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1.
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
2.
It has been reported that pretreatment of rats with lipopolysaccharide (LPS) increases myocardial functional recovery in ischemia/reperfusion
(I/R) hearts. However, the mechanisms by which LPS induces cardioprotection against I/R injury have not been fully elucidated.
In this study, we pretreated rats with LPS (1.0 mg/kg) 24 h before they were subjected to I/R injury, and then examined the
roles of heat shock protein-70 (HSP70) and nucleus factor-κB (NF-κB) in LPS-induced cardioprotection. We observed that pretreatment
with low-dose LPS resulted in significantly increased levels of HSP70 in the myocardium, which could dramatically inhibit
NF-κB translocation and reduce degradation of inhibitory κB. Inhibition of NF-κB, in turn, attenuated release of inflammatory
cytokines (tumor necrosis factor-α, interleukin (IL)-1β, and IL-6) and reduced apoptosis of myocardium and infarct area following
I/R injury. Moreover, HSP70 could ameliorate oxidative stress following I/R injury. To further investigate whether increase
of HSP70 might be responsible for protection of the myocardium against I/R injury, we co-administered the HSP70 inhibitor,
quercetin, with LPS before I/R injury. We found that LPS-induced cardioprotection was attenuated by co-administration with
quercetin. Herein, we concluded that increased levels of HSP70 through LPS pretreatment led to inhibition of NF-κB activity
in the myocardium after I/R injury. Our results indicated that LPS-induced cardioprotection was mediated partly through inhibition
of NF-κB via increase of HSP70, and LPS pretreatment could provide a means of reducing myocardial I/R injury. 相似文献
3.
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
4.
Summary Hydroxyhydroquinone or 1,2,4-benzenetriol (BT) detected in the beverages has a structure that coincides with the water-soluble
form of a sesame lignan, sesamol. We previously showed that sesame antioxidants had neuroprotective abilities due to their
antioxidant properties and/or inducible nitric oxide synthase (iNOS) inhibition. However, studies show that BT can induce
DNA damage through the generation of reactive oxygen species (ROS). Therefore, we were interested to investigate the neuroprotective
effect of BT in vitro and in vivo. The results showed that instead of enhancing free radical generation, BT dose-dependently (10–100 μM) attenuated nitrite
production, iNOS mRNA and protein expression in lipopolysaccharide (LPS)-stimulated murine BV-2 microglia. BT significantly
reduced LPS-induced NF-κB and p38 MAPK activation. It also significantly reduced the generation of ROS in H2O2-induced BV-2 cells and in H2O2-cellfree conditions. The neuroprotective effect of BT was further demonstrated in the focal cerebral ischemia model of Sprague–Dawley
rat. Taken together, the inhibition of LPS-induced nitrite production might be due to the suppression of NF-κB, p38 MAPK signal
pathway and the ROS scavenging effect. These effects might help to protect neurons from the ischemic injury. 相似文献
5.
Neuroprotective Effects of (-)-Epigallocatechin-3-gallate in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis 总被引:3,自引:0,他引:3
The purpose of this study is to evaluate neuroprotective effects of (-)-Epigallocatechin-3-gallate (EGCG) in a transgenic mouse model of Amyotrophic lateral sclerosis (ALS). SOD1-G93A transgenic mice and wild-type mice were randomly divided into EGCG-treated groups (10 mg/kg, p.o) and vehicle-treated control groups. Rotarod measurement was performed to assess the motor function of mice starting at the age of 70 days. Nissl staining to examine the number of motor neurons and CD11b immunohistochemical staining to evaluate activation of microglia in the lumbar spinal cords were conducted at the age of 120 days. In addition, for further observation of regulation of cell signaling pathways by EGCG, we used immunohistochemical analysis for nuclear factor kappa B (NF-κB) and cleaved caspase-3 as well as western blot analysis to determine the expression of nitric oxide synthase (iNOS) and NF-κB in the spinal cord. This study demonstrated that oral administration of EGCG beginning from a pre-symptomatic stage significantly delayed the onset of disease, and extended life span. Furthermore, EGCG-treated transgenic mice showed increased number of motor neurons, diminished microglial activation, reduced immunohistochemical reaction of NF-κB and cleaved caspase-3 as well as reduced protein level of iNOS and NF-κB in the spinal cords. In conclusion, this study provides further evidences that EGCG has multifunctional therapeutic effects in the mouse model of ALS. 相似文献
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Salsolinol, an endogenous neurotoxin, is known to be involved in the pathogenesis of Parkinson’s disease (PD). In the present
study, we have investigated the effects of salsolinol on the activation of two different signaling pathways that involve c-Jun
N-terminal kinase (JNK), and nuclear factor-κB, (NF-κB) in human dopaminergic neuroblastoma SH-SY5Y cells. Salsolinol treatment
caused upregulation in the levels of c-Jun and phosphorylated c-Jun. It also caused degradation of IκBα and translocated the
active NF-κB into the nucleus. The binding activity of NF-κB to DNA was enhanced by salsolinol in a concentration dependent
manner. Furthermore, salsolinol decreased the levels of the anti-apoptotic protein Bcl-2, and increased pro-apoptotic protein
Bax, while enhancing the release of cytochrome-c from mitochondria. Mitochondrial complex-I activity was significantly decreased and reactive oxygen species (ROS) were increased
in salsolinol treated cells. These results partly suggest that salsolinol-induced JNK and NF-κB signaling pathways may be
involved in induction of apoptosis in human dopaminergic neurons, as seen in Parkinson’s disease. 相似文献
11.
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
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13.
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
14.
Nakaizumi A Horie T Kida T Kurimoto T Sugiyama T Ikeda T Oku H 《Cellular and molecular neurobiology》2012,32(1):95-106
Modulation of enzyme activity through nitrosylation has recently been identified as a new physiological activity of nitric
oxide (NO). We hypothesized that NO enhances the TNF-α-induced death of retinal neurons through a suppression of nuclear factor-κB
(NF-κB) by nitrosylation. In this study, cells from the RGC-5 line were exposed to different concentrations (2.0, 10, and
50 ng/ml) of TNF-α, and the degree of TNF-α-induced cell death was determined by the WST-8 assay and by flow cytometric measurements
of the externalization of phosphatidylserine. The effects of etanercept, a soluble TNFR-Fc fusion protein, and S-nitroso-N-penicillamine (SNAP), an NO donor, on the toxicity were determined. Experiments were also performed to determine whether
nitric oxide synthase (NOS) was associated with the toxicity of TNF-α. The activation of NF-κB was determined by the detection
of the p65 subunit in the nuclear extracts. Our results showed that exposure of RGC-5 cells to different concentrations of
TNF-α significantly decreased the number of living cells in a dose-dependent way. The death was partially due to apoptosis
with an externalization of phosphatidylserine, and the death was suppressed by etanercept. Exposure to TNF-α increased the
activation of NF-κB and the expression of iNOS. Although NF-κB inhibitors suppressed the increase of iNOS, they also potentiated
the TNF-α-induced death. Both L-NAME and aminoguanidine, both NOS inhibitors, rescued the cells from death. In contrast, addition
of SNAP caused nitrosylation of the inhibitory κB kinase, and suppressed the NF-κB activation and potentiated the TNF-α-induced
neurotoxicity. These results indicate that NO potentiates the neurotoxicity of TNF-α by suppressing NF-κB. 相似文献
15.
Jun Hu Chun Xia Luo Wei Hua Chu You An Shan Zhong-Ming Qian Gang Zhu Yan Bing Yu Hua Feng 《PloS one》2012,7(12)
Oxidative stress plays an important role in the pathological processes of ischemic brain damage. Many antioxidants have been shown to protect against cerebral ischemia injury by inhibiting oxidative stress both in vitro and in vivo. 20-Hydroxyecdysone (20E), an ecdysteroid hormone, exhibits antioxidative effects. For the work described in this paper, we used an in vitro oxidative damage model and an in vivo ischemic model of middle cerebral artery occlusion (MCAO) to investigate the neuroprotective effects of 20E and the mechanisms related to these effects. Treatment of cells with H2O2 led to neuronal injury, intracellular ROS/RNS generation, mitochondrial membrane potential dissipation, cellular antioxidant potential descent, an increase in malondialdehyde (MDA) and an elevation of intracellular [Ca2+], all of which were markedly attenuated by 20E. Inhibition of the activation of the ASK1-MKK4/7-JNK stress signaling pathway and cleaved caspase-3 induced by oxidative stress were involved in the neuroprotection afforded by 20E. In addition, 20E reduced the expression of iNOS protein by inhibition of NF-κB activation. The neuroprotective effect of 20E was also confirmed in vivo. 20E significantly decreased infarct volume and the neurological deficit score, restored antioxidant potential and inhibited the increase in MDA and TUNEL-positive and cleaved caspase-3-positive cells in the cerebral cortex in MCAO rats. Together, these results support that 20E protects against cerebral ischemia injury by inhibiting ROS/RNS production and modulating oxidative stress-induced signal transduction pathways. 相似文献
16.
The present study attempts to investigate the effects of S-propargyl-cysteine (SPRC), a sulfur-containing amino acid, on lipopolysaccharide (LPS)-induced inflammatory response in H9c2
cardiac myocytes. We found that SPRC prevented nuclear factor-κB (NF-κB) activation assessed by NF-κB p65 phosphorylation
and IκBα degradation, suppressed LPS-induced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and intracellular
reactive oxygen species (ROS) production. Furthermore, incubation of H9c2 cells with SPRC induced phosphorylation of Akt in
a time- and concentration-dependent manner. In addition, SPRC attenuated LPS-induced mRNA and protein expression of tumor
necrosis factor-α (TNF-α), and mRNA expression of intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase
(iNOS). The effects of SPRC were abolished by cystathionine γ-lyase [CSE-an enzyme that synthesizes hydrogen sulfide (H2S)] inhibitor, dl-propargylglycine (PAG), SPRC-induced Akt phosphorylation and TNF-α release was also abolished by the phosphoinositide 3-kinase
(PI3K) inhibitor LY294002. Furthermore, SPRC also increased LPS-induced down-regulation expression of CSE and H2S level in H9c2 cells. PAG abolished SPRC-induced up-regulation of H2S level. Therefore, we concluded that SPRC produced an anti-inflammatory effect in LPS-stimulated H9c2 cells partly through
the CSE/H2S pathway by impairing IκBα/NF-κB signaling and by activating PI3K/Akt signaling pathway. 相似文献
17.
Jin Ming Di Jun Pang Qi Peng Sun Yan Zhang You Qiang Fang Xiao Pen Liu Jian Hua Zhou Xing Xing Ruan Xin Gao 《Molecular biology reports》2010,37(4):1849-1855
CpG-oligonucleotides (CpG-ODNs), mimicking bacterial DNA, have recently been shown to stimulate prostate cancer invasion in
vitro via Toll-like receptor 9 (TLR9). Since cyclooxygenase 2 (COX-2), frequently overexpressed in multiple tumor types including
prostate cancer, is a causal factor for tumor development, invasion and metastasis, an interesting question is raised whether
TLR9 regulates COX-2 expression in prostate cancer cells. To address this question, herein we examined COX-2 expression in
PC-3 cells stimulated with different doses and time courses of CpG-ODNs. The regulatory role of NF-κB in TLR9-mediated COX-2
expression was also investigated. CpG-ODN was found to up-regulate the expression of COX-2 in PC-3 cells in a dose- and time-dependent
manner, but have little impact on COX-1 expression. Moreover, CpG-ODN also promoted nuclear translocation and activation of
NF-κB, which appeared to be required for COX-2 induction by CpG-ODN. Overall, TLR9 up-regulates COX-2 expression in prostate
cancer cells, at least partially through the activation of NF-κB, which may be implicated in tumor invasion and metastasis. 相似文献
18.
Adriamycin is one of the most effective and useful antineoplastic agents. Acute doxorubicin cardiotoxicity involved cardiomyocyte
apoptosis. In this study, we investigated whether adriamycin induced myocardium apoptosis through activation of nuclear factor
κB in rat. Forty male Wistar rats were randomly divided into five groups: control, ADR 5 mg/kg, ADR 10 mg/kg, ADR 15 mg/kg
group and ADR + PDTC 200 mg/ml group. Myocardial apoptosis was detected by DNA fragmentation assay and TUNEL assay; Location
and distribution of p-IκBα was observed by immunohistochemical assay; Myocardial expression of p-IκBα protein was assessed
by Western blot analysis; Activity of NF-κB was evaluated by Electrophoretic Mobility Shift Assay. The myocardial apoptotic
index, expression of p-IκBα, and binding activity of NF-κB increased significantly in ADR groups in dose-dependent manner.
PDTC as a nonspecific inhibitor of NF-κB protected myocardium from apoptosis by inhibiting NF-κB activation. Adriamycin induces
myocardium apoptosis through activation of nuclear factor κB in rat and NF-κB activation requires IκBα degradation. 相似文献
19.