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Multicellular organisms rely upon diverse and complex intercellular communications networks for a myriad of physiological processes. Disruption of these processes is implicated in the onset and propagation of disease and disorder, including the mechanisms of senescence at both cellular and organismal levels. In recent years, secreted extracellular vesicles (EVs) have been identified as a particularly novel vector by which cell-to-cell communications are enacted. EVs actively and specifically traffic bioactive proteins, nucleic acids, and metabolites between cells at local and systemic levels, modulating cellular responses in a bidirectional manner under both homeostatic and pathological conditions. EVs are being implicated not only in the generic aging process, but also as vehicles of pathology in a number of age-related diseases, including cancer and neurodegenerative and disease. Thus, circulating EVs-or specific EV cargoes-are being utilised as putative biomarkers of disease. On the other hand, EVs, as targeted intercellular shuttles of multipotent bioactive payloads, have demonstrated promising therapeutic properties, which can potentially be modulated and enhanced through cellular engineering. Furthermore, there is considerable interest in employing nanomedicinal approaches to mimic the putative therapeutic properties of EVs by employing synthetic analogues for targeted drug delivery. Herein we describe what is known about the origin and nature of EVs and subsequently review their putative roles in biology and medicine (including the use of synthetic EV analogues), with a particular focus on their role in aging and age-related brain diseases. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) delivery of anti-inflammatory cytokines, such as interleukin 4 (IL4), holds promise as treatment for multiple sclerosis (MS). We have previously shown that short-term herpes simplex virus type 1-mediated IL4 gene therapy is able to inhibit experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in mice and non-human primates. Here, we show that a single administration of an IL4-expressing helper-dependent adenoviral vector (HD-Ad) into the cerebrospinal fluid (CSF) circulation of immunocompetent mice allows persistent transduction of neuroepithelial cells and long-term (up to 5 months) CNS transgene expression without toxicity. Mice affected by chronic and relapsing EAE display clinical and neurophysiological recovery from the disease once injected with the IL4-expressing HD-Ad vector. The therapeutic effect is due to the ability of IL4 to increase, in inflamed CNS areas, chemokines (CCL1, CCL17 and CCL22) capable of recruiting regulatory T cells (CD4+CD69−CD25+Foxp3+) with suppressant functions. CSF delivery of HD-Ad vectors expressing anti-inflammatory molecules might represent a valuable therapeutic option for CNS inflammatory disorders.Gene Therapy (2008) 15, 504–515; doi:10.1038/gt.2008.10; published online 31 January 2008 [ABSTRACT FROM AUTHOR]

The sensitivity of various isolated organs to catecholamines was tested before and after block of catechol-O-methyl transferase (COMT) by U-0521 (3′,4′-dihydroxy-2-methyl propiophenone; 18 μg/ml for 20 min). Isolated Nictitating Membrane of the Cat. The sensitivity to catecholamines was increased by inhibition of COMT whenever the experimental conditions resulted in a high potency of the amine, i.e., when the ED50 of the amine (in the absence of U-0521) was below about 10 M. Thus, block of COMT potentiated the effects of (−)-noradrenaline and (−)-adrenaline after denervation (or in the presence of cocaine) but not on muscles with an intact adrenergic innervation; it also increased the sensitivity to the β-effects but not to the α-effects of isoprenaline. No potentiation was observed for dopamine which has a low potency even after denervation. The relation between potency of the catecholamine and the degree of the sensitizing effect of U-0521 was not due to saturation of COMT or of access to the enzyme. Measurements in denervated muscles of the production of O-methylated metabolites from (±)-noradrenaline-H (added to the bath for 20 min in concentrations of about 10 to 10 M), and of the extraneuronal accumulation of noradrenaline-H did not reveal any saturation of either the enzyme or the extraneuronal accumulation of the amine. When block of COMT resulted in supersensitivity to a catecholamine, the time required to reach steady-state responses was usually increased. This is consistent with the view that block of the enzyme impaired a site of loss. Block of COMT failed to produce any substantial potentiation of the effects of the indirectly acting amines, tyramine and mephentermine. O-methylation of the released transmitter seems to occur after the amine has reached the receptors of the effector cells. Isolated Strips of Cat and Bat Spleen. Results were quantitatively similar, since block of COMT potentiated the effects of (−)-noradrenaline and (−)-adrenaline in the presence but not (or only very little) in the absence of cocaine. However, the degree of supersensitivity after block of COMT (in the presence of cocaine) was smaller than in the nictitating membrane. In the cat spleen, cocaine causes a small but significant degree of supersensitivity to isoprenaline but not to methoxamine. Isolated Sat Aorta, Block of COMT did not increase the effect of cocaine. It is suggested that differences in the morphology of the adrenergic innervation contribute to the observed organ differences. [ABSTRACT FROM AUTHOR]

Polyreactive (auto)antibodies are frequently found in healthy subjects and are bona fide considered to be nonpathogenic. However, autoreactive B cells and circulating (auto)antibodies have been associated with several neurological syndromes, including demyelinating disorders. Whether these antibodies can have a real impact on disease development is still a matter of debate. Here, we briefly summarize some of the most recently published data on both the deleterious and the protective effects of antibodies in autoimmune demyelinating disorders of the central nervous system. [ABSTRACT FROM AUTHOR]