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51.
Jürgen Schnekenburger Ina-Alexandra Weber Daniela Hahn Igor Buchwalow Burkhard Krüger Elke Albrecht Wolfram Domschke Markus M. Lerch 《Cellular and molecular life sciences : CMLS》2009,66(15):2525-2537
The regulated secretion of pancreatic zymogens depends on a functional cytoskeleton and intracellular vesicle transport. To
study the dynamics of tubulin and its motor proteins dynein and kinesin during secretion in pancreatic acinar cells, we infused
rats with 0.1 μg/kg/h caerulein. Electron and fluorescence microscopy detected neither dynein nor kinesin at the apical secretory
pole, nor on the surface of mature zymogen granules. After 30 min of secretagogue stimulation, kinesin and the Golgi marker
protein 58 K were reallocated towards the apical plasma membrane and association of kinesin with tubulin was enhanced. Disruption
of acinar cell microtubules had no effect on initial caerulein-induced amylase release but completely blocked secretion during
a second stimulus. Our results suggest that mature zymogen granule exocytosis is independent of intact microtubules, kinesin
and dynein. However, microtubule-dependent mechanisms seem to be important for the replenishment of secretory vesicles by
redistribution of Golgi elements towards the apical cell pole.
J. Schnekenburger and I.-A. Weber have contributed equally to this work. 相似文献
52.
Daniela Corda Pasquale Zizza Alessia Varone Beatrice Maria Filippi Stefania Mariggiò 《Cellular and molecular life sciences : CMLS》2009,66(21):3449-3467
The glycerophosphoinositols are cellular products of phospholipase A2 and lysolipase activities on the membrane phosphoinositides. Their intracellular concentrations can vary upon oncogenic transformation,
cell differentiation and hormonal stimulation. Specific glycerophosphodiester phosphodiesterases are involved in their catabolism,
which, as with their formation, is under hormonal regulation. With their mechanisms of action including modulation of adenylyl
cyclase, intracellular calcium levels, and Rho-GTPases, the glycerophosphoinositols have diverse effects in multiple cell
types: induction of cell proliferation in thyroid cells; modulation of actin cytoskeleton organisation in fibroblasts; and
reduction of the invasive potential of tumour cell lines. More recent investigations include their effects in inflammatory
and immune responses. Indeed, the glycerophosphoinositols enhance cytokine-dependent chemotaxis in T-lymphocytes induced by
SDF-1α-receptor activation, indicating roles for these compounds as modulators of T-cell signalling and T-cell responses. 相似文献
53.
Ferrari D Zalfa C Nodari LR Gelati M Carlessi L Delia D Vescovi AL De Filippis L 《Cellular and molecular life sciences : CMLS》2012,69(7):1193-1210
Cell therapy is reaching the stage of phase I clinical trials for post-traumatic, post-ischemic, or neurodegenerative disorders,
and the selection of the appropriate cell source is essential. In order to assess the capacity of different human neural stem
cell lines (hNSC) to contribute to neural tissue regeneration and to reduce the local inflammation after an acute injury,
we transplanted GMP-grade non-immortalized hNSCs and v-myc (v-IhNSC), c-myc T58A (T-IhNSC) immortalized cells into the corpus
callosum of adult rats after 5 days from focal demyelination induced by lysophosphatidylcholine. At 15 days from transplantation,
hNSC and T-IhNSC migrated to the lesioned area where they promoted endogenous remyelination and differentiated into mature
oligodendrocytes, while the all three cell lines were able to integrate in the SVZ. Moreover, where demyelination was accompanied
by an inflammatory reaction, a significant reduction of microglial cells’ activation was observed. This effect correlated
with a differential migratory pattern of transplanted hNSC and IhNSC, significantly enhanced in the former, thus suggesting
a specific NSC-mediated immunomodulatory effect on the local inflammation. We provide evidence that, in the subacute phase
of a demyelination injury, different human immortalized and non-immortalized NSC lines, all sharing homing to the stem niche,
display a differential pathotropism, both through cell-autonomous and non-cell autonomous effects. Overall, these findings
promote IhNSC as an inexhaustible cell source for large-scale preclinical studies and non-immortalized GMP grade hNSC lines
as an efficacious, safe, and reliable therapeutic tool for future clinical applications. 相似文献
54.
55.
James P. Garnett Daniela Braun Alex J. McCarthy Matthew R. Farrant Emma H. Baker Jodi A. Lindsay Deborah L. Baines 《Cellular and molecular life sciences : CMLS》2014,71(23):4665-4673
Hyperglycaemia as a result of diabetes mellitus or acute illness is associated with increased susceptibility to respiratory infection with Staphylococcus aureus. Hyperglycaemia increases the concentration of glucose in airway surface liquid (ASL) and promotes the growth of S. aureus in vitro and in vivo. Whether elevation of other sugars in the blood, such as fructose, also results in increased concentrations in ASL is unknown and whether sugars in ASL are directly utilised by S. aureus for growth has not been investigated. We obtained mutant S. aureus JE2 strains with transposon disrupted sugar transport genes. NE768(fruA) exhibited restricted growth in 10 mM fructose. In H441 airway epithelial-bacterial co-culture, elevation of basolateral sugar concentration (5–20 mM) increased the apical growth of JE2. However, sugar-induced growth of NE768(fruA) was significantly less when basolateral fructose rather than glucose was elevated. This is the first experimental evidence to show that S. aureus directly utilises sugars present in the ASL for growth. Interestingly, JE2 growth was promoted less by glucose than fructose. Net transepithelial flux of d-glucose was lower than d-fructose. However, uptake of d-glucose was higher than d-fructose across both apical and basolateral membranes consistent with the presence of GLUT1/10 in the airway epithelium. Therefore, we propose that the preferential uptake of glucose (compared to fructose) limits its accumulation in ASL. Pre-treatment with metformin increased transepithelial resistance and reduced the sugar-dependent growth of S. aureus. Thus, epithelial paracellular permeability and glucose transport mechanisms are vital to maintain low glucose concentration in ASL and limit bacterial nutrient sources as a defence against infection. 相似文献
56.
Delneri D Hoyle DC Gkargkas K Cross EJ Rash B Zeef L Leong HS Davey HM Hayes A Kell DB Griffith GW Oliver SG 《Nature genetics》2008,40(1):113-117
Using competition experiments in continuous cultures grown in different nutrient environments (glucose limited, ammonium limited, phosphate limited and white grape juice), we identified genes that show haploinsufficiency phenotypes (reduced growth rate when hemizygous) or haploproficiency phenotypes (increased growth rate when hemizygous). Haploproficient genes (815, 1,194, 733 and 654 in glucose-limited, ammonium-limited, phosphate-limited and white grape juice environments, respectively) frequently show that phenotype in a specific environmental context. For instance, genes encoding components of the ubiquitination pathway or the proteasome show haploproficiency in nitrogen-limited conditions where protein conservation may be beneficial. Haploinsufficiency is more likely to be observed in all environments, as is the case with genes determining polar growth of the cell. Haploproficient genes seem randomly distributed in the genome, whereas haploinsufficient genes (685, 765, 1,277 and 217 in glucose-limited, ammonium-limited, phosphate-limited and white grape juice environments, respectively) are over-represented on chromosome III. This chromosome determines a yeast's mating type, and the concentration of haploinsufficient genes there may be a mechanism to prevent its loss. 相似文献
57.
58.
Chiara F. Valori Liliana Brambilla Francesca Martorana Daniela Rossi 《Cellular and molecular life sciences : CMLS》2014,71(2):287-297
Despite indisputable progress in the molecular and genetic aspects of amyotrophic lateral sclerosis (ALS), a mechanistic comprehension of the neurodegenerative processes typical of this disorder is still missing and no effective cures to halt the progression of this pathology have yet been developed. Therefore, it seems that a substantial improvement of the outcome of ALS treatments may depend on a better understanding of the molecular mechanisms underlying neuronal pathology and survival as well as on the establishment of novel etiological therapeutic strategies. Noteworthy, a convergence of recent data from multiple studies suggests that, in cellular and animal models of ALS, a complex pathological interplay subsists between motor neurons and their non-neuronal neighbours, particularly glial cells. These observations not only have drawn attention to the physiopathological changes glial cells undergo during ALS progression, but they have moved the focus of the investigations from intrinsic defects and weakening of motor neurons to glia–neuron interactions. In this review, we summarize the growing body of evidence supporting the concept that different glial populations are critically involved in the dreadful chain of events leading to motor neuron sufferance and death in various forms of ALS. The outlined observations strongly suggest that glial cells can be the targets for novel therapeutic interventions in ALS. 相似文献
59.
Polyamines are essential organic polycations with multiple cellular functions relevant for cell division, cancer and ageing. Regulation of polyamine synthesis is mainly achieved by controlling the activity of ornithine decarboxylase (ODC) through an unusual mechanism involving ODC antizyme, the binding of which disrupts homodimeric ODC and targets it for ubiquitin-independent degradation by the 26S proteasome. Whereas mammals express several antizyme genes, we have identified a single orthologue, termed OAZ1, in Saccharomyces cerevisiae. Similar to its mammalian counterparts, OAZ1 synthesis is induced with rising intracellular polyamine concentrations, which also inhibit ubiquitin-dependent degradation of the OAZ1 protein. Together, these mechanisms contribute to a homeostatic feedback regulation of polyamines. Antizyme synthesis involves a conserved +1 ribosomal frameshifting (RFS) event at an internal STOP codon during decoding of its messenger RNA. Here we used S. cerevisiae OAZ1 to dissect the enigmatic mechanism underlying polyamine regulation of RFS. In contrast with previous assumptions, we report here that the nascent antizyme polypeptide is the relevant polyamine sensor that operates in cis to negatively regulate upstream RFS on the polysomes, where its own mRNA is being translated. At low polyamine levels, the emerging antizyme polypeptide inhibits completion of its synthesis causing a ribosome pile-up on antizyme mRNA, whereas polyamine binding to nascent antizyme promotes completion of its synthesis. Thus, our study reveals a novel autoregulatory mechanism, in which binding of a small metabolite to a nascent sensor protein stimulates the latter's synthesis co-translationally. 相似文献
60.