Overexpression of a family of RPEL proteins modifies cell shape

AbstractProteins containing RPEL motifs (e.g., MAL) are important in the regulation of gene expression by the actin cytoskeleton. Screening the ENSEMBL database for RPEL proteins identified four additional proteins that contain RPEL motifs and nuclear localisation sequences, three of which (RPEL-A, RPEL-B and RPEL-C) are expressed in adult mouse tissues with different expression profiles. The mRNAs encoding RPEL-B and RPEL-C were subject to alternative splicing. Expression of these genes in cells indicated that they had a marked effect on cell shape. Furthermore, when expressed with a nuclear localised actin all of the different forms became restricted to the nucleus

Persistent Neuroadaptations in the Expression of Genes Involved in Cholesterol Homeostasis Induced by Chronic, Voluntary Alcohol Intake in Rats

Alcohol use disorder (AUD) is associated with persistent adaptations in the brain that are believed to participate in the long-lasting vulnerability to relapse after abstinence. Cholesterol, the major sterol compound found in the central nervous system (CNS), plays a major role in maintenance of neuronal morphology, synaptogenesis and synaptic communication and may be involved in alcohol-induced neuroadaptations. In this study, we investigated whether alcohol consumption in a two-bottle choice paradigm followed by 3 weeks of abstinence could alter the expression of genes encoding proteins involved in cholesterol homeostasis in brain regions involved in addiction and relapse, namely the prefrontal cortex (PFC), the nucleus accumbens (NAc), the mesencephalon and the amygdala. We found that voluntary alcohol intake followed by 3 weeks of forced abstinence produces changes in the transcription of several genes encoding proteins directly involved in cholesterol synthesis such as 3-hydroxyl-3-methylglutaryl-coenzyme A (HMGCoA) reductase, farnesyl-diphosphate farnesyltransferase 1 (FDFT1) and farnesyl diphosphate synthase (FDPS) and in its regulation such as sterol regulatory element-binding factor-2 (SREBF2), in cholesterol transport such as ATP-binding cassette subfamily A member 1 (ABCA1) and in cholesterol degradation such as CYP46A1. Interestingly, these changes appeared to be region-specific and suggest that previous chronic exposure to alcohol might durably increase cholesterol metabolism in the PFC, the NAc and the mesencephalon and decrease cholesterol metabolism in the amygdala. Altogether, these results suggest that alcohol consumption leads to durable deregulations in cholesterol metabolism in key areas involved in loss of control over drug use and addiction. These long-term neuroadaptations may participate in the changes in brain structure and functioning that are responsible for the long-lasting risks of relapse to alcohol

Delphinidin inhibits endothelial cell proliferation and cell cycle progression through a transient activation of ERK-1/-2

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Persistent Neuroadaptations in the Expression of Genes Involved in Cholesterol Homeostasis Induced by Chronic, Voluntary Alcohol Intake in Rats

International audienceAlcohol use disorder (AUD) is associated with persistent adaptations in the brain that are believed to participate in the long-lasting vulnerability to relapse after abstinence. Cholesterol, the major sterol compound found in the central nervous system (CNS), plays a major role in maintenance of neuronal morphology, synaptogenesis and synaptic communication and may be involved in alcohol-induced neuroadaptations. In this study, we investigated whether alcohol consumption in a two-bottle choice paradigm followed by 3 weeks of abstinence could alter the expression of genes encoding proteins involved in cholesterol homeostasis in brain regions involved in addiction and relapse, namely the prefrontal cortex (PFC), the nucleus accumbens (NAc), the mesencephalon and the amygdala. We found that voluntary alcohol intake followed by 3 weeks of forced abstinence produces changes in the transcription of several genes encoding proteins directly involved in cholesterol synthesis such as 3-hydroxyl-3-methylglutaryl-coenzyme A (HMGCoA) reductase, farnesyl-diphosphate farnesyltransferase 1 (FDFT1) and farnesyl diphosphate synthase (FDPS) and in its regulation such as sterol regulatory element-binding factor-2 (SREBF2), in cholesterol transport such as ATP-binding cassette subfamily A member 1 (ABCA1) and in cholesterol degradation such as CYP46A1. Interestingly, these changes appeared to be region-specific and suggest that previous chronic exposure to alcohol might durably increase cholesterol metabolism in the PFC, the NAc and the mesencephalon and decrease cholesterol metabolism in the amygdala. Altogether, these results suggest that alcohol consumption leads to durable deregulations in cholesterol metabolism in key areas involved in loss of control over drug use and addiction. These long-term neuroadaptations may participate in the changes in brain structure and functioning that are responsible for the long-lasting risks of relapse to alcohol

Cytokine Signature and Involvement in Chronic Rhinosinusitis with Nasal Polyps

Cytokines are well known to play a central role in chronic rhinosinusitis with nasal polyps (CRSwNP), particularly in maintenance of the inflammatory response and the recruitment of eosinophils. The pathophysiological concepts concerning the involvement of inflammatory cytokines in CRSwNP have gradually evolved. Although the Th2 cytokines environment associated with an eosinophilic infiltration has retained a central role in the genesis of polyps, the role of other cytokine subpopulations has also and more recently been detailed, leading to a specific and complex signature in CRSwNP. The purpose of this review is to summarize the current state of knowledge about the cytokine signature in CRSwNP, the role of cytokines in the pathogenesis of this disease and in the intercellular dialog between epithelial cells, fibroblasts and inflammatory cells. Knowledge of this precise cytokine signature in CRSwNP is fundamental in the perspective of potential targeting biotherapies

Oncostatin M Counteracts the Fibrotic Effects of TGF-β1 and IL-4 on Nasal-Polyp-Derived Fibroblasts: A Control of Fibrosis in Chronic Rhinosinusitis with Nasal Polyps?

Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with inflammation and tissue remodeling including myofibroblasts differentiation and extracellular matrix (ECM) deposition mediated by TGF-β1 and IL-4. Oncostatin M (OSM) is a cytokine involved in fibrotic processes in other cellular subtypes. We investigated the mechanisms of action of OSM in the fibrosis process associated with CRSwNP. The expression of IL-4, OSM and TGF-β1 was assessed by RT-qPCR. Primary human cultures of nasal-polyp-derived fibroblasts were established and stimulated by TGF-β1 and/or IL-4 and/or OSM. The expression of ECM components and αSMA was determined by RT-qPCR and Western blot. TGF-β1-Smad3 signaling was investigated by immunofluorescence. TGF-β1, IL-4 and OSM as well as αSMA were overexpressed in nasal polyps when compared to noninflammatory nasal mucosa. In TGF-β1-stimulated nasal-polyp-derived fibroblasts, ECM genes and αSMA gene and protein were overexpressed, as well as αSMA in IL-4-stimulated fibroblasts. OSM counteracted the profibrotic effect of TGF-β1 on ECM components and αSMA. TGF-β1-induced nuclear translocation of Smad3 was completely reversed by OSM. OSM counteracts the profibrotic effect of IL-4 and also TGF-β1, by inhibiting the nuclear translocation of Smad3. We suggest OSM could be an efficient tool to protect against fibrosis in CRSwNP

Design, synthesis and biological evaluation of new thalidomide analogues as TNF-alpha and IL-6 production inhibitors

International audienceSeveral thalidomide analogues were synthesized and compared to thalidomide and its more active analogue, lenalidomide, for their ability to inhibit the production of the pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 by LPS-activated peripheral blood mononuclear cells (PBMCs). Among these compounds, two analogues containing sulfonyl group displayed interesting downregulation of TNF-alpha and IL-6 production. (C) 2010 Elsevier Ltd. All rights reserved