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1.
Jun Yang Xiao-Dong Zhang Jian Yang Jia-Wang Ding Zhao-Qi Liu Shu-Guo Li Rui Yang 《Molecular biology reports》2011,38(5):3037-3044
To determine whether the cardioprotection effect of fluvastatin mediates by toll-like receptor 4 (TLR4) signaling pathway,
fifty Sprague–Dawley rats were randomly divided into five groups: sham operation group, ischemia/reperfusion (I/R) group,
fluvastatin groups (high-dosage, medium-dosage, low-dosage, n = 10 in each group). Except sham operation group, the rest four groups of rats were artificially afflicted with coronary
occlusion for 30 min, then reperfusion 2 h. Light microscope and transmission electronic microscope were used to observe structural
changes of myocardium. RT–PCR was used to measure TLR4 mRNA expression level, TLR4 protein expression was detected by immunohistochemistry.
Western blot was used to measure myocardial NF-κB protein level; ELISA was used to measure the level of TNF-α in myocardium.
The results demonstrated that fluvastatin treatment markedly decreased ischemic injury caused by ischemia/reperfusion, and
inhibited the expression levels of TLR4, TNF-α and NF-κB, all of which up-regulated by ischemia/reperfusion. Taken together,
our results suggest that proper dosage of fluvastatin may have protective effect on the ischemic injury mediated by ischemia/reperfusion
in the hearts, which might be associated with inhibition of TLR4 signaling pathway and inflammatory response during ischemia/reperfusion. 相似文献
2.
Both TLR4 and TLR2 participated in the mediation of the inflammatory injury in the process of partial cerebral ischemia/reperfusion.
However, it still remains unclear whether a crosstalk exists between TLR2 and TLR4 in ischemic cerebral damage. In the present
study, we investigated the effect of TLR4 signaling on TLR2 expression during mimic cerebral I/R in vitro. BV-2 cells were cultured and treated with ischemia/reperfusion, then transfected with the plasmid pEGFP-H1/TLR4-siRNA, the
plasmid pEGFP-H1/control sequence-siRNA and the blank plasmid, respectively. Interestingly, the expression of TLR2 and TLR4
mRNA and protein, NF-κB p65 mRNA and supernatant TNF-α level were significantly higher in ischemia/reperfusion treated cells
than those lack of ischemia/reperfusion treatment, and as compared with those in ischemia/reperfusion treated cells without
transfection, no significant differences about the above mentioned gene and protein expression were found in the blank plasmid
tranfected cells and the plasmid pEGFP-H1/control sequence-siRNA transfected cells respectively, while the expression levels
in the plasmid pEGFP-H1/TLR4-siRNA transfected cells were significantly lower. Additionally, in order to determine the effects
of pyrrolidinediethyldithiocarbamate (PDTC), an NF-κB inhibitor, on the TLR4-induced TLR2 expression in BV-2 cells treated
with ischemia/reperfusion, it was found that TLR4 and TLR2 mRNA expressions in PDTC pretreated cells were significantly lower
in comparison with normal saline pretreated cells and non-pretreated cells. The data suggested that TLR2 activation, signaled
by TLR4 and regulated by NF-κB, might be directly involved play an important role in ischemia/reperfusion induced brain damage. 相似文献
3.
4.
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
5.
Yoo KY Yoo DY Hwang IK Park JH Lee CH Choi JH Kwon SH Her S Lee YL Won MH 《Neurochemical research》2011,36(12):2417-2426
Innate immune system is very important to modulate the host defense against a large variety of pathogens. Toll-like receptors
(TLRs) play a key role in controlling innate immune response. Among TLRs, TLR4 is a specific receptor for lipopolysaccharide
and associated with the release of pro-inflammatory cytokines. In the present study, we investigated ischemia-related changes
of TLR4 immunoreactivity and its protein level, and nuclear factor κB (NF-κB) p65 immunoreactivity regarding inflammatory
responses in the hippocampal CA1 region after 5 min of transient cerebral ischemia to identify the correlation between transient
ischemia and inflammation. In the sham-operated group, TLR4 immunoreactivity was easily detected in pyramidal neurons of the
hippocampal CA1 region (CA1). TLR4 immunoreactivity in pyramidal neurons was distinctively decreased after ischemia/reperfusion
(I/R); instead, based on double immunofluorescence study, TLR4 immunoreactivity was expressed in non-pyramidal neurons and
astrocytes from 2 days postischemia. In addition, TLR4 protein level was lowest at 1 day postischemia and highest 4 days after
I/R. On the other hand, NF-κB p65 immunoreactivity was not detected in the CA1 of the sham-operated group, and NF-κB p65 immunoreactivity
was not observed until 1 day after I/R. However, NF-κB p65 immunoreactivity began to be expressed in astrocytes at 2 days
postischemia, and the immunoreactivity was strong 4 days postischemia. Our results indicate that TLR4 and NF-κB p65 immunoreactivity
are changed in CA1 pyramidal neurons and newly expressed in astrocytes, not in microglia, in the CA1 region after transient
cerebral ischemia. 相似文献
6.
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
7.
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
8.
9.
Gypenoside XLIX isolated from Gynostemma pentaphyllum inhibits nuclear factor-kappaB activation via a PPAR-alpha-dependent pathway 总被引:2,自引:0,他引:2
Huang TH Li Y Razmovski-Naumovski V Tran VH Li GQ Duke CC Roufogalis BD 《Journal of biomedical science》2006,13(4):535-548
Summary Nuclear factor (NF)-κB is important in the generation of inflammation. Besides regulating lipid metabolism, peroxisome proliferator-activated receptor (PPAR)-α activators also reduce NF-κB activation to terminate activation of inflammatory pathways. Gynostemma pentaphyllum (GP) has been used to treat various inflammatory diseases and hyperlipidemia. Here, we demonstrate that GP extract and one of its main components, Gypenoside XLIX (Gyp-XLIX) inhibited LPS-induced NF-κB activation in murine macrophages. Furthermore, Gyp-XLIX restored the LPS- and TNF-α-induced decrease in cytosolic I-κBα protein expression and inhibited the translocation of NF-κB(p65) to the nucleus in THP-1 monocyte and HUVEC cells. The inhibition of LPS- and TNF-α-induced NF-κB luciferase activity in macrophages was abolished by MK-886, a selective PPAR-α antagonist. GP extract and Gyp-XLIX (EC50: 10.1 μM) enhanced PPAR-α luciferase activity in HEK293 cells transfected with the tK-PPREx3-Luc reporter plasmid and expression vectors for PPAR-α. Additionally, Gyp-XLIX specifically enhanced PPAR-α mRNA and protein expression in THP-1-derived macrophage cells. The selectivity of Gyp-XLIX for PPAR-α was demonstrated by the activation of only PPAR-α in HEK293 cells transfected with expression vectors for PPAR-α, PPAR-β/δ or PPAR-γ1 plasmids and in THP-1-derived macrophage naturally expressing all three PPAR isoforms. The present study demonstrates that Gyp-XLIX, a naturally occurring gynosaponin, inhibits NF-κB activation via a PPAR-α-dependent pathway.Tom Hsun-Wei Huang and Yuhao Li contributed equally. 相似文献
10.
Fei Guo Yuanlei Lou Nianhua Feng Guohui Li An Xie Xueming Huang Yang Wang 《Biometals》2010,23(4):669-680
Lanthanum chloride, a rare earth compound, possesses antibacterial and cellular immunity regulating properties. However, the
underlying molecular mechanisms remain largely unknown. In this study, we examined the effects of lanthanum chloride on the
production of nitric oxide (NO) and tumor necrosis factor-α (TNF-α), the expression of inducible NO synthase (iNOS) and TNF-α
in RAW 264.7 cells, a mouse macrophage cell line. We found that the LPS-elicited excessive production of NO and TNF-α in RAW
264.7 cells was inhibited significantly in the presence of lanthanum chloride, and the attenuation of iNOS and TNF-α occurred
at mRNA level. Furthermore, the possible signaling components affected by lanthanum chloride in the pathway that lead to LPS-induced
iNOS and TNF-α expression were explored. The results indicated the involvements of PKC/Ca2+ and NF-κB in the attenuation of NO and pro-inflammatory cytokine production by lanthanum chloride. Our observations suggest
a possible therapeutic application of this agent for treating inflammatory diseases. 相似文献
11.
Effects of glutamine on the nuclear factor-kappaB signaling pathway of murine peritoneal macrophages
Marcelo Macedo Rogero Primavera Borelli Ricardo Ambrósio Fock Maria Carolina Borges Marco Aurélio Ramirez Vinolo Rui Curi Karina Nakajima Amanda Rabello Crisma Aline Domingas Ramos Julio Tirapegui 《Amino acids》2010,39(2):435-441
The aim of this study was to evaluate the effect of glutamine on the expression of proteins involved in the nuclear factor-kappaB
(NF-κB) signaling pathway of murine peritoneal macrophages. Since glutamine is essential for the normal functioning of macrophages,
it was hypothesized that in vitro glutamine supplementation would increase NF-κB activation. Peritoneal macrophages were pretreated
with glutamine (0, 0.6, 2 and 10 mM) before incubation with lipopolysaccharide (LPS), and the effects of glutamine on the
production of tumor necrosis factor-alpha and on the expression and activity of proteins involved in the NF-κB signaling pathway
were studied by an enzyme linked immuno-sorbent assay, Western blotting, and an electrophoretic mobility shift assay. Glutamine
treatment (2 and 10 mM) increased the activation of NF-κB in LPS-stimulated peritoneal macrophages (P < 0.05). In non-stimulated cells, glutamine treatment (2 and 10 mM) significantly reduced IκB-α protein expression (P < 0.05). Glutamine modulates NF-κB signaling pathway by reducing the level of IκB-α, leading to an increase in NF-κB within
the nucleus in peritoneal macrophages. 相似文献
12.
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
13.
14.
Taxifolin ameliorates cerebral ischemia-reperfusion injury in rats through
its anti-oxidative effect and modulation of NF-kappa B activation 总被引:15,自引:0,他引:15
Wang YH Wang WY Chang CC Liou KT Sung YJ Liao JF Chen CF Chang S Hou YC Chou YC Shen YC 《Journal of biomedical science》2006,13(1):127-141
Summary Infarction in adult rat brain was induced by middle cerebral arterial occlusion (MCAO) followed by reperfusion to examine
whether taxifolin could reduce cerebral ischemic reperfusion (CI/R) injury. Taxifolin administration (0.1 and 1.0 μg/kg, i.v.)
60 min after MCAO ameliorated infarction (by 42%±7% and 62%±6%, respectively), which was accompanied by a dramatic reduction
in malondialdehyde and nitrotyrosine adduct formation, two markers for oxidative tissue damage. Overproduction of reactive
oxygen species (ROS) and nitric oxide (NO) via oxidative enzymes (e.g., COX-2 and iNOS) was responsible for this oxidative damage. Taxifolin inhibited leukocyte infiltration,
and COX-2 and iNOS expressions in CI/R-injured brain. Taxifolin also prevented Mac-1 and ICAM-1 expression, two key counter-receptors
involved in firm adhesion/transmigration of leukocytes to the endothelium, which partially accounted for the limited leukocyte
infiltration. ROS, generated by leukocytes and microglial cells, activated nuclear factor-kappa B (NF-κB) that in turn signaled
up-regulation of inflammatory proteins. NF-κB activity in CI/R was enhanced 2.5-fold over that of sham group and was inhibited
by taxifolin. Production of both ROS and NO by leukocytes and microglial cells was significantly antagonized by taxifolin.
These data suggest that amelioration of CI/R injury by taxifolin may be attributed to its anti-oxidative effect, which in
turn modulates NF-κB activation that mediates CI/R injury.
Yea-Hwey Wang, Wen-Yen Wang, Chia-Che Chang, and Kuo-Tong Liou contributed equally to this work. 相似文献
15.
Toll-like receptors (TLRs) play a critical role in sensing microbial components and inducing innate immune and inflammatory
responses by recognizing invading microbial pathogens. Lipopolysaccharide-induced dimerization of TLR4 is required for the
activation of downstream signaling pathways including nuclear factor-kappa B (NF-κB). Therefore, TLR4 dimerization may be
an early regulatory event in activating ligand-induced signaling pathways and induction of subsequent immune responses. Here,
we report biochemical evidence that 6-shogaol, the most bioactive component of ginger, inhibits lipopolysaccharide-induced
dimerization of TLR4 resulting in the inhibition of NF-κB activation and the expression of cyclooxygenase-2. Furthermore,
we demonstrate that 6-shogaol can directly inhibit TLR-mediated signaling pathways at the receptor level. These results suggest
that 6-shogaol can modulate TLR-mediated inflammatory responses, which may influence the risk of chronic inflammatory diseases. 相似文献
16.
17.
ShuangQuan Liu ShiPing Wang YiMou Wu FeiJun Zhao TieBing Zeng YueJun Zhang QiuGui Zhang DongMei Gao 《中国科学:生命科学英文版》2010,53(2):229-233
The tissue destruction characteristic of syphilis infection may be caused by inflammation due to Treponema pallidum and the ensuing immune responses to the pathogen. T. pallidum membrane proteins are thought to be potent inducers of inflammation during the early stages of infection. However, the actual
membrane proteins that induce inflammatory cytokine production are not known, nor are the molecular mechanisms responsible
for triggering and sustaining the inflammatory cascades. In the present study, Tp0751 recombinant protein from T. pallidum was found to induce the production of proinflammatory cytokines, including TNF-α, IL-1βand IL-6, in a THP-1 human monocyte
cell line. The signal transduction pathways involved in the production of these cytokines were then further investigated.
No inhibition of TNF-a, IL-1β, or IL-6 production was observed following treatment with the SAPK/JNK specific inhibitor SP600125
or with an ERK inhibitor PD98059. By contrast, anti-TLR2 mAb, anti-CD14 mAb, and the p38 inhibitor SB203580 significantly
inhibited the production of all three cytokines. In addition, pyrrolidine dithiocarbamate (PDTC), a specific inhibitor of
NF-κB, profoundly inhibited the production of these cytokines. Tp0751 treatment strongly activated NF-κB, as revealed by Western
blotting. However, NF-κB translocation was significantly inhibited by treatment with PDTC. These results indicated that TLR2,
CD14, MAPKs/p38, and NF-κB might be implicated in the inflammatory reaction caused by T. pallidum infection. 相似文献
18.
19.
Ya Wen Xiangjian Zhang Lipeng Dong Jingru Zhao Cong Zhang Chunhua Zhu 《Molecular medicine (Cambridge, Mass.)》2015,21(1):197-209
Inflammatory responses play a critical role in ischemic brain injury. MicroRNA-155 (miR-155) induces the expression of inflammatory cytokines, and acetylbritannilactone (ABL) exerts potent antiinflammatory actions by inhibiting expression of inflammation-related genes. However, the functions of miR-155 and the actual relationship between ABL and miR-155 in ischemia-induced cerebral inflammation remain unclear. In this study, cerebral ischemia of wild-type (WT) and miR-155−/− mice was induced by permanent middle cerebral artery occlusion (MCAO). pAd-miR-155 was injected into the lateral cerebral ventricle 24 h before MCAO to induce miR-155 overexpression. MCAO mice and oxygen-glucose deprivation (OGD)-treated BV2 cells were used to examine the effects of ABL and miR-155 overexpression or deletion on the expression of proinflammatory cytokines. We demonstrated that ABL treatment significantly reduced neurological deficits and cerebral infarct volume by inhibiting tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) expression in ischemic cerebral tissue and OGD-treated BV2 cells. Mechanistic studies suggested that the observed decrease in TNF-α and IL-1β expression was attributable to the ABL-induced suppression of the expression of nuclear factor-kappa B (NF-κB) and Toll-like receptor 4 (TLR4). We further found that miR-155 promoted TNF-α and IL-1β expression by upregulating TLR4 and downregulating the expression of suppressor of cytokine signaling 1 (SOCS1) and myeloid differentiation primary response gene 88 (MyD88), while ABL exerted an inhibitory effect on miR-155-mediated gene expression. In conclusion, miR-155 mediates inflammatory responses in ischemic cerebral tissue by modulating TLR4/MyD88 and SOCS1 expression, and ABL exerts its antiinflammatory action by suppressing miR-155 expression, suggesting a novel miR-155-based therapy for ischemic stroke. 相似文献
20.
Tumor necrosis factor alpha (TNFα) activates the nuclear factor-kappaB (NF-κB) pathway in various cell types, leading to expression
of cell survival and inflammatory proteins. One mechanism of cell survival brought about by NF-κB is the inhibition of Activator
Protein-1 (AP-1), which when activated, could lead to cell death. However, TNFα can also induce the AP-1 pathway, and the
mechanisms by which these two pathways are regulated in response to TNFα are poorly understood. We proposed that Inhibitor
of κB Kinase gamma (IKKγ) (which is also known as NF-κB essential modulator, NEMO) plays a key role in integrating and coordinating
these two pathways. Our results showed that IKKγ activates the AP-1 pathway, via a mechanism that is dependent on the first
leucine zipper (LZ) domain of IKKγ, by interacting with two proteins of the AP-1 complex, c-Jun and c-Fos, and changing the
phosphorylation status of c-Jun. Even though IKKγ is required for the activation of NF-κB, we found that it reduced the activity
of NF-κB when it was overexpressed. In summary, we demonstrated that transfected IKKγ, while inhibiting the NF-κB pathway,
directly interacts with the AP-1 proteins and activates the AP-1 pathway independent of its effects on NF-κB. Our results
indicate that IKKγ regulates TNFα signaling by coordinating cell responses mediated by the AP-1 and NF-κB pathways.
A. S. Shifera and J. M. Friedman contributed equally to this article.
Marshall S. Horwitz—Deceased: This article is dedicated to his loving memory. 相似文献