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排序方式: 共有404条查询结果,搜索用时 742 毫秒
171.
172.
Lee J Reddy R Barsky L Scholes J Chen H Shi W Driscoll B 《American journal of physiology. Lung cellular and molecular physiology》2009,296(1):L57-L70
Shortened telomeres are a normal consequence of cell division. However, telomere shortening past a critical point results in cellular senescence and death. To determine the effect of telomere shortening on lung, four generations of B6.Cg-Terc(tm1Rdp) mice, null for the terc component of telomerase, the holoenzyme that maintains telomeres, were bred and analyzed. Generational inbreeding of terc-/- mice caused sequential shortening of telomeres. Lung histology from the generation with the shortest telomeres (terc-/- F4) showed alveolar wall thinning and increased alveolar size. Morphometric analysis confirmed a significant increase in mean linear intercept (MLI). terc-/- F4 lung showed normal elastin deposition but had significantly decreased collagen content. Both airway and alveolar epithelial type 1 cells (AEC1) appeared normal by immunohistochemistry, and the percentage of alveolar epithelial type 2 cells (AEC2) per total cell number was similar to wild type. However, because of a decrease in distal lung cellularity, the absolute number of AEC2 in terc-/- F4 lung was significantly reduced. In contrast to wild type, terc-/- F4 distal lung epithelium from normoxia-maintained mice exhibited DNA damage by terminal deoxynucleotidyltransferase (TdT)-mediated dUTP nick end labeling (TUNEL) and 8-oxoguanine immunohistochemistry. Western blotting of freshly isolated AEC2 lysates for stress signaling kinases confirmed that the stress-activated protein kinase (SAPK)/c-Jun NH(2)-terminal kinase (JNK) stress response pathway is stimulated in telomerase-null AEC2 even under normoxic conditions. Expression of downstream apoptotic/stress markers, including caspase-3, caspase-6, Bax, and HSP-25, was also observed in telomerase-null, but not wild-type, AEC2. TUNEL analysis of freshly isolated normoxic AEC2 showed that DNA strand breaks, essentially absent in wild-type cells, increased with each successive terc-/- generation and correlated strongly with telomere length (R(2) = 0.9631). Thus lung alveolar integrity, particularly in the distal epithelial compartment, depends on proper telomere maintenance. 相似文献
173.
Byles V Chmilewski LK Wang J Zhu L Forman LW Faller DV Dai Y 《International journal of biological sciences》2010,6(6):599-612
SIRT1, an NAD-dependent histone/protein deacetylase, has classically been thought of as a nuclear protein. In this study, we demonstrate that SIRT1 is mainly localized in the nucleus of normal cells, but is predominantly localized in the cytoplasm of the cancer / transformed cells we tested. We found this predominant cytoplasmic localization of SIRT1 is regulated by elevated mitotic activity and PI3K/IGF-1R signaling in cancer cells. We show that aberrant cytoplasmic localization of SIRT1 is due to increased protein stability and is regulated by PI3K/IGF-1R signaling. In addition, we determined that SIRT1 is required for PI3K-mediated cancer cell growth. Our study represents the first identification that aberrant cytoplasm localization is one of the specific alternations to SIRT1 that occur in cancer cells, and PI3K/IGF-1R signaling plays an important role in the regulation of cytoplasmic SIRT1 stability. Our findings suggest that the over-expressed cytoplasmic SIRT1 in cancer cells may greatly contribute to its cancer-specific function by working downstream of the PI3K/IGF-1R signaling pathway. 相似文献
174.
Jacobs M Hayakawa K Swenson L Bellon S Fleming M Taslimi P Doran J 《The Journal of biological chemistry》2006,281(1):260-268
ROCK or Rho-associated kinase, a serine/threonine kinase, is an effector of Rho-dependent signaling and is involved in actin-cytoskeleton assembly and cell motility and contraction. The ROCK protein consists of several domains: an N-terminal region, a kinase catalytic domain, a coiled-coil domain containing a RhoA binding site, and a pleckstrin homology domain. The C-terminal region of ROCK binds to and inhibits the kinase catalytic domains, and this inhibition is reversed by binding RhoA, a small GTPase. Here we present the structure of the N-terminal region and the kinase domain. In our structure, two N-terminal regions interact to form a dimerization domain linking two kinase domains together. This spatial arrangement presents the kinase active sites and regulatory sequences on a common face affording the possibility of both kinases simultaneously interacting with a dimeric inhibitory domain or with a dimeric substrate. The kinase domain adopts a catalytically competent conformation; however, no phosphorylation of active site residues is observed in the structure. We also determined the structures of ROCK bound to four different ATP-competitive small molecule inhibitors (Y-27632, fasudil, hydroxyfasudil, and H-1152P). Each of these compounds binds with reduced affinity to cAMP-dependent kinase (PKA), a highly homologous kinase. Subtle differences exist between the ROCK- and PKA-bound conformations of the inhibitors that suggest that interactions with a single amino acid of the active site (Ala215 in ROCK and Thr183 in PKA) determine the relative selectivity of these compounds. Hydroxyfasudil, a metabolite of fasudil, may be selective for ROCK over PKA through a reversed binding orientation. 相似文献
175.
Heisler LK Jobst EE Sutton GM Zhou L Borok E Thornton-Jones Z Liu HY Zigman JM Balthasar N Kishi T Lee CE Aschkenasi CJ Zhang CY Yu J Boss O Mountjoy KG Clifton PG Lowell BB Friedman JM Horvath T Butler AA Elmquist JK Cowley MA 《Neuron》2006,51(2):239-249
The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT1BRs), modulates the endogenous release of both agonists and antagonists of the melanocortin receptors, which are a core component of the central circuitry controlling body weight homeostasis. We also show that serotonin-induced hypophagia requires downstream activation of melanocortin 4, but not melanocortin 3, receptors. These results identify a primary mechanism underlying the serotonergic regulation of energy balance and provide an example of a centrally derived signal that reciprocally regulates melanocortin receptor agonists and antagonists in a similar manner to peripheral adiposity signals. 相似文献
176.
Kim DC Hsu FI Barrett NA Friend DS Grenningloh R Ho IC Al-Garawi A Lora JM Lam BK Austen KF Kanaoka Y 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(7):4440-4448
The Th2 cell-dependent inflammatory response is a central component of asthma, and the ways in which it is regulated is a critical question. The cysteinyl leukotrienes (cys-LTs) are 5-lipoxygenase pathway products implicated in asthma, in particular, by their function as smooth muscle constrictors of airways and microvasculature. To elucidate additional roles for cys-LTs in the pathobiology of pulmonary inflammation, we used an OVA sensitization and challenge protocol with mice lacking leukotriene C(4) synthase (LTC(4)S), the terminal enzyme for cys-LT generation. Ag-induced pulmonary inflammation, characterized by eosinophil infiltration, goblet cell hyperplasia with mucus hypersecretion, and accumulation and activation of intraepithelial mast cells was markedly reduced in LTC(4)S(null) mice. Furthermore, Ag-specific IgE and IgG1 in serum, Th2 cell cytokine mRNA expression in the lung, and airway hyperresponsiveness to methacholine were significantly reduced in LTC(4)S(null) mice compared with wild-type controls. Finally, the number of parabronchial lymph node cells from sensitized LTC(4)S(null) mice and their capacity to generate Th2 cell cytokines ex vivo after restimulation with Ag were also significantly reduced. In contrast, delayed-type cutaneous hypersensitivity, a prototypic Th1 cell-dependent response, was intact in LTC(4)S(null) mice. These findings provide direct evidence of a role for cys-LTs in regulating the initiation and/or amplification of Th2 cell-dependent pulmonary inflammation. 相似文献
177.
Ma B Liu W Homer RJ Lee PJ Coyle AJ Lora JM Lee CG Elias JA 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(8):4968-4978
IL-13 is a major effector at sites of Th2 inflammation and tissue remodeling. In these locations, it frequently coexists with the CCR5 chemokine receptor and its ligands MIP-1alpha/CCL3 and MIP-1beta/CCL4. We hypothesized that CCR5 induction and activation play important roles in the pathogenesis of IL-13-induced tissue responses. To test this hypothesis, we evaluated the effects of IL-13 on the expression of CCR5 in the murine lung. We also compared the effects of lung-targeted transgenic IL-13 in mice treated with anti-CCR5 or an Ab control and mice with wild-type or null CCR5 loci. These studies demonstrate that IL-13 is a potent stimulator of epithelial cell CCR5 expression. They also demonstrate that CCR5 neutralization or a deficiency of CCR5 significantly decreases IL-13-induced inflammation, alveolar remodeling, structural and inflammatory cell apoptosis, and respiratory failure and death. Lastly, these studies provide mechanistic insights by demonstrating that CCR5 is required for optimal IL-13 stimulation of select chemokines (MIP-1alpha/CCL3, MIP-1beta/CCL4, MCP-1/CCL-2), matrix metalloproteinase-9 and cell death regulators (Fas, TNF, TNFR1, TNFR2, Bid), optimal IL-13 inhibition of alpha1-antitrypsin, and IL-13-induction of and activation of caspases-3, -8, and-9. Collectively, these studies demonstrate that CCR5 plays a critical role in the pathogenesis of IL-13-induced inflammation and tissue remodeling. 相似文献
178.
Sohini Mukherjee Carrie L. Partch Rebecca E. Lehotzky Cecilia V. Whitham Hiutung Chu Charles L. Bevins Kevin H. Gardner Lora V. Hooper 《The Journal of biological chemistry》2009,284(8):4881-4888
Members of the RegIII family of intestinal C-type lectins are directly
antibacterial proteins that play a vital role in maintaining host-bacterial
homeostasis in the mammalian gut, yet little is known about the mechanisms
that regulate their biological activity. Here we show that the antibacterial
activities of mouse RegIIIγ and its human ortholog, HIP/PAP, are tightly
controlled by an inhibitory N-terminal prosegment that is removed by trypsin
in vivo. NMR spectroscopy revealed a high degree of conformational
flexibility in the HIP/PAP inhibitory prosegment, and mutation of either
acidic prosegment residues or basic core protein residues disrupted prosegment
inhibitory activity. NMR analyses of pro-HIP/PAP variants revealed distinctive
colinear backbone amide chemical shift changes that correlated with
antibacterial activity, suggesting that prosegment-HIP/PAP interactions are
linked to a two-state conformational switch between biologically active and
inactive protein states. These findings reveal a novel regulatory mechanism
governing C-type lectin biological function and yield new insight into the
control of intestinal innate immunity.The gastrointestinal tracts of mammals are heavily colonized with vast
symbiotic microbial communities and are also a major portal of entry for
bacterial pathogens. To cope with these complex microbial challenges,
intestinal epithelial cells produce a diverse repertoire of protein
antibiotics from multiple distinct protein families
(1). These proteins are
secreted apically into the luminal environment of the intestine where they
play a pivotal role in protecting against enteric infections
(2,
3) and may also function to
limit opportunistic invasion by symbiotic bacteria
(4).We previously identified lectins as a novel class of secreted antibacterial
proteins in the mammalian intestine. RegIIIγ is a member of the RegIII
subgroup of the C-type lectin family and is expressed in the small intestine
in response to microbial cues
(5), stored in epithelial cell
secretory granules, and released into the small intestinal lumen
(5). Similarly, HIP/PAP
(hepatointestinal pancreatic/pancreatitis-associated protein; the human
ortholog of
RegIIIγ)6 is
expressed in the human intestine
(6) and is up-regulated in
patients with inflammatory bowel disease
(7). These proteins are
produced in multiple epithelial lineages, including enterocytes and Paneth
cells (5,
6). Both RegIIIγ and
HIP/PAP are directly bactericidal at low micromolar concentrations for
Gram-positive bacteria (5),
revealing a previously unappreciated biological function for mammalian
lectins. The antibacterial functions of RegIIIγ and HIP/PAP are
dependent upon binding bacterial targets through interactions with
peptidoglycan (5). As
peptidoglycan is localized on surfaces of Gram-positive bacteria but is buried
in the periplasmic space of Gram-negative bacteria, this binding activity
provides a molecular explanation for the Gram-positive specific bactericidal
effects of these lectins. Although the mechanism of lectin-mediated
antibacterial activity remains unclear, RegIIIγ and HIP/PAP have been
shown to elicit extensive damage to the cell surfaces of targeted bacteria
(5).In this study, we show that C-type lectin bactericidal activity is under
stringent post-translational control. RegIIIγ and HIP/PAP each undergo
in vivo proteolytic removal of a flexible anionic N-terminal
prosegment that maintains the proteins in a biologically inactive state. NMR
spectroscopy suggests that the prosegment functions by controlling a two-state
conformational switch between the biologically active and inactive states of
the protein. We propose that this regulatory mechanism allows the host to
restrict expression of RegIII lectin antibacterial activity to the intestinal
lumen. Together, our findings represent a unique example of post-translational
control of C-type lectin biological activity, and provide novel insight into
the regulation of lectin-mediated innate immunity in the mammalian
intestine. 相似文献
179.
Hałas A Orzechowska A Derrien V Chumakov AI Sebban P Fiedor J Lipińska M Zając M Slęzak T Strzałka K Matlak K Korecki J Fiedor L Burda K 《Biochimica et biophysica acta》2012,1817(12):2095-2102
We investigate the dynamical properties of the non-heme iron (NHFe) in His-tagged photosynthetic bacterial reaction centers (RCs) isolated from Rhodobacter (Rb.) sphaeroides. M?ssbauer spectroscopy and nuclear inelastic scattering of synchrotron radiation (NIS) were applied to monitor the arrangement and flexibility of the NHFe binding site. In His-tagged RCs, NHFe was stabilized only in a high spin ferrous state. Its hyperfine parameters (IS=1.06±0.01mm/s and QS=2.12±0.01mm/s), and Debye temperature (θ(D0)~167K) are comparable to those detected for the high spin state of NHFe in non-His-tagged RCs. For the first time, pure vibrational modes characteristic of NHFe in a high spin ferrous state are revealed. The vibrational density of states (DOS) shows some maxima between 22 and 33meV, 33 and 42meV, and 53 and 60meV and a very sharp one at 44.5meV. In addition, we observe a large contribution of vibrational modes at low energies. This iron atom is directly connected to the protein matrix via all its ligands, and it is therefore extremely sensitive to the collective motions of the RC protein core. A comparison of the DOS spectra of His-tagged and non-His-tagged RCs from Rb. sphaeroides shows that in the latter case the spectrum was overlapped by the vibrations of the heme iron of residual cytochrome c(2), and a low spin state of NHFe in addition to its high spin one. This enabled us to pin-point vibrations characteristic for the low spin state of NHFe. 相似文献
180.
Zheng W Watts LT Holstein DM Prajapati SI Keller C Grass EH Walter CA Lechleiter JD 《PloS one》2010,5(12):e14401
Treatments to improve the neurological outcome of edema and cerebral ischemic stroke are severely limited. Here, we present the first in vivo single cell images of cortical mouse astrocytes documenting the impact of single vessel photothrombosis on cytotoxic edema and cerebral infarcts. The volume of astrocytes expressing green fluorescent protein (GFP) increased by over 600% within 3 hours of ischemia. The subsequent growth of cerebral infarcts was easily followed as the loss of GFP fluorescence as astrocytes lysed. Cytotoxic edema and the magnitude of ischemic lesions were significantly reduced by treatment with the purinergic ligand 2-methylthioladenosine 5' diphosphate (2-MeSADP), an agonist with high specificity for the purinergic receptor type 1 isoform (P2Y(1)R). At 24 hours, cytotoxic edema in astrocytes was still apparent at the penumbra and preceded the cell lysis that defined the infarct. Delayed 2MeSADP treatment, 24 hours after the initial thrombosis, also significantly reduced cytotoxic edema and the continued growth of the brain infarction. Pharmacological and genetic evidence are presented indicating that 2MeSADP protection is mediated by enhanced astrocyte mitochondrial metabolism via increased inositol trisphosphate (IP(3))-dependent Ca(2+) release. We suggest that mitochondria play a critical role in astrocyte energy metabolism in the penumbra of ischemic lesions, where low ATP levels are widely accepted to be responsible for cytotoxic edema. Enhancement of this energy source could have similar protective benefits for a wide range of brain injuries. 相似文献