Dexamethasone inhibits food intake suppression induced by low doses of interleukin-1 beta administered intracerebroventricularly.

Intracerebroventricular (ICV) microinfusion of recombinant human interleukin-1 beta (rhIL-1 beta, 0.125 to 2.0 ng/rat) dose-dependently suppressed 2 h and nighttime food intake in rats. The following daytime food intake did not change or increased. ICV infusion of bovine serum albumin (BSA), or heat-treated rhIL-1 beta had no effect on food intake. Pretreatment with dexamethasone (200 micrograms/rat, intraperitoneal) blocked the food intake suppression induced by low doses of rhIL-1 beta. This ability of dexamethasone, a synthetic corticosteroid, may have potential therapeutic implications in acute and chronic pathological processes associated with increased levels of IL-1 and appetite suppression.     

Effects of galanin on insulin and glucagon secretion in the rat

Galanin-like immunoreactivity has been visualized in nerve fibers in the islets of Langerhans, suggesting an involvement of galanin in the neural regulation of islet function. In this study, we investigated the effects of galanin on basal and stimulated insulin and glucagon secretion by infusing the peptide at three different dose rates in rats. We also studied the direct effect of galanin on insulin secretion from freshly isolated rat islets. At 320 pmol/kg/min, but not at 20 or 80 pmol/kg/min, galanin lowered basal plasma insulin levels. In contrast, basal plasma glucagon levels were lowered by galanin already at 20 and 80 pmol/kg/min. Furthermore, galanin inhibited both glucose- and arginine-induced insulin release at all three dose levels, whereas arginine-induced glucagon release was not affected by galanin. Glucose-stimulated insulin secretion from isolated rat islets was dose-dependently suppressed by galanin (10^-6-10^-8M). Therefore, it is concluded that galanin in rats inhibits insulin secretion, both in vivo and in vitro, and that at lower dose levels, the peptide also inhibits basal glucagon release.     

CD44 ligation induces apoptosis via caspase- and serine protease-dependent pathways in acute promyelocytic leukemia cells.

We have recently reported that ligation of the CD44 cell surface antigen with A3D8 monoclonal antibody (mAb) triggers incomplete differentiation and apoptosis of the acute promyelocytic leukemia (APL)-derived NB4 cells. The present study characterizes the mechanisms underlying the apoptotic effect of A3D8 in NB4 cells. We show that A3D8 induces activation of both initiator caspase-8 and -9 and effector caspase-3 and -7 but only inhibition of caspase-3/7 and caspase-8 reduces A3D8-induced apoptosis. Moreover, A3D8 induces mitochondrial alterations (decrease in mitochondrial membrane potential DeltaPsi m and cytochrome c release), which are reduced by caspase-8 inhibitor, suggesting that caspase-8 is primarily involved in A3D8-induced apoptosis of NB4 cells. However, the apoptotic process is independent of TNF-family death receptor signalling. Interestingly, the general serine protease inhibitor 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF) decreases A3D8-induced apoptosis and when combined with general caspase inhibitor displays an additive effect resulting in complete prevention of apoptosis. These results suggest that both caspase-dependent and serine protease-dependent pathways contribute to A3D8-induced apoptosis. Finally, A3D8 induces apoptosis in all-trans-retinoic acid-resistant NB4-derived cells and in APL primary blasts, characterizing the A3D8 anti-CD44 mAb as a novel class of apoptosis-inducing agent in APL.     

The in vitro permeability of human skin to benzene, ethylene glycol, formaldehyde, and n-hexane

The permeability of human skin to benzene, ethylene glycol, formaldehyde, and n-hexane was studied using excised skin in a flow-through diffusion cell. The rate of resorption was determined by measuring the amount of substance found in the receptor fluid beneath the skin at steady-state. The rates of resorption (microgram X cm-2 X hr-1) were: benzene 99. ethylene glycol 118, formaldehyde from a concentrated solution of formalin 319, formaldehyde from a solution of 10% formalin in phosphate buffer 16.7, and n-hexane 0.83. The amount of substance in the skin at steady-state and after 0.5 hr of exposure was also determined. For all substances, the sum of the amount in the receptor medium and in the skin at steady-state, were larger than the amount obtained by multiplying the resorption rate by the time of exposure. For benzene, ethylene glycol and n-hexane the amount absorbed during the first half-hour of exposure was considerable larger than the amount resorbed during a same unit of time at steady-state. These data call attention to the fact that the absorption rate is higher before steady state is attained.     

Immunoregulators in the nervous system

The nervous system, through the production of neuroregulators (neurotransmitters, neuromodulators and neuropeptides) can regulate specific immune system functions, while the immune system, through the production of immunoregulators (immunomodulators and immunopeptides) can regulate specific nervous system functions. This indicates a reciprocal communication between the nervous and immune systems. The presence of immunoregulators in the brain and cerebrospinal fluid is the result of local synthesis--by intrinsic and blood-derived macrophages, activated T-lymphocytes that cross the blood-brain barrier, endothelial cells of the cerebrovasculature, microglia, astrocytes, and neuronal components--and/or uptake from the peripheral blood through the blood-brain barrier (in specific cases) and circumventricular organs. Acute and chronic pathological processes (infection, inflammation, immunological reactions, malignancy, necrosis) stimulate the synthesis and release of immunoregulators in various cell systems. These immunoregulators have pivotal roles in the coordination of the host defense mechanisms and repair, and induce a series of immunological, endocrinological, metabolical and neurological responses. This review summarizes studies concerning immunoregulators--such as interleukins, tumor necrosis factor, interferons, transforming growth factors, thymic peptides, tuftsin, platelet activating factor, neuro-immunoregulators--in the nervous system. It also describes the monitoring of immunoregulators by the central nervous system (CNS) as part of the regulatory factors that induce neurological manifestations (e.g., fever, somnolence, appetite suppression, neuroendocrine alterations) frequently accompanying acute and chronic pathological processes.     

Effect of oxygen withdrawal on active and passive electrical properties of arterially perfused rabbit ventricular muscle

Oxygen withdrawal from myocardial cells leads to changes of the transmembrane action potential (mainly action potential shortening), to cellular uncoupling, and to changes of vascular permeability. This study was aimed at the simultaneous measurement of electrical activity and passive electrical properties (extracellular and intracellular longitudinal resistance) in arterially perfused rabbit papillary muscles under different conditions of changed oxygen supply. These included 1) complete anoxia (erythrocyte-free perfusate), 2) hypoxia (PO2 between 23-28 mm Hg, erythrocytes present) in the presence and absence of glucose, and 3) normoxia with erythrocyte-free perfusate. Similarly to myocardial ischemia, rapid cellular uncoupling occurred only after an initial stable period of approximately 17 minutes, and it required complete anoxia. The marked shortening of the action potential developed before cellular uncoupling. In six out of eight experiments, the fibers were inexcitable when uncoupling started. In severe hypoxia, no significant change of internal longitudinal resistance was observed over 35-40 minutes. The time course of the extracellular longitudinal resistance was different from the change in intracellular resistance: A marked decrease occurred almost immediately after the onset of oxygen withdrawal. This decrease was followed by a small increase in conduction velocity, which was most likely due to a change in the interstitial compartment (edema). It was observed during anoxic as well as during hypoxic perfusion. We conclude that 1) cellular uncoupling in arterially perfused tissue requires almost complete oxygen lack and occurs with a delay of more than 10 minutes, 2) marked action potential shortening precedes uncoupling, and therefore can not simply be attributed to an increase in free, intracellular calcium, and 3) vascular endothelial function is more sensitive to oxygen withdrawal than the myocyte.