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51.
Marika Cordaro Irene Paterniti Rosalba Siracusa Daniela Impellizzeri Emanuela Esposito Salvatore Cuzzocrea 《Molecular neurobiology》2017,54(4):2415-2427
Autophagy is an intracellular catabolic mechanism for the degradation of cytoplasmic constituents in the autophagosomal–lysosomal pathway. This mechanism plays an important role in homeostasis and it is defective in certain diseases. Preceding studies have revealed that autophagy is developing as an important moderator of pathological responses associated to spinal cord injury (SCI) and plays a crucial role in secondary injury initiating a progressive degeneration of the spinal cord. Thus, based on this evidence in this study, we used two different selective inhibitors of mTOR activity to explore the functional role of autophagy in an in vivo model of SCI as well as to determine whether the autophagic process is involved in spinal cord tissue damage. We treated animals with a novel synthetic inhibitor temsirolimus and with a dual mTORC1 and mTORC2 inhibitor KU0063794 matched all with the well-known inhibitor of mTOR the rapamycin. Our results demonstrated that mTOR inhibitors could regulate the neuroinflammation associated to SCI and the results that we obtained evidently demonstrated that rapamycin and temsirolimus significantly diminished the expression of iNOS, COX2, GFAP, and re-established nNOS levels, but the administration of KU0063794 is able to blunt the neuroinflammation better than rapamycin and temsirolimus. In addition, neuronal loss and cell mortality in the spinal cord after injury were considerably reduced in the KU0063794-treated mice. Accordingly, taken together our results denote that the administration of KU0063794 produced a neuroprotective function at the lesion site following SCI, representing a novel therapeutic approach after SCI. 相似文献
52.
Soares RP Cardoso TL Barron T Araújo MS Pimenta PF Turco SJ 《International journal for parasitology》2005,35(3):245-253
During metacyclogenesis of Leishmania in its sand fly vector, the parasite differentiates from a noninfective, procyclic form to an infective, metacyclic form, a process characterised by morphological changes of the parasite and also biochemical transformations in its major surface lipophosphoglycan (LPG). This lipid-anchored polysaccharide is polymorphic among species with variations in sugars that branch off the conserved Gal(beta1,4)Man(alpha1)-PO4 backbone of repeat units and the oligosaccharide cap. Lipophosphoglycan has been implicated as an adhesion molecule that mediates the interaction with the midgut epithelium of the sand fly in the subgenus Leishmania. This paper describes the LPG structure for the first time in a species from the subgenus Viannia, Leishmania (Viannia) braziliensis. The LPG from the procyclic form of L. braziliensis was found to lack side chain sugar substitutions. In contrast to other species from the subgenus Leishmania, metacyclic forms of L. braziliensis makes less LPG and add 1-2 (beta1-3) glucose residues that branch off the disaccharide-phosphate repeat units of LPG. Thus, this represents a novel mechanism in the regulation of LPG structure during metacyclogenesis. 相似文献
53.
In this study, we have examined the role of two cAMP downstream effectors protein kinase A (PKA) and Epac, in forskolin-induced macrophage proliferation. Treatment of macrophages with forskolin enhanced [(3)H]thymidine uptake and increased cell number, and both were profoundly reduced by prior treatment of cells with H-89, a specific PKA inhibitor. Incubation of macrophages with forskolin triggered the activation of Akt, predominantly by phosphorylation of Ser-473, as measured by Western blotting and assay of its kinase activity. Akt activation was significantly inhibited by LY294002 and wortmannin, specific inhibitors of phosphatidylinositol 3-kinase, but not by H-89. Incubation of macrophages with forskolin also increased Epac1 and Rap1.GTP. Immunoprecipitation of Epac1 in forskolin-stimulated cells co-immunoprecipitated Rap1, p-Akt(Thr-308), and p-Akt(Ser-473). Silencing of CREB gene expression by RNA interference prior to forskolin treatment not only decreased CREB protein and its phosphorylation at Ser-133, but also phosphorylation of Akt at Ser-473, and Thr-308. Concomitantly, this treatment inhibited [(3)H]thymidine uptake and reduced forskolin-induced proliferation of macrophages. Forskolin treatment also inhibited activation of the apoptotic mechanism while promoting up-regulation of the anti-apoptotic pathway. We conclude that forskolin mediates cellular proliferation via cAMP-dependent activation of both PKA and Epac. 相似文献
54.
Recombinant Mitochondrial Manganese Containing Superoxide Dismutase Protects Against Ochratoxin A‐Induced Nephrotoxicity 下载免费PDF全文
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Hay DC Pernagallo S Diaz-Mochon JJ Medine CN Greenhough S Hannoun Z Schrader J Black JR Fletcher J Dalgetty D Thompson AI Newsome PN Forbes SJ Ross JA Bradley M Iredale JP 《Stem cell research》2011,6(2):92-102
Maintaining stable differentiated somatic cell function in culture is essential to a range of biological endeavors. However, current technologies, employing, for example, primary hepatic cell culture (essential to the development of a bio-artificial liver and improved drug and toxicology testing), are limited by supply, expense, and functional instability even on biological cell culture substrata. As such, novel biologically active substrates manufacturable to GMP standards have the potential to improve cell culture-based assay applications. Currently hepatic endoderm (HE) generated from pluripotent stem cells is a genotypically diverse, cheap, and stable source of "hepatocytes"; however, HE routine applications are limited due to phenotypic instability in culture. Therefore a manufacturable subcellular matrix capable of supporting long-term differentiated cell function would represent a step forward in developing scalable and phenotypically stable hESC-derived hepatocytes. Adopting an unbiased approach we screened polymer microarrays and identified a polyurethane matrix which promoted HE viability, hepatocellular gene expression, drug-inducible metabolism, and function. Moreover, the polyurethane supported, when coated on a clinically approved bio-artificial liver matrix, long-term hepatocyte function and growth. In conclusion, our data suggest that an unbiased screening approach can identify cell culture substrate(s) that enhance the phenotypic stability of primary and stem cell-derived cell resources. 相似文献
57.
Di Paola R Caporarello N Marucci A Dimatteo C Iadicicco C Del Guerra S Prudente S Sudano D Miele C Parrino C Piro S Beguinot F Marchetti P Trischitta V Frittitta L 《PloS one》2011,6(5):e19462
The aim of this study was to deeper investigate the mechanisms through which ENPP1, a negative modulator of insulin receptor (IR) activation, plays a role on insulin signaling, insulin secretion and eventually glucose metabolism. ENPP1 cDNA (carrying either K121 or Q121 variant) was transfected in HepG2 liver-, L6 skeletal muscle- and INS1E beta-cells. Insulin-induced IR-autophosphorylation (HepG2, L6, INS1E), Akt-Ser(473), ERK1/2-Thr(202)/Tyr(204) and GSK3-beta Ser(9) phosphorylation (HepG2, L6), PEPCK mRNA levels (HepG2) and 2-deoxy-D-glucose uptake (L6) was studied. GLUT 4 mRNA (L6), insulin secretion and caspase-3 activation (INS1E) were also investigated. Insulin-induced IR-autophosphorylation was decreased in HepG2-K, L6-K, INS1E-K (20%, 52% and 11% reduction vs. untransfected cells) and twice as much in HepG2-Q, L6-Q, INS1E-Q (44%, 92% and 30%). Similar data were obtained with Akt-Ser(473), ERK1/2-Thr(202)/Tyr(204) and GSK3-beta Ser(9) in HepG2 and L6. Insulin-induced reduction of PEPCK mRNA was progressively lower in untransfected, HepG2-K and HepG2-Q cells (65%, 54%, 23%). Insulin-induced glucose uptake in untransfected L6 (60% increase over basal), was totally abolished in L6-K and L6-Q cells. GLUT 4 mRNA was slightly reduced in L6-K and twice as much in L6-Q (13% and 25% reduction vs. untransfected cells). Glucose-induced insulin secretion was 60% reduced in INS1E-K and almost abolished in INS1E-Q. Serum deficiency activated caspase-3 by two, three and four folds in untransfected INS1E, INS1E-K and INS1E-Q. Glyburide-induced insulin secretion was reduced by 50% in isolated human islets from homozygous QQ donors as compared to those from KK and KQ individuals. Our data clearly indicate that ENPP1, especially when the Q121 variant is operating, affects insulin signaling and glucose metabolism in skeletal muscle- and liver-cells and both function and survival of insulin secreting beta-cells, thus representing a strong pathogenic factor predisposing to insulin resistance, defective insulin secretion and glucose metabolism abnormalities. 相似文献
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59.
Amy M. Van Cise Robin W. Baird Charles Scott Baker Salvatore Cerchio Diane Claridge Russell Fielding Brittany Hancock‐Hanser Jacobo Marrero Karen K. Martien Antonio A. Mignucci‐Giannoni Erin M. Oleson Marc Oremus M. Michael Poole Patricia E. Rosel Barbara L. Taylor Phillip A. Morin 《Molecular ecology》2019,28(11):2886-2902
Genomic phylogeography plays an important role in describing evolutionary processes and their geographic, ecological, or cultural drivers. These drivers are often poorly understood in marine environments, which have fewer obvious barriers to mixing than terrestrial environments. Taxonomic uncertainty of some taxa (e.g., cetaceans), due to the difficulty in obtaining morphological data, can hamper our understanding of these processes. One such taxon, the short‐finned pilot whale, is recognized as a single global species but includes at least two distinct morphological forms described from stranding and drive hunting in Japan, the “Naisa” and “Shiho” forms. Using samples (n = 735) collected throughout their global range, we examine phylogeographic patterns of divergence by comparing mitogenomes and nuclear SNP loci. Our results suggest three types within the species: an Atlantic Ocean type, a western/central Pacific and Indian Ocean (Naisa) type, and an eastern Pacific Ocean and northern Japan (Shiho) type. mtDNA control region differentiation indicates these three types form two subspecies, separated by the East Pacific Barrier: Shiho short‐finned pilot whale, in the eastern Pacific Ocean and northern Japan, and Naisa short‐finned pilot whale, throughout the remainder of the species' distribution. Our data further indicate two diverging populations within the Naisa subspecies, in the Atlantic Ocean and western/central Pacific and Indian Oceans, separated by the Benguela Barrier off South Africa. This study reveals a process of divergence and speciation within a globally‐distributed, mobile marine predator, and indicates the importance of the East Pacific Barrier to this evolutionary process. 相似文献
60.
E Villa R Vukotic C Cammà S Petta A Di Leo S Gitto E Turola A Karampatou L Losi V Bernabucci A Cenci S Tagliavini E Baraldi N De Maria R Gelmini E Bertolini M Rendina A Francavilla 《PloS one》2012,7(9):e44624