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91.
We have recently reported that the inhibition of endothelial cell COX-2 by non-steroidal anti-inflammatory drugs suppresses alpha(V)beta(3)- (but not alpha(5)beta(1)-) dependent Rac activation, endothelial cell spreading, migration, and angiogenesis (Dormond, O., Foletti, A., Paroz, C., and Ruegg, C. (2001) Nat. Med. 7, 1041-1047). Here we investigated the role of the COX-2 metabolites PGE(2) and TXA2 in regulating human umbilical vein endothelial cell (HUVEC) adhesion and spreading. We report that PGE(2) accelerated alpha(V)beta(3)-mediated HUVEC adhesion and promoted Rac activation and cell spreading, whereas the TXA2 agonist retarded adhesion and inhibited spreading. We show that the cAMP level and the cAMP-regulated protein kinase A (PKA) activity are critical mediators of these PGE(2) effects. alpha(V)beta(3)-mediated adhesion induced a transient COX-2-dependent rise in cAMP levels, whereas the cell-permeable cAMP analogue 8-brcAMP accelerated adhesion, promoted Rac activation, and cell spreading in the presence of the COX-2 inhibitor NS-398. Pharmacological inhibition of PKA completely blocked alpha(V)beta(3)-mediated adhesion. A constitutively active Rac mutant (L61Rac) rescued alpha(V)beta(3)-dependent spreading in the presence of NS398 or, but did not accelerate adhesion, whereas a dominant negative Rac mutant (N17Rac) suppressed spreading without affecting adhesion. alpha(5)beta(1)-mediated HUVEC adhesion, Rac activation, and spreading were not affected by PGE(2), 8-brcAMP, or the inhibition of PKA. In conclusion, these results demonstrate that PGE(2) accelerates alpha(V)beta(3)-mediated endothelial cell adhesion through cAMP-dependent PKA activation and induces alpha(V)beta(3)-dependent spreading via cAMP- and PKA-dependent Rac activation and may contribute to the further understanding of the regulation of vascular integrins alpha(V)beta(3) by COX-2/PGE(2) during tumor angiogenesis and inflammation. 相似文献
92.
Inhibition of lymphoproliferation by a synthetic peptide with sequence identity to gp41 of human immunodeficiency virus type 1. 总被引:12,自引:8,他引:4
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Peptides were synthesized that contained sequences from two regions (env amino acids [aa] 581 to 597 and 655 to 671) of the transmembrane protein gp41 and one region of the external envelope glycoprotein gp120 (aa 457 to 464) of human immunodeficiency virus type 1. Selection of these sequences was based on their homology to the highly conserved and immunosuppressive sequence contained within the transmembrane proteins p15E and gp21 of animal and human retroviruses, respectively. Peptide aa581-597 was found to specifically inhibit human and murine lymphoproliferation, whereas peptides aa655-671 and aa457-464 had no activity. These results suggest a mechanism by which human immunodeficiency virus type 1 gp41 exerts a direct immunosuppressive effect in vivo, analogous to that postulated for p15E and gp21, which could contribute to the immune dysfunction observed in patients suffering from acquired immunodeficiency syndrome. It is of particular interest that the sequence aa 584 to 609, shown to contain B- and T-helper-cell epitopes, overlaps with the sequence aa 581 to 597 that is shown here to inhibit lymphoproliferation. The potential implications of this overlap of immunologic activities are discussed. 相似文献
93.
Baicalein inhibits acinar‐to‐ductal metaplasia of pancreatic acinal cell AR42J via improving the inflammatory microenvironment
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94.
F Negro M Curzio M V Torrielli H Esterbauer M U Dianzani 《Bollettino della Società italiana di biologia sperimentale》1981,57(24):2472-2478
The effect of low concentrations of 4-hydroxy-2-trans-pentenal, 4-hydroxy-2-trans-nonenal and 4-hydroxy-2-trans-tetradecenal (4-hydroxyalkenals produced during lipid peroxidation) was evaluated on the phagocytic activity of polymorphonuclear cells obtained from rat peritoneum. Our results show that the above compounds can influence, at different degrees, the endocytic powers, as measured "in vitro", of leukocytes through an inhibition that appears, to some extent, dose-related. Since lipoperoxidative processes can take place at the inflammed area, aldehydes originating from the peroxidative derangement of fatty acids may play a role in interfering with the cellular reactions at the inflammatory site. 相似文献
95.
96.
Nenad Filipovic Kedar Ghimire Igor Saveljic Zarko Milosevic Curzio Ruegg 《Computer methods in biomechanics and biomedical engineering》2016,19(6):581-590
Vascular endothelial cells are continuously exposed to hemodynamic shear stress. Intensity and type of shear stress are highly relevant to vascular physiology and pathology. Here, we modeled shear stress distribution in a tissue culture well (R = 17.5 mm, fill volume 2 ml) under orbital translation using computational fluid dynamics with the finite element method. Free surface distribution, wall shear stress, inclination angle, drag force, and oscillatory index on the bottom surface were modeled. Obtained results predict nonuniform shear stress distribution during cycle, with higher oscillatory shear index, higher drag force values, higher circular component, and larger inclination angle of the shear stress at the periphery of the well compared with the center of the well. The oscillatory index, inclination angle, and drag force are new quantitative parameters modeled in this system, which provide a better understanding of the hydrodynamic conditions experienced and reflect the pulsatile character of blood flow in vivo. Validation experiments revealed that endothelial cells at the well periphery aligned under flow and increased Kruppel-like Factor 4 (KLF-4), cyclooxygenase-2 (COX-2) expression and endothelial nitric oxide synthase (eNOS) phosphorylation. In contrast, endothelial cells at the center of the well did not show clear directional alignment, did not induce the expression of KLF-4 and COX-2 nor increased eNOS phosphorylation. In conclusion, this improved computational modeling predicts that the orbital shaker model generates different hydrodynamic conditions at the periphery versus the center of the well eliciting divergent endothelial cell responses. The possibility of generating different hydrodynamic conditions in the same well makes this model highly attractive to study responses of distinct regions of the same endothelial monolayer to different types of shear stresses thereby better reflecting in vivo conditions. 相似文献
97.
Agrin is a heparan sulfate proteoglycan that is best known for its crucial involvement in the organization and maintenance
of postsynaptic structures at the neuromuscular junction. Consistent with this role, mice deficient of agrin die at birth
due to respiratory failure. Here we examined the early postnatal development of agrin-deficient mice in which perinatal death
was prevented by transgenic expression of neural agrin in motor neurons. Such transgenic, agrin-deficient mice were born at
Mendelian ratio but exhibited severe postnatal growth retardation. Growth plate morpholgy was markedly altered in these mice,
with changes being most prominent in the hypertrophic zone. Compression of this zone was not caused by reduced viability of
hypertrophic chondrocytes, as no differences in the apoptosis rates could be observed. Furthermore, deposition of the major
cartilage matrix components collagen type II and aggrecan was slightly reduced in these mice. Consistent with a role for agrin
in skeletal development, we show for the first time that agrin is highly expressed by chondrocytes and localizes to the growth
plate in wild-type mice. Our data show that agrin is expressed in cartilage and that it plays a critical role in normal skeletal
growth. 相似文献
98.
The present model of the motoneuronal (MN) pool – muscle complex (MNPMC) is deterministic and designed for steady isometric
muscle activation. Time-dependent quantities are treated as time-averages. The character of the model is continuous in the
sense that the motor unit (MU) population is described by a continuous density function. In contrast to most already published
models, the wiring (synaptic weight) between the input fibers to the MNPMC and the MNs (about which no detailed data are known)
is deduced, whereas the input–force relation is given. As suggested by experimental data, this relation is assumed to be linear
during MU recruitment, but the model allows other, nonlinear relations. The input to the MN pool is defined as the number
of action potentials per second in all input fibers, and the excitatory postsynaptic potential (EPSP) conductance in MNs evoked
by the input is assumed to be proportional to the input. A single compartment model with a homogeneous membrane is used for
a MN. The MNs start firing after passing a constant voltage threshold. The synaptic current–frequency relation is described
by a linear function and the frequency–force transformation of a MU by an exponential function. The sum of the MU contraction
forces is the muscle force, and the activation of the MUs obeys the size principle. The model parameters were determined a
priori, i.e., the model was not used for their estimation. The analysis of the model reveals special features of the activation
curve which we define as the relation between the input normalized by the threshold input of the MN pool and the force normalized
by the maximal muscle force. This curve for any muscle turned out to be completely determined by the activation factor, the
slope of the linear part of the activation curve (during MU recruitment). This factor determines quantitatively the relation
between MU recruitment and rate modulation. This property of the model (the only known model with this property) allows a
quantification of the recruitment gain (Kernell and Hultborn 1990). The interest of the activation factor is illustrated using
two human muscles, namely the first dorsal interosseus muscle, a small muscle with a relatively small force at the end of
recruitment, and the medial gastrocnemius muscle, a strong muscle with a relatively large force at the end of recruitment.
It is concluded that the present model allows us to reproduce the main features of muscle activation in the steady state.
Its analytical character facilitates a deeper understanding of these features.
Received: 24 November 1997 / Accepted in revised form: 30 November 1998 相似文献
99.
A P Li C Lu J A Brent C Pham A Fackett C E Ruegg P M Silber 《Chemico-biological interactions》1999,121(1):17-35
Cryopreserved human hepatocytes were extensively characterized in our laboratory. The post-thaw viability, measured via dye exclusion, ranged from 55 to 83%, for hepatocytes cryopreserved from 17 donors. Post-thaw viability and yield (viable cells per vial) were found to be stable up to the longest storage duration evaluated of 120 days. Drug-metabolizing enzyme activities of the cryopreserved hepatocytes (mean of ten donors) as percentages of the freshly isolated cells were: 97%, for cytochrome P450 isoform (CYP) 1A2, 78% for CYP2A6, 96% for CYP2C9. 86% for CYP2Cl9, 90% for CYP2D6, 164% for CYP3A4, 76% for UDP-glucuronidase, and 88% for umbelliferone sulfotransferase. Known species-differences in 7-ethoxycoumarin (7-EC) metabolism were reproduced by cryopreserved hepatocytes from human, rat, rabbit, dog, and monkey, illustrating the utility of cryopreserved hepatocytes from multiple animal species in the evaluation of species-differences in drug metabolism. Higher throughput screening (HTS) assays were developed using cryopreserved human hepatocytes for hepatotoxicity, metabolic stability, and inhibitory drug-drug interactions. Dose-dependent cytotoxicity, measured using MTT metabolism as an endpoint, was observed for the known hepatotoxic chemicals tamoxifen, clozapine, cadmium chloride, diclofenac, amiodarone, tranylcypromine, precocene II, but not for 2-thiouracil. Cell density- and time-dependent metabolism of 7-EC and dextromethorphan were observed in the HTS assay for metabolic stability. Known CYP isoform-specific inhibitors were evaluated in the HTS assay for inhibitory drug-drug interactions. Furafylline, sulfaphenazole, quinidine, and ketoconazole were found to be specific inhibitors of CYP1A2, CYP2C9, CYP2D6, and CYP3A4, respectively. Tranylcypromine and diethyldithiocarbamate were found to be less specific, with inhibitory effects towards several CYP isoforms, including CYP2A6, CYP2C9, CYP2C19, and CYP2E1. These results suggest that cryopreserved human hepatocytes represent a useful experimental tool for the evaluation of drug metabolism, toxicity, and inhibitory drug-drug interaction potential. 相似文献
100.