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1.
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been shown to reduce the progression of renal disease
independent of cholesterol-lowering effect, but the mechanism of potential protective effect remains unclear. Here, we investigate
the effect of fluvastatin on activation of nuclear factor-κB (NF-κB) induced by angiotensin II (AngII) in rat kidney tubule
epithelial cells (NRK-52E). Electrophoretic mobility shift assays (EMSA) was used to detect NF-κB activation. Phosphorylation
of cellular p38 mitogen-activated protein kinase (p38MAPK) was determined by western blot analysis. AngII stimulated the DNA-binding
activity of NF-κB and phosphorylation of p38MAPK in cultured NRK-52E cells in a dose-dependent (10−9–10−6 mol/l) manner (P < 0.01). AngII (10−6 mol/l) induced a rapid (5 min) increase of the p38MAPK phosphorylation. NF-κB DNA-binding activity was increased at as early
as 30 min, peaked at 2 h after AngII treatment. This stimulatory effect of AngII on NF-κB was blocked by SB203580 (a specific
inhibitor of p38MAPK). Incubation of cells with fluvastatin significantly inhibited the AngII-induced NF-κB activation in
a dose-dependent (10−7–10−5 mol/l) manner (P < 0.05). Exogenous mevalonate (10−4mol/l) prevented the effect of fluvastatin on NF-κB activation. These results suggest the fluvastatin reduced AngII-induced
NF-κB activation via the p38MAPK pathway in NRK-52E cells. The effect is at least partly due to blocking the biosynthesis
of mevalonate. 相似文献
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Marisa Freitas Ana Gomes Graça Porto Eduarda Fernandes 《Journal of biological inorganic chemistry》2010,15(8):1275-1283
Many lines of evidence have suggested that oxidative stress and inflammation play a pivotal role in the toxicity of nickel
salts. Considering that neutrophils are active participants in inflammatory processes, namely by producing high amounts of
reactive oxygen species, the aim of the present study was to evaluate the putative activation of human neutrophils’ oxidative
burst by nickel. Subsequently, the influence of nickel in the pathways leading to NADPH oxidation in neutrophils was evaluated
by measuring protein kinase C (PKC) activation. The effects of nickel on neutrophils’ nuclear factor κB (NF-κB) activation
and on the production of the proinflammatory mediators interleukin (IL)-1β, IL-6, IL-8 and tumour necrosis factor α were also
evaluated. The results obtained showed that nickel, at concentrations that may be attained in vivo, stimulates the production of superoxide radical (O2
·−), hydrogen peroxide (H2O2), and hypochlorous acid (HOCl) in human neutrophils in vitro, via activation of PKC. In addition, nickel was shown to activate
NF-κB and to induce the production of IL-8 in these cells. These observations indicate that the sustained activation of human
neutrophils by nickel may contribute for the long-term adverse effects on human health mediated by this metal. 相似文献
5.
Dendritic cells are the major antigen-presenting and antigen-priming cells of the immune system. We review the antigen-presenting
and proinflammatory roles played by dendritic cells in the initiation of rheumatoid arthritis (RA) and atherosclerosis, which
complicates RA. Various signals that promote the activation of NF-κB and the secretion of TNF and IL-1 drive the maturation
of dendritic cells to prime self-specific responses, and drive the perpetuation of synovial inflammation. These signals may
include genetic factors, infection, cigarette smoking, immunostimulatory DNA and oxidized low-density lipoprotein, with major
involvement of autoantibodies. We propose that the pathogenesis of RA and atherosclerosis is intimately linked, with the vascular
disease of RA driven by similar and simultaneous triggers to NF-κB. 相似文献
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Adenosine serves a number of important physiological roles in the body, which is the most widely studied endogenous signal
molecules, and the underlying mechanism responsible for such cardioprotection needs more understood, particularly adenosine
postconditioning in myocardial ischemia/reperfusion model. In the present study we performed to investigate the inflammatory
response of adenosine postconditioning on the cardiac TNF-α expression and NF-κB activation. Eighteen rats were randomly divided
into 4 groups: (1) Group A: sham operation group; (2) Group B: ischemia/reperfusion group; (3) Group C: postconditioned groups,
four cycles of 30-s reperfusion/30-s occlusion were started immediately after release of the index ischemia (n = 6 each); (4) Group D: adenosine was infused 40 μg kg−1 min−1 5 min before the onset of reperfusion without subsequent postconditioning cycles. Hearts were removed at the termination
of experiments, which were preserved in frozen tube and stored at −70°C refrigerator for Measurement of malonyldialdehyde
(MDA), activities of the NF-κB and TNF-α and IL-10 assay. The results of this study indicate that adenosine postconditioning
immediately after myocardial ischemia can reduce the myocardial tissue MDA generation and infarct size, improve cardiac function,
which is coincidence with conventional postconditioning. The study also found that modulation of NF-κB activation and accordingly
reduces inflammatory factor TNF-α expression may be a molecular mechanism of adenosine down-regulation of inflammatory cytokine
production. 相似文献
8.
Sammy Grimaldo Fang Tian Lu-Yuan Li 《Apoptosis : an international journal on programmed cell death》2009,14(6):788-795
Vascular endothelial growth inhibitor (VEGI) is an endogenous inhibitor of endothelial cell growth and a promising candidate
for cancer therapy. VEGI is able to inhibit tumor growth by specifically targeting the tumor neovasculature. Increasing the
anti-angiogenic potential of this cytokine is of great interest for its therapeutic potential. NF-κB is known to have an integral
role in TNF superfamily signaling, acting as a pro-survival factor. A role of VEGI-induced NF-κB activation in endothelial
cells has yet to be described. Here we show that suppression of the NF-κB pathway can increase the apoptotic potential of
VEGI. We used siRNA to deplete NF-κB or its activator IKK2 from adult bovine aortic endothelial cells. The siRNA treatments
diminished VEGI-induced NF-κB activation, evidenced from a reduced extent of NF-κB nuclear translocation and diminished expression
of NF-κB-target genes such as interleukins-6 and -1β. The siRNA-treated endothelial cells when exposed to VEGI exhibited a marked decrease in cell viability and a significant
increase in apoptosis. These results confirm that VEGI utilizes NF-κB as a pro-survival role factor in endothelial cells.
We then examined whether a combination of VEGI with NF-κB inhibitors would constitute a more potential therapeutic regiment.
We found that in the presence of the NF-κB inhibitors curcumin or BMS-345541 there was a marked increase in the apoptotic
potential of VEGI on endothelial cells. These findings indicate that a combination therapy using VEGI and NF-κB inhibitors
could be a potent approach for cancer treatment. 相似文献
9.
Shu-Yan Li Wen-Ge Sun Yu-Hong Jia Guo-Sheng Wu Guo-Shun An Ju-Hua Ni Hong-Ti Jia 《Biochemistry. Biokhimii?a》2010,75(1):101-110
We demonstrate that activation of nuclear factor κB (NF-κB) in neurons is neuroprotective in response to kainic acid (KA)-induced
excitotoxicity. Combination of Western blotting, immunocytochemistry, and electrophoresis mobility shift assay showed that
KA exposure induced a fast but transient nuclear translocation of the NF-κB p65 subunit and increased DNA-binding activity
of NF-κB in primary cultured cortical neurons. The transient NF-κB activity was associated with upregulation of antiapoptotic
Bcl-xL and XIAP gene products revealed by real-time PCR. Knockdown of p65 decreased neuronal viability and antiapoptotic gene
expression. In addition, we showed that KA-stimulated DNA-binding activity of NF-κB was associated with reactive oxygen species
and calcium signals, using AMPA/KA receptor antagonist, calcium chelator, and antioxidant. These results suggest that the
fast and transient activation of NF-κB initiated by calcium signals is one of the important proximal events in response to
KA-induced excitotoxicity, which has neuroprotective effect against KA-induced apoptosis. 相似文献
10.
Summary Electrical stimulation of efferent thoracic vagus nerve (TVN) evoked neurogenic inflammation in respiratory tract of atropine-treated
rats by an undefined mechanism. We explored whether efferent TVN stimulation via substance P facilitates neurogenic inflammation
via action of nuclear factor-κB (NF-κB) activation and reactive oxygen species (ROS) production. Our results showed that increased
frequency of TVN stimulation concomitantly increased substance P-enhanced hypotension, and bronchoconstriction (increases
in smooth muscle electromyographic activity and total pulmonary resistance). The enhanced SP release evoked the appearance
of endothelial gap in silver-stained leaky venules, India-ink labeled extravasation, and accumulations of inflammatory cells
in the respiratory tract, contributing to trachea plasma extravasation as well as increases in blood O2− and H2O2 ROS amount. L-732138 (NK1 receptor antagonist), SR-48968 (NK2 receptor antagonist), dimethylthiourea (H2O2 scavenger) or catechins (O2− and H2O2 scavenger) pretreatment reduced efferent TVN stimulation-enhanced hypotension, bronchoconstriction, and plasma extravasation.
Increased frequency of TVN stimulation significantly upregulated the expression of nuclear factor-κB (NF-κB) in nuclear protein
and intercellular adhesion molecule-1 (ICAM-1) in total protein of the lower respiratory tract tissue. The upregulation of
NF-κB and ICAM-1 was attenuated by NK receptor antagonist and antioxidants. In conclusion, TVN efferent stimulation increases
substance P release to trigger NF-κB mediated ICAM-1 expression and O2− and H2O2 ROS production in the respiratory tract. 相似文献
11.
Osteopontin (OPN) is a secreted, non-collagenous, sialic-acid rich, glycosylated adhesive phospho- protein. Several highly
metastatic transformed cells synthesized a higher level of OPN compared with non-tumorigenic cells. We have recently reported
that OPN induces nuclear factor-κB (NF-κB)-mediated promatrix metalloproteinase-2 activation through IκBα/IKK signaling pathways.
However, the molecular mechanism(s) by which OPN regulates pro-matrix metalloproteinase-9 (pro-MMP-9) activation and involvement
of upstream kinases in regulation of these processes that ultimately control cell motility and tumor growth in murine melanoma
cells are not well defined. Here we report that OPN induces αvβ3 integrin-mediated phosphorylation and activation of nuclear
factor inducing kinase (NIK) and enhances the interaction between phosphorylated NIK and IκBα kinase α/β (IKKα/β) in B16F10
cells. Moreover, NIK is involved in OPN-induced phosphorylations of MEK-1 and ERK1/2 in these cells. OPN induces NIK-dependent
NF-κB activation through ERK/IKKα/β-mediated pathways. Furthermore, OPN enhances NIK-regulated urokinase-type plasminogen
activator (uPA) secretion, uPA-dependent pro-MMP-9 activation, and cell motility. Pretreatment of cells with anti-MMP-2 antibody
along with anti-MMP-9 antibody drastically inhibited the OPN-induced cell migration and chemoinvasion, whereas cells pretreated
with anti-MMP-2 antibody had no effect on OPN-induced pro-MMP-9 activation suggesting that OPN induces pro-MMP-2 and pro-MMP-9
activations through two distinct pathways. Taken together, NIK acts as crucial regulator in OPN-induced MAPK/IKK-mediated
NF-κB-dependent uPA secretion and MMP-9 activation thereby controlling melanoma cell motility and chemoinvasion.
An erratum to this article is available at . 相似文献
12.
The mechanism of lead (Pb2+)-induced neurotoxicity has not yet been fully elucidated. The purpose of this study was to examine the effects of Pb2+ on several protein kinase C (PKC) isoforms and the nuclear factor-κB (NF-κB)–I-κB kinase-alpha (IKK-α) axis in cultured neuronal
cells. Neurons were isolated from rat fetal brain at the 18th day of gestation of pregnant Sprague Dawley rats and cultured
for 10 days before use. Neurons were exposed to Pb2+ at concentrations of 10−10, 10−9, 10−8, and 10−7 mol/L for 14 h and antigens of typical PKC-α,β,γ; novel PKC (ε, δ), atypical PKC (λ), NF-κB (p50), and IKK-α were enriched
by immunoprecipitation and determined by western blotting. Total, calcium-dependent and independent PKC activities were also
determined by counting the transferred γ-32 P in the substrate-histone. The results indicated that inorganic Pb2+ significantly reduced all PKC isoforms (α,β,γ, ε, λ) except δ, inhibiting the total, calcium-dependent and calcium-independent
PKC activities in a dose-dependent manner. Additionally, Pb2+ gradually reduced NF-κB (p50) and IKK-α protein levels. This suggests that Pb2+ exhibits varying preference for individual PKC isoforms but reduces the NF-κB–IKK-α axis to a similar extent. 相似文献
13.
Hypoxia of skin is an important physiopathological process in many diseases, such as pressure ulcer, diabetic ulcer, and varicose
ulcer. Although cellular injury and inflammation have been involved in hypoxia-induced dermatic injury, the underlying mechanisms
remain largely unknown. This study was conducted to investigate the effects of cobalt chloride (CoCl2), a hypoxia-mimicking agent, on human skin keratinocytes (HaCaT cells) and to explore the possible molecular mechanisms.
Exposure of HaCaT cells to CoCl2 reduced cell viability and caused overproduction of reactive oxygen species (ROS) and oversecretion of interleukin-6 (IL-6)
and interleukin-8 (IL-8). Importantly, CoCl2 exposure elicited overexpression of cyclooxygenase-2 (COX-2) and phosphorylation of nuclear factor-kappa B (NF-κB) p65 subunit.
Inhibition of COX-2 by NS-398, a selective inhibitor of COX-2, significantly repressed the cytotoxicity, as well as secretion
of IL-6 and IL-8 induced by CoCl2. Inhibition of NF-κB by PDTC (a selective inhibitor of NF-κB) or genetic silencing of p65 by RNAi (Si-p65), attenuated not
only the cytotoxicity and secretion of IL-6 and IL-8, but also overexpression of COX-2 in CoCl2-treated HaCaT cells. Neutralizing anti-IL-6 or anti-IL-8 antibody statistically alleviated CoCl2-induced cytotoxicity in HaCaT cells. N-acetyl-L-cysteine (NAC), a well characterized ROS scavenger, obviously suppressed
CoCl2-induced cytotoxicity in HaCaT cells, as well as secretion of IL-6 and IL-8. Additionally, NAC also repressed overexpression
of COX-2 and phosphorylation of NF- B κ p65 subunit induced by CoCl2 in HaCaT cells. In conclusion, our results demonstrated that oxidative stress mediates chemical hypoxia-induced injury and
inflammatory response through activation of NF-κB-COX-2 pathway in HaCaT cells. 相似文献
14.
Lu H Shi JX Zhang DM Shen J Lin YX Hang CH Yin HX 《Cellular and molecular neurobiology》2009,29(1):87-95
In order to determine the possible effects of hemolysate on brain microvascular endothelial cells (BMECs), we examined the
effects of hemolysate on the expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1
(MCP-1), generation of reactive oxygen species (ROS), and NF-κB activation in rat BMECs. Hemolysate induced the expression
of ICAM-1 and MCP-1 in endothelial cells. In addition, hemolysate stimulated nuclear translocation of the p65 subunit of NF-κB,
and NF-κB DNA-binding activity in BMECs. Furthermore, hemolysate increased ROS generation, and hemolysate-induced ICAM-1and
MCP-1 expression and NF-κB activation were abrogated in the presence of the direct scavenger of ROS. Taken together, our results
indicate that hemolysate can induce inflammatory responses that increase expression of ICAM-1 and MCP-1, through ROS-dependent
NF-κB activation in BMECs. 相似文献
15.
Asmaa Sina Sébastien Proulx-Bonneau Alain Roy Laurent Poliquin Jian Cao Borhane Annabi 《Journal of cell communication and signaling》2010,4(1):31-38
The lectin from Canavalia ensiformis (Concanavalin-A, ConA), one of the most abundant lectins known, enables one to mimic biological lectin/carbohydrate interactions
that regulate extracellular matrix protein recognition. As such, ConA is known to induce membrane type-1 matrix metalloproteinase
(MT1-MMP) which expression is increased in brain cancer. Given that MT1-MMP correlated to high expression of cyclooxygenase
(COX)-2 in gliomas with increasing histological grade, we specifically assessed the early proinflammatory cellular signaling
processes triggered by ConA in the regulation of COX-2. We found that treatment with ConA or direct overexpression of a recombinant
MT1-MMP resulted in the induction of COX-2 expression. This increase in COX-2 was correlated with a concomitant decrease in
phosphorylated AKT suggestive of cell death induction, and was independent of MT1-MMP’s catalytic function. ConA- and MT1-MMP-mediated
intracellular signaling of COX-2 was also confirmed in wild-type and in Nuclear Factor-kappaB (NF-κB) p65−/− mutant mouse embryonic fibroblasts (MEF), but was abrogated in NF-κB1 (p50)−/− and in I kappaB kinase (IKK) γ−/− mutant MEF cells. Collectively, our results highlight an IKK/NF-κB-dependent pathway linking MT1-MMP-mediated intracellular
signaling to the induction of COX-2. That signaling pathway could account for the inflammatory balance responsible for the
therapy resistance phenotype of glioblastoma cells, and prompts for the design of new therapeutic strategies that target cell
surface carbohydrate structures and MT1-MMP-mediated signaling. Concise summary Concanavalin-A (ConA) mimics biological lectin/carbohydrate interactions that regulate the proinflammatory phenotype of cancer
cells through yet undefined signaling. Here we highlight an IKK/NF-κB-dependent pathway linking MT1-MMP-mediated intracellular
signaling to the induction of cyclooxygenase-2, and that could be responsible for the therapy resistance phenotype of glioblastoma
cells. 相似文献
16.
Xiao-Yan Dong Kiichiro Teruya Yoshinori Katakura Yingpei Zhang Takumi Miura Yoshihito Daimon Tetsuya Mori Hideya Ohashi Sanetaka Shirahata 《Cytotechnology》2003,43(1-3):11-17
We previously developed a promoter-activated production (PAP) system using amplified ras oncogene to activate the cytomegalovirus (CMV) promoter controlling the foreign gene in mammalian cells. CHO cells were demonstrated to be suitable for the PAP system. Here, we show that very high-level production of a recombinant protein was achieved when the human CMV promoter was inserted into a glutamine synthetase (GS) minigene expression plasmid, pEE14. A highly productive host CHO cell line, ras clone I containing amplified ras oncogene, was further transfected with the plasmid expressing both hIL-6 gene and GS minigene, and selected with methionine sulphoximine. We were able to establish a hIL-6 hyper-producing cell line, D29, which exhibited a peak productivity rate of approximately 40 μg hIL-6 10?6 cells day?1 through a combination of the PAP system and the GS gene amplification system. The cellular productivity of D29 cells was about 13-fold higher than control hIL-6-producing cells derived from CHO cells whose hIL-6 gene was amplified by the GS gene amplification system, and about 5-fold higher than the I13 cells established by the PAP system, which contains amplified ras oncogene and non-amplified hIL-6 gene. When D29 cells were cultured for a month, an accumulation rate of approximately 80 μg hIL-6 ml?1 per 3 days was achieved on the 9th day. These results indicate that this PAP and GS hybrid system enables the efficient and rapid establishment of recombinant protein hyper-producing cell lines. 相似文献
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Sun CS Wu KT Lee HH Uen YH Tian YF Tzeng CC Wang AH Cheng CJ Tsai SL 《Journal of biomedical science》2008,15(5):633-643
The link of proto-oncogenic protein Wnt-1 production with NF-κB activation has been functionally demonstrated in PC12 cells, a rat pheochromocytoma cell line of neural
crest lineage, while it is not yet verified in human cells. The link can be indirectly supported in our previous report that
functional proteomics identifies enhanced expression of NF-κB-associated Wnt-1 production in human hepatocellular carcinoma tissues. This study aimed to further validate this link in human cells using
anti-sense strategy. The effects of sequence-specific anti-sense morpholino oligonucleotides (ONs) targeting against pre-mRNA
sequences of human p50 and p65 subunits of NF-κB as well as Wnt-1 genes were investigated. It revealed that all the three morpholino ONs inhibited NF-κB activation in human hepatoblastoma
cell line HepG2 cells along with decreased Wnt-1 production. Chromatin immunoprecipitation assay ascertained the direct binding of NF-κB-p50 to the Wnt-1 promoter. Additionally, anti-P50 and anti-P65 morpholino ONs also repressed the phosphorylation of Iκ Bα which temporarily
correlated with the inhibition of NF-κB activation accompanied by decreased Wnt-1 production by HepG2 cells. In summary, NF-κB activation is critically involved in the production of Wnt-1 by HepG2 cells. These results may have important oncology implications in treating patients with NF-κB-associated Wnt-1-producing cancers.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
19.
Kanokporn Noy Rithidech Paiboon Reungpatthanaphong Louise Honikel Adam Rusek Sanford R. Simon 《Radiation and environmental biophysics》2010,49(3):405-419
The objective of this study was to determine the kinetics of nuclear factor-kappa B (NF-κB) activation and cytokine expression
in bone marrow (BM) cells of exposed mice as a function of the dose rate of protons. The cytokines included in this study
are pro-inflammatory [i.e., tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and IL-6] and anti-inflammatory
cytokines (i.e., IL-4 and IL-10). We gave male BALB/cJ mice a whole-body exposure to 0 (sham-controls) or 1.0 Gy of 100 MeV
protons, delivered at 5 or 10 mGy min−1, the dose and dose rates found during solar particle events in space. As a reference radiation, groups of mice were exposed
to 0 (sham-controls) or 1 Gy of 137Cs γ rays (10 mGy min−1). After irradiation, BM cells were collected at 1.5, 3, 24 h, and 1 month for analyses (five mice per treatment group per
harvest time). The results indicated that the in vivo time course of effects induced by a single dose of 1 Gy of 100 MeV protons
or 137Cs γ rays, delivered at 10 mGy min−1, was similar. Although statistically significant levels of NF-κB activation and pro-inflammatory cytokines in BM cells of
exposed mice when compared to those in the corresponding sham controls (Student’s t-test, p < 0.05 or <0.01) were induced by either dose rate, these levels varied over time for each protein. Further, only a dose rate
of 5 mGy min−1 induced significant levels of anti-inflammatory cytokines. The results indicate dose-rate effects of protons. 相似文献