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Cyclic AMP (cAMP) and cyclic GMP (cGMP) are key second messengers involved in a multitude of cellular events. From the wealth of synthetic analogs of cAMP and cGMP,only a few have been explored with regard to their therapeutic potential. Some of the first-generation cyclic nucleotide analogs were promising enough to be tested as drugs,for instance N(6),O(2)'-dibutyryl-cAMP and 8-chloro-cAMP (currently in clinical Phase II trials as an anticancer agent). Moreover,8-bromo and dibutyryl analogs of cAMP and cGMP have become standard tools for investigations of biochemical and physiological signal transduction pathways. The discovery of the Rp-diastereomers of adenosine 3',5'-cyclic monophosphorothioate and guanosine 3',5'-cyclic monophosphorothioate as competitive inhibitors of cAMP- and cGMP-dependent protein kinases,as well as subsequent development of related analogs,has proven very useful for studying the molecular basis of signal transduction. These analogs exhibit a higher membrane permeability,increased resistance against degradation,and improved target specificity. Furthermore,better understanding of signaling pathways and ligand/protein interactions has led to new therapeutic strategies. For instance,Rp-8-bromo-adenosine 3',5'-cyclic monophosphorothioate is employed against diseases of the immune system. This review will focus mainly on recent developments in cyclic nucleotide-related biochemical and pharmacological research,but also highlights some historical findings in the field. View Publication

The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720,Rottlerin and quercetin were found to inhibit many protein kinases,sometimes much more potently than their presumed targets,and conclusions drawn from their use in cell-based experiments are likely to be erroneous. Ro 318220 and related bisindoylmaleimides,as well as H89,HA1077 and Y 27632,were more selective inhibitors,but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. The compounds with the most impressive selectivity profiles were KN62,PD 98059,U0126,PD 184352,rapamycin,wortmannin,SB 203580 and SB 202190. U0126 and PD 184352,like PD 98059,were found to block the mitogen-activated protein kinase (MAPK) cascade in cell-based assays by preventing the activation of MAPK kinase (MKK1),and not by inhibiting MKK1 activity directly. Apart from rapamycin and PD 184352,even the most selective inhibitors affected at least one additional protein kinase. Our results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure. We propose guidelines for the use of protein kinase inhibitors in cell-based assays. View Publication

There is no known treatment for fatty liver,a ubiquitous cause of chronic liver disease. However,because it is associated with hyperinsulinemia and insulin-resistance,insulin-sensitizing agents might be beneficial. To evaluate this possibility,insulin-resistant ob/ob mice with fatty livers were treated with metformin,an agent that improves hepatic insulin-resistance. Metformin improved fatty liver disease,reversing hepatomegaly,steatosis and aminotransferase abnormalities. The therapeutic mechanism likely involves inhibited hepatic expression of tumor necrosis factor (TNF) alpha and TNF-inducible factors that promote hepatic lipid accumulation and ATP depletion. These findings suggest a mechanism of action for metformin and identify novel therapeutic targets in insulin-resistant states. View Publication

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The synthetic retinoid 6-[3-(adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437),which can bind to and activate the nuclear retinoic acid receptors beta and gamma (RARbeta/gamma),is a potent inducer of apoptosis in various cancer cell lines. However,this effect was reported to be independent of RARs. In this study,we compared and contrasted the potencies and mechanisms of action of CD437 and several other receptor-selective retinoids in induction of apoptosis and modulation of squamous differentiation in UMSCC22B human head and neck squamous cell carcinoma cell line. CD437 and the structurally related retinoid CD2325 exhibited almost equal potency in inducing apoptosis,whereas several other retinoids failed to induce apoptosis. The RAR-specific pan antagonist AGN193109 failed to suppress CD437-induced apoptosis,indicating that the induction of apoptosis by CD437 was RAR-independent. c-Fos expression was induced by CD437 and CD2325 that induced apoptosis in the cell line but not by other retinoids that failed to induce apoptosis,suggesting a role for c-Fos in CD437-induced apoptosis. At low concentration (0.01 microM),CD437 shared with several other receptor-selective retinoids the ability to suppress the mRNA levels of the squamous differentiation markers Spr1,involucrin,and cytokeratin 1. This effect of CD437 could be blocked by AGN193109. We conclude that CD437 can exert its effects in UMSCC22B human human head and neck squamous cell carcinoma cells by at least two mechanisms: RAR-mediated suppression of squamous differentiation and RAR-independent induction of apoptosis. View Publication

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* The high rate of proliferation required of the bone marrow renders it highly susceptible to the influence of external factors. * Anaemia is the most common haematological abnormality seen in systemic disorders. * In the anaemia of chronic disease,erythropoietin production is reduced and proliferation of erythroid progenitor cells is also impaired; this anaemia can generally be alleviated by correction of the underlying disease process. * The status of the endocrine system must always be considered in evaluation of a normocytic,normochromic anaemia. * Anaemia in infection can be due to host or parasite factors or to the treatment administered. * Anaemia due to malignant disease responds to erythropoietin therapy in many cases; failure to respond is a poor prognostic sign. View Publication

OBJECT In Japan fasudil hydrochloride (HA1077),a protein kinase inhibitor,is widely administered to prevent vasospasm in patients after subarachnoid hemorrhage. The effects of fasudil on experimental spinal cord injury (SCI) were investigated and compared with those obtained using methylprednisolone. METHODS Spinal cord contusion was induced in rats by applying an aneurysm clip extradurally to the spinal cord at T-3 for 1 minute. After injury three groups of rats were treated with intravenously administered saline (control),intraperitoneally administered fasudil (10 mg/kg),or intravenously administered methylprednisolone (four 30 mg/kg injections). Neurological recovery was evaluated periodically over 1 month by using a modified combined behavioral scale and histopathological examination. Leukocyte infiltration near the injury site was evaluated by measuring myeloperoxidase (MPO) activity at 24 hours. Spinal cord blood flow was measured at intervals up to 3 hours after injury by using laser Doppler flowmetry. In rats in the fasudil-treated group significant improvement in modified combined behavioral score was demonstrated at each time point,whereas in the methylprednisolone-treated rats no beneficial effects were shown. In the fasudil-treated group,reduction of traumatic spinal cord damage was evident histologically in the caudal portion of the injured areas,and tissue MPO activity in tissue samples was reduced. Spinal cord blood flow was not significantly different between fasudil-treated and control group rats. CONCLUSIONS Fasudil hydrochloride showed promise of effectiveness in promoting neurological recovery after traumatic SCI. Possible mechanisms of this effect include protein kinase inhibition and decreased infiltration by neutrophils. View Publication

Oxidative stress is implicated in the pathogenesis of neuronal degenerative diseases. Oxidative stress has been shown to activate extracellular signal-regulated kinases (ERK)1/2. We investigated the role of these mitogen-activated protein kinases (MAPKs) in oxidative neuronal injury by using a mouse hippocampal cell line (HT22) and rat primary cortical cultures. Here,we show that a novel MAPK/ERK kinase (MEK) specific inhibitor U0126 profoundly protected HT22 cells against oxidative stress induced by glutamate,which was accompanied by an inhibition of phosphorylation of ERK1/2. U0126 also protected rat primary cultured cortical neurons against glutamate or hypoxia. However,U0126 was not protective against death caused by tumor necrosis factor alpha (TNFalpha),A23187,or staurosporine. These results indicate that MEK plays a central role in the neuronal death caused by oxidative stress. View Publication