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91.
Siltanen A Kitabayashi K Lakkisto P Mäkelä J Pätilä T Ono M Tikkanen I Sawa Y Kankuri E Harjula A 《PloS one》2011,6(4):e19161
After severe myocardial infarction (MI), heart failure results from ischemia, fibrosis, and remodeling. A promising therapy to enhance cardiac function and induce therapeutic angiogenesis via a paracrine mechanism in MI is myoblast sheet transplantation. We hypothesized that in a rat model of MI-induced chronic heart failure, this therapy could be further improved by overexpression of the antiapoptotic, antifibrotic, and proangiogenic hepatocyte growth factor (HGF) in the myoblast sheets. We studied the ability of wild type (L6-WT) and human HGF-expressing (L6-HGF) L6 myoblast sheet-derived paracrine factors to stimulate cardiomyocyte, endothelial cell, or smooth muscle cell migration in culture. Further, we studied the autocrine effect of hHGF-expression on myoblast gene expression profiles by use of microarray analysis. We induced MI in Wistar rats by left anterior descending coronary artery (LAD) ligation and allowed heart failure to develop for 4 weeks. Thereafter, we administered L6-WT (n = 15) or L6-HGF (n = 16) myoblast sheet therapy. Control rats (n = 13) underwent LAD ligation and rethoracotomy without therapy, and five rats underwent a sham operation in both surgeries. We evaluated cardiac function with echocardiography at 2 and 4 weeks after therapy, and analyzed cardiac angiogenesis and left ventricular architecture from histological sections at 4 weeks. Paracrine mediators from L6-HGF myoblast sheets effectively induced migration of cardiac endothelial and smooth muscle cells but not cardiomyocytes. Microarray data revealed that hHGF-expression modulated myoblast gene expression. In vivo, L6-HGF sheet therapy effectively stimulated angiogenesis in the infarcted and non-infarcted areas. Both L6-WT and L6-HGF therapies enhanced cardiac function and inhibited remodeling in a similar fashion. In conclusion, L6-HGF therapy effectively induced angiogenesis in the chronically failing heart. Cardiac function, however, was not further enhanced by hHGF expression. 相似文献
92.
Understanding how amyloid-β peptide interacts with living cells on a molecular level is critical to development of targeted treatments for Alzheimer's disease. Evidence that oligomeric Aβ interacts with neuronal cell membranes has been provided, but the mechanism by which membrane binding occurs and the exact stoichiometry of the neurotoxic aggregates remain elusive. Physiologically relevant experimentation is hindered by the high Aβ concentrations required for most biochemical analyses, the metastable nature of Aβ aggregates, and the complex variety of Aβ species present under physiological conditions. Here we use single molecule microscopy to overcome these challenges, presenting direct optical evidence that small Aβ(1-40) oligomers bind to living neuroblastoma cells at physiological Aβ concentrations. Single particle fluorescence intensity measurements indicate that cell-bound Aβ species range in size from monomers to hexamers and greater, with the majority of bound oligomers falling in the dimer-to-tetramer range. Furthermore, while low-molecular weight oligomeric species do form in solution, the membrane-bound oligomer size distribution is shifted towards larger aggregates, indicating either that bound Aβ oligomers can rapidly increase in size or that these oligomers cluster at specific sites on the membrane. Calcium indicator studies demonstrate that small oligomer binding at physiological concentrations induces only mild, sporadic calcium leakage. These findings support the hypothesis that small oligomers are the primary Aβ species that interact with neurons at physiological concentrations. 相似文献
93.
Menju T Hashimoto S Hashimoto A Otsuka Y Handa H Ogawa E Toda Y Wada H Date H Sabe H 《PloS one》2011,6(9):e25301
Overexpression of Her2/ErbB2/Neu in cancer is often correlated with recurrent distant metastasis, although the mechanism still remains largely elusive. We have previously shown that EGFR, when tyrosine-phosphorylated, binds to GEP100/BRAG2 to activate Arf6, which induces cancer invasion and metastasis. We now show that overexpressed Her2 in lung adenocarcinoma cells also employs GEP100. Like EGFR-GEP100 binding, this association is primarily mediated by the pleckstrin homology (PH) domain of GEP100 and Tyr1139/Tyr1196 of Her2. Tyr1139/Tyr1196 are autonomously phosphorylated, when Her2 is overexpressed. Accordingly, invasive activities mediated by the Her2-GEP100 pathway are not dependent on external factors. Blocking Her2-GEP100 binding, as well as its signaling pathway all inhibit cancer invasive activities. Moreover, our clinical study indicates that co-overexpression of Her2 with GEP100 in primary lung adenocarcinomas of patients is correlated with the presence of their node-metastasis with a statistical significance. Since the GEP100 PH domain interacts with both Her2 and EGFR, targeting this domain may provide novel cancer therapeutics. 相似文献
94.
Johan?PahlbergEmail author Magnus?Lindstr?m Petri?Ala-Laurila Nanna?Fyhrquist-Vanni Ari?Koskelainen Kristian?Donner 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》2005,191(9):837-844
We report the first study of the relation between the wavelength of maximum absorbance (λmax) and the photoactivation energy (E
a) in invertebrate visual pigments. Two populations of the opossum shrimp Mysis relicta were compared. The two have been separated for 9,000 years and have adapted to different spectral environments (“Sea” and
“Lake”) with porphyropsins peaking at λmax=529 nm and 554 nm, respectively. The estimation of E
a was based on measurement of temperature effects on the spectral sensitivity of the eye. In accordance with theory (Stiles
in Transactions of the optical convention of the worshipful company of spectacle makers. Spectacle Makers’ Co., London, 1948), relative sensitivity to long wavelengths increased with rising temperature. The estimates calculated from this effect are
E
a,529=47.8±1.8 kcal/mol and E
a,554=41.5±0.7 kcal/mol (different at P<0.01). Thus the red-shift of λmax in the “Lake” population, correlating with the long-wavelength dominated light environment, is achieved by changes in the
opsin that decrease the energy gap between the ground state and the first excited state of the chromophore. We propose that
this will carry a cost in terms of increased thermal noise, and that evolutionary adaptation of the visual pigment to the
light environment is directed towards maximizing the signal-to-noise ratio rather than the quantum catch. 相似文献
95.
UDP-glucose:glycoprotein glucosyltransferase (GT) is a key component of the glycoprotein-specific folding and quality control system in the endoplasmic reticulum. By exclusively reglucosylating incompletely folded and assembled glycoproteins, it serves as a folding sensor that prolongs the association of newly synthesized glycoproteins with the chaperone-like lectins calnexin and calreticulin. Here, we address the mechanism by which GT recognizes and labels its substrates. Using an improved inhibitor assay based on soluble conformers of pancreatic ribonuclease in its glycosylated (RNase B) and unglycosylated (RNase A) forms, we found that the protein moiety of a misfolded conformer alone is sufficient for specific recognition by GT in vitro. To investigate the relationship between recognition and glucosylation, we tested a variety of glycosylation mutants of RNase S-Protein and an RNase mutant with a local folding defect [RNase C65S, C72S], as well as a series of loop insertion mutants. The results indicated that local folding defects in an otherwise correctly folded domain could be recognized by GT. Only glycans attached to the polypeptide within the misfolded sites were glucosylated. 相似文献
96.
We investigated infant response toward novel food in captive chimpanzees under the condition in which they can explore such items freely together with their mother. Infants first approached novel foods rather than familiar ones when presented simultaneously. However, they did not ingest novel food immediately, but always sniff-licked it first. Infants tended to pay attention to their mothers before mouthing or ingesting novel foods themselves, but never did so with familiar ones. In response to the infant's activity, mother chimpanzees were tolerant rather than actively interfering. Those results imply that chimpanzee infants respond to novel foods in a neophobic way and refer to their mother for some kind of cue before attempting to ingest them. 相似文献
97.
Nascent and newly synthesized glycoproteins enter the calnexin (Cnx)/calreticulin (Crt) cycle when two out of three glucoses in the core N-linked glycans have been trimmed sequentially by endoplasmic reticulum (ER) glucosidases I (GI) and II (GII). By analyzing arrested glycopeptides in microsomes, we found that GI removed the outermost glucose immediately after glycan addition. However, although GII associated with singly glycosylated nascent chains, trimming of the second glucose only occurred efficiently when a second glycan was present in the chain. Consistent with a requirement for multiple glycans to activate GII, pancreatic RNase in live cells needed more than one glycan to enter the Cnx/Crt cycle. Thus, whereas GI trimming occurs as an automatic extension of glycosylation, trimming by GII is a regulated process. By adjusting the number and location of glycans, glycoproteins can instruct the cell to engage them in an individually determined folding and quality control pathway. 相似文献
98.
By law in the evolutionary jungle, any host defense mechanism that efficiently kills microbes also exerts a strong selective pressure for tolerant variants to emerge. As a consequence, pathogens can be exploited as powerful tools to examine host defense mechanisms. Recent studies of the confrontation between macrophages and the opportunistic pathogen Legionella pneumophila have revealed a regulatory mechanism that may link autophagy to pyroptosis, a type of programmed cell death. Building from the extensive literature on autophagy, cell death, and innate immunity, we propose here a testable model in which the NOD-LRR protein Naip5 dictates whether murine macrophages elevate autophagy or pyroptosis as a barrier to infection. 相似文献
99.
Clathrin- and caveolin-1-independent endocytosis: entry of simian virus 40 into cells devoid of caveolae
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Damm EM Pelkmans L Kartenbeck J Mezzacasa A Kurzchalia T Helenius A 《The Journal of cell biology》2005,168(3):477-488
Simian Virus 40 (SV40) has been shown to enter host cells by caveolar endocytosis followed by transport via caveosomes to the endoplasmic reticulum (ER). Using a caveolin-1 (cav-1)-deficient cell line (human hepatoma 7) and embryonic fibroblasts from a cav-1 knockout mouse, we found that in the absence of caveolae, but also in wild-type embryonic fibroblasts, the virus exploits an alternative, cav-1-independent pathway. Internalization was rapid (t1/2 = 20 min) and cholesterol and tyrosine kinase dependent but independent of clathrin, dynamin II, and ARF6. The viruses were internalized in small, tight-fitting vesicles and transported to membrane-bounded, pH-neutral organelles similar to caveosomes but devoid of cav-1 and -2. The viruses were next transferred by microtubule-dependent vesicular transport to the ER, a step that was required for infectivity. Our results revealed the existence of a virus-activated endocytic pathway from the plasma membrane to the ER that involves neither clathrin nor caveolae and that can be activated also in the presence of cav-1. 相似文献
100.
Proteomic profiling of bone marrow mesenchymal stem cells upon transforming growth factor beta1 stimulation 总被引:6,自引:0,他引:6
Wang D Park JS Chu JS Krakowski A Luo K Chen DJ Li S 《The Journal of biological chemistry》2004,279(42):43725-43734
Bone marrow mesenchymal stem cells (MSCs) can differentiate into different types of cells and have tremendous potential for cell therapy and tissue engineering. Transforming growth factor beta1 (TGF-beta) plays an important role in cell differentiation and vascular remodeling. We showed that TGF-beta induced cell morphology change and an increase in actin fibers in MSCs. To determine the global effects of TGF-beta on MSCs, we employed a proteomic strategy to analyze the effect of TGF-beta on the human MSC proteome. By using two-dimensional gel electrophoresis and electrospray ionization coupled to quadrupole/time-of-flight tandem mass spectrometers, we have generated a proteome reference map of MSCs, and we identified approximately 30 proteins with an increase or decrease in expression or phosphorylation in response to TGF-beta. The proteins regulated by TGF-beta included cytoskeletal proteins, matrix synthesis proteins, membrane proteins, metabolic enzymes, etc. TGF-beta increased the expression of smooth muscle alpha-actin and decreased the expression of gelsolin. Overexpression of gelsolin inhibited TGF-beta-induced assembly of smooth muscle alpha-actin; on the other hand, knocking down gelsolin expression enhanced the assembly of alpha-actin and actin filaments without significantly affecting alpha-actin expression. These results suggest that TGF-beta coordinates the increase of alpha-actin and the decrease of gelsolin to promote MSC differentiation. This study demonstrates that proteomic tools are valuable in studying stem cell differentiation and elucidating the underlying molecular mechanisms. 相似文献