scholarly journals Cholera Toxin Induces a Shift from Inactive to Active Cyclooxygenase 2 in Alveolar Macrophages Activated by Mycobacterium bovis BCG

2012 ◽  
Vol 81 (1) ◽  
pp. 373-380
Author(s):  
Mari Kogiso ◽  
Tsutomu Shinohara ◽  
C. Kathleen Dorey ◽  
Yoshimi Shibata
Keyword(s):  
Cholera Toxin ◽  
Mycobacterium Bovis ◽  
Alveolar Macrophages ◽  
Mucosal Vaccine ◽  
Prostaglandin E ◽  
Lung Cells ◽  
Cox 2 ◽  
Cox 1

Intranasal vaccination stimulates formation of cyclooxygenases (COX) and release of prostaglandin E2(PGE2) by lung cells, including alveolar macrophages. PGE2plays complex pro- or anti-inflammatory roles in facilitating mucosal immune responses, but the relative contributions of COX-1 and COX-2 remain unclear. Previously, we found thatMycobacterium bovisBCG, a human tuberculosis vaccine, stimulated increased release of PGE2by macrophages activatedin vitro; in contrast, intranasal BCG activated no PGE2release in the lungs, because COX-1 and COX-2 in alveolar macrophages were subcellularly dissociated from the nuclear envelope (NE) and catalytically inactive. This study tested the hypothesis that intranasal administration of BCG with cholera toxin (CT), a mucosal vaccine component, would shift the inactive, NE-dissociated COX-1/COX-2 to active, NE-associated forms. The results showed increased PGE2release in the lungs and NE-associated COX-2 in the majority of COX-2+macrophages. These COX-2+macrophages were the primary source of PGE2release in the lungs, since there was only slight enhancement of NE-associated COX-1 and there was no change in COX-1/COX-2 levels in alveolar epithelial cells following treatment with CT and/or BCG. To further understand the effect of CT, we investigated the timing of BCG versus CT administration forin vivoandin vitromacrophage activations. When CT followed BCG treatment, macrophagesin vitrohad elevated COX-2-mediated PGE2release, but macrophagesin vivoexhibited less activation of NE-associated COX-2. Our results indicate that inclusion of CT in the intranasal BCG vaccination enhances COX-2-mediated PGE2release by alveolar macrophages and further suggest that the effect of CTin vivois mediated by other lung cells.

scholarly journals Are there attacking points in the eicosanoid cascade for chemotherapeutic options in benign meningiomas?

2007 ◽  
Vol 23 (4) ◽  
pp. E8 ◽  
Author(s):  
Christina Pfister ◽  
Rainer Ritz ◽  
Heike Pfrommer ◽  
Antje Bornemann ◽  
Marcos S. Tatagiba ◽  
...  
Keyword(s):  
World Health ◽  
Pcr Analysis ◽  
Prostaglandin E ◽  
Tissue Samples ◽  
Human Cortex ◽  
Normal Human ◽  
Cox 2 ◽  
Cox 1

Object The current treatment for recurrent or malignant meningiomas with adjuvant therapies has not been satisfactory, and there is an intense interest in evaluating new molecular markers to act as therapeutic targets. Enzymes of the arachidonic acid (AA) cascade such as cyclooxygenase (COX)–2 or 5-lipoxygenase (5-LO) are upregulated in a number of epithelial tumors, but to date there are hardly any data about the expression of these markers in meningiomas. To find possible targets for chemotherapeutic intervention, the authors evaluated the expression of AA derivatives at different molecular levels in meningiomas. Methods One hundred and twenty-four meningioma surgical specimens and normal human cortical tissue samples were immunohistochemically and cytochemically stained for COX-2, COX-1, 5-LO, and prostaglandin E receptor 4 (PTGER4). In addition, Western blot and polymerase chain reaction (PCR) analyses were performed to detect the presence of eicosanoids in vivo and in vitro. Results Sixty (63%) of 95 benign meningiomas, 21 (88%) of 24 atypical meningiomas, all five malignant meningiomas, and all normal human cortex samples displayed high COX-2 immunoreactivity. All cultured specimens and IOMM-Lee cells stained positive for COX-2, COX-1, 5-LO, and PTGER4. The PCR analysis demonstrated no changes in eicosanoid expression among meningiomas of different World Health Organization grades and in normal human cortical and dura mater tissue. Conclusions Eicosanoid derivatives COX-1, COX-2, 5-LO, and PTGER4 enzymes show a high universal expression in meningiomas but are not upregulated in normal human cortex and dura tissue. This finding of the ubiquitous presence of these enzymes in meningiomas offers an excellent baseline for testing upcoming chemotherapeutic treatments.

scholarly journals Inhibitory Effects of Traditional Herbal Formula Pyungwi-San on Inflammatory ResponseIn VitroandIn Vivo

2013 ◽  
Vol 2013 ◽  
pp. 1-19 ◽  
Author(s):  
Ji Young Cha ◽  
Ji Yun Jung ◽  
Jae Yup Jung ◽  
Jong Rok Lee ◽  
Il Je Cho ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Mediators ◽  
Raw 264.7 Cells ◽  
Prostaglandin E ◽  
Herbal Formula ◽  
Paw Edema ◽  
Cox 2 ◽  
Anti Inflammatory

Pyungwi-san (PWS) is a traditional basic herbal formula. We investigated the effects of PWS on induction of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), pro-inflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor-α(TNF-α)) and nuclear factor-kappa B (NF-κB) as well as mitogen-activated protein kinases (MAPKs) in lipopolysaccharide-(LPS-) induced Raw 264.7 cells and on paw edema in rats. Treatment with PWS (0.5, 0.75, and 1 mg/mL) resulted in inhibited levels of expression of LPS-induced COX-2, iNOS, NF-κB, and MAPKs as well as production of prostaglandin E2(PGE2), nitric oxide (NO), IL-6, and TNF-αinduced by LPS. Our results demonstrate that PWS possesses anti-inflammatory activities via decreasing production of pro-inflammatory mediators through suppression of the signaling pathways of NF-κB and MAPKs in LPS-induced macrophage cells. More importantly, results of the carrageenan-(CA-) induced paw edema demonstrate an anti-edema effect of PWS. In addition, it is considered that PWS also inhibits the acute edematous inflammations through suppression of mast cell degranulations and inflammatory mediators, including COX-2, iNOS and TNF-α. Thus, our findings may provide scientific evidence to explain the anti-inflammatory properties of PWSin vitroandin vivo.

scholarly journals Increased cyclooxygenase-2 expression and prostaglandin E2production in pressurized renal medullary interstitial cells

2010 ◽  
Vol 299 (3) ◽  
pp. R823-R831 ◽  
Author(s):  
Inge Carlsen ◽  
Kaitlin E. Donohue ◽  
Anja M. Jensen ◽  
Angela L. Selzer ◽  
Jie Chen ◽  
...  
Keyword(s):  
Mechanical Stress ◽  
Ureteral Obstruction ◽  
Interstitial Cells ◽  
Inflammatory Stress ◽  
Protein Levels ◽  
Cox 2 ◽  
Cox 1 ◽  
Expression And Activity

Renal medullary interstitial cells (RMICs) are subjected to osmotic, inflammatory, and mechanical stress as a result of ureteral obstruction, which may influence the expression and activity of cyclooxygenase type 2 (COX-2). Inflammatory stress strongly induces COX-2 in RMICs. To explore the direct effect of mechanical stress on the expression and activity of COX-2, cultured RMICs were subjected to varying amounts of pressure over time using a novel pressure apparatus. COX-2 mRNA and protein were induced following 60 mmHg pressure for 4 and 6 h, respectively. COX-1 mRNA and protein levels were unchanged. PGE2production in the RMICs was increased when cells were subjected to 60 mmHg pressure for 6 h and was prevented by a selective COX-2 inhibitor. Pharmacological inhibition indicating that pressure-induced COX-2 expression is dependent on p38 MAPK and biochemical knockdown experiments showed that NF-κB might be involved in the COX-2 induction by pressure. Importantly, terminal deoxyneucleotidyl transferase-mediated dUTP nick-end labeling and methylthiazoletetetrazolium assay studies showed that subjecting RMICs to 60 mmHg pressure for 6 h does not affect cell viability, apoptosis, and proliferation. To further examine the regulation of COX-2 in vivo, rats were subjected to unilateral ureteral obstruction (UUO) for 6 and 12 h. COX-2 mRNA and protein level was increased in inner medulla in response to 6- and 12-h UUO. COX-1 mRNA and protein levels were unchanged. These findings suggest that in vitro application of pressure recapitulates the effects on RMICs found after in vivo UUO. This directly implicates pressure as an important regulator of renal COX-2 expression.

scholarly journals Pleiotropic mechanisms facilitated by resveratrol and its metabolites

2010 ◽  
Vol 429 (2) ◽  
pp. 273-282 ◽  
Author(s):  
Barbara Calamini ◽  
Kiira Ratia ◽  
Michael G. Malkowski ◽  
Muriel Cuendet ◽  
John M. Pezzuto ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Molecular Targets ◽  
Quinone Reductase ◽  
Sirtuin 1 ◽  
Direct Result ◽  
Promote Cell Survival ◽  
Cox 2 ◽  
Cox 1

Resveratrol has demonstrated cancer chemopreventive activity in animal models and some clinical trials are underway. In addition, resveratrol was shown to promote cell survival, increase lifespan and mimic caloric restriction, thereby improving health and survival of mice on high-calorie diet. All of these effects are potentially mediated by the pleiotropic interactions of resveratrol with different enzyme targets including COX-1 (cyclo-oxygenase-1) and COX-2, NAD+-dependent histone deacetylase SIRT1 (sirtuin 1) and QR2 (quinone reductase 2). Nonetheless, the health benefits elicited by resveratrol as a direct result of these interactions with molecular targets have been questioned, since it is rapidly and extensively metabolized to sulfate and glucuronide conjugates, resulting in low plasma concentrations. To help resolve these issues, we tested the ability of resveratrol and its metabolites to modulate the function of some known targets in vitro. In the present study, we have shown that COX-1, COX-2 and QR2 are potently inhibited by resveratrol, and that COX-1 and COX-2 are also inhibited by the resveratrol 4′-O-sulfate metabolite. We determined the X-ray structure of resveratrol bound to COX-1 and demonstrate that it occupies the COX active site similar to other NSAIDs (non-steroidal anti-inflammatory drugs). Finally, we have observed that resveratrol 3- and 4′-O-sulfate metabolites activate SIRT1 equipotently to resveratrol, but that activation is probably a substrate-dependent phenomenon with little in vivo relevance. Overall, the results of this study suggest that in vivo an interplay between resveratrol and its metabolites with different molecular targets may be responsible for the overall beneficial health effects previously attributed only to resveratrol itself.

Regulation of prostaglandin biosynthesis in vivo by glutathione

1998 ◽  
Vol 274 (2) ◽  
pp. R294-R302 ◽  
Author(s):  
Alon Margalit ◽  
Scott D. Hauser ◽  
Ben S. Zweifel ◽  
Melissa A. Anderson ◽  
Peter C. Isakson
Keyword(s):  
Reduced Glutathione ◽  
Intraperitoneal Administration ◽  
Peritoneal Macrophages ◽  
Urate Crystal ◽  
Cox 2 ◽  
Cox 1 ◽  
Urate Crystals

Intraperitoneal administration of urate crystals to mice reduced subsequent macrophage conversion of arachidonic acid (AA) to prostaglandins (PGs) and 12-hydroxyeicosatetraenoic acid for up to 6 h. In contrast, levels of 12-hydroxyheptadecatrienoic acid (12-HHT) were markedly elevated. This metabolic profile was previously observed in vitro when recombinant cyclooxygenase (COX) enzymes were incubated with reduced glutathione (GSH). Analysis of peritoneal GSH levels revealed a fivefold elevation after urate crystal administration. The GSH synthesis inhibitorl-buthionine-[ S, R]-sulfoximine partially reversed the urate crystal effect on both GSH elevation and PG synthesis. Moreover, addition of exogenous GSH to isolated peritoneal macrophages shifted AA metabolism from PGs to 12-HHT. Urate crystal administration reduced COX-1, but induced COX-2 expression in peritoneal cells. The reduction of COX-1 may contribute to the attenuation of PG synthesis after 1 and 2 h, but PG synthesis remained inhibited up to 6 h, when COX-2 levels were high. Overall, our results indicate that elevated GSH levels inhibit PG production in this model and provide in vivo evidence for the role of GSH in the regulation of PG biosynthesis.

Selectivity of cyclooxygenase isoform activity and prostanoid production in normal and diseased Han:SPRD-cy rat kidneys

2006 ◽  
Vol 290 (4) ◽  
pp. F897-F904 ◽  
Author(s):  
Lori Warford-Woolgar ◽  
Claudia Yu-Chen Peng ◽  
Jamie Shuhyta ◽  
Andrew Wakefield ◽  
Deepa Sankaran ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Relative Difference ◽  
Prostaglandin E ◽  
Mrna Levels ◽  
Relative Contribution ◽  
Prostanoid Production ◽  
Prostaglandin F ◽  
Cox 2 ◽  
Cox 1

Renal prostanoids are important regulators of normal renal function and maintenance of renal homeostasis. In diseased kidneys, renal cylooxygenase (COX) expression and prostanoid formation are altered. With the use of the Han:Sprague-Dawley- cy rat, the aim of this study was to determine the relative contribution of renal COX isoforms (protein, gene expression, and activity) on renal prostanoid production [thromboxane B2 (TXB2, stable metabolite of TXA2), prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1α (6-keto-PGF1α, stable metabolite of PGI2)] in normal and diseased kidneys. In diseased kidneys, COX-1-immunoreactive protein and mRNA levels were higher and COX-2 levels were lower compared with normal kidneys. In contrast, COX activities were higher in diseased compared with normal kidneys for both COX-1 [0.05 ± 0.02 vs. 0.45 ± 0.11 ng prostanoids·min−1·mg protein−1 ( P < 0.001)] and COX-2 [0.64 ± 0.10 vs. 2.32 ± 0.22 ng prostanoids·min−1·mg protein−1 ( P < 0.001)]. As the relative difference in activity was greater for COX-1, the ratio of COX-1/COX-2 was higher in diseased compared with normal kidneys, although the predominant activity was still due to the COX-2 isoform in both genotypes. Endogenous and steady-state in vitro levels of prostanoids were ∼2–10 times higher in diseased compared with normal kidneys. The differences between normal and diseased kidney prostanoids were in the order of TXB2 > 6-keto-PGF1α > PGE2, as determined by higher renal prostanoid levels and COX activity ratios of TXB2/6-keto-PGF1α, TXB2/PGE2, and 6-keto-PGF1α/PGE2. This specificity in both the COX isoform type and for the prostanoids produced has implications for normal and diseased kidneys in treatments involving selective inhibition of COX isoforms.

scholarly journals Bifidobacterium bifidum reduces apoptosis in the intestinal epithelium in necrotizing enterocolitis

2010 ◽  
Vol 299 (5) ◽  
pp. G1118-G1127 ◽  
Author(s):  
Ludmila Khailova ◽  
Sarah K. Mount Patrick ◽  
Kelly M. Arganbright ◽  
Melissa D. Halpern ◽  
Toshi Kinouchi ◽  
...  
Keyword(s):  
Necrotizing Enterocolitis ◽  
Intestinal Epithelium ◽  
Mucosal Injury ◽  
In Vitro Models ◽  
Bifidobacterium Bifidum ◽  
Epithelial Cell Line ◽  
Prostaglandin E ◽  
Cox 2

Necrotizing enterocolitis (NEC) is a devastating intestinal disease of neonates, and clinical studies suggest the beneficial effect of probiotics in NEC prevention. Recently, we have shown that administration of Bifidobacterium bifidum protects against NEC in a rat model. Intestinal apoptosis can be suppressed by activation of cyclooxygenase-2 (COX-2) and increased production of prostaglandin E2 (PGE2). The present study investigates the effect of B. bifidum on intestinal apoptosis in the rat NEC model and in an intestinal epithelial cell line (IEC-6), as a mechanism of protection against mucosal injury. Premature rats were divided into the following three groups: dam fed, hand fed with formula (NEC), or hand fed with formula supplemented with B. bifidum (NEC + B. bifidum ). Intestinal Toll-like receptor-2 (TLR-2), COX-2, PGE2, and apoptotic regulators were measured. The effect of B. bifidum was verified in IEC-6 cells using a model of cytokine-induced apoptosis. Administration of B. bifidum increased expression of TLR-2, COX-2, and PGE2 and significantly reduced apoptosis in the intestinal epithelium of both in vivo and in vitro models. The Bax-to-Bcl-w ratio was shifted toward cell survival, and the number of cleaved caspase-3 positive cells was markedly decreased in B. bifidum -treated rats. Experiments in IEC-6 cells showed anti-apoptotic effect of B. bifidum . Inhibition of COX-2 signaling blocked the protective effect of B. bifidum treatment in both in vivo and in vitro models. In conclusion, oral administration of B. bifidum activates TLR-2 in the intestinal epithelium. B. bifidum increases expression of COX-2, which leads to higher production of PGE2 in the ileum and protects against intestinal apoptosis associated with NEC. This study indicates the ability of B. bifidum to downregulate apoptosis in the rat NEC model and in IEC-6 cells by a COX-2-dependent matter and suggests a molecular mechanism by which this probiotic reduces mucosal injury and preserves intestinal integrity.

scholarly journals Studies in 3,4-diaryl-1,2,5-oxadiazoles and their N-oxides: Search for better COX-2 inhibitors

2007 ◽  
Vol 57 (1) ◽  
pp. 13-30 ◽  
Author(s):  
Mange Yadav ◽  
Shrikant Shirude ◽  
Devendra Puntambekar ◽  
Pinkal Patel ◽  
Hetal Prajapati ◽  
...  
Keyword(s):  
Enzyme Inhibition ◽  
Docking Studies ◽  
Inflammatory Activity ◽  
Rat Paw Edema ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 2 Inhibitors ◽  
Cox 1

Studies in 3,4-diaryl-1,2,5-oxadiazoles and theirN-oxides: Search for better COX-2 inhibitorsA series of 3,4-diaryl-1,2,5-oxadiazoles and 3,4-diaryl-1,2,5-oxadiazoleN-oxides were prepared and evaluated for COX-2 and COX-1 binding affinityin vitroand for anti-inflammatory activity by the rat paw edema method.p-Methoxy (p-OMe) substituted compounds 9, 21, 34, 41, 42 showed COX-2 enzyme inhibition higher than that showed by compounds with other substituents. 3,4-Di(4-methoxyphenyl)-1,2,5-oxadiazoleN-oxide (42) showed COX-2 enzyme inhibition of 54% at 22 μmol L-1and COX-1 enzyme inhibition of 44% at 88 μmol L-1concentrations, but showed very lowin vivoanti-inflammatory activity. Its deoxygenated derivative (21) showed lower COX-2 enzyme inhibition (26% at 22 μmol L-1) and higher COX-1 enzyme inhibition (53% at 88 μmol L-1) but, markedin vivoanti-inflammatory activity (71% at 25 mg kg-1)vs.celecoxib (48% at 12.5 mg kg-1). Molecular modeling (docking) studies showed that the methoxy group is positioned in the vicinity of COX-2 secondary pocket and it also participates in hydrogen bonding interactions in the COX-2 active site. These preliminary studies suggest thatp-methoxy (p-OMe) group in one of benzene rings may give potentially active leads in this series of oxadiazole/N-oxides.

Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo

2000 ◽  
Vol 278 (6) ◽  
pp. R1496-R1505 ◽  
Author(s):  
Yasushi Takahashi ◽  
Christine Roman ◽  
Sylvain Chemtob ◽  
Mary M. Tse ◽  
Emil Lin ◽  
...  
Keyword(s):  
Ductus Arteriosus ◽  
Plasma Concentrations ◽  
Additional Increase ◽  
Cox Inhibitors ◽  
Fetal Plasma ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents; however, they also have adverse fetal effects such as constriction of the fetal ductus arteriosus. Recently, selective COX-2 inhibitors have been used in the management of preterm labor in the hope of avoiding fetal complications. However, both COX-1 and -2 are expressed by cells of the ductus arteriosus. We used fetal lambs (0.88 gestation) to assess the ability of selective COX-2 inhibitors celecoxib and NS398 to affect the ductus arteriosus. Both selective COX-2 inhibitors decreased PGE2 and 6ketoPGF1α production in vitro; both inhibitors constricted the isolated ductus in vitro. The nonselective COX-1/COX-2 inhibitor indomethacin produced a further reduction in PG release and an additional increase in ductus tension in vitro. We used a prodrug of celecoxib to achieve 1.4 ± 0.6 μg/ml, mean ± standard deviation, of the active drug in vivo. This concentration of celecoxib produced both an increase in pressure gradient and resistance across the ductus; celecoxib also decreased fetal plasma concentrations of PGE2 and 6ketoPGF1α. Indomethacin (0.7 ± 0.2 μg/ml) produced a significantly greater fall in ductus blood flow than celecoxib and tended to have a greater effect on ductus resistence in vivo. We conclude that caution should be used when recommending COX-2 inhibitors for use in pregnant women, because COX-2 appears to play a significant role in maintaining patency of the fetal ductus arteriosus.

scholarly journals Anti-Arthritic and Anti-Inflammatory Potential of Spondias mangifera Extract Fractions: An In Silico, In Vitro and In Vivo Approach

Plants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 825
Author(s):  
Mohammad Khalid ◽  
Mohammed H. Alqarni ◽  
Ambreen Shoaib ◽  
Muhammad Arif ◽  
Ahmed I. Foudah ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Arthritis Score ◽  
Beneficial Effects ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

The fruits of Spondias mangifera (S. mangifera) have traditionally been used for the management of rheumatism in the northeast region of India. The present study explores the probable anti-arthritis and anti-inflammatory potential of S. mangifera fruit extract’s ethanolic fraction (EtoH-F). To support this study, we first approached the parameters in silico by means of the active constituents of the plant (beta amyrin, beta sitosterol, oleonolic acid and co-crystallised ligands, i.e., SPD-304) via molecular docking on COX-1, COX-2 and TNF-α. Thereafter, the absorption, distribution, metabolism, excretion and toxicity properties were also determined, and finally experimental activity was performed in vitro and in vivo. The in vitro activities of the plant extract fractions were evaluated by means of parameters like 1,1-Diphenyl-2- picrylhydrazyl (DPPH), free radical-reducing potential, albumin denaturation, and protease inhibitory activity. The in vivo activity was evaluated using parameters like COX, TNF-α and IL-6 inhibition assay and arthritis score in Freund Adjuvant (CFA) models at a dose of 400 mg/kg b.w. per day of different fractions (hexane, chloroform, alcoholic). The molecular docking assay was performed on COX-1, COX-2 and TNF-α. The results of in vitro studies showed concentration-dependent reduction in albumin denaturation, protease inhibitors and scavenging activity at 500 µg/mL. Administration of the S. mangifera alcoholic fraction at the abovementioned dose resulted in a significant reduction (p < 0.01) in arthritis score, paw diameters, TNF-α, IL-6 as compared to diseased animals. The docking results showed that residues show a critical binding affinity with TNF-α and act as the TNF-α antagonist. The alcoholic fraction of S. mangifera extract possesses beneficial effects on rheumatoid arthritis as well as anti-inflammatory potential, and can further can be used as a possible agent for novel target-based therapies for the management of arthritis.

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