Current pharmaceutical design
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Accumulating evidence indicates that circulating endothelial progenitor cells (EPCs) derived from bone marrow contribute to reendothelialization of injuried vessels as well as neo-vascularization of ischemic lesions in either a direct or an indirect way. Moreover, the number and/or the functional activity of EPCs are inversely correlated with risk factors for cardiovascular disease. ⋯ In particular, we show the recent observation on the effects of active and second hand smoke (SHS) exposure on EPC number and functional activity. This review also considers the effects of nicotine and other smoke compounds on EPC number and activity, in in vitro and in vivo models.
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Active and passive exposure to cigarette smoke (CS) increases the risk of, and has deleterious effects in, ischaemic heart disease. Exposure to CS increases infarct size in experimental models of coronary occlusion and reperfusion. ⋯ Many, if not all, of these alterations are caused by oxidative stress, either as a direct consequence of inhalation of free radicals, or by induction from the vast range of chemicals present in both the gas and solid phase of tobacco smoke. Here, some of the proposed mechanisms will be reviewed and their impact on the cardiomyocytes and peripheral vasculature discussed.
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The systemic administration of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists has been considered as a pharmacological model of schizophrenia. In the present work, we used in vivo microdialysis to examine: first, the effects of MK-801, on the efflux of glutamate and serotonin (5-HT) in the medial prefrontal cortex (mPFC) of the rat; second, whether the MK-801-induced changes in the cortical efflux of both transmitters could be blocked by atypical (clozapine and olanzapine) and classical (haloperidol and chlorpromazine) antipsychotic drugs given intra-mPFC; and third, the role of local blockade of dopamine D(2)/D(3)/D(4), serotonin 5-HT(2A) and alpha(1)-adrenergic receptors as well as agonism at dopamine D(1)/D(5) and 5-HT(1A) receptors in the mPFC on the increased efflux of glutamate and 5-HT elicited by MK-801. The four antipsychotic drugs blocked the MK-801-induced increase in glutamate, whereas only clozapine and olanzapine were able to block the increased efflux of 5-HT. ⋯ Moreover, we propose that D(2)/D(3)/D(4) receptor antagonists would act predominantly on a subpopulation of GABAergic interneurons of the mPFC, thus enhancing cortical inhibition, which would prevent an excessive glutamatergic transmission. Dopamine D(1)/D(5) agonists would further stimulate GABA release from other subpopulation of interneurons controlling cortical output to the dorsal raphe nucleus. Atypical antipsychotic drugs might further act upon 5-HT(2A), 5-HT(1A) and alpha(1)-adrenoceptors present in pyramidal cells (including those projecting to the dorsal raphe nucleus), which would directly inhibit an excessive excitability of these cells.
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Chemokines and chemokine receptors play diverse roles in homeostasis. The chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 have critical functions in the immune, circulatory, and central nervous systems and have also been implicated in tumor biology and metastasis. Here we review the current data regarding the role of the CXCR4/SDF-1 chemokine axis in the development of bone metastases, derived from tumor models of breast or prostate cancers. ⋯ In short, the effects of the CXCR4/SDF-1 axis on tumor cell growth within the bone are not yet fully defined. Further, there are theoretical risks that blockade of this chemokine axis could impair immune function or mobilize tumor cells leading to other sites of metastasis. As such, caution should be taken when designing therapeutic strategies targeting this chemokine axis.
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Alzheimer's disease (AD) is the most common neurodegenerative disorder that affects the elderly. The increase of life-expectancy is transforming AD into a major health-care problem. AD is characterized by a progressive impairment of memory and other cognitive skills leading to dementia. ⋯ This review discusses current knowledge about the involvement of neuroinflammation in AD pathogenesis, focusing on phenotypic and functional responses of microglia, astrocytes and neurons in this process. The abnormal production by glia cells of pro-inflammatory cytokines, chemokines and the complement system, as well as reactive oxygen and nitrogen species, can disrupt nerve terminals activity causing dysfunction and loss of synapses, which correlates with memory decline; these are phenomena preceding the neuronal death associated with late stages of AD. Thus, therapeutic strategies directed at controlling the activation of microglia and astrocytes and the excessive production of pro-inflammatory and pro-oxidant factors may be valuable to control neurodegeneration in dementia.