scholarly journals Probing into the Mechanism of Alkaline Citrus Extract Promoted Apoptosis in Pulmonary Fibroblasts of Bleomycin-Induced Pulmonary Fibrosis Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-11
Author(s):  
Qi Wu ◽  
Yao Zhou ◽  
Fan-chao Feng ◽  
Yi-han Jin ◽  
Zhi-chao Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Fibrosis ◽  
Fas Ligand ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Expression Intensity ◽  
Pulmonary Fibroblasts ◽  
Cox 2 ◽  
Pulmonary Fibroblast ◽  
Functioning Mechanism

We extracted the primary pulmonary fibroblasts of the normal and bleomycin-induced pulmonary fibrosis mice and investigated the functioning mechanism of citrus alkaline extract (CAE) in the induction of pulmonary fibroblast apoptosis. The expression intensity of vimentin of the pulmonary fibroblasts in the model mice was higher than that in the normal mice. Meanwhile, the positive expression rate and expression intensity of alpha smooth muscle actin (α-SMA) of the pulmonary fibroblasts in the model mice were higher than those in the normal mice. Results of MTT showed that pulmonary fibroblast activity of the normal and model mice has been significantly inhibited by CAE in a concentration-dependent manner. The results of flow cytometer analysis showed that the proportion of pulmonary fibroblast apoptosis in the model mice has been profoundly increased by CAE treatment in a dosage-dependent manner. Besides we found that the expression of Cleaved-Caspase 3, Cleaved-Caspase 8, Cleaved-poly-ADP-ribose polymerase (Cleaved-PARP), and Fas and Fas Ligand (FasL) was markedly increased after CAE treatment. A further study showed that the expression of Cyclooxygenase-2 (COX-2) and prostaglandin E receptor 2 (EP2) was dependant on the concentration of CAE, indicating that CAE-regulated receptor apoptosis of Fas was probably related to COX-2. The results of fluorescence detection of oxidative stress showed that the level of oxidative stress was significantly increased after CAE treatment. Furthermore, the results of Western Blot showed that the phosphorylation level of p38 (p-p38) was markedly increased, suggesting that CAE probably has regulated COX-2 through increased p-p38 following oxidative stress. Our results therefore suggest that CAE can effectively induce pulmonary fibroblast apoptosis of the normal and model mice, and its functioning mechanism is probably related to the p38/COX-2/Fas signaling pathway regulated by oxidative stress.

scholarly journals Oleifolioside A, a New Active Compound, Attenuates LPS-Stimulated iNOS and COX-2 Expression through the Downregulation of NF-κB and MAPK Activities in RAW 264.7 Macrophages

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Hai Yang Yu ◽  
Kyoung-Sook Kim ◽  
Young-Choon Lee ◽  
Hyung-In Moon ◽  
Jai-Heon Lee
Keyword(s):  
Nitric Oxide ◽  
Mapk Signaling ◽  
Binding Activity ◽  
Prostaglandin E ◽  
Raw 264.7 ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Raw 264.7 Macrophages ◽  
Dendropanax Morbifera ◽  
Cox 2

Oleifolioside A, a new triterpenoid compound isolated fromDendropanax morbiferaLeveille (D. morbifera), was shown in this study to have potent inhibitory effects on lipopolysaccharide (LPS-)stimulated nitric oxide (NO) and prostaglandin E2(PGE2) production in RAW 264.7 macrophages. Consistent with these findings, oleifolioside A was further shown to suppress the expression of LPS-stimulated inducible nitric oxide synthase (iNOS) and cyclooxigenase-2 (COX-2) in a dose-dependent manner at both the protein and mRNA levels and to significantly inhibit the DNA-binding activity and transcriptional activity of NF-κB in response to LPS. These results were found to be associated with the inhibition of the degradation and phosphorylation of IκB-αand subsequent translocation of the NF-κB p65 subunit to the nucleus. Inhibition of NF-κB activation by oleifolioside A was also shown to be mediated through the prevention of p38 MAPK and ERK1/2 phosphorylation. Taken together, our results suggest that oleifolioside A has the potential to be a novel anti-inflammatory agent capable of targeting both the NF-κB and MAPK signaling pathways.

scholarly journals Honokiol ameliorates radiation-induced brain injury via the activation of SIRT3

2020 ◽  
Vol 48 (10) ◽  
pp. 030006052096399
Author(s):  
Guixiang Liao ◽  
Zhihong Zhao ◽  
Hongli Yang ◽  
Xiaming Li
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Interleukin 1 ◽  
Dependent Manner ◽  
Ht22 Cells ◽  
Tnf Α ◽  
Radiation Induced ◽  
Cox 2

Objective Sirtuin 3 (SIRT3) plays a vital role in regulating oxidative stress in tissue injury. The aim of this study was to evaluate the radioprotective effects of honokiol (HKL) in a zebrafish model of radiation-induced brain injury and in HT22 cells. Methods The levels of reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) were evaluated in the zebrafish brain and HT22 cells. The expression levels of SIRT3 and cyclooxygenase-2 (COX-2) were measured using western blot assays and real-time polymerase chain reaction (RT-PCR). Results HKL treatment attenuated the levels of ROS, TNF-α, and IL-1β in both the in vivo and in vitro models of irradiation injury. Furthermore, HKL treatment increased the expression of SIRT3 and decreased the expression of COX-2. The radioprotective effects of HKL were achieved via SIRT3 activation. Conclusions HKL attenuated oxidative stress and pro-inflammatory responses in a SIRT3-dependent manner in radiation-induced brain injury.

scholarly journals Celecoxib Induces Functional Recovery after Intracerebral Hemorrhage with Reduction of Brain Edema and Perihematomal Cell Death

2004 ◽  
Vol 24 (8) ◽  
pp. 926-933 ◽  
Author(s):  
Kon Chu ◽  
Sang-Wuk Jeong ◽  
Keun-Hwa Jung ◽  
So-Young Han ◽  
Soon-Tae Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Functional Recovery ◽  
Autologous Blood ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Behavioral Tests ◽  
Adult Rats ◽  
Cox 2

The selective cyclooxygenase-2 (COX-2) inhibitor has been reported to have antiinflammatory, neuroprotective, and antioxidant effects in ischemia models. In this study, the authors examined whether a selective COX-2 inhibitor (celecoxib) reduces cerebral inflammation and edema after intracerebral hemorrhage (ICH), and whether functional recovery is sustained with longer treatment. ICH was induced using collagenase in adult rats. Celecoxib (10 or 20 mg/kg) was administered intraperitoneally 20 minutes, 6 hours, and 24 hours after ICH and then daily thereafter. Seventy-two hours after ICH induction, the rats were killed for histologic assessment and measurement of brain edema and prostaglandin E2. Behavioral tests were performed before and 1, 7, 14, 21, and 28 days after ICH. The brain water content of celecoxib-treated rats decreased both in lesioned and nonlesioned hemispheres in a dose-dependent manner. Compared with the ICH-only group, the number of TUNEL-positive, myeloperoxidase-positive, or OX42-positive cells was decreased in the periphery of hematoma and brain prostaglandin E2 level was reduced in the celecoxib-treated group. Celecoxib-treated rats recovered better by the behavioral tests at 7 days after ICH throughout the 28-day period, and the earlier the drug was administered, the better the functional recovery. Evidence of similar effects in an autologous blood–injected model showed that direct collagenase toxicity was not the major cause of inflammation or cell death. These data suggest that celecoxib treatment after ICH reduces prostaglandin E2 production, brain edema, inflammation, and perihematomal cell death in the perihematomal zone and induces better functional recovery.

scholarly journals The Induction of Cyclooxygenase-2 in IL-1β-Treated Endothelial Cells is Inhibited by Prostaglandin E2 through cAMP

1999 ◽  
Vol 8 (6) ◽  
pp. 287-294 ◽  
Author(s):  
Pravit Akarasereenont ◽  
Kitirat Techatrisak ◽  
Sirikul Chotewuttakorn ◽  
Athiwat Thaworn
Keyword(s):  
Endothelial Cells ◽  
Biological Activities ◽  
Umbilical Vein ◽  
The Body ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Negative Feedback Regulation ◽  
Cox 2 ◽  
Arachidonic Acids ◽  
Cox 1

Prostaglandins (PGS) have numerous cardiovascular and inflammatory effects. Cyclooxygenase (COX), which exists as COX-1 and COX-2 isoforms, is the first enzyme in the pathway in which arachidonic acid is converted to PGs. Prostaglandin E2 (PGE2) exerts a variety of biological activities for the maintenance of local homeostasis in the body. Elucidation of PGE2 involvement in the signalling molecules such as COX could lead to potential therapeutic interventions. Here, we have investigated the effects of PGE2 on the induction of COX-2 in human umbilical vein endothelial cells (HUVEC) treated with interleukin-1β (IL-1β 1 ng/ml). COX activity was measured by the production of 6-keto-PGF1α, PGE2, PGF2α and thromboxane B2 (TXB2) in the presence of exogenous arachidonic acids (10 μM for 10 min) using enzyme immunoassay (EIA). COX-1 and COX-2 protein was measured by immunoblotting using specific antibody. Untreated HUVEC contained only COX-1 protein while IL-1β treated HUVEC contained COX-1 and COX-2 protein. PGE2 (3 μM for 24 h) did not affect on COX activity and protein in untreated HUVEC. Interestingly, PGE2 (3 μM for 24 h) can inhibit COX-2 protein, but not COX-1 protein, expressed in HUVEC treated with IL1 β. This inhibition was reversed by coincubation with forskolin (100 μM). The increased COX activity in HUVEC treated with IL-1β was also inhibited by PGE2 (0.03, 0.3 and 3 μM for 24 h) in a dose-dependent manner. Similarly, forskolin (10, 50 or 100 μM) can also reverse the inhibition of PGE2 on increased COX activity in IL-1β treated HUVEC. The results suggested that (i) PGE2 can initiate negative feedback regulation in the induction of COX-2 elicited by IL-1β in endothelial cells, (ii) the inhibition of PGE2 on COX-2 protein and activity in IL-1β treated HUVEC is mediated by cAMP and (iii) the therapeutic use of PGE2 in the condition which COX-2 has been involved may have different roles.

Effects of Celecoxib and Nimesulide on the Proliferation of Ectopic Endometrial Stromal Cells in vitro

2008 ◽  
Vol 36 (5) ◽  
pp. 1032-1038 ◽  
Author(s):  
B Kong ◽  
Y Tian ◽  
W Zhu ◽  
S Su ◽  
Y Kan
Keyword(s):  
Cell Cycle ◽  
Stromal Cells ◽  
Prostaglandin E ◽  
Apoptotic Cells ◽  
Dependent Manner ◽  
Selective Inhibitors ◽  
Endometrial Stromal Cells ◽  
Cox 2 ◽  
Dose Dependent

The effects of cyclooxygenase 2 (COX-2) selective inhibitors on the proliferation of ectopic endometrial stromal cells in vitro were investigated. Ectopic endometrial stromal cells were treated with either celecoxib or nimesulide for 24 and 48 h. The results showed that (i) both celecoxib and nimesulide inhibited the proliferation of ectopic endometrial stromal cells in vitro in a time- and dose-dependent manner; (ii) the expression of prostaglandin E2 was significantly inhibited by both celecoxib and nimesulide in a dose-dependent manner; (iii) the percentage of apoptotic cells was significantly higher for cells treated with celecoxib or nimesulide than for untreated cells; and (iv) the percentage of the cells in the G0/G1 phase increased after the cells were treated with either agent in a dose-dependent manner. These data suggest that celecoxib and nimesulide inhibited proliferation of ectopic endometrial stromal cells by inducing apoptosis and blocking the cell cycle at the G0/G1 phase.

scholarly journals Glucosamine Hydrochloride Specifically Inhibits COX-2 by Preventing COX-2 N-Glycosylation and by Increasing COX-2 Protein Turnover in a Proteasome-dependent Manner

2007 ◽  
Vol 282 (38) ◽  
pp. 27622-27632 ◽  
Author(s):  
Byeong-Churl Jang ◽  
Su-Haeng Sung ◽  
Jong-Gu Park ◽  
Jong-Wook Park ◽  
Jae Hoon Bae ◽  
...  
Keyword(s):  
Molecular Mass ◽  
Protein Turnover ◽  
A549 Cells ◽  
Lung Epithelial Cells ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Glucosamine Hydrochloride ◽  
Cox 2 ◽  
Factor Α

COX-2 and its products, including prostaglandin E2, are involved in many inflammatory processes. Glucosamine (GS) is an amino monosaccharide and has been widely used for alternative regimen of (osteo) arthritis. However, the mechanism of action of GS on COX-2 expression remains unclear. Here we describe a new action mechanism of glucosamine hydrochloride (GS-HCl) to tackle endogenous and agonistdriven COX-2 at protein level. GS-HCl (but not GS sulfate, N-acetyl GS, or galactosamine HCl) resulted in a shift in the molecular mass of COX-2 from 72–74 to 66–70 kDa and concomitant inhibition of prostaglandin E2 production in a concentration-dependent manner in interleukin (IL)-1β-treated A549 human lung epithelial cells. Remarkably, GS-HCl-mediated decrease in COX-2 molecular mass was associated with inhibition of COX-2 N-glycosylation during translation, as assessed by the effect of tunicamycin, the protein N-glycosylation inhibitor, or of cycloheximide, the translation inhibitor, on COX-2 modification. Specifically, the effect of low concentration of GS-HCl (1 mm) or of tunicamycin (0.1 μg/ml) to produce the aglycosylated COX-2 was rescued by the proteasomal inhibitor MG132 but not by the lysosomal or caspase inhibitors. However, the proteasomal inhibitors did not show an effect at 5 mm GS-HCl, which produced the aglycosylated or completely deglycosylated form of COX-2. Notably, GS-HCl (5 mm) also facilitated degradation of the higher molecular species of COX-2 in IL-1β-treated A549 cells that was retarded by MG132. GS-HCl (5 mm) was also able to decrease the molecular mass of endogenous and IL-1β- or tumor necrosis factor-α-driven COX-2 in different human cell lines, including Hep2 (bronchial) and H292 (laryngeal). However, GS-HCl did not affect COX-1 protein expression. These results demonstrate for the first time that GS-HCl inhibits COX-2 activity by preventing COX-2 co-translational N-glycosylation and by facilitating COX-2 protein turnover during translation in a proteasome-dependent manner.

11,12-Epoxyeicosatrienoic Acid Attenuates Synthesis of Prostaglandin E2 in Rat Monocytes Stimulated with Lipopolysaccharide

2003 ◽  
Vol 228 (7) ◽  
pp. 786-794 ◽  
Author(s):  
Wieslaw Kozak ◽  
David M. Aronoff ◽  
Olivier Boutaud ◽  
Anna Kozak
Keyword(s):  
Cell Culture ◽  
Arachidonic Acid ◽  
Negative Feedback ◽  
Inhibitory Effect ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Epoxyeicosatrienoic Acid ◽  
Concentration Dependent Manner ◽  
Cox 2 ◽  
Cytochrome P 450

Cytochrome P-450 monooxygenase (epoxygenase)-derived arachidonic acid (AA) metabolites, including 11,12-epoxyeicosatrienoic acid (11,12-EET), possess anti-inflammatory and antipyretic properties. Prostaglandin E2 (PGE2), a cyclooxygenase (COX)-derived metabolite of AA, is a well-defined mediator of fever and inflammation. We have tested the hypothesis that 11,12-EET attenuates synthesis of PGE2 in monocytes, which are the cells that are indispensable for induction of fever and initiation of inflammation. Monocytes isolated from freshly collected rat blood were stimulated with lipopolysaccharide (LPS; 100 ng/2 × 105 cells) to induce COX-2 and stimulate generation of PGE2. SKF-525A, an inhibitor of epoxygenases, significantly augmented the lipopolysaccharide-provoked synthesis of PGE2 in cell culture in a concentration-dependent manner. It did not affect, however, elevation of the expression of COX-2 protein in monocytes stimulated with LPS. 11,12-EET also did not affect the induction of COX-2 in monocytes incubated with lipopolysaccharide. However, 11,12-EET suppressed, in a concentration-dependent fashion, the generation of PGE2 in incubates. Preincubation of a murine COX-2 preparation for 0–5 min with three concentrations of 11,12-EET (1, 5, and 10 μM) inhibited the oxygenation of [14C]-labeled AA by the enzyme. The inhibitory effect of 11,12-EET on COX-2 was time-and-concentration-dependent, suggesting a mechanism-based inhibition. Based on these data, we conclude that 11,12-EET suppresses generation of PGE2 in monocytes via modulating the activity of COX-2. These data support the hypothesis that epoxygenasederived AA metabolites constitute a negative feedback on the enhanced synthesis of prostaglandins upon inflammation.

The inhibitory effect of celecoxib on mouse hepatoma H22 cell line on the arachidonic acid metabolic pathwayThis paper is one of a selection of papers published in this special issue entitled “Second International Symposium on Recent Advances in Basic, Clinical, and Social Medicine” and has undergone the Journal's usual peer review process.

2010 ◽  
Vol 88 (4) ◽  
pp. 603-609 ◽  
Author(s):  
Zhigang Xu ◽  
Ming Zhang ◽  
Xiaoyan Lv ◽  
Dan Xiang ◽  
Xuewen Zhang ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Peer Review Process ◽  
Inhibitory Effect ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Important Indicator ◽  
Protein Levels ◽  
Mouse Hepatoma ◽  
Cox 2 ◽  
Risk Of Cancer

Celecoxib is a selective inhibitor of cyclooxygenase-2 (COX-2). It may reduce the risk of cancer formation by affecting the metabolism of arachidonic acid (AA), which has been implicated in the development of cancer. Accordingly, this study was designed to determine the effects of celecoxib on the AA pathway in mouse hepatoma H22 cells. Celecoxib was found to inhibit the proliferation of H22 cells in a dose- and time-dependent manner. Low doses (50 and 100 µmol·L–1) of celecoxib caused an increase in the expression of cytosolic phospholipase A2 (cPLA2), but did not affect the expression of COX-2 in terms of the mRNA and protein levels. Surprisingly, the amount of AA was elevated and the level of prostaglandin E2 (PGE2) was unaltered in the culture supernatant. At higher celecoxib doses (200 and 400 µmol·L–1), the mRNA and protein of both COX-2 and cPLA2 were inhibited. The concentration of AA was increased, and PGE2 level was depressed in H22 cells. The ratio of AA to PGE2 was increased in a dose-dependent manner. Our findings suggest that the imbalance between AA and PGE2, characterized by increased AA at a low dosage and decreased PGE2 at a high dosage of celecoxib, was an important indicator of cytotoxicity of celecoxib on H22 cells.

scholarly journals Extracellular CIRP Induces an Inflammatory Phenotype in Pulmonary Fibroblasts via TLR4

2021 ◽  
Vol 12 ◽  
Author(s):  
Siavash Bolourani ◽  
Ezgi Sari ◽  
Max Brenner ◽  
Ping Wang
Keyword(s):  
Pulmonary Fibrosis ◽  
Inflammatory Cytokines ◽  
Rna Binding ◽  
Critical Role ◽  
Dependent Manner ◽  
Gene Expressions ◽  
Pulmonary Fibroblasts ◽  
Molecular Pattern ◽  
Fibrotic Process ◽  
Inflammatory Phenotype

Extracellular cold-inducible RNA-binding protein (eCIRP), a new damage-associated molecular pattern (DAMP), has been recently shown to play a critical role in promoting the development of bleomycin-induced pulmonary fibrosis. Although fibroblast activation is a critical component of the fibrotic process, the direct effects of eCIRP on fibroblasts have never been examined. We studied eCIRP’s role in the induction of inflammatory phenotype in pulmonary fibroblasts and its connection to bleomycin-induced pulmonary fibrosis in mice. We found that eCIRP causes the induction of proinflammatory cytokines and differentially expression-related pathways in a TLR4-dependent manner in pulmonary fibroblasts. Our analysis further showed that the accessory pathways MD2 and Myd88 are involved in the induction of inflammatory phenotype. In order to study the connection of the enrichment of these pathways in priming the microenvironment for pulmonary fibrosis, we investigated the gene expression profile of lung tissues from mice subjected to bleomycin-induced pulmonary fibrosis collected at various time points. We found that at day 14, which corresponds to the inflammatory-to-fibrotic transition phase after bleomycin injection, TLR4, MD2, and Myd88 were induced, and the transcriptome was differentially enriched for genes in those pathways. Furthermore, we also found that inflammatory cytokines gene expressions were induced, and the cellular responses to these inflammatory cytokines were differentially enriched on day 14. Overall, our results show that eCIRP induces inflammatory phenotype in pulmonary fibroblasts in a TLR4 dependent manner. This study sheds light on the mechanism by which eCIRP induced inflammatory fibroblasts, contributing to pulmonary fibrosis.

scholarly journals Osthole Attenuates Bleomycin-Induced Pulmonary Fibrosis by Modulating NADPH Oxidase 4-Derived Oxidative Stress in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Lijun Fang ◽  
Wei Wang ◽  
Jiazheng Chen ◽  
Anju Zuo ◽  
Hongmei Gao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Fibrosis ◽  
Lung Fibroblasts ◽  
Ros Generation ◽  
Dependent Manner ◽  
Active Constituent ◽  
Concentration Dependent Manner ◽  
Nadph Oxidase 4 ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the extensive accumulation of myofibroblasts and collagens. However, the exact mechanism that underlies this condition is unclear. Growing evidence suggests that NADPH oxidases (NOXs), especially NOX4-derived oxidative stress, play an important role in the development of lung fibrosis. Bleomycin (BLM) is a tumor chemotherapeutic agent, which has been widely employed to establish IPF animal models. Osthole (OST) is an active constituent of the fruit of Cnidium ninidium. Here, we used an in vivo mouse model and found that OST suppressed BLM-induced body weight loss, lung injury, pulmonary index increase, fibroblast differentiation, and pulmonary fibrosis. OST also significantly downregulated BLM-induced NOX4 expression and oxidative stress in the lungs. In vitro, OST could inhibit TGF-β1-induced Smad3 phosphorylation, differentiation, proliferation, collagen synthesis, NOX4 expression, and ROS generation in human lung fibroblasts in a concentration-dependent manner. Moreover, NOX4 overexpression could prevent the above effects of OST. We came to the conclusion that OST could significantly attenuate BLM-induced pulmonary fibrosis in mice, via the mechanism that involved downregulating TGF-β1/NOX4-mediated oxidative stress in lung fibroblasts.

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