian cell signalling transducer, plays an important role also in plant physiology. This paper explains the current knowledge of NO production, function and mechanisms of action in plants. Nitric oxide in plants is synthesized by the enzymes of similar activity to the mammalian nitric oxide synthases. Alternatively, it can be produced by nitrate reductases, which are a plant-specific source of NO. Non-enzymatic formation of NO by redox reactions was also observed. Nitric oxide mediates a variety of stress responses to pathogens, UV irradiation, mechanical damage, has been particularly well documented. NO influences the stress related secondary metabolism as well as participates in regulation of some developmental processes. The coexistence of several NO signal transduction pathways has been reported in plants. Elements taking part therein are: cycli nucleotides (cGMP, cADP-ribose), salicylic acid, reactive oxygen species, protein kinases, and most probably some other compounds, still to be discovered. Some of the most urgent problems to be studied in the next future are also presented. The significance of NO as a non-typical plant growth regulator and universal stress-signalling mediator is discussed.

Key words: nitric oxide, stress, plant immunity, free radicals

Plasmodesmata as the Part of the Communication System in Plants

Summary: Plazmodesmata – cytoplasmic bridges joining cells – are one of the features specific to plants. In spite of discovery of plasmodesmata as early as more than 100 years ago, the mechanism of their functioning as the way for metabolite and sygnaling molecules exchange between cells was not clear until the last decade. The information on plasmodesmata role in protein and nucleic acids transport are of particular interest. Current discoveries suggest existing in plants the new communication system, involving proteins and/or nucleic acids as signalling molecules.

Key words: apoplast, macromolecules, phloem, plant wiruses, plasmodesmata, signalling, short distance transport, symplast
 

The Effect of Morphine on Iimmunity of Vertebrates

Summary: Interest in the effects of drugs, especially opiates, on the immune system has increased with progression in the number of abusers and patients using morphine to relief pain. Morphine shows a diversity of effects on the immune system, inhibiting or enhancing the response. Opiates can alter a variety of immune responses either indirectly, via classical opioid receptors in CNS, what induces release of calecholamine and glucocoricosteroids or directly via selective - m₃ opiate receptor localised on leukocytes. Studies on morphine-dependent rodents demonstrated that suppressed NK-cell cytotoxicity was mediated by opiate receptors in the brain. While in vitro studies on phagocytes confirm theory about direct effects of opiates. For example incubation of leukocytes with morphine inhibits their migratory activity due to heterologous desensitization of chemokine receptors. Morphine reduces also phagocytic activity, but enhances the respiratory burst of phagocytes. Morphine also modulates inflammation; injected to peritoneal cavity together with an irritant reduced number of elicited leukocytes and the level of chemotactic factors in mice and fish, but not in amphibians and birds. Morphine also reduces lymphocyte-mediates immunity as it reduces proliferative response and production of antibodies.

Key words: morphine, opioid receptors, immunoneuroendocrinology

The Hereditary Haemolytic Anaemias in Mice: from Complete Characteristics to Gene Therapy

Summary: Haemolytic anaemias in mice resemble hereditary defects in humans. These defects allow the precise analyses of the molecular basis of  the diseases. Moreover, they allow attempts of   “gene therapy” to correct these defects. An example of such a procedure was reported by Dooner et al. (Exp. Hematol. 2000; 28: 765-774). Techniques developed should have relevance to the development of gene therapy approaches to human hereditary disorders such as sickle cell anemia, thalassaemia, recessive spherocytosis and elliptocytosis.

Key words: inherited haemolytic anaemias, gene therapy, erythrocyte membrane.

Regulation of Expression of Nuclear Genes by Plastid Signals.

Summary: A considerable body of experimental evidence has been accumulated over recent years to suggest that an expression of defined nuclear genes, particularly the ones coding for chloroplast proteins, are controlled in retrograde fashion by signals of plastid origin. Transcription and translation level of expression of nuclear genes appear to be affected by retrograde signalling. Some plastid-to-nucleus signals have already been identified; they involve metabolic precursors of chlorophyll, redox state of plastoquinone, thioredoxin and glutathione pools as well as a phosphoenolopyruvate/phosphate translocator localised to an inner membrane of chloroplast envelope. In some cases the nature of plastid signals remains elusive; for instance the retrograde signals controlling cell differentiation and leaf morphogenesis have not been identified. Plastid-to-nucleus and light-dependent signalling are linked by rather complicated relations; in some cases the signalling pathways are separable, but in other cases the signalling may proceed, at least partially, through common steps. Retrograde signalling appears to be a seminal element of global regulatory network controlling plant cell development and metabolism.

Key words: chlorophyll, chloroplast, gen, plastid, redox state, retrograde signalling

Antigen Presentation in the Brain

Summary: The brain was considered as the immune-privileged organ. This view has been shaken, among others, by the discovery, that the antigen presentation takes place inside the CNS. It is not known precisely, which of endogenous cells of the brain are responsible for this process. Experiments concentrate on expression of MHCII and costimulatory molecules on the surface of these cells, as well as on their capability to stimulate T-lymphocyte activation. In this paper, studies concerning the role of glial cells – astocytes, microglia, and also endothelium and perivascular macrophages  in antigen presentation in the brain are reviewed.

Key words: antigen presentation, astrocytes, microglia, macrophages