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.

Quercetin attenuates cyclooxygenase-2 expression in response to acute ureteral obstruction

2015 ◽  
Vol 308 (11) ◽  
pp. F1297-F1305 ◽  
Author(s):  
Inge Carlsen ◽  
Jørgen Frøkiær ◽  
Rikke Nørregaard
Keyword(s):  
Oxidative Stress ◽  
Mechanical Stress ◽  
Ureteral Obstruction ◽  
Naturally Occurring ◽  
Renal Inner Medulla ◽  
Cox 2 ◽  
And Oxidative Stress ◽  
Quercetin Treatment

Unilateral ureteral obstruction (UUO) is associated with increased hydrostatic pressure, inflammation, and oxidative stress in the renal parenchyma. Previous studies have demonstrated marked cyclooxygenase (COX)-2 induction in renal medullary interstitial cells (RMICs) in response to UUO. The aim of the present study was to evaluate the effect of quercetin, a naturally occurring antioxidant, on COX-2 induction in vivo and in vitro. Rats subjected to 24 h of UUO were treated intraperitoneally with quercetin (50 mg·kg−1·day−1). Quercetin partly prevented COX-2 induction in the renal inner medulla in response to UUO. Moreover, RMICs exposed to conditions associated with obstruction, inflammation (produced by IL-1β), oxidative stress (produced by H2O2), and mechanical stress (produced by stretch) showed increased COX-2 expression. Interestingly, quercetin reduced COX-2 induction in RMICs subjected to stretched. Similarly, PGE2 production was markedly increased in RMICs exposed to stretch and was reversed to control levels by quercetin treatment. Furthermore, stretch-induced phosphorylation of ERK1/2 was blocked by quercetin, and inhibition of ERK1/2 attenuated stretch-induced COX-2 induction in RMICs. These results indicate that quercetin attenuated the induction of COX-2 expression and activity in RMICs exposed to mechanical stress as a consequence of acute UUO and that the MAPK ERK1/2 pathway might be involved in this quercetin-mediated reduction in COX-2.

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.

ROS dependence of cyclooxygenase-2 induction in rats subjected to unilateral ureteral obstruction

2014 ◽  
Vol 306 (2) ◽  
pp. F259-F270 ◽  
Author(s):  
Martin Østergaard ◽  
Michael Christensen ◽  
Line Nilsson ◽  
Inge Carlsen ◽  
Jørgen Frøkiær ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ureteral Obstruction ◽  
Oxidase Inhibitor ◽  
Unilateral Ureteral Obstruction ◽  
Tubular Damage ◽  
Ros Production ◽  
Cox 2 ◽  
And Oxidative Stress

Oxidative stress resulting from unilateral ureteral obstruction (UUO) may be aggravated by increased production of ROS. Previous studies have demonstrated increased cyclooxygenase (COX)-2 expression in renal medullary interstitial cells (RMICs) in response to UUO. We investigated, both in vivo and in vitro, the role of ROS in the induction of COX-2 in rats subjected to UUO and in RMICs exposed to oxidative and mechanical stress. Rats subjected to 3-day UUO were treated with two mechanistically distinct antioxidants, the NADPH oxidase inhibitor diphenyleneiodonium (DPI) and the complex I inhibitor rotenone (ROT), to interfere with ROS production. We found that UUO-mediated induction of COX-2 in the inner medulla was attenuated by both antioxidants. In addition, DPI and ROT reduced tubular damage and oxidative stress after UUO. Moreover, mechanical stretch induced COX-2 and oxidative stress in RMICs. Likewise, RMICs exposed to H2O2 as an inducer of oxidative stress showed increased COX-2 expression and activity, both of which were reduced by DPI and ROT. Similarly, ROS production, which was increased after exposure of RMICs to H2O2, was also reduced by DPI and ROT. Furthermore, oxidative stress-induced phosphorylation of ERK1/2 and p38 was blocked by both antioxidants, and inhibition of ERK1/2 and p38 attenuated the induction of COX-2 in RMICs. Notably, COX-2 inhibitors further exacerbated the oxidative stress level in H2O2-exposed RMICs. We conclude that oxidative stress as a consequence of UUO stimulates COX-2 expression through the activation of multiple MAPKs and that the induction of COX-2 may exert a cytoprotective function in RMICs.

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.

scholarly journals Inhibition of Carrageenan-Induced Acute Inflammation in Mice by Oral Administration of Anthocyanin Mixture from Wild Mulberry and Cyanidin-3-Glucoside

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Neuza Mariko Aymoto Hassimotto ◽  
Vanessa Moreira ◽  
Neide Galvão do Nascimento ◽  
Pollyana Cristina Maggio de Castro Souto ◽  
Catarina Teixeira ◽  
...  
Keyword(s):  
Polymorphonuclear Leukocytes ◽  
Acute Inflammation ◽  
Biological Activities ◽  
Inhibitory Effect ◽  
Experimental Models ◽  
Protein Levels ◽  
Paw Oedema ◽  
Cox 2

Anthocyanins are flavonoids which demonstrated biological activities inin vivoandin vitromodels. Here in the anti-inflammatory properties of an anthocyanin-enriched fraction (AF) extracted from wild mulberry and the cyanidin-3-glucoside (C3G), the most abundant anthocyanin in diet, were studied in two acute inflammation experimental models, in the peritonitis and in the paw oedema assays, both of which were induced by carrageenan (cg) in mice. In each trial, AF and C3G (4 mg/100 g/animal) were orally administered in two distinct protocols: 30 min before and 1 h after cg stimulus. The administration of both AF and C3G suppresses the paw oedema in both administration times (P<0.05). In the peritonitis, AF and C3G reduced the polymorphonuclear leukocytes (PMN) influx in the peritoneal exudates when administered 1 h after cg injection. AF was more efficient reducing the PMN when administered 30 min before cg. Both AF and C3G were found to suppress mRNA as well as protein levels of COX-2 upregulated by cg in both protocols, but the inhibitory effect on PGE2production in the peritoneal exudates was observed when administered 30 min before cg (P<0.05). Our findings suggest that AF and C3G minimize acute inflammation and they present positive contributions as dietary supplements.

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.

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.

Synthesis of new hexahydropyrimido[1,2-a]azepine derivatives bearing functionalized aryl and heterocyclic moieties as anti-inflammatory agents

2021 ◽  
Author(s):  
Hassanein H Hassanein ◽  
Doaa E Abdel Rahman ◽  
Marwa A Fouad ◽  
Rehab F Ahmed
Keyword(s):  
Molecular Docking ◽  
Binding Sites ◽  
Docking Study ◽  
In Vivo Studies ◽  
Molecular Docking Study ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

New hexahydropyrimido[1,2- a]azepine derivatives bearing functionalized aryl and heterocyclic moieties were synthesized as anti-inflammatory agents with better safety profiles. All synthesized compounds were assessed in vitro for their COX-1 and COX-2 inhibition activities. The most selective compounds, 2f, 5 and 6, were further evaluated for their in vivo anti-inflammatory activity and PGE2 inhibitory activity. To rationalize their selectivity, molecular docking within COX-1 and COX-2 binding sites was performed. Their physicochemical properties and drug-like nature profile were also calculated. The good activity and selectivity of compounds 2f, 5 and 6 were rationalized using a molecular docking study and supported by in vivo studies. These promising findings are encouraging for performing future investigations of these derivatives.

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