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101.
Giuseppe Poli Barbara Sottero Simona Gargiulo Gabriella Leonarduzzi 《Molecular aspects of medicine》2009,30(3):180-189
Like the other oxidation products of the lipid moiety of plasma low density lipoproteins (LDL), cholesterol oxidation products are consistently found within the characteristic lesions of atherosclerosis, both in experimental animals and in man. A growing bulk of evidence suggests that oxysterols make a significant contribution to the vascular remodeling that occurs in atherosclerosis, being involved in various key steps of this complex process: endothelial cell dysfunction, adhesion of circulating blood cells, foam cell and fibrous cap formation, modulation of the extracellular matrix (ECM), vascular cell apoptosis and plaque’s instability. Moreover, oxysterols have been demonstrated to be at least one or two orders of magnitude more reactive than unoxidized cholesterol in exerting pro-inflammatory, pro-apoptotic, and pro-fibrogenic effects. Thus, a pathological level of cholesterol oxidation in the vasculature may be the missing molecular link between hypercholesterolemia and the formation of atherosclerotic lesions. 相似文献
102.
Jessica Sabourin Coralie Lamiche Aurelie Vandebrouck Christophe Magaud Jerome Rivet Christian Cognard Nicolas Bourmeyster Bruno Constantin 《The Journal of biological chemistry》2009,284(52):36248-36261
The dystrophin-associated protein complex (DAPC) is essential for skeletal muscle, and the lack of dystrophin in Duchenne muscular dystrophy results in a reduction of DAPC components such as syntrophins and in fiber necrosis. By anchoring various molecules, the syntrophins may confer a role in cell signaling to the DAPC. Calcium disorders and abnormally elevated cation influx in dystrophic muscle cells have suggested that the DAPC regulates some sarcolemmal cationic channels. We demonstrated previously that mini-dystrophin and α1-syntrophin restore normal cation entry in dystrophin-deficient myotubes and that sarcolemmal TRPC1 channels associate with dystrophin and the bound PDZ domain of α1-syntrophin. This study shows that small interfering RNA (siRNA) silencing of α1-syntrophin dysregulated cation influx in myotubes. Moreover, deletion of the PDZ-containing domain prevented restoration of normal cation entry by α1-syntrophin transfection in dystrophin-deficient myotubes. TRPC1 and TRPC4 channels are expressed at the sarcolemma of muscle cells; forced expression or siRNA silencing showed that cation influx regulated by α1-syntrophin is supported by TRPC1 and TRPC4. A molecular association was found between TRPC1 and TRPC4 channels and the α1-syntrophin-dystrophin complex. TRPC1 and TRPC4 channels may form sarcolemmal channels anchored to the DAPC, and α1-syntrophin is necessary to maintain the normal regulation of TRPC-supported cation entry in skeletal muscle. Cation channels with DAPC form a signaling complex that modulates cation entry and may be crucial for normal calcium homeostasis in skeletal muscles. 相似文献
103.
Colotta V Capelli F Lenzi O Catarzi D Varano F Poli D Vincenzi F Varani K Borea PA Dal Ben D Volpini R Cristalli G Filacchioni G 《Bioorganic & medicinal chemistry》2009,17(1):401-410
The study of novel 2-arylpyrazolo[3,4-c]quinolin-4-(hetero)arylamides, designed as human (h) A(3) adenosine receptor antagonists, is reported. The new derivatives are endowed with nanomolar hA(3) receptor affinity and high selectivity versus hA(1), hA(2A) and hA(2B) receptors. Among the (hetero)aroyl residues introduced on the 4-amino group, the 2-furyl and 4-pyridyl rings turned out to be the most beneficial for hA(3) affinity (K(i)=3.4 and 5.0nM, respectively). An intensive molecular docking study to a rhodopsin-based homology model of the hA(3) receptor was carried out to obtain a 'structure-based pharmacophore model' that proved to be helpful for the interpretation of the observed affinities of the new hA(3) pyrazoloquinoline antagonists. 相似文献
104.
Amine Ghozlane Agnel Praveen Joseph Aurelie Bornot Alexandre G de Brevern 《Bioinformation》2009,3(9):367-369
Conversion of local structural state of a protein from an α-helix to a β-strand is usually associated with a major change in the
tertiary structure. Similar changes were observed during the self assembly of amyloidogenic proteins to form fibrils, which
are implicated in severe diseases conditions, e.g., Alzheimer disease. Studies have emphasized that certain protein sequence
fragments known as chameleon sequences do not have a strong preference for either helical or the extended conformations.
Surprisingly, the information on the local sequence neighborhood can be used to predict their secondary at a high accuracy
level. Here we report a large scale-analysis of chameleon sequences to estimate their propensities to be associated with
different local structural states such as α -helices, β-strands and coils. With the help of the propensity information derived
from the amino acid composition, we underline their complexity, as more than one quarter of them prefers coil state over to
the regular secondary structures. About half of them show preference for both α-helix and β-sheet conformations and either
of these two states is favored by the rest. 相似文献
105.
Annarita Poli Ida Romano Paolo Cordella Pierangelo Orlando Barbara Nicolaus Cristina Ceschi Berrini 《Extremophiles : life under extreme conditions》2009,13(6):867-874
A novel aerobe thermophilic endospore-forming bacterium designated strain AF/04T was isolated from thermal mud located in Euganean hot springs, Abano Terme, Padova, Italy. Strain AF/04T was Gram-positive, motile, rod-shaped, occurring in pairs, or filamentous. The isolate grew between 55 and 67°C (optimum
65°C) and at pH 6.0–7.5 (optimum pH 7.2). The strain was aerobic and grew on maltose, trehalose, and sodium acetate as sole
carbon sources. The G + C content of DNA was 53.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that
strain AF/04T falls within the genus Anoxybacillus. Levels of 16S rRNA gene sequence similarity between strain AF/04T and the type strains of recognized Anoxybacillus species ranged from 95 to 99%. Chemotaxonomic data (major isoprenoid quinone–menaquinone-7; major fatty acid iso-C15:0 and anteiso-C17:0) supported the affiliation of strain AF/04T to the genus Anoxybacillus. Based on phenotypic and chemotaxonomic characteristics, 16S rRNA gene sequence analysis and DNA–DNA hybridization data, it was proposed that strain AF/04T (=DSM 17141T = ATCC BAA 1156T) should be placed in the genus Anoxybacillus as the type strain of a novel species, Anoxybacillus thermarum sp. nov. 相似文献
106.
107.
RNA motifs can be defined broadly as recurrent structural elements containing multiple intramolecular RNA-RNA interactions, as observed in atomic-resolution RNA structures. They constitute the modular building blocks of RNA architecture, which is organized hierarchically. Recent work has focused on analyzing RNA backbone conformations to identify, define and search for new instances of recurrent motifs in X-ray structures. One current view asserts that recurrent RNA strand segments with characteristic backbone configurations qualify as independent motifs. Other considerations indicate that, to characterize modular motifs, one must take into account the larger structural context of such strand segments. This follows the biologically relevant motivation, which is to identify RNA structural characteristics that are subject to sequence constraints and that thus relate RNA architectures to sequences. 相似文献
108.
Hoffmann T Bös M Stadler H Schnider P Hunkeler W Godel T Galley G Ballard TM Higgins GA Poli SM Sleight AJ 《Bioorganic & medicinal chemistry letters》2006,16(5):1362-1365
The discovery of a novel, achiral pyridine class of potent and orally active neurokinin-1 (NK(1)) receptor antagonists is described. The evaluation of this class is briefly outlined, leading to the identification of netupitant 21 and befetupitant 29, two new proprietary chemical entities with high affinity and excellent CNS penetration. 相似文献
109.
Crotti A Neri F Corti D Ghezzi S Heltai S Baur A Poli G Santagostino E Vicenzi E 《Journal of virology》2006,80(21):10663-10674
Infection with human immunodeficiency virus (HIV)-encoding defective nef variants may contribute to a relatively benign course of disease in a minority of long-term nonprogressors (LTNP). We have examined the functions of nef alleles from six individuals belonging to the same cohort of hemophiliacs infected with HIV-1 prior to 1985 and classified as LTNP in 1995. Three out of six individuals have progressed to HIV disease (late progressors [LP]), whereas the three remainders have maintained their LTNP status at least up to 2003. The nef alleles were obtained from both plasma virus and peripheral blood mononuclear cells of all six individuals in 1995 and 1998. The proportion of sequences containing mutations not yielding Nef expression significantly diminished in 1998 versus that in 1995. Several previously defined functional regions of intact nef alleles were highly conserved. However, the major variant obtained in 1998 from plasma RNA of five out of six individuals significantly reduced HIV infectivity/replication and impaired Nef-mediated CD4 but not major histocompatibility complex class I antigen down-modulation from the cell surface. Thus, functional alterations of the nef gene are present in both LP and LTNP, suggesting that Nef defectiveness in vitro is not necessarily associated with the long-term maintenance of LTNP status. Of interest is the fact that isolates from three out of three LP showed a dual CCR5/CXCR4 coreceptor use (R5X4), in contrast to those from LTNP, which were exclusively R5. Thus, in vivo evolution of gp120 Env to CXCR4 use appears to be associated with HIV disease progression in individuals infected with nef-defective viruses. 相似文献
110.
Celso Arango Elena Dragioti Marco Solmi Samuele Cortese Katharina Domschke Robin M. Murray Peter B. Jones Rudolf Uher Andre F. Carvalho Abraham Reichenberg Jae II Shin Ole A. Andreassen Christoph U. Correll Paolo FusarPoli 《World psychiatry》2021,20(3):417
Decades of research have revealed numerous risk factors for mental disorders beyond genetics, but their consistency and magnitude remain uncertain. We conducted a “meta‐umbrella” systematic synthesis of umbrella reviews, which are systematic reviews of meta‐analyses of individual studies, by searching international databases from inception to January 1, 2021. We included umbrella reviews on non‐purely genetic risk or protective factors for any ICD/DSM mental disorders, applying an established classification of the credibility of the evidence: class I (convincing), class II (highly suggestive), class III (suggestive), class IV (weak). Sensitivity analyses were conducted on prospective studies to test for temporality (reverse causation), TRANSD criteria were applied to test transdiagnosticity of factors, and A Measurement Tool to Assess Systematic Reviews (AMSTAR) was employed to address the quality of meta‐analyses. Fourteen eligible umbrella reviews were retrieved, summarizing 390 meta‐analyses and 1,180 associations between putative risk or protective factors and mental disorders. We included 176 class I to III evidence associations, relating to 142 risk/protective factors. The most robust risk factors (class I or II, from prospective designs) were 21. For dementia, they included type 2 diabetes mellitus (risk ratio, RR from 1.54 to 2.28), depression (RR from 1.65 to 1.99) and low frequency of social contacts (RR=1.57). For opioid use disorders, the most robust risk factor was tobacco smoking (odds ratio, OR=3.07). For non‐organic psychotic disorders, the most robust risk factors were clinical high risk state for psychosis (OR=9.32), cannabis use (OR=3.90), and childhood adversities (OR=2.80). For depressive disorders, they were widowhood (RR=5.59), sexual dysfunction (OR=2.71), three (OR=1.99) or four‐five (OR=2.06) metabolic factors, childhood physical (OR=1.98) and sexual (OR=2.42) abuse, job strain (OR=1.77), obesity (OR=1.35), and sleep disturbances (RR=1.92). For autism spectrum disorder, the most robust risk factor was maternal overweight pre/during pregnancy (RR=1.28). For attention‐deficit/hyperactivity disorder (ADHD), they were maternal pre‐pregnancy obesity (OR=1.63), maternal smoking during pregnancy (OR=1.60), and maternal overweight pre/during pregnancy (OR=1.28). Only one robust protective factor was detected: high physical activity (hazard ratio, HR=0.62) for Alzheimer’s disease. In all, 32.9% of the associations were of high quality, 48.9% of medium quality, and 18.2% of low quality. Transdiagnostic class I‐III risk/protective factors were mostly involved in the early neurodevelopmental period. The evidence‐based atlas of key risk and protective factors identified in this study represents a benchmark for advancing clinical characterization and research, and for expanding early intervention and preventive strategies for mental disorders. 相似文献