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Sample records for nonselective cox inhibitor

  1. Similar reductions in the risk of human colon cancer by selective and nonselective cyclooxygenase-2 (COX-2 inhibitors

    Directory of Open Access Journals (Sweden)

    Alshafie Galal A

    2008-08-01

    Full Text Available Abstract Background Epidemiologic and laboratory investigations suggest that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs have chemopreventive effects against colon cancer perhaps due at least in part to their activity against cyclooxygenase-2 (COX-2, the rate-limiting enzyme of the prostaglandin cascade. Methods We conducted a case control study of colon cancer designed to compare effects of selective and non-selective COX-2 inhibitors. A total of 326 incident colon cancer patients were ascertained from the James Cancer Hospital, Columbus, Ohio, during 2003–2004 and compared with 652 controls with no history of cancer and matched to the cases at a 2:1 ratio on age, race, and county of residence. Data on the past and current use of prescription and over the counter medications and colon cancer risk factors were ascertained using a standardized risk factor questionnaire. Effects of COX-2 inhibiting agents were quantified by calculating odds ratios (OR and 95% confidence intervals. Results Results showed significant risk reductions for selective COX-2 inhibitors (OR = 0.31, 95% CI = 0.16–0.57, regular aspirin (OR = 0.33, 95% CI = 0.20–0.56, and ibuprofen or naproxen (0.28, 95% CI = 0.15–0.54. Acetaminophen, a compound with negligible COX-2 activity and low dose aspirin (81 mg produced no significant change in the risk of colon cancer. Conclusion These results suggest that both non-selective and selective COX-2 inhibitors produce significant reductions in the risk of colon cancer, underscoring their strong potential for colon cancer chemoprevention.

  2. Reduction in cancer risk by selective and nonselective cyclooxygenase-2 (COX-2) inhibitors

    OpenAIRE

    Harris, Randall; Beebe,; Alshafie,

    2012-01-01

    Randall E Harris,1 Joanne Beebe,1 Galal A Alshafie21College of Medicine and College of Public Health, 2College of Pharmacy, The Ohio State University, Columbus, Ohio, USAAbstract: We conducted a series of epidemiologic studies to evaluate the chemopreventive effects of aspirin, ibuprofen, and selective cyxlooxygenase-2 (COX-2) inhibitors (coxibs) against cancers of the breast, colon, prostate, and lung. Composite results across all four cancer sites revealed that regular intake of 325 mg aspi...

  3. COX-2 Inhibitors and Gastric Cancer

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    Zhen Wang

    2014-01-01

    Full Text Available The evidence that cyclooxygenase-2 (COX-2 is upregulated and plays an important role in carcinogenesis of gastric cancer has triggered the topic of COX-2 inhibitors as chemopreventive agents for gastric cancer. Studies find that COX-2 inhibitors are associated not only with chemoprophylactic effects, but also with chemotherapeutic potentials in gastric cancer. Both COX-dependent and COX-independent pathways have a role in the anticancer efficiency of COX-2 inhibitors. However, enthusiasm is thwarted by the potential toxicity, that is, gastrointestinal toxicity of nonselective COX-2 inhibitors and cardiovascular risk of selective COX-2 inhibitors. Therefore, more studies are needed to develop new targeted antitumor agents (such as prostaglandin E receptor antagonist and to define fundamental questions such as optimal treatment regimens, integration of cotherapy, and careful selection of candidates.

  4. Study of gastrointestinal toxicity of selective COX-2 inhibitors in comparison with conventional NSAIDs

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    Hima Bindu K.

    2016-12-01

    Conclusions: In our short-term study, selective COX-2 inhibitors did not show any advantage over non-selective NSAIDs regarding their gastrointestinal toxicity. [Int J Res Med Sci 2016; 4(12.000: 5180-5184

  5. Cyclooxygenase (COX) Inhibitors and the Newborn Kidney

    OpenAIRE

    Wei Qi; Smith, Francine G.; Megan L. Lewis; Wade, Andrew W

    2012-01-01

    This review summarizes our current understanding of the role of cyclo-oxygenase inhibitors (COXI) in influencing the structural development as well as the function of the developing kidney. COXI administered either during pregnancy or after birth can influence kidney development including nephronogenesis, and can decrease renal perfusion and ultrafiltration potentially leading to acute kidney injury in the newborn period. To date, which COX isoform (COX-1 or COX-2) plays a more important role...

  6. Binding Energy Calculation of Patchouli Alcohol Isomer Cyclooxygenase Complexes Suggested as COX-1/COX-2 Selective Inhibitor

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    Sentot Joko Raharjo

    2014-01-01

    Full Text Available To understand the structural features that dictate the selectivity of the two isoforms of the prostaglandin H2 synthase (PGHS/COX, the three-dimensional (3D structure of COX-1/COX-2 was assessed by means of binding energy calculation of virtual molecular dynamic with using ligand alpha-Patchouli alcohol isomers. Molecular interaction studies with COX-1 and COX-2 were done using the molecular docking tools by Hex 8.0. Interactions were further visualized by using Discovery Studio Client 3.5 software tool. The binding energy of molecular interaction was calculated by AMBER12 and Virtual Molecular Dynamic 1.9.1 software. The analysis of the alpha-Patchouli alcohol isomer compounds showed that all alpha-Patchouli alcohol isomers were suggested as inhibitor of COX-1 and COX-2. Collectively, the scoring binding energy calculation (with PBSA Model Solvent of alpha-Patchouli alcohol isomer compounds (CID442384, CID6432585, CID3080622, CID10955174, and CID56928117 was suggested as candidate for a selective COX-1 inhibitor and CID521903 as nonselective COX-1/COX-2.

  7. Ibudilast: a non-selective phosphodiesterase inhibitor in brain disorders

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    Joanna Schwenkgrub

    2017-03-01

    Full Text Available Ibudilast (IBD is a non-selective (3, 4, 10, 11 phosphodiesterase (PDE inhibitor, used mainly as a bronchodilator for the treatment of bronchial asthma. PDE play a central role in cellular function (e.g. differentiation, synaptic plasticity and inflammatory response by metabolizing cyclic nucleotides. The results from preclinical and clinical studies indicate that IBD has a broader range of action through suppression of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α, toll-like receptor 4 blockade (TLR-4, inhibition of a macrophage migration inhibitory factor (MIF, up-regulation the anti-inflammatory cytokine (IL-10, and promotion of neurotrophic factors (GDNF, NGF, NT-4. Recent data indicate that the efficacy of IBD appears to be independent from PDE inhibition activity and rather linked to glial activity attenuation. Additional advantages of IBD, such as crossing the blood–brain barrier, good tolerance and activity by oral administration, makes it a promising therapeutic candidate for treating neuroinflammatory conditions, where the currently available treatment remains unsatisfying due to poor tolerability and/or sub-optimal efficacy. IBD has no direct receptor affinity with exemption of some undefined effect on adenosine receptors that makes the drug devoid of its receptors-mediated adverse effects. Current article provides an overview of the pharmacology of IBD with a focus on preclinical and clinical data supporting its potential neuroprotective benefits for neurological conditions, including multiple sclerosis, neuropathic pain, medication overuse headache, stroke, opioid, alcohol and methamphetamine abuse.

  8. Cyclooxygenase (COX Inhibitors and the Newborn Kidney

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    Wei Qi

    2012-10-01

    Full Text Available This review summarizes our current understanding of the role of cyclo-oxygenase inhibitors (COXI in influencing the structural development as well as the function of the developing kidney. COXI administered either during pregnancy or after birth can influence kidney development including nephronogenesis, and can decrease renal perfusion and ultrafiltration potentially leading to acute kidney injury in the newborn period. To date, which COX isoform (COX-1 or COX-2 plays a more important role in during fetal development and influences kidney function early in life is not known, though evidence points to a predominant role for COX-2. Clinical implications of the use of COXI in pregnancy and in the newborn infant are also evaluated herein, with specific reference to the potential effects of COXI on nephronogenesis as well as newborn kidney function.

  9. Use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs in high doses increases mortality and risk of reinfarction in patients with prior myocardial infarction

    DEFF Research Database (Denmark)

    Sørensen, Rikke; Abildstrøm, Steen Zabell; Torp-Pedersen, C.

    2008-01-01

    The selective cyclooxygenase-2 (COX-2) inhibitors and other nonselective nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with increased cardiovascular risk, but the risk in patients with established cardiovascular disease is unknown. In the present study, we analyzed the risk of...

  10. Randomized controlled trials of COX-2 inhibitors

    DEFF Research Database (Denmark)

    Stefansdottir, Gudrun; De Bruin, Marie L; Knol, Mirjam J

    2011-01-01

    BACKGROUND: Naproxen, ibuprofen and diclofenac are frequently used as comparators in randomized controlled trials (RCTs) on the safety and efficacy of cyclooxygenase (COX)-2 inhibitors. Different comparator doses may influence the results of RCTs. It has been hypothesized that RCTs of COX-2...... 1995 and 2009 in which celecoxib or rofecoxib were compared with naproxen, ibuprofen or diclofenac. All articles labelled as RCTs mentioning rofecoxib or celecoxib and one or more of the comparator drugs in the title and/or abstract were included. We extracted information on doses of both non...... dose trends in the case of rofecoxib. CONCLUSIONS: Although the dose trends over time differed for RCTs comparing rofecoxib and celecoxib with diclofenac, ibuprofen or naproxen, the results of our study do not support the hypothesis that dose trends influenced the decision to continue marketing...

  11. Is COX-2 a perpetrator or a protector? Selective COX-2 inhibitors remain controversial

    Institute of Scientific and Technical Information of China (English)

    Cheng LUO; Ming-liang HE; Lars BOHLIN

    2005-01-01

    Aim: COX-2(cyclooxygenase-2) has sparked a surge in pharmaceutical interest since its discovery at the beginning of the 1990s. Several COX-2 selective inhibitors that avoid gastrointestinal side effects have been successfully launched into the market in recent years. The first selective COX-2 inhibitor, celecoxib, entered the market in December 1999. However, there are a few organs that physiologically and functionally express COX-2, particularly the glomeruli of the kidney and the cortex of the brain. Inhibition of COX-2 expression in these organs possibly causes heart attack and stroke in long-term COX-2 inhibitor users. Recently, a USA Food and Drug Agency (FDA) advisory panel re-evaluated COX-2 inhibitors and unanimously concluded that the entire class of COX-2 inhibitors increase the risk of cardiovascular problems. Thus the use of COX-2 inhibitors is still controversial, and there is a challenge for not only pharmacologists, but also the pharmaceutical industry, to develop improved painkilling and anti-inflammatory drugs. This may involve exploring a new generation of COX-2 inhibitors with different inhibitory mechanisms through computer-aided design, screening different sources of inhibitors with lower Selectivity, or seeking completely new targets.Synthetic COX-2 inhibitors have high selectivity and the advantage of irreversible inhibition, whereas naturally derived COX-2 inhibitors have lower selectivity and fewer side effects, with the medical effects in general not being as striking as those achieved using synthetic inhibitors. This review discusses the mechanism of COX-2 inhibitor therapy and a possible new way of exploration in the development of anti-inflammatory, analgetic, and antipyretic drugs.

  12. Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2 inhibitors

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    Alshafie Galal A

    2006-01-01

    Full Text Available Abstract Background Epidemiologic and laboratory investigations suggest that nonsteroidal anti-inflammatory drugs (NSAIDs have chemopreventive effects against breast cancer due to their activity against cyclooxygenase-2 (COX-2, the rate-limiting enzyme of the prostaglandin cascade. Methods We conducted a case control study of breast cancer designed to compare effects of selective and non-selective COX-2 inhibitors. A total of 323 incident breast cancer patients were ascertained from the James Cancer Hospital, Columbus, Ohio, during 2003–2004 and compared with 649 cancer free controls matched to the cases at a 2:1 ratio on age, race, and county of residence. Data on the past and current use of prescription and over the counter medications and breast cancer risk factors were ascertained using a standardized risk factor questionnaire. Effects of COX-2 inhibiting agents were quantified by calculating odds ratios (OR and 95% confidence intervals. Results Results showed significant risk reductions for selective COX-2 inhibitors as a group (OR = 0.29, 95% CI = 0.14–0.59, regular aspirin (OR = 0.49, 95% CI = 0.26–0.94, and ibuprofen or naproxen (0.36, 95% CI = 0.18–0.72. Acetaminophen, a compound with negligible COX-2 activity and low dose aspirin (81 mg produced no significant change in the risk of breast cancer. Conclusion Selective COX-2 inhibitors (celecoxib and rofecoxib were only recently approved for use in 1999, and rofecoxib (Vioxx was withdrawn from the marketplace in 2004. Nevertheless, even in the short window of exposure to these compounds, the selective COX-2 inhibitors produced a significant (71% reduction in the risk of breast cancer, underscoring their strong potential for breast cancer chemoprevention.

  13. Cox-2 inhibitors and the risk of cardiovascular thrombotic events.

    LENUS (Irish Health Repository)

    Khan, M

    2012-04-01

    In 1971, Vane showed that the analgesic action of traditional NSAIDs relies on inhibition of the cyclo-oxygenase (COX) enzyme, which in turn results in reduced synthesis of proalgesic prostaglandins. Two decades later COX was shown to exist as two distinct isoforms. The constitutive isoform COX-1, supports the beneficial homeostatic functions whereas the inducible isoform, COX-2 becomes up regulated by inflammatory mediators and its products cause many of the symptoms of inflammatory diseases such as rheumatoid and osteoarthritis. Despite the benefits of NSAIDs for acute and chronic pain one of the most clinically significant and well characterized adverse effect is on GI mucosa. The search for NSAIDs with less gastrointestinal toxicity led to the introduction of the selective cyclo-oxygenase-2 (COX-2) inhibitors. The COX-2 selective (COX-1 sparing) inhibitors are associated with reduced GI mucosal damage as demonstrated in several trials. In light of the overwhelming and sometimes contradictory information for patients and physicians regarding the safety of COX-2 agents this article will summarize the available evidence regarding cardiovascular (CV) safety data and contemporary recommendations for prescribing of COX-2-selective NSAIDs.

  14. [Tubulointerstitial nephritis associated with treatment with selective Cox-2 inhibitors, celecoxib and rofecoxib].

    Science.gov (United States)

    Ortiz, M; Mon, C; Fernández, M J; Sánchez, R; Mampaso, F; Alvarez Ude, F

    2005-01-01

    The nephrotoxic effect of nonselective nonsteroidal anti-inflamatory drugs (NSAIDS) has been widely described. The main benefit of the Cox-2 inhibitors in relation to the NSAIDS is the production of a very similar analgesic effect, but with fewer gastrointestinal side effects. However, their effects on renal function are little known as yet and their long-term safety is still pending definition. The use of selective Cox-2 inhibitors as anti-inflamatory analgesic is becoming more and more common in our environment. We report two cases of tubulointersticial nephritis confirmed by renal biopsy, associated with administration of the two Cox-2 inhibitors currently available on the market, celecoxib and rofecoxib. In both cases, we were talking about elderly women, with deterioration of the general condition and acute renal failure. In the former case, renal biopsy showed an acute tubulo-intersticial nephritis (TIN) so highly "variegated" in its histologic expression. In the second case, was associated with strong indications of chronicity. Treatment with steroid was initiated in both patients and improvement of renal function was observed.

  15. Seizure following the Use of the COX-2 Inhibitor Etoricoxib

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    Arnao, Valentina; Riolo, Marianna; Fierro, Brigida

    2017-01-01

    We describe a case of epileptic seizures occurring after the use of a COX-2 inhibitor. A 61-year-old man was admitted to our department because of a generalized tonic-clonic seizure. EEG showed generalized slowdown of the activity. Neuroimaging and blood samples studies did not evidence alterations, but a careful pharmacological history revealed that the patient had taken the COX-2 inhibitor etoricoxib to treat lumbago few days before the onset of clinical symptoms. No seizures were reported after etoricoxib discontinuation and an EEG resulted to be normal two months after this. Conclusion. Knowing the pharmacological history of a patient is important for understanding the clinical presentation and selecting appropriate treatment. This is, to the best of our knowledge, the first reported case of generalized seizures associated with the use of COX-2 inhibitors. PMID:28210513

  16. Multifocal fixed drug eruption with COX-2 inhibitor-celecoxib

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    Shikha Chugh

    2013-01-01

    Full Text Available Cyclooxygenase-2 (COX-2 inhibitors are rapidly becoming the first choice nonsteroidal anti-inflammatory drugs (NSAIDs for various rheumatological and other painful conditions. However, they might not be as safe or free of side effects as they are considered to be. These COX-2inhibitors may cause a variety of dermatological and systemic side effects of which we should be aware to avoid their indiscriminate use. We hereby report a case of multifocal fixed drug eruption (FDE with celecoxib which has not yet been reported in Indian settings.

  17. Multifocal Fixed Drug Eruption with COX-2 Inhibitor-Celecoxib

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    Chugh, Shikha; Sarkar, Rashmi; Garg, Vijay K; Singh, Avninder; Keisham, Chitralekha

    2013-01-01

    Cyclooxygenase-2 (COX-2) inhibitors are rapidly becoming the first choice nonsteroidal anti-inflammatory drugs (NSAIDs) for various rheumatological and other painful conditions. However, they might not be as safe or free of side effects as they are considered to be. These COX-2inhibitors may cause a variety of dermatological and systemic side effects of which we should be aware to avoid their indiscriminate use. We hereby report a case of multifocal fixed drug eruption (FDE) with celecoxib which has not yet been reported in Indian settings. PMID:23716804

  18. Prescriber adoption of newly approved selective COX-2 inhibitors

    NARCIS (Netherlands)

    Layton, Deborah; Souverein, Patrick C.; Heerdink, Eibert R.; Shakir, Saad A. W.; Egberts, A. G. C.

    2008-01-01

    Introduction There is no consistent definition of prescribers who adopt new drug treatments early. This study examines if COX-2 inhibitors (coxibs) were prescribed by subsets of practitioners and describes GP adoption patterns of coxibs and existing NSAIDs over time. Methods A population-based drug

  19. [New studies of COX-inhibitors, yet issues remain].

    Science.gov (United States)

    Wollheim, Frank A

    2003-09-18

    Advantages and risks related to the use of selective COX-2 inhibitors when treating arthritis are currently being scrutinized by authorities and public. The discussion tends towards exaggerated claims for or against their usefulness. The issue of cardiovascular safety is still not finally settled. In an experimental study using patients with severe coronary disease, administration of celecoxib resulted in improved endothelial function together with reduced CRP levels. Gastrointestinal tolerance was studied in patients who had recently recovered from peptic ulcer bleeding. In this group of high risk patients, celecoxib was as safe as combined therapy using omeprazol and diclofenac when given for 6 months. However, both COX inhibitors caused hypertension and adverse renal effects. The second generation of selective inhibitors is being launched. Etoricoxib--related to rofecoxib--was shown to be as potent as indomethacin in the treatment of acute gout, but it caused fewer adverse reactions. In general, however, any advantage of second generation as compared to first generation COX-2 inhibitors remains to be proven. The Swedish Council on Technology Assessment in Health Care, in its "SBU Alert", has published an appraisal of celecoxib and rofecoxib, in which the need for further long-term safety studies is emphasized.

  20. Cyclo-oxygenase-2 inhibitors or nonselective NSAIDs plus gastroprotective agents: What to prescribe in daily clinical practice?

    NARCIS (Netherlands)

    G.M.C. Masclee (Gwen); V.E. Valkhoff (Vera); E.M. van Soest; R. Schade (René); G. Mazzaglia (Giampiero); M. Molokhia (Mariam); G. Trifiro (Gianluca); J.L. Goldstein; S. Hernández-Díaz (Sonia); E.J. Kuipers (Ernst); M.C.J.M. Sturkenboom (Miriam)

    2013-01-01

    textabstractBackground Two strategies for prevention of upper gastrointestinal (UGI) events for nonselective nonsteroidal anti-inflammatory drug (nsNSAID) users are replacement of the nsNSAID by a cyclo-oxygenase-2-selective inhibitor (coxib) or co-prescription of a gastroprotective agent (GPA). Aim

  1. Cyclo-oxygenase-2 inhibitors or nonselective NSAIDs plus gastroprotective agents: What to prescribe in daily clinical practice?

    NARCIS (Netherlands)

    G.M.C. Masclee (Gwen); V.E. Valkhoff (Vera); E.M. van Soest; R. Schade (René); G. Mazzaglia (Giampiero); M. Molokhia (Mariam); G. Trifiro (Gianluca); J.L. Goldstein; S. Hernández-Díaz (Sonia); E.J. Kuipers (Ernst); M.C.J.M. Sturkenboom (Miriam)

    2013-01-01

    textabstractBackground Two strategies for prevention of upper gastrointestinal (UGI) events for nonselective nonsteroidal anti-inflammatory drug (nsNSAID) users are replacement of the nsNSAID by a cyclo-oxygenase-2-selective inhibitor (coxib) or co-prescription of a gastroprotective agent (GPA). Aim

  2. Ivermectin is a nonselective inhibitor of mammalian P-type ATPases.

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    Pimenta, Paulo Henrique Cotrim; Silva, Claudia Lucia Martins; Noël, François

    2010-02-01

    Ivermectin is a large spectrum antiparasitic drug that is very safe at the doses actually used. However, as it is being studied for new applications that would require higher doses, we should pay attention to its effects at high concentrations. As micromolar concentrations of ivermectin have been reported to inhibit the sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA), we decided to investigate its putative inhibitory effect on other two important P-type ATPases, namely the Na(+) , K(+)-ATPase and H(+)/K(+)-ATPase. We first extended the data on SERCA, using preparations from rat enriched in SERCA1a (extensor digitorum longus) and 1b (heart) isoforms. Secondly, we tested the effect of ivermectin in two preparations of rat Na(+), K(+)-ATPase in order to appreciate its putative selectivity towards the alpha(1) isoform (kidney) and the alpha(2)/alpha(3) isoforms (brain), and in an H(+)/K(+)-ATPase preparation from rat stomach. Ivermectin inhibited all these ATPases with similar IC(50) values (6-17 microM). With respect to the inhibition of the Na(+), K(+)-ATPase, ivermectin acts by a mechanism different from the classical cardiac glycosides, based on selectivity towards the isoforms, sensibility to the antagonistic effect of K(+) and to ionic conditions favoring different conformations of the enzyme. We conclude that ivermectin is a nonselective inhibitor of three important mammalian P-type ATPases, which is indicative of putative important adverse effects if this drug were used at high doses. As a consequence, we propose that novel analogs of ivermectin should be developed and tested both for their parasitic activity and in vitro effects on P-type ATPases.

  3. COX-2 Inhibitors for Cancer Treatment in Dogs

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    Andrigo Barboza De Nardi*, Talita Mariana Morata Raposo1, Rafael Ricardo Huppes1, Carlos Roberto Daleck2 and Renée Laufer Amorim3

    2011-10-01

    Full Text Available Cancer is one of the main causes of death in canines and felines, and this fact is probably related to the increase in the longevity of these species. The longer the animals live, the higher the exposure to carcinogenic agents will be. With the high incidence of cancer in companion animals, new studies are currently being performed with the aim of finding therapeutic options which make the complete inhibition of the development of neoplasms in animals possible in the future. The correlation of cyclooxygenase-2 (COX-2 whith the development of cancer opens the way for the use of new therapeutic approaches. This relationship has been suggested based on various studies which established an association between the chronic use of nonsteroidal anti-inflammatory drugs (NSAID and a decrease in the incidence of colon carcinoma. As cancer progresses, COX-2 participates in the arachidonic acid metabolism by synthesizing prostaglandins which can mediate various mechanisms related to cancer development such as: increase in angiogenesis, inhibition of apoptosis, suppression of the immune response, acquisition of greater invasion capacity and metastasis. Accordingly, overexpression of this enzyme in tumors has been associated with the most aggressive, poor-prognosis cancer types, especially carcinomas. Therefore, treatments which use COX-2 inhibitors such as coxibs, whether administered as single agents or in combination with conventional antineoplastic chemotherapy, are an alternative for extending the survival of our cancer patients.

  4. COX-2 inhibitors: a CLASS act or Just VIGORously promoted.

    Science.gov (United States)

    Malhotra, Samir; Shafiq, N; Pandhi, P

    2004-03-23

    Abstract Selective cyclo-oxygenase (COX)-2 inhibitors were developed with the hope of producing lesser gastrointestinal (GI) side effects as compared with the conventional nonsteroidal anti-inflammatory drugs (NSAIDs). Soon after their introduction into the market, the sales of celecoxib and rofecoxib went up considerably. Most of this was attributed to the results of the Celecoxib Long-term Arthritis Safety Study (CLASS) and Vioxx Gastrointestinal Outcome Research (VIGOR) trials. However, several discrepancies were noted in the presentation of the actual trial results submitted to the US Food and Drug Administration (FDA) and those used for the purpose of publication in scientific journals. These issues were discussed subsequently by the way of scientific communications. Moreover, with increasing use of these agents, evidence of their adverse effects is coming to light. The present review aims at discussing the above issues, with emphasis on the results of the CLASS and VIGOR trials.

  5. Use of cox-2 inhibitors in patients with retinal venous occlusive disease.

    Science.gov (United States)

    Recchia, Franco M; Chen, Eric; Li, Chun; Maguluri, Srilakshmi

    2008-01-01

    To determine the prevalence of prior or current usage of COX-2 inhibitors among patients with retinal venous occlusion (RVO). Records of all patients with RVO and control patients matched by age and gender without the diagnosis of RVO seen in a retina referral practice between May 1999 and October 2004 were reviewed. Prevalence of COX-2 inhibitor usage was compared. Multivariable analysis was used to assess the independent correlation of COX-2 inhibitor usage with RVO. A total of 111 consecutive patients with RVO and 316 controls without RVO were identified. There was no significant difference in race or presence of hypertension between cases and controls. Ten of the RVO patients (9%) had a history of using COX-2 inhibitors. Of these 10 patients, one had a central RVO, one had a hemi-central RVO, and eight had a branch RVO. Thirty-nine of the 321 controls (12%) had a history of COX-2 inhibitor use. The prevalence of COX-2 inhibitor usage among RVO patients was not significantly different from that of controls (9% versus 12%; P = 0.37). In a multivariable analysis adjusting for effects of age, gender, hypertension, diabetes, and cardiovascular disease, the association of COX-2 inhibitor usage and RVO was still not significant (P = 0.48). A few patients with RVO had prior or concurrent use of COX-2 inhibitors. The prevalence of COX-2 inhibitor usage does not appear to be significantly higher in patients with RVO.

  6. Radiolabeled COX-2 Inhibitors for Non-Invasive Visualization of COX-2 Expression and Activity — A Critical Update

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    Torsten Kniess

    2013-05-01

    Full Text Available Cyclooxygenase-2 (COX-2 is a key player in inflammation. Its overexpression is directly associated with various inflammatory diseases and, additionally, with several processes of carcinogenesis. The development of new selective COX-2 inhibitors (COXIBs for use in cancer treatment is in the focus of the medicinal chemistry research field. For this purpose, a set of methods is available to determine COX-2 expression and activity in vitro and ex vivo but it is still a problem to functionally characterize COX-2 in vivo. This review focusses on imaging agents targeting COX-2 which have been developed for positron emission tomography (PET and single photon emission computed tomography (SPECT since 2005. The literature reveals that different radiochemical methods are available to synthesize COXIBs radiolabeled with fluorine-18, carbon-11, and isotopes of radioiodine. Unfortunately, most of the compounds tested did not show sufficient stability in vivo due to de[18F]fluorination or de[11C]methylation or they failed to bind specifically in the target region. So, suitable stability in vivo, matching lipophilicity for the target compartment and both high affinity and selectivity for COX-2 were identified as prominent criteria for radiotracer development. Up to now, it is not clear what approach and which model is the most suited to evaluate COX-2 targeting imaging agents in vivo. However, for proof of principle it has been shown that some radiolabeled compounds can bind specifically in COX-2 overexpressing tissue which gives hope for future work in this field.

  7. Synthesis and biological evaluation of 3-amino-2-pyrones as selective cyclooxygenase-1 (COX-1) inhibitors

    Institute of Scientific and Technical Information of China (English)

    Xue-Ping Chu; Qing-Fa Zhou; Shen Zhao; Fei-Fei Ge; Mian Fu; Jia-Peng Chen; Tao Lu

    2013-01-01

    A group of 3-amino-2-pyrones were synthesized and their biological activities were evaluated for inhibiting cyclooxygenase (COX) activity.This study has led to the identification of COX-1-selective inhibitors.Among the tested compounds,the compound 5j exhibited the most potent COX-1 inhibitory activity (IC50 =19.32 μg/mL) and COX-1 selectivity index (SI =41.98).

  8. Do Different Cyclooxygenase Inhibitors Impair Rotator Cuff Healing in a Rabbit Model?

    Directory of Open Access Journals (Sweden)

    Yi Lu

    2015-01-01

    Conclusions: Nonsteroidal anti-inflammatory drugs can delay tendon healing in the early stage after rotator cuff repair. Compared with nonselective COX inhibitors, selective COX-2 inhibitors significantly impact tendon healing.

  9. A high-throughput, nonisotopic, competitive binding assay for kinases using nonselective inhibitor probes (ED-NSIP).

    Science.gov (United States)

    Vainshtein, Inna; Silveria, Scott; Kaul, Poonam; Rouhani, Riaz; Eglen, Richard M; Wang, John

    2002-12-01

    A novel competitive binding assay for protein kinase inhibitors has been developed for high-throughput screening (HTS). Unlike functional kinase assays, which are based on detection of substrate phosphorylation by the enzyme, this novel method directly measures the binding potency of compounds to the kinase ATP binding site through competition with a conjugated binding probe. The binding interaction is coupled to a signal amplification system based on complementation of beta-galactosidase enzyme fragments, a homogeneous, nonisotopic assay technology platform developed by DiscoveRx Corp. In the present study, staurosporine, a potent, nonselective kinase inhibitor, was chemically conjugated to a small fragment of beta-galactosidase (termed ED-SS). This was used as the binding probe to the kinase ATP binding pocket. The binding potencies of several inhibitors with diverse structures were assessed by displacement of ED-SS from the kinase. The assay format was specifically evaluated with GSK3alpha, an enzyme previously screened in a radioactive kinase assay (i.e., measurement of [(33)P]-gamma-ATP incorporation into the kinase peptide substrate). Under optimized assay conditions, nonconjugated staurosporine inhibited ED-SS binding in a concentration-dependent manner with an apparent potency (IC(50)) of 11 nM, which was similar to the IC(50) value determined in a radioactive assay. Furthermore, 9 kinase inhibitors with diverse structures, previously identified from chemical compound library screening, were screened using the competitive binding assay. The potencies in the binding assay were in very good agreement with those obtained previously in the isotopic functional activity assay. The binding assay was adapted for automated HTS using selected compound libraries in a 384-well microtiter plate format. The HTS assay was observed to be highly robust and reproducible (Z' factors > 0.7) with high interassay precision (R(2) > 0.96). Interference of compounds with the beta

  10. Effects of the non-selective phosphodiesterase inhibitor pentoxifylline on regional cerebral blood flow and large arteries in healthy subjects

    DEFF Research Database (Denmark)

    Kruuse, Christina; Jacobsen, T B; Thomsen, Lars Lykke

    2000-01-01

    -inhalation SPECT. High-frequency ultrasound was used for measurements of temporal and radial artery diameter. Cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) concentrations were assessed in plasma. Except for increased heart rate (P blood pressure (P ... or to other mechanisms is not clear. In the present double-blind crossover study, 10 healthy subjects received pentoxifylline 300 mg or placebo intravenously on separate days. Blood flow velocity in the middle cerebral artery (V(mca)) was recorded by transcranial Doppler and rCBF was measured using (133)Xenon......The vasodilating properties of the non-selective phosphodiesterase (PDE) inhibitor pentoxifylline were evaluated. Pentoxifylline has been reported to increase cerebral blood flow (CBF) and improve recovery rate of stroke patients. Whether these results are due to a dilating effect on arteries...

  11. Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Zhen [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Gan, Ye-Hua, E-mail: kqyehuagan@bjmu.edu.cn [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China)

    2015-05-01

    Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocation and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.

  12. In vitro and In Silico Studies on Curcumin and Its Analogues as Dual Inhibitors for cyclooxygenase-1 (COX-1 and cyclooxygenase-2 (COX-2

    Directory of Open Access Journals (Sweden)

    Nunung Yuniarti

    2012-03-01

    Full Text Available Curcumin has been widely reported as an anti-inflammatory agent isolated from the plant Curcuma longa L. (turmeric. This anti-inflammatory activity was associated with the ability of this compound to inhibit the activity of both cyclooxygenase-1 (COX-1 and cyclooxygenase-2 (COX-2 in arachidonic acid metabolism. Dual COX-1 and COX-2 inhibitors are preferred to be employed in the therapy of chronic inflammatory diseases compared to selective inhibitors, since it was reported that the use of selective inhibitors led to severe adverse side effect. In the present study, in vitro and in silico assays on curcumin and its analogues as dual inhibitors for both COX-1 and COX-2 were performed. The results provide theoretical contribution in understanding the ligand-protein interactions at the molecular level to develop new curcumin analogues which possess better anti-inflammatory activity as well as to avoid unsolicited side effects.

  13. In Silico Analysis of the Potential of the Active Compounds Fucoidan and Alginate Derived from Sargassum Sp. as Inhibitors of COX-1 and COX-2

    Science.gov (United States)

    Dewi, Lestari

    2016-01-01

    Introduction: The enzyme cyclooxygenase (COX) is an enzyme that catalyzes the formation of one of the mediators of inflammation, the prostaglandins. Inhibition of COX allegedly can improve inflammation-induced pathological conditions. Aim: The purpose of the present study was to evaluate the potential of Sargassum sp. components, Fucoidan and alginate, as COX inhibitors. Material and methods: The study was conducted by means of a computational (in silico) method. It was performed in two main stages, the docking between COX-1 and COX-2 with Fucoidan, alginate and aspirin (for comparison) and the analysis of the amount of interactions formed and the residues directly involved in the process of interaction. Results: Our results showed that both Fucoidan and alginate had an excellent potential as inhibitors of COX-1 and COX-2. Fucoidan had a better potential as an inhibitor of COX than alginate. COX inhibition was expected to provide a more favorable effect on inflammation-related pathological conditions. Conclusion: The active compounds Fucoidan and alginate derived from Sargassum sp. were suspected to possess a good potential as inhibitors of COX-1 and COX-2. PMID:27594740

  14. Design, Synthesis, and Evaluation of New Tripeptides as COX-2 Inhibitors

    Directory of Open Access Journals (Sweden)

    Ermelinda Vernieri

    2013-01-01

    Full Text Available Cyclooxygenase (COX is a key enzyme in the biosynthetic pathway leading to the formation of prostaglandins, which are mediators of inflammation. It exists mainly in two isoforms COX-1 and COX-2. The conventional nonsteroidal anti-inflammatory drugs (NSAIDs have gastrointestinal side effects because they inhibit both isoforms. Recent data demonstrate that the overexpression of these enzymes, and in particular of cyclooxygenases-2, promotes multiple events involved in tumorigenesis; in addition, numerous studies show that the inhibition of cyclooxygenases-2 can delay or prevent certain forms of cancer. Agents that inhibit COX-2 while sparing COX-1 represent a new attractive therapeutic development and offer a new perspective for a further use of COX-2 inhibitors. The present study extends the evaluation of the COX activity to all 203 possible natural tripeptide sequences following a rational approach consisting in molecular modeling, synthesis, and biological tests. Based on data obtained from virtual screening, only those peptides with better profile of affinity have been selected and classified into two groups called S and E. Our results suggest that these novel compounds may have potential as structural templates for the design and subsequent development of the new selective COX-2 inhibitors drugs.

  15. Network Meta-Analysis Comparing Relatively Selective COX-2 Inhibitors Versus Coxibs for the Prevention of NSAID-Induced Gastrointestinal Injury

    Science.gov (United States)

    Yang, Man; Wang, Hong-Tao; Zhao, Miao; Meng, Wen-Bo; Ou, Jin-Qing; He, Jun-Hui; Zou, Bing; Lei, Ping-Guang

    2015-01-01

    Abstract Currently 2 difference classes of cyclooxygenase (COX)-2 inhibitors, coxibs and relatively selective COX-2 inhibitors, are available for patients requiring nonsteroidal anti-inflammatory drug (NSAID) therapy; their gastroprotective effect is hardly directly compared. The aim of this study was to compare the gastroprotective effect of relatively selective COX-2 inhibitors with coxibs. MEDLINE, EMBASE, and the Cochrane Library (from their inception to March 2015) were searched for potential eligible studies. We included randomized controlled trials comparing coxibs (celecoxib, etoricoxib, parecoxib, and lumiracoxib), relatively selective COX-2 inhibitors (nabumetone, meloxicam, and etodolac), and nonselective NSAIDs with a study duration ≥4 weeks. Comparative effectiveness and safety data were pooled by Bayesian network meta-analysis. The primary outcomes were ulcer complications and symptomatic ulcer. Summary effect-size was calculated as risk ratio (RR), together with the 95% confidence interval (CI). This study included 36 trials with a total of 112,351 participants. Network meta-analyses indicated no significant difference between relatively selective COX-2 inhibitors and coxibs regarding ulcer complications (RR, 1.38; 95% CI, 0.47–3.27), symptomatic ulcer (RR, 1.02; 95% CI, 0.09–3.92), and endoscopic ulcer (RR, 1.18; 95% CI, 0.37–2.96). Network meta-analyses adjusting potential influential factors (age, sex, previous ulcer disease, and follow-up time), and sensitivity analyses did not reveal any major change to the main results. Network meta-analyses suggested that relatively selective COX-2 inhibitors and coxibs were associated with comparable incidences of total adverse events (AEs) (RR, 1.09; 95% CI, 0.93–1.31), gastrointestinal AEs (RR, 1.04; 95% CI, 0.87–1.25), total withdrawals (RR, 1.00; 95% CI, 0.74–1.33), and gastrointestinal AE-related withdrawals (RR, 1.02; 95% CI, 0.57–1.74). Relatively selective COX-2 inhibitors appear to be

  16. In Silico Analysis of the Potential of the Active Compounds Fucoidan and Alginate Derived from Sargassum Sp. as Inhibitors of COX-1 and COX-2

    OpenAIRE

    Dewi, Lestari

    2016-01-01

    Introduction: The enzyme cyclooxygenase (COX) is an enzyme that catalyzes the formation of one of the mediators of inflammation, the prostaglandins. Inhibition of COX allegedly can improve inflammation-induced pathological conditions. Aim: The purpose of the present study was to evaluate the potential of Sargassum sp. components, Fucoidan and alginate, as COX inhibitors. Material and methods: The study was conducted by means of a computational (in silico) method. It was performed in two main ...

  17. Effect of nimesulide-a preferential COX-2 inhibitor on arterial blood pressure, compared to ketoprofen.

    Science.gov (United States)

    Saran, Tomasz; Sodolski, Wojciech; Sodolska, Katarzyna; Danilkiewicz, Wit Cezary; Schabowski, Janusz

    2004-01-01

    Clinical and experimental studies have shown that renal and cardiovascular effects of most selective COX-2 inhibitors (rofecoxib, celecoxib) are similar to other traditional NSAIDs (dual COX inhibitors). In these study the effect of nimesulide--preferential COX-2 inhibitor, administration on 24-hour blood pressure profile was investigated in 40 adult individuals on antihypertensive therapy with pain states caused by osteoartritis. Nimesulide was administered orally, twice a day at the conventional dose of 0.1 g for five days. In the next (or previous) 5 days the same patients were administered with ketoprofen at the dose of 0.05 g three times a day. On the last day of the NSAID administration period, 24-hour blood pressure monitoring was performed. Our results indicate no difference between nimesulide and ketoprofen effects on mean blood pressure values during antihypertensive therapy.

  18. Assessing the cost-effectiveness of COX-2 specific inhibitors for arthritis in the Veterans Health Administration.

    Science.gov (United States)

    Schaefer, Monica; DeLattre, Melissa; Gao, Xin; Stephens, Jennifer; Botteman, Marc; Morreale, Anthony

    2005-01-01

    This study was designed to assess the cost-effectiveness of cyclooxygenase-2 specific (COX-2) inhibitors (rofecoxib and celecoxib) over nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in high-risk arthritis patients from the perspective of the Veterans Health Administration (VA). This literature-based economic analysis (with data summarized from MEDLINE-indexed and other published sources, FDA reports, and data on file at VA San Diego Healthcare System) compared rofecoxib and celecoxib to NSAIDS in two arthritis patient populations considered at higher risk of developing clinically significant upper gastrointestinal events (CSUGIEs): (1) patients of any age with previous medical history of perforation/ulcer/bleed (PUB); and (2) patients 65 years and older (regardless of history of PUB). Two outcome measures were reported: (1) incremental cost per CSUGIE averted over 1 year; and (2) incremental cost per quality-adjusted life-year (QALY) gained, considering both the mortality and morbidity associated with gastrointestinal (including CSUGIEs) and cardiovascular-related adverse events. When possible, costs were modeled to reflect the VA perspective. Sensitivity analyses were conducted to test the robustness of the analysis. Compared to NSAIDS, rofecoxib and celecoxib increased costs but reduced the incidence of CSUGIE. Cost per CSUGIE avoided were $7476 and $16,379 (in patients with a PUB history) and $14,294 and $18,376 (in patients aged > or = 65 years) for celecoxib and rofecoxib, respectively. In both populations, celecoxib was associated with a cost per QALY less than $50,000. In contrast, rofecoxib was found to cost more and result in a net QALY loss, due in particular to the increase in the risk of cardiovascular complications, and was therefore considered cost-ineffective. Results were most dependent on assumptions about the incidence of cardiovascular events and CSUGIE and the COX-2 inhibitors' acquisition price. This analysis suggests that COX-2

  19. Overcoming paclitaxel resistance in uterine endometrial cancer using a COX-2 inhibitor.

    Science.gov (United States)

    Hasegawa, Kiyoshi; Ishikawa, Kunimi; Kawai, Satoshi; Torii, Yutaka; Kawamura, Kyoko; Kato, Rina; Tsukada, Kazuhiko; Udagawa, Yasuhiro

    2013-12-01

    Cyclooxygenase (COX)-2 inhibitors have been reported to potentially modulate the resistance of cancer cells to chemotherapeutic drugs by affecting multidrug resistance 1 (MDR1) expression. In the present study, we investigated the association between COX-2 and MDR1 expression in endometrial cancers and evaluated the effects of the COX-2 inhibitor, etodolac, in combination with paclitaxel on paclitaxel-resistant endometrial cancer cells. The relationship between COX-2 and MDR1 mRNA expression was examined by quantitative PCR in 36 endometrial cancer specimens. The paclitaxel-resistant cell line OMC-2P was established from OMC-2 cells. Paclitaxel (1 µg/ml) with or without etodolac (10 µg/ml) was added to OMC-2 and OMC-2P cells, and COX-2 and MDR1 mRNA expression levels were examined. The concentration of prostaglandin E2 (PGE2) in the supernatant of each cell line was examined by enzyme-linked immunosorbent assay. The function of MDR1 was determined by intracellular accumulation of rhodamine 123 using flow cytometry, and the concentration of intracellular paclitaxel was determined by high-performance liquid chromatography. We found a positive relationship between COX-2 and MDR1 mRNA expression in endometrial cancer. Both COX-2 mRNA expression and PGE2 production were elevated in resistant OMC-2P cells when compared to non-resistant OMC-2 cells. Additionally, MDR1 mRNA expression was markedly upregulated in OMC-2P cells. In OMC-2 cells, COX-2 and MDR1 mRNA levels were significantly upregulated by paclitaxel treatment and downregulated by co-administration with etodolac. In OMC-2P cells, COX-2 mRNA expression was also significantly upregulated by paclitaxel treatment and tended to be downregulated by co-administration with etodolac. Moreover, co-administration of paclitaxel and etodolac suppressed the induction of MDR1 mRNA. Rhodamine 123 efflux was increased in OMC-2P cells when compared to the efflux in the OMC-2 cells and was increased in response to paclitaxel

  20. A COX-2 inhibitor combined with chemoradiation of locally advanced rectal cancer

    DEFF Research Database (Denmark)

    Jakobsen, Anders; Mortensen, John Pløen; Bisgaard, Claus;

    2008-01-01

    BACKGROUND AND AIM: The aim of this study was to investigate the possible effect of a COX-2 inhibitor in addition to chemoradiation of locally advanced rectal cancer. MATERIALS AND METHODS: The study included 35 patients with rectal adenocarcinoma. All patients had a tumor localised....

  1. Effects of COX-2 and COX-2 inhibitors in the vascular targeted therapy of pancreatic cancer%环氧合酶-2及其抑制剂在胰腺癌血管靶向治疗中的作用

    Institute of Scientific and Technical Information of China (English)

    刘丽燕; 高苏俊; 李雷

    2011-01-01

    胰腺癌的诊治目前仍是医学界的难题,血管生成是胰腺癌生长和转移的必要因素.环氧合酶(cyclooxygenase,COX)为花生四烯酸代谢过程中的关键酶,存在COX-1及COX-2两种同工酶,其中COX-2在胰腺癌的发生发展及胰腺癌血管生成中发挥重要作用.COX-2抑制剂可分为非选择性及选择性两种,两种COX-2抑制剂都对胰腺癌及其血管形成的发生与进展存在抑制作用,COX-2抑制剂抗肿瘤血管形成的机制可能是抑制血管内皮生长因子(VEGF)、缺氧诱导因子-1及基质金属蛋白酶(MMP)的表达、降低前列腺素(PGs)及其他血管生成因子的表达、促进内皮细胞凋亡、抑制内皮细胞侵袭力和影响一氧化氮合酶(NOS)的表达.%The diagnosis and treatment of pancreatic cancers are still a difficult subject in the medical profession at present.Angiogenesis is necessary for the growth and metastasis of pancreatic cancers.Cyclooxygenase (COX) is a key enzyme in the process of arachidonic acid metabolism; there are two isoenzymes of COX ( COX-1 and COX-2).COX-2 plays an important role in the development and angiogenesis of pancreatic cancers.COX-2 inhibitors can be classified into selective and non-selective types.The occurrence, progression and angiogenesis of pancreatic cancers are inhibited by both COX-2 inhibitors.The mechanism underlying anti-angiogenesis of COX-2 inhibitors includes down-regulating VEGF, hypoxia inducible factor-1 and matrix metalloproteinase (MMP) expres sions, reducing the expression of prostaglandins (PGs) and other angiogenic factors, promoting endothelial cells apoptosis, inhibiting invasion of endothelial cells and modulating the nitric oxide synthase (NOS) expression.

  2. Potential of a COX-2 inhibitor in lowering chemotherapy-induced neutropenia%Potential of a COX-2 inhibitor in lowering chemotherapy induced neutropenia

    Institute of Scientific and Technical Information of China (English)

    Louis Wing-Cheong Chow; Adrian Yun-San Yip; Eleanor Yuen-Yuen Ong; Chi-Kei Lam; Masakazu Toi

    2010-01-01

    Objective This study was initially designed to evaluate the effect of celecoxib on the regimen of 5 fluorouracil, epirubicin, and cyclophosphamide (FEC) combination, followed by docetaxel (T) in neoadjuvant setting. An unplanned preliminary review on safety was conducted after a halt of the study due to the concerned potential cardiovascular risk of using COX 2 inhibitors.Methods We studied 23 consecutive cases of operable breast cancer having received four cycles of FEC(500 mg/m2, 100 mg/m2, 500 mg/m2) followed by four cycles of T(100 mg/m2) with concurrent celecoxib (400 mg twice daily) (group A) or same chemotherapy regimen but without concurrent celecoxib (group B). These combined chemotherapies were administered every 3 weeks. The Chi square test or Fisher's exact test were used to assess the difference in incidence of limiting hematological toxicites between groups. Results 23 patients (group A: n=12; group B, n=11) received a total of 183 out of 184 planned treatment cycles; one (4%, 1/23) of them omitted the fourth cycle of FEC owing to repeated incidences of febrile neutropenia. Received dose intensity (RDI) for FEC in group A (90%±11%) was higher than that in group B (80%±8%) while RDI for T was similar between group A (93%±8%) and group B (96%±9%). Of the first 91 treatment cycles of FEC, limiting hematological toxicity, severe neutropenia including febrile neutropenia, was significantly different between group A and B [(10.4%, 5/48) vs.( 32.6%, 14/43), P=0.009]. Other toxicities commonly observed in chemotherapy receiving patients were manageable. Conclusions Neoadjuvant use of FEC followed by T with concurrent celecoxib appeared to be safe for treatment of operable invasive breast cancer. The observed lower incidence of chemotherapy induced neutropenia is possibly contributed by the administration of COX inhibitor. We believe that further investigation might provide more evidence on the use of COX 2 inhibitors in breast cancer.

  3. Design and synthesis of benzimidazole analogs endowed with oxadiazole as selective COX-2 inhibitor.

    Science.gov (United States)

    Rathore, Ankita; Rahman, Mujeeb Ur; Siddiqui, Anees Ahamad; Ali, Abuzer; Shaharyar, Mohammad

    2014-12-01

    New molecules of benzimidazole endowed with oxadiazole were designed and synthesized from 2-(2-((pyrimidin-2-ylthio)methyl)-1H-benzo[d]imidazol-1-yl)acetohydrazide as 1-((5-substituted alkyl/aryl-1,3,4-oxadiazol-2-yl)methyl)-2-((pyrimidin-2-ylthio)methyl)-1H-benzimidazoles (5a-r) with the aim to acquire selective cyclooxygenase (COX-2) inhibitor activity. The synthesized compounds were screened by in vitro cyclooxygenase assays to determine COX-1 and COX-2 inhibitory potency and the results showed that they had good-to-remarkable activity with an IC50 range of 11.6-56.1 µM. The most active compounds were further screened for their in vivo anti-inflammatory activity by using the carrageenan-induced rat paw edema model. In vitro anticancer activities of the hybrid compounds were assessed by the National Cancer Institute (NCI), USA, against 60 human cell lines, and the results showed a good spectrum. Compound 5l exhibited significant COX-2 inhibition with an IC50 value of 8.2 µM and a percent protection of 68.4%. Compound 5b evinced moderate cytotoxicity toward the UO-31 cell line of renal cancer. A docking study was performed using Maestro 9.0, to provide the binding mode into the binding sites of the cyclooxygenase enzyme. Hopefully, in the future, compound 5l could serve as a lead compound for developing new COX-2 inhibitors.

  4. Expression of beta-catenin, COX-2 and iNOS in colorectal cancer: relevance of COX-2 adn iNOS inhibitors for treatment in Malaysia.

    Science.gov (United States)

    Hong, Seok Kwan; Gul, Yunus A; Ithnin, Hairuszah; Talib, Arni; Seow, Heng Fong

    2004-01-01

    Promising new pharmacological agents and gene therapy targeting cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) could modulate treatment of colorectal cancer in the future. The aim of this study was to elucidate the expression fo beta-catenin and teh presence of COX-2 and iNOS in colorectal cancer specimens in Malaysia. This is a useful prelude to future studies investigating interventions directed towards COX-2 adn iNOS. A cross-section study using retrospective data over a 2-year period (1999-2000) involved 101 archival, formalin-fixed, paraffin-embedded tissue samples of colorectal cancers that were surgically resected in a tertiary referral. COX-2 production was detected in adjacent normal tissue in 34 sample (33.7%) and in tumour tissue in 60 samples (59.4%). More tumours expressed iNOS (82/101, 81.2%) than COX-2. No iNOS expression was detected in adjacent normal tissue. Intense beta-catenin immunoreactivity at the cell-to-cell border. Poorly differentiated tumours had significantly lower total beta-catenin (p = 0.009) and COX-2 scores (p = 0.031). No significant relationships were established between pathological stage and beta-catenin, COX-2 and iNOS scores. the accumulation of beta-catenin does not seem to be sufficient to activate pathways that lead to increased COX-2 and iNOS expression. A high proportion of colorectal cancers were found to express COX-2 and a significant number produced iNOS, suggesting that their inhibitors may be potentially useful as chemotherapeutic agents in the management of colorectal cancer.

  5. Isoorientin, a Selective Inhibitor of Cyclooxygenase-2 (COX-2) from the Tubers of Pueraria tuberosa.

    Science.gov (United States)

    Sumalatha, Manne; Munikishore, Rachakunta; Rammohan, Aluru; Gunasekar, Duvvuru; Kumar, Kotha Anil; Reddy, Kakularam Kumar; Azad, Rajaram; Reddanna, Pallu; Bodo, Bernard

    2015-10-01

    Bioassay-guided fraction of the methanol extract of the roots of Pueraria tuberose DC yielded puerarin, an isoflavone C-glycoside (PT-1), isoorientin, a flavone C-glycoside (PT-2) and mangiferin, a xanthone C-glycoside (PT-3). The extracts and the isolated compounds were screened for potent anti-inflammatory components inhibiting the cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX), the target enzymes of inflammation, by employing spectroscopic/polorographic methods. Among these, isoorientin was found to be a potent inhibitor of COX-2with an IC50 value of 39 μM. Docking studies were carried out to understand the interactions of isorientin (PT-2) with COX-2.The structures of the isolates were determined by mass spectrometry and 2D-NMR techniques including HSQC, HMBC, NOESY and 1H-1H COSY experiments. Although isoorientin and mangiferin have been reported from several plant sources, this is the first report of their isolation from a Pueraria species.

  6. [Effect of COX-2 inhibitor celecoxib on proliferation, apoptosis of HL-60 cells and its mechanism].

    Science.gov (United States)

    Xie, Xia; Li, Jie; Wang, Rui-Cang; Geng, Rui-Li; Wang, Su-Yun; Wang, Chao; Zhao, Xiao-Yun; Hao, Hong-Ling

    2014-06-01

    This study was aimed to investigate the effect of COX-2 inhibitor celecoxib on proliferation, apoptosis of human acute myeloid leukemia cell line HL-60 and its mechanism. HL-60 cells were cultured with different concentrations of celecoxib for 24 h. Cell proliferation was analyzed by CCK-8 assay, cell apoptosis and cell cycle distribution were detected by flow cytometry. Cyclin D1, cyclin E1 and COX-2 mRNA expressions were determined by RT-PCR. The results showed that after the HL-60 cells were treated with different concentrations of celecoxib for 24 h, the cell growth was significantly inhibited in a dose-dependent manner(r = 0.955), IC50 was 63.037 µmol/L of celecoxib. Celecoxib could effectively induce apoptosis in HL-60 cells also in dose-dependent manner(r = 0.988), blocked the HL-60 cells in the G0/G1 phase. The expression of cyclin D1, cyclin E1 and COX-2 mRNA were downregulated. It is concluded that celecoxib can inhibit the proliferation of HL-60 cells in dose-dependent manner, celecoxib causes cell G0/G1 arrest and induces cell apoptosis possibly through down-regulation of the cyclin D1 and cyclin E1 expression, and down-regulation of COX-2 expression respectively.

  7. The synthesis of isotopic fluorine and iodine-labeled COX-II inhibitor and in vitro validation

    Energy Technology Data Exchange (ETDEWEB)

    An, Gwang Gil; Lee, Tae Sub; Lee, Kyo Chul; Moon, Byung Seok; Choi, Chang Woon; Chun, Kwon Soo [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2005-07-01

    In these day, NASIDs (non-steroidal antiinflammatory drugs) such as aspirin, diclofenac and ibuprofen are the most common medications used to reduce pain and inflammation. However, they act by inhibiting both COX-I and COX-II which can cause serious gastrointestinal side effects such as ulcers, stomach perforations and bleeds. COX-I produces prostaglandins believed to be responsible for the protection of the stomach lining. However, COX-II produces prostaglandins believed to be responsible for pain and inflammation. Recently, the most widely studied selective COX-II inhibitor such as celecoxib and rofecoxib' one work by inhibiting the effect of COX-II on pain and inflammation without inhibiting COX-I which protects gastrointestinal lining.

  8. Design and synthesis of a biotinylated probe of COX-2 inhibitor nimesulide analog JCC76.

    Science.gov (United States)

    Zhong, Bo; Lama, Rati; Smith, Kerri M; Xu, Yan; Su, Bin

    2011-09-15

    JCC76 is a derivative of cyclooxygenase-2(COX-2) selective inhibitor nimesulide and exhibits potent anti-breast cancer activity. It selectively induces apoptosis of Her2 positive breast cancer cells. However, the specific molecular targets of JCC76 still remain unclear, which significantly withdraw the further drug development of JCC76. To identify the molecular targets of JCC76, a six carbon linker and biotin conjugated JCC76 probe was designed and synthesized. The anti-proliferation activity of the probe and its analogs was evaluated.

  9. Synthesis and evaluation of benzimidazole derivatives as selective COX-2 inhibitors.

    Science.gov (United States)

    Rathore, Ankita; Mujeeb-Ur-Rahman; Siddiqui, Anees A; Ali, Abuzer; Yar, Mohammad Shahar

    2015-01-01

    A new series of 1-{(5-substituted-alkyl/aryl-1,3,4-oxadiazol-2-yl)methyl}-2-(piperidin-1-ylmethyl)-1Hbenzimidazoles (5a-5r) was synthesized and screened for their inhibitory activity against COX (1 and 2). In vivo antiinflammatory activity of potent compounds was done by carrageenan-induced rat paw edema model. In vitro anticancer activity of synthesized compounds was also performed at the National Cancer Institute (NCI) against NCI 60 cell lines panel. Out of the 18 compounds screened, 5h, 5i, 5j and 5l were found to be potent COX-2 inhibitors in the range of IC50 0.06-0.81 μM. In vivo anti-inflammatory screening results revealed that the compounds 5h and 5j manifested profound percent protection of 72.8 and 75.0%, respectively. Compound 5f exhibited moderate cytotoxicity with 58.79% growth inhibition against SNB-75 (CNS Cancer) cell lines and moderate activity against COX-2 (IC50 = 8.0 μM).

  10. Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation

    Science.gov (United States)

    Bu, Li-Jia; Yu, Han-Qing; Fan, Lu-Lu; Li, Xiao-Qiu; Wang, Fang; Liu, Jia-Tao; Zhong, Fei; Zhang, Cong-Jun; Wei, Wei; Wang, Hua; Sun, Guo-Ping

    2017-01-01

    AIM To clarify the mechanisms involved in the critical endoplasmic reticulum (ER) stress initiating unfolded protein response pathway modified by melatonin. METHODS Hepatoma cells, HepG2, were cultured in vitro. Flow cytometry and TUNEL assay were used to measure HepG2 cell apoptosis. Western blotting and quantitative reverse transcription-polymerase chain reaction methods were used to determine the protein and messenger RNA levels of ER stress and apoptosis related genes’ expression, respectively. Tissue microarray construction from patients was verified by immunohistochemical analysis. RESULTS In the present study, we first identified that melatonin selectively blocked activating transcription factor 6 (ATF-6) and then inhibited cyclooxygenase-2 (COX-2) expression, leading to enhanced liver cancer cell apoptosis under ER stress condition. Dramatically increased CCAAT-enhancer-binding protein homologous protein level, suppressed COX-2 and decreased Bcl-2/Bax ratio by melatonin or ATF-6 siRNA contributed the enhanced HepG2 cell apoptosis under tunicamycin (an ER stress inducer) stimulation. In clinical hepatocellular carcinoma patients, the close relationship between ATF-6 and COX-2 was further confirmed. CONCLUSION These findings indicate that melatonin as a novel selective ATF-6 inhibitor can sensitize human hepatoma cells to ER stress inducing apoptosis. PMID:28246472

  11. Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation.

    Science.gov (United States)

    Bu, Li-Jia; Yu, Han-Qing; Fan, Lu-Lu; Li, Xiao-Qiu; Wang, Fang; Liu, Jia-Tao; Zhong, Fei; Zhang, Cong-Jun; Wei, Wei; Wang, Hua; Sun, Guo-Ping

    2017-02-14

    To clarify the mechanisms involved in the critical endoplasmic reticulum (ER) stress initiating unfolded protein response pathway modified by melatonin. Hepatoma cells, HepG2, were cultured in vitro. Flow cytometry and TUNEL assay were used to measure HepG2 cell apoptosis. Western blotting and quantitative reverse transcription-polymerase chain reaction methods were used to determine the protein and messenger RNA levels of ER stress and apoptosis related genes' expression, respectively. Tissue microarray construction from patients was verified by immunohistochemical analysis. In the present study, we first identified that melatonin selectively blocked activating transcription factor 6 (ATF-6) and then inhibited cyclooxygenase-2 (COX-2) expression, leading to enhanced liver cancer cell apoptosis under ER stress condition. Dramatically increased CCAAT-enhancer-binding protein homologous protein level, suppressed COX-2 and decreased Bcl-2/Bax ratio by melatonin or ATF-6 siRNA contributed the enhanced HepG2 cell apoptosis under tunicamycin (an ER stress inducer) stimulation. In clinical hepatocellular carcinoma patients, the close relationship between ATF-6 and COX-2 was further confirmed. These findings indicate that melatonin as a novel selective ATF-6 inhibitor can sensitize human hepatoma cells to ER stress inducing apoptosis.

  12. Low-dose aspirin, non-steroidal anti-inflammatory drugs, selective COX-2 inhibitors and breast cancer recurrence

    DEFF Research Database (Denmark)

    Cronin-Fenton, Deirdre P; Heide-Jørgensen, Uffe; Ahern, Thomas P

    2016-01-01

    BACKGROUND: Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and selective COX-2 inhibitors may improve outcomes in breast cancer patients. We investigated the association of aspirin, NSAIDs, and use of selective COX-2 inhibitors with breast cancer recurrence. METHODS: We identified incident...... stage I-III Danish breast cancer patients in the Danish Breast Cancer Cooperative Group registry, who were diagnosed during 1996-2008. Prescriptions for aspirin (>99% low-dose aspirin), NSAIDs, and selective COX-2 inhibitors were ascertained from the National Prescription Registry. Follow-up began...... on the date of breast cancer primary surgery and continued until the first of recurrence, death, emigration, or 1 January 2013. We used Cox regression models to compute hazard ratios (HR) and corresponding 95% confidence intervals (95% CI) associating prescriptions with recurrence, adjusting for confounders...

  13. Effect of COX-2 inhibitor after TNBS-induced colitis in Wistar rats.

    Science.gov (United States)

    Paiotti, Ana Paula Ribeiro; Miszputen, Sender Jankiel; Oshima, Celina Tizuko Fujiyama; de Oliveira Costa, Henrique; Ribeiro, Daniel Araki; Franco, Marcello

    2009-08-01

    Inflammatory bowel disease (IBD) is a common chronic gastrointestinal disorder characterized by alternating periods of remission and active intestinal inflammation. Some studies suggest that antiinflammatory drugs are a promising alternative for treatment of the disease. Thus, this study aimed to evaluate the effect of lumiracoxib, a selective-cyclooxygenase-2 (COX-2) inhibitor, on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis. Wistar rats (n = 25) were randomized into four groups, as follows: Group (1) Sham group: sham induced-colitis rats; Group (2) TNBS group: nontreated induced-colitis rats; Group (3) Lumiracoxib control group; and Group (4) Lumiracoxib-treated induced-colitis rats. Our results showed that rats from groups 2 and 4 presented similar histopathological damage and macroscopic injury in the distal colon as depicted by significant statistically differences (P TNBS-induced experimental colitis. Thus, the use of COX-2 inhibitors for treating IBD should be considered with caution and warrants further experimental investigation to elucidate their applicability.

  14. COX inhibitors Indomethacin and Sulindac derivatives as antiproliferative agents: synthesis, biological evaluation, and mechanism investigation.

    Science.gov (United States)

    Chennamaneni, Snigdha; Zhong, Bo; Lama, Rati; Su, Bin

    2012-10-01

    Cyclooxygenase (COX) inhibitors Indomethacin and its structural analogs Sulindac exhibit cell growth inhibition and apoptosis inducing activities in various cancer cell lines via COX independent mechanisms. In this study, the molecular structures of Indomethacin and Sulindac were used as starting scaffolds to design novel analogs and their effects on the proliferation of human cancer cells were evaluated. Compared to Indomethacin and Sulindac inhibiting cancer cell proliferation with IC(50)s of more than 1 mM, the derivatives displayed significantly increased activities. Especially, one of the Indomethacin analogs inhibited the growth of a series of cancer cell lines with IC(50)s around 0.5 μM-3 μM. Mechanistic investigation revealed that the new analog was in fact a tubulin inhibitor, although the parental compound Indomethacin did not show any tubulin inhibitory activity. Tubulin polymerization assay indicated this compound inhibited tubulin assembly at high concentrations, but promoted this process at low concentrations which is a very unique mechanism. The binding mode of this compound in tubulin was predicted using the molecular docking simulation.

  15. QSAR analysis of furanone derivatives as potential COX-2 inhibitors: kNN MFA approach

    Directory of Open Access Journals (Sweden)

    Ruchi Bhatiya

    2014-12-01

    Full Text Available A series of thirty-two furanone derivatives with their cyclooxygenase-2 inhibitory activity were subjected to quantitative structural–activity relationship analysis to derive a correlation between biological activity as a dependent variable and various descriptors as independent variables by using V-LIFE MDS3.5 software. The significant 2D QSAR model showed correlation coefficient (r2 = 0.840, standard error of estimation (SEE = 0.195, and a cross-validated squared correlation coefficient (q2 = 0.773. The descriptors involved in the building of 2D QSAR model are retention index for six membered rings, total number of oxygen connected with two single bonds, polar surface area excluding P and S plays a significant role in COX-2 inhibition. 3D-QSAR performed via Step Wise K Nearest Neighbor Molecular Field Analysis [(SW kNN MFA] with partial least-square (PLS technique showed high predictive ability (r2 = 0.7622, q2 = 0.7031 and standard error = 0.3660 explaining the majority of the variance in the data with two principle components. The results of the present study may be useful in the design of more potent furanone derivatives as COX-2 inhibitors.

  16. Effects of selective and non-selective inhibitors of nitric oxide synthase on morphine- and endomorphin-1-induced analgesia in acute and neuropathic pain in rats.

    Science.gov (United States)

    Makuch, Wioletta; Mika, Joanna; Rojewska, Ewelina; Zychowska, Magdalena; Przewlocka, Barbara

    2013-12-01

    Nitric oxide (NO) has been reported to be involved in the mechanisms of pain generation throughout the nervous system. We examined the effects of intrathecally (i.t.) administered nitric oxide synthase (NOS) inhibitors on the antinociceptive effects of morphine and endomorphin-1 during acute pain and in chronic constriction injury (CCI)-exposed rats. We used N(G)-nitro-l-arginine methyl ester (l-NAME), a non-selective NOS inhibitor; 7-nitroindazole (7-NI) or 1-(2-trifluoromethyl-phenyl)-imidazole (TRIM), selective inhibitors of neuronal NOS (NOS1); and 1400W dihydrochloride, a selective inhibitor of inducible NOS (NOS2). Morphine (0.5-2.5 μg) and endomorphin-1 (2.5-20 μg) in acute pain and morphine (10-40 μg) and endomorphin-1 (5-20 μg) after CCI-injury were combined with NOS inhibitors. For acute pain, the ED50 for endomorphin-1 (7.1 μg) was higher than that of morphine (1.3 μg) in the tail-flick test. For neuropathic pain, the ED50 value for morphine was much higher (43.2 μg) than that of endomorphin-1 (9.2 μg) in von Frey test. NOS inhibitors slightly influenced pain thresholds in both pain models. Moreover, in neuropathic pain, the effects of morphine were more potentiated by L-NAME, TRIM, 7-NI and 1400W (12×, 8.6×, 4.1× and 5.3×, respectively) than were the effects of endomorphin-1 (2.7×, 4.3×, 3.4× and 2.1×, respectively) in the von Frey test. Minocycline which is known to enhance the efficiency of morphine in neuropathic pain, decreased the mRNA expression of NOS1 in the DRG and NOS2 and C1q in the spinal cord after CCI. Both NOS2 and IBA-1 protein levels in the spinal cord and NOS1, NOS2 and IBA1 protein levels in DRG decreased after minocycline administration. In conclusion, our results provide evidence that both neuronal and non-neuronal NOS/NO pathways contribute to the behavioural pain responses evoked by nerve injury. The NOS inhibitors regardless of the type of pain enhanced morphine antinociception and, to a lesser extent, altered the

  17. Resistance of prostate cancer cell lines to COX-2 inhibitor treatment.

    Science.gov (United States)

    Wagner, Matthew; Loos, James; Weksler, Nicole; Gantner, Marin; Corless, Christopher L; Barry, John M; Beer, Tomasz M; Garzotto, Mark

    2005-07-08

    Targeting of cyclooxygenase-2 (COX-2) for cancer chemoprevention is well supported for several tumor types, most notably colon cancer. In contrast, the data for its role in prostate cancer carcinogenesis are correlative only. Thus, we compared the COX-2 expression, activity, and effects of inhibition in prostate cancer cells on COX-2-dependent colon cancer cells. COX-2 levels in benign and malignant human prostate tissue were determined by immunohistochemistry. Compared to colon cancer cells, prostate cancer cells expressed lower levels of COX-2, produced less PGE2, and were resistant to selective COX-2 inhibition. Examination of benign prostatic epithelium from prostatectomy samples demonstrated rare foci of COX-2. Whereas, human prostate cancer sections were uniformly negative for COX-2. In conclusion, these studies indicate the lack of a putative role for COX-2 in prostate cancer development. Direct evidence for the involvement of COX-2 in prostate cancer carcinogenesis is desperately needed.

  18. A computer simulation of progesterone and Cox2 inhibitor treatment for preterm labor.

    Directory of Open Access Journals (Sweden)

    Ozlem Equils

    Full Text Available BACKGROUND: Sufficient information from in vitro and in vivo studies has become available to permit computer modeling of the processes that occur in the myometrium during labor. This development allows the in silico investigation of pathological mechanisms and the trialing of potential treatments. METHODS/RESULTS: Based on the human literature, we developed a computer model of the immune-endocrine environment of the myometrial cell. The interactions between molecules are represented by differential equations. The model is designed to simulate the estrogen and progesterone receptor changes during pregnancy and particularly the changes in the progesterone receptor (PR isoforms A and B that are thought to mediate functional progesterone withdrawal in the human at labor. Parturition is represented by an increase in the PRA to PRB ratio to levels seen in women in labor. Infection is shown by inducing inflammation in the system by increasing phospho-IkB kinase concentration (IKK levels; which lead to increased NF-kappaB activation, causing an increase in the PRA/PRB ratio. We examined the effects of progesterone or cyclo-oxygenase 2 (Cox2 inhibitor treatments on the PRA/PRB ratio in silico. The model predicted that high doses of progesterone and Cox2 inhibition would be effective in preventing an NF-kappaB-induced PRA/PRB ratio increase to the levels found during labor. CONCLUSIONS: Our data illustrate the use of dynamic biological computer simulations to test the effectiveness of therapeutic interventions. This may allow the early rejection of ineffective therapies prior to expensive field trials.

  19. Radiosensitizing potential of the selective cyclooygenase-2 (COX-2) inhibitor meloxicam on human glioma cells

    NARCIS (Netherlands)

    Bijnsdorp, Irene; Berg, van den Jaap; Kuipers, Gitta; Wedekind, Laurine; Slotman, Ben; Rijn, van Johannes; Lafleur, M.; Sminia, Peter

    2007-01-01

    The COX-2 protein is frequently overexpressed in human malignant gliomas. This expression has been associated with their aggressive growth characteristics and poor prognosis for patients. Targeting the COX-2 pathway might improve glioma therapy. In this study, the effects of the selective COX-2 in

  20. The selective and non-selective cyclooxygenase inhibitors valdecoxib and piroxicam induce the same postoperative analgesia and control of trismus and swelling after lower third molar removal

    Directory of Open Access Journals (Sweden)

    V. Benetello

    2007-08-01

    Full Text Available We compared the clinical efficacy of orally administered valdecoxib and piroxicam for the prevention of pain, trismus and swelling after removal of horizontally and totally intrabony impacted lower third molars. Twenty-five patients were scheduled to undergo removal of symmetrically positioned lower third molars in two separate appointments. Valdecoxib (40 mg or piroxicam (20 mg was administered in a double-blind, randomized and crossed manner for 4 days after the surgical procedures. Objective and subjective parameters were recorded for comparison of postoperative courses. Both agents were effective for postoperative pain relief (N = 19. There was a similar mouth opening at suture removal compared with the preoperative values (86.14 ± 4.36 and 93.12 ± 3.70% of the initial measure for valdecoxib and piroxicam, respectively; ANOVA. There was no significant difference regarding the total amount of rescue medication taken by the patients treated with valdecoxib or piroxicam (173.08 ± 91.21 and 461.54 ± 199.85 mg, respectively; Wilcoxon test. There were no significant differences concerning the swelling observed on the second postoperative day compared to baseline measures (6.15 ± 1.84 and 8.46 ± 2.04 mm for valdecoxib and piroxicam, respectively; ANOVA or on the seventh postoperative day (1.69 ± 1.61 and 2.23 ± 2.09 mm for valdecoxib and piroxicam, respectively; ANOVA. The cyclooxygenase-2 selective inhibitor valdecoxib is as effective as the non-selective cyclooxygenase inhibitor piroxicam for pain, trismus and swelling control after removal of horizontally and totally intrabony impacted lower third molars.

  1. The Gastrointestinal and Cardiovascular Safety of COX-2 selective inhibitors in general practice: the contribution of Prescription-Event Monitoring

    NARCIS (Netherlands)

    Layton, D.

    2007-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for many conditions, especially in the elderly. Whilst effective, they also have side-effects, most commonly on the stomach. Advances in the understanding of how NSAIDs work in the body led to newer NSAIDs (COX-2 selective inhibitors whi

  2. JTE-522, a selective COX-2 inhibitor, inhibits growth of pulmonary metastases of colorectal cancer in rats

    Directory of Open Access Journals (Sweden)

    Enomoto Masayuki

    2005-03-01

    Full Text Available Abstract Background Epidemiological studies have shown that individuals who regularly consume NSAIDs have lower rates of mortality associated with colorectal cancer. Because COX-2 inhibitors prevent tumor growth through some mechanisms, we assessed the effect of JTE-522, a selective COX-2 inhibitor, on pulmonary metastases of colon cancer in a rat model. Methods A suspension of 5 × 106 RCN-9 (rat colon cancer cells was injected into the tail vein of 24 anesthetized male F344/DuCrj rats. Oral JTE-522 (0, 3, 10, or 30 mg/kg/day was administered from the day before RCN-9 injection until the end of the study. Twenty-four days later, the lungs were removed from sacrificed rats and weighed. Pulmonary metastatic tumors were microscopically evaluated in the largest cross sections. We also performed immunohistochemical staining for both COX-2 and VEGF. Results JTE-522 dose-dependently decreased lung weight (p = 0.001 and the size of pulmonary metastatic tumors (p = 0.0002. However, the differences in the number of metastatic tumors among 4 groups were insignificant. Significant adverse effects of JTE-522 were undetectable. Immunohistochemical staining showed high levels of both COX-2 and VEGF in pulmonary metastatic tumors. Conclusion JTE-522 dose-dependently decreased the size, but not the number of pulmonary metastases. COX-2 inhibitors might block metastatic tumor growth, but not actual metastasis. Selective COX-2 inhibitors might be useful as therapeutic agents that inhibit the growth of metastatic tumors, as well as the tumorigenesis of colorectal cancer.

  3. Limited efficacy of COX-2 inhibitors on nerve growth factor and metalloproteinases expressions in human synovial fibroblasts.

    Science.gov (United States)

    Yorifuji, Makiko; Sawaji, Yasunobu; Endo, Kenji; Kosaka, Taiichi; Yamamoto, Kengo

    2016-05-01

    Nerve growth factor (NGF) is associated with arthritic pain and metalloproteinases are implicated in collagen and aggrecan degradation. Although selective COX-2 inhibitors are recommended for the treatment of arthritic diseases, their effects on NGF and metalloproteinases remain unclear. This study investigated the regulations of NGF and metalloproteinases by selective COX-2 inhibitors in isolated human synovial cells. The isolated human synovial cells were stimulated with IL-1β in the presence of selective COX-2 inhibitors (NS-398 or celecoxib) with or without exogenous PGE2 or its receptor (EP1-4) agonists. The expressions of NGF, MMP-1, -3, -13, ADAMTS-4, and -5 were quantified by real-time PCR and their proteins were determined by Western blotting. The amount of PGE2 released was measured by enzyme-linked immunosorbent assay (ELISA). The IL-1β inductions of NGF and MMP-1 and MMP-13 were augmented by the COX-2 inhibitors, whereas the inductions of ADAMTS-4 and ADAMTS-5 were inhibited. These actions were reversed by supplementing PGE2 or the EP4 agonist exogenously. Our comprehensive analysis revealed that COX-2 inhibitors may be beneficial for suppressing aggrecan degradation and for reducing inflammatory pain by inhibiting PGE2 release, although they may have limited efficacy in suppressing collagen degradation and nerve growth. This study suggests the feedback roles of PGE2 in the negative regulation of NGF and MMP-1 and MMP-13 and the positive regulation of ADAMTS-4 and ADAMTS-5. Copyright © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

  4. A STUDY OF COX-2 INHIBITOR CELECOXIB AND CHEMORADIATION IN PATIENTS WITH LOCALLY ADVANCED CERVICAL CANCER

    Directory of Open Access Journals (Sweden)

    Kuppa Prakash

    2016-08-01

    Full Text Available AIMS AND OBJECTIVES To evaluate efficacy of concurrent oral Cox-2 Inhibitor (celecoxib and chemoradiation in locoregional control, distant control, disease free survival and/or overall survival in patients with locally advanced cervical cancer. To determine treatment related toxicity rates in patients with locally advanced cervical cancer treated by oral celecoxib, intravenous cisplatin and concurrent pelvic radiation therapy. MATERIALS AND METHODS Study was done for a period of 2 years in a tertiary care cancer hospital which caters to the cancer patients. Advanced squamous, adenocarcinoma or adenosquamous carcinoma of uterine cervix, Patients with age <70 years, ECOG performance status 0-2, Normal haematological investigations, Normal renal function test, Normal liver function test, No disease outside of pelvis. RESULTS This prospective study consisted 30 patients, 15 patients on either arm. Overall pooled mean age for both study and comparison group was 50.3 years with a probability value P=0.91 for age. 14 patients (93.33% in both the arms had a performance status of ECOG 0 or 1 and 1 patient in both arms had ECOG PS-2. Stage distribution of the patients in study arm was 3 in IB2, 2 in IIA, 5 in IIB, 4 in III and 1 in stage IVA. In control arm, out of the 15 patients 2 are in IB2, 2 in IIA, 5 in IIB, 5 in III and 1 in stage IVA. The mean probability value was P=0.65 for stage distribution. 15 patients in arm-A (study arm received pelvic RT 50Gy 2Gy/Fr 5#/week followed by HDR –ICR 3 Fr. 700 cGy/Fr after pelvic RT on an average of 1 week along with weekly cisplatin 40 mg/m2 (50 mg (D1, D8, D15, D22 and Cox-2 inhibitor oral celecoxib 400 mg twice daily (800 mg/d starting from day 1 to throughout the duration of the chemoradiation. 15 patients in arm-B (Control arm received pelvic RT 50Gy 2Gy/Fr 5#/week followed by HDR –ICR 3 Fr. 700 cGy/Fr on an average of 1 week after pelvic RT along with weekly cisplatin 40 mg/m2 (50 mg (D1, D8, D15, D22

  5. Role of bile acids, prostaglandins and COX inhibitors in chronic esophagitis in a mouse model

    Institute of Scientific and Technical Information of China (English)

    C Poplawski; D Sosnowski; A Szaflarska-Poplawska; J Sarosiek; R McCallum; Z Bartuzi

    2006-01-01

    AIM: To develop a new experimental model of esophagitis that serves a complementary tool to clinical investigation in an insight into the mechanism of the damage to the esophagus mucosa by aggressive factors, and role of COX inhibitors in this process.METHODS: The study was conducted in 56 male mice.Animals were divided into seven groups: (1) perfused with HCl, (2) perfused with HCl and physiologic concentration of pepsin (HCl/P), (3) perfused with similar HCl/P solution enriched with conjugated bile acids (glycho- and tauro-sodium salts) designated esophageal infusion catheter under the general anesthesia, (4) perfused as in group 2 treated with indometacin, (5) perfused as in group 2 treated with NS-398, (6) perfused as in group 3 treated with indometacin, and (7) perfused as in group 3 treated with NS-398.The esophagus was divided into 3 parts: upper, middle and lower. The PGE2 concentration was measured in all parts of esophagus using RIA method. Esophagus of sacrificed animals was macroscopically evaluated using a low power dissecting microscope (20x). Specimeris, representing the most frequently seen changes were fixed,stained with H&E and assessed microscopically using the damage score, and inflammatory score.RESULTS: The macroscopic changes were significantly severer in HCl/P than those in HCl animals (77%) and in HCl/P/BA group (43%). In HCl/P NS-398 group we noticed significantly less changes than those in not treated group (42%) and in analogical group treated with indometacine (45%). In HCl/P/BA INDO group we observed significantly severer changes than that in not treated group (52%). We noticed less changes in HCl/P NS-398 than that in group with indometacine (46%). In HCl/P/BA NS-398 group we had less changes than that in indometacin group (34%). The microscopic changes observed in HCl/P/BA INDO group were severer than that in not treated group (48%). Esophagitis index in HCl group was significantly lower than in HCl/P and also HCl/P/BA group (32% and

  6. Molecular Dynamic Screening Sesquiterpenoid Pogostemon Herba as Suggested Cyclooxygenase Inhibitor.

    Science.gov (United States)

    Raharjo, Sentot Joko; Kikuchi, Takeshi

    2016-10-01

    Virtual molecular dynamic sesquiterpenoid Pogostemon Herba (CID56928117, CID94275, CID107152, and CID519743) have screening as cyclooxygenase (COX-1/COX-2) selective inhibitor. Molecular interaction studies sesquiterpenoid compounds with COX-1 and COX-2 were using the molecular docking tools by Hex 8.0 and interactions were further visualized using by Discovery Studio Client 3.5 software tool and Virtual Molecular Dynamic 1.9.1 software. The binding energy calculation of molecular dynamic interaction was calculated by AMBER12 software. The analysis of the sesquiterpenoid compounds showed that CID56928117, CID94275, CID107152, and CID519743 have suggested as inhibitor of COX-1 and COX-2. Collectively, the scoring binding energy calculation (with PBSA Model Solvent) sesquiterpenoid compounds: CID519743 had suggested as candidate for non-selective inhibitor; CID56928117 and CID94275 had suggested as candidate for a selective COX-1 inhibitor; and CID107152 had suggested as candidate for a selective COX-2 inhibitor.

  7. Coumarin sulfonamides derivatives as potent and selective COX-2 inhibitors with efficacy in suppressing cancer proliferation and metastasis.

    Science.gov (United States)

    Lu, Xiao-Yuan; Wang, Zhong-Chang; Ren, Shen-Zhen; Shen, Fa-Qian; Man, Ruo-Jun; Zhu, Hai-Liang

    2016-08-01

    Cyclooxygenase-2 is frequently overexpression in malignant tumors and the product PGE2 promotes cancer cell progression and metastasis. We designed novel series of coumarin sulfonamides derivatives to improve biological activities of COX-2 inhibition and anticancer. Among them, compound 7t showed most powerful selective inhibitory and antiproliferative activity (IC50=0.09μM for COX-2, IC50=48.20μM for COX-1, IC50=0.36μM against HeLa cells), comparable to the control positive compound Celecoxib (0.31μM, 43.37μM, 7.79μM). Cancer cell apoptosis assay were performed and results indicated that compound 7t effectively fuels HeLa cells apoptosis in a dose and time-dependent manner. Moreover, 7t could significantly suppress cancer cell adhesion, migration and invasion which were essential process of cancer metastasis. Docking simulations results was further indicated that compound 7t could bind well to the COX-2 active site and guided a reasonable design of selective COX-2 inhibitor with anticancer activities in future.

  8. A COX-2 inhibitor reduces muscle soreness, but does not influence recovery and adaptation after eccentric exercise

    DEFF Research Database (Denmark)

    Paulsen, G; Egner, I M; Drange, M

    2010-01-01

    The aim of this study was to investigate the effect of a cyclooxygenase (COX)-2 inhibitor on the recovery of muscle function, inflammation, regeneration after, and adaptation to, unaccustomed eccentric exercise. Thirty-three young males and females participated in a double-blind, placebo...... by celecoxib. In summary, celecoxib, a COX-2 inhibitor, did not detectably affect recovery of muscle function or markers of inflammation and regeneration after unaccustomed eccentric exercise, nor did the drug influence the repeated-bout effect. However, it alleviated muscle soreness.......-controlled experiment. Seventy unilateral, voluntary, maximal eccentric actions with the elbow flexors were performed twice (bouts 1 and 2) with the same arm, separated by 3 weeks. The test group participants were administered 400 mg/day of celecoxib for 9 days after bout 1. After both bouts 1 and 2, concentric...

  9. COX-2: A Pivotal Enzyme in Mucosal Protection and Resolution of Inflammation

    Directory of Open Access Journals (Sweden)

    John L. Wallace

    2006-01-01

    Full Text Available The discovery of a second form of cyclooxygenase, COX-2, led to a burst of research aimed at the development of nonsteroidal anti-inflammatory drugs that would not damage the gastrointestinal tract. In the years since, this promise has only been partially fulfilled. Selective COX-2 inhibitors cause less gastric damage than conventional, nonselective COX inhibitors, but their use is still associated with significant gastrointestinal injury, and with toxicity in the renal and cardiovascular systems. COX-2 is now recognized as a source of mediators that produce many beneficial and detrimental effects in the digestive system. In this review, the roles of COX-2 in mucosal defense and injury are discussed. Furthermore, contributions of COX-2–derived products to the long-term consequences of intestinal inflammation, including cancer, are reviewed.

  10. Evaluation of risk profiles for gastrointestinal and cardiovascular adverse effects in nonselective NSAID and COX-2 inhibitor users - A cohort study using pharmacy dispensing data in the Netherlands

    NARCIS (Netherlands)

    Layton, Deborah; Souverein, Patrick C.; Heerdink, Eibert R.; Shakir, Saad A. W.; Egberts, Antoine C. G.

    2008-01-01

    Background: Newly approved drugs, in comparison with older drugs, are more often prescribed to patients who have not responded satisfactorily to established related drugs or as first-line therapy to patients with a high baseline risk for adverse outcomes (i.e. channelling). However, these patients a

  11. Mitochondrial toxicity of selective COX-2 inhibitors via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria

    DEFF Research Database (Denmark)

    Syed, Muzeeb; Skonberg, Christian; Hansen, Steen Honoré

    2016-01-01

    Cyclooxygenase-2 (COX-2) inhibitors (coxibs) are non-steroidal anti-inflammatory drugs (NSAIDs) designed to selectively inhibit COX-2. However, drugs of this therapeutic class are associated with drug induced liver injury (DILI) and mitochondrial injury is likely to play a role. The effects...... of selective COX-2 inhibitors on inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria were investigated. The order of potency of inhibition of ATP synthesis was: lumiracoxib (IC50: 6.48 ± 2.74 μM)>celecoxib (IC50: 14.92 ± 6.40 μM)>valdecoxib (IC50: 161.4 ± 28.6 μM)>rofecoxib (IC50...... correlation (with r(2)=0.921) was observed between the potency of inhibition of ATP synthesis and the log P values. The in vitro metabolism of coxibs in rat liver mitochondria yielded for each drug substance a major single metabolite and identified a hydroxy metabolite with each of the coxibs...

  12. Insights from the docking analysis of biologically active compounds from plant Litsea Genus as potential COX-2 inhibitors.

    Science.gov (United States)

    Gogoi, Dhrubajyoti; Bezbaruah, Rajib Lochan; Bordoloi, Manabjyoti; Sarmah, Rajeev; Bora, Tarun Chandra

    2012-01-01

    Litsea spp of Laural family are traditionally used as herbal medicine for treating inflammation including gastroenterologia, oedema and rheumatic arthritis. Therefore, it is of interest to investigate and understand the molecular principles for such actions. Here, we have illustrated the binding of thirteen Litsea derived biologically active compounds against the inflammation associated target COX (cyclo-oxygenase) -2 enzymes. We compared the binding information of these compounds with a selected number of already known COX-2 inhibitors. The comparison reflected that some of these compounds such as linderol, catechin, 6'-hydroxy-2',3',4' - trimethoxy-chalcone and litseaone have better or equivalent binding features compared to already known inhibitory compounds namely celecoxib, acetylsalicylic acid, rofecoxib. Therefore, all these small compounds reported from plant Litsea spp were found to possess potential medicinal values with anti-inflammatory properties.

  13. Insights from the docking analysis of biologically active compounds from plant Litsea Genus as potential COX-2 inhibitors

    Science.gov (United States)

    Gogoi, Dhrubajyoti; Bezbaruah, Rajib Lochan; Bordoloi, Manabjyoti; Sarmah, Rajeev; Bora, Tarun Chandra

    2012-01-01

    Litsea spp of Laural family are traditionally used as herbal medicine for treating inflammation including gastroenterologia, oedema and rheumatic arthritis. Therefore, it is of interest to investigate and understand the molecular principles for such actions. Here, we have illustrated the binding of thirteen Litsea derived biologically active compounds against the inflammation associated target COX (cyclo-oxygenase) -2 enzymes. We compared the binding information of these compounds with a selected number of already known COX-2 inhibitors. The comparison reflected that some of these compounds such as linderol, catechin, 6'-hydroxy-2',3',4' - trimethoxy-chalcone and litseaone have better or equivalent binding features compared to already known inhibitory compounds namely celecoxib, acetylsalicylic acid, rofecoxib. Therefore, all these small compounds reported from plant Litsea spp were found to possess potential medicinal values with anti-inflammatory properties. PMID:23139590

  14. Efficacy and tolerability of naproxen/esomeprazole magnesium tablets compared with non-specific NSAIDs and COX-2 inhibitors: a systematic review and network analyses

    Directory of Open Access Journals (Sweden)

    Datto C

    2013-02-01

    Full Text Available Catherine Datto,1 Richard Hellmund,1 Mohd Kashif Siddiqui21AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA; 2HERON PVT India, Chandigarh, UT, IndiaAbstract: Non-steroidal anti-inflammatory drugs (NSAIDs, such as non-selective NSAIDs (nsNSAIDs or selective cyclooxygenase-2 (COX-2 inhibitors, are commonly prescribed for arthritic pain relief in patients with osteoarthritis (OA, rheumatoid arthritis (RA, or ankylosing spondylitis (AS. Treatment guidelines for chronic NSAID therapy include the consideration for gastroprotection for those at risk of gastric ulcers (GUs associated with the chronic NSAID therapy. The United States Food and Drug Administration has approved naproxen/esomeprazole magnesium tablets for the relief of signs and symptoms of OA, RA, and AS, and to decrease the risk of developing GUs in patients at risk of developing NSAID-associated GUs. The European Medical Association has approved this therapy for the symptomatic treatment of OA, RA, and AS in patients who are at risk of developing NSAID-associated GUs and/or duodenal ulcers, for whom treatment with lower doses of naproxen or other NSAIDs is not considered sufficient. Naproxen/esomeprazole magnesium tablets have been compared with naproxen and celecoxib for these indications in head-to-head trials. This systematic literature review and network meta-analyses of data from randomized controlled trials was performed to compare naproxen/esomeprazole magnesium tablets with a number of additional relevant comparators. For this study, an original review examined MEDLINE®, Embase®, and the Cochrane Controlled Trials Register from database start to April 14, 2009. Using the same methodology, a review update was conducted to December 21, 2009. The systematic review and network analyses showed naproxen/esomeprazole magnesium tablets have an improved upper gastrointestinal tolerability profile (dyspepsia and gastric or gastroduodenal ulcers over several active comparators (naproxen

  15. Selective COX-2 inhibitor, NS-398, suppresses cellular proliferation in human hepatocellular carcinoma cell lines via cell cycle arrest

    Institute of Scientific and Technical Information of China (English)

    Ji Yeon Baek; Wonhee Hur; Jin Sang Wang; Si Hyun Bae; Seung Kew Yoon

    2007-01-01

    AIM: To investigate the growth inhibitory mechanism of NS-398, a selective cyclooxygenase-2 (COX-2) inhibitor,in two hepatocellular carcinoma (HCC) cell lines (HepG2and Huh7).METHODS: HepG2 and Huh7 cells were treated with NS-398. Its effects on cell viability, cell proliferation,cell cycles, and gene expression were respectively evaluated by water-soluble tetrazolium salt (WST-1)assay, 4'-6-diamidino-2-phenylindole (DAPI) staining,flow cytometer analysis, and Western blotting,with dimethyl sulfoxide (DMSO) as positive control.RESULTS: NS-398 showed dose- and time-dependent growth-inhibitory effects on the two cell lines.Proliferating cell nuclear antigen (PCNA) expressions in HepG2 and Huh7 cells, particularly in Huh7 cells were inhibited in a time- and dose-independent manner.NS-398 caused cell cycle arrest in the G1 phase with cell accumulation in the sub-G1 phase in HepG2 and Huh7cell lines. No evidence of apoptosis was observed in two cell lines.CONCLUSION: NS-398 reduces cell proliferation by inducing cell cycle arrest in HepG2 and Huh7 cell lines,and COX-2 inhibitors may have potent chemoprevention effects on human hepatocellular carcinoma.

  16. Evaluation of Cytotoxicity Effects of Chalcone Epoxide Analogues as a Selective COX-II Inhibitor in the Human Liver Carcinoma Cell Line

    Directory of Open Access Journals (Sweden)

    Pouran Makhdoumi

    2017-09-01

    Full Text Available Objectives: Study of the mechanisms involved in cancer progression suggests that cyclooxygenase enzymes play an important role in the induction of inflammation, tumor formation, and metastasis of cancer cells. Thus, cyclooxygenase enzymes could be considered for cancer chemotherapy. Among these enzymes, cyclooxygenase 2 (COX-2 is associated with liver carcinogenesis. Various COX-2 inhibitors cause growth inhibition of human hepatocellular carcinoma cells, but many of them act in the COX-2 independent mechanism. Thus, the introduction of selective COX-2 inhibitors is necessary to achieve a clear result. The present study was aimed to determine the growth-inhibitory effects of new analogues of chalcone epoxide as selective COX-2 inhibitors on the human hepatocellular carcinoma (HepG2 cell line. Methods: Estimation of both cell growth and the amount of prostaglandin E2 (PGE2 production were used to study the effect of selective COX-2 inhibitors on the hepatocellular carcinoma cell. Cell growth determination has done by MTT assay in 24 h, 48 h and 72 h, and PGE2 production has estimated by using ELYSA kit in 48 h and 72 h. Results: The results showed growth inhibition of the HepG2 cell line in a concentration and time-dependent manner, as well as a reduction in the formation of PGE2 as a product of COX-2 activity. Among the compounds those analogues with methoxy and hydrogen group showed more inhibitory effect than others. Conclusion: The current in-vitro study indicates that the observed significant growth-inhibitory effect of chalcone-epoxide analogues on the HepG2 cell line may involve COX-dependent mechanisms and the PGE2 pathway parallel to the effect of celecoxib. It can be said that these analogues might be efficient compounds in chemotherapy of COX-2 dependent carcinoma specially preventing and treatment of hepatocellular carcinomas.

  17. Efficacy of COX-2 inhibitors in a case of congenital nephrogenic diabetes insipidus.

    Science.gov (United States)

    Soylu, Alper; Kasap, Belde; Oğün, Nilüfer; Oztürk, Yeşim; Türkmen, Mehmet; Hoefsloot, Lies; Kavukçu, Salih

    2005-12-01

    A 17-month-old boy presented with failure to thrive, polyuria, and vomiting. He had been diagnosed clinically with nephrogenic diabetes insipidus and treated by amiloride and hydrochlorothiazide combination without a satisfactory outcome at another center since 1 year of age. The diagnosis was confirmed by genetic analysis (AVPR2mutation), and the treatment was modified to include rofecoxib (a selective cyclooxygenase-2 inhibitor) in addition to hydrochlorothiazide and amiloride. This combination along with a low-salt diet resulted in a dramatic decrease in urinary free-water loss, while no side effect was noted. Because of prohibition of rofecoxib, it had to be substituted first by indomethacin and then by ibuprofen. However, both drugs were ineffective in controlling water diuresis. Thus, we had to replace these drugs by celecoxib (another selective cyclooxygenase-2 inhibitor). We conclude that the combination hydrochlorothiazide/amiloride/cyclooxygenase-2 inhibitor could be successfully used to treat congenital nephrogenic diabetes insipidus.

  18. A randomised feasibility study of EPA and Cox-2 inhibitor (Celebrex versus EPA, Cox-2 inhibitor (Celebrex, Resistance Training followed by ingestion of essential amino acids high in leucine in NSCLC cachectic patients - ACCeRT Study

    Directory of Open Access Journals (Sweden)

    Rogers Elaine S

    2011-11-01

    Full Text Available Abstract Background Cancer cachexia is a syndrome of progressive weight loss. Non-small cell lung cancer patients experience a high incidence of cachexia of 61%. Research into methods to combat cancer cachexia in various tumour sites has recently progressed to the combination of agents. The combination of the anti-cachectic agent Eicosapentaenoic acid (EPA and the cyclo-oxygenase-2 (COX-2 inhibitor celecoxib has been tested in a small study with some benefit. The use of progressive resistance training (PRT followed by the oral ingestion of essential amino acids (EAA, have shown to be anabolic on skeletal muscle and acceptable in older adults and other cancer groups. The aim of this feasibility study is to evaluate whether a multi-targeted approach encompassing a resistance training and nutritional supplementation element is acceptable for lung cancer patients experiencing cancer cachexia. Methods/Design Auckland's Cancer Cachexia evaluating Resistance Training (ACCeRT is an open label, prospective, randomised controlled feasibility study with two parallel arms. All patients will be treated with EPA and the COX-2 inhibitor celecoxib on an outpatient basis at the study site. In the experimental group patients will participate in PRT twice a week, followed by the ingestion of essential amino acids high in leucine. A total of 21 patients are planned to be enrolled. Patients will be randomised using 1:2 ratio with 7 patients enrolled into the control arm, and 14 patients into the treatment arm. The primary endpoint is the acceptability of the above multi-targeted approach, determined by an acceptability questionnaire. Discussion To our knowledge ACCeRT offers for the first time the opportunity to investigate the effect of stimulating the anabolic skeletal muscle pathway with the use of PRT along with EAA alongside the combination of EPA and celecoxib in this population. Trial registration Netherlands Trial Register (NTR: ACTRN12611000870954

  19. Treating lithium-induced nephrogenic diabetes insipidus with a COX-2 inhibitor improves polyuria via upregulation of AQP2 and NKCC2.

    Science.gov (United States)

    Kim, Gheun-Ho; Choi, Nak Won; Jung, Ju-Young; Song, Ji-Hyun; Lee, Chang Hwa; Kang, Chong Myung; Knepper, Mark A

    2008-04-01

    Prostaglandin E(2) may antagonize vasopressin-stimulated salt absorption in the thick ascending limb and water absorption in the collecting duct. Blockade of prostaglandin E(2) synthesis by nonsteroidal anti-inflammatory drugs (NSAIDs) enhances urinary concentration, and these agents have antidiuretic effects in patients with nephrogenic diabetes insipidus (NDI) of different etiologies. Because renal prostaglandins are derived largely from cyclooxygenase-2 (COX-2), we hypothesized that treatment of NDI with a COX-2 inhibitor may relieve polyuria through increased expression of Na-K-2Cl cotransporter type 2 (NKCC2) in the thick ascending limb and aquaporin-2 (AQP2) in the collecting duct. To test this hypothesis, semiquantitative immunoblotting and immunohistochemistry were carried out from the kidneys of lithium-induced NDI rats with and without COX-2 inhibition. After male Sprague-Dawley rats were fed an LiCl-containing rat diet for 3 wk, the rats were randomly divided into control and experimental groups. The COX-2 inhibitor DFU (40 mg.kg(-1).day(-1)) was orally administered to the experimental rats for an additional week. Treatment with the COX-2 inhibitor significantly relieved polyuria and raised urine osmolality. Semiquantitative immunoblotting using whole-kidney homogenates revealed that COX-2 inhibition caused significant increases in the abundance of AQP2 and NKCC2. Immunohistochemistry for AQP2 and NKCC2 confirmed the effects of COX-2 inhibition in lithium-induced NDI rats. The upregulation of AQP2 and NKCC2 in response to the COX-2 inhibitor may underlie the therapeutic mechanisms by which NSAIDs enhance antidiuresis in patients with NDI.

  20. The David Y. Graham lecture: use of nonsteroidal antiinflammatory drugs in a COX-2 restricted environment.

    Science.gov (United States)

    Chan, Francis K L

    2008-01-01

    Recent evidence suggests that both cyclooxygenase-2 (COX-2) inhibitors and nonselective NSAIDs, with the possible exception of naproxen, increase cardiovascular (CV) hazard. Clinicians should assess not only patients' GI risk but also their CV risk before prescribing these drugs. Patients with low CV risk can be managed according to their GI risk-low-risk patients (without risk factors) receive nonselective NSAIDs, medium risk patients (1-2 risk factors) receive COX-2 inhibitors or nonselective NSAIDs plus a proton pump inhibitor (PPI) or misoprostol, whereas high-risk patients (multiple risk factors, previous ulcer complications, or concomitant anticoagulants) receive a COX-2 inhibitor plus a PPI or misoprostol. Among patients with high CV risk (e.g., prior cardiothrombotic events) who require NSAIDs, naproxen is preferred. These patients should receive a prophylactic PPI or misoprostol because the risk of ulcer bleeding is substantially increased with concomitant use of naproxen and low-dose aspirin. Substitution of clopidogrel for aspirin is not recommended in patients at risk for upper GI bleeding who require antiplatelet therapy. Patients with high GI and high CV risk should avoid NSAIDs and COX-2 inhibitors. If antiinflammatory analgesics are required, the choice of therapy depends on the relative importance of GI and CV risks of individual patients. Combination of naproxen, low-dose aspirin, and a PPI or misoprostol is recommended if CV risk is the major concern (e.g., recent myocardial infarction). In contrast, combination of low-dose COX-2 inhibitor, low-dose aspirin, and a PPI or misoprostol is preferred if GI risk outweighs CV risk (e.g., recent ulcer bleeding and stable CV disease).

  1. Assessment of Alloxan-Induced Diabetic Rats as a Periodontal Disease Model Using a Selective Cyclooxygenase (COX)-2 Inhibitor.

    Science.gov (United States)

    Nakahara, Yutaka; Ozaki, Kiyokazu; Sano, Tomoya; Kodama, Yasushi; Matsuura, Tetsuro

    2014-07-01

    Several recent studies have reported that alloxan-treated rats with long-term hyperglycemia can develop naturally occurring periodontal disease (PD). Our previous studies detected dental caries in the same model. Therefore, these two lesions of different etiologies are expected to occur concurrently. In this study, we evaluated the use of diabetic rats as a PD model by employing a selective COX-2 inhibitor reported to be effective against PD. Six-week-old female F344 rats were divided into 3 groups: intact rats (control), alloxan-induced diabetic rats fed a standard diet (AL) and alloxan-induced diabetic rats fed a diet containing 0.01% etodolac (AL+Et). The animals were euthanized at 26 weeks of age, and their oral tissues were examined histopathologically. Gingivitis, marginal periodontitis and alveolar bone resorption were markedly enhanced along with dental caries in the AL group compared with the control group. However, the COX-2 inhibitor had no effect on periodontal inflammation in the AL+Et group. In addition, in the AL group, periodontitis was notably nonexistent around the normal molars, and gingivitis was scarcely worse than that in the control group. In the diabetic rats, the progression of periodontal inflammation was closely correlated with the severity of adjacent dental caries, and marginal periodontitis was frequently continuous with apical periodontitis. In conclusion, an alloxan-induced diabetic rat is not a model of PD but of dental caries. It is probable that in this model, hyperglycemia may enable crown caries to progress to apical periodontitis, while the associated inflammation may rostrally expand to surrounding periodontal tissue.

  2. Risk Factors for Upper Gastrointestinal Bleeding in Patients Taking Selective COX-2 Inhibitors: A Nationwide Population-Based Cohort Study.

    Science.gov (United States)

    Lin, Xi-Hsuan; Young, Shih-Hao; Luo, Jiing-Chyuan; Peng, Yen-Ling; Chen, Ping-Hsien; Lin, Chung-Chi; Chen, Wei-Ming; Hou, Ming-Chih; Lee, Fa-Yauh

    2017-04-28

     Cyclooxygenase-2 inhibitors (coxibs) are associated with less upper gastrointestinal bleeding (UGIB) than traditional nonsteroidal anti-inflammatory drugs (tNSAIDs). However, they also increase the risk of UGIB in high-risk patients. We aimed to identify the risk factors of UGIB in coxibs users. Retrospective cohort study. 2000-2010 National Health Insurance Research Database of Taiwan. Patients taking coxibs as the study group and patients not taking any coxibs as controls. After age, gender, and comorbidity matching by propensity score, 12,145 coxibs users and 12,145 matched controls were extracted for analysis. The primary end point was the occurrence of UGIB. Cox multivariate proportional hazard regression models were used to determine the risk factors for UGIB among all the enrollees and coxibs users. During a mean follow-up of three years, coxibs users had significantly higher incidence of UGIB than matched controls ( P  risk of UGIB in all participants (hazard ratio = 1.37, 95% confidence interval = 1.19-1.55, P  risk factors for UGIB among coxibs users were age, male gender, diabetes, chronic renal disease, cirrhosis, history of peptic ulcer disease, PU bleeding (PUB), Helicobacter pylori ( H. pylori ) infection, and concomitant use of tNSAIDs, acetylsalicylic acid, or thienopyridines. Among coxibs users, H. pylori infection and history of PUB were especially important risk factors for UGIB. Further studies are needed to determine whether proton pump inhibitors might play a protective role in these at-risk patients.

  3. Therapeutic applications of selective and non-selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation.

    Science.gov (United States)

    Youdim, Moussa B H; Weinstock, Marta

    2004-01-01

    The major side effect with the use of first generation of non selective monoamine oxidase (MAO) inhibitors as neuropsychiatric drugs was what became known as the "cheese reaction". Namely, potentiation of sympathomimetic activity of ingested tyramine present in cheese and other food stuff, resulting from its ability to release noradrenaline, when prevented from metabolism by MAO. The identification of two forms of MAO, termed types A and B and their selective irreversible inhibitors resolved some of this problems. However irreversible MAO-A inhibitors continue to induce a cheese reaction, whereas MAO-B inhibitors at their selective dosage did not and led to introduction of L-deprenyl (selegiline) as an anti-Parkinson drug, since dopamine is equally well metabolized by both enzyme forms. The cheese reaction is a consequence of inhibition of MAO-A, the enzyme responsible for metabolism of noradrenaline and serotonin, located in peripheral adrenergic neurons. The consequence of these findings were the development of reversible MAO-A inhibitors (RIMA), moclobemide and brofaromin, as antidepressants and possible anti-Parkinson activity, with limited tyramine potentiation, since the amine can displace the inhibitor from its binding site on the enzyme. It has always been deemed a greater pharmacological advantage to inhibit both forms of the enzymes to get the full functional activities of the amine neurotransmitters, and without inducing a "cheese reaction". This was not possible until recently, with the development of the novel cholinesterase-brain selective MAO-AB inhibitor, TV3326 (N-propargyl-(3R)-aminoidnan-5-yl-ethyl methylcarbamate hemitartiate), a carbamate derivative of the irreversible MAO-B inhibitor anti-Parkinson drug, rasagiline. This drug is a brain selective MAO-A and B inhibitor, with little inhibition of liver and small intestine enzymes. Pharmacologically it has limited tyramine potentiation, very similar to moclobemide and being a MAO-AB inhibitor it

  4. Perioperative Pain Relief by a COX-2 Inhibitor Affects Ileal Repair and Provides a Model for Anastomotic Leakage in the Intestine

    NARCIS (Netherlands)

    Vijver, R.J. van der; Laarhoven, C.J. van; Man, B.M. de; Lomme, R.M.L.M.; Hendriks, T.

    2013-01-01

    The authors examined the potential of the cyclooxygenase 2 (COX-2) inhibitor carprofen to reproducibly induce anastomotic leakage. In experiment 1, an anastomosis was constructed in both ileum and colon of 20 rats, and they were given carprofen (5 mg/kg subcutaneously every 24 hours) or buprenorphin

  5. Additive antithrombotic effect of ASP6537, a selective cyclooxygenase (COX)-1 inhibitor, in combination with clopidogrel in guinea pigs.

    Science.gov (United States)

    Sakata, Chinatsu; Suzuki, Ken-Ichi; Morita, Yoshiaki; Kawasaki, Tomihisa

    2017-03-05

    Clopidogrel (Plavix(®), Sanofi-Aventis), the adenosine diphosphate P2Y12 receptor antagonist, is reported to be effective in the prevention of cardiovascular events and is often used in combination with aspirin, particularly in high-risk patients. ASP6537 is a reversible cyclooxygenase (COX)-1 inhibitor that is under investigation as an anti-platelet agent. First, we investigated the reversibility of the antiplatelet effect of ASP6537 and its interaction with ibuprofen to compare the usability of ASP6537 with that of aspirin. We then evaluated the antithrombotic effect of ASP6537 in combination with clopidogrel using a FeCl3-induced thrombosis model in guinea pigs. ASP6537 exerted reversible antiplatelet activity, and no pharmacodynamic interaction with ibuprofen was noted. When administered as monotherapy, ASP6537 exerted a significant antithrombotic effect at ≥3mg/kg, while aspirin inhibited thrombosis at 100mg/kg. ASP6537 exerted significant additive effects in combination with clopidogrel, and the minimum antithrombotic dose was reduced by concomitant administration of clopidogrel. Our study showed that ASP6537 did not interact with ibuprofen and has clear additive effects in combination with clopidogrel. ASP6537 may therefore represent a promising antiplatelet agent for use in clinical settings in combination with clopidogrel.

  6. Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs (ibuprofen, diclofenac, and nabumetone).

    Science.gov (United States)

    Reicin, Alise S; Shapiro, Deborah; Sperling, Rhoda S; Barr, Eliav; Yu, Qinfen

    2002-01-15

    Aspirin, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and specific cyclooxygenase-2 (COX-2) inhibitors each have distinctive effects on COX-1-mediated thromboxane biosynthesis, the major determinant of platelet aggregation. It is unclear whether these effects are associated with differences in thrombogenic risks. To compare the risk for thrombotic cardiovascular events among patients receiving rofecoxib, nonselective NSAIDs, and placebo, cardiovascular safety was assessed in 5,435 participants in 8 phase IIB/III osteoarthritis trials. The median treatment exposure was 31/2 months. The primary end point assessed was the risk of any arterial or venous thrombotic cardiovascular adverse event (AE). A second analysis assessed differences in the Anti-Platelet Trialists' Collaboration (APTC) events, a cluster end point that consists of the combined incidence of (1) cardiovascular, hemorrhagic, and unknown death; (2) myocardial infarction; and (3) cerebrovascular accident. Similar rates of thrombotic cardiovascular AEs were reported with rofecoxib, placebo, and comparator nonselective NSAIDs (ibuprofen, diclofenac, or nabumetone). In trials that compared rofecoxib with NSAIDs, the incidence of thrombotic cardiovascular AEs was 1.93/100 patient-years in the rofecoxib treatment group compared with 2.27/100 patient-years in the combined nonselective NSAID group. In trials that compared rofecoxib with placebo, the incidence of thrombotic cardiovascular AEs was 2.71/100 patient-years in the rofecoxib group compared with 2.57/100 patient-years in the placebo group. Consistent with the risks of cardiovascular AEs, similar rates of APTC events were reported with rofecoxib, placebo, and comparator nonselective NSAIDs. Thus, in the rofecoxib osteoarthritis development program, there was no difference between rofecoxib, comparator nonselective NSAIDs, and placebo in the risks of cardiovascular thrombotic events.

  7. The influence of COX - 2 inhibitor on the expression of HPV18 - E6 and COX - 2 in Hela cells%环氧化酶2抑制剂对宫颈癌 Hela 细胞中 HPV18- E6和 COX -2表达的影响

    Institute of Scientific and Technical Information of China (English)

    吴丽; 陶光实; 陈亦乐; 唐真姿; 杨俊

    2016-01-01

    Objective:To explore the influence of COX - 2 inhibitor Celecoxib on the expression of HPV18 - E6 and COX - 2 in Hela cells and its viability and apoptosis. Methods:Human uterine cervix cancer Hela cells were treated with different concentrations of Celecoxib. The expression of HPV18 - E6 and COX - 2 were detected by im-munocytochemical SP method and reverse transcription - polymerase chain reaction. Cell survival viability was tested by using the MTT assay. The change of cell apoptosis was detected by flow cytometry and its morphology was observed under microscope after Hoechst staining. Results:The expression of HPV18 - E6 and COX - 2 protein was inhibited by COX - 2 inhibitor,with time/ dose - dependent manner and they were positively related in Hela cells. The growth was inhibited and the apoptosis of Hela cells was induced by COX - 2 inhibitor. Conclusion:COX - 2 inhibitor can lower HPV18 - E6 and COX - 2 expression at the same time inhibit Hela cells viability and enhance its apoptosis.%目的:探讨环氧化酶2抑制剂 Celecoxib 对宫颈癌细胞 Hela 中 HPV18- E6、COX -2表达及其细胞增殖和凋亡的影响。方法:用不同浓度 Celecoxib 处理 Hela 细胞株后,免疫细胞化学 SP 法检测 HPV18- E6和COX -2蛋白的表达变化。RT - PCR 检测 HPV18- E6及 COX -2 mRNA 表达的改变。MTT 法检测其对细胞增殖的影响。流式细胞仪测定细胞凋亡情况。Hoechst33258染色观察细胞的形态学变化。结果:Celecoxib 作用 Hela 细胞后 HPV18- E6和 COX -2基因 mRNA 及蛋白表达量明显低于对照组,且随着药物浓度增加表达呈梯度下降。各组之间差异具有显著性(P <0.05),且两者之间具有显著相关性(P <0.01)。Celecoxib 抑制Hela 细胞增殖,作用呈量-效关系(P <0.05)。流式细胞仪显示各实验组凋亡率随浓度升高而增加,与对照组之间有显著差异(P <0.05)。Hoechst33258荧光染色显示经20μmol/ L 药物作用 Hela

  8. Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals.

    Science.gov (United States)

    Harwood, H James; Petras, Stephen F; Shelly, Lorraine D; Zaccaro, Lawrence M; Perry, David A; Makowski, Michael R; Hargrove, Diane M; Martin, Kelly A; Tracey, W Ross; Chapman, Justin G; Magee, William P; Dalvie, Deepak K; Soliman, Victor F; Martin, William H; Mularski, Christian J; Eisenbeis, Shane A

    2003-09-26

    Inhibition of acetyl-CoA carboxylase (ACC), with its resultant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favorably affect the multitude of cardiovascular risk factors associated with the metabolic syndrome. To achieve maximal effectiveness, an ACC inhibitor should inhibit both the lipogenic tissue isozyme (ACC1) and the oxidative tissue isozyme (ACC2). Herein, we describe the biochemical and acute physiological properties of CP-610431, an isozyme-nonselective ACC inhibitor identified through high throughput inhibition screening, and CP-640186, an analog with improved metabolic stability. CP-610431 inhibited ACC1 and ACC2 with IC50s of approximately 50 nm. Inhibition was reversible, uncompetitive with respect to ATP, and non-competitive with respect to bicarbonate, acetyl-CoA, and citrate, indicating interaction with the enzymatic carboxyl transfer reaction. CP-610431 also inhibited fatty acid synthesis, triglyceride (TG) synthesis, TG secretion, and apolipoprotein B secretion in HepG2 cells (ACC1) with EC50s of 1.6, 1.8, 3.0, and 5.7 microm, without affecting either cholesterol synthesis or apolipoprotein CIII secretion. CP-640186, also inhibited both isozymes with IC50sof approximately 55 nm but was 2-3 times more potent than CP-610431 in inhibiting HepG2 cell fatty acid and TG synthesis. CP-640186 also stimulated fatty acid oxidation in C2C12 cells (ACC2) and in rat epitrochlearis muscle strips with EC50s of 57 nm and 1.3 microm. In rats, CP-640186 lowered hepatic, soleus muscle, quadriceps muscle, and cardiac muscle malonyl-CoA with ED50s of 55, 6, 15, and 8 mg/kg. Consequently, CP-640186 inhibited fatty acid synthesis in rats, CD1 mice, and ob/ob mice with ED50s of 13, 11, and 4 mg/kg, and stimulated rat whole body fatty acid oxidation with an ED50 of approximately 30 mg/kg. Taken together, These observations indicate that isozyme-nonselective ACC inhibition has the potential to favorably affect risk

  9. COX-2 mRNA expression in esophageal squamous cell carcinoma (ESCC) and effect by NSAID.

    Science.gov (United States)

    Liu, X; Li, P; Zhang, S-T; You, H; Jia, J-D; Yu, Z-L

    2008-01-01

    To investigate cyclooxygenase-2 (COX-2) mRNA expression in human esophageal squamous cell carcinoma and the effect of a non-steroidal anti-inflammatory drug (NSAID) on it, in order to explore the mechanism of COX-2 in esophageal squamous cell carcinoma (ESCC) carcinogenesis and the ability of NSAID to prevent or treat ESCC. Frozen specimens of human ESCC and adjacent normal esophageal squamous epithelium pairs (n = 22) were examined for COX-2 mRNA expression by reverse-transcription polymerase chain reaction (RT-PCR). After incubation with aspirin (a non-selective COX inhibitor) or Nimesulide (a selective COX-2 inhibitor), the proliferation status of two human esophageal squamous cancer cell lines, EC-9706 and EC-109, was quantified by 3-(4,5-dimethyl-thiazol-2yl)-2,5-diphenyltetrazolium bromide assay. The expression of COX-2 mRNA in these cells was detected by RT-PCR. COX-2 mRNA was expressed in 12 of 22 (54.5%) ESCC tissue samples, but it was undetectable in all the specimens of adjacent normal esophageal squamous epithelium COX-2 mRNA expression. Both aspirin (5-20 mmol/L) and Nimesulide (0.1-0.8 mmol/L) inhibited EC-9706 cell line proliferation and suppressed its COX-2 mRNA expression dose-dependently. However, only aspirin (5-20 mmol/L) could inhibit proliferation in the EC-109 cell line and suppress COX-2 mRNA expression. Nimesulide (0.1-0.8 mmol/L) could neither inhibit EC-109 cell growth nor suppress COX-2 mRNA expression. COX-2 mRNA expression is a frequent phenomenon in human ESCC tissue samples and plays an important role in the carcinogenesis of ESCC. NSAID may be useful in the chemoprevention and therapy of human ESCC and its effects are likely to be mediated by modulating COX-2 activity.

  10. The furoxan system: design of selective nitric oxide (NO) donor inhibitors of COX-2 endowed with anti-aggregatory and vasodilating activities.

    Science.gov (United States)

    Del Grosso, Erika; Boschi, Donatella; Lazzarato, Loretta; Cena, Clara; Di Stilo, Antonella; Fruttero, Roberta; Moro, Stefano; Gasco, Alberto

    2005-07-01

    Several NO donor 3,4-diphenylfuroxan (= 3,4-diphenyl-1,2,5-oxadiazole 2-oxide) derivatives were synthesized and tested for their COX-inhibiting activities. The products were found to be selective COX-2 inhibitors, similar to the structurally related furazans (3,4-diphenyl-1,2,5-oxadiazole), devoid of the NO release property. This behavior was confirmed by a molecular-docking study. The NO-dependent platelet anti-aggregatory and vasodilating activities of the new furoxans 5-7 were studied in vitro. These properties can be modulated by inserting an appropriate spacer between the 4-phenyl group and the furoxan ring, giving rise to new, selective COX-2 furoxan derivatives endowed with anti-aggregatory and vasodilating activities, and with potentially reduced cardiotoxicities.

  11. Evidence for a central mode of action for etoricoxib (COX-2 inhibitor) in patients with painful knee osteoarthritis.

    Science.gov (United States)

    Arendt-Nielsen, Lars; Egsgaard, Line Lindhardt; Petersen, Kristian Kjær

    2016-08-01

    The COX-2 inhibitor etoricoxib modulates the peripheral and central nociceptive mechanisms in animals. This interaction has not been studied in patients with pain. This randomized, double-blind, placebo-controlled, 2-way crossover, 4-week treatment study investigated the pain mechanisms modulated by etoricoxib in patients with painful knee osteoarthritis. Patients were randomized to group A (60 mg/d etoricoxib followed by placebo) or B (placebo followed by 60 mg/d etoricoxib). The quantitative, mechanistic pain biomarkers were pressure pain thresholds, temporal summation (TS), and conditioning pain modulation. Clinical readouts were Brief Pain Inventory, WOMAC, painDETECT questionnaire (PD-Q), and time and pain intensity during walking and stair climbing. Etoricoxib as compared with placebo significantly modulated the pressure pain thresholds (P = 0.012, localized sensitization) at the knee and leg (control site) (P = 0.025, spreading sensitization) and TS assessed from the knee (P = 0.038) and leg (P = 0.045). Conditioning pain modulation was not modulated. The Brief Pain Inventory (pain scores), PD-Q, WOMAC, and walking and stair climbing tests were all significantly improved by etoricoxib. Based on a minimum of 30% or 50% pain alleviation (day 0-day 28), responders and nonresponders were defined. The nonresponders showed a significant association between increased facilitation of TS and increased pain alleviation. None of the other parameters predicted the degree of pain alleviation. Generally, a responder to etoricoxib has the most facilitated TS. In conclusion, etoricoxib (1) modulated central pain modulatory mechanisms and (2) improved pain and function in painful osteoarthritis. Stronger facilitation of TS may indicate a better response to etoricoxib, supporting the central mode-of-action of the drug.

  12. Effects of dexamethasone and cox inhibitors on intracranial pressure and cerebral perfusion in the lipopolysaccharide treated rats with hyperammonemia.

    Directory of Open Access Journals (Sweden)

    Johan Rohde

    Full Text Available Systemic inflammation may affect the brain by aggravating the stage of encephalopathy and increasing intracranial pressure (ICP especially if liver insufficiency with hyperammonemia is present. The aim of this study was to determine if the influence of concomitant hyperammonemia and lipopolysaccharide (LPS on the brain can be prevented by dexamethasone and cyclooxygenase (COX inhibitors.Fifty-four male Wistar rats, 6 in each group, were divided into the following groups: Saline+ saline; LPS (2 mg/kg+saline; LPS+indomethacin (10 mg/kg; LPS+diclofenac (10mg/kg; LPS+dexamethasone (2mg/kg in experiment A. Experiment-B included the following groups: LPS+NH3 (140 μmol/kg/min+saline; LPS+NH3+indomethacin; LPS+NH3+diclofenac and LPS+NH3+dexamethasone. ICP was monitored via a catheter placed in cisterna magna and changes in CBF were recorded by laser Doppler flowmetry.LPS with and without NH3 induced a similar increase in plasma 6-keto-prostaglandin-F1α (6-keto-PGF1α concentration together with a concomitant rise in CBF and ICP. Indomethacin and diclofenac prevented the increase in ICP by LPS alone, and with the addition of NH3 the increase in both CBF and ICP, which was associated with a decrease in 6-keto-PGF1α. Dexamethasone only reduced the LPS induced increase in ICP but not CBF, and partly the 6-keto-PGF1α plasma concentration in the combined setup.These data indicate that activation of cycloooxygenases is of central importance for development of cerebral hyperemia and high ICP during concomitant systemic inflammation and hyperammonemia.

  13. Changes of three COX isoforms expression after formalin induced inflammatory pain in brain and analgesic effects of different COX inhibitors%福尔马林所致炎性痛后脑内三种COX亚型的变化及不同选择性COX抑制剂的镇痛效应比较

    Institute of Scientific and Technical Information of China (English)

    路志红; 熊晓云; 孟静茹; 刘振国; 王志鹏; 梅其炳

    2005-01-01

    目的:比较炎性痛后三种环氧合酶(cyclooxygenase,COX)亚型的表达变化,以及选择性COX抑制剂不同应用方式对炎性痛的镇痛效应.方法:小鼠足底注射福尔马林诱导炎性痛.用放射免疫分析及RT-PCR分别评估脑COX-1、COX-2及COX-3在福尔马林注射前、注射后1、12 h、1、3、7、14、30、60 d的变化.在镇痛效应的比较中,动物被分成5组:对照组、SC组、NS组、IN组及NS+SC组.前4组分别灌胃生理盐水、SC-560、NS-398和indomethacin.NS+SC组在前一个月接受NS-398,后一个月接受SC-560.测定各组动物在福尔马林注射前、注射后1、12 h、1、3、7、14、30、60 d的热痛阈.结果:COX-2的表达在炎性痛后12 h到3 d升高显著,而COX-1的表达在2周到2月升高显著.在整个观察时限内COX-3的表达无明显变化.与其他组相比,NS+SC组动物的热痛阈在整个炎性痛过程中均明显提高.结论:炎性痛后早期COX-2升高而晚期COX-1升高.COX-3变化不明显.COX-1抑制剂和COX-2抑制剂的结合使用比单纯使用其中一种能取得更好的镇痛效果.%AIM: To compare the expression of three cyclooxygenase (COX) isoforms in the process of inflammatory pain and evaluate the analgesic effects of different protocols about usage of COX inhibitors on inflammatory pain. METHODS: Formalin was injected subplantarly to mice to induce inflammatory pain. The expression of COX-1, COX-2 and COX-3 was evaluated by radioimmunoassay and RT-PCR, respectively. For the analgesic effect assay, animals were divided into 5 groups including control, SC, NS, IN and NS + SC group. The former 4 spectively. In the NS + SC group, animals received NS398 during the first 1 month and SC-560 during the second month in the NS + SC group. RESULTS: The expression of COX-1 was higher at the late phase while that of COX-2 was higher at the early phase of inflammatory pain. The expression of COX-3 did not significantly change in the process of inflammatory pain

  14. Density functional theory analysis and molecular docking evaluation of 1-(2, 5-dichloro-4-sulfophenyl)-3-methyl-5-pyrazolone as COX2 inhibitor against inflammatory diseases

    Science.gov (United States)

    Kavitha, T.; Velraj, G.

    2017-08-01

    The molecular structure of 1-(2, 5-Dichloro-4-Sulfophenyl)-3-Methyl-5-Pyrazolone (DSMP) was optimized using DFT/B3LYP/6-31++G(d,p) level and its corresponding experimental as well as theoretical FT-IR, FT-Raman vibrational frequencies and UV-Vis spectral analysis were carried out. The vibrational assignments and total energy distributions of each vibration were presented with the aid of Veda 4xx software. The molecular electrostatic potential, HOMO-LUMO energies, global and local reactivity descriptors and natural bond orbitals were analyzed in order to find the most possible reactive sites of the molecule and it was found that DSMP molecule possess enhanced nucleophilic activity. One of the common known COX2 inhibitor, celecoxib (CXB) was also found to exhibit similar reactivity properties and hence DSMP was also expected to inhibit COX enzymes. In order to detect the COX inhibition nature of DSMP, molecular docking analysis was carried out with the help of Autodock software. For that, the optimized structure was in turn used for docking DSMP with COX enzymes. The binding energy scores and inhibitory constant values reveal that the DSMP molecule possess good binding affinity and low inhibition constant towards COX2 enzyme and hence it can be used as an anti-inflammatory drug after carrying out necessary biological tests.

  15. Parawixin2, a novel non-selective GABA uptake inhibitor from Parawixia bistriata spider venom, inhibits pentylenetetrazole-induced chemical kindling in rats.

    Science.gov (United States)

    Gelfuso, Erica A; Liberato, José L; Cunha, Alexandra O S; Mortari, Márcia R; Beleboni, Renê O; Lopes, Norberto P; Dos Santos, Wagner F

    2013-05-24

    The aims of the present work were to investigate the effects of the repeated administration of Parawixin2 (2-amino-5-ureidopentanamide; formerly FrPbAII), a novel GABA and glycine uptake inhibitor, in rats submitted to PTZ-induced kindling. Wistar rats were randomly divided in groups (n=6-8) for different treatments. Systemic injections of PTZ were administered every 48 h in the dose of 33 mg/kg; i.p., that is sufficient to induce fully kindled seizures in saline i.c.v. treated rats in a short period of time (28 days). Treatments in two types of positive controls (diazepam - DZP and nipecotic acid - NA groups) consisted in daily systemic injections of DZP (2mg/kg; i.p.) or i.c.v. injections of NA (12 μg/μL), while in experimental groups in daily i.c.v. injections of different doses of Parawixin2 (0.15; 0.075; 0.015 μg/μL). Seizures were analyzed using the Lamberty & Klitgaard score and kindling was considered as established after at least three consecutive seizures of score 4 or 5. Cumulative seizure scores for each group were analyzed using repeated measures of ANOVA followed by Tukey test. PTZ induced 4 and 5-score seizures after 12 injections in saline treated rats, whereas daily injection of Parawixin2 inhibited the onset of seizures in a dose dependent manner. Also, the challenging administration of PTZ did not raise seizure score in animals treated with the highest dose of Parawixin2 or those treated with DZP or NA. These findings together with previous data from our laboratory show that Parawixin2 could be a useful probe to design new antiepileptic drugs.

  16. Synthesis of 4-(4-Methylsulfonylphenyl)-3-phenyl-2(3H)-thiazole Thione Derivatives as New Potential COX-2 Inhibitors

    Institute of Scientific and Technical Information of China (English)

    EMAMI Saeed; FOROUMADI Alireza

    2006-01-01

    Synthesis of novel 4-(4-methylsulfonylphenyl)-3-phenyl-2(3H)-thiazole thione derivatives with functionalized diarylheterocycle pharmacophore as potential COX-2 inhibitors was described. The title compounds were synthesized by cyclocondensation of corresponding dithiocarbamate and 2-bromo-1-(4-methylsulfonylphenyl)ethanone,followed by dehydration with H2SO4. All of the target compounds were characterized by 1H NMR, IR and mass spectral data.

  17. COX-2 selective inhibitors: a literature review of analgesic efficacy and safety in oral-maxillofacial surgery.

    Science.gov (United States)

    Cicconetti, Andrea; Bartoli, Adriano; Ripari, Francesca; Ripari, Andrea

    2004-02-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed analgesic agents in surgical outpatients. Major limitations of NSAIDs are their gastrointestinal (GI) adverse events (perforation, ulceration, and bleeding), impairment of hemostatic function, and renal failure (with long-term therapy). A new class of NSAIDs, the COX-2 selective inhibitors (CSIs or Coxibs), have been developed with the aim of reducing the GI adverse events of traditional NSAIDs while maintaining their effective anti-inflammatory and analgesic properties. This is a narrative review of the literature aimed to discuss analgesic efficacy, clinical safety and cost-benefit ratio of CSIs in the treatment of post-oral surgery pain. Relevant drug and clinical studies of analgesic efficacy and safety of CSIs in the management of postoperative dental pain were identified through searches of MEDLINE/PubMed, in peer-reviewed journals of medicine and dentistry. The Food and Drug Administration Web site was searched for data of tolerability. Hand-searching included several dental journals and bibliographies of relevant studies. The last electronic search was conducted in April 2003. Data from well-designed, randomized, controlled trials of CSIs on the management of post-oral surgery pain indicate that these drugs are as well-effective analgesic agents as traditional NSAIDs and offer clinical advantages in terms of GI safety and unimpaired platelet function. CSIs do not offer advantages of renal safety over traditional NSAIDs. Although CSIs display analgesic efficacy similar to that of traditional NSAIDs in the treatment of acute, post-oral surgery pain, there is reasonable evidence that these new drugs are preferable in patients who are at an increased risk of developing serious upper-GI complications, in patients who take aspirin for cardiovascular comorbid conditions, and in those allergic to aspirin. Furthermore, CSIs may be given more safely than NSAIDs in perioperative settings

  18. The study of dual COX-2/5-LOX inhibitors by using electronic-topological approach based on data on the ligand-receptor interactions.

    Science.gov (United States)

    Aksakal, Fatma; Shvets, Natali; Dimoglo, Anatholy

    2015-07-01

    Structural and electronic factors influencing selective inhibition of cyclooxygenase-2 and 5-lipoxygenase (COX-2/5-LOX) were studied by using Electronic-Topological Method combined with Neural Networks (ETM-NN), molecular docking, and Density Functional Theory (DFT) in a large set of molecules. The results of the ETM-NN calculations allowed for the selection of pharmacophoric molecular fragments, which could be taken as a basis for a system capable of predicting the COX-2/5-LOX inhibitory activity. For the more effective extraction of the pharmacophoric molecular fragments, docking of molecules into the active sites of the two enzymes was carried out to get data on the ligand-receptor interaction. To make an assessment of these interactions, stabilization energies were calculated by using Natural Bond Orbital (NBO) analysis. Docking and data on the electronic structures of active sites of enzymes helped to reveal effectively the peculiarities of the ligand-receptor binding. The system for the selective COX-2/5-LOX inhibitory activity prediction that has been developed as the result of the ETM-NN study recognized correctly 93% of compounds as highly active ones. Thus, this system can be successfully used for carrying out computer screening and synthesis of potent inhibitors of COX-2/5-LOX with diverse molecular skeletons.

  19. Evidence for inflammation-mediated memory dysfunction in gastropods: putative PLA2 and COX inhibitors abolish long-term memory failure induced by systemic immune challenges.

    Science.gov (United States)

    Hermann, Petra M; Park, Deborah; Beaulieu, Emily; Wildering, Willem C

    2013-08-06

    Previous studies associate lipid peroxidation with long-term memory (LTM) failure in a gastropod model (Lymnaea stagnalis) of associative learning and memory. This process involves activation of Phospholipase A2 (PLA2), an enzyme mediating the release of fatty acids such as arachidonic acid that form the precursor for a variety of pro-inflammatory lipid metabolites. This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein. Systemic immune challenges by means of β-glucan laminarin injections induced elevated H2O2 release from L. stagnalis circulatory immune cells within 3 hrs of treatment. This effect dissipated within 24 hrs after treatment. Laminarin exposure has no direct effect on neuronal activity. Laminarin injections disrupted LTM formation if training followed within 1 hr after injection but had no behavioural impact if training started 24 hrs after treatment. Intermediate term memory was not affected by laminarin injection. Chemosensory and motor functions underpinning the feeding response involved in this learning model were not affected by laminarin injection. Laminarin's suppression of LTM induction was reversed by treatment with aristolochic acid, a PLA2 inhibitor, or indomethacin, a putative COX inhibitor, but not by treatment with nordihydro-guaiaretic acid, a putative LOX inhibitor. A systemic immune challenge administered shortly before behavioural training impairs associative LTM function in our model that can be countered with putative inhibitors of PLA2 and COX, but not LOX. As such, this study establishes a mechanistic link between the state of activity of this gastropod's innate immune system and higher order nervous system function. Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.

  20. Design, synthesis and pharmacological evaluation of 4-[2-alkylthio-5(4)-(4-substitutedphenyl)imidazole-4(5)yl]benzenesulfonamides as selective COX-2 inhibitors

    Institute of Scientific and Technical Information of China (English)

    Mona SALIMI; Mohammad Hossein GHAHREMANI; Nima NADERI; Mohsen AMINI; Elika SALIMI; Massoud AMANLOU; Khosrou ABDI; Ra-ha SALEHI; Abbas SHAFIEE

    2007-01-01

    Aim: To design and synthesize a series of benzenesulfonamide derivatives, 4-[2-alkylthio-5(4)-(4-substitutedphenyl)imidazole-4(5)-yl]benzenesulfonamides (4a-4j),which are intended to act as cyclooxygenase-2 (COX-2) inhibitors with good COX-2 inhibitor activity, and which will exert anti-inflammatory activities in vivo.Methods: Benzenesulfonamide derivatives were designed and synthesized through multi-step chemical reactions. All the synthesized compounds were evaluated in an in vitro assay. The active compound 4a-4f was selected for further evaluation in a carrageenan-induced rat paw edema model. Results: Docking studies showed that compound 4 bind into the primary binding site of COX-2 with the sulfonamide SO2NH2 moiety interacting with the secondary pocket amino acid residues. In the in vitro assay, compound 4 inhibited COX-2 with an inhibition concentration IC50 value of 1.23-8 nmol/L, compared to celecoxib with ICso value of 1.5 nmol/L. Com- pound 4b and 4c had good potency and selectivity in comparison to the celecoxib. In the in vivo model, compound 4a-4f exhibited a moderate potency to inhibit 50% carrageenan-induced paw edema with value of 1.58-4.3 mg/kg. In the latter experiment, compound 4c was the most active compound. Conclusion: The anti-inflammatory effects obtained for compound 4a-4j could be due to the presence of fluorine or hydrogen substituents in the para position of the phenyl ring of these compounds.

  1. The effects of cyclo-oxygenase inhibitors on bile-injured and normal equine colon.

    Science.gov (United States)

    Campbell, N B; Jones, S L; Blikslager, A T

    2002-07-01

    A potential adverse effect of cyclo-oxygenase (COX) inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs]) in horses is colitis. In addition, we have previously shown an important role for COX-produced prostanoids in recovery of ischaemic-injured equine jejunum. It was hypothesised that the nonselective COX inhibitor flunixin would retard repair of bile-injured colon by preventing production of reparative prostaglandins, whereas the selective COX-2 inhibitor, etodolac would not inhibit repair as a result of continued COX-1 activity. Segments of the pelvic flexure were exposed to 1.5 mmol/l deoxycholate for 30 min, after which they were recovered for 4 h in Ussing chambers. Contrary to the proposed hypothesis, recovery of bile-injured colonic mucosa was not affected by flunixin or etodolac, despite significantly depressed prostanoid production. However, treatment of control tissue with flunixin led to increases in mucosal permeability, whereas treatment with etodolac had no significant effect. Therefore, although recovery from bile-induced colonic injury maybe independent of COX-elaborated prostanoids, treatment of control tissues with nonselective COX inhibitors may lead to marked increases in permeability. Alternatively, selective inhibition of COX-2 may reduce the incidence of adverse effects in horses requiring NSAID therapy.

  2. Isolation of linoleic and alpha-linolenic acids as COX-1 and -2 inhibitors in rose hip

    DEFF Research Database (Denmark)

    Jäger, Anna; Petersen, K N; Thomasen, G.

    2008-01-01

    Rose hip has previously shown clinical efficacy in the treatment of osteoarthritis, and organic solvent extracts of rose hip have showed inhibition of cyclooxygenase-1 and -2. A petroleum ether extract of rose hip was fractioned by VLC on silica; on a C-18 column and by HPLC. Each step was COX-1/...

  3. [Cyclooxygenases inhibitors and other compounds with antiinflammatory potential in osteoarthrosis--part I].

    Science.gov (United States)

    Dzielska-Olczak, Małgorzata

    2011-01-01

    Nonsteroidal antiinflammatory drugs (NSAIDs) contain conventional nonselective drugs and selective inhibitors cyclooxygenase-2 (ICOX-2). NSAIDs frequently cause adverse effects tied with cyclooxygenases (COX, COXs) inhibition and prostaglandins (PG, PGs) synthesis, which exerts different physiological effects and are involved in the patophysiology of osteoarthritis. NSAIDs don't inhibit leucotriens (LT LTs) generation. Nonselective drugs cause detrimental results in the gastrointestinal tract. Selective COX-2 inhibitors exert thrombotic cardiovascular events and other negative effects in cardiovascular system. NSAIDs can intensify symptoms of OA and accelerate its progress. Analgetic and antiinflammatory properties possess also licofelone, a competitive inhibitor of cyclooxygenases and 5-lipooxygenase (5-LOX), which presents well gastrointestinal tract tolerability in contrast to NSAIDs. Licofelone decreases the production of proinflammatory leucotrienes and prostaglandins. Moreover inhibition of 5-lipooxygenase activity can delay of cartilago degradation.

  4. Structure-based design, synthesis, molecular docking study and biological evaluation of 1,2,4-triazine derivatives acting as COX/15-LOX inhibitors with anti-oxidant activities.

    Science.gov (United States)

    Khoshneviszadeh, Mehdi; Shahraki, Omolbanin; Khoshneviszadeh, Mahsima; Foroumadi, Alireza; Firuzi, Omidreza; Edraki, Najmeh; Nadri, Hamid; Moradi, Alireza; Shafiee, Abbas; Miri, Ramin

    2016-12-01

    A set of 1,2,4-triazine derivatives were designed as cyclooxygenase-2 (COX-2) inhibitors. These compounds were synthesized and screened for inhibition of cyclooxygenases (COX-1 and COX-2) based on a cellular assay using human whole blood (HWB) and lipoxygenase (LOX-15) that are key enzymes in inflammation. The results showed that 3-(2-(benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (G11) was identified as the most potent COX-2 inhibitor (78%) relative to COX-1 (50%). Ferric reducing anti-oxidant power (FRAP) assay revealed that compound G10 possesses the highest anti-oxidant activity. The compound G3 with IC50 value of 124 μM was the most potent compound in LOX inhibitory assay. Molecular docking was performed and a good agreement was observed between computational and experimental results.

  5. In-Silico search of Tailored Cox-2 Inhibitors: Screening of Quinazolinone derivatives via molecular modeling Tools

    Directory of Open Access Journals (Sweden)

    Samad Abdul

    2014-06-01

    Full Text Available Novel Quinazoline derivatives were designed through in silico studies including Molecular properties prediction, Toxicity risk prediction and by Molecular Docking approaches. The hypothetically designed molecules were studied for Lipinski rule of 5 properties. The successful molecules were subjected to toxicity risk prediction by Osiris property calculator.The docking methodology applied in the study was first validated by redocking the celecoxib in cox-2 domain with the co-crystallized one. Cox-2 protein was explored for the residues imperative for activity by analyzing the binding pattern of celecoxib and selected compounds of quinazolinone derivatives in the active domain. All the selected molecules passed Lipinski rule of five successfully and they were safe. The docking results explored that compound IQ1, IQ2, IQ5, IQ8 and IQ12 have binding affinity -9.3, which indicated that these compounds may prove successful anti-inflammatory oral candidates.

  6. Specific COX-2 inhibitor NS398 induces apoptosis in human liver cancer cell line HepG2 through BCL-2

    Institute of Scientific and Technical Information of China (English)

    Dong-Sheng Huang; Ke-Zhen Shen; Jian-Feng Wei; Ting-Bo Liang; Shu-Sen Zheng; Hai-Yang Xie

    2005-01-01

    AIM: To evaluate the effects of NS-398, a cyclooxygenase2 (COX-2) inhibitor, on the proliferation and apoptosis of HepG2 cells.METHODS: The effects of NS-398 on the proliferation of HepG2 cells were evaluated by MTT. DNA fragmentation gel analysis was used to analyze the apoptotic cells. DNA ploidy and apoptotic cell percentage were calculated by flow cytometry.The expression of COX-2 and Bcl-2 mRNA was identified by competitive RT-PCR. Furthermore, expression level of Bcl-2 was detected using Western blot in HepG2 after treated with NS-398.RESULTS: NS-398 inhibited cell proliferation and induced apoptosis of HepG2 cells in a concentration-dependent manner. DNA ploidy analysis showed that S phase cells were significantly decreased with increase of NS-398 concentration.The quiescent G0/G1 phase was accumulated with decrease of Bcl-2 mRNA. Whereas NS-398 had no effect on the expression of COX-2 mRNA, and no correlations were found between COX-2 mRNA and HepG2 cell proliferation and apoptosis induced by NS-398 (r = 0.056 and r= 0.119,respectively). Bcl-2 protein level was inhibited after treated with NS-398.CONCLUSION: NS-398 significantly inhibits the proliferation and induces apoptosis of HepG2 cells. Mechanisms involved may be accumulation of quiescent G0/G1 phase and decrease of Bcl-2 expression.

  7. Effect of licofelone--a dual COX/5-LOX inhibitor in intracerebroventricular streptozotocin-induced behavioral and biochemical abnormalities in rats.

    Science.gov (United States)

    Kumar, Ashok; Sharma, Sorabh; Prashar, Ashwani; Deshmukh, Rahul

    2015-03-01

    The present study was designed to investigate the effect of licofelone-a dual cyclooxygenase/5-lipoxygenase (COX/5-LOX) inhibitor in intracerebroventricular streptozotocin (ICV-STZ)-induced cognitive deficit and biochemical abnormalities in rats. ICV-STZ is a widely used model of sporadic Alzheimer's disease. In this study, STZ was administered intracerebroventricular (i.c.v.)-bilaterally 3 mg/kg in rats. The STZ-injected rats were treated with different doses of licofelone (2.5, 5, and 10 mg/kg, p.o.) for 21 days. Cognitive functions were assessed by using Morris water maze and passive avoidance task. Levels of malondialdehyde (MDA), nitrite, reduced glutathione (GSH), and acetylcholinesterase (AChE) activity were determined to check oxidative stress and cholinergic function. Cytokine levels (IL-1β and TNF-α) were also determined as markers of neuroinflammation. Administration of STZ caused a significant increase in AChE activity and cognitive dysfunction. Increased oxidative stress and the proinflammatory cytokine levels were also observed following STZ administration in rats. Licofelone treatment attenuated STZ-induced cholinergic hypofunction and cognitive deficit in rats. In addition, licofelone attenuated STZ-induced oxidative stress and elevated cytokine levels. The cognitive enhancement following licofelone administration in STZ rats may be due to its ability to restore cholinergic functions or its antioxidant activity. These observed results suggest the therapeutic potential of dual COX/5-LOX inhibitors in neurodegenerative disorders associated with oxidative stress and cognitive impairment.

  8. Molecular Dynamic Screening Sesquiterpenoid Pogostemon Herba as Suggested Cyclooxygenase Inhibitor

    Science.gov (United States)

    Raharjo, Sentot Joko; Kikuchi, Takeshi

    2016-01-01

    Objective: Virtual molecular dynamic sesquiterpenoid Pogostemon Herba (CID56928117, CID94275, CID107152, and CID519743) have screening as cyclooxygenase (COX-1/COX-2) selective inhibitor. Methods: Molecular interaction studies sesquiterpenoid compounds with COX-1 and COX-2 were using the molecular docking tools by Hex 8.0 and interactions were further visualized using by Discovery Studio Client 3.5 software tool and Virtual Molecular Dynamic 1.9.1 software. The binding energy calculation of molecular dynamic interaction was calculated by AMBER12 software. Result: The analysis of the sesquiterpenoid compounds showed that CID56928117, CID94275, CID107152, and CID519743 have suggested as inhibitor of COX-1 and COX-2. Conclusion: Collectively, the scoring binding energy calculation (with PBSA Model Solvent) sesquiterpenoid compounds: CID519743 had suggested as candidate for non-selective inhibitor; CID56928117 and CID94275 had suggested as candidate for a selective COX-1 inhibitor; and CID107152 had suggested as candidate for a selective COX-2 inhibitor. PMID:28077888

  9. Effect of COX-2 inhibitor lumiracoxib and the TNF-α antagonist etanercept on TNBS-induced colitis in Wistar rats.

    Science.gov (United States)

    Paiotti, Ana Paula Ribeiro; Ribeiro, Daniel Araki; Silva, Roseane Mendes; Marchi, Patrícia; Oshima, Celina Tizuko Fujiyama; Neto, Ricardo Artigiani; Miszputen, Sender Jankiel; Franco, Marcello

    2012-06-01

    Crohn's disease (CD) is associated with gut barrier dysfunction. Besides the baseline barrier defect, a subgroup of patients also expresses an intestinal barrier hyperresponsiveness to nonsteroidal anti-inflammatory drugs. On the other hand, the anti-tumour necrosis factor alpha (TNF-α) treatment has brought benefits to these patients. Thus, this study aimed to evaluate the effect of lumiracoxib, a selective-cyclooxygenase-2 (COX-2) inhibitor, and Etanercept (ETC), a TNF-α antagonist on the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis. A total of 47 Wistar rats were randomized into seven groups, as follows: (1) Sham: sham induced-colitis; (2) TNBS: nontreated induced-colitis; (3) Lumiracoxib control; (4) Lumiracoxib-treated induced-colitis; (5) ETC control; (6) ETC-treated induced-colitis; (7) Lumiracoxib-ETC-treated induced-colitis. Rats from groups 6 and 7 presented significant improvement of macroscopic and histopathological damages in the distal colon. The gene expression of COX-2 mRNA, as well of TNF-α mRNA, decreased significantly in groups 6 and 7 compared to the TNBS nontreated and lumiracoxib-treated groups. The treatment only with lumiracoxib did not reduce the inflammation on TNBS-induced experimental colitis. ETC attenuated the damage seen in the colon and reduced the inflammation caused by TNBS. Our results suggest that down-regulation of TNF-α and COX-2 resulted in a decrease in inflammation caused by TNBS and thus provided some protection from the colonic damage caused by TNBS.

  10. Discovery of novel (4-piperidinyl)-piperazines as potent and orally active acetyl-CoA carboxylase 1/2 non-selective inhibitors: F-Boc and triF-Boc groups are acid-stable bioisosteres for the Boc group.

    Science.gov (United States)

    Chonan, Tomomichi; Wakasugi, Daisuke; Yamamoto, Daisuke; Yashiro, Miyoko; Oi, Takahiro; Tanaka, Hiroaki; Ohoka-Sugita, Ayumi; Io, Fusayo; Koretsune, Hiroko; Hiratate, Akira

    2011-03-01

    Novel (4-piperidinyl)-piperazine derivatives were synthesized and evaluated as ACC1/2 non-selective inhibitors. Optimization of the substituents on the nitrogen of the piperidine ring led to the identification of the fluorine substituted tert-butoxycarbonyl group. Advanced analog, 1,1,1-trifluoro-2-methylpropan-2-yl 4-{4-[(2-amino-6-methyl-1-benzothiophen-3-yl)carbonyl]piperazin-1-yl}piperidine-1-carboxylate (12c) showed potent inhibitory activities in enzyme-assay and cell-based assays. Compound 12c also exhibited reduction of hepatic de novo fatty acid synthesis in rats after oral administration.

  11. Combined treatment with the Cox-2 inhibitor niflumic acid and PPARγ ligand ciglitazone induces ER stress/caspase-8-mediated apoptosis in human lung cancer cells.

    Science.gov (United States)

    Kim, Byeong Mo; Maeng, Kyungah; Lee, Kee-Ho; Hong, Sung Hee

    2011-01-28

    The present study was performed to investigate the possible combined use of the Cox-2 inhibitor niflumic acid and the PPARγ ligand ciglitazone and to elucidate the mechanisms underlying enhanced apoptosis by this combination treatment in human lung cancer cells. Combined niflumic acid-ciglitazone treatment synergistically induced apoptotic cell death, activated caspase-9, caspase-3, and induced caspase-3-mediated PARP cleavage. The combination treatment also triggered apoptosis through caspase-8/Bid/Bax activation, and the inhibition of caspase-8 suppressed caspase-8/Bid activation, caspase-3-mediated PARP cleavage, and concomitant apoptosis. In addition, combined niflumic acid-ciglitazone treatment significantly induced ER stress responses, and suppression of CHOP expression significantly attenuated the combined niflumic acid-ciglitazone treatment-induced activation of caspase-8 and caspase-3, and the subsequent apoptotic cell death, indicating a role of ER stress in caspase-8 activation and apoptosis. Interestingly, the pro-apoptotic effects of combined niflumic acid-ciglitazone treatment were realized through Cox-2- and PPARγ-independent mechanisms. Taken together, these results suggest that sequential ER stress and caspase-8 activation are critical in combined niflumic acid-ciglitazone treatment-induced apoptosis in human lung cancer cells.

  12. IL-1β stimulates COX-2 dependent PGE₂ synthesis and CGRP release in rat trigeminal ganglia cells.

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    Lars Neeb

    Full Text Available OBJECTIVE: Pro-inflammatory cytokines like Interleukin-1 beta (IL-1β have been implicated in the pathophysiology of migraine and inflammatory pain. The trigeminal ganglion and calcitonin gene-related peptide (CGRP are crucial components in the pathophysiology of primary headaches. 5-HT1B/D receptor agonists, which reduce CGRP release, and cyclooxygenase (COX inhibitors can abort trigeminally mediated pain. However, the cellular source of COX and the interplay between COX and CGRP within the trigeminal ganglion have not been clearly identified. METHODS AND RESULTS: 1. We used primary cultured rat trigeminal ganglia cells to assess whether IL-1β can induce the expression of COX-2 and which cells express COX-2. Stimulation with IL-1β caused a dose and time dependent induction of COX-2 but not COX-1 mRNA. Immunohistochemistry revealed expression of COX-2 protein in neuronal and glial cells. 2. Functional significance was demonstrated by prostaglandin E2 (PGE(2 release 4 hours after stimulation with IL-1β, which could be aborted by a selective COX-2 (parecoxib and a non-selective COX-inhibitor (indomethacin. 3. Induction of CGRP release, indicating functional neuronal activation, was seen 1 hour after PGE(2 and 24 hours after IL-1β stimulation. Immunohistochemistry showed trigeminal neurons as the source of CGRP. IL-1β induced CGRP release was blocked by parecoxib and indomethacin, but the 5-HT1B/D receptor agonist sumatriptan had no effect. CONCLUSION: We identified a COX-2 dependent pathway of cytokine induced CGRP release in trigeminal ganglia neurons that is not affected by 5-HT1B/D receptor activation. Activation of neuronal and glial cells in the trigeminal ganglion by IL-β leads to an elevated expression of COX-2 in these cells. Newly synthesized PGE(2 (by COX-2 in turn activates trigeminal neurons to release CGRP. These findings support a glia-neuron interaction in the trigeminal ganglion and demonstrate a sequential link between COX-2

  13. The pharmacologic inhibition of the xc- antioxidant system improves the antitumor efficacy of COX inhibitors in the in vivo model of 3-MCA tumorigenesis.

    Science.gov (United States)

    Balza, Enrica; Castellani, Patrizia; Delfino, Laura; Truini, Mauro; Rubartelli, Anna

    2013-03-01

    The chemopreventive and therapeutic efficacy of the cyclooxygenase (COX) inhibitor ibuprofen (IB) and of sulfasalazine (SASP), a drug that targets the antioxidant xc- system, were exploited in the experimental model of 3-methylcholantrene (3-MCA)-induced mouse sarcoma. The chemopreventive treatments gave unsatisfactory results because administration of IB one day after the 3-MCA injection only slightly delayed the tumor development, whereas SASP dispensed under the same conditions resulted in accelerated tumorigenesis. Similarly, the therapeutic treatment with either drug, administrated daily from the tumor detection, decreased the proliferation rate of tumor cells and increased the survival of treated mice only at a low extent. Remarkably, the combined chemopreventive treatment with IB and therapeutic treatment with SASP displayed a better efficacy, with strong delay of sarcoma growth, reduced tumor size and increased survival of treated mice. The two drugs target not only tumor cells but also tumor-associated macrophages that were dramatically decreased in the tumor infiltrate of mice subjected to the combined treatment. The synergistic effects of the association between a broad anti-inflammatory compound, such as IB, and a redox-directed drug, such as SASP, shed new light in the role of inflammation and of the redox response in chemical tumorigenesis and point to the combined chemopreventive plus therapeutic treatment with IB and SASP as a promising novel approach for antitumor therapy.

  14. Theoretical research on the interaction modes of diclofenac analogues as COX-2 inhibitors%一类双氯芬酸类似物环氧合酶抑制剂作用模式的理论研究

    Institute of Scientific and Technical Information of China (English)

    李顺来; 王存铎; 李秀艳; 杜洪光

    2011-01-01

    基于1PXX晶体结构以及以晶体中双氯芬酸DIF701为模版的双氯芬酸类似物2型环氧合酶(COX-2)抑制剂的结构,利用药效团和自组织分子力场分析方法,探讨了COX-2与抑制剂的相互作用模式.建立了双氯芬酸药效团模型和COx一2抑制剂三维定量构效关系模型,并且两种方法所得的模型吻合;确定的COX-2与抑制剂的作用模式,可以指导抑制剂的设计,用于开发抗炎药物.%Diclofenac analogues are important medicines belonging to the pharmaceutical family known as non-steroidal anti-inflammatory drugs (NSAIDs). Theoretical research on the interactions between COX-2 and diclofenac analogues as inhibitors has been carried out in order to identify new potent inhibitors. The pharmacophore model of diclofenac was generated based on a ligand-macromolecule complex interpretation from pdb 1PXX. We aligned the optimized structures of the diclofenac analogues onto a template structure and 36 diclofenac analogues were investigated with the aim of developing a 3D-QSAR model using self-organizing molecular field analysis (SOMFA). The interactions between COX-2 and diclofenac analogues as inhibitor were illustrated clearly, and the pharmacophore models and 3D-QSAR model were fitted very well by the data. The results obtained in this work will be useful for designing new active inhibitors.

  15. Role of an indole-thiazolidine molecule PPAR pan-agonist and COX inhibitor on inflammation and microcirculatory damage in acute gastric lesions.

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    José Roberto Santin

    Full Text Available The present study aimed to show the in vivo mechanisms of action of an indole-thiazolidine molecule peroxisome-proliferator activated receptor pan-agonist (PPAR pan and cyclooxygenase (COX inhibitor, LYSO-7, in an ethanol/HCl-induced (Et/HCl gastric lesion model. Swiss male mice were treated with vehicle, LYSO-7 or Bezafibrate (p.o. 1 hour before oral administration of Et/HCl (60%/0.03M. In another set of assays, animals were injected i.p. with an anti-granulocyte antibody, GW9962 or L-NG-nitroarginine methyl ester (L-NAME before treatment. One hour after Et/HCl administration, neutrophils were quantified in the blood and bone marrow and the gastric microcirculatory network was studied in situ. The gastric tissue was used to quantify the percentage of damaged area, as well as myeloperoxidase (MPO, inducible nitric oxide synthase (iNOS, endothelial nitric oxide synthase (eNOS protein and PPARγ protein and gene expression. Acid secretion was evaluated by the pylorus ligation model. LYSO-7 or Bezafibrate treatment reduced the necrotic area. LYSO-7 treatment enhanced PPARγ gene and protein expression in the stomach, and impaired local neutrophil influx and stasis of the microcirculatory network caused by Et/HCl administration. The effect seemed to be due to PPARγ agonist activity, as the LYSO-7 effect was abolished in GW9962 pre-treated mice. The reversal of microcirculatory stasis, but not neutrophil influx, was mediated by nitric oxide (NO, as L-NAME pre-treatment abolished the LYSO-7-mediated reestablishment of microcirculatory blood flow. This effect may depend on enhanced eNOS protein expression in injured gastric tissue. The pH and concentration of H(+ in the stomach were not modified by LYSO-7 treatment. In addition, LYSO-7 may induce less toxicity, as 28 days of oral treatment did not induce weight loss, as detected in pioglitazone treated mice. Thus, we show that LYSO-7 may be an effective treatment for gastric lesions by controlling

  16. Study the role of COX-2 and its Selective Inhibitor NS-398 in the Laser Wound Healing%COX-2及其选择性抑制剂NS-398对激光术后创面修复的实验研究

    Institute of Scientific and Technical Information of China (English)

    周莹; 曾维惠; 覃静净; 徐磊; 耿松梅; 乔莉; 张磐谏

    2011-01-01

    目的:探讨COX-2及其选择性抑制剂NS-398对激光术后大鼠创面修复的影响.方法:点阵CO2激光照射形成大鼠创伤模型,分为正常、术后第1、3、5、7、10、14天共7个时相点,基质对照组、NS-398药物组术后分别外用75%酒精、NS-398,肉眼观察创面结痂及愈合时间,HE染色计数中性粒细胞、成纤维样细胞,免疫组化方法检测COX-2、PGE2及TGF-β1的表达情况.结果:NS-398药物组结痂时间明显短于对照组,各组间愈合时间无统计学差异;术后第1、3天,NS-398药物组中性粒细胞的数量及PGE2、TGF-β1表达量均明显低于对照组;术后第5天,NS-398药物组成纤维样细胞的数量明显高于对照组;激光术后(尤炎症期)大鼠创面明显表达COX-2.结论:COX-2对大鼠创面修复的炎症期及细胞增殖期具有重要作用;NS-398能降低激光术后创面炎症反应及瘢痕形成率,同时不会延缓创面愈合.%Objective To investigate the role of COX-2 and its selective inhibitor NS-398 during rat wound healing caused by factional laser. Methods Wound samples were removed from day 0 (normal)、 1、3、5、7、10、14 after injury, 75% ethanol、NS-398 were administrated respectively between matrix-control and NS-398-drug group.comparing the crust-formation and healing time, numbers of neutrophils and fibroblasts with HE staining, and the expression of COX-2 ,PGE2,TGF-P1 with IHC. Results The crust-formation time of NS-398-drug group was shorter than the control groups, but the healing time had no satistical difference. The numbers of neutrophils,expression of PGE2 and TGF-01 of NS-398-drug group were less than contro groups on day 1、3;and the fibroblasts were more than control groups on day 5.Wound expressed COX-2 obviously (special during inflammatory phase) after injury. Conclusion COX-2 plays a pivotal role during the inflammotary and cell proliferate phase of wound healing; selective COX-2 inhibitors NS-398 could reduce

  17. Effect of selected cyclooxygenase-2 inhibitor and dual COX-2/5-lipoxygenase inhibitor on the proliferation of esophageal squamous cell carcinoma cells%选择性环氧合酶-2抑制剂与COX-2/5-脂氧合酶双酶抑制剂对食管鳞状细胞癌细胞增殖的影响

    Institute of Scientific and Technical Information of China (English)

    庄则豪; 魏晶晶; 王凤霞; 孙静文; 邹方明; 王承党; 杨立勇

    2011-01-01

    Objective To investigate the effect of NS-398, a selected cyclooxygenase-2 (COX-2) inhibitor and licofelone, a dual COX-2/5-lipoxygenase (5-LOX) inhibitor on the proliferation of TE-1, an esophageal squamous cell carcinoma (ESCC) cell line, and explore the potential limitation of sole COX-2 inhibition on the negative regulation of ESCC cell proliferation. Methods TE-1 cells were divided into drug treatment group, DMSO control group and blank control group. Cells were treated by licofelone or NS-398 in 4 concentrations, including 25 μ mol/L, 50 μmol/L, 75 μmol/L and 100 μmol/L. Cell proliferation was assessed by Cell Counting Kit-8 assay. The expression of COX-2 and 5LOX were determined by both RT-PCR (mRNA) and Western blot (protein), respectively. The concentrations of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) were measured by ELISA. Flow cytometer was used for the cell cycle measurement. Results Cell proliferation inhibition was found in both time and concentration-dependent manners in licofelone treated TE-1 cells, but not in those treated by NS-398. Time and concentration-dependent inhibition of COX-2 mRNA, protein and PGE2 expression were found in TE-1 cells treated with either licofelone or NS-398, while downregulation of 5-LOX mRNA, protein and LTB4 expression were found only in cells treated with licofelone. The level of LTB4 showed an upregulation tendency in cells treated with NS-398, but a significant difference was found only under the coneentration of 100 μmol/L. After 24 h treatment with 100 μmol/L of licofelone and 50 μmol/L of NS-398, the percentages of TE-1 cells in G0/G1-phase were 67.1% and 63.8% , respectively, which were significantly higer than those in control group (P <0.05). Conclusion Selected COX-2 inhibitor alone may induce ESCC cell proliferation in several specific concentrations, which may be due to the activation of 5-LOX shunt. A dual COX-2/5-LOX inhibitor should be more effective for the inhibition of

  18. COX-1 and COX-2 expression in canine cutaneous, oral and ocular melanocytic tumours.

    Science.gov (United States)

    Pires, I; Garcia, A; Prada, J; Queiroga, F L

    2010-01-01

    In order to evaluate the potential value of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of canine malignant melanoma, expression of cyclooxygenase (COX)-1 and COX-2 was determined in 20 cutaneous, nine oral and two ocular malignant melanomas, and in nine cutaneous melanocytomas. Almost all tumours expressed COX-1, but COX-2 expression was restricted to the malignant tumours being found in 11 of the 20 cutaneous malignant melanomas, all oral malignant melanomas and in one of two ocular malignant melanomas. COX-1 expression did not differ significantly between benign and malignant skin lesions, but COX-2 expression was significantly greater in cutaneous malignant melanoma compared with melanocytoma (P=0.047). COX-2 labelling was particularly intense in the more highly malignant oral tumours. The results of the study suggest that NSAIDs, particularly COX-2 inhibitors, may be useful in the treatment of canine malignant melanoma.

  19. Isolation, identification and molecular docking as cyclooxygenase (COX) inhibitors of the main constituents of Matricaria chamomilla L. extract and its synergistic interaction with diclofenac on nociception and gastric damage in rats.

    Science.gov (United States)

    Ortiz, Mario I; Fernández-Martínez, Eduardo; Soria-Jasso, Luis Enrique; Lucas-Gómez, Isaac; Villagómez-Ibarra, Roberto; González-García, Martha P; Castañeda-Hernández, Gilberto; Salinas-Caballero, Mireya

    2016-03-01

    Chamomile (Matricaria chamomilla L., Asteraceae) is a medicinal plant widely used as remedy for pain and gastric disorders. The association of non-steroidal anti-inflammatory drugs (NSAIDs) with medicinal plant extracts may increase its antinociceptive activity, permit the use of lower doses and limit side effects. The aim was to isolate and identify the main chemical constituents of Matricaria chamomilla ethanolic extract (MCE) as well as to explore their activity as cyclooxygenase (COX) inhibitors in silico; besides, to examine the interaction between MCE and diclofenac on nociception in the formalin test by isobolographic analysis, and to determine the level of gastric injury in rats. Three terpenoids, α-bisabolol, bisabolol oxide A, and guaiazulene, were isolated and identified by (1)H NMR. Docking simulation predicted COX inhibitory activity for those terpenoids. Diclofenac, MCE, or their combinations produced an antinociceptive effect. The sole administration of diclofenac and the highest combined dose diclofenac-MCE produced significant a gastric damage, but that effect was not seen with MCE alone. An isobologram was constructed and the derived theoretical ED35 for the antinociceptive effect was significantly different from the experimental ED35; hence, the interaction between diclofenac and MCE that mediates the antinociceptive effect is synergist. The MCE contains three major terpenoids with plausible COX inhibitory activity in silico, but α-bisabolol showed the highest affinity. Data suggest that the diclofenac-MCE combination can interact at the systemic level in a synergic manner and may have therapeutic advantages for the clinical treatment of inflammatory pain.

  20. Renal effects of nabumetone, a COX-2 antagonist: impairment of function in isolated perfused rat kidneys contrasts with preserved renal function in vivo.

    Science.gov (United States)

    Reichman, J; Cohen, S; Goldfarb, M; Shina, A; Rosen, S; Brezis, M; Karmeli, F; Heyman, S N

    2001-01-01

    The constitutive cyclooxygenase (COX)-1 enzyme has been considered the physiologically important isoform for prostaglandin synthesis in the normal kidney. It has, therefore, been suggested that selective inhibitors of the 'inducible' isoform (COX-2) may be free from renal adverse effects. We studied the renal effects of the predominantly COX-2 antagonist nabumetone in isolated perfused kidneys. As compared with controls, kidneys removed after in vivo administration of oral nabumetone (15 mg/kg) disclosed altered renal function with reduced glomerular filtration rate, filtration fraction, and urine volume and enhanced hypoxic outer medullary tubular damage. By contrast, renal function and morphology were not affected in vivo by nabumetone or its active metabolite 6-methoxy-2-naphthylacetic acid. The latter agent (10-20 mg/kg i.v.) did not significantly alter renal microcirculation, as opposed to a selective substantial reduction in medullary blood flow noted with the nonselective COX inhibitor indomethacin (5 mg/kg i.v.). In a rat model of acute renal failure, induced by concomitant administration of radiocontrast, nitric oxide synthase, and COX inhibitors, the decline in kidney function and the extent of hypoxic medullary damage with oral nabumetone (80 mg/kg) were comparable to a control group, and significantly less than those induced by indomethacin. In rats subjected to daily oral nabumetone for 3 consecutive weeks, renal function and morphology were preserved as well. Both nabumetone and 6-methoxy-2-naphthylacetic acid reduced renal parenchymal prostaglandin E2 to the same extent as indomethacin. It is concluded that while nabumetone adversely affects renal function and may intensify hypoxic medullary damage ex vivo, rat kidneys are not affected by this agent in vivo, both in acute and chronic studies. COX selectivity may not explain the renal safety of nabumetone.

  1. Reduced Risk of Human Lung Cancer by Selective Cyclooxygenase 2 (Cox-2 Blockade: Results of a Case Control Study

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    Randall E. Harris, Joanne Beebe-Donk, Galal A. Alshafie

    2007-01-01

    Full Text Available We conducted a case control study of selective cyclooxygenase-2 (COX-2 blocking agents and lung cancer. A total of 492 newly diagnosed lung cancer cases were ascertained during January 1, 2002 to September 30, 2004, at The Ohio State University Medical Center, Columbus, Ohio. All cases were confirmed by examination of the pathology report. Healthy population controls without cancer were ascertained during the same time period. Controls were frequency matched at a rate of 2:1 to the cases by age, gender, and county of residence. We collected information on type, frequency, and duration of use of selective COX-2 inhibitors (primarily celecoxib or rofecoxib and nonselective NSAIDs such as ibuprofen and aspirin. Estimates of odds ratios (OR were obtained with adjustment for cigarette smoking, age and other potential confounders using logistic regression analysis. Odds Ratios for selective COX-2 inhibitors were adjusted for past use of other NSAIDs. Use of any selective COX-2 inhibitor for more than one year produced a significant (60% reduction in the risk of lung cancer (OR=0.40, 95% CI=0.19-0.81. Observed risk reductions were consistent for men (OR=0.26, 95% CI=0.10-0.62 and women (OR=0.52, 95% CI=0.24-1.13 and for individual COX-2 inhibitors (OR=0.28, 95% CI=-0.12-0.67, for celecoxib and OR=0.55, 95% CI=0.19-1.56, for rofecoxib. Intake of ibuprofen or aspirin also produced significant risk reductions (OR=0.40, 95% CI=0.23-0.73 and OR=0.53, 95% CI=0.34-0.82, respectively, whereas acetaminophen, an analgesic with negligible COX-2 activity, had no effect on the risk (OR=1.36, 95% CI=0.53-3.37. This investigation demonstrates for the first time that selective COX-2 blocking agents have strong potential for the chemoprevention of human lung cancer.

  2. Lactobacillus casei reduces the inflammatory joint damage associated with collagen-induced arthritis (CIA) by reducing the pro-inflammatory cytokines: Lactobacillus casei: COX-2 inhibitor.

    Science.gov (United States)

    Amdekar, Sarika; Singh, Vinod; Singh, Rambir; Sharma, Poonam; Keshav, Poonam; Kumar, Avnish

    2011-04-01

    This study evaluated the therapeutic efficacy of Lactobacillus casei in treating rheumatoid arthritis using collagen-induced arthritis (CIA) animal model. Healthy female Wistar rats (weight-180-200 g) were included in this study. Oral administration of L. casei was started on the same day. Indomethacin was used as standard reference drug. Serum level of IL-6, α-TNF, and IL-10 were observed. Four-point arthritis indexes were also assessed at the end of week for 28th day. L. casei-treated rats had shown normal histopathology without any synovial infiltration, pannus formation, cartilage, and bone destruction. Arthritis score was also lower for the group treated with L. casei. Oral administration of L. casei significantly decreased the pro-inflammatory cytokines. Present study suggests that L. casei has potent antiarthritic effect in CIA model. Inhibition of COX-2 via inhibiting the pro-inflammatory cytokines is an understanding of the complex interactions involved in these pathways.

  3. Cellular and molecular studies of the effects of a selective COX-2 inhibitor celecoxib in the cardiac cell line H9c2 and their correlation with death mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Sakane, K.K. [Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraíba, São José dos Campos, SP (Brazil); Monteiro, C.J.; Silva, W.; Silva, A.R. [Núcleo de Pesquisa em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG (Brazil); Santos, P.M. [Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraíba, São José dos Campos, SP (Brazil); Lima, K.F. [Núcleo de Pesquisa em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG (Brazil); Moraes, K.C.M. [Instituto de Biociências, Departamento de Biologia, Universidade Estadual Paulista ‘‘Júlio de Mesquita Filho’’, Rio Claro, SP (Brazil)

    2013-11-29

    Cardiovascular disease is one of the leading causes of death worldwide, and evidence indicates a correlation between the inflammatory process and cardiac dysfunction. Selective inhibitors of cyclooxygenase-2 (COX-2) enzyme are not recommended for long-term use because of potentially severe side effects to the heart. Considering this and the frequent prescribing of commercial celecoxib, the present study analyzed cellular and molecular effects of 1 and 10 µM celecoxib in a cell culture model. After a 24-h incubation, celecoxib reduced cell viability in a dose-dependent manner as also demonstrated in MTT assays. Furthermore, reverse transcription-polymerase chain reaction analysis showed that the drug modulated the expression level of genes related to death pathways, and Western blot analyses demonstrated a modulatory effect of the drug on COX-2 protein levels in cardiac cells. In addition, the results demonstrated a downregulation of prostaglandin E2 production by the cardiac cells incubated with celecoxib, in a dose-specific manner. These results are consistent with the decrease in cell viability and the presence of necrotic processes shown by Fourier transform infrared analysis, suggesting a direct correlation of prostanoids in cellular homeostasis and survival.

  4. Towards the design of cyclooxygenase (COX) inhibitors based on 4',5 di-substituted biphenyl acetic acid molecules: a QSAR study with a new DFT based descriptor - nucleus independent chemical shift.

    Science.gov (United States)

    Sarkar, Ananda; Mostafa, Golam

    2009-10-01

    Cyclooxygenase (COX) is a well-known enzyme, which converts arachidonic acid to prostaglandins H(2) (PGH(2)), which are the effective mediators of inflammation. 4', 5 di-substituted 3-biphenyl acetic acids (BPA) and several alpha-methyl derivatives (MBPA) of it are widely used as powerful nonsteroidal anti-inflammatory and analgesic agents. We have chosen these activity data because the relation between the substituents and activity is not obvious and is hard to explain and also to show the superiority of DFT method. From the DFT results, various quantum chemical based descriptors were computed but the QSAR results showed that the descriptors based on frontier electron density and a new DFT based quantum chemical descriptor, nucleus independent chemical shift (NICS) are likely to be responsible for the in vitro inhibiting activity of BPA and MPBA. It has been proposed that NICS accounts for pi...pi interaction and indeed leads to a better result. To the best of our knowledge, this is the first use of NICS as a descriptor to get a better relationship to facilitate the design of COX inhibitors with potentially higher biological activity.

  5. Lack of influence of the COX inhibitors metamizol and diclofenac on platelet GPIIb/IIIa and P-selectin expression in vitro

    Directory of Open Access Journals (Sweden)

    Gröschel Werner

    2004-04-01

    Full Text Available Abstract Background The effect of non-steroidal anti-inflammatory drugs (NSAIDs for reduced platelet aggregation and thromboxane A2 synthesis has been well documented. However, the influence on platelet function is not fully explained. Aim of this study was to examine the influence of the COX-1 inhibiting NSAIDs, diclofenac and metamizol on platelet activation and leukocyte-platelet complexes, in vitro. Surface expression of GPIIb/IIIa and P-selectin on platelets, and the percentage of platelet-leukocyte complexes were investigated. Methods Whole blood was incubated with three different concentrations of diclofenac and metamizol for 5 and 30 minutes, followed by activation with TRAP-6 and ADP. Rates of GPIIb/IIIa and P-selectin expression, and the percentage of platelet-leukocyte complexes were analyzed by a flow-cytometric assay. Results There were no significant differences in the expression of GPIIb/IIIa and P-selectin, and in the formation of platelet-leukocyte complexes after activation with ADP and TRAP-6, regarding both the time of incubation and the concentrations of diclofenac and metamizol. Conclusions Accordingly, the inhibitory effect of diclofenac and metamizol on platelet aggregation is not related to a reduced surface expression of P-selectin and GPIIb/IIIa on platelets.

  6. Lack of influence of the COX inhibitors metamizol and diclofenac on platelet GPIIb/IIIa and P-selectin expression in vitro

    Science.gov (United States)

    Scheinichen, Dirk; Elsner, Holger-Andreas; Osorio, Rodin; Jüttner, Björn; Gröschel, Werner; Jaeger, Karsten; Piepenbrock, Siegfried

    2004-01-01

    Background The effect of non-steroidal anti-inflammatory drugs (NSAIDs) for reduced platelet aggregation and thromboxane A2 synthesis has been well documented. However, the influence on platelet function is not fully explained. Aim of this study was to examine the influence of the COX-1 inhibiting NSAIDs, diclofenac and metamizol on platelet activation and leukocyte-platelet complexes, in vitro. Surface expression of GPIIb/IIIa and P-selectin on platelets, and the percentage of platelet-leukocyte complexes were investigated. Methods Whole blood was incubated with three different concentrations of diclofenac and metamizol for 5 and 30 minutes, followed by activation with TRAP-6 and ADP. Rates of GPIIb/IIIa and P-selectin expression, and the percentage of platelet-leukocyte complexes were analyzed by a flow-cytometric assay. Results There were no significant differences in the expression of GPIIb/IIIa and P-selectin, and in the formation of platelet-leukocyte complexes after activation with ADP and TRAP-6, regarding both the time of incubation and the concentrations of diclofenac and metamizol. Conclusions Accordingly, the inhibitory effect of diclofenac and metamizol on platelet aggregation is not related to a reduced surface expression of P-selectin and GPIIb/IIIa on platelets. PMID:15107131

  7. Pharmacologic inhibition of COX-1 and COX-2 in influenza A viral infection in mice.

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    Michelle A Carey

    Full Text Available BACKGROUND: We previously demonstrated that cyclooxygenase (COX-1 deficiency results in greater morbidity and inflammation, whereas COX-2 deficiency leads to reduced morbidity, inflammation and mortality in influenza infected mice. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effects of COX-1 and COX-2 inhibitors in influenza A viral infection. Mice were given a COX-1 inhibitor (SC-560, a COX-2 inhibitor (celecoxib or no inhibitor beginning 2 weeks prior to influenza A viral infection (200 PFU and throughout the course of the experiment. Body weight and temperature were measured daily as indicators of morbidity. Animals were sacrificed on days 1 and 4 post-infection and bronchoalveolar lavage (BAL fluid was collected or daily mortality was recorded up to 2 weeks post-infection. Treatment with SC-560 significantly increased mortality and was associated with profound hypothermia and greater weight loss compared to celecoxib or control groups. On day 4 of infection, BAL fluid cells were modestly elevated in celecoxib treated mice compared to SC-560 or control groups. Viral titres were similar between treatment groups. Levels of TNF-alpha and G-CSF were significantly attenuated in the SC-560 and celecoxib groups versus control and IL-6 levels were significantly lower in BAL fluid of celecoxib treated mice versus control and versus the SC-560 group. The chemokine KC was significantly lower in SC-560 group versus control. CONCLUSIONS/SIGNIFICANCE: Treatment with a COX-1 inhibitor during influenza A viral infection is detrimental to the host whereas inhibition of COX-2 does not significantly modulate disease severity. COX-1 plays a critical role in controlling the thermoregulatory response to influenza A viral infection in mice.

  8. The effect of COX-2 inhibitor on capecitabine-induced hand-foot syndrome in patients with stage II/III colorectal cancer: a phase II randomized prospective study.

    Science.gov (United States)

    Zhang, Rong-Xin; Wu, Xiao-Jun; Lu, Shi-Xun; Pan, Zhi-Zhong; Wan, De-Sen; Chen, Gong

    2011-06-01

    Hand-foot syndrome (HFS) is a common adverse event that can be induced by capecitabine. It is hypothesized that capecitabine (Hoffmann-La Roche Inc.) based chemotherapy can cause overexpression of COX-2 in tumor and healthy tissue, which finally induced HFS in hands and feet. Based on this, we believed that a selected COX-2 inhibitor (celecoxib, Pfizer Pharmaceuticals LLC) could ease HFS. We designed a prospective clinical study to test the hypothesis. From August 2008 to January 2010, 110 patients with stage II/III colorectal cancer who were eligible for adjuvant chemotherapy were enrolled in the study and divided into 4 groups by random, but 9 patients did not finish at least 4 cycles of chemotherapy. There were sixteen patients in capecitabine group, and fifteen patients in capecitabine and celecoxib group. Thirty-four patients were in XELOX (capecitabine plus oxaliplatine) group, and thirty-six patients in XELOX+ celecoxib group. All 101 patients finished chemotherapy and follow-up interviews. The group that had received capecitabine and celecoxib had a significantly reduced frequency of  >grade 1 hand-foot syndrome (29 vs. 72% P grade 2 (11.76% vs. 30% P = 0.024). Five patients experienced grade 3 HFS in capecitabine group and only 1 patient had grade 3 HFS in capecitabine and celecoxib group. There were 5 patients in capecitabine group who refused to go on chemotherapy because of HFS, but there was none in capecitabine and celecoxib group. From the result of this study, we could learn that celecoxib could reduce HFS that was induced by capecitabine. So we recommend that celecoxib can be used in capecitabine-based chemotherapy.

  9. Do Different Cyclooxygenase Inhibitors Impair Rotator Cuff Healing in a Rabbit Model?

    Institute of Scientific and Technical Information of China (English)

    Yi Lu; Yue Li; Feng-Long Li; Xu Li; Hong-Wu Zhuo; Chun-Yan Jiang

    2015-01-01

    Background:The effect of selective and non-selective cyclooxygenase (COX) inhibitors on tendon healing was variable.The purpose of the study was to evaluate the influence of non-selective COX inhibitor,ibuprofen and flurbiprofen axetil and selective COX-2 inhibitor,celecoxib on the tendon healing process in a rabbit model.Methods:Ninety-six New Zealand rabbits were used as rotator cuff repair models.After surgery,they were divided randomly into four groups:Ibuprofen (10 mg·kg-1·d-1),celecoxib (8 mg·kg 1·d 1),flurbiprofen axetil (2 mg·kg 1·d-1),and control group (blank group).All drugs were provided for 7 days.Rabbits in each group were sacrificed at 3,6,and 12 weeks after tendon repair.Tendon biomechanical load failure tests were performed.The percentage of type Ⅰ collagen on the bone tendon insertion was calculated by Picric acid Sirius red staining and image analysis.All data were compared among the four groups at the same time point.All data in each group were also compared across the different time points.Qualitative histological evaluation of the bone tendon insertion was also performed among groups.Results:The load to failure increased significantly with time in each group.There were significantly lower failure loads in the celecoxib group than in the control group at 3 weeks (0.533 vs.0.700,P =0.002),6 weeks (0.607 vs.0.763,P =0.01),and 12 weeks (0.660 vs.0.803,P =0.002),and significantly lower percentage of type Ⅰ collagen at 3 weeks (l 1.5% vs.27.6%,P =0.001),6 weeks (40.5% vs.66.3%,P =0.005),and 12 weeks (59.5% vs.86.3%,P =0.001).Flurbiprofen axetil showed significant differences at 3 weeks (failure load:0.600 vs.0.700,P =0.024;percentage of type Ⅰ collagen:15.6% vs.27.6%,P =0.001),but no significant differences at 6 and 12 weeks comparing with control group,whereas the ibuprofen groups did not show any significant difference at each time point.Conclusions:Nonsteroidal anti-inflammatory drugs can delay tendon healing in the

  10. Enhancement on reactive oxygen species and COX-1 mRNA levels modulate the vascular relaxation induced by sodium nitroprusside in denuded mice aorta.

    Science.gov (United States)

    Kangussu, Lucas M; Olivon, Vania C; Arifa, Raquel D do N; Araújo, Natália; Reis, Daniela; Assis, Marieta T de A; Soriani, Frederico M; de Souza, Daniele da G; Bendhack, Lusiane M; Bonaventura, Daniella

    2015-04-01

    This study aimed to investigate the modulation of nitric oxide/reactive oxygen species in sodium nitroprusside relaxation in mice aorta. Sodium nitroprusside induced relaxation in endothelium-intact (e+) and endothelium-denuded (e-) aortas with greater potency in e+ than in e-. The nitric oxide synthase inhibitor did not alter the sodium nitroprusside relaxation in both e+ and e- aortas. However, the superoxide anion scavenger abolished the difference in sodium nitroprusside potency between e+ and e-. Sodium nitroprusside reduced dihydroethidium-derived fluorescent products in both groups; however, the difference between intact and denuded mice aorta remains. The glutathione levels and basal antioxidant activity of superoxide dismutase were reduced in e- aorta when compared with e+, and these values were not altered by sodium nitroprusside. Confirming these results, the levels of lipid peroxidation in e+ were significantly lower when compared to e-, and these values were not altered by sodium nitroprusside. The sodium nitroprusside potency in the presence of a nonselective COX inhibitor or the EP/DP prostaglandin receptor antagonist in endothelium denuded was similar to that in intact mice aorta. Based on these results, we performed the COX-1 and COX-2 mRNA level studies, and in denuded mice aorta, there was an upregulation in COX-1 mRNA levels. Taken together, our findings show that in the absence of endothelium, there is an enhancement of superoxide levels, leading to GSH consumption and higher levels of lipid peroxidation, showing an intense redox status. Furthermore, in denuded mice aorta, there was an upregulation of COX-1 mRNA expression, leading to vasoconstrictor prostanoids synthesis. The interaction of vasoconstrictor prostanoids with its receptors EP/DP negatively modulates the vascular relaxation induced by SNP in denuded mice aorta. © 2015 Société Française de Pharmacologie et de Thérapeutique.

  11. COX, LOX and platelet aggregation inhibitory properties of Lauraceae neolignans.

    Science.gov (United States)

    Coy, Ericsson David; Cuca, Luis Enrique; Sefkow, Michael

    2009-12-15

    The anti-inflammatory potential of 26 neolignans (14 of the bicyclooctane-type and 12 of the benzofuran-type), isolated from three Lauraceae species (Pleurothyrium cinereum, Ocotea macrophylla and Nectandra amazonum), was evaluated in vitro through inhibition of COX-1, COX-2, 5-LOX and agonist-induced aggregation of rabbit platelets. Benzofuran neolignans were found to be selective COX-2 inhibitors, whereas bicyclooctane neolignans inhibit selectively the PAF-action as well as COX-1 and 5-LOX. The neolignan 9-nor-7,8-dehydro-isolicarin B 15 and cinerin C 7 were found to be the most potent COX-2 inhibitor and PAF-antagonist, respectively. Nectamazin C 10 exhibited dual 5-LOX/COX-2 inhibition.

  12. Effect of cyclooxygenase inhibitors on gentamicin-induced nephrotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Hosaka E.M.

    2004-01-01

    Full Text Available The frequent use of nonsteroidal anti-inflammatory drugs (NSAID in combination with gentamicin poses the additional risk of nephrotoxic renal failure. Cyclooxygenase-1 (COX-1 is the main enzyme responsible for the synthesis of renal vasodilator prostaglandins, while COX-2 participates predominantly in the inflammatory process. Both are inhibited by non-selective NSAID such as indomethacin. Selective COX-2 inhibitors such as rofecoxib seem to have fewer renal side effects than non-selective inhibitors. The objective of the present study was to determine whether the combined use of rofecoxib and gentamicin can prevent the increased renal injury caused by gentamicin and indomethacin. Male Wistar rats (250-300 g were treated with gentamicin (100 mg/kg body weight, ip, N = 7, indomethacin (5 mg/kg, orally, N = 7, rofecoxib (1.4 mg/kg, orally, N = 7, gentamicin + rofecoxib (100 and 1.4 mg/kg, respectively or gentamicin + indomethacin (100 and 5 mg/kg, respectively, N = 8 for 5 days. Creatinine clearance and alpha-glutathione-S-transferase concentrations were used as markers of renal injury. Animals were anesthetized with ether and sacrificed for blood collection. The use of gentamicin plus indomethacin led to worsened renal function (0.199 ± 0.019 ml/min, as opposed to the absence of a nephrotoxic effect of rofecoxib when gentamicin plus rofexicob was used (0.242 ± 0.011 ml/min. These results indicate that COX-2-selective inhibitors can be used as an alternative treatment to conventional NSAID, especially in situations in which risk factors for nephrotoxicity are present.

  13. Isobolographic analysis of interaction between cyclooxygenase inhibitors and tramadol in acetic acid-induced writhing in mice.

    Science.gov (United States)

    Satyanarayana, Padi S V; Jain, Naveen K; Singh, Amarjit; Kulkarni, Shrinivas K

    2004-07-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used analgesics in the management of acute and chronic pain. Combined use of NSAIDs and opioids has been indicated for achieving better analgesia with reduced side effects. The present study was aimed at evaluating the combination of different NSAIDs, which inhibit cyclooxygenase (COX) enzymes and tramadol against acetic acid-induced writhing in mice. The expected beneficial effect of combination regimen was analyzed by isobolographic analysis. The oral and intrathecally administered tramadol, a mu-opioid and naproxen, a nonselective COX inhibitor produced dose-dependent antinociception, however, rofecoxib, a selective COX-2 inhibitor lacked analgesic efficacy in writhing test. Isobolographic analysis showed synergistic or supra-additive interactions for the combinations of naproxen and tramadol after oral and intrathecal administration. However, similar interaction was not observed when tramadol was combined with rofecoxib. Pretreatment with naloxone partially reversed the antinociceptive effect of tramadol per se and its combination with naproxen without modifying the per se effect of NSAID. The results demonstrated marked synergistic interaction between naproxen and tramadol and such interaction involved opioid as well as non-opioid mechanisms of tramadol and inhibition of COX-1 but not COX-2 by naproxen.

  14. Incremental cost-effectiveness of cyclooxygenase 2-selective versus nonselective nonsteroidal, anti-inflammatory drugs in a cohort of coumarin users : A pharmacoeconomic analysis linked to a case-control study

    NARCIS (Netherlands)

    Knijff-Dutmer, EAJ; Postma, MJ; van der Palen, J; Brouwers, JRBJ; van de Laar, MAFJ

    2004-01-01

    Background: A previous case-control study involving concomitant users of coumarin and nonsteroidal anti-inflammatory drugs (NSAIDs) found that cyclooxygenase 2 (COX-2)-selective NSAIDs were associated with fewer bleeding complications than nonselective NSAIDs. Objective: The goal of this study was t

  15. Incremental cost-effectiveness of cyclooxygenase 2-selective versus nonselective nonsteroidal anti-inflammatory drugs in a cohort of coumarin users: A pharmacoeconomic analysis linked to a case-control study

    NARCIS (Netherlands)

    Knijff-Dutmer, Ellen A.J.; Postma, Maarten J.; Palen, van der Job; Brouwers, Jacobus R.B.J.; Laar, van de Martin A.F.J.

    2004-01-01

    Background: A previous case-control study involving concomitant users of coumarin and nonsteroidal anti-inflammatory drugs (NSAIDs) found that cyclooxygenase 2 (COX-2)-selective NSAIDs were associated with fewer bleeding complications than nonselective NSAIDs. Objective: The goal of this study was

  16. HER2 and COX2 expression in human prostate cancer.

    Science.gov (United States)

    Edwards, J; Mukherjee, R; Munro, A F; Wells, A C; Almushatat, A; Bartlett, J M S

    2004-01-01

    COX2 and HER2 expression are associated with a poor prognosis in prostate cancer and HER2 has been linked to COX2 expression in colorectal cancer. The association between COX2 and HER2 expression was investigated in 117 patients with prostate cancer (89) or Benign prostatic hyperplasia (BPH) (28). Tissue was analysed for HER2 amplification by fluorescent in situ hybridisation, and HER2 and COX2 protein expression by immunohistochemistry (IHC). All tumours analysed expressed COX2 at a significantly higher level than BPH tissue (P=0.041). Only low levels of HER2 gene amplification (8%, 7/89) and HER2 protein expression (12%, 11/89) were observed. HER2 protein expression was rarely observed and did not correlate with HER2 amplification or COX2 expression. Although HER2 does not drive COX2 expression in prostate cancer, this study identified high levels of COX2 expressed in locally advanced prostate cancer, suggesting COX2 could be a potential therapeutic target. COX2 inhibitors are currently being used in clinical trials for the treatment of other tumour types.

  17. Selective and nonselective inhibition of competitors in picture naming.

    Science.gov (United States)

    Shao, Zeshu; Meyer, Antje S; Roelofs, Ardi

    2013-11-01

    The present study examined the relation between nonselective inhibition and selective inhibition in picture naming performance. Nonselective inhibition refers to the ability to suppress any unwanted response, whereas selective inhibition refers to the ability to suppress specific competing responses. The degree of competition in picture naming was manipulated by presenting targets along with distractor words that could be semantically related (e.g., a picture of a dog combined with the word cat) or unrelated (tree) to the picture name. The mean naming response time (RT) was longer in the related than in the unrelated condition, reflecting semantic interference. Delta plot analyses showed that participants with small mean semantic interference effects employed selective inhibition more effectively than did participants with larger semantic interference effects. The participants were also tested on the stop-signal task, which taps nonselective inhibition. Their performance on this task was correlated with their mean naming RT but, importantly, not with the selective inhibition indexed by the delta plot analyses and the magnitude of the semantic interference effect. These results indicate that nonselective inhibition ability and selective inhibition of competitors in picture naming are separable to some extent.

  18. The Effect of Diet Mixing on a Nonselective Herbivore.

    Directory of Open Access Journals (Sweden)

    Sophie Groendahl

    Full Text Available The balanced-diet hypothesis states that a diverse prey community is beneficial to consumers due to resource complementarity among the prey species. Nonselective consumer species cannot differentiate between prey items and are therefore not able to actively regulate their diet intake. We thus wanted to test whether the balanced-diet hypothesis is applicable to nonselective consumers. We conducted a laboratory experiment in which a nonselective model grazer, the freshwater gastropod Lymnaea stagnalis, was fed benthic green algae as single species or as a multi-species mixture and quantified the snails' somatic growth rates and shell lengths over a seven-week period. Gastropods fed the mixed diet were found to exhibit a higher somatic growth rate than the average of the snails fed single prey species. However, growth on the multi-species mixture did not exceed the growth rate obtained on the best single prey species. Similar results were obtained regarding the animals' shell height increase over time. The mixed diet did not provide the highest growth rate, which confirms our hypothesis. We thus suggest that the balanced-diet hypothesis is less relevant for non-selective generalist consumers, which needs to be considered in estimates of secondary production.

  19. Non-Selective Lexical Access in Different-Script Bilinguals

    Science.gov (United States)

    Moon, Jihye; Jiang, Nan

    2012-01-01

    Lexical access in bilinguals is known to be largely non-selective. However, most studies in this area have involved bilinguals whose two languages share the same script. This study aimed to examine bilingual lexical access among bilinguals whose two languages have distinct scripts. Korean-English bilinguals were tested in a phoneme monitoring task…

  20. Hepatic ischemia and reperfusion injury in the absence of myeloid cell-derived COX-2 in mice.

    Directory of Open Access Journals (Sweden)

    Sergio Duarte

    Full Text Available Cyclooxygenase-2 (COX-2 is a mediator of hepatic ischemia and reperfusion injury (IRI. While both global COX-2 deletion and pharmacologic COX-2 inhibition ameliorate liver IRI, the clinical use of COX-2 inhibitors has been linked to increased risks of heart attack and stroke. Therefore, a better understanding of the role of COX-2 in different cell types may lead to improved therapeutic strategies for hepatic IRI. Macrophages of myeloid origin are currently considered to be important sources of the COX-2 in damaged livers. Here, we used a Cox-2flox conditional knockout mouse (COX-2-M/-M to examine the function of COX-2 expression in myeloid cells during liver IRI. COX-2-M/-M mice and their WT control littermates were subjected to partial liver ischemia followed by reperfusion. COX-2-M/-M macrophages did not express COX-2 upon lipopolysaccharide stimulation and COX-2-M/-M livers showed reduced levels of COX-2 protein post-IRI. Nevertheless, selective deletion of myeloid cell-derived COX-2 failed to ameliorate liver IRI; serum transaminases and histology were comparable in both COX-2-M/-M and WT mice. COX-2-M/-M livers, like WT livers, developed extensive necrosis, vascular congestion, leukocyte infiltration and matrix metalloproteinase-9 (MMP-9 expression post-reperfusion. In addition, myeloid COX-2 deletion led to a transient increase in IL-6 levels after hepatic reperfusion, when compared to controls. Administration of celecoxib, a selective COX-2 inhibitor, resulted in significantly improved liver function and histology in both COX-2-M/-M and WT mice post-reperfusion, providing evidence that COX-2-mediated liver IRI is caused by COX-2 derived from a source(s other than myeloid cells. In conclusion, these results support the view that myeloid COX-2, including myeloid-macrophage COX-2, is not responsible for the hepatic IRI phenotype.

  1. Non-Selective SiGe Graphic Epitaxial by MBE

    Institute of Scientific and Technical Information of China (English)

    Qian Zhou; Chun Han; Jing-Chun Li

    2007-01-01

    To handle the thermal budget in SiGe BiCMOS process, a nonselective graphic epitaxial technology using molecular beam epitaxial (MBE) has been developed. SEM, AFM, XRD, and dislocation density measurements are carried out. The SiGe film's RMS roughness is 0.45nm, and dislocation density is 0.3×103cm2~1.2×103cm2. No dislocation accumulation exists on the boundary of the windows; this indicates the high quality of the SiGe film. The experiment results show that the technology presented in this paper meets the fabrication requirements of SiGe BiCMOS.

  2. Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib

    DEFF Research Database (Denmark)

    Macdonald, Thomas M; Hawkey, Chris J; Ford, Ian;

    2016-01-01

    BACKGROUND: Selective cyclooxygenase-2 inhibitors and conventional non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) have been associated with adverse cardiovascular (CV) effects. We compared the CV safety of switching to celecoxib vs. continuing nsNSAID therapy in a European setting...... primary events per 1000 patient-years exposure. There were only 15 adjudicated secondary upper gastrointestinal complication endpoints (0.078/100 patient-years on celecoxib vs. 0.053 on nsNSAIDs OT, 0.078 vs. 0.053 ITT). More gastrointestinal serious adverse reactions and haematological adverse reactions...

  3. Properties of spatial Cox process models

    DEFF Research Database (Denmark)

    Møller, Jesper

    Probabilistic properties of Cox processes of relevance for statistical modelling and inference are studied. Particularly, we study the most important classes of Cox processes, including log Gaussian Cox processes, shot noise Cox processes, and permanent Cox processes. We consider moment propertie...

  4. Green tea constituent epigallocatechin-3-gallate selectively inhibits COX-2 without affecting COX-1 expression in human prostate carcinoma cells.

    Science.gov (United States)

    Hussain, Tajamul; Gupta, Sanjay; Adhami, Vaqar M; Mukhtar, Hasan

    2005-02-10

    Overexpression of cyclooxygenase (COX)-2 has been implicated in many pathologic conditions, including cancer. One practical inference of this finding is that sustained inhibition of COX-2 could serve as a promising target for prevention or therapy of cancer. Conventional nonsteroidal antiinflammatory drugs (NSAIDs) and recently developed COX-2-specific inhibitors have shown considerable promise in prevention of some forms of human cancer; however, its application is limited due to severe toxic side effects on normal cells. Therefore, there is a need to define novel, nontoxic dietary constituents with proven chemopreventive effects through other pathways that also possess COX-2 but not COX-1 inhibitory activity. Recent studies on green tea and its major polyphenolic constituent (-)epigallocatechin-3-gallate (EGCG) have established its remarkable cancer preventive and some cancer therapeutic effects. Here, we show that EGCG inhibits COX-2 without affecting COX-1 expression at both the mRNA and protein levels, in androgen-sensitive LNCaP and androgen-insensitive PC-3 human prostate carcinoma cells. Based on our study, it is tempting to suggest that a combination of EGCG with chemotherapeutic drugs could be an improved strategy for prevention and treatment of prostate cancer.

  5. Effect of COX-2 inhibitor on 5-LO expression of hippocampus in chronic aluminum overload-induced neurodegenerative rats%COX-2抑制剂对慢性铝过负荷大鼠海马5-脂氧酶表达的影响

    Institute of Scientific and Technical Information of China (English)

    苏强; 杨俊卿; 唐捷

    2012-01-01

    目的 探讨COX-2抑制剂美洛昔康对慢性铝过负荷大鼠海马5-LO表达的影响.方法 葡萄糖酸铝灌胃给予Wistar大鼠,1次/d,每周5d,连续20 w,建立慢性铝过负荷致神经元退变大鼠模型.美洛昔康(1和3 mg/kg),在每次给予铝盐后30 min灌胃给予.RT-PCR检测大鼠海马5-LO mRNA的表达变化,Western印迹方法检测5-LO蛋白表达情况.结果 慢性铝过负荷致大鼠海马5-LO mRNA和蛋白表达明显增加.美洛昔康能明显阻遏慢性铝过负荷诱导的大鼠海马5-LO mRNA和蛋白表达的增加.结论 COX-2抑制剂明显下调慢性铝过负荷大鼠海马5-LO表达.%Objective To investigate the effect of meloxicam on 5-LO expression of hippocampus in chronic aluminum overload induced neurodegeneration rats. Methods Neurodegeneration model of Wistar rats were established by intragastric administration of aluminum gluconate ( Al3 + 200 mg/kg) , once a day, 5 d/week, for 20 weeks. Meloxicam (1 and 3 mg/kg) was intragastrically administered 30 min after each aluminum administration. The expression of 5-LO mRNA and protein in hippocampus were detected by RT-PCR and Western blot respectively. Results Expression of 5-LO mRNA and protein in hippocampus obviously were increased. Meloxicam obviously protected rats from learning and memory function impairment and neuron death, significantly inhibited increase of the expression of 5-LO mRNA and protein induced by chronic aluminum overload. Conclusions Meloxicam can downregulate the 5-LO expression of hippocampus in chronic aluminum overload induced neurodegenerative rats.

  6. Flurbiprofen, a cyclooxygenase inhibitor, reduces the brain arachidonic acid signal in response to the cholinergic muscarinic agonist, arecoline, in awake rats.

    Science.gov (United States)

    Basselin, Mireille; Villacreses, Nelly E; Lee, Ho-Joo; Bell, Jane M; Rapoport, Stanley I

    2007-11-01

    Cholinergic muscarinic receptors, when stimulated by arecoline, can activate cytosolic phospholipase A(2) (cPLA(2)) to release arachidonic acid (AA) from membrane phospholipid. This signal can be imaged in the brain in vivo using quantitative autoradiography following the intravenous injection of radiolabeled AA, as an increment in a regional brain AA incorporation coefficient k*. Arecoline increases k* significantly in brain regions having muscarinic M(1,3,5) receptors in wild-type but not in cyclooxygenase (COX)-2 knockout mice. To further clarify the roles of COX enzymes in the AA signal, in this paper we imaged k* following arecoline (5 mg/kg i.p.) or saline in each of 81 brain regions of unanesthetized rats pretreated 6 h earlier with the non-selective COX inhibitor flurbiprofen (FB, 60 mg/kg s.c.) or with vehicle. Baseline values of k* were unaffected by FB treatment, which however reduced by 80% baseline brain concentrations of prostaglandin E(2) (PGE(2)) and thromboxane B(2) (TXB(2)), eicosanoids preferentially derived from AA via COX-2 and COX-1, respectively. In vehicle-pretreated rats, arecoline increased the brain PGE(2) but not TXB(2) concentration, as well as values for k* in 77 of the 81 brain regions. FB-pretreatment prevented these arecoline-provoked changes. These results and those reported in COX-2 knockout mice suggest that the AA released in brain following muscarinic receptor-mediated activation is lost via COX-2 to PGE(2) but not via COX-1 to TXB(2), and that increments in k* following arecoline largely represent replacement by unesterified plasma AA of this loss.

  7. Nonselective and polarization effects in time-resolved optogalvanic spectroscopy

    Science.gov (United States)

    Zhechev, D.; Steflekova, V.

    2016-02-01

    Three interfering effects in optogalvanic (OG) spectroscopy are identified in a hollow cathode discharge (HCD) - OG detector. The laser beam is found to generate two nonselective processes, namely photoelectron emission (PE) from the cathode surface with a sub-breakdown bias applied, and nonresonant space ionization. The convolution of these galvanic contributions was determined experimentally as an instrumental function and a deconvolution procedure to determine the actual OG signal was developed. Specific plasma conductance is detected dependent on the polarization of the laser beam irradiating. Linearly/circularly polarized light beam is found to induce OG signals differ in amplitude (and their shape parameters in the time-resolved OG signals (TROGS)). The phenomena coherence and specific conductance are found to be in causal relationship. The additional conductance due to coherent states of atoms manifests itself as an intrinsic instrumental property of OG detector.

  8. The expression of COX-2 in VEGF-treated endothelial cells is mediated through protein tyrosine kinase

    Directory of Open Access Journals (Sweden)

    Pravit Akarasereenont

    2002-01-01

    Full Text Available Cyclooxygenase (COX, existing as the COX-1 and COX-2 isoforms, converts arachidonic acid to prostaglandin H2, which is then further metabolized to various prostaglandins. Vascular endothelial growth factor (VEGF has been shown to play important roles in inflammation and is upregulated by the prostaglandin E series through COX-2 in several cell types. Here, we have investigated the effects of VEGF on the COX isoform expressed in human umbilical vein endothelial cells (HUVEC. The signalling mechanism of the COX isoform expressed in endothelial cells activated with VEGF will be also investigated using the tyrosine kinase inhibitor, genistein, and protein kinase C inhibitor, staurosporine. The activity of COX2 was assessed by measuring the production of 6-keto-prostaglandin F1α in the presence of exogenous arachidonic acids (10 μM, 10 min by enzyme immunoassay. The expression of COX isoform protein was detected by immunoblot using specific antibodies. Untreated HUVEC contained no COX-2 protein. In HUVEC treated with VEGF (0.01-50 ng/ml, COX-2 protein, but not COX-1, and COX activity were increased in a dose-dependent manner. Interestingly, the increased COX-2 protein and activity in response to VEGF (10 ng/ml was inhibited by the tyrosine kinase inhibitor, genistein (0.05-5 μg/ml, but not by the protein kinase C inhibitor, staurosporine (0.1-10 ng/ml. Thus, the induction of COX-2 by VEGF in endothelial cells was mediated through protein tyrosine kinase, and the uses of specific COX-2 inhibitors in these conditions, in which VEGF was involved, might have a role.

  9. Niacin and biosynthesis of PGD₂ by platelet COX-1 in mice and humans

    DEFF Research Database (Denmark)

    Song, Wen-Liang; Stubbe, Jane; Ricciotti, Emanuela

    2012-01-01

    The clinical use of niacin to treat dyslipidemic conditions is limited by noxious side effects, most commonly facial flushing. In mice, niacin-induced flushing results from COX-1-dependent formation of PGD₂ and PGE₂ followed by COX-2-dependent production of PGE₂. Consistent with this, niacin......-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD₂ receptor DP1. NSAID-mediated suppression of COX-2-derived PGI₂ has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD₂. Here, we show that PGD₂ biosynthesis is augmented....... Furthermore, COX inhibitors in humans, as well as platelet depletion, COX-1 knockdown, and COX-2 deletion in mice, revealed that niacin evoked platelet COX-1-derived PGD₂ biosynthesis. Finally, ADP-induced spreading on fibrinogen was augmented by niacin in washed human platelets, coincident with increased...

  10. Properties of spatial Cox process models

    DEFF Research Database (Denmark)

    Møller, Jesper

    2005-01-01

    Particularly, we study the most important classes of Cox processes, including log Gaussian Cox processes, shot noise Cox processes, and permanent Cox processes. We consider moment properties and point process operations such as thinning, displacements, and super positioning. We also discuss how t...

  11. Effect of cyclooxygenase-2 inhibitor in the treatment of nocturia caused by benign prostatic hyperplasia%COX-2抑制剂治疗良性前列腺增生症引起夜尿症的临床研究

    Institute of Scientific and Technical Information of China (English)

    左立; 李寿春; 邹建纲; 周忠兴; 吴小鹏; 陆曙炎

    2012-01-01

      目的:研究COX-2抑制剂对BPH患者发生夜尿症的疗效.方法:100名患有良性前列腺增生症的患者,平均年龄67岁(59~79岁),均有夜尿频的症状,并且夜尿次数>2次,均服用α-受体阻滞剂,但夜尿症改善不明显,随机分为两组:一组给予100 mg塞来昔布每晚口服;另一组给予100 mg安慰剂每晚口服,总共持续2周.对比两组服药前后夜尿症改善情况.结果:服用COX-2抑制剂组后,平均夜尿次数由(6.05±2.3)次/晚降为(2.4±1.8)次/晚(P0.05).未发现COX-2抑制剂有明显的不良反应.结论:COX-2抑制剂对患有难治性夜尿症的BPH患者是有效安全的.%  Objective:To estimate the efficacy of celecoxib, a cyclooxygenase-2 inhibitor, in the treatment of patients with BPH complaining of nocturia. Methods:We assessed 100 BPH patients with symptoms of nocturia at average age 67 (59~79). Among them, the nocturnal frequency should be more than 2, associated with the failure treatment of alpha-blocker. They were randomly divided into two groups:experimental group was received 100 mg of celecoxib at 9 PM for 2 weeks and control group was treated with placebo. Results:The nocturnal frequency was decreased from (6.05±2.3) to (2.4±1.8) (P<0.01) in experimental group with no significant side effects observed. Conclusion:Cyclooxygenase-2 inhibitor is effective in treatment of patients with BPH complaining of refractory nocturia.

  12. Primary repair of colon injuries: clinical study of nonselective approach

    Directory of Open Access Journals (Sweden)

    Krivokapic Zoran V

    2010-12-01

    Full Text Available Abstract Background This study was designed to determine the role of primary repair and to investigate the possibility of expanding indications for primary repair of colon injuries using nonselective approach. Methods Two groups of patients were analyzed. Retrospective (RS group included 30 patients managed by primary repair or two stage surgical procedure according to criteria published by Stone (S/F and Flint (Fl. In this group 18 patients were managed by primary repair. Prospective (PR group included 33 patients with primary repair as a first choice procedure. In this group, primary repair was performed in 30 cases. Results Groups were comparable regarding age, sex, and indexes of trauma severity. Time between injury and surgery was shorter in PR group, (1.3 vs. 3.1 hours. Stab wounds were more frequent in PR group (9:2, and iatrogenic lesions in RS group (6:2. Associated injuries were similar, as well as segmental distribution of colon injuries. S/F criteria and Flint grading were similar. In RS group 15 primary repairs were successful, while in two cases relaparotomy and colostomy was performed due to anastomotic leakage. One patient died. In PR group, 25 primary repairs were successful, with 2 immediate and 3 postoperative (7-10 days deaths, with no evidence of anastomotic leakage. Conclusions Results of this study justify more liberal use of primary repair in early management of colon injuries. Trial registration Current Controlled Trials ISRCTN94682396

  13. Non-selective cation channels mediate chloroquine-induced relaxation in precontracted mouse airway smooth muscle.

    Directory of Open Access Journals (Sweden)

    Ting Zhang

    Full Text Available Bitter tastants can induce relaxation in precontracted airway smooth muscle by activating big-conductance potassium channels (BKs or by inactivating voltage-dependent L-type Ca2+ channels (VDLCCs. In this study, a new pathway for bitter tastant-induced relaxation was defined and investigated. We found nifedipine-insensitive and bitter tastant chloroquine-sensitive relaxation in epithelium-denuded mouse tracheal rings (TRs precontracted with acetylcholine (ACH. In the presence of nifedipine (10 µM, ACH induced cytosolic Ca2+ elevation and cell shortening in single airway smooth muscle cells (ASMCs, and these changes were inhibited by chloroquine. In TRs, ACH triggered a transient contraction under Ca2+-free conditions, and, following a restoration of Ca2+, a strong contraction occurred, which was inhibited by chloroquine. Moreover, the ACH-activated whole-cell and single channel currents of non-selective cation channels (NSCCs were blocked by chloroquine. Pyrazole 3 (Pyr3, an inhibitor of transient receptor potential C3 (TRPC3 channels, partially inhibited ACH-induced contraction, intracellular Ca2+ elevation, and NSCC currents. These results demonstrate that NSCCs play a role in bitter tastant-induced relaxation in precontracted airway smooth muscle.

  14. Antiinflamatórios não-hormonais: inibidores da ciclooxigenase 2 Nonsteroidal anti-inflammatory drugs: cyclooxygenase 2 inhibitors

    Directory of Open Access Journals (Sweden)

    Maria Odete Esteves Hilário

    2006-11-01

    within the last 5 years. SUMMARY OF THE FINDINGS: The principal indications for NSAID are for control of pain and acute and chronic inflammation. There is no overwhelming evidence that demonstrates the superiority of one NSAID over another in terms of effectiveness. To date none of the COX 2 inhibitors has been liberated for use in the pediatric age group. Only meloxicam and etoricoxib can be prescribed for adolescents (13 and 16 years, respectively. Selective COX 2 inhibitors are indicated for patients with adverse effects that have proven to be associated with nonselective NSAID use. Selective COX 2 inhibitors can be prescribed in some cases of allergy to aspirin, but they must be used with care. Principal adverse effects include cardiovascular events and thrombotic phenomena. CONCLUSIONS: Selective COX 2 inhibitors are medicines that have been used in certain well-defined clinical situations and which may offer certain advantages over nonselective NSAID. Nevertheless, taking into consideration the higher cost involved and the potential for adverse cardiovascular effects, they should be employed only in accordance with strict criteria.

  15. Targeting Estrogen-Induced COX-2 Activity in Lymphangioleiomyomatosis (LAM)

    Science.gov (United States)

    2014-12-01

    rapamycin treatment. However both Torin 1 treatment and Rictor knockdown, led to reduced COX-2 expression and phospho-Akt-S473. Prostaglandin... rapamycin complex 1 (mTORC1), a master regulator of cell growth, protein translation, and metabolism. In LAM patients the mTORC1 inhibitor Rapamycin ...published PLOS One 2014. “ Rapamycin -insensitive up-regulation of adipocyte phospholipase A2 in tuberous sclerosis complex and

  16. 环加氧酶-2抑制剂尼美舒利通过改善内皮功能和增加NO含量对抗大鼠心肌氧化应激损伤%COX-2 inhibitor nimesulide protects rat heart against oxidative stress by improving endothelial function and enhancing NO production

    Institute of Scientific and Technical Information of China (English)

    吕萍萍; 范莹; 陈文良; 沈岳良; 朱立; 王琳琳; 陈莹莹

    2007-01-01

    依赖性血管舒张功能和增加心肌NO含量起作用.%Since a cyclooxygenase 2 (COX-2) inhibitor can reduce infarct size and improve contractility in ischemic myocardium, the aim of the present study was to explore whether COX-2 inhibitor nimesulide could protect myocardial function against oxidative stress injury in rat hearts, and to investigate the underlying mechanisms. The isolated rat hearts perfused by Langendorff method were exposed to 140 μmol/L of H2O2, and the cardiac contractility was measured. Then, the responses of coronary arteries, precontracted with U-46619, to the endothelium-dependent vasodilator serotonin (5-HT) and the endothelium-independent vasodilator sodium nitroprusside (SNP) were evaluated. The results were as follows: (1) In hearts exposed to H2O2 for 20 min, the left ventricular developed pressure [LVDP, (54.8±4.0)%] and maximal rate of rise/fall of ventricular pressure [±dp/dtmax, (50.8±3.1)% and (46.2±2.9)%]were reduced compared with that in the control group (100%). After pretreatment with nimesulide (5 μmol/L) for 10 min before H2O2perfusion, LVDP and ±dp/dtmax were enhanced to (79.9±2.8)%, (80.3±2.6)% and (81.4±2.6)%, respectively (P<0.01), and this was partially abolished by the nitric oxide synthase (NOS) inhibitor L-NAME [(60.2±2.1)%, (63.9±2.4)% and (63.1±2.9)%, respectively,P<0.01]. (2) The vasodilatation induced by 5-HT and SNP in H2O2-treated group was significantly less than that in the control group. Pretreatment with nimesulide for 10 min antagonized the decrease of endothelium-dependent vasodilatation in H2O2-treated group [(-22.2±4.2)% vs (-6.0±2.5)%, P<0.01 ], but had no effect on the decline of endothelium-independent vasodilatation [(-2.0± 1.8)%vs (-7.0±3.5)%, P>0.05]. (3) Pretreatment with nimesulide for 10 min increased the NO production in H2O2-treated hearts[(2.63±0.40) vs (1.36±0.23) nmol/g protein, P<0.05], and this was inhibited by L-NAME. (4) Pretreatment with the selective

  17. Safety of the nonselective NSAID nabumetone : focus on gastrointestinal tolerability.

    Science.gov (United States)

    Bannwarth, Bernard

    2008-01-01

    Although effective in the treatment of pain associated with rheumatic conditions such as osteoarthritis and rheumatoid arthritis, long-term use of NSAIDs is primarily limited by their association with upper gastrointestinal (GI) toxicity. Adverse effects range from dyspepsia and abdominal pain to ulceration and bleeding. GI damage elicited by NSAIDs arises as the result of biochemically induced topical irritant effects and by topical and systemic pharmacological suppression of gastroprotective prostaglandins. Variation in the physicochemical properties and pharmacological profiles among the individual NSAIDs translate into inter-agent differences regarding propensity to cause adverse GI effects. Nabumetone is a nonselective NSAID that offers distinct advantages over other agents in this class with regard to GI tolerability. Its non-acidic nature and pro-drug formulation, together with the lack of biliary secretion of its active metabolite, 6-methoxy-2-naphthylacetic acid, are thought to contribute to the improved GI tolerability of this drug. In head-to-head trials with other NSAIDs, nabumetone has demonstrated significant benefits regarding the incidence of GI events and more serious perforations, ulcers and bleeds (PUBs). Pooled data from eight postmarketing, randomized, controlled trials demonstrated a lower cumulative frequency of PUBs with nabumetone (0.03%; 95% CI 0.0, 0.08) versus comparator NSAIDs (1.4%; 95% CI 0.5, 2.4). Large-scale database studies also indicate that risk of serious GI complications is lower with nabumetone than comparator NSAIDs. Limited comparative data suggest that nabumetone offers a GI tolerability profile similar to that of cyclo-oxygenase-2 selective NSAIDs (coxibs). Although adverse cardiovascular outcomes appear to be a class effect of the coxibs, conventional NSAIDs may also have the potential for causing atherothrombotic complications. However, based on available data, nabumetone does not appear to be associated with increased

  18. Decomposition of variance for spatial Cox processes

    DEFF Research Database (Denmark)

    Jalilian, Abdollah; Guan, Yongtao; Waagepetersen, Rasmus

    2013-01-01

    Spatial Cox point processes is a natural framework for quantifying the various sources of variation governing the spatial distribution of rain forest trees. We introduce a general criterion for variance decomposition for spatial Cox processes and apply it to specific Cox process models...

  19. Decomposition of variance for spatial Cox processes

    DEFF Research Database (Denmark)

    Jalilian, Abdollah; Guan, Yongtao; Waagepetersen, Rasmus

    Spatial Cox point processes is a natural framework for quantifying the various sources of variation governing the spatial distribution of rain forest trees. We introducea general criterion for variance decomposition for spatial Cox processes and apply it to specific Cox process models with additive...

  20. Decomposition of variance for spatial Cox processes

    DEFF Research Database (Denmark)

    Jalilian, Abdollah; Guan, Yongtao; Waagepetersen, Rasmus

    Spatial Cox point processes is a natural framework for quantifying the various sources of variation governing the spatial distribution of rain forest trees. We introduce a general criterion for variance decomposition for spatial Cox processes and apply it to specific Cox process models...

  1. Counteracting effect of TRPC1-associated Ca2+ influx on TNF-α-induced COX-2-dependent prostaglandin E2 production in human colonic myofibroblasts.

    Science.gov (United States)

    Hai, Lin; Kawarabayashi, Yasuhiro; Imai, Yuko; Honda, Akira; Inoue, Ryuji

    2011-08-01

    TNF-α-NF-κB signaling plays a central role in inflammation, apoptosis, and neoplasia. One major consequence of this signaling in the gut is increased production of prostaglandin E(2) (PGE(2)) via cyclooxygenase-2 (COX-2) induction in myofibroblasts, which has been reported to be dependent on Ca(2+). In this study, we explored a potential role of canonical transient receptor potential (TRPC) proteins in this Ca(2+)-mediated signaling using a human colonic myofibroblast cell line CCD-18Co. In CCD-18Co cell, treatment with TNF-α greatly enhanced Ca(2+) influx induced by store depletion along with increased cell-surface expression of TRPC1 protein (but not of the other TRPC isoforms) and induction of a Gd(3+)-sensitive nonselective cationic conductance. Selective inhibition of TRPC1 expression by small interfering RNA (siRNA) or functionally effective TRPC1 antibody targeting the near-pore region of TRPC1 (T1E3) antagonized the enhancement of store-dependent Ca(2+) influx by TNF-α, whereas potentiated TNF-α induced PGE(2) production. Overexpression of TRPC1 in CCD-18Co produced opposite consequences. Inhibitors of NF-κB (curcumin, SN-50) attenuated TNF-α-induced enhancement of TRPC1 expression, store-dependent Ca(2+) influx, and COX-2-dependent PGE(2) production. In contrast, inhibition of calcineurin-nuclear factor of activated T-cell proteins (NFAT) signaling by FK506 or NFAT Activation Inhibitor III enhanced the PGE(2) production without affecting TRPC1 expression and the Ca(2+) influx. Finally, the suppression of store-dependent Ca(2+) influx by T1E3 antibody or siRNA knockdown significantly facilitated TNF-α-induced NF-κB nuclear translocation. In aggregate, these results strongly suggest that, in colonic myofibroblasts, NF-κB and NFAT serve as important positive and negative transcriptional regulators of TNF-α-induced COX-2-dependent PGE(2) production, respectively, at the downstream of TRPC1-associated Ca(2+) influx.

  2. Thrombosis is reduced by inhibition of COX-1, but unaffected by inhibition of COX-2, in an acute model of platelet activation in the mouse.

    Directory of Open Access Journals (Sweden)

    Paul C Armstrong

    Full Text Available BACKGROUND: Clinical use of selective inhibitors of cyclooxygenase (COX-2 appears associated with increased risk of thrombotic events. This is often hypothesised to reflect reduction in anti-thrombotic prostanoids, notably PGI(2, formed by COX-2 present within endothelial cells. However, whether COX-2 is actually expressed to any significant extent within endothelial cells is controversial. Here we have tested the effects of acute inhibition of COX on platelet reactivity using a functional in vivo approach in mice. METHODOLOGY/PRINCIPAL FINDINGS: A non-lethal model of platelet-driven thromboembolism in the mouse was used to assess the effects of aspirin (7 days orally as control diclofenac (1 mg.kg(-1, i.v. and parecoxib (0.5 mg.kg(-1, i.v. on thrombus formation induced by collagen or the thromboxane (TX A(2-mimetic, U46619. The COX inhibitory profiles of the drugs were confirmed in mouse tissues ex vivo. Collagen and U46619 caused in vivo thrombus formation with the former, but not latter, sensitive to oral dosing with aspirin. Diclofenac inhibited COX-1 and COX-2 ex vivo and reduced thrombus formation in response to collagen, but not U46619. Parecoxib inhibited only COX-2 and had no effect upon thrombus formation caused by either agonist. CONCLUSIONS/SIGNIFICANCE: Inhibition of COX-1 by diclofenac or aspirin reduced thrombus formation induced by collagen, which is partly dependent upon platelet-derived TXA(2, but not that induced by U46619, which is independent of platelet TXA(2. These results are consistent with the model demonstrating the effects of COX-1 inhibition in platelets, but provide no support for the hypothesis that acute inhibition of COX-2 in the circulation increases thrombosis.

  3. Synthesis of dihydropyrazole sulphonamide derivatives that act as anti-cancer agents through COX-2 inhibition.

    Science.gov (United States)

    Qiu, Han-Yue; Wang, Peng-Fei; Li, Zhen; Ma, Jun-Ting; Wang, Xiao-Ming; Yang, Yong-Hua; Zhu, Hai-Liang

    2016-02-01

    COX-2 has long been exploited in the treatment of inflammation and relief of pain; however, research increasingly suggests COX-2 inhibitors might possess potential benefits to thwart tumour processes. In the present study, we designed a series of novel COX-2 inhibitors based on analysis of known inhibitors combined with an in silico scaffold modification strategy. A docking simulation combined with a primary screen in vitro were performed to filter for the lead compound, which was then substituted, synthesized and evaluated by a variety of bioassays. Derivative 4d was identified as a potent COX-2 enzyme inhibitor and exerted an anticancer effect through COX-2 inhibition. Further investigation confirmed that 4d could induce A549 cell apoptosis and arrest the cell cycle at the G2/M phase. Moreover, treatment with 4d reduced A549 cell adhesive ability and COX-2 expression. The morphological variation of treated cells was also visualized by confocal microscopy. Overall, the biological profile of 4d suggests that this compound may be developed as a potential anticancer agent.

  4. COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells.

    Science.gov (United States)

    Ramer, Robert; Heinemann, Katharina; Merkord, Jutta; Rohde, Helga; Salamon, Achim; Linnebacher, Michael; Hinz, Burkhard

    2013-01-01

    The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-γ in cannabidiol's proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiol was suppressed by NS-398 (COX-2 inhibitor), GW9662 (PPAR-γ antagonist), and siRNA targeting COX-2 and PPAR-γ. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-γ mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-γ mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2-dependent prostaglandins (PG) among which PGD(2) and 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) caused a translocation of PPAR-γ to the nucleus and induced a PPAR-γ-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-γ in tumor tissue and tumor regression that was reversible by GW9662. Together, our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-γ and a subsequent nuclear translocation of PPAR-γ by COX-2-dependent PGs.

  5. Cox1 mutation abrogates need for Cox23 in cytochrome c oxidase biogenesis

    Directory of Open Access Journals (Sweden)

    Richard Dela Cruz

    2016-06-01

    Full Text Available Cox23 is a known conserved assembly factor for cytochrome c oxidase, although its role in cytochrome c oxidase (CcO biogenesis remains unresolved. To gain additional insights into its role, we isolated spontaneous suppressors of the respiratory growth defect in cox23∆ yeast cells. We recovered independent colonies that propagated on glycerol/lactate medium for cox23∆ cells at 37°C. We mapped these mutations to the mitochondrial genome and specifically to COX1 yielding an I101F substitution. The I101F Cox1 allele is a gain-of-function mutation enabling yeast to respire in the absence of Cox23. CcO subunit steady-state levels were restored with the I101F Cox1 suppressor mutation and oxygen consumption and CcO activity were likewise restored. Cells harboring the mitochondrial genome encoding I101F Cox1 were used to delete genes for other CcO assembly factors to test the specificity of the Cox1 mutation as a suppressor of cox23∆ cells. The Cox1 mutant allele fails to support respiratory growth in yeast lacking Cox17, Cox19, Coa1, Coa2, Cox14 or Shy1, demonstrating its specific suppressor activity for cox23∆ cells.

  6. COX-2-dependent PGE2 acts as a growth factor in mycosis fungoides (MF)

    DEFF Research Database (Denmark)

    Kopp, Katharina Luise Maria; Kauczok, C. S.; Lauenborg, Britt Thyssing

    2010-01-01

    production of PGE(2) in malignant T cells in vitro. These cells express prostaglandin receptors EP3 and EP4 and the receptor antagonist as well as small interfering RNA (siRNA) directed against COX-2, and specific COX-2 inhibitors strongly reduce their spontaneous proliferation. In conclusion, our data...... in prostaglandin synthesis. Aberrant COX-2 expression and prostaglandin E(2) (PGE(2)) production have been implicated in tumorigenesis. In this study we show that COX-2 is ectopically expressed in malignant T-cell lines from patients with cutaneous T-cell lymphoma (CTCL) as well as in situ in lymphocytic cells...... in 21 out of 22 patients suffering from mycosis fungoides (MF) in plaque or tumor stage. COX-2 is not expressed in lymphocytes of 11 patients with patch-stage MF, whereas sporadic COX-2 staining of stromal cells is observed in the majority of patients. COX-2 expression correlates with a constitutive...

  7. COX-1 and COX-2 expression in feline oral squamous cell carcinoma.

    Science.gov (United States)

    Hayes, A; Scase, T; Miller, J; Murphy, S; Sparkes, A; Adams, V

    2006-01-01

    This study demonstrated immunohistochemically the expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in feline oral squamous cell carcinoma (FOSCC), with primary polyclonal antibodies raised against human epitopes. COX-2 immunolabelling was intracytoplasmic and, in some neoplastic cells, perinuclear; it was demonstrated in a small proportion (tissues showed extensive nuclear and cytoplasmic COX-1 immunolabelling. Cytoplasmic COX-1 immunolabelling was less intense than nuclear labelling in neoplastic tissue. In the adjacent histologically normal oral mucosa, COX-2 immunolabelling was absent. The cytoplasmic and nuclear intensity and distribution of COX-1 immunolabelling was significantly higher in neoplastic tissue than in adjacent normal oral mucosa. The results indicate that COX-1 and COX-2 are overexpressed in FOSCC, but the clinical and pathophysiological significance of this finding remains to be determined.

  8. Digestive disease and COX - 1, COX - 2%COX-1和COX-2抑制剂与胃肠道疾病

    Institute of Scientific and Technical Information of China (English)

    李文晰; 梅冬艳; 段芳龄

    2001-01-01

    @@ COX(cvclo-oxygenase)有两种异构体:COX-1和COX-2,阿斯匹林和其它NSAIDs既有消炎镇痛作用也有较多的副作用,主要是由于其抑制COX的非选择性,因而较少副作用的选择性COX抑制剂(抑制COX异构体COX-2)在近几年越来越受到人们重视,这些药物有meloxicam、nimesulin、celecoxib、etodolac、尼美舒利(nimesulide)等.

  9. Loss of COX5B inhibits proliferation and promotes senescence via mitochondrial dysfunction in breast cancer.

    Science.gov (United States)

    Gao, Shui-Ping; Sun, He-Fen; Jiang, Hong-Lin; Li, Liang-Dong; Hu, Xin; Xu, Xiao-En; Jin, Wei

    2015-12-22

    COX5B, a peripheral subunit of the cytochrome c oxidase complex, has previously been reported to maintain the stability of this complex. However, its functions and mechanisms involved in breast cancer progression remain unclear. Here, by performing SILAC assays in breast cancer cell models and detecting COX5B expression in tissues, we found that COX5B expression was elevated in breast cancer. Down-regulation of COX5B in breast cancer cell lines can suppress cell proliferation and induced cell senescence which was accompanied by elevating production of IL-8 and other cytokines. Interestingly, conditioned medium from COX5B knockdown cells could promote breast cancer cell migration. Mechanistic studies reveal that COX5B silence induces an increase in production of ROS, depolarization of MMP and a decrease in ATP. What's more, silence of COX5B leads to metabolic disorders, such as increased glucose uptake and decreased lactate secretion. Collectively, our study shows that loss of COX5B induces mitochondrial dysfunction and subsequently leads to cell growth suppression and cell senescence. Cytokines such as IL-8 secreted by senescent cells may in turn alter the microenvironment which could enhance cell migration. These findings may provide a novel paradigm for the treatment which combined anti-cancer drugs with particular cytokine inhibitors such as IL-8 blockers.

  10. Cox-2 expression in ovarian malignancies: a review of the clinical aspects.

    Science.gov (United States)

    Menczer, Joseph

    2009-10-01

    COX-2 is an inducible enzyme expressed only in response to stimuli such as mitogens, cytokines, growth factors or hormones, and is pro-inflammatory. It plays an important role in tumorigenesis. The purpose of the present report is to review the clinical aspects of COX-2 expression in ovarian malignancies. A PubMed (http://www.pubmed.gov/) search of investigations published from July 2001 until August 2008 and containing the term COX-2 in combination with ovarian malignancies was conducted. The clinical aspects of the relevant investigations were reviewed. COX-2 is expressed in ovarian tumors of low malignant potential (LMP), in epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma (PPC) and apparently plays a role in their carcinogenesis. Its expression seems to be correlated with VEGF that serves as a predictor of poor prognosis in some non-gynecologic malignancies. COX-2 expression is higher in EOC than in LMPs. The results with regard to the association between COX-2 expression and prognostic factors, response to treatment and outcome in ovarian malignancies are inconsistent. Clinical studies dealing with the effect of COX-2 inhibitors on outcome are scarce. The use of COX-2 expression in gynecological malignancies in clinical practice remains to be elucidated.

  11. Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis?

    DEFF Research Database (Denmark)

    Thiele, Maja; Wiest, Reiner; Gluud, Lise Lotte

    2013-01-01

    Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta-blockers decrease the incidence and growth of hepatocellular...... carcinoma via a reduction of the inflammatory load from the gut to the liver and inhibition of angiogenesis. Due to their effect on the portal pressure, non-selective beta-blockers are used for prevention of esophageal variceal bleeding. Recently, non-hemodynamic effects of beta-blockers have received...... reduce hepatic inflammation. Blockage of β-adrenoceptors also decrease angiogenesis by inhibition of vascular endothelial growth factors. Because gut-derived inflammation and neo-angiogenesis are important in hepatic carcinogenesis, non-selective beta-blockers can potentially reduce the development...

  12. 环氧化酶-2抑制剂依托考昔治疗急性痛风性关节炎的疗效和安全性分析%Analysis of the clinical effect and safety of cyclooxygenase -2 (COX -2)inhibitors of etoricoxib in treatment of acute gout arthritis

    Institute of Scientific and Technical Information of China (English)

    李善敬; 陈玲; 陈艳; 陈庞何; 苏成标

    2016-01-01

    Objective To probe into the clinical effects and safety of cyclooxygenase -2 (COX -2)inhibitors of etoricoxib in treatment of acute gout arthritis.Method 94 patients with acute gout arthritis who accepted treatments were taken as the re-search objects,and these patients were randomly divided into the control group (47 cases)and the observation group (47 cases) according to the different treatment methods.In the control group,they were given diclofenac sodium treatment while in the obser-vation group,they were treated with the etoricoxib.Then,the treatment effects of these two groups of patients were com-pared.Results The indexes in the observation group were significantly better than those of the control group,the difference was statistically significant (P <0.05);After the treatment,the pain scores of the two groups were decreased,and the pain score of the observation group was significantly better than that of the control group,the difference was statistically significant (P <0.05).Conclusion The clinical effects of yclooxygenase -2 (COX -2)inhibitors of etoricoxib in treatment of acute gout arthritis are good enough,and it is safety and reliable.%目的:探讨环氧化酶-2抑制剂依托考昔治疗急性痛风性关节炎的疗效和安全性。方法:选择收治的急性痛风性关节炎患者94例作为研究对象,根据治疗方式的不同随机将患者分为对照组(47例)和观察组(47例),对照组给予患者双氯芬酸钠治疗,观察组给予患者依托考昔治疗。观察两组患者治疗效果。结果:观察组各项指标显著优于对照组,差异有统计学意义(P <0.05);两组患者治疗后疼痛评分均下降,观察组疼痛评分显著优于对照组,差异有统计学意义(P <0.05)。结论:环氧化酶-2抑制剂依托考昔治疗急性痛风性关节炎的疗效佳,安全可靠。

  13. Palm distributions for log Gaussian Cox processes

    DEFF Research Database (Denmark)

    Coeurjolly, Jean-Francois; Møller, Jesper; Waagepetersen, Rasmus

    This paper reviews useful results related to Palm distributions of spatial point processes and provides a new result regarding the characterization of Palm distributions for the class of log Gaussian Cox processes. This result is used to study functional summary statistics for a log Gaussian Cox...

  14. Non-selective β-blockers do not affect mortality in cirrhosis patients with ascites

    DEFF Research Database (Denmark)

    Bossen, Lars; Krag, Aleksander; Vilstrup, Hendrik

    2016-01-01

    The safety of non-selective β-blockers (NSBBs) in advanced cirrhosis has been questioned. We used data from three satavaptan trials to examine whether NSBBs increase mortality in cirrhosis patients with ascites. The trials were conducted in 2006-2008 and included 1198 cirrhosis patients with asci...

  15. Non-selective beta-blockers decrease thrombotic events in patients with heart failure

    NARCIS (Netherlands)

    De Peuter, Olav R.; Souverein, Patrick C.; Klungel, Olaf H.; Lip, Gregory Y.; Buller, Harry R.; De Boer, Anthonius; Kamphuisen, Pieter W.

    2010-01-01

    Background: Beta-blockers are often prescribed to patients with heart failure (HF) without distinctions between types of beta-blockers. The 2002 COMET study showed superiority of carvedilol (a non-selective beta-blocker) over metoprolol (selective beta-blocker) on mortality and cardiovascular events

  16. Memory Outcomes Following Selective versus Nonselective Temporal Lobe Removal: A Systematic Review

    Science.gov (United States)

    Girgis, Fady

    2012-01-01

    The surgical removal of brain tissue for the treatment of temporal lobe epilepsy can be either nonselective, as with an anterior temporal lobectomy (ATL), or selective, as with a selective amygdalohippocampectomy (SAH). Although seizure outcomes are similar with both procedures, cognitive and memory outcomes remain a matter of debate. This study…

  17. Nonselective Harvesting of a Prey-Predator Fishery with Gompertz Law of Growth

    Science.gov (United States)

    Purohit, D.; Chaudhuri, K. S.

    2002-01-01

    This paper develops a mathematical model for the nonselective harvesting of a prey-predator system in which both the prey and the predator obey the Gompertz law of growth and some prey avoid predation by hiding. The steady states of the system are determined, and the dynamical behaviour of both species is examined. The possibility of existence of…

  18. COX-2 Induces Breast Cancer Stem Cells via EP4/PI3K/AKT/NOTCH/WNT Axis.

    Science.gov (United States)

    Majumder, Mousumi; Xin, Xiping; Liu, Ling; Tutunea-Fatan, Elena; Rodriguez-Torres, Mauricio; Vincent, Krista; Postovit, Lynne-Marie; Hess, David; Lala, Peeyush K

    2016-09-01

    Cancer stem-like cells (SLC) resist conventional therapies, necessitating searches for SLC-specific targets. We established that cyclo-oxygenase(COX)-2 expression promotes human breast cancer progression by activation of the prostaglandin(PG)E-2 receptor EP4. Present study revealed that COX-2 induces SLCs by EP4-mediated NOTCH/WNT signaling. Ectopic COX-2 over-expression in MCF-7 and SKBR-3 cell lines resulted in: increased migration/invasion/proliferation, epithelial-mesenchymal transition (EMT), elevated SLCs (spheroid formation), increased ALDH activity and colocalization of COX-2 and SLC markers (ALDH1A, CD44, β-Catenin, NANOG, OCT3/4, SOX-2) in spheroids. These changes were reversed with COX-2-inhibitor or EP4-antagonist (EP4A), indicating dependence on COX-2/EP4 activities. COX-2 over-expression or EP4-agonist treatments of COX-2-low cells caused up-regulation of NOTCH/WNT genes, blocked with PI3K/AKT inhibitors. NOTCH/WNT inhibitors also blocked COX-2/EP4 induced SLC induction. Microarray analysis showed up-regulation of numerous SLC-regulatory and EMT-associated genes. MCF-7-COX-2 cells showed increased mammary tumorigenicity and spontaneous multiorgan metastases in NOD/SCID/IL-2Rγ-null mice for successive generations with limiting cell inocula. These tumors showed up-regulation of VEGF-A/C/D, Vimentin and phospho-AKT, down-regulation of E-Cadherin and enrichment of SLC marker positive and spheroid forming cells. MCF-7-COX-2 cells also showed increased lung colonization in NOD/SCID/GUSB-null mice, an effect reversed with EP4-knockdown or EP4A treatment of the MCF-7-COX-2 cells. COX-2/EP4/ALDH1A mRNA expression in human breast cancer tissues were highly correlated with one other, more marked in progressive stage of disease. In situ immunostaining of human breast tumor tissues revealed co-localization of SLC markers with COX-2, supporting COX-2 inducing SLCs. High COX-2/EP4 mRNA expression was linked with reduced survival. Thus, EP4 represents a novel SLC

  19. COX-2 activation is associated with Akt phosphorylation and poor survival in ER-negative, HER2-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Goodman Julie E

    2010-11-01

    Full Text Available Abstract Background Inducible cyclooxgenase-2 (COX-2 is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the association of COX-2 with breast cancer survival and how this association is influenced by tumor estrogen and HER2 receptor status and Akt pathway activation. Methods Tumor COX-2, HER2 and estrogen receptor α (ER expression and phosphorylation of Akt, BAD, and caspase-9 were analyzed immunohistochemically in 248 cases of breast cancer. Spearman's correlation and multivariable logistic regression analyses were used to examine the relationship between COX-2 and tumor characteristics. Kaplan-Meier survival and multivariable Cox proportional hazards regression analyses were used to examine the relationship between COX-2 and disease-specific survival. Results COX-2 was significantly associated with breast cancer outcome in ER-negative [Hazard ratio (HR = 2.72; 95% confidence interval (CI, 1.36-5.41; comparing high versus low COX-2] and HER2 overexpressing breast cancer (HR = 2.84; 95% CI, 1.07-7.52. However, the hazard of poor survival associated with increased COX-2 was highest among patients who were both ER-negative and HER2-positive (HR = 5.95; 95% CI, 1.01-34.9. Notably, COX-2 expression in the ER-negative and HER2-positive tumors correlated significantly with increased phosphorylation of Akt and of the two Akt targets, BAD at Ser136 and caspase-9 at Ser196. Conclusions Up-regulation of COX-2 in ER-negative and HER2-positive breast tumors is associated with Akt pathway activation and is a marker of poor outcome. The findings suggest that COX-2-specific inhibitors and inhibitors of the Akt pathway may act synergistically as anticancer drugs in the ER-negative and HER2-positive breast cancer subtype.

  20. Leptin induces CREB-dependent aromatase activation through COX-2 expression in breast cancer cells.

    Science.gov (United States)

    Kim, Hyung Gyun; Jin, Sun Woo; Kim, Yong An; Khanal, Tilak; Lee, Gi Ho; Kim, Se Jong; Rhee, Sang Dal; Chung, Young Chul; Hwang, Young Jung; Jeong, Tae Cheon; Jeong, Hye Gwang

    2017-08-01

    Leptin plays a key role in the control of adipocyte formation, as well as in the associated regulation of energy intake and expenditure. The goal of this study was to determine if leptin-induced aromatase enhances estrogen production and induces tumor cell growth stimulation. To this end, breast cancer cells were incubated with leptin in the absence or presence of inhibitor pretreatment, and changes in aromatase and cyclooxygenase-2 (COX-2) expression were evaluated at the mRNA and protein levels. Transient transfection assays were performed to examine the aromatase and COX-2 gene promoter activities and immunoblot analysis was used to examine protein expression. Leptin induced aromatase expression, estradiol production, and promoter activity in breast cancer cells. Protein levels of phospho-STAT3, PKA, Akt, ERK, and JNK were increased by leptin. Leptin also significantly increased cAMP levels, cAMP response element (CRE) activation, and CREB phosphorylation. In addition, leptin induced COX-2 expression, promoter activity, and increased the production of prostaglandin E2. Finally, a COX-2 inhibitor and aromatase inhibitor suppressed leptin-induced cell proliferation in MCF-7 breast cancer cells. Together, our data show that leptin increased aromatase expression in breast cancer cells, which was correlated with COX-2 upregulation, mediated through CRE activation and cooperation among multiple signaling pathways. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Increased COX2 in the trigeminal nucleus caudalis is involved in orofacial pain induced by experimental tooth movement.

    Science.gov (United States)

    Gao, Yuan; Duan, Yin-Zhong

    2010-03-01

    Pain is among the major problems during orthodontic treatment. Recent studies have shown that central Cyclooxygenase2 (COX2) pathway was involved in several pain models. The present study investigated whether inducible COX2 within the trigeminal nucleus caudalis (Vc) contributed to experimental tooth movement pain in freely moving rats. Elastic rubber bands were inserted between the first and second maxillary molars bilaterally to establish tooth movement model. The directed mouth wiping behavior was used to evaluate the pain during tooth movement. COX2 distribution in Vc was studied by immunohistochemistry and the changes of COX2 expression were detected by Western blot at different time point after rubber band insertion. Our results showed that tooth movement significantly increased COX2 expression in Vc and the time spent on mouth wiping, reaching a maximum at 1 day and then decreasing gradually. Furthermore, the rhythm change of COX2 expression in Vc and the mouth wiping behavior were much correlative with each other. All of the COX2-immunoreactive structures in Vc exhibited NeuN-immunopositive staining and most of these COX2-immunoreactive neurons were Fos-immunopositive. Importantly, the mouth wiping behavior could be attenuated by intracisternal injection of NS-398 (a selective COX2 inhibitor) but not by periodontal administration of NS-398. All these results suggested that increased COX2 in Vc was involved in tooth movement pain and thus may be a central target for orthodontic pain treatment.

  2. In vitro import and assembly of the nucleus-encoded mitochondrial subunit III of cytochrome c oxidase (Cox3).

    Science.gov (United States)

    Vázquez-Acevedo, Miriam; Rubalcava-Gracia, Diana; González-Halphen, Diego

    2014-11-01

    The cox3 gene, encoding subunit III of cytochrome c oxidase (Cox3) is in mitochondrial genomes except in chlorophycean algae, where it is localized in the nucleus. Therefore, algae like Chlamydomonas reinhardtii, Polytomella sp. and Volvox carteri, synthesize the Cox3 polypeptide in the cytosol, import it into mitochondria, and integrate it into the cytochrome c oxidase complex. In this work, we followed the in vitro internalization of the Cox3 precursor by isolated, import-competent mitochondria of Polytomella sp. In this colorless alga, the precursor Cox3 protein is synthesized with a long, cleavable, N-terminal mitochondrial targeting sequence (MTS) of 98 residues. In an import time course, a transient Cox3 intermediate was identified, suggesting that the long MTS is processed more than once. The first processing step is sensitive to the metalo-protease inhibitor 1,10-ortophenantroline, suggesting that it is probably carried out by the matrix-located Mitochondrial Processing Protease. Cox3 is readily imported through an energy-dependent import pathway and integrated into the inner mitochondrial membrane, becoming resistant to carbonate extraction. Furthermore, the imported Cox3 protein was assembled into cytochrome c oxidase, as judged by the presence of a labeled band co-migrating with complex IV in Blue Native Electrophoresis. A model for the biogenesis of Cox3 in chlorophycean algae is proposed. This is the first time that the in vitro mitochondrial import of a cytosol-synthesized Cox3 subunit is described.

  3. Inhibition of COX-2 expression by topical diclofenac enhanced radiation sensitivity via enhancement of TRAIL in human prostate adenocarcinoma xenograft model

    OpenAIRE

    Inoue Takeshi; Anai Satoshi; Onishi Sayuri; Miyake Makito; Tanaka Nobumichi; Hirayama Akihide; Fujimoto Kiyohide; Hirao Yoshihiko

    2013-01-01

    Abstract Background COX-2 inhibitors have an antitumor potential and have been verified by many researchers. Treatment of cancer cells with external stressors such as irradiation can stimulate the over-expression of COX-2 and possibly confer radiation resistance. In this study, we tested if topical diclofenac, which inhibits both COX-1 and COX-2, administration rendered prostate tumor cells sensitize to the effects of radiation. Methods LNCaP-COX-2 and LNCaP-Neo cells were treated with 0 to 1...

  4. Demethoxycurcumin Preserves Renovascular Function by Downregulating COX-2 Expression in Hypertension

    Science.gov (United States)

    2016-01-01

    Hypertension-associated endothelial dysfunction is largely due to the exaggerated vasoconstrictor generation by cyclooxygenase-2 (COX-2). COX-2 is induced under inflammatory condition. Demethoxycurcumin (DMC) is a major component of Curcuma longa L, which possesses anti-inflammatory action. This study aimed to examine whether DMC protects endothelial function in hypertension by modulating COX-2. Changes in isometric tension showed that in vivo and ex vivo treatment with DMC rescued the attenuated endothelium-dependent relaxations (EDRs) and elevated endothelium-dependent contractions (EDCs) in the renal arteries of SHR, which were also corrected by acute usage of the COX-2 inhibitor celecoxib. The restoration of renovascular activity by DMC was accompanied by the normalization of COX-2 expression. The enhanced COX-2 expression observed in the renal arteries of hypertensive patients was suppressed by incubation of excised arteries with DMC for 12 hrs. In the renal arteries of Wistar-Kyoto rats (WKY), DMC prevented the endothelial dysfunction caused by angiotensin II. The reduction in the generation of nitric oxide (NO) and expression of eNOS phosphorylation (Ser1177) in human umbilical vein endothelial cells caused by angiotensin II (Ang II) were restored by DMC or celecoxib. Our findings suggest that DMC may decrease COX-2 expression and improve endothelial function in hypertension. PMID:28105253

  5. An Exponential Bound for Cox Regression☆

    Science.gov (United States)

    Kosorok, M. R.

    2012-01-01

    We present an asymptotic exponential bound for the deviation of the survival function estimator of the Cox model. We show that the bound holds even when the proportional hazards assumption does not hold. PMID:23565013

  6. An Exponential Bound for Cox Regression.

    Science.gov (United States)

    Goldberg, Y; Kosorok, M R

    2012-07-01

    We present an asymptotic exponential bound for the deviation of the survival function estimator of the Cox model. We show that the bound holds even when the proportional hazards assumption does not hold.

  7. Role of COX-2-derived PGE2 on vascular stiffness and function in hypertension.

    Science.gov (United States)

    Avendaño, M S; Martínez-Revelles, S; Aguado, A; Simões, M R; González-Amor, M; Palacios, R; Guillem-Llobat, P; Vassallo, D V; Vila, L; García-Puig, J; Beltrán, L M; Alonso, M J; Cachofeiro, M V; Salaices, M; Briones, A M

    2016-05-01

    Prostanoids derived from COX-2 and EP receptors are involved in vascular remodelling in different cardiovascular pathologies. This study evaluates the contribution of COX-2 and EP1 receptors to vascular remodelling and function in hypertension. Spontaneously hypertensive rats (SHR) and angiotensin II (AngII)-infused (1.44 mg · kg(-1) · day(-1), 2 weeks) mice were treated with the COX-2 inhibitor celecoxib (25 mg · kg(-1) · day(-1) i.p) or with the EP1 receptor antagonist SC19220 (10 mg · kg(-1) · day(-1) i.p.). COX-2(-/-) mice with or without AngII infusion were also used. Celecoxib and SC19220 treatment did not modify the altered lumen diameter and wall : lumen ratio in mesenteric resistance arteries from SHR-infused and/or AngII-infused animals. However, both treatments and COX-2 deficiency decreased the augmented vascular stiffness in vessels from hypertensive animals. This was accompanied by diminished vascular collagen deposition, normalization of altered elastin structure and decreased connective tissue growth factor and plasminogen activator inhibitor-1 gene expression. COX-2 deficiency and SC19220 treatment diminished the increased vasoconstrictor responses and endothelial dysfunction induced by AngII infusion. Hypertensive animals showed increased mPGES-1 expression and PGE2 production in vascular tissue, normalized by celecoxib. Celecoxib treatment also decreased AngII-induced macrophage infiltration and TNF-α expression. Macrophage conditioned media (MCM) increased COX-2 and collagen type I expression in vascular smooth muscle cells; the latter was reduced by celecoxib treatment. COX-2 and EP1 receptors participate in the increased extracellular matrix deposition and vascular stiffness, the impaired vascular function and inflammation in hypertension. Targeting PGE2 receptors might have benefits in hypertension-associated vascular damage. © 2016 The British Pharmacological Society.

  8. Role of nonselective cation channels as Ca2+ entry pathway in endothelin-1-induced contraction and their suppression by nitric oxide.

    Science.gov (United States)

    Zhang, X F; Komuro, T; Miwa, S; Minowa, T; Iwamuro, Y; Okamoto, Y; Ninomiya, H; Sawamura, T; Masaki, T

    1998-07-10

    The present study was carried out to clarify the role of nonselective cation channels as a Ca2+ entry pathway in the contraction and the increase in [Ca2+]i induced by endothelin- in endothelium-denuded rat thoracic aorta rings, and their suppression by nitric oxide (NO). In Ca2+-free medium, the endothelin-1-induced contraction was suppressed to about 20% of control values, although the increase in [Ca2+]i became negligible. The contraction and the increase in [Ca2+]i monitored by fura 2 fluorescence were unaffected by a blocker of L-type voltage-operated Ca2+ channels nifedipine. A blocker of nonselective cation channels 1-[beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenethyl]-1H-imida zole . HCl(SK&F 96365) suppressed the endothelin-1-induced contraction and increase in [Ca2+]i to the level similar to that after removal of extracellular Ca2+. SK&F 96365 had no further effect on the endothelin-1-induced contraction in the absence of extracellular Ca2+. The endothelin-1-induced contraction and increase in [Ca2+]i were abolished by a donor of NO sodium nitroprusside. The effects of another NO donor 3-morpholinosydnonimine (SIN-1) were also tested and yielded essentially similar results to those for sodium nitroprusside on the endothelin-1-induced contraction. Furthermore, the inhibitory effects of sodium nitroprusside could be blocked with a guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) at 30 microM. These findings suggest that Ca2+ entry through nonselective cation channels but not voltage-operated Ca2+ channels plays a critical role in the endothelin-1-induced increase in [Ca2+]i and the resulting contraction and that inhibition by NO of the endothelin-1-induced contraction is mainly the result of blockade of Ca2+ entry through these channels.

  9. Activation of COX-2/PGE2 Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production.

    Science.gov (United States)

    Alfajaro, Mia Madel; Choi, Jong-Soon; Kim, Deok-Song; Seo, Ja-Young; Kim, Ji-Yun; Park, Jun-Gyu; Soliman, Mahmoud; Baek, Yeong-Bin; Cho, Eun-Hyo; Kwon, Joseph; Kwon, Hyung-Jun; Park, Su-Jin; Lee, Woo Song; Kang, Mun-Il; Hosmillo, Myra; Goodfellow, Ian; Cho, Kyoung-Oh

    2017-02-01

    Enteric caliciviruses in the genera Norovirus and Sapovirus are important pathogens that cause severe acute gastroenteritis in both humans and animals. Cyclooxygenases (COXs) and their final product, prostaglandin E2 (PGE2), are known to play important roles in the modulation of both the host response to infection and the replicative cycles of several viruses. However, the precise mechanism(s) by which the COX/PGE2 pathway regulates sapovirus replication remains largely unknown. In this study, infection with porcine sapovirus (PSaV) strain Cowden, the only cultivable virus within the genus Sapovirus, markedly increased COX-2 mRNA and protein levels at 24 and 36 h postinfection (hpi), with only a transient increase in COX-1 levels seen at 24 hpi. The treatment of cells with pharmacological inhibitors, such as nonsteroidal anti-inflammatory drugs or small interfering RNAs (siRNAs) against COX-1 and COX-2, significantly reduced PGE2 production, as well as PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE2 pathway. We observed that pharmacological inhibition of COX-2 dramatically increased NO production, causing a reduction in PSaV replication that could be restored by inhibition of nitric oxide synthase via the inhibitor N-nitro-l-methyl-arginine ester. This study identified a pivotal role for the COX/PGE2 pathway in the regulation of NO production during the sapovirus life cycle, providing new insights into the life cycle of this poorly characterized family of viruses. Our findings also reveal potential new targets for treatment of sapovirus infection. Sapoviruses are among the major etiological agents of acute gastroenteritis in both humans and animals, but little is known about sapovirus host factor requirements. Here, using only cultivable porcine sapovirus (PSaV) strain Cowden, we demonstrate that PSaV induced the vitalization of the cyclooxygenase (COX) and prostaglandin E2 (PGE2) pathway. Targeting

  10. Minimizing the cancer-promotional activity of cox-2 as a central strategy in cancer prevention.

    Science.gov (United States)

    McCarty, Mark F

    2012-01-01

    A recent meta-analysis examining long-term mortality in subjects who participated in controlled studies evaluating the impact of daily aspirin on vascular risk, has concluded that aspirin confers substantial protection from cancer mortality. Remarkably, low-dose aspirin was as effective as higher-dose regimens; hence this protection may be achievable with minimal risk. There is reason to believe that this protection stems primarily from inhibition of cox-2 in pre-neoplastic lesions. Since safe aspirin regimens can only achieve a partial and transitory inhibition of cox-2, it may be feasible to complement the cancer-protective benefit of aspirin with other measures which decrease cox-2 expression or which limit the bioactivity of cox-2-derived PGE2. Oxidative stress boosts cox-2 expression by up-regulating activation of NF-kappaB and MAP kinases; NADPH oxidase activation may thus promote carcinogenesis by increasing cox-2 expression while also amplifying oxidant-mediated mutagenesis. A prospective cohort study has observed that relatively elevated serum bilirubin levels are associated with a marked reduction in subsequent cancer mortality; this may reflect bilirubin's physiological role as a potent inhibitor of NADPH oxidase. It may be feasible to mimic this protective effect by supplementing with spirulina, a rich source of a phycobilin which shares bilirubin's ability to inhibit NADPH oxidase. Ancillary antioxidant measures - phase 2 inducing phytochemicals, melatonin, N-acetylcysteine, and astaxanthin - may also aid cox-2 down-regulation. The cancer protection often associated with high-normal vitamin D status may be attributable, in part, to the ability of the activated vitamin D receptor to decrease cox-2 expression while promoting PGE2 catabolism and suppressing the expression of PGE2 receptors. Diets with a relatively low ratio of omega-6 to long-chain omega-3 fats may achieve cancer protection by antagonizing the production and bioactivity of PGE2. Growth

  11. Soman increases neuronal COX-2 levels: possible link between seizures and protracted neuronal damage.

    Science.gov (United States)

    Angoa-Pérez, Mariana; Kreipke, Christian W; Thomas, David M; Van Shura, Kerry E; Lyman, Megan; McDonough, John H; Kuhn, Donald M

    2010-12-01

    Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4h to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the initial cholinergic crisis is assured. COX-2 inhibitors should be considered as adjunct therapy in nerve agent poisoning to minimize nerve agent-induced seizure activity.

  12. Interaction of apoptotic cells with macrophages upregulates COX-2/PGE2 and HGF expression via a positive feedback loop.

    Science.gov (United States)

    Byun, Ji Yeon; Youn, Young-So; Lee, Ye-Ji; Choi, Youn-Hee; Woo, So-Yeon; Kang, Jihee Lee

    2014-01-01

    Recognition of apoptotic cells by macrophages is crucial for resolution of inflammation, immune tolerance, and tissue repair. Cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and hepatocyte growth factor (HGF) play important roles in the tissue repair process. We investigated the characteristics of macrophage COX-2 and PGE2 expression mediated by apoptotic cells and then determined how macrophages exposed to apoptotic cells in vitro and in vivo orchestrate the interaction between COX-2/PGE2 and HGF signaling pathways. Exposure of RAW 264.7 cells and primary peritoneal macrophages to apoptotic cells resulted in induction of COX-2 and PGE2. The COX-2 inhibitor NS-398 suppressed apoptotic cell-induced PGE2 production. Both NS-398 and COX-2-siRNA, as well as the PGE2 receptor EP2 antagonist, blocked HGF expression in response to apoptotic cells. In addition, the HGF receptor antagonist suppressed increases in COX-2 and PGE2 induction. The in vivo relevance of the interaction between the COX-2/PGE2 and HGF pathways through a positive feedback loop was shown in cultured alveolar macrophages following in vivo exposure of bleomycin-stimulated lungs to apoptotic cells. Our results demonstrate that upregulation of the COX-2/PGE2 and HGF in macrophages following exposure to apoptotic cells represents a mechanism for mediating the anti-inflammatory and antifibrotic consequences of apoptotic cell recognition.

  13. Interaction of Apoptotic Cells with Macrophages Upregulates COX-2/PGE2 and HGF Expression via a Positive Feedback Loop

    Directory of Open Access Journals (Sweden)

    Ji Yeon Byun

    2014-01-01

    Full Text Available Recognition of apoptotic cells by macrophages is crucial for resolution of inflammation, immune tolerance, and tissue repair. Cyclooxygenase-2 (COX-2/prostaglandin E2 (PGE2 and hepatocyte growth factor (HGF play important roles in the tissue repair process. We investigated the characteristics of macrophage COX-2 and PGE2 expression mediated by apoptotic cells and then determined how macrophages exposed to apoptotic cells in vitro and in vivo orchestrate the interaction between COX-2/PGE2 and HGF signaling pathways. Exposure of RAW 264.7 cells and primary peritoneal macrophages to apoptotic cells resulted in induction of COX-2 and PGE2. The COX-2 inhibitor NS-398 suppressed apoptotic cell-induced PGE2 production. Both NS-398 and COX-2-siRNA, as well as the PGE2 receptor EP2 antagonist, blocked HGF expression in response to apoptotic cells. In addition, the HGF receptor antagonist suppressed increases in COX-2 and PGE2 induction. The in vivo relevance of the interaction between the COX-2/PGE2 and HGF pathways through a positive feedback loop was shown in cultured alveolar macrophages following in vivo exposure of bleomycin-stimulated lungs to apoptotic cells. Our results demonstrate that upregulation of the COX-2/PGE2 and HGF in macrophages following exposure to apoptotic cells represents a mechanism for mediating the anti-inflammatory and antifibrotic consequences of apoptotic cell recognition.

  14. Hopf Bifurcation Analysis of a Predator-Prey Biological Economic System with Nonselective Harvesting

    OpenAIRE

    Biwen Li; Zhenwei Li; Boshan Chen; Gan Wang

    2015-01-01

    A modified predator-prey biological economic system with nonselective harvesting is investigated. An important mathematical feature of the system is that the economic profit on the predator-prey system is investigated from an economic perspective. By using the local parameterization method and Hopf bifurcation theorem, we analyze the Hopf bifurcation of the proposed system. In addition, the modified model enriches the database for the predator-prey biological economic system. Finally, numeric...

  15. Reaching Hard-to-Reach Individuals: Nonselective Versus Targeted Outbreak Response Vaccination for Measles

    OpenAIRE

    2013-01-01

    Current mass vaccination campaigns in measles outbreak response are nonselective with respect to the immune status of individuals. However, the heterogeneity in immunity, due to previous vaccination coverage or infection, may lead to potential bias of such campaigns toward those with previous high access to vaccination and may result in a lower-than-expected effective impact. During the 2010 measles outbreak in Malawi, only 3 of the 8 districts where vaccination occurred achieved a measureabl...

  16. Chiral Derivatives of Xanthones: Investigation of the Effect of Enantioselectivity on Inhibition of Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum Albumin

    Science.gov (United States)

    Fernandes, Carla; Palmeira, Andreia; Ramos, Inês I.; Carneiro, Carlos; Afonso, Carlos; Tiritan, Maria Elizabeth; Cidade, Honorina; Pinto, Paula C.A.G.; Saraiva, M. Lúcia M.F.S.; Reis, Salette; Pinto, Madalena M.M.

    2017-01-01

    Searching of new enantiomerically pure chiral derivatives of xanthones (CDXs) with potential pharmacological properties, particularly those with anti-inflammatory activity, has remained an area of interest of our group. Herein, we describe in silico studies and in vitro inhibitory assays of cyclooxygenases (COX-1 and COX-2) for different enantiomeric pairs of CDXs. The evaluation of the inhibitory activities was performed by using the COX Inhibitor Screening Assay Kit. Docking simulations between the small molecules (CDXs; known ligands and decoys) and the enzyme targets were undertaken with AutoDock Vina embedded in PyRx—Virtual Screening Tool software. All the CDXs evaluated exhibited COX-1 and COX-2 inhibition potential as predicted. Considering that the (S)-(−)-enantiomer of the nonsteroidal anti-inflammatory drug ketoprofen preferentially binds to albumin, resulting in lower free plasma concentration than (R)-(+)-enantiomer, protein binding affinity for CDXs was also evaluated by spectrofluorimetry as well as in in silico. For some CDXs enantioselectivity was observed. PMID:28561772

  17. Losartan reverses COX-2-dependent vascular dysfunction in offspring of hyperglycaemic rats.

    Science.gov (United States)

    de Queiroz, Diego Barbosa; Ramos-Alves, Fernanda Elizabethe; Santos-Rocha, Juliana; Duarte, Gloria Pinto; Xavier, Fabiano Elias

    2017-09-01

    This study examined whether chronic treatment with losartan, an angiotensin II type 1 receptor (AT1R) antagonist, might reverse COX-2-mediated vascular dysfunction in mesenteric resistance arteries (MRA) from offspring of hyperglycaemic rats. Male 12-month-old offspring of hyperglycaemic (O-DR) and normoglycaemic (O-CR) rats were treated with losartan (15mg·kg·day(-1)) during 2months. Third order MRA of untreated and losartan-treated O-DR and O-CR were mounted in wire myograph for isometric tension measurements. COX-2 expression was analyzed by Western blot; TxA2, PGE2 and PGF2α release was measured using commercial kits. O-DR showed increased blood pressure, impaired acetylcholine-induced vasodilation and increased noradrenaline-induced vasoconstriction than O-CR. All these parameters were normalized by losartan in O-DR. Pre-incubation of MRA with indomethacin (COX-1/2 inhibitor), NS-398 (COX-2 inhibitor) or tempol (superoxide dismutase mimetic) increased relaxation to acetylcholine and reduced contraction to noradrenaline only in O-DR. COX-2 expression, TxA2, PGE2 and PGF2α release were increased in O-DR. In losartan-treated O-DR, NS-398, indomethacin or tempol failed to produce any effect on acetylcholine or noradrenaline responses. Losartan treatment reduced COX-2 expression, TxA2, PGE2 and PGF2α release in O-DR. The present results reveal that chronic losartan administration in O-DR normalizes endothelial function in MRA by correcting the existing COX-2 overexpression and the imbalance between endothelium-derived relaxing and contracting factors. These findings not only support the beneficial effects of AT1 receptor antagonist in O-DR, but also suggest the implication of angiotensin II as a putative mediator of hyperglycemia-programmed vascular dysfunction in rats. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. COX-2, VEGF and tumour angiogenesis.

    LENUS (Irish Health Repository)

    Toomey, D P

    2009-06-01

    Epidemiological evidence suggests a protective effective of regular NSAID use against developing cancer. Cyclooxygenase-2, a target of NSAIDs, is upregulated in many cancers and has been associated with increased VEGF production and angiogenesis. Angiogenesis is the formation of new vessels from existing vasculature and as an essential process for tumour development represents an important therapeutic target. Following an extensive review of the literature this article details the current knowledge on the role of COX-2 in tumorigenesis focusing on its relationship to angiogenesis and VEGF production by tumour cells. While COX-2 is clearly detrimental to prognosis and NSAIDs have a beneficial effect, the possibility of COX-2 independent effects being partly or wholly responsible for this benefit cannot be excluded.

  19. Effects of COX-2 inhibition on expression of vascular endothelial growth factor and interleukin-8 in lung cancer cells

    Directory of Open Access Journals (Sweden)

    Yu Danny CW

    2008-07-01

    Full Text Available Abstract Background Cyclooxygenase (COX-2 has been implicated in tumour progression, angiogenesis and metastasis in non-small cell lung cancer (NSCLC. We speculated that inhibition of COX-2 activity might reduce expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF and interleukin-8 (IL-8 in lung cancer cells. Methods The levels of IL-8, VEGF and prostaglandin E2 (PGE2 were measured by ELISA. Expression of COX-1 and COX-2 was determined by Western blotting. Inhibition or knockdown of COX-2 was achieved by treating NSCLC cells with specific COX-2 inhibitor NS-398 or COX-2 siRNA, respectively. Results We found that NSCLC cell lines produced more IL-8 than VEGF (p 2 was significantly higher in NSCLC cell lines than SCLC cell lines (p 2 production. VEGF was significantly reduced following the treatment of NS-398 in A549 (by 31% and MOR/P (by 47% cells lines which expressing strong COX-2, but not in H460 cell line which expressing very low COX-2. However, IL-8 was not reduced in these cell lines. To confirm these results, we knocked down COX-2 expression with COX-2 siRNA in these cell lines. VEGF was significantly decreased in A549 (by 24% and in MOR/P (by 53%, but not in H460 whereas IL-8 was not affected in any cell line. Conclusion We conclude that NSCLC cells produce much higher levels of IL-8 than SCLC cells whereas both NSCLC and SCLC cells produce similar levels of VEGF. COX-2 is only expressed in NSCLC cells, but not in SCLC cells. VEGF is produced in both NSCLC and SCLC cells regardless of COX-2 expression. However, VEGF production is, at least partly, COX-2 dependent in NSCLC cells expressing COX-2. In contrast, IL-8 production is COX-2 independent in both NSCLC and SCLC cells. We speculate that combined targeting of COX-2 and IL-8 may be useful in the treatment of patients with NSCLC and targeting VEGF may be useful in the treatment of patients with SCLC.

  20. COX-independent mechanisms of cancer chemoprevention by anti-inflammatory drugs

    Directory of Open Access Journals (Sweden)

    Evrim eGurpinar

    2013-07-01

    Full Text Available Epidemiological and clinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs, including cyclooxygenase (COX-2 selective inhibitors, reduce the risk of developing cancer. Experimental studies in human cancer cell lines and rodent models of carcinogenesis support these observations by providing strong evidence for the antineoplastic properties of NSAIDs. The involvement of COX-2 in tumorigenesis and its overexpression in various cancer tissues suggest that inhibition of COX-2 is responsible for the chemopreventive efficacy of these agents. However, the precise mechanisms by which NSAIDs exert their antiproliferative effects are still a matter of debate. Numerous other studies have shown that NSAIDs can act through COX-independent mechanisms. This review provides a detailed description of the major COX-independent molecular targets of NSAIDs and discusses how these targets may be involved in their anticancer effects. Toxicities resulting from COX inhibition and the suppression of prostaglandin synthesis preclude the long-term use of NSAIDs for cancer chemoprevention. Furthermore, chemopreventive efficacy is incomplete and treatment often leads to the development of resistance. Identification of alternative NSAID targets and elucidation of the biochemical processes by which they inhibit tumor growth could lead to the development of safer and more efficacious drugs for cancer chemoprevention.

  1. Transcription factor Ets-1 inhibits glucose-stimulated insulin secretion of pancreatic β-cells partly through up-regulation of COX-2 gene expression.

    Science.gov (United States)

    Zhang, Xiong-Fei; Zhu, Yi; Liang, Wen-Biao; Zhang, Jing-Jing

    2014-08-01

    Increased cyclooxygenase-2 (COX-2) expression is associated with pancreatic β-cell dysfunction. We previously demonstrated that the transcription factor Ets-1 significantly up-regulated COX-2 gene promoter activity. In this report, we used the pancreatic β-cell line INS-1 and isolated rat islets to investigate whether Ets-1 could induce β-cell dysfunction through up-regulating COX-2 gene expression. We investigated the effects of ETS-1 overexpression and the effects of ETS-1 RNA interference on endogenous COX-2 expression in INS-1 cells. We used site-directed mutagenesis and a dual luciferase reporter assay to study putative Ets-1 binding sites in the COX-2 promoter. The effect of ETS-1 1 overexpression on the insulin secretion function of INS-1 cells and rat islets and the potential reversal of these effects by a COX-2 inhibitor were determined in a glucose-stimulated insulin secretion (GSIS) assay. ETS-1 overexpression significantly induces endogenous COX-2 expression, but ETS-1 RNA interference has no effect on basal COX-2 expression in INS-1 cells. Ets-1 protein significantly increases COX-2 promoter activity through the binding site located in the -195/-186 region of the COX-2 promoter. ETS-1 overexpression significantly inhibited the GSIS function of INS-1 cells and islet cells and COX-2 inhibitor treatment partly reversed this effect. These findings indicated that ETS-1 overexpression induces β-cell dysfunction partly through up-regulation of COX-2 gene expression. Moreover, Ets-1, the transcriptional regulator of COX-2 expression, may be a potential target for the prevention of β-cell dysfunction mediated by COX-2.

  2. An observational study of the discrediting of COX-2 NSAIDs in Australia: Vioxx or class effect?

    Directory of Open Access Journals (Sweden)

    Parkinson Lynne

    2011-11-01

    Full Text Available Abstract Background When a medicine such as rofecoxib (Vioxx is withdrawn, or a whole class of medicines discredited such as the selective COX-2 inhibitors (COX-2s, follow-up of impacts at consumer level can be difficult and costly. The Australian Longitudinal Study on Women's Health provides a rare opportunity to examine individual consumer medicine use following a major discrediting event, the withdrawal of rofecoxib and issuing of safety warnings on the COX-2 class of medicines. The overall objective of this paper was to examine the impact of this discrediting event on dispensing of the COX-2 class of medicines, by describing medicine switching behaviours of older Australian women using rofecoxib in September 2004; the uptake of other COX-2s; and the characteristics of women who continued using a COX-2. Methods Participants were concessional beneficiary status women from the Older cohort (born 1921-26 of the Australian Longitudinal Study on Women's Health who consented to linkage to Pharmaceutical Benefits Scheme data, with at least one rofecoxib prescription dispensed in the 12 months before rofecoxib withdrawal. A prescription was defined as one dispensing occasion. Women were grouped by rofecoxib pattern of use: continuous (nine or more prescriptions dispensed in the 12 months prior to rofecoxib withdrawal or non-continuous (eight or less prescriptions dispensed in the 12 months prior to rofecoxib withdrawal users. Incidence rate per 100,000 person days and incidence risk ratio described uptake of alternate medicines, following rofecoxib withdrawal. Kaplan-Meier curves described differences in uptake patterns by medicine and pattern of rofecoxib use. Patterns of use of COX-2s in the next 100 days after first COX-2 uptake were described. Results Medicine switches and pattern of medicines uptake differed significantly depending upon whether a woman was a continuous or non-continuous rofecoxib user prior to rofecoxib discrediting. Continuous

  3. Maitotoxin activates a nonselective cation channel and stimulates Ca2+ entry in MDCK renal epithelial cells.

    Science.gov (United States)

    Dietl, P; Völkl, H

    1994-02-01

    We examined the mechanisms of maitotoxin (MTX), a water-soluble polyether from the marine dinoflagellate Gambierdiscus toxicus, in stimulation of Ca2+ entry into Mardin-Darby canine kidney cells. In the presence of bath Ca2+, MTX (3 nM) caused an elevation of the intracellular calcium concentration ([Ca2+]i), which was partially inhibited by SK&F 96365 (25 microM) or La3+ (100 microM). A stimulation of Ca(2+)-dependent K+ channels in cell-attached membrane patches coincided with this rise in [Ca2+]i and was also partially inhibited by SK&F 96365. Before the rise in [Ca2+]i, a nonselective cation current (Ins), studied by the whole-cell patch-clamp technique, was irreversibly activated. Ins poorly discriminated between Na+, K+, and Cs+, was unaffected by replacement of Cl- with gluconate-, and was not voltage gated. MTX-induced Ins was partially blocked by La3+ ions (100 microM) but not by SK&F 96365 (25 microM) or nifedipine (10 microM). SK&F 96365 by itself induced a small but significant stimulation of Ins and a rise in [Ca2+]i. The activation of Ins by MTX was instantaneous and depended on the presence of extracellular Ca2+ ions. In the absence of other cations, the inward current of Ins was dependent on the bath Ca2+ concentration. Cell-attached and excised single-channel measurements revealed that MTX activated a SK&F 96365-insensitive, approximately 40-pS, nonselective cation channel from the outside. We conclude that the initial action of MTX is the stimulation of a nonselective cation channel, which requires the presence of extracellular Ca2+ ions. The subsequent rise in [Ca2+]i is at least in part caused by another, SK&F 96365-sensitive, Ca2+ entry pathway, which may be activated as a result of or independently of Ins.

  4. How to sell successfully a perfume in the non-selective market?

    OpenAIRE

    Ramalho, Maria Rita Pinto Coelho de Magalhães

    2009-01-01

    A Work Project, presented as part of the requirements for the Award of a Masters Degree in Management from the NOVA – School of Business and Economics This document presents a market research on the positioning of perfumes in the non selective market. This project’s main goal had been to analyze the challenge of “successfully selling a perfume in the non-selective market” in order to propose potential solutions. To address this marketing problem, an exploratory research had been c...

  5. The effects of cyclooxygenase-2 inhibitors on urological cancer cells.

    Science.gov (United States)

    Yoshimura, Rikio; Matsuyama, Masahide; Kawahito, Yutaka; Takemoto, Yoshiaki; Tsuchida, Kenji; Kuratsukuri, Katsuyuki; Segawa, Yoshihiro; Shinnka, Toshiaki; Sano, Hajime; Nakatani, Tatsuya

    2004-06-01

    Cyclooxygenase (COX)-2 plays an important role in the development of various cancers due to its angiogenic function. We have demonstrated that the expression of COX-2 was up-regulated in human renal cell carcinoma (RCC), bladder tumor (BT) and prostate cancer (PC). In this study, we examined the effects of COX-2 inhibitors on cell proliferation in RCC, BT and PC-derived cell lines using MTT assay and Hoechst staining. COX-2 inhibitors did not induce a reduction of cell viability with the half-maximal concentration of growth inhibition of RCC, BT and PC cell lines. Furthermore, counting cells at days 1, 2 and 3, showed no inhibition of cell proliferation using COX-2 inhibitors. COX-2 inhibitors could not stop the growth of RCC, BT and PC cells. Typical characteristics of apoptosis, i.e. chromatin condensation, cellular shrinkage, small membrane-bound bodies (apoptotic bodies) and cytoplasmic condensation, did not occur. Although the expression of COX-2 was up-regulated in human RCC, BT and PC tissues, COX-2 inhibitors have only slight anti-proliferative effects against RCC, BT and PC cells through differentiation. Thus, using only down-regulation of arachidonic acid (AA) metabolizing enzyme, COX may be an unsuccessful approach in providing new anti-cancer therapies.

  6. COX-2 Elevates Oncogenic miR-526b in Breast Cancer by EP4 Activation.

    Science.gov (United States)

    Majumder, Mousumi; Landman, Erin; Liu, Ling; Hess, David; Lala, Peeyush K

    2015-06-01

    MicroRNAs (miRs) are small regulatory molecules emerging as potential biomarkers in cancer. Previously, it was shown that COX-2 expression promotes breast cancer progression via multiple mechanisms, including induction of stem-like cells (SLC), owing to activation of the prostaglandin E2 receptor EP4 (PTGER4). COX-2 overexpression also upregulated microRNA-526b (miR-526b), in association with aggressive phenotype. Here, the functional roles of miR-526b in breast cancer and the mechanistic role of EP4 signaling in miR-526b upregulation were examined. A positive correlation was noted between miR-526b and COX-2 mRNA expression in COX-2 disparate breast cancer cell lines. Stable overexpression of miR-526b in poorly metastatic MCF7 and SKBR3 cell lines resulted in increased cellular migration, invasion, EMT phenotype and enhanced tumorsphere formation in vitro, and lung colony formation in vivo in immunodeficient mice. Conversely, knockdown of miR-526b in aggressive MCF7-COX-2 and SKBR3-COX-2 cells reduced oncogenic functions and reversed the EMT phenotype, in vitro. Furthermore, it was determined that miR-526b expression is dependent on EP4 receptor activity and downstream PI3K-AKT and cyclic AMP (cAMP) signaling pathways. PI3K-AKT inhibitors blocked EP4 agonist-mediated miR-526b upregulation and tumorsphere formation in MCF7 and SKBR3 cells. NF-κB inhibitor abrogates EP agonist-stimulated miRNA expression in MCF7 and T47D cells, indicating that the NF-κB pathway is also involved in miR-526b regulation. In addition, inhibition of COX-2, EP4, PI3K, and PKA in COX-2-overexpressing cells downregulated miR-526b and its functions in vitro. Finally, miR-526b expression was significantly higher in cancerous than in noncancerous breast tissues and associated with reduced patient survival. In conclusion, miR-526b promotes breast cancer progression, SLC-phenotype through EP4-mediated signaling, and correlates with breast cancer patient survival. This study presents novel

  7. The Mitochondrial Genome of Conus textile, coxI-coxII Intergenic Sequences and Conoidean Evolution

    OpenAIRE

    2007-01-01

    The cone snails belong to the superfamily Conoidea, comprising ∼10,000 venomous marine gastropods. We determined the complete mitochondrial DNA sequence of Conus textile. The gene order is identical in Conus textile, Lophiotoma cerithiformis (another Conoidean gastropod), and the neogastropod Ilyanassa obsoleta, (not in the superfamily Conoidea). However, the intergenic interval between the coxI/coxII genes, was much longer in C. textile (165 bp) than in any other previously analyzed gastropo...

  8. Effect of selective cyclooxygenase-2 inhibitor NS398 on the proliferation and apoptosis of prostate cancer cell line PC0-3 in vitro%选择性COX-2抑制剂NS398对前列腺癌PC-3细胞增殖与凋亡的影响

    Institute of Scientific and Technical Information of China (English)

    王功成; 浦金贤; 丁翔

    2007-01-01

    目的 观察环氧化酶-2(COX-2)抑制剂NS398对前列腺癌细胞PC-3增殖和凋亡的影响.方法 采用四甲基偶氮唑蓝法(MTT法)检测不同浓度和不同时间NS398对PC-3细胞增殖的影响;RT-PCR法检测不同浓度NS398作用PC-3细胞24 h后COX-2 mRNA的表达;酶联免疫测定法(ELISA)检测不同浓度NS398作用PC-3细胞24 h后PGE2释放水平,流式细胞仪检测不同浓度NS398作用PC-3细胞24 h后细胞凋亡情况.结果 NS398可以抑制PC-3细胞的增殖,呈时间和剂量依赖性;RTPCR和ELISA法检测结果显示,随着NS398浓度增高,PC-3细胞COX-2 mRNA表达和PGE2释放水平呈下调趋势,细胞凋亡检测结果显示100,200 μmol/L NS398对PC-3细胞具有诱导凋亡的作用.结论 NS398可能通过COX-2依赖性途径抑制前列腺癌PC-3细胞增殖,促进肿瘤细胞凋亡.

  9. Involvement of COX2-thromboxane pathway in TCDD-induced precardiac edema in developing zebrafish.

    Science.gov (United States)

    Teraoka, Hiroki; Okuno, Yuki; Nijoukubo, Daisuke; Yamakoshi, Ayumi; Peterson, Richard E; Stegeman, John J; Kitazawa, Takio; Hiraga, Takeo; Kubota, Akira

    2014-09-01

    The cardiovascular system is one of the most characteristic and important targets for developmental toxicity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in fish larvae. However, knowledge of the mechanism of TCDD-induced edema after heterodimerization of aryl hydrocarbon receptor type 2 (AHR2) and AHR nuclear translocator type 1 (ARNT1) is still limited. In the present study, microscopic analysis with a high-speed camera revealed that TCDD increased the size of a small cavity between the heart and body wall in early eleutheroembryos, a toxic effect that we designate as precardiac edema. A concentration-response curve for precardiac edema at 2 days post fertilization (dpf) showed close similarity to that for conventional pericardial edema at 3 dpf. Precardiac edema caused by TCDD was reduced by morpholino knockdown of AHR2 and ARNT1, as well as by an antioxidant (ascorbic acid). A selective inhibitor of cyclooxygenase type 2 (COX2), NS398, also markedly inhibited TCDD-induced precardiac edema. A thromboxane receptor (TP) antagonist, ICI-192,605 almost abolished TCDD-induced precardiac edema and this effect was canceled by U46619, a TP agonist, which was not influential in the action of TCDD by itself. Knockdown of COX2b and thromboxane A synthase 1 (TBXS), but not COX2a, strongly reduced TCDD-induced precardiac edema. Knockdown of COX2b was without effect on mesencephalic circulation failure caused by TCDD. The edema by TCDD was also inhibited by knockdown of c-mpl, a thrombopoietin receptor necessary for thromobocyte production. Finally, induction of COX2b, but not COX2a, by TCDD was seen in eleutheroembryos at 3 dpf. These results suggest a role of the COX2b-thromboxane pathway in precardiac edema formation following TCDD exposure in developing zebrafish.

  10. Ester Prodrugs of Ketoprofen: Synthesis, In Vitro Stability, In Vivo Biological Evaluation and In Silico Comparative Docking Studies Against COX-1 and COX-2.

    Science.gov (United States)

    Ahmed, Musa; Azam, Faizul; Gbaj, Abdul; Zetrini, Abdulmottaleb E; Abodlal, Amna Salem; Rghigh, Abir; Elmahdi, Eman; Hamza, Amel; Salama, Mabruk; Bensaber, Salah M

    2016-01-01

    Prompted by the ineptness of the currently used non-steroidal antiinflammatory drugs (NSAIDs) to control gastric mucosal and renal adverse reactions, several ester prodrugs of ketoprofen were synthesized and characterized by IR, 1H NMR and mass spectral data. Physicochemical properties such as aqueous solubility, octanol-water partition coefficient log P, chemical stability and enzymatic hydrolysis of the synthesized molecules have been studied to assess their potential as prodrugs. The obtained results confirmed that all ester prodrugs are chemically stable, possess increased lipophilicity compared to their parent compounds and converted to the active drugs in vivo. All of the tested ester prodrugs exhibited marked anti-inflammatory activity ranging from 91.8% to 113.3% in comparison with the parent drug, ketoprofen. A mutual prodrug obtained from two antiinflammatory molecules, ketoprofen and salicylic acid has been noted to potentiate the activity making it most active molecule of the series. The ulcerogenic index of the ester prodrugs was significantly lower than the parent drug, ketoprofen. Comparative docking studies against X-ray crystal structures of COX-1 and COX-2 further provided understanding of their interaction with the cyclooxygenases that will facilitate design of better inhibitors (or prodrugs) with sufficient specificity for COX-2 against COX-1. The study offers an innovative strategy for finding a molecule with safer therapeutic profile for longterm treatment of inflammatory diseases.

  11. Associations between COX-2 polymorphisms, blood cholesterol and risk of acute coronary syndrome

    DEFF Research Database (Denmark)

    Vogel, Ulla Birgitte; Segel, Stine; Dethlefsen, Claus

    2010-01-01

    significant interactions between genotypes and alcohol intake, smoking and NSAID use in relation to risk of ACS. Among males, there was interaction between COX-2 T8473C and alcohol in relation to total cholesterol, non-HDL cholesterol and LDL levels (p for interaction: 0.003, 0.007 and 0.01, respectively......Background: The use of specific COX-2 inhibitors in cancer prevention has been associated with higher risk of acute coronary syndrome (ACS) and myocardial infarction. The aim of this study was to investigate if the polymorphisms COX2 T8473C (rs5275), and COX2 A-1195G (rs689466), which modify...... the enzyme levels of COX-2, were associated with risk of ACS and if alcohol intake, smoking, and use of NSAID would modify the associations. We also wanted to investigate associations with blood lipid levels. Methods: A case–cohort study including 1031 ACS cases and a sub-cohort of 1703 persons was nested...

  12. Reaching hard-to-reach individuals: Nonselective versus targeted outbreak response vaccination for measles.

    Science.gov (United States)

    Minetti, Andrea; Hurtado, Northan; Grais, Rebecca F; Ferrari, Matthew

    2014-01-15

    Current mass vaccination campaigns in measles outbreak response are nonselective with respect to the immune status of individuals. However, the heterogeneity in immunity, due to previous vaccination coverage or infection, may lead to potential bias of such campaigns toward those with previous high access to vaccination and may result in a lower-than-expected effective impact. During the 2010 measles outbreak in Malawi, only 3 of the 8 districts where vaccination occurred achieved a measureable effective campaign impact (i.e., a reduction in measles cases in the targeted age groups greater than that observed in nonvaccinated districts). Simulation models suggest that selective campaigns targeting hard-to-reach individuals are of greater benefit, particularly in highly vaccinated populations, even for low target coverage and with late implementation. However, the choice between targeted and nonselective campaigns should be context specific, achieving a reasonable balance of feasibility, cost, and expected impact. In addition, it is critical to develop operational strategies to identify and target hard-to-reach individuals.

  13. Profiling targets of the irreversible palmitoylation inhibitor 2-bromopalmitate

    OpenAIRE

    Davda, Dahvid; El Azzouny, Mahmoud A.; Tom, Christopher T.M.B.; Hernandez, Jeannie L.; Majmudar, Jaimeen D.; Kennedy, Robert T.; Martin, Brent R.

    2013-01-01

    2-bromohexadecanoic acid, or 2-bromopalmitate, was introduced nearly 50 years ago as a non-selective inhibitor of lipid metabolism. More recently, 2-bromopalmitate re-emerged as a general inhibitor of protein S-palmitoylation. Here, we investigate the cellular targets of 2-bromopalmitate through the synthesis and application of click-enabled analogues. In cells, 2-bromopalmitate is converted to 2-bromopalmitoyl-CoA, although less efficiently than free palmitate. Once conjugated to CoA, probe ...

  14. 选择性环氧化酶-2抑制剂对卵巢癌细胞抑制作用的体内体外研究%Inhibitory effects of selective COX -2 inhibitor on the growth of ovarian cancers in vitro and in vivo

    Institute of Scientific and Technical Information of China (English)

    辛兵; 王敏

    2015-01-01

    目的:研究选择性环氧化酶-2抑制剂美洛昔康在体内体外对卵巢癌生长侵袭的抑制作用。方法:使用2种卵巢癌细胞株,研究不同浓度的美洛昔康对于卵巢癌细胞增殖的抑制作用。利用移植卵巢癌细胞株小鼠模型,研究美洛昔康对小鼠背部皮下移植瘤生长以及肿瘤中 VEGF 表达、微血管密度以及细胞凋亡的影响,并将之与顺铂的作用相比较。结果:在体外实验中,美洛昔康对2种卵巢癌细胞的增殖均有抑制作用,且呈剂量依赖性。体内实验证明美洛昔康明显抑制小鼠皮下移植瘤的生长,其抑制率为30.79%(P <0.0001)。各组肿瘤组织中 VEGF 的表达经半定量测定分别为:每高倍视野对照组5.17±0.52、、顺铂组4.32±0.73及美洛昔康组4.81±0.58。与对照组相比,美洛昔康饲养的小鼠肿瘤中 VEGF 的表达受到明显抑制(P <0.0001)并伴随微血管密度的明显减低。TUNEL 法对肿瘤组织中凋亡细胞计数,结果分别为:对照组12.8±1.3、顺铂组11.5±1.8及美洛昔康组23.3±2.7。与对照组比较,美洛昔康饲养的小鼠肿瘤中,细胞凋亡的数量明显增多(P <0.001)。美洛昔康的抗肿瘤效果在某些方面优于顺铂。结论:美洛昔康在体内体外实验中表现出抗卵巢肿瘤生长和侵袭的作用。选择性环氧化酶-2抑制剂或许可以作为潜在的新型抗卵巢癌药物应用于临床。%Objective:To investigate the inhibitory effects of meloxicam,a selective COX -2 inhibitor on growth of epithelial ovarian cancer (EOC)in vitro and in vivo.Methods:To investigate whether meloxicam inhibit the prolifer-ation of human ovarian cancer cell lines and evaluated the ability of meloxicam on tumor growth,apoptosis,vascular endothelial growth factor (VEGF)level,microvessel density(MVD)and angiogenesis of xenografted tumors derived from EOC cells and compared

  15. Novel selective inhibitors of hydroxyxanthone derivatives for human cyclooxygenase-2

    Institute of Scientific and Technical Information of China (English)

    Yu-chian CHEN; Kun-tze CHEN

    2007-01-01

    Aim: To screen the selective inhibitors for human cyclooxygenase-2 ((h)COX-2) utilizing molecular simulation. Methods: Eight xanthone derivatives, compounds A-H, were employed by the structure-based research methodology. Resveratrol and NS-398 were selected as the control compounds for COX-1 and COX-2, respectively. The docking results were scored and the interaction energies of the complexes were calculated by CHARMm forcefield. Results: NS-398 could not dock into the active site of COX-1. However, resveratrol, the specific selective compound for COX-1, gained lower interaction energy while docked in COX-1. The lower interaction energies were investigated, while compound B and F were docked into the catalytic sites of COX-1 and COX-2, respectively. Compound A, 1,3,6,7-tetrahydroxyxanthone, revealed high inhibitory potency to both COX-1 and COX-2. Conclusion: The conformations of the docking would influence the values of interaction energies. The hydrogen bond could also increase the stabi- lity of the whole complex, which might suggest that compound B had a suitable conformation in the tunnel-like active site of COX-1. Compound F, a potent agent for COX-2, revealed a strong hydrogen bond with Set516 in human COX-2 to form a stable complex.

  16. DNA Damage Drives an Activin A-Dependent Induction of COX-2 in Premalignant Cells and Lesions

    Science.gov (United States)

    Fordyce, Colleen; Fessenden, Tim; Pickering, Curtis; Jung, Jason; Singla, Veena; Berman, Hal; Tlsty, Thea

    2010-01-01

    COX-2 catalyzes the rate-limiting step in the synthesis of prostaglandins. Its overexpression induces numerous tumor-promoting phenotypes and is associated with cancer metastasis and poor clinical outcome. Although COX-2 inhibitors are promising chemotherapeutic and chemopreventative agents for cancer, the risk of significant cardiovascular and gastrointestinal complications currently outweighs their potential benefits. Systemic complications of COX-2 inhibition could be avoided by specifically decreasing COX-2 expression in epithelial cells. To that end, we have investigated the signal transduction pathway regulating COX-2 expression in response to DNA damage in breast epithelial cells. In variant human mammary epithelial cells that have silenced p16 (vHMEC), double strand DNA damage or telomere malfunction results in a p53-and activin A-dependent induction of COX-2 and continued proliferation. In contrast, telomere malfunction in HMEC with an intact p16/Rb pathway induces cell cycle arrest. Importantly, in ductal carcinoma in situ (DCIS) lesions, high COX-2 expression is associated with high γH2AX, TRF2, activin A and telomere malfunction. These data demonstrate that DNA damage and telomere malfunction can have both cell autonomous and cell non-autonomous consequences and provides a novel mechanism for the propagation of tumorigenesis. PMID:20028875

  17. Effects of non-selective (piroxicam and selective (meloxicam cyclo-oxygenase inhibitors on the intestinal contractility of rabbits

    Directory of Open Access Journals (Sweden)

    Warida M. El-Rwegi

    2015-10-01

    Conclusions: Data of the present study may indicate that piroxicam and meloxicam could be used effectively and safely in rabbits for their anti-inflammatory actions in small therapeutic doses. However, in large doses, they (particularly, piroxicam may produce depressant effects on gastrointestinal tract motility that should be taken in consideration in the case of introducing these drugs in therapy with larger doses [Int J Basic Clin Pharmacol 2015; 4(5.000: 924-930

  18. Induction of apoptosis by cyclooxygenase-2 inhibitors in prostate cancer cell lines.

    Science.gov (United States)

    Kamijo, T; Sato, T; Nagatomi, Y; Kitamura, T

    2001-07-01

    Prostaglandins are thought to play an important role in the proliferation of prostate cancer and are highly expressed in prostate cancer tissue. Cyclooxygenase-2 (COX-2), or prostaglandin endoperoxide synthase, is a key enzyme in the conversion of arachidonic acid into prostaglandin. In several cancers, COX-2 contributes to the proliferation and metastasis of cancer cells. To assess the role of COX-2 in prostate cancer, we investigated whether the inhibition of COX-2 affected the proliferation of prostate cancer cells. The human prostate cancer cell lines, LNCaP and PC 3, and a normal prostate stromal cell line (PrSC) were treated with COX-2 inhibitors NS 398 and Etodolac. The proliferation rate of the cell lines was examined using 3(4,5-dimethylethiazoly 1-2-) 2,5-diphonyl tetrazolium bromide (MTT) assays. A DNA fragmentation assay was also used for proof of apoptosis. COX-2 inhibitors could suppress the proliferation of LNCaP and PC 3 cells. In contrast, PrSC was not affected by COX-2 inhibitors. These suppressive effects occurred in a time- and dose-dependent manner. One of mechanisms responsible for cell death was apoptosis. COX-2 seems to play a significant role in the progression of prostate cancer. COX-2 may be a therapeutic target for prostate cancer. Since COX-2 inhibitors suppress proliferation and induce apoptosis in prostate cancer cells, and have no effect in normal prostate stromal cells, COX-2 inhibitors will be useful for the treatment of prostate cancer.

  19. Reducing cardiovascular risk factors in non-selected outpatients with schizophrenia

    DEFF Research Database (Denmark)

    Hansen, Mette Vinther; Hjorth, Peter; Kristiansen, Christina Blanner;

    2016-01-01

    glucose, serum lipids, and information on smoking and alcohol were obtained. Results: On average, small significant increases in body mass index (BMI) and waist circumferences were observed while small non-significant improvements in other cardiovascular risk factors were seen. Patients with high baseline......Objectives: Cardiovascular diseases are the most common causes of premature death in patients with schizophrenia. We aimed at reducing cardiovascular risk factors in non-selected outpatients with schizophrenia using methods proven effective in short-term trials. Furthermore, we examined whether any...... motivated to participate in the interventions, and it was difficult to monitor the recommended metabolic risk measures in the patient group. Future research should focus on simple strategies in health promotion that can be integrated into routine care....

  20. Autosomal mutants of proton-exposed kidney cells display frequent loss of heterozygosity on nonselected chromosomes.

    Science.gov (United States)

    Grygoryev, Dmytro; Dan, Cristian; Gauny, Stacey; Eckelmann, Bradley; Ohlrich, Anna P; Connolly, Marissa; Lasarev, Michael; Grossi, Gianfranco; Kronenberg, Amy; Turker, Mitchell S

    2014-05-01

    High-energy protons found in the space environment can induce mutations and cancer, which are inextricably linked. We hypothesized that some mutants isolated from proton-exposed kidneys arose through a genome-wide incident that causes loss of heterozygosity (LOH)-generating mutations on multiple chromosomes (termed here genomic LOH). To test this hypothesis, we examined 11 pairs of nonselected chromosomes for LOH events in mutant cells isolated from the kidneys of mice exposed to 4 or 5 Gy of 1 GeV protons. The mutant kidney cells were selected for loss of expression of the chromosome 8-encoded Aprt gene. Genomic LOH events were also assessed in Aprt mutants isolated from isogenic cultured kidney epithelial cells exposed to 5 Gy of protons in vitro. Control groups were spontaneous Aprt mutants and clones isolated without selection from the proton-exposed kidneys or cultures. The in vivo results showed significant increases in genomic LOH events in the Aprt mutants from proton-exposed kidneys when compared with spontaneous Aprt mutants and when compared with nonmutant (i.e., nonselected) clones from the proton-exposed kidneys. A bias for LOH events affecting chromosome 14 was observed in the proton-induced Aprt mutants, though LOH for this chromosome did not confer increased radiation resistance. Genomic LOH events were observed in Aprt mutants isolated from proton-exposed cultured kidney cells; however the incidence was fivefold lower than in Aprt mutants isolated from exposed intact kidneys, suggesting a more permissive environment in the intact organ and/or the evolution of kidney clones prior to their isolation from the tissue. We conclude that proton exposure creates a subset of viable cells with LOH events on multiple chromosomes, that these cells form and persist in vivo, and that they can be isolated from an intact tissue by selection for a mutation on a single chromosome.

  1. Nonselective Blocking of the Sympathetic Nervous System Decreases Detrusor Overactivity in Spontaneously Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Chang-Shin Park

    2012-04-01

    Full Text Available The involuntary dual control systems of the autonomic nervous system (ANS in the bladder of awake spontaneously hypertensive rats (SHRs were investigated through simultaneous registrations of intravesical and intraabdominal pressures to observe detrusor overactivity (DO objectively as a core symptom of an overactive bladder. SHRs (n = 6 showed the features of overactive bladder syndrome during urodynamic study, especially DO during the filling phase. After injection of the nonselective sympathetic blocking agent labetalol, DO disappeared in 3 of 6 SHRs (50%. DO frequency decreased from 0.98 ± 0.22 min−1 to 0.28 ± 0.19 min−1 (p < 0.01, and DO pressure decreased from 3.82 ± 0.57 cm H2O to 1.90 ± 0.86 cm H2O (p < 0.05. This suggests that the DO originating from the overactive parasympathetic nervous system is attenuated by the nonselective blocking of the sympathetic nervous system. The detailed mechanism behind this result is still not known, but parasympathetic overactivity seems to require overactive sympathetic nervous system activity in a kind of balance between these two systems. These findings are consistent with recent clinical findings suggesting that patients with idiopathic overactive bladder may have ANS dysfunction, particularly a sympathetic dysfunction. The search for newer and better drugs than the current anticholinergic drugs as the mainstay for overactive bladder will be fueled by our research on these sympathetic mechanisms. Further studies of this principle are required.

  2. An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists

    Directory of Open Access Journals (Sweden)

    Xia Chen

    2012-01-01

    Full Text Available Various 2,3 subtype selective partial GABA-A agonists are in development to treat anxiety disorders. These compounds are expected to be anxiolytic with fewer undesirable side effects, compared to nonselective GABA-A agonists like benzodiazepines. Several 2,3 subtype selective and nonselective GABA-A agonists have been examined in healthy volunteers, using a battery addressing different brain domains. Data from five placebo-controlled double-blind studies were pooled. Lorazepam 2 mg was the comparator in three studies. Three 2,3-selective GABAA agonists (i.e., TPA023, TPACMP2, SL65.1498, one 1-selective GABAA agonists (zolpidem, and another full agonist (alprazolam were examined. Pharmacological selectivity was assessed by determination of regression lines for the change from baseline of saccadic-peak-velocity- (ΔSPV- relative effect, relative to changes in different pharmacodynamic endpoints (ΔPD. SPV was chosen for its sensitivity to the anxiolysis of benzodiazepines. Slopes of the ΔSPV-ΔPD relations were consistently lower with the 2,3 selective GABA-A agonists than with lorazepam, indicating that their PD effects are less than their SPV-effects. The ΔSPV-ΔPD relations of lorazepam were comparable to alprazolam. Zolpidem showed relatively higher impairments in ΔPD relative to ΔSPV, but did not significantly differ from lorazepam. These PD results support the pharmacological selectivity of the 2,3-selective GABA-A agonists, implying an improved therapeutic window.

  3. Acute upregulation of COX-2 by renal artery stenosis

    DEFF Research Database (Denmark)

    Mann, Birgitte; Hartner, A; Jensen, B L

    2001-01-01

    This study aimed to characterize the influence of acute renal artery stenosis on cyclooxygenase-2 (COX-2) and renin expression in the juxtaglomerular apparatus. For this purpose, male Sprague-Dawley rats received a left renal artery clip, and COX-2 mRNA, COX-2 immunoreactivity, plasma renin...... causal relationship between the changes of COX-2 and of renin expression, clipped rats were treated with the COX-2 blocker celecoxib (40 mg. kg(-1). day(-1)). This treatment, however, did not change renin mRNA either in the clipped or in the contralateral intact kidney. Our findings indicate that renal...... artery stenosis causes ipsilaterally an acute upregulation and contralaterally a downregulation of juxtaglomerular COX-2 expression. The lacking effect of celecoxib on renin gene expression does not support the concept of a direct mediator function of COX-2-derived prostaglandins in the control of renin...

  4. Acute upregulation of COX-2 by renal artery stenosis

    DEFF Research Database (Denmark)

    Mann, Birgitte; Hartner, A; Jensen, B L

    2001-01-01

    This study aimed to characterize the influence of acute renal artery stenosis on cyclooxygenase-2 (COX-2) and renin expression in the juxtaglomerular apparatus. For this purpose, male Sprague-Dawley rats received a left renal artery clip, and COX-2 mRNA, COX-2 immunoreactivity, plasma renin...... activity, and renin mRNA levels were determined. COX-2 mRNA and COX-2 immunoreactivity in the macula densa region in the clipped kidneys increased as early as 6 h after clipping and reached a maximal expression 1-2 days after clipping. Although values for plasma renin activity were elevated markedly at all...... artery stenosis causes ipsilaterally an acute upregulation and contralaterally a downregulation of juxtaglomerular COX-2 expression. The lacking effect of celecoxib on renin gene expression does not support the concept of a direct mediator function of COX-2-derived prostaglandins in the control of renin...

  5. 25-Hydroxycholesterol exerts both a cox-2-dependent transient proliferative effect and cox-2-independent cytotoxic effect on bovine endothelial cells in a time- and cell-type-dependent manner

    Directory of Open Access Journals (Sweden)

    Cantarutti Alyssa

    2010-11-01

    Full Text Available Abstract Background 25-hydroxycholesterol (25-OHC is a product of oxidation of dietary cholesterol present in human plasma. 25-OHC and other oxidized forms of cholesterol are implicated in modulating inflammatory responses involved in development of atherosclerosis and colon carcinogenesis. Methods Primary lymphatic, venous and arterial endothelial cells isolated from bovine mesentery (bmLEC, bmVEC, bmAEC were treated with 25-OHC and tested for several different cellular parameters. Results We found 25-OHC to be a potent inducer of cyclooxygenase-2 (Cox-2, prostaglandin G-H synthase-2 expression in bovine mesenteric lymphatic, venous, and arterial endothelial cells. The induction of Cox-2 expression in endothelial cells by 25-OHC led to an initial increase in cellular proliferation that was inhibited by the Cox-2 selective inhibitor celecoxib (Celebrex. Prolonged exposure to 25-OHC was cytotoxic. Furthermore, endothelial cells induced to express Cox-2 by 25-OHC were more sensitive to the effects of the Cox-2 selective inhibitor celecoxib (Celebrex. These results suggest that some effects of 25-OHC on cells may be dependent on Cox-2 enzymatic activity. Conclusions Cox-2 dependent elevating effects of 25-OHC on endothelial cell proliferation was transient. Prolonged exposure to 25-OHC caused cell death and enhanced celecoxib-induced cell death in a cell-type dependent manner. The lack of uniform response by the three endothelial cell types examined suggests that our model system of primary cultures of bmLECs, bmVECs, and bmAECs may aid the evaluation of celecoxib in inhibiting proliferation of different types of tumour-associated endothelial cells.

  6. Ellagic acid facilitates indomethacin-induced gastric ulcer healing via COX-2 up-regulation

    Institute of Scientific and Technical Information of China (English)

    Ananya Chatterjee; Sirshendu Chatterjee; Smita Das; Arpita Saha; Subrata Chattopadhyay; Sandip K. Bandyopadhyay

    2012-01-01

    The mechanism of indomethacin-induced gastric ulcer healing by ellagic acid (EA) in experimental mice model is described in our study.Ulcer index (UI) and myeloperoxidase (MPO) activity of the stomach tissues showed maximum ulceration on the third day after indomethacin (18 mg/kg,single dose) administration.Preliminary observation of UI and MPO activity suggests that EA possesses ulcer-healing activity.Other anti-ulcer parameters such as the levels of prostaglandin E2,cyclooxygenase (COX) 1 and 2 enzymes,anti-inflammatory cytokines [interleukin (IL)-4 and -5J,pro-angiogenic factors,e.g.vascular endothelial growth factor,hepatocyte growth factor (HGF),and endothelial growth factor (EGF) were down-regulated by indomethacin.EA (7 mg/kg/day) treatment for 3 days shifted the indomethacin-induced pro-inflammatory biochemical parameters to the healing side.These activities were correlated with the ability of EA to alter the COX-2-dependent healing pathways.The ulcer-healing activity of EA was,however,compromised by pre-administration of the specific COX-2 inhibitor,celecoxib,and NS-398.Taken together,these results suggested that the EA treatment accelerates ulcer healing by inducing IL-4,EGF/HGF levds and enhances COX-2 expression.

  7. Differentials of Cox rings: Jaczewski's theorem revisited

    CERN Document Server

    Kedzierski, Oskar

    2011-01-01

    A generalized Euler sequence over a complete normal variety X is the unique "identity" extension of the trivial bundle H^1(X,\\Omega_X) \\otimes O_X by the sheaf of differentials \\Omega_X. We prove that, if X is a smooth Mori Dream Space and the bundle arising from the Euler sequence splits into a direct sum of line bundles, then X is a toric variety. The proof of this characterization of toric varieties depends on a somewhat more general result which, in the case of a Mori Dream Space, identifies the module of sections of the twisted sheaf coming from the Euler extension with the module of differentials of the Cox ring of the variety in question.

  8. COX-2 Inhibition Reduces Brucella Bacterial Burden in Draining Lymph Nodes

    Science.gov (United States)

    Gagnaire, Aurélie; Gorvel, Laurent; Papadopoulos, Alexia; Von Bargen, Kristine; Mège, Jean-Louis; Gorvel, Jean-Pierre

    2016-01-01

    Brucella is a Gram-negative facultative intracellular bacterium responsible for a chronic disease known as brucellosis, the most widespread re-emerging zoonosis worldwide. Establishment of a Th1-mediated immune response characterized by the production of IL-12 and IFNγ is essential to control the disease. Leukotrienes derived from arachidonic acid (AA) metabolism are known to negatively regulate a protective Th1 immune response against bacterial infections. Here, using genomics approaches we demonstrate that Brucella abortus strongly stimulates the prostaglandin (PG) pathway in dendritic cells (DC). We also show an induction of AA production by infected cells. This correlates with the expression of Ptgs2, a gene encoding the downstream cyclooxygenase-2 (COX-2) enzyme in infected DC. By comparing different infection routes (oral, intradermal, intranasal and conjunctival), we identified the intradermal inoculation route as the more potent in inducing Ptgs2 expression but also in inducing a local inflammatory response in the draining cervical lymph nodes (CLN). NS-398, a specific inhibitor of COX-2 enzymatic activity decreased B. melitensis burden in the CLN after intradermal infection. This effect was accompanied by a decrease of Il10 and a concomitant increase of Ifng expression. Altogether, these results suggest that Brucella has evolved to take advantage of the PG pathway in the harsh environment of the CLN in order to persist and subvert immune responses. This work also proposes that novel strategies to control brucellosis may include the use of COX-2 inhibitors. PMID:28018318

  9. Palbociclib inhibits epithelial-mesenchymal transition and metastasis in breast cancer via c-Jun/COX-2 signaling pathway.

    Science.gov (United States)

    Qin, Ge; Xu, Fei; Qin, Tao; Zheng, Qiufan; Shi, Dingbo; Xia, Wen; Tian, Yun; Tang, Yanlai; Wang, Jingshu; Xiao, Xiangshen; Deng, Wuguo; Wang, Shusen

    2015-12-08

    Palbociclib, a highly selective CDK4/6 inhibitor, has been shown to be a novel anti-tumor agent that suppresses breast cancer cell proliferation. However, its anti-metastasis activity remains controversial. In the present study, we evaluated whether palbociclib prevented breast cancer cell metastasis and revealed its regulatory mechanism. We found that palbociclib inhibited migration and invasion in the breast cancer cells MDA-MB-231 and T47D. The epithelial-mesenchymal transition (EMT) markers, vimentin and Snail, were down-regulated with palbociclib treatment. Moreover, we revealed that this inhibition was mediated by the c-Jun/COX-2 pathway. COX-2 was decreased after palbociclib treatment. The production of PGE2 was also reduced along with COX-2. Additionally, our data showed that c-Jun, a crucial transcriptional regulator of COX-2, was down-regulated by palbociclib. We found that palbociclib weakened the COX-2 promoter binding activity of c-Jun and prevented its translocation from the cytoplasm to cell nuclei. Bioluminescence imaging and tail intravenous injection were used to evaluate the anti-metastasis effect of palbociclib in vivo. The data demonstrated that palbociclib reduced breast cancer metastasis to the lung. These results therefore demonstrated that the anti-metastasis activity of palbociclib is mediated via the c-Jun/COX-2 signaling pathway by inhibiting EMT in breast cancer cells.

  10. Genomic saturation mutagenesis and polygenic analysis identify novel yeast genes affecting ethyl acetate production, a non-selectable polygenic trait

    Directory of Open Access Journals (Sweden)

    Tom Den Abt

    2016-03-01

    Full Text Available Isolation of mutants in populations of microorganisms has been a valuable tool in experimental genetics for decades. The main disadvantage, however, is the inability of isolating mutants in non-selectable polygenic traits. Most traits of organisms, however, are non-selectable and polygenic, including industrially important properties of microorganisms. The advent of powerful technologies for polygenic analysis of complex traits has allowed simultaneous identification of multiple causative mutations among many thousands of irrelevant mutations. We now show that this also applies to haploid strains of which the genome has been loaded with induced mutations so as to affect as many non-selectable, polygenic traits as possible. We have introduced about 900 mutations into single haploid yeast strains using multiple rounds of EMS mutagenesis, while maintaining the mating capacity required for genetic mapping. We screened the strains for defects in flavor production, an important non-selectable, polygenic trait in yeast alcoholic beverage production. A haploid strain with multiple induced mutations showing reduced ethyl acetate production in semi-anaerobic fermentation, was selected and the underlying quantitative trait loci (QTLs were mapped using pooled-segregant whole-genome sequence analysis after crossing with an unrelated haploid strain. Reciprocal hemizygosity analysis and allele exchange identified PMA1 and CEM1 as causative mutant alleles and TPS1 as a causative genetic background allele. The case of CEM1 revealed that relevant mutations without observable effect in the haploid strain with multiple induced mutations (in this case due to defective mitochondria can be identified by polygenic analysis as long as the mutations have an effect in part of the segregants (in this case those that regained fully functional mitochondria. Our results show that genomic saturation mutagenesis combined with complex trait polygenic analysis could be used

  11. Characteristics of the Nonselective Cation Current (NSCCs) in Rabbit Left Ventricular Epicardial, Midmyocardial and Endocardial Myocytes

    Institute of Scientific and Technical Information of China (English)

    Min Zong; Xinchun Yang; Xiulan Liu; Liang Shi; Taifeng Liu

    2007-01-01

    Recent studies have described regional differences in the electrophysiology and pharmacology of ventricular myocardium in canine,feline,rat,guinea pig,and human hearts.This has been shown to be due to a smaller IKs and a lager sodium-calcium exchange current (INa-Ca ) and late INa in M region (deep subepicardial to midmyocardial).Studies from our laboratory have found a new repolarization current-nonselective cation current (NSCCs) existing in rabbit right ventricular myocytes.Methods We examined the characteristics of NSCCs in epicardial,M region,and endocardial cells isolated from the rabbit left ventricle with standard microelectrode and whole-cell patch-clamp techniques.The permeability to Na+,K + ,Li + ,Cs + but not to Cl-indicating that it was a nonselective cation current.Gd3+ (0.1 mmol/1) and La3+ (0.1 mmol/1) can block the current markedly.Results Further characterization of NSCCs was significantly smaller in M cells than in epicardial and endocardial cells.NSCCs current density was significantly smaller in M cells than in epicardial and endocardial cells.With repolarization to-80 mV,INs current density was (-0.44 ±0.05) PA/PF in endocardial cells,(-0.12 ±0.05) PA/PF in M cells and (-0.28 ±0.07) PA/PF in epicardial cells;and with repolarization to + 30 mV,INs current density was ( 1.09 ± 0.29) PA/PF in endocardial cells,(0.38 ± 0.09) PA/PF in M cells and (0.91 ± 0.32) PA/PF in epicardial cells.Conclusions Transmural dispersion of repolarization was due to the heterogeneity of NSCCs in rabbit left ventricle epicardial,endocardial myocytes and M cells.These findings may advance our understanding of the ionic basis for our understanding of factors contributing to the development of cardiac arrhythmias.

  12. Cyclooxygenase-2 inhibitors and free flap complications after autologous breast reconstruction

    DEFF Research Database (Denmark)

    Bonde, Christian; Khorasani, Hoda; Højvig, Jens

    2017-01-01

    because of the well-known side effects of NSAID treatment (bleeding/gastrointestinal ulcers). However, COX-2 inhibitors have been suggested to increase flap failure rates. We report our experience in using COX-2 inhibitors as part of our post-operative MOSA after ABR using free flaps. MATERIALS......BACKGROUND: A key component of modern analgesics is the use of multimodal opioid-sparing analgesia (MOSA). In the past, our analgesic regime after autologous breast reconstruction (ABR) included either NSAID or a selective cyclooxygenase-2 (COX-2) inhibitor. COX-2 inhibitors are superior to NSAIDs...... focus on reoperations due to bleeding/haematomas and flap thrombosis/failure. Comparisons between the COX-2 inhibitor and NSAID were made. RESULTS: Median age, ischaemia time, blood loss and operating time were similar in the two periods. Significantly, more patients were re-operated because of post...

  13. Nonselective beta-blockers in cirrhotic patients with no or small varices: A meta-analysis.

    Science.gov (United States)

    Qi, Xing-Shun; Bao, Yong-Xin; Bai, Ming; Xu, Wen-Da; Dai, Jun-Na; Guo, Xiao-Zhong

    2015-03-14

    To explore effects of nonselective beta-blockers (NSBBs) in cirrhotic patients with no or small varices. The PubMed, EMBASE, Science Direct, and Cochrane library databases were searched for relevant papers. A meta-analysis was performed using ORs with 95%CI as the effect sizes. Subgroup analysis was conducted according to the studies including patients without varices and those with small varices. Overall, 784 papers were initially retrieved from the database searches, of which six randomized controlled trials were included in the meta-analysis. The incidences of large varices development (OR = 1.05, 95%CI: 0.25-4.36; P = 0.95), first upper gastrointestinal bleeding (OR = 0.59, 95%CI: 0.24-1.47; P = 0.26), and death (OR = 0.70, 95%CI: 0.45-1.10; P = 0.12) were similar between NSBB and placebo groups. However, the incidence of adverse events was significantly higher in the NSBB group compared with the placebo group (OR = 3.47, 95%CI: 1.45-8.33; P = 0.005). The results of subgroup analyses were similar to those of overall analyses. The results of this meta-analysis indicate that NSBBs should not be recommended for cirrhotic patients with no or small varices.

  14. The characteristics of action potential and nonselective cation current of cardiomyocytes in rabbit superior vena cava

    Institute of Scientific and Technical Information of China (English)

    WANG Pan; YANG XinChun; LIU XiuLan; BAO RongFeng; LIU TaiFeng

    2008-01-01

    As s special focus in initiating and maintaining atrial fibrillation (AF), cardiomyocytes in superior vena cavs (SVC) have distinctive electrophysiological characters. In this study, we found that comparing with the right atrial (RA) cardiomyoctyes, the SVC cardiomyoctyes had longer APD90 at the different basic cycle lengths; the conduction block could be observed on both RA and SVC cardiomyoctyes. A few of SVC cardiomyoctyes showed slow response action potentials with automatic activity and some others showed early afterdepolarization (EAD) spontaneously. Further more, we found that there are nonselective cation current (INs) in both SVC and RA cardiomyocytes. The peak density of INs in SVC cardiomyocytes was smaller than that in RA cardiomyocytes. Removal of extracellular divalent cation and glucose could increase INs in SVC cardiomyocytes. The agonist or the antagonist of INs may increase or decrease APD. To sum up, some SVC cardiomyocytes possess the ability of spontaneous activity; the difference of transmembrane action potentials between SVC and RA cardiomyocytes is partly because of the different density of INs between them; the agonist or the antagonist of INs can increase or decrease APD leading to the enhancement or reduction of EAD genesis in SVC cardiomyocytes. INs in rabbit myocytes is fairly similar to TRPC3 current in electrophysiological property, which might play an important role in the mechanisms of AF.

  15. COX2 genetic variation, NSAIDs, and advanced prostate cancer risk

    OpenAIRE

    Cheng, I.; Liu, X.; Plummer, S J; Krumroy, L M; Casey, G; Witte, J S

    2007-01-01

    Collective evidence suggests that cyclooxygenase 2 (COX2) plays a role in prostate cancer risk. Cyclooxygenase 2 is the major enzyme that converts arachidonic acid to prostaglandins, which are potent mediators of inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the enzymatic activity of COX2 and long-term use of NSAIDs appears to modestly lower the risk of prostate cancer. We investigated whether common genetic variation in COX2 influences the risk of advanced prostate canc...

  16. Inhibition of COX-2 expression by topical diclofenac enhanced radiation sensitivity via enhancement of TRAIL in human prostate adenocarcinoma xenograft model

    Directory of Open Access Journals (Sweden)

    Inoue Takeshi

    2013-01-01

    Full Text Available Abstract Background COX-2 inhibitors have an antitumor potential and have been verified by many researchers. Treatment of cancer cells with external stressors such as irradiation can stimulate the over-expression of COX-2 and possibly confer radiation resistance. In this study, we tested if topical diclofenac, which inhibits both COX-1 and COX-2, administration rendered prostate tumor cells sensitize to the effects of radiation. Methods LNCaP-COX-2 and LNCaP-Neo cells were treated with 0 to 1000 μM diclofenac. Next, a clonogenic assay was performed in which cells were subjected to irradiation (0 to 4 Gy with or without diclofenac. COX-2 expression and other relevant molecules were measured by real-time PCR and immunohistochemistry after irradiation and diclofenac treatment. In addition, we assessed the tumor volumes of xenograft LNCaP-COX-2 cells treated with topical diclofenac with or without radiation therapy (RT. Results LNCaP-COX-2 and LNCaP-Neo cell lines experienced cytotoxic effects of diclofenac in a dose related manner. Clonogenic assays demonstrated that LNCaP-COX-2 cells were significantly more resistant to RT than LNCaP-Neo cells. Furthermore, the addition of diclofenac sensitized LNCaP-COX-2 not but LNCaP-Neo cells to the cytocidal effects of radiation. In LNCaP-COX-2 cells, diclofenac enhanced radiation-induced apoptosis compared with RT alone. This phenomenon might be attributed to enhancement of RT-induced TRAIL expression as demonstrated by real-time PCR analysis. Lastly, tumor volumes of LNCaP-COX-2 cells xenograft treated with diclofenac or RT alone was >4-fold higher than in mice treated with combined diclofenac and radiation (p Conclusions These in vitro and in vivo findings suggest that conventional COX inhibitor, diclofenac enhances the effect of RT on prostate cancer cells that express COX-2. Thus, diclofenac may have potential as radiosensitizer for treatment of prostate cancer.

  17. COX-2 expression positively correlates with PD-L1 expression in human melanoma cells.

    Science.gov (United States)

    Botti, Gerardo; Fratangelo, Federica; Cerrone, Margherita; Liguori, Giuseppina; Cantile, Monica; Anniciello, Anna Maria; Scala, Stefania; D'Alterio, Crescenzo; Trimarco, Chiara; Ianaro, Angela; Cirino, Giuseppe; Caracò, Corrado; Colombino, Maria; Palmieri, Giuseppe; Pepe, Stefano; Ascierto, Paolo Antonio; Sabbatino, Francesco; Scognamiglio, Giosuè

    2017-02-23

    The resistance to PD-1/PD-L1 inhibitors for the treatment of melanoma have prompted investigators to implement novel clinical trials which combine immunotherapy with different treatment modalities. Moreover is also important to investigate the mechanisms which regulate the dynamic expression of PD-L1 on tumor cells and PD-1 on T cells in order to identify predictive biomarkers of response. COX-2 is currently investigated as a major player of tumor progression in several type of malignancies including melanoma. In the present study we investigated the potential relationship between COX-2 and PD-L1 expression in melanoma. Tumor samples obtained from primary melanoma lesions and not matched lymph node metastases were analyzed for both PD-L1 and COX-2 expression by IHC analysis. Status of BRAF and NRAS mutations was analyzed by sequencing and PCR. Co-localization of PD-L1 and COX-2 expression was analyzed by double fluorescence staining. Lastly the BRAF(V600E) A375 and NRAS(Q61R) SK-MEL-2 melanoma cell lines were used to evaluate the effect of COX-2 inhibition by celecoxib on expression of PD-L1 in vitro. BRAF(V600E/V600K) and NRAS(Q61R/Q61L) were detected in 57.8 and 8.9% of the metastatic lesions, and in 65.9 and 6.8% of the primary tumors, respectively. PD-L1 and COX-2 expression were heterogeneously expressed in both primary melanoma lesions and not matched lymph node metastases. A significantly lower number of PD-L1 negative lesions was found in primary tumors as compared to not matched metastatic lesions (P = 0.002). COX-2 expression significantly correlated with PD-L1 expression in both primary (P = 0.001) and not matched metastatic (P = 0.048) lesions. Furthermore, in melanoma tumors, cancer cells expressing a higher levels of COX-2 also co-expressed a higher level of PD-L1. Lastly, inhibition of COX-2 activity by celecoxib down-regulated the expression of PD-L1 in both BRAF(V600E) A375 and NRAS(Q61R) SK-MEL-2 melanoma cell lines. COX-2 expression

  18. Transport Properties of the Tunnel Junctions Al1-xCox/{Al1-xCox-oxide}/Al

    Institute of Scientific and Technical Information of China (English)

    X.F.Han; J. Murai; H.Kubota; Y.Ando; Q.Y.Wang; N.Tezuka; T.Miyazaki

    2000-01-01

    The oxides of Al1-xCox (x=0,0.25,0.5,0.75, and 1.0) alloys were chosen as barrier materials in this work. The tunnel junction consists of the bottom electrode Al1-xCox and the top electrode Al with an insulating layer { Al1-xCox-oxide} which was formed by natural oxidation in a baking-box at 333K. The oxidation time for forming an Al1-xCox-oxide layer on the surface of the bottom Al1-xCox layers were optimized.The resistance of Al1-xCox/{ Al1-xCox-oxide}/Al tunnel junctions varied between 101 and 106 Ω measured at 1 my and 4.2 K. The effective barrier height and width of insulating layers Al1-xCox-oxide ( x=0.25, 0.5, and 0.75 )varied between 0.6 and 2.7 eV and between 1.3 and 2.1 nm. It is shown that the thin oxide layer of Al1-xCox alloys can be chosen as barrier materials.

  19. The heme a synthase Cox15 associates with cytochrome c oxidase assembly intermediates during Cox1 maturation.

    Science.gov (United States)

    Bareth, Bettina; Dennerlein, Sven; Mick, David U; Nikolov, Miroslav; Urlaub, Henning; Rehling, Peter

    2013-10-01

    Cox1, the core subunit of the cytochrome c oxidase, receives two heme a cofactors during assembly of the 13-subunit enzyme complex. However, at which step of the assembly process and how heme is inserted into Cox1 have remained an enigma. Shy1, the yeast SURF1 homolog, has been implicated in heme transfer to Cox1, whereas the heme a synthase, Cox15, catalyzes the final step of heme a synthesis. Here we performed a comprehensive analysis of cytochrome c oxidase assembly intermediates containing Shy1. Our analyses suggest that Cox15 displays a role in cytochrome c oxidase assembly, which is independent of its functions as the heme a synthase. Cox15 forms protein complexes with Shy1 and also associates with Cox1-containing complexes independently of Shy1 function. These findings indicate that Shy1 does not serve as a mobile heme carrier between the heme a synthase and maturing Cox1 but rather cooperates with Cox15 for heme transfer and insertion in early assembly intermediates of cytochrome c oxidase.

  20. COX-2 is associated with periodontitis in Europeans

    NARCIS (Netherlands)

    Schaefer, A.S.; Richter, G.M.; Nothnagel, M.; Laine, M.L.; Noack, B.; Glas, J.; Schrezenmeir, J.; Groessner-Schreiber, B.; Jepsen, S.; Loos, B.G.; Schreiber, S.

    2010-01-01

    COX-2 plays an important role in periodontitis by mediating inflammatory reactions in periodontal tissues, and the COX-2 polymorphisms rs20417 and rs689466 have been reported to be associated with periodontitis in populations of Taiwanese and Chinese ethnicity. To test whether these variants were

  1. On spatio-temporal Lévy based Cox processes

    DEFF Research Database (Denmark)

    Prokesova, Michaela; Hellmund, Gunnar; Jensen, Eva Bjørn Vedel

    2006-01-01

    The paper discusses a new class of models for spatio-temporal Cox point processes. In these models, the driving field is defined by means of an integral of a weight function with respect to a Lévy basis. The relations to other Cox process models studied previously are discussed and formulas for t...

  2. Extensions and Applications of the Cox-Aalen Survival Model

    DEFF Research Database (Denmark)

    Scheike, Thomas H.; Zhang, Mei-Jie

    2003-01-01

    Aalen additive risk model; competing risk; counting processes; Cox model; cumulative incidence function; goodness of fit; prediction of survival probability; time-varying effects......Aalen additive risk model; competing risk; counting processes; Cox model; cumulative incidence function; goodness of fit; prediction of survival probability; time-varying effects...

  3. COX-2 is associated with periodontitis in Europeans

    NARCIS (Netherlands)

    Schaefer, A.S.; Richter, G.M.; Nothnagel, M.; Laine, M.L.; Noack, B.; Glas, J.; Schrezenmeir, J.; Groessner-Schreiber, B.; Jepsen, S.; Loos, B.G.; Schreiber, S.

    2010-01-01

    COX-2 plays an important role in periodontitis by mediating inflammatory reactions in periodontal tissues, and the COX-2 polymorphisms rs20417 and rs689466 have been reported to be associated with periodontitis in populations of Taiwanese and Chinese ethnicity. To test whether these variants were as

  4. Cilantro microbiome before and after nonselective pre-enrichment for Salmonella using 16S rRNA and metagenomic sequencing

    OpenAIRE

    Jarvis, Karen G.; White, James R; Grim, Christopher J.; Ewing, Laura; Ottesen, Andrea R; Beaubrun, Junia Jean-Gilles; Pettengill, James B.; Brown, Eric; Hanes, Darcy E.

    2015-01-01

    Background Salmonella enterica is a common cause of foodborne gastroenteritis in the United States and is associated with outbreaks in fresh produce such as cilantro. Salmonella culture-based detection methods are complex and time consuming, and improvments to increase detection sensitivity will benefit consumers. In this study, we used 16S rRNA sequencing to determine the microbiome of cilantro. We also investigated changes to the microbial community prior to and after a 24-hour nonselective...

  5. Potassium current inhibition by nonselective cation channel-mediated sodium entry in rat pheochromocytoma (PC-12) cells.

    OpenAIRE

    Strübing, C; J Hescheler

    1996-01-01

    Under physiological conditions, nonselective cation (NSC) channels mediate the entry of cations into cells, the most important being Na+ and Ca2+. In contrast to the Ca(2+)-dependent signaling mechanisms, little is known about the consequences and the spatial distribution of intracellular [Na+] elevation. In this study we demonstrate that Na+ entry, during the opening of ATP-activated NSC channels, leads to an inhibition of voltage-dependent K+ currents (IK) in cromaffin-like undifferentiated...

  6. A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-κB-signaling pathways

    Science.gov (United States)

    Suh, Yewseok; Afaq, Farrukh; Johnson, Jeremy J.; Mukhtar, Hasan

    2009-01-01

    Overexpression of cyclooxygenase 2 (COX2) and uncontrolled wingless and Int (Wnt)-signaling pathway have long been suggested to play crucial roles in colorectal cancer. Studies show that selective COX2 inhibitors possess great potential as chemopreventive agents for colon cancer. Recent studies suggest that targeting COX2 and epidermal growth factor receptor (EGFR) may provide better therapeutic strategy than inhibiting either single target and that this may alleviate the problem of COX2 inhibitor-associated side effects. Therefore, there have been intensive efforts to develop novel dietary substances that target COX2 and EGFR activation. Fisetin is a naturally occurring flavonoid commonly found in various vegetables and fruits. We found that the treatment of COX2-overexpressing HT29 human colon cancer cells with fisetin (30–120 μM) resulted in induction of apoptosis, downregulation of COX2 protein expression without affecting COX1 and inhibited the secretion of prostaglandin E2. Treatment of cells with fisetin also inhibited Wnt-signaling activity through downregulation of β-catenin and T cell factor 4 and decreased the expression of target genes such as cyclin D1 and matrix metalloproteinase 7. Fisetin treatment of cells also inhibited the activation of EGFR and nuclear factor-kappa B (NF-κB). Finally, the formation of colonies in soft agar was suppressed by fisetin treatment. Taken together, we provide evidence that the plant flavonoid fisetin can induce apoptosis and suppress the growth of colon cancer cells by inhibition of COX2- and Wnt/EGFR/NF-κB-signaling pathways. We suggest that fisetin could be a useful agent for prevention and treatment of colon cancer. PMID:19037088

  7. Evaluation of anticonvulsant effect of celecoxib, a selective cyclooxygenase-2 inhibitor in experimentally induced convulsions in albino rats

    OpenAIRE

    Mohammed Naseeruddin Nadeem; Maliha Maqdoom

    2016-01-01

    Background: Cyclooxygenase-2 (COX-2) exists as the inducible form of the cyclooxygenase enzyme, the levels of which are elevated in inflammatory conditions. COX-2 is located in regions of brain like hippocampus and cerebral cortex. When induced, COX-2 forms prostaglandin E2 (PGE2), which is responsible for CNS excitation, in turn leading to generation of seizures. COX-2 inhibitors by preventing the formation of PGE2 may serve as effective anticonvulsants. Since none of the anti-epileptics in ...

  8. Effects of β-glucosidase hydrolyzed products of harpagide and harpagoside on cyclooxygenase-2 (COX-2) in vitro.

    Science.gov (United States)

    Zhang, Liuqiang; Feng, Li; Jia, Qi; Xu, Jinwen; Wang, Rui; Wang, Zhengtao; Wu, Yingchun; Li, Yiming

    2011-08-15

    Harpagide (1) and harpagoside (2) are two iridoid glycosides existing in many medicinal plants. Although they are believed to be the main bioactive compounds related to the anti-inflammatory efficacy of these plants, the mechanisms of their anti-inflammatory activities remain unclear. The results of our present study showed that 1 and 2 had no effects on inhibitions of cyclooxygenase (COX)-1/2 enzyme activity, tumor necrosis factor-α (TNF-α) release, and nitric oxide (NO) production in vitro. However, the hydrolyzed products of 1 and 2 with β-glucosidase treatment showed a significant inhibitory effect on COX-2 activity at 2.5-100 μM in a concentration-dependent manner. Our further study revealed that the hydrolyzed 2 product was structurally the same as the hydrolyzed 1 product (H-harpagide (3)). The structure of 3 was 2-(formylmethyl)-2,3,5-trihydroxy-5-methylcyclopentane carbaldehyde, with a backbone similar to prostaglandins and COX-2 inhibitors such as celecoxib. All of them have a pentatomic ring with two adjacent side chains. The result of molecular modeling and docking study showed that 3 could bind to the COX-2 active domain well through hydrophobic and hydrogen-bonding interactions, whereas 1 and 2 could not, implying that the hydrolysis of the glycosidic bond of 1 and 2 is a pre-requisite step for their COX-2 inhibitory activity.

  9. Physical exercise regulates p53 activity targeting SCO2 and increases mitochondrial COX biogenesis in cardiac muscle with age.

    Directory of Open Access Journals (Sweden)

    Zhengtang Qi

    Full Text Available The purpose of this study was to outline the timelines of mitochondrial function, oxidative stress and cytochrome c oxidase complex (COX biogenesis in cardiac muscle with age, and to evaluate whether and how these age-related changes were attenuated by exercise. ICR/CD-1 mice were treated with pifithrin-μ (PFTμ, sacrificed and studied at different ages; ICR/CD-1 mice at younger or older ages were randomized to endurance treadmill running and sedentary conditions. The results showed that mRNA expression of p53 and its protein levels in mitochondria increased with age in cardiac muscle, accompanied by increased mitochondrial oxidative stress, reduced expression of COX subunits and assembly proteins, and decreased expression of most markers in mitochondrial biogenesis. Most of these age-related changes including p53 activity targeting cytochrome oxidase deficient homolog 2 (SCO2, p53 translocation to mitochondria and COX biogenesis were attenuated by exercise in older mice. PFTμ, an inhibitor blocking p53 translocation to mitochondria, increased COX biogenesis in older mice, but not in young mice. Our data suggest that physical exercise attenuates age-related changes in mitochondrial COX biogenesis and p53 activity targeting SCO2 and mitochondria, and thereby induces antisenescent and protective effects in cardiac muscle.

  10. Prolactin (PRL) induction of cyclooxygenase 2 (COX2) expression and prostaglandin (PG) production in hamster Leydig cells.

    Science.gov (United States)

    Matzkin, María Eugenia; Ambao, Verónica; Carino, Mónica Herminia; Rossi, Soledad Paola; González, Lorena; Turyn, Daniel; Campo, Stella; Calandra, Ricardo Saúl; Frungieri, Mónica Beatriz

    2012-01-02

    Serum prolactin (PRL) variations play a crucial role in the photoperiodic-induced testicular regression-recrudescence transition in hamsters. We have previously shown that cyclooxygenase 2 (COX2), a key enzyme in the biosynthesis of prostaglandins (PGs), is expressed mostly in Leydig cells of reproductively active hamsters with considerable circulating and pituitary levels of PRL. In this study, we describe a stimulatory effect of PRL on COX2/PGs in hamster Leydig cells, which is mediated by IL-1β and prevented by P38-MAPK and JAK2 inhibitors. Furthermore, by preparative isoelectric focusing (IEF), we isolated PRL charge analogues from pituitaries of active [isoelectric points (pI): 5.16, 4.61, and 4.34] and regressed (pI: 5.44) hamsters. More acidic PRL charge analogues strongly induced COX2 expression, while less acidic ones had no effect. Our studies suggest that PRL induces COX2/PGs in hamster Leydig cells through IL-1β and activation of P38-MAPK and JAK2. PRL microheterogeneity detected in active/inactive hamsters may be responsible for the photoperiodic variations of COX2 expression in Leydig cells.

  11. Intestinal toxicity of non-steroideal anti-inflammatory drugs with differential cyclooxigenase inhibition selectivity Toxicidad intestinal de los fármacos antiinflamatorios no esteroideos con una selectividad diferenciada en la inhibición de la ciclooxigenasa

    OpenAIRE

    Chopra, S; R. Kishore Saini; S. Nath Sanyal

    2007-01-01

    The present study was designed to investigate the gastrointestinal side effects of cycloxygenase (COX) inhibitor with varying selectivity, called the non-steroidal antiinflammatory drugs (NSAIDs) viz., non-selective COX-1 & 2 inhibitor -aspirin, prefentially selective COX-2 inhibitor- nimesulide and highly selective COX-2 inhibitor- celecoxib. Treatment with NSAIDs exhibited a decrease in the activity of rat intestinal brush border membrane associated enzymes such as sucrase, lactase, maltase...

  12. Simultaneous abrogation of NOS-2 and COX-2 activities is lethal in partially hepatectomised mice.

    Science.gov (United States)

    Zeini, Miriam; Hortelano, Sonsoles; Través, Paqui G; Martín-Sanz, Paloma; Boscá, Lisardo

    2004-06-01

    We have investigated the role of the nitric oxide (NO) and prostaglandins (PGs), respectively, synthesized by nitric oxide synthase 2 (NOS-2) and cyclooxygenase-2 (COX-2), in the outcome of liver regeneration after partial hepatectomy (PH). Liver mass recovery and molecular parameters related to cell proliferation and apoptotic death have been determined. NOS-2 and COX-2 are normally both expressed in the remnant liver after PH, and inhibition of either one delays regeneration. We found, however, that simultaneous suppression of the activities of NOS-2 (by gene knockout) and COX-2 (by pharmacological inhibition) resulted in animal death between 24 and 72 h after PH. Analysis of liver mass recovery and molecular parameters related to cell proliferation and apoptotic death revealed increased liver-cell apoptosis and an insufficient proliferative response. Broad-specificity caspase inhibitors, such as z-Val-Ala-Asp.fmk (z-VAD), or administration of NO-donors, rescued animals from death, revealing a critical apoptotic bias at this stage of proliferation. These findings demonstrate that simultaneous signaling by NO and prostaglandins plays an important role in the mechanism of liver regeneration after PH by protecting the remnant tissue from apoptotic death.

  13. Free radical scavenging and COX-2 inhibition by simple colon metabolites of polyphenols: A theoretical approach.

    Science.gov (United States)

    Amić, Ana; Marković, Zoran; Marković, Jasmina M Dimitrić; Jeremić, Svetlana; Lučić, Bono; Amić, Dragan

    2016-12-01

    Free radical scavenging and inhibitory potency against cyclooxygenase-2 (COX-2) by two abundant colon metabolites of polyphenols, i.e., 3-hydroxyphenylacetic acid (3-HPAA) and 4-hydroxyphenylpropionic acid (4-HPPA) were theoretically studied. Different free radical scavenging mechanisms are investigated in water and pentyl ethanoate as a solvent. By considering electronic properties of scavenged free radicals, hydrogen atom transfer (HAT) and sequential proton loss electron transfer (SPLET) mechanisms are found to be thermodynamically probable and competitive processes in both media. The Gibbs free energy change for reaction of inactivation of free radicals indicates 3-HPAA and 4-HPPA as potent scavengers. Their reactivity toward free radicals was predicted to decrease as follows: hydroxyl>alkoxyls>phenoxyl≈peroxyls>superoxide. Shown free radical scavenging potency of 3-HPAA and 4-HPPA along with their high μM concentration produced by microbial colon degradation of polyphenols could enable at least in situ inactivation of free radicals. Docking analysis with structural forms of 3-HPAA and 4-HPPA indicates dianionic ligands as potent inhibitors of COX-2, an inducible enzyme involved in colon carcinogenesis. Obtained results suggest that suppressing levels of free radicals and COX-2 could be achieved by 3-HPAA and 4-HPPA indicating that these compounds may contribute to reduced risk of colon cancer development. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Effects of intrathecal administration of nitric oxide synthase inhibitors on carrageenan-induced thermal hyperalgesia

    OpenAIRE

    Osborne, Michael G; Coderre, Terence J

    1999-01-01

    We examined the effects of various nitric oxide synthase (NOS) inhibitors on carrageenan-induced thermal hyperalgesia.First, we determined the time point at which a subcutaneous plantar injection of carrageenan into the rat hindpaw produced maximum thermal hyperalgesia. Subsequently, we demonstrated that intrathecal administration of the non-selective NOS inhibitor L-NG-nitro-arginine methyl ester (L-NAME) produces a dose-dependent reduction of carrageenan-induced thermal hyperalgesia.Four re...

  15. Saturated fatty acids up-regulate COX-2 expression in prostate epithelial cells via toll-like receptor 4/NF-κB signaling.

    Science.gov (United States)

    Liu, Jie; Hu, Shuai; Cui, Yun; Sun, Meng-Kui; Xie, Feng; Zhang, Qian; Jin, Jie

    2014-04-01

    Cyclooxygenase-2 (COX-2) has been implicated in prostate carcinogenesis, and recently it has been confirmed to be a molecular target of saturated fatty acids (SFAs). In the present study, we investigated the effect of stearic acid (SA) and palmitic acid (PA), two of the most abundant SFAs contained in dietary fat, on COX-2 expression in prostate epithelial cells and the signaling transduction pathway involved. First, we demonstrated that both SA and PA increased the mRNA and protein expression of COX-2, and consistently induced the activation of NF-κB in RWPE-1, BPH-1 and PC-3 prostate epithelial cell lines. The effect of SA and PA on COX-2 over-expression and NF-κB activation was in a dose-dependent manner, and PA was more potent than SA at the same concentration. Then, we demonstrated inhibition of NF-κB using its specific inhibitor strikingly attenuated PA-induced COX-2 expression. Toll-like receptor 4 (TLR4) was revealed to be expressed on RWPE-1, BPH-1 and PC-3 cell lines by PCR and immunofluorescence staining, and blocking its signaling significantly inhibited PA induced COX-2 over-expression and NF-κB activation. Taken together, we demonstrated that SFAs can up-regulate COX-2 expression in prostate epithelial cells, and this effect was mediated mainly through the TLR4/NF-κB signaling pathway.

  16. Resveratrol inhibits BK-induced COX-2 transcription by suppressing acetylation of AP-1 and NF-κB in human rheumatoid arthritis synovial fibroblasts.

    Science.gov (United States)

    Yang, Chuen-Mao; Chen, Yu-Wen; Chi, Pei-Ling; Lin, Chih-Chung; Hsiao, Li-Der

    2017-05-15

    Bradykinin (BK) induces inflammation in rheumatoid arthritis (RA). Resveratrol is a potent activator of Sirt1 which could modulate inflammation through deacetylating histones of transcription factors. Here, we investigated the mechanisms underlying BK-induced COX-2 expression which is modulated by resveratrol/Sirt1 in human rheumatoid arthritis synovial fibroblasts (RASFs). We found that BK-induced COX-2 protein and mRNA expression associated with PGE2 synthesis, and promoter activity was mediated through B2R receptors, which were attenuated by selective B2R antagonist Hoe140 or transfection with B2R siRNA. BK-induced responses were mediated through PKCμ, MAPKs, AP-1 and NF-κB which were inhibited by their respective inhibitors or siRNAs. Up-regulation of Sirt1 by resveratrol suppressed the BK-induced COX-2/PGE2 production through inhibiting the interaction of AP-1 and NF-κB with COX-2 promoter in RASFs. BK-induced COX-2/PGE2 expression is mediated through a B2R-PKCμ-dependent MAPKs, AP-1, and NF-κB cascade. Resveratrol inhibited the phosphorylation and acetylation of p65, c-Jun, and Fos and reduced the binding to the COX-2 promoter, thereby attenuated the COX-2 expression. Therefore, resveratrol may be a promising therapeutic intervention for treatment of inflammatory arthritis. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Tumor initiation inhibition through inhibition COX-1 activity of a traditional Korean herbal prescription, Geiji-Bokryung-Hwan, in human hepatocarcinoma cells.

    Science.gov (United States)

    Park, Won-Hwan; Lee, Soo-Kyung; Oh, Hoon-Kyu; Bae, Jong-Yub; Kim, Cheorl-Ho

    2005-01-01

    Some Korean and oriental herbal prescriptions used for a syndrome expressed as chest paralysis and heartache are thought to be effective for angina pectoris. We investigated the effects of an oriental medicinal prescription, Geiji-Bokryung-Hwan (GBH) consisting of herbs of Cinnamomi Ramulus, Poria Cocos Hoelen (Pachymae Fungus), Moutan Cortex Radicis, Paeoniae Radix, and Persicae Semen, on growth-inhibitory activity and cancer chemopreventive activity in assays representing three major stages of carcinogenesis. The GBH was found to act as an potent inhibitor of cyclooxygenase (COX)-1 only but not as COX-2 inhibitor. Furthermore, the extract mediated anti-inflammatory effects and inhibited COX-associated hydroperoxidase functions (anti-promotion activity). Inhibitory effect of the GBH on the growth of cancer cell lines such as HepG2 cell and Hep3B cell was shown. These data suggest that GBH extracts merit investigation as a potential cancer chemopreventive agent in humans, especially in hepatological cancers.

  18. Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model.

    Science.gov (United States)

    Xin, Xiping; Majumder, Mousumi; Girish, Gannareddy V; Mohindra, Vik; Maruyama, Takayuki; Lala, Peeyush K

    2012-08-01

    We reported that cyclo-oxygenase (COX)-2 expression in human breast cancer stimulated cancer cell migration and invasiveness, production of vascular endothelial growth factor (VEGF)-C and lymphangiogenesis in situ, largely from endogenous PGE2-mediated stimulation of prostaglandin E (EP)1 and EP4 receptors, presenting them as candidate therapeutic targets against lymphatic metastasis. As human breast cancer xenografts in immuno-compromised mice have limitations for preclinical testing, we developed a syngeneic murine breast cancer model of spontaneous lymphatic metastasis mimicking human and applied it for mechanistic and therapeutic studies. We tested the roles of COX-2 and EP receptors in VEGF-C and -D production by a highly metastatic COX-2 expressing murine breast cancer cell line C3L5. These cells expressed all EP receptors and produced VEGF-C and -D, both inhibited with COX-2 inhibitors or EP4 (but not EP1, EP2 or EP3) antagonists. C3H/HeJ mice, when implanted SC in both inguinal regions with C3L5 cells suspended in growth factor-reduced Matrigel, exhibited rapid tumor growth, tumor-associated angiogenesis and lymphangiogenesis (respectively measured with CD31 and LYVE-1 immunostaining), metastasis to the inguinal and axillary lymph nodes and the lungs. Chronic oral administration of COX-1/COX-2 inhibitor indomethacin, COX-2 inhibitor celecoxib and an EP4 antagonist ONO-AE3-208, but not an EP1 antagonist ONO-8713 at nontoxic doses markedly reduced tumor growth, lymphangiogenesis, angiogenesis, and metastasis to lymph nodes and lungs. Residual tumors in responding mice revealed reduced VEGF-C and -D proteins, AkT phosphorylation and increased apoptotic/proliferative cell ratios consistent with blockade of EP4 signaling. We suggest that EP4 antagonists deserve clinical testing for chemo-intervention of lymphatic metastasis in human breast cancer.

  19. A Comparative Study of Cox Regression vs. Log-Logistic ...

    African Journals Online (AJOL)

    Journal of Medical and Biomedical Sciences ... using non-parametric Cox model and parametric Log-logistic model, factors influencing survival of ... colorectal cancer referred to Taleghani Medical and Training Center of Tehran between 2001 ...

  20. COX-2 and p53 in human sinonasal cancer

    DEFF Research Database (Denmark)

    Holmila, Reetta; Cyr, Diane; Luce, Danièle

    2008-01-01

    the exposures and p53 accumulation were found; however, the p53 accumulation pattern (p = 0.062 for wood dust exposure) resembled that of COX-2 expression. In summary, our findings show increased COX-2 expression in SNC adenocarcinoma with wood dust exposure, suggesting a role for inflammatory components......The causal role of wood-dust exposure in sinonasal cancer (SNC) has been established in epidemiological studies, but the mechanisms of SNC carcinogenesis are still largely unknown. Increased amounts of COX-2 are found in both premalignant and malignant tissues, and experimental evidence link COX-2......; 41 for p53). Occupational histories and smoking habits were available for majority of the cases. Most of the adenocarcinoma cases with exposure history data had been exposed to wood dust at work in the past (88%, 14/16). For smokers, 63% (12/19) presented with SSC, whereas 64% (7/11) of nonsmokers...

  1. Convergence of posteriors for discretized log Gaussian Cox processes

    DEFF Research Database (Denmark)

    Waagepetersen, Rasmus Plenge

    2004-01-01

    In Markov chain Monte Carlo posterior computation for log Gaussian Cox processes (LGCPs) a discretization of the continuously indexed Gaussian field is required. It is demonstrated that approximate posterior expectations computed from discretized LGCPs converge to the exact posterior expectations...

  2. MicroRNA-144 is regulated by CP2 and decreases COX-2 expression and PGE2 production in mouse ovarian granulosa cells.

    Science.gov (United States)

    Zhou, Jiawei; Lei, Bin; Li, Huanan; Zhu, Lihua; Wang, Lei; Tao, Hu; Mei, Shuqi; Li, Fenge

    2017-02-09

    Mammalian folliculogenesis is a complex process in which primordial follicles develop into pre-ovulatory follicles, followed by ovulation to release mature oocytes. In this study, we explored the role of miR-144 in ovulation. miR-144 was one of the differentially expressed microRNAs, which showed 5.59-fold changes, in pre-ovulatory ovarian follicles between Large White and Chinese Taihu sows detected by Solexa deep sequencing. We demonstrated that overexpression of miR-144 significantly decreased the luciferase reporter activity under the control of the cyclooxygenase-2 (COX-2) or mothers against decapentaplegic homologue 4 (Smad4) 3'-untranslated region (3'-UTR) and suppressed COX-2 and Smad4 expression. In contrast, a miR-144 inhibitor increased COX-2 and Smad4 expression in mouse granulosa cells (mGCs). Meanwhile, Smad4 upregulated COX-2 expression, but this effect was abolished when the mGCs were treated with the transforming growth factor beta signalling pathway inhibitor SB431542. Moreover, luciferase reporter, chromatin immunoprecipitation and electrophoretic mobility shift assay results showed that the transcription factor CP2 upregulated miR-144 expression, which partially contributed to the suppression of COX-2 in mGCs. Both CP2 and miR-144 alter prostaglandin E2 (PGE2) production by regulating COX-2 expression. In addition, miR-144 regulated mGC apoptosis and affected follicular atresia, but these activities did not appear to be through COX-2 and Smad4. Taken together, we revealed an important CP2/miR-144/COX-2/PGE2/ovulation pathway in mGCs.

  3. Comparison of Cox and Gray's survival models in severe sepsis

    DEFF Research Database (Denmark)

    Kasal, Jan; Andersen, Zorana Jovanovic; Clermont, Gilles

    2004-01-01

    Although survival is traditionally modeled using Cox proportional hazards modeling, this approach may be inappropriate in sepsis, in which the proportional hazards assumption does not hold. Newer, more flexible models, such as Gray's model, may be more appropriate.......Although survival is traditionally modeled using Cox proportional hazards modeling, this approach may be inappropriate in sepsis, in which the proportional hazards assumption does not hold. Newer, more flexible models, such as Gray's model, may be more appropriate....

  4. Simultaneous confidence bands for Cox regression from semiparametric random censorship.

    Science.gov (United States)

    Mondal, Shoubhik; Subramanian, Sundarraman

    2016-01-01

    Cox regression is combined with semiparametric random censorship models to construct simultaneous confidence bands (SCBs) for subject-specific survival curves. Simulation results are presented to compare the performance of the proposed SCBs with the SCBs that are based only on standard Cox. The new SCBs provide correct empirical coverage and are more informative. The proposed SCBs are illustrated with two real examples. An extension to handle missing censoring indicators is also outlined.

  5. Cyclooxygenase-1-selective inhibitors based on the (E)-2'-des-methyl-sulindac sulfide scaffold.

    Science.gov (United States)

    Liedtke, Andy J; Crews, Brenda C; Daniel, Cristina M; Blobaum, Anna L; Kingsley, Philip J; Ghebreselasie, Kebreab; Marnett, Lawrence J

    2012-03-08

    Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclooxygenases (COX-1 and COX-2) followed by metabolism of endoperoxide intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2'-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents.

  6. Methodological comparison of marginal structural model, time-varying Cox regression, and propensity score methods : the example of antidepressant use and the risk of hip fracture

    NARCIS (Netherlands)

    Ali, M Sanni; Groenwold, Rolf H H; Belitser, S.; Souverein, Patrick C; Martín, Elisa; Gatto, Nicolle M; Huerta, Consuelo; Gardarsdottir, Helga; Roes, Kit C B; Hoes, Arno W; de Boer, Anthonius; Klungel, Olaf H

    2016-01-01

    BACKGROUND: Observational studies including time-varying treatments are prone to confounding. We compared time-varying Cox regression analysis, propensity score (PS) methods, and marginal structural models (MSMs) in a study of antidepressant [selective serotonin reuptake inhibitors (SSRIs)] use and

  7. COX2 genetic variation, NSAIDs, and advanced prostate cancer risk.

    Science.gov (United States)

    Cheng, I; Liu, X; Plummer, S J; Krumroy, L M; Casey, G; Witte, J S

    2007-08-20

    Collective evidence suggests that cyclooxygenase 2 (COX2) plays a role in prostate cancer risk. Cyclooxygenase 2 is the major enzyme that converts arachidonic acid to prostaglandins, which are potent mediators of inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the enzymatic activity of COX2 and long-term use of NSAIDs appears to modestly lower the risk of prostate cancer. We investigated whether common genetic variation in COX2 influences the risk of advanced prostate cancer. Nine single-nucleotide polymorphisms (SNPs) in COX2 were genotyped among 1012 men in our case-control study of advanced prostate cancer. Gene-environment interactions between COX2 polymorphisms and NSAID use were also evaluated. Information on NSAID use was obtained by questionnaire. Three SNPs demonstrated nominally statistically significant associations with prostate cancer risk, with the most compelling polymorphism (rs2745557) associated with a lower risk of disease (odds ratio (OR) GC vs GG=0.64; 95% confidence interval (CI): 0.49-0.84; P=0.002). We estimated through permutation analysis that a similarly strong result would occur by chance 2.7% of the time. Nonsteroidal anti-inflammatory drug use was associated with a lower risk of disease in comparison to no use (OR=0.67; 95% CI: 0.52-0.87). No significant statistical interaction between NSAID use and rs2745557 was observed (P=0.12). Our findings suggest that variation in COX2 is associated with prostate cancer risk.

  8. Involvement of COX2–thromboxane pathway in TCDD-induced precardiac edema in developing zebrafish

    Energy Technology Data Exchange (ETDEWEB)

    Teraoka, Hiroki, E-mail: hteraoka@rakuno.ac.jp [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu (Japan); Okuno, Yuki; Nijoukubo, Daisuke; Yamakoshi, Ayumi [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu (Japan); Peterson, Richard E. [School of Pharmacy, University of Wisconsin, Madison, WI (United States); Stegeman, John J. [Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA (United States); Kitazawa, Takio; Hiraga, Takeo [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu (Japan); Kubota, Akira [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu (Japan); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA (United States)

    2014-09-15

    Highlights: • We establish a new indicator of pericardial edema in developing zebrafish (precardiac edema). • Property of precardiac edema by TCDD is similar to that for conventional pericardial edema. • COX2b (but not COX2a)–thromboxane pathway is involved in precardiac edema by TCDD. - Abstract: The cardiovascular system is one of the most characteristic and important targets for developmental toxicity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in fish larvae. However, knowledge of the mechanism of TCDD-induced edema after heterodimerization of aryl hydrocarbon receptor type 2 (AHR2) and AHR nuclear translocator type 1 (ARNT1) is still limited. In the present study, microscopic analysis with a high-speed camera revealed that TCDD increased the size of a small cavity between the heart and body wall in early eleutheroembryos, a toxic effect that we designate as precardiac edema. A concentration–response curve for precardiac edema at 2 days post fertilization (dpf) showed close similarity to that for conventional pericardial edema at 3 dpf. Precardiac edema caused by TCDD was reduced by morpholino knockdown of AHR2 and ARNT1, as well as by an antioxidant (ascorbic acid). A selective inhibitor of cyclooxygenase type 2 (COX2), NS398, also markedly inhibited TCDD-induced precardiac edema. A thromboxane receptor (TP) antagonist, ICI-192,605 almost abolished TCDD-induced precardiac edema and this effect was canceled by U46619, a TP agonist, which was not influential in the action of TCDD by itself. Knockdown of COX2b and thromboxane A synthase 1 (TBXS), but not COX2a, strongly reduced TCDD-induced precardiac edema. Knockdown of COX2b was without effect on mesencephalic circulation failure caused by TCDD. The edema by TCDD was also inhibited by knockdown of c-mpl, a thrombopoietin receptor necessary for thromobocyte production. Finally, induction of COX2b, but not COX2a, by TCDD was seen in eleutheroembryos at 3 dpf. These results suggest a role of the COX2b

  9. COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro

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    Petasis Nicos A

    2008-05-01

    Full Text Available Abstract Background An increasing number of reports is challenging the notion that the antitumor potential of the selective COX-2 inhibitor celecoxib (Celebrex® is mediated primarily via the inhibition of COX-2. We have investigated this issue by applying two different analogs of celecoxib that differentially display COX-2-inhibitory activity: the first analog, called unmethylated celecoxib (UMC, inhibits COX-2 slightly more potently than its parental compound, whereas the second analog, 2,5-dimethyl-celecoxib (DMC, has lost the ability to inhibit COX-2. Results With the use of glioblastoma and pancreatic carcinoma cell lines, we comparatively analyzed the effects of celecoxib, UMC, and DMC in various short-term (≤48 hours cellular and molecular studies, as well as in long-term (≤3 months focus formation assays. We found that DMC exhibited the most potent antitumor activity; celecoxib was somewhat less effective, and UMC clearly displayed the overall weakest antitumor potential in all aspects. The differential growth-inhibitory and apoptosis-stimulatory potency of these compounds in short-term assays did not at all correlate with their capacity to inhibit COX-2, but was closely aligned with their ability to trigger endoplasmic reticulum stress (ERS, as indicated by the induction of the ERS marker CHOP/GADD153 and activation of the ERS-associated caspase 7. In addition, we found that these compounds were able to restore contact inhibition and block focus formation during long-term, chronic drug exposure of tumor cells, and this was achieved at sub-toxic concentrations in the absence of ERS or inhibition of COX-2. Conclusion The antitumor activity of celecoxib in vitro did not involve the inhibition of COX-2. Rather, the drug's ability to trigger ERS, a known effector of cell death, might provide an alternative explanation for its acute cytotoxicity. In addition, the newly discovered ability of this drug to restore contact inhibition and

  10. Antitumor Activity of Cytotoxic Cyclooxygenase-2 Inhibitors

    Science.gov (United States)

    Uddin, Md. Jashim; Crews, Brenda C.; Xu, Shu; Ghebreselasie, Kebreab; Daniel, Cristina K.; Kingsley, Philip J.; Banerjee, Surajit; Marnett, Lawrence J.

    2017-01-01

    Targeted delivery of chemotherapeutic agents to tumors has been explored as a means to increase the selectivity and potency of cytotoxicity. Most efforts in this area have exploited the molecular recognition of proteins highly expressed on the surface of cancer cells followed by internalization. A related approach that has received less attention is the targeting of intracellular proteins by ligands conjugated to anti-cancer drugs. An attractive target for this approach is the enzyme cyclooxygenase-2 (COX-2), which is highly expressed in a range of malignant tumors. Herein, we describe the synthesis and evaluation of a series of chemotherapeutic agents targeted to COX-2 by conjugation to indomethacin. Detailed characterization of compound 12, a conjugate of indomethacin with podophyllotoxin, revealed highly potent and selective COX-2 inhibition in vitro and in intact cells. Kinetics and X-ray crystallographic studies demonstrated that compound 12 is a slow, tight-binding inhibitor that likely binds to COX-2’s allosteric site with its indomethacin moiety in a conformation similar to that of indomethacin. Compound 12 exhibited cytotoxicity in cell culture similar to that of podophyllotoxin with no evidence of COX-2-dependent selectivity. However, in vivo, compound 12 accumulated selectively in and more effectively inhibited the growth of a COX-2-expressing xenograft compared to a xenograft that did not express COX-2. Compound 12, which we have named chemocoxib A, provides proof-of-concept for the in vivo targeting of chemotherapeutic agents to COX-2, but suggests that COX-2-dependent selectivity may not be evident in cell culture-based assays. PMID:27588346

  11. EFFECTS OF p53 GENE THERAPY COMBINED WITH CYCLOOXYGENASE-2 INHIBITOR ON CYCLOOXYGENASE-2 GENE EXPRESSION AND GROWTH INHIBITION OF HUMAN LUNG CANCER CELLS

    Institute of Scientific and Technical Information of China (English)

    WANG Zhao-Xia; LU Bin-Bin; WANG Teng; YIN Yong-Mei; DE Wei; SHU Yong-Qian

    2007-01-01

    Background Gene therapy by adenovirus-mediated wild-type p53 gene transfer has been shown to inhibit lung cancer growth in vitro, in animal models, and in human clinical trials. The antitumor effect of selective cyclooxygenase (COX)-2 inhibitors has been demonstrated in preclinical studies. However, no information is available on the effects of p53 gene therapy combined with selective COX-2 inhibitor on COX-2 gene expression and growth inhibition of human lung cancer cells. Methods We evaluated the effects of recombinant adenovirus-p53 (Ad-p53) gene therapy combined with selective COX-2 inhibitor on the proliferation, apoptosis, cell cycle arrest of human lung adenocarcinoma A549 cell line, and the effects of tumor suppressor exogenous wild type p53 on COX-2 gene expression. Results Ad-p53 gene therapy combined with selective COX-2 inhibitor celecoxib shows significant synergistic inhibition effects on the growth of human lung adenocarcinoma A549 cell line. Exogenous p53 gene can suppress COX-2 gene expression. Conclusions Significant synergistic inhibition effects of A549 cell line by the combined Ad-p53 and selective COX-2 inhibitor celecoxib may be achieved by enhancement of growth inhibition, apoptosis induction and suppression of COX-2 gene expression. This study provides first evidence that the administration of p53 gene therapy in combination with COX-2 inhibitors might be a new clinical strategy for the treatment or prevention of NSCLC.

  12. The SK-N-AS human neuroblastoma cell line develops osteolytic bone metastases with increased angiogenesis and COX-2 expression

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    Takahiro Tsutsumimoto

    2014-11-01

    Full Text Available Neuroblastoma (NB, which arises from embryonic neural crest cells, is the most common extra-cranial solid tumor of childhood. Approximately half of NB patients manifest bone metastasis accompanied with bone pain, fractures and bone marrow failure, leading to disturbed quality of life and poor survival. To study the mechanism of bone metastasis of NB, we established an animal model in which intracardiac inoculation of the SK-N-AS human NB cells in nude mice developed osteolytic bone metastases with increased osteoclastogenesis. SK-N-AS cells induced the expression of receptor activator of NF-κB ligand and osteoclastogenesis in mouse bone marrow cells in the co-culture. SK-N-AS cells expressed COX-2 mRNA and produced substantial amounts of prostaglandin E2 (PGE2. In contrast, the SK-N-DZ and SK-N-FI human NB cells failed to develop bone metastases, induce osteoclastogenesis, express COX-2 mRNA and produce PGE2. Immunohistochemical examination of SK-N-AS bone metastasis and subcutaneous tumor showed strong expression of COX-2. The selective COX-2 inhibitor NS-398 inhibited PGE2 production and suppressed bone metastases with reduced osteoclastogenesis. NS-398 also inhibited subcutaneous SK-N-AS tumor development with decreased angiogenesis and vascular endothelial growth factor-A expression. Of interest, metastasis to the adrenal gland, a preferential site for NB development, was also diminished by NS-398. Our results suggest that COX2/PGE2 axis plays a critical role in the pathophysiology of osteolytic bone metastases and tumor development of the SK-NS-AS human NB. Inhibition of angiogenesis by suppressing COX-2/PGE2 may be an effective therapeutic approach for children with NB.

  13. Effusanin E suppresses nasopharyngeal carcinoma cell growth by inhibiting NF-κB and COX-2 signaling.

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    Mingzhu Zhuang

    Full Text Available Rabdosia serra is well known for its antibacterial, anti-inflammatory and antitumor activities, but no information has been available for the active compounds derived from this plant in inhibiting human nasopharyngeal carcinoma (NPC cell growth. In this study, we isolated and purified a natural diterpenoid from Rabdosia serra and identified its chemical structure as effusanin E and elucidated its underlying mechanism of action in inhibiting NPC cell growth. Effusanin E significantly inhibited cell proliferation and induced apoptosis in NPC cells. Effusanin E also induced the cleavage of PARP, caspase-3 and -9 proteins and inhibited the nuclear translocation of p65 NF-κB proteins. Moreover, effusanin E abrogated the binding of NF-κB to the COX-2 promoter, thereby inhibiting the expression and promoter activity of COX-2. Pretreatment with a COX-2 or NF-κB-selective inhibitor (celecoxib or ammonium pyrrolidinedithiocarbamate had an additive effect on the effusanin E-mediated inhibition of proliferation, while pretreatment with an activator of NF-κB/COX-2 (lipopolysaccharides abrogated the effusanin E-mediated inhibition of proliferation. Effusanin E also significantly suppressed tumor growth in a xenograft mouse model without obvious toxicity, furthermore, the expression of p50 NF-κB and COX-2 were down-regulated in the tumors of nude mice. These data suggest that effusanin E suppresses p50/p65 proteins to down-regulate COX-2 expression, thereby inhibiting NPC cell growth. Our findings provide new insights into exploring effusanin E as a potential therapeutic compound for the treatment of human nasopharyngeal carcinoma.

  14. Protective Role of Cyclooxygenase (COX)-2 in Experimental Lung Injury: Evidence of a Lipoxin A(4)-Mediated Effect.

    LENUS (Irish Health Repository)

    2012-02-01

    BACKGROUND: Polymorphoneutrophils (PMNs) are activated by inflammatory mediators following splanchnic ischemia\\/reperfusion (I\\/R), potentially injuring organs such as the lung. As a result, some patients develop respiratory failure following abdominal aortic aneurysm repair. Pulmonary cyclooxygenase (COX)-2 protects against acid aspiration and bacterial instillation via lipoxins, a family of potent anti-inflammatory lipid mediators. We explored the role of COX-2 and lipoxin A(4) in experimental I\\/R-mediated lung injury. MATERIALS AND METHODS: Sprague-Dawley rats were assigned to one of the following five groups: (1) controls; (2) aortic cross-clamping for 45 min and reperfusion for 4 h (I\\/R group); (3) I\\/R and SC236, a selective COX-2 inhibitor; (4) I\\/R and aspirin; and (5) I\\/R and iloprost, a prostacyclin (PGI(2)) analogue. Lung injury was assessed by wet\\/dry ratio, myeloperoxidase (MPO) activity, and bronchoalveolar lavage (BAL) neutrophil counts. BAL levels of thromboxane, PGE(2), 6-keto-PGF(1)alpha (a hydrolysis product of prostacyclin), lipoxin A(4), and 15-epi-lipoxin A(4) were analyzed by enzyme immunoassay (EIA). Immunostaining for COX-2 was performed. RESULTS: I\\/R significantly increased tissue MPO, the wet\\/dry lung ratio, and neutrophil counts. These measures were significantly further aggravated by SC236 and improved by iloprost. I\\/R increased COX-2 immunostaining and both PGE(2) and 6-keto-PGF(1alpha) levels in BAL. SC236 markedly reduced these prostanoids and lipoxin A(4) compared with I\\/R alone. Iloprost markedly increased lipoxin A(4) levels. The deleterious effect of SC236 and the beneficial effect of iloprost was associated with a reduction and an increase, respectively, in lipoxin A(4) levels. CONCLUSIONS: Lipoxin A(4) warrants further evaluation as a mediator of COX-2 regulated lung protection.

  15. HER2 induces cell proliferation and invasion of non-small-cell lung cancer by upregulating COX-2 expression via MEK/ERK signaling pathway

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    Chi F

    2016-05-01

    Full Text Available Feng Chi, Rong Wu, Xueying Jin, Min Jiang, Xike Zhu Department of Medical Oncology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China Abstract: HER2 positivity has been well studied in various cancers, but its importance in non-small-cell lung cancer (NSCLC is still being explored. In this study, quantitative reverse transcription polymerase chain reaction (qRT-PCR was performed to detect HER2 and COX-2 expression in NSCLC tissues. Then, pcDNA3.1-HER2 was used to overexpress HER2, while HER2 siRNA and COX-2 siRNA were used to silence HER2 and COX-2 expression. MTT assay and invasion assay were used to detect the effects of HER2 on cell proliferation and invasion. Our study revealed that HER2 and COX-2 expression were upregulated in NSCLC tissues and HER2 exhibited a significant positive correlation with the levels of COX-2 expression. Overexpression of HER2 evidently elevated COX-2 expression, while silencing of HER2 evidently decreased COX-2 expression. Furthermore, overexpressed HER2 induced the ERK phosphorylation, and this was abolished by the treatment with U0126, a pharmacological inhibitor of MEK, an upstream kinase of ERK. HER2-induced expression and promoter activity of COX-2 were also suppressed by U0126, suggesting that the MEK/ERK signaling pathway regulates COX-2 expression. In addition, HER2 induced activation of AKT signaling pathway, which was reversed by pretreatment with U0126 and COX-2 siRNA. MTT and invasion assays revealed that HER2 induced cell proliferation and invasion that were reversed by pretreatment with U0126 and COX-2 siRNA. In this study, our results demonstrated for the first time that HER2 elevated COX-2 expression through the activation of MEK/ERK pathway, which subsequently induced cell proliferation and invasion via AKT pathway in NSCLC tissues. Keywords: HER2, MEK/ERK, COX-2, AKT signaling pathway, non-small-cell lung cancer

  16. Synthesis, anti-inflammatory, analgesic, COX1/2-inhibitory activity, and molecular docking studies of hybrid pyrazole analogues

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    Alam MJ

    2016-10-01

    Full Text Available Md Jahangir Alam,1 Ozair Alam,1 Suroor Ahmad Khan,1 Mohd Javed Naim,1 Mohammad Islamuddin,2 Girdhar Singh Deora3 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, 2Parasite Immunology Laboratory, Department of Biotechnology, Faculty of Science, Jamia Hamdard, New Delhi, 3Institute of Life Sciences, University of Hyderabad, Hyderabad, India Abstract: This article reports on the design, synthesis, and pharmacological activity of a new series of hybrid pyrazole analogues: 5a–5u. Among the series 5a–5u, the compounds 5u and 5s exhibited potent anti-inflammatory activity of 80.63% and 78.09% and inhibition of 80.87% and 76.56% compared with the standard drug ibuprofen, which showed 81.32% and 79.23% inhibition after 3 and 4 hours, respectively. On the basis of in vivo studies, 12 compounds were selected for assessment of their in vitro inhibitory action against COX1/2 and TNFα. The compounds 5u and 5s showed high COX2-inhibitory activity, with half-maximal inhibitory concentrations of 1.79 and 2.51 µM and selectivity index values of 72.73 and 65.75, respectively, comparable to celecoxib (selectivity index =78.06. These selected compounds were also tested for TNFα, cytotoxicity, and ulcerogenicity. Docking studies were also carried out to determine possible interactions of the potent compounds (5u and 5s, which also showed high docking scores of -12.907 and -12.24 compared to celecoxib, with a -9.924 docking score. These selective COX2 inhibitors were docked into the active site of COX2, and showed the same orientation and binding mode to that of celecoxib (selective COX2 inhibitor. Docking studies also showed that the SO2NH2 of 5u and 5s is inserted deep inside the selective pocket of the COX2-active site and formed a hydrogen-bond interaction with His90, Arg513, Phe518, Ser353, Gln192, and Ile517, which was further validated by superimposed docked pose with celecoxib. Keywords: anti-inflammatory activity, analgesic activity

  17. The mouse defense test battery: evaluation of the effects of non-selective and BZ-1 (omega1) selective, benzodiazepine receptor ligands.

    Science.gov (United States)

    Griebel, G.; Sanger, D.J.; Perrault, G.

    1996-11-01

    The behavioral effects of several benzodiazepine (BZ) (omega) receptor ligands were compared using the Mouse Defense Test Battery which has been designed to assess defensive reactions of Swiss mice confronted with a natural threat (a rat) and situations associated with this threat. Primary measures taken before, during and after rat confrontation were escape attempts, flight, risk assessment and defensive threat and attack. The drugs used included non-selective BZ (omega) full (clonazepam, clorazepate, chlordiazepoxide and diazepam) and partial (bretazenil and imidazenil) agonists, and BZ-1 (omega1) selective (abecarnil, CL 218,872 and zolpidem) receptor ligands. With the exception of clonazepam, non-selective BZ (omega) receptor compounds only partially affected flight behaviors. The drugs reduced some but not all flight measures in response to the approaching rat, whereas clonazepam attenuated all flight reactions. In contrast to their mild and inconsistent actions on flight, the non-selective BZ (omega) receptor agonists displayed clear effects on risk assessment when subjects were chased by the rat. When contact was forced between the subject and the rat, the non-selective BZ (omega) receptor full agonists reduced defensive threat and attack reactions, while the partial agonists imidazenil and bretazenil only weakly attenuated defensive attack behavior. Similarly, after the rat had been removed from the test area, the non-selective BZ (omega) receptor full agonists displayed greater efficacy than the partial agonists in reducing escape attempts. Overall, results obtained with the selective BZ-1 (omega1) receptor ligands demonstrated either no clear effects or no specific action on defensive reactions. Taken together, these data demonstrate that: (1) non-selective BZ (omega) agonists displaying high intrinsic activity affect a wider range of defensive behaviors than non-selective BZ (omega) receptor partial agonists; (2) the defense system does not involve

  18. Early Recovery of Salmonella from Food Using a 6-Hour Non-selective Pre-enrichment and Reformulation of Tetrathionate Broth

    Science.gov (United States)

    Daquigan, Ninalynn; Grim, Christopher J.; White, James R.; Hanes, Darcy E.; Jarvis, Karen G.

    2016-01-01

    Culture based methods are commonly employed to detect pathogens in food and environmental samples. These methods are time consuming and complex, requiring multiple non-selective and selective enrichment broths, and usually take at least 1 week to recover and identify pathogens. Improving pathogen detection in foods is a primary goal for regulatory agencies and industry. Salmonella detection in food relies on a series of culture steps in broth formulations optimized to resuscitate Salmonella and reduce the abundance of competitive bacteria. Examples of non-selective pre-enrichment broths used to isolate Salmonella from food include Lactose, Universal Pre-enrichment, BPW, and Trypticase Soy broths. Tetrathionate (TT) and Rappaport–Vassiliadis (RV) broths are employed after a 24-h non-selective enrichment to select for Salmonella and hamper the growth of competitive bacteria. In this study, we tested a new formulation of TT broth that lacks brilliant green dye and has lower levels of TT . We employed this TT broth formulation in conjunction with a 6-h non-selective pre-enrichment period and determined that Salmonella recovery was possible one day earlier than standard food culture methods. We tested the shortened culture method in different non-selective enrichment broths, enumerated Salmonella in the non-selective enrichments, and used 16S rRNA gene sequencing to determine the proportional abundances of Salmonella in the TT and RV selective enrichments. Together these data revealed that a 6-h non-selective pre-enrichment reduces the levels of competitive bacteria inoculated into the selective TT and RV broths, enabling the recovery of Salmonella 1 day earlier than standard culture enrichment methods. PMID:28082968

  19. Capillary electrophoresis for the characterization of quantum dots after non-selective or selective bioconjugation with antibodies for immunoassay

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    Lai Edward PC

    2008-10-01

    Full Text Available Abstract Capillary electrophoresis coupled with laser-induced fluorescence was used for the characterization of quantum dots and their conjugates to biological molecules. The CE-LIF was laboratory-built and capable of injection (hydrodynamic and electrokinetic from sample volumes as low as 4 μL via the use of a modified micro-fluidic chip platform. Commercially available quantum dots were bioconjugated to proteins and immunoglobulins through the use of established techniques (non-selective and selective. Non-selective techniques involved the use of EDCHCl/sulfo-NHS for the conjugation of BSA and myoglobin to carboxylic acid-functionalized quantum dots. Selective techniques involved 1 the use of heterobifunctional crosslinker, sulfo-SMCC, for the conjugation of partially reduced IgG to amine-functionalized quantum dots, and 2 the conjugation of periodate-oxidized IgGs to hydrazide-functionalized quantum dots. The migration times of these conjugates were determined in comparison to their non-conjugated QD relatives based upon their charge-to-size ratio values. The performance of capillary electrophoresis in characterizing immunoconjugates of quantum dot-labeled IgGs was also evaluated. Together, both QDs and CE-LIF can be applied as a sensitive technique for the detection of biological molecules. This work will contribute to the advancements in applying nanotechnology for molecular diagnosis in medical field.

  20. Allan V. Cox: AGU President 1978”1980

    Science.gov (United States)

    Richman, Barbara T.

    When Allan V. Cox was presented AGU's John Adam Fleming Medal in 1969, John Verhoogen described Cox's work as “characterized by painstaking care, proper attention to and use of statistics, and great insight.” Those same thoughts were echoed on February 3, 1987, during the memorial service for Cox, who died in a bicycling accident on January 27. The Stanford Memorial Church was crowded with colleagues, students, and friends.The Fleming Medal was presented to Cox in recognition of his studies on the fluctuation of the geomagnetic field. These studies helped to confirm theories of continental drift and seafloor spreading. The medal is awarded annually by AGU for original research and technical leadership in geomagnetism, atmospheric electricity, aeronomy, and related sciences. In addition to the Fleming Medal, Cox received the Antarctic Service Medal in 1970, the Vetlesen Prize in 1971, and the Arthur L. Day Prize of the National Academy of Sciences in 1984. He was a Fellow of AGU and a member of the National Academy of Sciences.

  1. Human COX20 cooperates with SCO1 and SCO2 to mature COX2 and promote the assembly of cytochrome c oxidase.

    Science.gov (United States)

    Bourens, Myriam; Boulet, Aren; Leary, Scot C; Barrientos, Antoni

    2014-06-01

    Cytochrome c oxidase (CIV) deficiency is one of the most common respiratory chain defects in patients presenting with mitochondrial encephalocardiomyopathies. CIV biogenesis is complicated by the dual genetic origin of its structural subunits, and assembly of a functional holoenzyme complex requires a large number of nucleus-encoded assembly factors. In general, the functions of these assembly factors remain poorly understood, and mechanistic investigations of human CIV biogenesis have been limited by the availability of model cell lines. Here, we have used small interference RNA and transcription activator-like effector nucleases (TALENs) technology to create knockdown and knockout human cell lines, respectively, to study the function of the CIV assembly factor COX20 (FAM36A). These cell lines exhibit a severe, isolated CIV deficiency due to instability of COX2, a mitochondrion-encoded CIV subunit. Mitochondria lacking COX20 accumulate CIV subassemblies containing COX1 and COX4, similar to those detected in fibroblasts from patients carrying mutations in the COX2 copper chaperones SCO1 and SCO2. These results imply that in the absence of COX20, COX2 is inefficiently incorporated into early CIV subassemblies. Immunoprecipitation assays using a stable COX20 knockout cell line expressing functional COX20-FLAG allowed us to identify an interaction between COX20 and newly synthesized COX2. Additionally, we show that SCO1 and SCO2 act on COX20-bound COX2. We propose that COX20 acts as a chaperone in the early steps of COX2 maturation, stabilizing the newly synthesized protein and presenting COX2 to its metallochaperone module, which in turn facilitates the incorporation of mature COX2 into the CIV assembly line.

  2. Evaluation of the immunoexpression of COX-1, COX-2 and p53 in Crohn's disease Avaliação da imunoexpressão de COX-1, COX-2 e p53 na doença de Crohn

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    Mônica Romero

    2008-12-01

    Full Text Available BACKGROUND: Crohn's disease accompanied by nonspecific or idiopathic ulcerative proctocolitis corresponds to a condition called intestinal inflammatory disease. The immunoexpression of cyclooxygenase 2 (COX-2 in Crohn's disease becomes more marked with progression of the disease and the presence of wild-type p53 suppresses the transcription of COX-2. AIMS: To investigate the immunoexpression of cyclooxygenase 1 (COX-1, COX-2 and p53 in Crohn's ileocolitis and to correlated this expression with clinical and histopathological parameters. METHODS: Forty-five cases of Crohn's disease, 16 cases of actinic colitis (diseased-control group and 11 cases without a history of intestinal disease (normal control group were studied. Hematoxylin-eosin-stained sections were submitted to histopathological analysis and the immunohistochemical expression of COX-1, COX-2 and p53 was evaluated by the streptavidin-biotin-peroxidase method. RESULTS: Sixty percent of the Crohn's disease patients were women and 40% were men, with 75.5% whites and 25.5% non-whites. The disease involved the terminal ileum in 44.5% of cases, ileum in 33.3%, colon in 20% and duodenum-ileum in 2.2%. A significant association was observed between COX-2 immunoreactivity and age RACIONAL: A doença de Crohn, junto com a colite ulcerativa idiopática ou inespecífica constituem a doença inflamatória intestinal. A imunoexpressão de ciclooxigenase 2 (COX-2 na doença de Crohn acentua-se com a progressão da doença, enquanto que a presença do tipo selvagem de p53 suprime a transcrição de COX-2. OBJETIVOS: Investigar a imunoexpressão de ciclooxigenase 1 (COX-1, COX-2 e p53 na doença de Crohn e correlacionar os achados com parâmetros clínico-histopatológicos. MÉTODOS: Foram estudados 45 casos de doença de Crohn (grupo teste, 16 casos de colite actínica (grupo controle-doente e 11 casos sem história de doença intestinal (grupo controle normal. A avaliação histopatológica foi feita

  3. Post-translational regulation of COX2 activity by FYN in prostate cancer cells.

    Science.gov (United States)

    Alexanian, Anna; Miller, Bradley; Chesnik, Marla; Mirza, Shama; Sorokin, Andrey

    2014-06-30

    While increased COX2 expression and prostaglandin levels are elevated in human cancers, the mechanisms of COX2 regulation at the post-translational level are unknown. Initial observation that COX2 forms adduct with non-receptor tyrosine kinase FYN, prompted us to study FYN-mediated post-translational regulation of COX2. We found that FYN increased COX2 activity in prostate cancer cells DU145, independent of changes in COX2 or COX1 protein expression levels. We report that FYN phosphorylates human COX2 on Tyr 446, and while corresponding phospho-mimetic COX2 mutation promotes COX2 activity, the phosphorylation blocking mutation prevents FYN-mediated increase in COX2 activity.

  4. The effects of a cyclooxygenase-2 (COX-2 expression and inhibition on human uveal melanoma cell proliferation and macrophage nitric oxide production

    Directory of Open Access Journals (Sweden)

    Marshall Jean-Claude

    2007-01-01

    Full Text Available Abstract Background Cyclooxygenase-2 (COX-2 expression has previously been identified in uveal melanoma although the biological role of COX-2 in this intraocular malignancy has not been elucidated. This study aimed to investigate the effect of a COX-2 inhibitor on the proliferation rate of human uveal melanoma cells, as well as its effect on the cytotoxic response of macrophages. Methods Human uveal melanoma cell lines were transfected to constitutively express COX-2 and the proliferative rate of these cells using two different methods, with and without the addition of Amfenac, was measured. Nitric oxide production by macrophages was measured after exposure to melanoma-conditioned medium from both groups of cells as well as with and without Amfenac, the active metabolite of Nepafenac. Results Cells transfected to express COX-2 had a higher proliferation rate than those that did not. The addition of Amfenac significantly decreased the proliferation rate of all cell lines. Nitric oxide production by macrophages was inhibited by the addition of melanoma conditioned medium, the addition of Amfenac partially overcame this inhibition. Conclusion Amfenac affected both COX-2 transfected and non-transfected uveal melanoma cells in terms of their proliferation rates as well as their suppressive effects on macrophage cytotoxic activity.

  5. Opposing Effects of Cyclooxygenase-2 (COX-2) on Estrogen Receptor β (ERβ) Response to 5α-Reductase Inhibition in Prostate Epithelial Cells.

    Science.gov (United States)

    Liu, Teresa T; Grubisha, Melanie J; Frahm, Krystle A; Wendell, Stacy G; Liu, Jiayan; Ricke, William A; Auchus, Richard J; DeFranco, Donald B

    2016-07-08

    Current pharmacotherapies for symptomatic benign prostatic hyperplasia (BPH), an androgen receptor-driven, inflammatory disorder affecting elderly men, include 5α-reductase (5AR) inhibitors (i.e. dutasteride and finasteride) to block the conversion of testosterone to the more potent androgen receptor ligand dihydrotestosterone. Because dihydrotestosterone is the precursor for estrogen receptor β (ERβ) ligands, 5AR inhibitors could potentially limit ERβ activation, which maintains prostate tissue homeostasis. We have uncovered signaling pathways in BPH-derived prostate epithelial cells (BPH-1) that are impacted by 5AR inhibition. The induction of apoptosis and repression of the cell adhesion protein E-cadherin by the 5AR inhibitor dutasteride requires both ERβ and TGFβ. Dutasteride also induces cyclooxygenase type 2 (COX-2), which functions in a negative feedback loop in TGFβ and ERβ signaling pathways as evidenced by the potentiation of apoptosis induced by dutasteride or finasteride upon pharmacological inhibition or shRNA-mediated ablation of COX-2. Concurrently, COX-2 positively impacts ERβ action through its effect on the expression of a number of steroidogenic enzymes in the ERβ ligand metabolic pathway. Therefore, effective combination pharmacotherapies, which have included non-steroidal anti-inflammatory drugs, must take into account biochemical pathways affected by 5AR inhibition and opposing effects of COX-2 on the tissue-protective action of ERβ.

  6. Cyclooxygenase-2 inhibitors in colorectal cancer prevention: point.

    Science.gov (United States)

    Arber, Nadir

    2008-08-01

    The limited success of current treatments for most advanced common malignancies highlights the importance of cancer prevention. Clinical trials on cyclooxygenase (COX) inhibitor drugs showed the potential of chemoprevention as a strategy for reducing cancer incidence, although not without associated side effects. The attractiveness of these drugs partly stems from an ability to engage multiple mechanisms of action by their potential to influence multiple components of the carcinogenesis pathway, from initiation to progression. There are two isoforms of the COX enzymes. COX-1 is constitutively expressed in normal tissues and serves as a "housekeeper" of mucosal integrity, whereas COX-2 is an immediate early response gene that is highly inducible by neoplastic and inflammatory stimuli. COX-2 is significantly overexpressed in colorectal neoplasms, making it an attractive therapeutic target. The drug market has been revolutionized by the development of preparations targeted selectively against COX-2, and a proof of concept has been achieved. Chemoprevention of colorectal cancer is already possible with celecoxib, but it is still not the ultimate drug of choice especially because of the cardiovascular risk associated with COX-2 inhibitors. Better patient selection and more effective and safer drugs are needed. Celecoxib is probably best used in a subset of individuals at moderate to high colorectal cancer risk and low risk of cardiovascular disease.

  7. COX-1 inhibitory effect of medicinal plants of Ghana

    DEFF Research Database (Denmark)

    Larsen, Birgitte HV; Soelberg, Jens; Jäger, Anna

    2015-01-01

    Plants used to treat inflammatory ailments, pain, fever and infections in Ghana, were tested for COX-1 inhibitory activity. Ethanolic extracts of 17 species were tested in a COX-1 assay. The extracts of Gardenia ternifolia, Thonningia sanguinea, Triumfetta rhomboidea, and the root of Zanthoxylum...... zanthoxyloides showed an inhibitory effect over 90% in the final concentration 0.1 μg/μL. The HPLC profiles indicated that the extracts of the four active species did not contain tannins. The observed in vitro activities support the use of some of the plant species in the traditional medicine system in Ghana....

  8. Highlights of the Latest Advances in Research on CDK Inhibitors

    Directory of Open Access Journals (Sweden)

    Jonas Cicenas

    2014-10-01

    Full Text Available Uncontrolled proliferation is the hallmark of cancer and other proliferative disorders and abnormal cell cycle regulation is, therefore, common in these diseases. Cyclin-dependent kinases (CDKs play a crucial role in the control of the cell cycle and proliferation. These kinases are frequently deregulated in various cancers, viral infections, neurodegenerative diseases, ischemia and some proliferative disorders. This led to a rigorous pursuit for small-molecule CDK inhibitors for therapeutic uses. Early efforts to block CDKs with nonselective CDK inhibitors led to little specificity and efficacy but apparent toxicity, but the recent advance of selective CDK inhibitors allowed the first successful efforts to target these kinases for the therapies of several diseases. Major ongoing efforts are to develop CDK inhibitors as monotherapies and rational combinations with chemotherapy and other targeted drugs.

  9. Cox-2 Inhibition Protects against Hypoxia/Reoxygenation-Induced Cardiomyocyte Apoptosis via Akt-Dependent Enhancement of iNOS Expression

    Directory of Open Access Journals (Sweden)

    Lei Pang

    2016-01-01

    Full Text Available The present study explored the potential causal link between ischemia-driven cyclooxygenase-2 (COX-2 expression and enhanced apoptosis during myocardial ischemia/reperfusion (I/R by using H9C2 cardiomyocytes and primary rat cardiomyocytes subjected to hypoxia/reoxygenation (H/R. The results showed that H/R resulted in higher COX-2 expression than that of controls, which was prevented by pretreatment with Helenalin (NFκB specific inhibitor. Furthermore, pretreatment with NS398 (COX-2 specific inhibitor significantly attenuated H/R-induced cell injury [lower lactate dehydrogenase (LDH leakage and enhanced cell viability] and apoptosis (higher Bcl2 expression and lower level of cleaved caspases-3 and TUNEL-positive cells in cardiomyocytes. The amelioration of posthypoxic apoptotic cell death was paralleled by significant attenuation of H/R-induced increases in proinflammatory cytokines [interleukin 6 (IL6 and tumor necrosis factor (TNFα] and reactive oxygen species (ROS production and by higher protein expression of phosphorylated Akt and inducible nitric oxide synthase (iNOS and enhanced nitric oxide production. Moreover, the application of LY294002 (Akt-specific inhibitor or 1400W (iNOS-selective inhibitor cancelled the cellular protective effects of NS398. Findings from the current study suggest that activation of NFκB during cardiomyocyte H/R induces the expression of COX-2 and that higher COX-2 expression during H/R exacerbates cardiomyocyte H/R injury via mechanisms that involve cross talks among inflammation, ROS, and Akt/iNOS/NO signaling.

  10. Identification and absolute configuration of dihydroxy-arachidonic acids formed by oxygenation of 5S-HETE by native and aspirin-acetylated COX-2

    Science.gov (United States)

    Mulugeta, Surafel; Suzuki, Takashi; Hernandez, Noemi Tejera; Griesser, Markus; Boeglin, William E.; Schneider, Claus

    2010-01-01

    Biosynthesis of the prostaglandin endoperoxide by the cyclooxygenase (COX) enzymes is accompanied by formation of a small amount of 11R-hydroxyeicosatetraenoic acid (HETE), 15R-HETE, and 15S-HETE as by-products. Acetylation of COX-2 by aspirin abrogates prostaglandin synthesis and triggers formation of 15R-HETE as the sole product of oxygenation of arachidonic acid. Here, we investigated the formation of by-products of the transformation of 5S-HETE by native COX-2 and by aspirin-acetylated COX-2 using HPLC-ultraviolet, GC-MS, and LC-MS analysis. 5S,15S- dihydroxy (di)HETE, 5S,15R-diHETE, and 5S,11R-diHETE were identified as by-products of native COX-2, in addition to the previously described di-endoperoxide (5S,15S-dihydroxy-9S,11R,8S,12S-diperoxy-6E,13E-eicosadienoic acid) as the major oxygenation product. 5S,15R-diHETE was the only product formed by aspirin-acetylated COX-2. Both 5,15-diHETE and 5,11-diHETE were detected in CT26 mouse colon carcinoma cells as well as in lipopolysaccharide-activated RAW264.7 cells incubated with 5S-HETE, and their formation was attenuated in the presence of the COX-2 specific inhibitor, NS-398. Aspirin-treated CT26 cells gave 5,15-diHETE as the most prominent product formed from 5S-HETE. 5S,15S-diHETE has been described as a product of the cross-over of 5-lipoxygenase (5-LOX) and 15-LOX activities in elicited rat mononuclear cells and human leukocytes, and our studies implicate cross-over of the 5-LOX and COX-2 pathways as an additional biosynthetic route. PMID:19752399

  11. Inhibition of COX-2 in Colon Cancer Modulates Tumor Growth and MDR-1 Expression to Enhance Tumor Regression in Therapy-Refractory Cancers In Vivo

    Directory of Open Access Journals (Sweden)

    Mahbuba Rahman

    2012-07-01

    Full Text Available Higher cyclooxygenase 2 (COX-2 expression is often observed in aggressive colorectal cancers (CRCs. Here, we attempt to examine the association between COX-2 expression in therapy-refractory CRC, how it affects chemosensitivity, and whether, in primary tumors, it is predictive of clinical outcomes. Our results revealed higher COX-2 expression in chemoresistant CRC cells and tumor xenografts. In vitro, the combination of either aspirin or celecoxib with 5-fluorouracil (5-FU was capable of improving chemosensitivity in chemorefractory CRC cells, but a synergistic effect with 5-FU could only be demonstrated with celecoxib. To examine the potential clinical significance of these observations, in vivo studies were undertaken, which also showed that the greatest tumor regression was achieved in chemoresistant xenografts after chemotherapy in combination with celecoxib, but not aspirin. We also noted that these chemoresistant tumors with higher COX-2 expression had a more aggressive growth rate. Given the dramatic response to a combination of celecoxib + 5-FU, the possibility that celecoxib may modulate chemosensitivity as a result of its ability to inhibit MDR-1 was examined. In addition, assessment of a tissue microarray consisting of 130 cases of CRCs revealed that, in humans, higher COX-2 expression was associated with poorer survival with a 68% increased risk of mortality, indicating that COX-2 expression is a marker of poor clinical outcome. The findings of this study point to a potential benefit of combining COX-2 inhibitors with current regimens to achieve better response in the treatment of therapy-refractory CRC and in using COX-2 expression as a prognostic marker to help identify individuals who would benefit the greatest from closer follow-up and more aggressive therapy.

  12. Inhibition of COX-2 in Colon Cancer Modulates Tumor Growth and MDR-1 Expression to Enhance Tumor Regression in Therapy-Refractory Cancers In Vivo12

    Science.gov (United States)

    Rahman, Mahbuba; Selvarajan, Krithika; Hasan, Mohammad R; Chan, Annie P; Jin, Chaoyang; Kim, Jieun; Chan, Simon K; Le, Nhu D; Kim, Young-Bae; Tai, Isabella T

    2012-01-01

    Higher cyclooxygenase 2 (COX-2) expression is often observed in aggressive colorectal cancers (CRCs). Here, we attempt to examine the association between COX-2 expression in therapy-refractory CRC, how it affects chemosensitivity, and whether, in primary tumors, it is predictive of clinical outcomes. Our results revealed higher COX-2 expression in chemoresistant CRC cells and tumor xenografts. In vitro, the combination of either aspirin or celecoxib with 5-fluorouracil (5-FU) was capable of improving chemosensitivity in chemorefractory CRC cells, but a synergistic effect with 5-FU could only be demonstrated with celecoxib. To examine the potential clinical significance of these observations, in vivo studies were undertaken, which also showed that the greatest tumor regression was achieved in chemoresistant xenografts after chemotherapy in combination with celecoxib, but not aspirin. We also noted that these chemoresistant tumors with higher COX-2 expression had a more aggressive growth rate. Given the dramatic response to a combination of celecoxib + 5-FU, the possibility that celecoxib may modulate chemosensitivity as a result of its ability to inhibit MDR-1 was examined. In addition, assessment of a tissue microarray consisting of 130 cases of CRCs revealed that, in humans, higher COX-2 expression was associated with poorer survival with a 68% increased risk of mortality, indicating that COX-2 expression is a marker of poor clinical outcome. The findings of this study point to a potential benefit of combining COX-2 inhibitors with current regimens to achieve better response in the treatment of therapy-refractory CRC and in using COX-2 expression as a prognostic marker to help identify individuals who would benefit the greatest from closer follow-up and more aggressive therapy. PMID:22904679

  13. Regulation of Matrix Metalloproteinase-2 Activity by COX-2-PGE2-pAKT Axis Promotes Angiogenesis in Endometriosis

    Science.gov (United States)

    Ray, Amlan K.; DasMahapatra, Pramathes; Swarnakar, Snehasikta

    2016-01-01

    Endometriosis is characterized by the ectopic development of the endometrium which relies on angiogenesis. Although studies have identified the involvement of different matrix metalloproteinases (MMPs) in endometriosis, no study has yet investigated the role of MMP-2 in endometriosis-associated angiogenesis. The present study aims to understand the regulation of MMP-2 activity in endothelial cells and on angiogenesis during progression of ovarian endometriosis. Histological and biochemical data showed increased expressions of vascular endothelial growth factor (VEGF), VEGF receptor-2, cycloxygenase (COX)-2, von Willebrand factor along with angiogenesis during endometriosis progression. Women with endometriosis showed decreased MMP-2 activity in eutopic endometrium as compared to women without endometriosis. However, ectopic ovarian endometrioma showed significantly elevated MMP-2 activity with disease severity. In addition, increased MT1MMP and decreased tissue inhibitors of metalloproteinases (TIMP)-2 expressions were found in the late stages of endometriosis indicating more MMP-2 activation with disease progression. In vitro study using human endothelial cells showed that prostaglandin E2 (PGE2) significantly increased MMP-2 activity as well as tube formation. Inhibition of COX-2 and/or phosphorylated AKT suppressed MMP-2 activity and endothelial tube formation suggesting involvement of PGE2 in regulation of MMP-2 activity during angiogenesis. Moreover, specific inhibition of MMP-2 by chemical inhibitor significantly reduced cellular migration, invasion and tube formation. In ovo assay showed decreased angiogenic branching upon MMP-2 inhibition. Furthermore, a significant reduction of lesion numbers was observed upon inhibition of MMP-2 and COX-2 in mouse model of endometriosis. In conclusion, our study establishes the involvement of MMP-2 activity via COX-2-PGE2-pAKT axis in promoting angiogenesis during endometriosis progression. PMID:27695098

  14. MEDV-13 for QSAR Studies on the COX-2 Inhibition by In domethacin Amides and Esters

    Institute of Scientific and Technical Information of China (English)

    LIU,Shu-Shen (刘树深); YIN,Chun-Sheng(印春生); SHI,Yun-Yu(施蕴渝); CAI,Shao-Xi(蔡绍皙); LI,Zhi-Liang(李志良)

    2001-01-01

    A molecular electronegativity distance vector based on 13 atomic types (MEDV-13), is a descriptor for predicting the biological activities of molecules based on the quantitative structure-activity relationship (QSAR). The MEDV-13 with 91 descriptors is employed to describe the structures of a series of selective cydooxygenase-2 (COX-2) inhibitors inchuding 16 indomethacin and its amide and ester derivatives (ImAE). A principal component regression (PCR) is used to derive a QSAR model relating the biological activities expressed by pIC50 values to the MEDV-13. With the number of principal components of 6, the correlation coeffcient (R) and the root mean square error (RMS) are 0.9245 and 0.1682 in modeling stage, and 0.8417 and 0.2389 in leave-one-out prediction step, respectively.

  15. Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists.

    Science.gov (United States)

    Kumar, V; Clark, M J; Traynor, J R; Lewis, J W; Husbands, S M

    2014-08-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse.

  16. Non-selective beta-adrenergic blockade prevents reduction of the cerebral metabolic ratio during exhaustive exercise in humans

    DEFF Research Database (Denmark)

    Larsen, T.S.; Rasmussen, P.; Overgaard, M.

    2008-01-01

    of a non-selective beta-adrenergic (beta(1) + beta(2)) receptor antagonist (propranolol) reduced heart rate (69 +/- 8 to 58 +/- 6 beats min(-1)) and exercise capacity (239 +/- 42 to 209 +/- 31 W; P exercise with propranolol, the increase in a......Intense exercise decreases the cerebral metabolic ratio of oxygen to carbohydrates [O(2)/(glucose + (1/2)lactate)], but whether this ratio is influenced by adrenergic stimulation is not known. In eight males, incremental cycle ergometry increased arterial lactate to 15.3 +/- 4.2 mm (mean +/- s.......d.) and the arterial-jugular venous (a-v) difference from -0.02 +/- 0.03 mm at rest to 1.0 +/- 0.5 mm (P increased from 0.7 +/- 0.3 to 0.9 +/- 0.1 mm (P

  17. A Computer Simulation of Progesterone and Cox2 Inhibitor Treatment for Preterm Labor

    OpenAIRE

    Ozlem Equils; Priya Nambiar; Hobel, Calvin J.; Roger Smith; Simmons, Charles F.; Shireen Vali

    2010-01-01

    BACKGROUND: Sufficient information from in vitro and in vivo studies has become available to permit computer modeling of the processes that occur in the myometrium during labor. This development allows the in silico investigation of pathological mechanisms and the trialing of potential treatments. METHODS/RESULTS: Based on the human literature, we developed a computer model of the immune-endocrine environment of the myometrial cell. The interactions between molecules are represented by differ...

  18. Isolation, synthesis and characterization of impurities in celecoxib, a COX-2 inhibitor.

    Science.gov (United States)

    Satyanarayana, U; Rao, D Sreenivas; Kumar, Y Ravindra; Babu, J Moses; Kumar, P Rajender; Reddy, J Tirupathi

    2004-06-29

    During the impurity profile of Celecoxib, four polar impurities (impurity I, II, III and IV) and one non-polar impurity (impurity V) with respect to Celecoxib were detected by HPLC. LC-MS has been employed in this impurity profile study. The three polar impurities (I, II and III) were found to be process related while impurities (IV and V) turned out to be isomers. The impurities III, IV and V were isolated with the help of preparative HPLC. The structure of impurities III, IV (ortho-isomer) and V (regio-isomer) were confirmed as [5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazole], 4-[5-(2'-methyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide, and 4-[4-(4'-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide, respectively. The structures of impurities I, II, III and IV were confirmed by synthesis and structural characterization using spectral data. However, the impurity V was not synthesized.

  19. Efficacy of COX-2 inhibitors in a case of congenital nephrogenic diabetes insipidus.

    NARCIS (Netherlands)

    Soylu, A.; Kasap, B.; Ogun, N.; Ozturk, Y.; Turkmen, M.; Hoefsloot, L.H.; Kavukcu, S.

    2005-01-01

    A 17-month-old boy presented with failure to thrive, polyuria, and vomiting. He had been diagnosed clinically with nephrogenic diabetes insipidus and treated by amiloride and hydrochlorothiazide combination without a satisfactory outcome at another center since 1 year of age. The diagnosis was confi

  20. DFT analysis and spectral characteristics of Celecoxib a potent COX-2 inhibitor

    Science.gov (United States)

    Vijayakumar, B.; Kannappan, V.; Sathyanarayanamoorthi, V.

    2016-10-01

    Extensive quantum mechanical studies are carried out on Celecoxib (CXB), a new generation drug to understand the vibrational and electronic spectral characteristics of the molecule. The vibrational frequencies of CXB are computed by HF and B3LYP methods with 6-311++G (d, p) basis set. The theoretical scaled vibrational frequencies have been assigned and they agreed satisfactorily with experimental FT-IR and Raman frequencies. The theoretical maximum wavelength of absorption of CXB are calculated in water and ethanol by TD-DFT method and these values are compared with experimentally determined λmax values. The spectral and Natural bonds orbital (NBO) analysis in conjunction with spectral data established the presence of intra molecular interactions such as mesomeric, hyperconjugative and steric effects in CXB. The electron density at various positions and reactivity descriptors of CXB indicate that the compound functions as a nucleophile and establish that aromatic ring system present in the molecule is the site of drug action. Electronic distribution and HOMO - LUMO energy values of CXB are discussed in terms of intra-molecular interactions. Computed values of Mulliken charges and thermodynamic properties of CXB are reported.

  1. The increased level of COX-dependent arachidonic acid metabolism in blood platelets from secondary progressive multiple sclerosis patients.

    Science.gov (United States)

    Morel, Agnieszka; Miller, Elzbieta; Bijak, Michal; Saluk, Joanna

    2016-09-01

    Platelet activation is increasingly postulated as a possible component of the pathogenesis of multiple sclerosis (MS), especially due to the increased risk of cardiovascular events in MS. Arachidonic acid cascade metabolized by cyclooxygenase (COX) is a key pathway of platelet activation. The aim of our study was to investigate the COX-dependent arachidonic acid metabolic pathway in blood platelets from secondary progressive multiple sclerosis (SP MS) patients. The blood samples were obtained from 50 patients (man n = 22; female n = 28), suffering from SP MS, diagnosed according to the revised McDonald criteria. Platelet aggregation was measured in platelet-rich plasma after arachidonic acid stimulation. The level of COX activity and thromboxane B2 concentration were determined by ELISA method. Lipid peroxidation was assessed by measuring the level of malondialdehyde. The results were compared with a control group of healthy volunteers. We found that blood platelets obtained from SP MS patients were more sensitive to arachidonic acid and their response measured as platelet aggregation was stronger (about 14 %) relative to control. We also observed a significantly increased activity of COX (about 40 %) and synthesis of thromboxane B2 (about 113 %). The generation of malondialdehyde as a marker of lipid peroxidation was about 10 % higher in SP MS than in control. Cyclooxygenase-dependent arachidonic acid metabolism is significantly increased in blood platelets of patients with SP MS. Future clinical studies are required to recommend the use of low-dose aspirin, and possibly other COX inhibitors in the prevention of cardiovascular risk in MS.

  2. Artesunate Induces Apoptosis of Bladder Cancer Cells by miR-16 Regulation of COX-2 Expression

    Directory of Open Access Journals (Sweden)

    Wei Zuo

    2014-08-01

    Full Text Available Bladder cancer is the most common malignant tumor of the urinary tract and remains one of the major causes of cancer death worldwide. In this study, we investigated the effect and mechanism of Artesunate (ART, a traditional Chinese medicine, on inducing apoptosis of human bladder cancer cells. In vivo antitumor activity was investigated in bladder cancer in rat by subcutaneous injection of different concentration of ART. The effect of ART on growth inhibition and apoptosis of bladder cancer cells was evaluated using dimethylthiazoly-2,5-diphenyltetrazolium bromide (MTT assay and flow cytometry analysis, respectively. Cyclooxygenase-2 (COX-2 and miR-16 expression levels were determined with real-time PCR. The concentrations of prostaglandin E2 (PGE2 in the supernatants of bladder cancer cells were measured with an ELISA kit. The miR-16 inhibitor or mimic were transfected into cells to up- or down-regulate miR-16 expression. ART efficiently inhibited orthotopic tumor growth in the bladder cancer rat, which is accompanied with an increase of miR-16 expression and a decrease of COX-2 expression. In vitro, ART could induce cytotoxicity and apoptosis in bladder cancer cells, but presented a much lighter toxicity effect against normal human urothelial cells. ART significantly increased miR-16 expression and decreased the expression of COX-2 and the production of PGE2. More importantly, down-regulation of miR-16 expression could reverse the effect of ART on apoptosis and COX-2 expression in bladder cells. Moreover, exogenous PGE2 could inhibit apoptosis of bladder cancer cells treated with ART. In conclusion, ART can elicit an anti-tumor effect against bladder cancer by up-regulation of miR-16 expression, which resulted in the decrease of COX-2 expression and PGE2 production. Hence, ART might be an effective drug for the treatment of bladder cancer.

  3. Post-translational regulation of COX2 activity by FYN in prostate cancer cells

    OpenAIRE

    Alexanian, Anna; Miller, Bradley; Chesnik, Marla; Mirza, Shama; Sorokin, Andrey

    2014-01-01

    While increased COX2 expression and prostaglandin levels are elevated in human cancers, the mechanisms of COX2 regulation at the post-translational level are unknown. Initial observation that COX2 forms adduct with non-receptor tyrosine kinase FYN, prompted us to study FYN-mediated post-translational regulation of COX2. We found that FYN increased COX2 activity in prostate cancer cells DU145, independent of changes in COX2 or COX1 protein expression levels. We report that FYN phosphorylates h...

  4. A time inhomogeneous Cox-Ingersoll-Ross diffusion with jumps

    CERN Document Server

    Hoepfner, Reinhard

    2009-01-01

    We consider a time inhomogeneous Cox-Ingersoll-Ross diffusion with positive jumps. We exploit a branching property to prove existence of a unique strong solution under a restrictive condition on the jump measure. We give Laplace transforms for the transition probabilities, with an interpretation in terms of limits of mixtures over Gamma laws.

  5. Role of COX-2 in microcirculatory disturbance in experimental pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Wen-Wei Yan; Zong-Guang Zhou; You-Dai Chen; Hong-Kai Gao

    2004-01-01

    AIM: To elucidate the role of COX-2 in the development of capillary leakage in rats with acute interstitial pancreatitis.METHODS: Rats with acute interstitial pancreatitis were induced by caerulein subcutaneous injection. Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the gene expression of COX-2 in pancreatic tissues, spectrophotometry was used to assay the parameters of acute pancreatitis such as the serum amylase and plasma myeloperoxidase, and determination of capillary permeability in the pancreas by quantifying the permeability index (PI) assisted response of pancreatic microvascular via intravital fluorescence microscope video image analysis system.RESULTS: A significant increase of COX-2 expression,elevation of serum amylase, and plasma myeloperoxidase were detected in rats with acute edematous pancreatitis compared with control rats. The changes of pancreatic microvascular after caerulein injection were as following: (a) the decrease of pancreatic capillary blood flow (4th h,0.56±0.09 nL/min, P<0.05; 8 th h, 0.34±0.10 nL/min, P<0.001);(b) reduction of functional capillary density (4 th h, 381±9 cm-1,P>0.05; 8th h, 277±13 cm-1 P<0.001); (c) irregular and intermittent capillary perfusion was observed at the 8th h and these vessels were also prone to permeation.CONCLUSION: COX-2 plays an important role in mediating capillary permeability in pancreatitis, thereby contributing to capillary leakage.

  6. Intravenous glutamine enhances COX-2 activity giving cardioprotection.

    LENUS (Irish Health Repository)

    McGuinness, Jonathan

    2009-03-01

    Preconditioning, a highly evolutionary conserved endogenous protective response, provides the most powerful form of anti-infarct protection known. We investigated whether acute intravenous glutamine, through an effect on cyclooxygenase (COX)-2 and heat shock protein (HSP) 72, might induce preconditioning.

  7. Cilantro microbiome before and after nonselective pre-enrichment for Salmonella using 16S rRNA and metagenomic sequencing.

    Science.gov (United States)

    Jarvis, Karen G; White, James R; Grim, Christopher J; Ewing, Laura; Ottesen, Andrea R; Beaubrun, Junia Jean-Gilles; Pettengill, James B; Brown, Eric; Hanes, Darcy E

    2015-08-12

    Salmonella enterica is a common cause of foodborne gastroenteritis in the United States and is associated with outbreaks in fresh produce such as cilantro. Salmonella culture-based detection methods are complex and time consuming, and improvments to increase detection sensitivity will benefit consumers. In this study, we used 16S rRNA sequencing to determine the microbiome of cilantro. We also investigated changes to the microbial community prior to and after a 24-hour nonselective pre-enrichment culture step commonly used by laboratory analysts to resuscitate microorganisms in foods suspected of contamination with pathogens. Cilantro samples were processed for Salmonella detection according to the method in the United States Food and Drug Administration Bacteriological Analytical Manual. Genomic DNA was extracted from culture supernatants prior to and after a 24-hour nonselective pre-enrichment step and 454 pyrosequencing was performed on 16S rRNA amplicon libraries. A database of Enterobacteriaceae 16S rRNA sequences was created, and used to screen the libraries for Salmonella, as some samples were known to be culture positive. Additionally, culture positive cilantro samples were examined for the presence of Salmonella using shotgun metagenomics on the Illumina MiSeq. Time zero uncultured samples had an abundance of Proteobacteria while the 24-hour enriched samples were composed mostly of Gram-positive Firmicutes. Shotgun metagenomic sequencing of Salmonella culture positive cilantro samples revealed variable degrees of Salmonella contamination among the sequenced samples. Our cilantro study demonstrates the use of high-throughput sequencing to reveal the microbiome of cilantro, and how the microbiome changes during the culture-based protocols employed by food safety laboratories to detect foodborne pathogens. Finding that culturing the cilantro shifts the microbiome to a predominance of Firmicutes suggests that changing our culture-based methods will improve

  8. Stretch-activated nonselective cation, Cl- and K+ channels in apical membrane of epithelial cells of Reissner's membrane.

    Science.gov (United States)

    Yeh, T H; Tsai, M C; Lee, S Y; Hsu, M M; Tran Ba Huy, P

    1997-07-01

    Ion channels on the apical membrane of epithelial cells (the surface facing the endolymph) of acutely isolated Reissner's membrane from guinea-pig cochlea were investigated by using patch-clamp technique in cell-attached and inside-out configurations. Three types of ion channel were identified: namely, a stretch-activated nonselective cation, a chloride and a potassium channel. When the pipette was filled with high-K+ endolymph-like solution, the most significant channel activity was nonselective cation channels (85/110, 77% patches). The current versus voltage relationship was linear with a unitary conductance of 22.1 +/- 0.4 pS and reversal potential (Vr) of 2.3 +/- 0.8 mV (n = 18). The channel exhibited a lower conductance (14.0 +/- 0.6 pS, n = 8) to Ca2+. The open probability was low (NPo approximately 0.1) in cell-attached configuration under +60 mV pipette potential and increased when the membrane was stretched with negative pressure. The channel was blocked by 10 microM extracellular Gd3+. The two other types of channels were a small voltage-sensitive Cl- channel (6.0 +/- 0.3 pS; 91/99, 92% patches) and a K+ channel (approximately 30 pS; 29/191, 15% patches). These channels might play roles in the regulation of cell volume, in balancing the hydrostatic pressure across Reissner's membrane and in maintaining the electrochemical composition of endolymph.

  9. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors.

    Science.gov (United States)

    Masferrer, J L; Leahy, K M; Koki, A T; Zweifel, B S; Settle, S L; Woerner, B M; Edwards, D A; Flickinger, A G; Moore, R J; Seibert, K

    2000-03-01

    We provide evidence that cyclooxygenase (COX)-2-derived prostaglandins contribute to tumor growth by inducing newly formed blood vessels (neoangiogenesis) that sustain tumor cell viability and growth. COX-2 is expressed within human tumor neovasculature as well as in neoplastic cells present in human colon, breast, prostate, and lung cancer biopsy tissue. COX-1 is broadly distributed in normal, as well as in neoplastic, tissues. The contribution of COX-2 to human tumor growth was indicated by the ability of celecoxib, an agent that inhibits the COX-2 enzyme, to suppress growth of lung and colon tumors implanted into recipient mice. Mechanistically, celecoxib demonstrated a potent antiangiogenic activity. In a rat model of angiogenesis, we observe that corneal blood vessel formation is suppressed by celecoxib, but not by a COX-1 inhibitor. These and other data indicate that COX-2 and COX-2-derived prostaglandins may play a major role in development of cancer through numerous biochemical mechanisms, including stimulation of tumor cell growth and neovascularization. The ability of celecoxib to block angiogenesis and suppress tumor growth suggests a novel application of this anti-inflammatory drug in the treatment of human cancer.

  10. Selective cyclooxygenase-2 (COX-2) inhibition reduces proteinuria in renal patients

    NARCIS (Netherlands)

    Vogt, Liffert; de Zeeuw, Dick; Woittiez, Arend Jan J.; Navis, Gerjan

    Background. Renoprotection is predicted by the antiproteinuric efficacy of a pharmacological agent. Nonsteroidal anti-inflammatory drugs (NSAIDs) interfering non-selectively in the prostaglandin system have strong antiproteinuric potency without reduction of systemic blood pressure. The effect of

  11. Cadmium-induced calcium release and prostaglandin E[sub 2] production in neonatal mouse calvaria are dependent on cox-2 induction and protein kinase C activation

    Energy Technology Data Exchange (ETDEWEB)

    Romare, A. (Department of Pharmacology, Faculty of Health Sciences, Univ. of Linkoeping (Sweden)); Lundholm, C.E. (Department of Pharmacology, Univ. of Linkoeping (Sweden) Astra Haessle AB, Regulatory Affairs, Moendal (Sweden))

    The mechanisms by which cadmium (Cd) causes skeletal impairment have not been fully clarified. Release of calcium from neonatal mouse calvaria in organ culture is stimulated by submicromolar concentrations of Cd, an effect that is associated with increased production of prostaglandin E[sub 2] (PGE[sub 2]). The prostaglandin-synthesising enzyme cyclooxygenase (cox) exists in two forms, one constitutive (cox-1) and the other inducible (cox-2). Cox-2 can be induced by mitogenic stimuli and inflammatory cytokines, such as parathyroid hormone (PTH), interleukin-1[alpha] and tumour necrosis factor-[alpha]. Cd potently activates protein kinase C (PKC), which in turn induces cox-2 production in several cell types. Our aim was to determine whether Cd-induced Ca release and PGE[sub 2] production in neonatal mouse calvaria involve induction of cox-2 and, if so, to ascertain whether that effect is mediated by activation of PKC. Cd dose-dependently stimulated Ca release from cultured neonatal mouse calvaria, with a maximal effect at 0.4-0.8 [mu]M. Different sensitivity was observed to Cd-induced Ca release between two breeds of mice suggesting that the susceptibility to Cd may be genetically determined. Dexamethasone (10 [mu]M) added to the culture medium abolished the Ca releasing effect of Cd, an effect not overcome by addition of arachidonic acid (10 [mu]M). The cox-2-selective inhibitors NS-398 and DFU and the less selective inhibitor meloxicam, potently impeded Cd-induced Ca release (IC[sub 50] of 1 nM, 41 nM and 7 nM, respectively) and calvarial production of PGE[sub 2]. Cd-induced and phorbol 12-myristate 13-acetate (PMA; 20 nM)-induced Ca release was inhibited by the PKC inhibitor calphostin C (0.5 [mu]M) and by NS-398. The effects of PMA and Cd on Ca release were not additive, suggesting that both operated via the PKC pathway. We suggest that Cd-induced Ca release from neonatal mouse calvaria in culture depends on induction of cox-2 that occurs via the PKC signalling

  12. Cadmium-induced calcium release and prostaglandin E{sub 2} production in neonatal mouse calvaria are dependent on cox-2 induction and protein kinase C activation

    Energy Technology Data Exchange (ETDEWEB)

    Romare, A. [Department of Pharmacology, Faculty of Health Sciences, Univ. of Linkoeping (Sweden); Lundholm, C.E. [Department of Pharmacology, Univ. of Linkoeping (Sweden)]|[Astra Haessle AB, Regulatory Affairs, Moendal (Sweden)

    1999-06-01

    The mechanisms by which cadmium (Cd) causes skeletal impairment have not been fully clarified. Release of calcium from neonatal mouse calvaria in organ culture is stimulated by submicromolar concentrations of Cd, an effect that is associated with increased production of prostaglandin E{sub 2} (PGE{sub 2}). The prostaglandin-synthesising enzyme cyclooxygenase (cox) exists in two forms, one constitutive (cox-1) and the other inducible (cox-2). Cox-2 can be induced by mitogenic stimuli and inflammatory cytokines, such as parathyroid hormone (PTH), interleukin-1{alpha} and tumour necrosis factor-{alpha}. Cd potently activates protein kinase C (PKC), which in turn induces cox-2 production in several cell types. Our aim was to determine whether Cd-induced Ca release and PGE{sub 2} production in neonatal mouse calvaria involve induction of cox-2 and, if so, to ascertain whether that effect is mediated by activation of PKC. Cd dose-dependently stimulated Ca release from cultured neonatal mouse calvaria, with a maximal effect at 0.4-0.8 {mu}M. Different sensitivity was observed to Cd-induced Ca release between two breeds of mice suggesting that the susceptibility to Cd may be genetically determined. Dexamethasone (10 {mu}M) added to the culture medium abolished the Ca releasing effect of Cd, an effect not overcome by addition of arachidonic acid (10 {mu}M). The cox-2-selective inhibitors NS-398 and DFU and the less selective inhibitor meloxicam, potently impeded Cd-induced Ca release (IC{sub 50} of 1 nM, 41 nM and 7 nM, respectively) and calvarial production of PGE{sub 2}. Cd-induced and phorbol 12-myristate 13-acetate (PMA; 20 nM)-induced Ca release was inhibited by the PKC inhibitor calphostin C (0.5 {mu}M) and by NS-398. The effects of PMA and Cd on Ca release were not additive, suggesting that both operated via the PKC pathway. We suggest that Cd-induced Ca release from neonatal mouse calvaria in culture depends on induction of cox-2 that occurs via the PKC signalling

  13. COX-2 gene promoter haplotypes and prostate cancer risk.

    Science.gov (United States)

    Panguluri, Ramesh C K; Long, Layron O; Chen, Weidong; Wang, Songping; Coulibaly, Aoua; Ukoli, Flora; Jackson, Aaron; Weinrich, Sally; Ahaghotu, Chiledum; Isaacs, William; Kittles, Rick A

    2004-06-01

    Cyclooxygenase-2 (COX-2) is a key rate-limiting enzyme that converts arachidonic acid into pro-inflammatory prostaglandins. COX-2 expression is strongly correlated with increased tumor microvasculature density and plays an important role in inhibiting apoptosis, stimulating angiogenesis and promoting tumor cell metastasis and invasion. However, little is known about the role that sequence variation of the COX-2 gene contributes to prostate cancer. Thus, we searched for polymorphisms in the promoter region of the COX-2 gene using denaturing high-performance liquid chromatography. Four single nucleotide polymorphisms (SNPs), -1285A/G, -1265G/A, -899G/C and -297C/G, were detected and confirmed by direct sequencing. Three of the SNPs in the promoter region of COX-2 gene create at least three putative transcription factor binding sites and eliminate CCAAT/enhancer binding protein alpha (C/EBP alpha) and NF-kappa B binding sites. A case-control study of the four SNPs in African American (n = 288), Bini Nigerian (n = 264) and European American (n = 184) prostate cancer cases and age-matched controls revealed that SNP -297G was associated with a decreased risk for prostate cancer [odds ratio (OR) = 0.49; CI = 0.2-0.9; P = 0.01]. The effect on risk was observed in both African Americans (OR = 0.51; CI = 0.2-0.9; P = 0.01) and European Americans (OR = 0.33; CI = 0.1-0.9; P = 0.02). In addition, SNPs -1265A and -899C were associated with increased prostate cancer risk in African Americans (OR = 2.72; CI = 1.3-5.8; P = 0.007 and OR = 3.67; CI = 1.4-9.9; P = 0.007, respectively). Haplotype analyses revealed modest effects on susceptibility to prostate cancer across populations. Haplotype GGCC conferred increased risk in the African American and Nigerian populations. Conversely, haplotype AGGG exhibited a negative association with prostate cancer risk in African Americans (OR = 0.4; CI = 0.1-0.9; P = 0.02) and European Americans (OR = 0.2; CI = 0.1-0.9; P = 0.03). These data

  14. Evidence for a pro-proliferative feedback loop in prostate cancer: the role of Epac1 and COX-2-dependent pathways.

    Directory of Open Access Journals (Sweden)

    Uma Kant Misra

    Full Text Available OBJECTIVE: In human prostate cancer cells, a selective Epac agonist, 8-CPT-2Me-cAMP, upregulates cell proliferation and survival via activation of Ras-MAPK and PI- 3-kinase-Akt-mTOR signaling cascades. Here we examine the role of inflammatory mediators in Epac1-induced cellular proliferation by determining the expression of the pro-inflammatory markers p-cPLA2, COX-2, and PGE2 in prostate cancer cells treated with 8-CPT-2Me-cAMP. METHODS: We employed inhibitors of COX-2, mTORC1, and mTORC2 to probe cyclic AMP-dependent pathways in human prostate cancer cells. RNAi targeting Epac1, Raptor, and Rictor was also employed in these studies. RESULTS: 8-CPT-2Me-cAMP treatment caused a 2-2.5-fold increase of p-cPLA2(S505, COX-2, and PGE2 levels in human prostate cancer cell lines. Pretreatment of cells with the COX-2 inhibitor SC-58125 or the EP4 antagonist AH-23848, or with an inhibitor of mTORC1 and mTORC2, Torin1, significantly reduced the Epac1-dependent increase of p-cPLA2 and COX-2, p-S6-kinase(T389, and p-AKT(S473. In addition, Epac1-induced protein and DNA synthesis were greatly reduced upon pretreatment of cells with either COX-2, EP4, or mTOR inhibitors. Transfection of prostate cancer cells with Epac1 dsRNA, Raptor dsRNA, or Rictor dsRNA profoundly reduced Epac1-dependent increases in p-cPLA2 and COX-2. CONCLUSION: We show that Epac1, a downstream effector of cAMP, functions as a pro-inflammatory modulator in prostate cancer cells and promotes cell proliferation and survival by upregulating Ras-MAPK, and PI 3-kinase-Akt-mTOR signaling.

  15. Cell swelling activates K+ and Cl- channels as well as nonselective, stretch-activated cation channels in ehrlich ascites tumor cells

    DEFF Research Database (Denmark)

    Christensen, Ove; Hoffmann, Else Kay

    1992-01-01

    Cell-attached patch-clamp recordings from Ehrlich ascites tumor cells reveal nonselective cation channels which are activated by mechanical deformation of the membrane. These channels are seen when suction is applied to the patch pipette or after osmotic cell swelling. The channel activation does...

  16. Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure

    DEFF Research Database (Denmark)

    Mookerjee, Rajeshwar P; Pavesi, Marco; Thomsen, Karen Louise

    2016-01-01

    BACKGROUND AND AIMS: Non-selective beta-blockers (NSBBs) have been shown to have deleterious outcomes in patients with refractory ascites, alcoholic hepatitis and spontaneous bacterial peritonitis leading many physicians to stop the drug in these cases. Acute on chronic liver failure (ACLF...

  17. Growth characteristics and ion contents of non-selected and salt-selected callus lines of highbush blueberry (Vacdnium corymbosum) cultivars Blue Crop and Denise Blue.

    Science.gov (United States)

    Muralitharan, M S; Van Steveninck, R F; Chandler, S E

    1990-07-01

    Non-selected and sodium chloride selected callus lines of Vacdnium corymbosum L.cv Blue Crop and cv. Denise Blue were grown on media supplemented with 0-100 mM NaCl. For both cultivars, fresh weight and dry weight yields were greater in selected lines on all levels of NaCl. Selected lines of Blue Crop displayed better growth than selected lines of Denise Blue at most concentrations of NaCl. Internal Na(+) and Cl(-) concentrations in selected and non-selected lines of both cultivars increased as external concentration was raised. However, selected lines of Blue Crop and Denise Blue accumulated more Na(+) and Cl(-) than non-selected lines. Selected lines of both cultivars maintained higher levels of K(+) than non-selected lines on all external NaCl levels. Selected lines of Blue Crop had higher levels of Na(+) and Cl(-) than that of Denise Blue. The results suggest Na(+) and Cl(-) accumulation could be a mechanism allowing better growth in selected lines at moderate salinity levels (50-75 mM NaCl).

  18. Comparison of subtypes of Listeria monocytogenes isolates from naturally contaminated watershed samples using a combination of non-selective and selective enrichment methods

    Science.gov (United States)

    Two enrichment methods for Listeria monocytogenes using Immuno Magnetic Separation were tested to determine if they selected the same subtypes of isolates. Both methods included a non-selective enrichment and one included subculture in Fraser Broth. Naturally contaminated watershed samples from the ...

  19. Multivariate Product-Shot-noise Cox Point Process Models

    DEFF Research Database (Denmark)

    Jalilian, Abdollah; Guan, Yongtao; Mateu, Jorge

    We introduce a new multivariate product-shot-noise Cox process which is useful for model- ing multi-species spatial point patterns with clustering intra-specific interactions and neutral, negative or positive inter-specific interactions. The auto and cross pair correlation functions of the proces...... can be obtained in closed analytical forms and approximate simulation of the process is straightforward. We use the proposed process to model interactions within and among five tree species in the Barro Colorado Island plot.......We introduce a new multivariate product-shot-noise Cox process which is useful for model- ing multi-species spatial point patterns with clustering intra-specific interactions and neutral, negative or positive inter-specific interactions. The auto and cross pair correlation functions of the process...

  20. Jackknifed random weighting for Cox proportional hazards model

    Institute of Scientific and Technical Information of China (English)

    LI Xiao; WU YaoHua; TU DongSheng

    2012-01-01

    The Cox proportional hazards model is the most used statistical model in the analysis of survival time data.Recently,a random weighting method was proposed to approximate the distribution of the maximum partial likelihood estimate for the regression coefficient in the Cox model.This method was shown not as sensitive to heavy censoring as the bootstrap method in simulation studies but it may not be second-order accurate as was shown for the bootstrap approximation.In this paper,we propose an alternative random weighting method based on one-step linear jackknife pseudo values and prove the second accuracy of the proposed method.Monte Carlo simulations are also performed to evaluate the proposed method for fixed sample sizes.

  1. Prostanoids in tumor angiogenesis: therapeutic intervention beyond COX-2.

    Science.gov (United States)

    Salvado, M Dolores; Alfranca, Arántzazu; Haeggström, Jesper Z; Redondo, Juan Miguel

    2012-04-01

    Prostanoids regulate angiogenesis in carcinoma and chronic inflammatory disease progression. Although prostanoid biosynthetic enzymes and signaling have been extensively analyzed in inflammation, little is known about how prostanoids mediate tumor-induced angiogenesis. Targeted cyclooxygenase (COX)-2 inhibition in tumor, stromal and endothelial cells is an attractive antiangiogenic strategy; however, the associated cardiovascular side effects have led to the development of a new generation of nonsteroidal anti-inflammatory drugs (NSAIDs) acting downstream of COX. These agents target terminal prostanoid synthases and prostanoid receptors, which may also include several peroxisome proliferator-activated receptors (PPARs). Here, we discuss the role of prostanoids as modulators of tumor angiogenesis and how prostanoid metabolism reflects complex cell-cell crosstalk that determines tumor growth. Finally, we discuss the potential of new NSAIDs for the treatment of angiogenesis-dependent tumor development.

  2. (4-Piperidinyl)-piperazine: a new platform for acetyl-CoA carboxylase inhibitors.

    Science.gov (United States)

    Chonan, Tomomichi; Oi, Takahiro; Yamamoto, Daisuke; Yashiro, Miyoko; Wakasugi, Daisuke; Tanaka, Hiroaki; Ohoka-Sugita, Ayumi; Io, Fusayo; Koretsune, Hiroko; Hiratate, Akira

    2009-12-01

    Acetyl-CoA carboxylases (ACCs), the rate limiting enzymes in de novo lipid synthesis, play important roles in modulating energy metabolism. The inhibition of ACC has demonstrated promising therapeutic potential for treating obesity and type 2 diabetes mellitus in transgenic mice and preclinical animal models. We describe herein the synthesis and structure-activity relationships of a series of disubstituted (4-piperidinyl)-piperazine derivatives as a new platform for ACC1/2 non-selective inhibitors.

  3. Meloxicam suppresses hepatocellular carcinoma cell proliferation and migration by targeting COX-2/PGE2-regulated activation of the β-catenin signaling pathway.

    Science.gov (United States)

    Li, Tao; Zhong, Jingtao; Dong, Xiaofeng; Xiu, Peng; Wang, Fuhai; Wei, Honglong; Wang, Xin; Xu, Zongzhen; Liu, Feng; Sun, Xueying; Li, Jie

    2016-06-01

    Recurrence and metastasis are the two leading causes of poor prognosis of hepatocellular carcinoma (HCC) patients. Cyclooxygenase (COX)-2 is overexpressed in many types of cancers including HCC and promotes its metastasis. Meloxicam is a selective COX-2 inhibitor that has been reported to exert an anti-proliferation and invasion/migration response in various tumors. In this study, we examined the role of meloxicam on HCC cell proliferation and migration and explored the molecular mechanisms underlying this effect. We found that meloxicam inhibited HCC cell proliferation and had a cell cycle arrest effect in human HCC cells. Furthermore, meloxicam suppressed the ability of HCC cells expressing higher levels of COX-2 and prostaglandin E2 (PGE2) to migration via potentiating expression of E-cadherin and alleviating expression of matrix metalloproteinase (MMP)-2 and -9. COX-2/PGE2 has been considered to activate the β-catenin signaling pathway which promotes cancer cell migration. We found that treatment with PGE2 significantly enhanced nuclear accumulation of β-catenin and the activation of GSK3β which could be reversed by meloxicam in HCC cells. We also observed that HCC cell migration and upregulation of the level of MMP-2/9 and downregulation of E-cadherin induced by PGE2 were suppressed by FH535, an inhibitor of β-catenin. Taken together, these findings provide a new treatment strategy against HCC proliferation and migration.

  4. Lasiodin inhibits proliferation of human nasopharyngeal carcinoma cells by simultaneous modulation of the Apaf-1/caspase, AKT/MAPK and COX-2/NF-κB signaling pathways.

    Directory of Open Access Journals (Sweden)

    Lianzhu Lin

    Full Text Available Rabdosia serra has been widely used for the treatment of the various human diseases. However, the antiproliferative effects and underlying mechanisms of the compounds in this herb remain largely unknown. In this study, an antiproliferative compound against human nasopharyngeal carcinoma (NPC cells from Rabdosia serra was purified and identified as lasiodin (a diterpenoid. The treatment with lasiodin inhibited cell viability and migration. Lasiodin also mediated the cell morphology change and induced apoptosis in NPC cells. The treatment with lasiodin induced the Apaf-1 expression, triggered the cytochrome-C release, and stimulated the PARP, caspase-3 and caspase-9 cleavages, thereby activating the apoptotic pathways. The treatment with lasiodin also significantly inhibited the phosphorylations of the AKT, ERK1/2, p38 and JNK proteins. The pretreatment with the AKT or MAPK-selective inhibitors considerably blocked the lasiodin-mediated inhibition of cell proliferation. Moreover, the treatment with lasiodin inhibited the COX-2 expression, abrogated NF-κB binding to the COX-2 promoter, and promoted the NF-κB translocation from cell nuclei to cytosol. The pretreatment with a COX-2-selective inhibitor abrogated the lasiodin-induced inhibition of cell proliferation. These results indicated that lasiodin simultaneously activated the Apaf-1/caspase-dependent apoptotic pathways and suppressed the AKT/MAPK and COX-2/NF-κB signaling pathways. This study also suggested that lasiodin could be a promising natural compound for the prevention and treatment of NPC.

  5. Some functional limit theorems for compound Cox processes

    Science.gov (United States)

    Korolev, Victor Yu.; Chertok, A. V.; Korchagin, A. Yu.; Kossova, E. V.; Zeifman, Alexander I.

    2016-06-01

    An improved version of the functional limit theorem is proved establishing weak convergence of random walks generated by compound doubly stochastic Poisson processes (compound Cox processes) to Lévy processes in the Skorokhod space under more realistic moment conditions. As corollaries, theorems are proved on convergence of random walks with jumps having finite variances to Lévy processes with variance-mean mixed normal distributions, in particular, to stable Lévy processes.

  6. Positively skewed data: revisiting the box-cox power transformation.

    OpenAIRE

    2015-01-01

    Although the normal probability distribution is the cornerstone of applying statistical methodology; data do not always meet the necessary normal distribution assumptions. In these cases, researchers often transform non-normal data to a distribution that is approximately normal. Power transformations constitute a family of transformations, which include logarithmic and fractional exponent transforms. The Box-Cox method offers a simple method for choosing the most appropriate power transformat...

  7. The aromatic volatile organic compounds toluene, benzene and styrene induce COX-2 and prostaglandins in human lung epithelial cells via oxidative stress and p38 MAPK activation.

    Science.gov (United States)

    Mögel, Iljana; Baumann, Sven; Böhme, Alexander; Kohajda, Tibor; von Bergen, Martin; Simon, Jan-Christoph; Lehmann, Irina

    2011-10-28

    Toluene, benzene and styrene are volatile organic compounds (VOCs) widely distributed in the environment. Tobacco smoke, traffic exposure and solvents used for paints, rubber and adhesives are known sources for these compounds. The aim of the present study was to investigate whether toluene, benzene and styrene can induce inflammatory reactions in lung cells and to characterize possible underlying mechanisms. A previous study gave evidence that expression of cyclooxygenase-2 (COX-2) is upregulated following exposure to the aromatic VOC chlorobenzene. Here, we investigated the effects of the aromatics toluene, benzene and styrene on human lung cells, with emphasis on COX-2, the rate-limiting enzyme of the prostaglandin pathway. In addition, we studied the potential role of oxidative stress and p38 MAPK activation in the toluene/benzene/styrene-dependent COX-2 induction. Following exposure to the aromatic compounds the expression level of COX-2 increased markedly. In addition, prostaglandin E(2) (PGE(2)) and prostaglandin F(2α) (PGF(2α)), major products of the COX enzyme, were found to be upregulated in response to toluene, benzene or styrene exposure. Furthermore, we observed an activation of p38 MAPK resulting from aromatic VOC exposure. Treatment of the cells with a specific p38 inhibitor (SB203580) or the antioxidant N-acetylcysteine (NAC) was able to prevent the toluene/benzene/styrene-dependent COX-2 activation, and subsequent increased PGE(2) and PGF(2α) secretion. These results suggest that toluene, benzene and styrene induce production and secretion of PGE(2) and PGF(2α) in lung epithelial cells via p38 MAPK and COX-2 activation in a redox sensitive manner. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  8. The antioxidant effects of isorhamnetin contribute to inhibit COX-2 expression in response to inflammation: a potential role of HO-1.

    Science.gov (United States)

    Seo, Kyuhwa; Yang, Ji Hye; Kim, Sang Chan; Ku, Sae Kwang; Ki, Sung Hwan; Shin, Sang Mi

    2014-06-01

    Previously, we reported that isorhamnentin, a 3'-O-methylated metabolite of quercetin, reduced inducible nitric oxide synthase (iNOS) expression and NO production. The present study further investigated the underlying mechanism of anti-inflammatory and antioxidant effects of isorhamnentin. Administration of isorhamnetin decreased the number of cyclooxygenase-2 (COX-2) positive cells in rats with carrageenan-induced paw edema. Isorhamnetin also suppressed lipopolysaccharide (LPS)-induced expression of COX-2 in cells. It is well known that LPS-induced reactive oxygen species (ROS) production leads to COX-2 induction. Isorhamnetin decreased LPS-induced ROS production and apoptosis. In addition, the basal expression of heme oxygenase-1 (HO-1) was increased by isorhamnetin treatment in agreement with the increase in nuclear translocation of NF-E2-related factor-2 (Nrf2), an essential transcription factor for the regulation of HO-1 expression. Moreover, pretreatment of tin protoporphyrin IX (SnPP), a chemical inhibitor of HO-1, reversed the ability of isothamnetin to inhibit COX-2 expression. These results demonstrate that induction of HO-1 by isorhamnetin leads to a reduction in ROS production and its antioxidant property might contribute to the inhibition of COX-2 expression in response to inflammation.

  9. Survival analysis of cervical cancer using stratified Cox regression

    Science.gov (United States)

    Purnami, S. W.; Inayati, K. D.; Sari, N. W. Wulan; Chosuvivatwong, V.; Sriplung, H.

    2016-04-01

    Cervical cancer is one of the mostly widely cancer cause of the women death in the world including Indonesia. Most cervical cancer patients come to the hospital already in an advanced stadium. As a result, the treatment of cervical cancer becomes more difficult and even can increase the death's risk. One of parameter that can be used to assess successfully of treatment is the probability of survival. This study raises the issue of cervical cancer survival patients at Dr. Soetomo Hospital using stratified Cox regression based on six factors such as age, stadium, treatment initiation, companion disease, complication, and anemia. Stratified Cox model is used because there is one independent variable that does not satisfy the proportional hazards assumption that is stadium. The results of the stratified Cox model show that the complication variable is significant factor which influent survival probability of cervical cancer patient. The obtained hazard ratio is 7.35. It means that cervical cancer patient who has complication is at risk of dying 7.35 times greater than patient who did not has complication. While the adjusted survival curves showed that stadium IV had the lowest probability of survival.

  10. Cyclooxygenase-2 inhibitor inhibits hippocampal synaptic reorganization in pilocarpine-induced status epilepticus rats

    Institute of Scientific and Technical Information of China (English)

    Hai-ju ZHANG; Ruo-peng SUN; Ge-fei LEI; Lu YANG; Chun-xi LIU

    2008-01-01

    Objective: To examine modulations caused by cyclooxygenase-2 (COX-2) inhibitors on altered microenvironments and overbalanced neurotransmitters in pilocarpine-induced epileptic status rats and to investigate possible mechanisms. Methods:Celecoxib (a COX-2 inhibitor) was administered 45 min prior to pilocarpine administration. The effects of COX-2 inhibitors on mIPSCs (miniature GABAergic inhibitory postsynaptic currents) of CA3 pyramidal cells in the hippocampus were recorded. Expressions of COX-2, c-Fos, newly generated neurons, and activated microgliosis wore analyzed by immunohistochemistry, and expressions of α-subunit of γ-amino butyric acid (GABAA) receptors and mitogen-activated protein kinase/extracellular sig-nal-regulated protein kinase (MAPK/ERK) activity were detected by Western blotting. Results: Pretreatment with celecoxib showed protection against pilocarpine-induced seizures. Celecoxib prevented microglia activation in the hilus and inhibited the abnormal neurogenesis and astrogliosis in the hippocampus by inhibiting MAPK/ERK activity and c-Fos transcription. Celecoxib also up-regulated the expression of GABAA receptors. NS-398 (N-2-cyclohexyloxy-4-nitrophenyl-methanesuifonamide), another COX-2 inhibitor, enhanced the frequency and decay time of mIPSCs. Conclusion: The COX-2 inhibitor celecoxib decreased neuronal excitability and prevented epileptogenesis in pilocarpine-induced status epilepticus rats. Celecoxib regulates synaptic reorganization by inhibiting astrogliosis and ectopic neurogenesis by attenuating MAPK/ERK signal activity, mediated by a GABAergic mechanism.

  11. Characteristic interactivity of landiolol, an ultra-short-acting highly selective β1-blocker, with biomimetic membranes: Comparisons with β1-selective esmolol and nonselective propranolol and alprenolol

    Directory of Open Access Journals (Sweden)

    Hironori eTsuchiya

    2013-12-01

    Full Text Available Although β1-blockers have been perioperatively used to reduce the cardiac disorders associated with general anesthesia, little is known about the mechanistic characteristics of ultra-short-acting highly selective β1-blocker landiolol. We studied its membrane-interacting property in comparison with other selective and nonselective β1-blockers. Biomimetic membranes prepared with phospholipids and cholesterol of varying compositions were treated with β1-selective landiolol and esmolol and nonselective propranolol and alprenolol at 0.5–200 µM. The membrane interactivity and the antioxidant activity were determined by measuring fluorescence polarization and by peroxidizing membrane lipids with peroxynitrite, respectively. Nonselective β1-blockers, but not selective ones, intensively acted on 1,2-dipalmitoylphosphatidylcholine liposomal membranes and cardiomyocyte-mimetic membranes to increase the membrane fluidity. Landiolol and its inactive metabolite distinctively decreased the fluidity of 1,2-dipalmitoylphosphatidylcholine liposomal membranes, suggesting that a membrane-rigidifying effect is attributed to the morpholine moiety in landiolol structure but unlikely to clinically contribute to the β1-blocking effect of landiolol. Propranolol and alprenolol interacted with lipid raft model membranes, whereas neither landiolol nor esmolol. All drugs fluidized mitochondria-mimetic membranes and inhibited the membrane lipid peroxidation with the potency correlating to their membrane interactivity. Landiolol is characterized as a drug devoid of the interactivity with membrane lipid rafts relating to β2-adrenergic receptor blockade. The differentiation between β1-blocking selectivity and nonselectivity is compatible with that between membrane noninteractivity and interactivity. The mitochondrial membrane fluidization by landiolol independent of blocking β1-adrenergic receptors is responsible for the antioxidant cardioprotection common to

  12. The effect of external divalent cations on spontaneous non-selective cation channel currents in rabbit portal vein myocytes.

    Science.gov (United States)

    Albert, A P; Large, W A

    2001-10-15

    1. The effects of external divalent cations on spontaneous single non-selective cation channel currents were studied in outside-out patches from rabbit portal vein smooth muscle cells in K+-free conditions. 2. In an external medium containing 1.5 mM Ca2+ (Ca2+o) the majority of spontaneous channel currents had a unitary conductance of 23 pS, reversal potential (Vr) of +10 mV and a low open probability (Po) at negative patch potentials. Some channels opened to a lower conductance state of about 13 pS suggesting that the cation channels have two conductance states. Open time and burst duration distributions could both be described by two exponentials with time constants of about of 1 ms and 7 ms for open times and 3 ms and 16 ms for burst durations. 3. In 0 Ca2+o the majority of spontaneous cation channels had a unitary conductance of 13 pS and Vr was shifted to +4 mV. Moreover the longer open time and longer burst duration time constants were both reduced to approximately half the values in 1.5 mM Ca2+o. 4. Compared to 0 Ca2+o the single channel currents in 3 microM and 100 microM Ca2+o had a 5- to 6-fold increase in Po which was accompanied by increases in both open times and burst durations. In 3 microM and 100 microM Ca2+o the unitary conductance of the single channel currents was between 22 and 26 pS. 5. At positive membrane potentials the single channel currents had an increased Po compared to negative potentials which was associated with increased open times and burst durations but these values were similar in 3 microM, 100 microM and 1.5 mM Ca2+o. 6. In 1.5 mM Sr2+o and 1.5 mM Ba2+o channels opened to the higher conductance state of about 22-25 pS and had a 3- to 7-fold greater Po than in 0 Ca2+o. 7. In conclusion, external divalent cations have marked effects on the unitary conductance and kinetic behaviour of non-selective cation channels in rabbit portal vein smooth muscle cells.

  13. Nontypeable Haemophilus influenzae induces COX-2 and PGE2 expression in lung epithelial cells via activation of p38 MAPK and NF-kappa B

    Directory of Open Access Journals (Sweden)

    Koga Tomoaki

    2008-01-01

    Full Text Available Abstract Background Nontypeable Haemophilus influenzae (NTHi is an important respiratory pathogen implicated as an infectious trigger in chronic obstructive pulmonary disease, but its molecular interaction with human lung epithelial cells remains unclear. Herein, we tested that the hypothesis that NTHi induces the expression of cyclooxygenase (COX-2 and prostaglandin E2 (PGE2 via activation of p38 mitogen-activated protein kinase (MAPK and nuclear factor (NF-kappa B in pulmonary alveolar epithelial cells. Methods Human alveolar epithelial A549 cells were infected with different concentrations of NTHi. The phosphorylation of p38 MAPK was detected by Western blot analysis, the DNA binding activity of NF-kappa B was assessed by electrophoretic mobility shift assay (EMSA, and the expressions of COX-1 and 2 mRNA and PGE2 protein were measured by reverse transcription-polymerase chain reaction (RT-PCR and enzyme linked immunosorbent assay (ELISA, respectively. The roles of Toll-like receptor (TLR 2 and TLR4, well known NTHi recognizing receptor in lung epithelial cell and gram-negative bacteria receptor, respectively, on the NTHi-induced COX-2 expression were investigated in the HEK293 cells overexpressing TLR2 and TLR4 in vitro and in the mouse model of NTHi-induced pneumonia by using TLR2 and TLR4 knock-out mice in vivo. In addition, the role of p38 MAPK and NF-kappa B on the NTHi-induced COX-2 and PGE2 expression was investigated by using their specific chemical inhibitors. Results NTHi induced COX-2 mRNA expression in a dose-dependent manner, but not COX-1 mRNA expression in A549 cells. The enhanced expression of PGE2 by NTHi infection was significantly decreased by pre-treatment of COX-2 specific inhibitor, but not by COX-1 inhibitor. NTHi induced COX-2 expression was mediated by TLR2 in the epithelial cell in vitro and in the lungs of mice in vivo. NTHi induced phosphorylation of p38 MAPK and up-regulated DNA binding activity of NF-kappa B

  14. NS-398, a selective cyclooxygenase-2 inhibitor, reduces experimental bladder carcinoma outgrowth by inhibiting tumor cell proliferation.

    NARCIS (Netherlands)

    Smakman, N.; Schaap, N.P.M.; Snijckers, C.M.; Rinkes, M.J.; Kranenburg, O.

    2005-01-01

    OBJECTIVES: To evaluate the efficacy of the selective cyclooxygenase-2 (COX-2) inhibitor NS-398 in treating experimental T24 bladder carcinoma, and to assess its effect on tumor cell proliferation and survival and tumor vascularization. COX-2 overexpression is frequently observed in bladder carcinom

  15. Derivation and evaluation of adverse outcome pathways for the effects of cyclooxygenase inhibitors on reproductive processes in fish

    Science.gov (United States)

    Cyclooxygenase (COX) inhibition is of concern in fish because COX inhibitors (e.g., ibuprofen) are ubiquitous in aquatic systems/fish tissues, and can disrupt synthesis of prostaglandins that modulate a variety of essential biological functions (e.g., reproduction). This study ut...

  16. 3-Dimensional quantitative structure-activity relationship and molecular docking studies of tetrasubstituted pyrazole derivatives as inhibitors of cyclooxygenase-2

    Directory of Open Access Journals (Sweden)

    Kulwinder Singh

    2014-04-01

    Conclusion: The present study shall help in rational drug design and synthesis of new selective COX-2 inhibitors with predetermined affinity and activity and provides valuable information for the understanding of interactions between COX-2 and the novel tetrasubstituted pyrazole derivative compounds. [Int J Res Med Sci 2014; 2(2.000: 612-619

  17. Effect of isolated fractions of Harpagophytum procumbens D.C. (devil's claw) on COX-1, COX-2 activity and nitric oxide production on whole-blood assay.

    Science.gov (United States)

    Anauate, Maria Cecilia; Torres, Luce Maria; de Mello, Suzana Beatriz Veríssimo

    2010-09-01

    The present study evaluates the effect of isolated fractions of Harpagophytum procumbens (devil's claw) on cyclooxygenase (COX-1 and COX-2) activities and NO production using a whole blood assay. The activity of COX-1 was quantified as platelet thromboxane B(2) production in blood clotting and COX-2 as prostaglandin E(2) production in LPS-stimulated whole blood. Total NO(2) (-)/NO(3) (-) concentration was determined by Griess reaction in LPS stimulated blood. Assays were performed by incubation of isolated fractions obtained by flash chromatography monitored with HPLC, TLC and identified by (1)HNMR, containing different amounts of harpagoside with blood from healthy donors. Indomethacin and etoricoxib were the positive controls of COX-1 and COX-2 Inhibition. Data shows that fraction containing the highest concentration of harpagoside inhibited indistinctively COX-1 and COX-2 (37.2 and 29.5% respectively) activity and greatly inhibited NO production (66%). In contrast the fraction including iridoid pool increased COX-2 and did not alter NO and COX-1 activities. The fraction containing cinnamic acid was able to reduce only NO production (67%). Our results demonstrated that the harpagoside fraction is the main responsible for the effect of devils claw on these enzyme activities. However, other components from devil's claw crude extract could antagonize or increase the synthesis of inflammatory mediators.

  18. Expression of gelatinases (MMP-2, MMP-9) and cyclooxygenases (COX-1, COX-2) in some benign salivary gland tumors.

    Science.gov (United States)

    Lipari, L; Mauro, A; Gallina, S; Tortorici, S; Buscemi, M; Tete, S; Gerbino, A

    2012-01-01

    Salivary gland tumors, most of which are rare benign tumors, represent a histologically heterogenous group with the greatest diversity of morphological and cellular features. The aim of this study is to analyse the expression and possible interactions between gelatinases (MMP-2, MMP-9) and cyclooxygenases (COX-1, COX-2) in some benign salivary gland tumors. We investigated the expression of gelatinases and cyclooxigenases in control salivary gland, Pleomorphic adenoma and Warthin's tumor through immunohistochemistry and Reverse Transcription - Polymerase Chain Reaction (PCR). We identified the expression of both classes of enzyme in normal samples and in the two types of pathological samples without any quantitative differences. From the present data no significant differences emerge in the expression of these enzymes among the different pathologies examined. Nevertheless, due to the small number of samples included in this study, general statements regarding correlation between the degree of severity of the tumoral pathology and the quantitative expression of these potential tumoral markers can not be made.

  19. Immunohistochemical and morphometric evaluation of COX 1 and COX-2 in the remodeled lung in idiopathic pulmonary fibrosis and systemic sclerosis

    Directory of Open Access Journals (Sweden)

    Edwin Roger Parra

    2013-12-01

    Full Text Available OBJECTIVE: To study the expression of COX-1 and COX-2 in the remodeled lung in systemic sclerosis (SSc and idiopathic pulmonary fibrosis (IPF patients, correlating that expression with patient survival.METHODS: We examined open lung biopsy specimens from 24 SSc patients and 30 IPF patients, using normal lung tissue as a control. The histological patterns included fibrotic nonspecific interstitial pneumonia (NSIP in SSc patients and usual interstitial pneumonia (UIP in IPF patients. We used immunohistochemistry and histomorphometry to evaluate the expression of COX-1 and COX-2 in alveolar septa, vessels, and bronchioles. We then correlated that expression with pulmonary function test results and evaluated its impact on patient survival.RESULTS: The expression of COX-1 and COX-2 in alveolar septa was significantly higher in IPF-UIP and SSc-NSIP lung tissue than in the control tissue. No difference was found between IPF-UIP and SSc-NSIP tissue regarding COX-1 and COX-2 expression. Multivariate analysis based on the Cox regression model showed that the factors associated with a low risk of death were younger age, high DLCO/alveolar volume, IPF, and high COX-1 expression in alveolar septa, whereas those associated with a high risk of death were advanced age, low DLCO/alveolar volume, SSc (with NSIP, and low COX-1 expression in alveolar septa.CONCLUSIONS: Our findings suggest that strategies aimed at preventing low COX-1 synthesis will have a greater impact on SSc, whereas those aimed at preventing high COX-2 synthesis will have a greater impact on IPF. However, prospective randomized clinical trials are needed in order to confirm that.

  20. The Arabidopsis COX11 Homolog is Essential for Cytochrome c Oxidase Activity.

    Science.gov (United States)

    Radin, Ivan; Mansilla, Natanael; Rödel, Gerhard; Steinebrunner, Iris

    2015-01-01

    Members of the ubiquitous COX11 (cytochrome c oxidase 11) protein family are involved in copper delivery to the COX complex. In this work, we characterize the Arabidopsis thaliana COX11 homolog (encoded by locus At1g02410). Western blot analyses and confocal microscopy identified Arabidopsis COX11 as an integral mitochondrial protein. Despite sharing high sequence and structural similarities, the Arabidopsis COX11 is not able to functionally replace the Saccharomyces cerevisiae COX11 homolog. Nevertheless, further analysis confirmed the hypothesis that Arabidopsis COX11 is essential for COX activity. Disturbance of COX11 expression through knockdown (KD) or overexpression (OE) affected COX activity. In KD lines, the activity was reduced by ~50%, resulting in root growth inhibition, smaller rosettes and leaf curling. In OE lines, the reduction was less pronounced (~80% of the wild type), still resulting in root growth inhibition. Additionally, pollen germination was impaired in COX11 KD and OE plants. This effect on pollen germination can only partially be attributed to COX deficiency and may indicate a possible auxiliary role of COX11 in ROS metabolism. In agreement with its role in energy production, the COX11 promoter is highly active in cells and tissues with high-energy demand for example shoot and root meristems, or vascular tissues of source and sink organs. In COX11 KD lines, the expression of the plasma-membrane copper transporter COPT2 and of several copper chaperones was altered, indicative of a retrograde signaling pathway pertinent to copper homeostasis. Based on our data, we postulate that COX11 is a mitochondrial chaperone, which plays an important role for plant growth and pollen germination as an essential COX complex assembly factor.

  1. Relationship between NOC/oFQ, dynorphin, and COX-2 activation in impaired NMDA cerebrovasodilation after brain injury.

    Science.gov (United States)

    Kulkarni, Miriam; Armstead, William M

    2002-08-01

    Previous studies have observed that the recently described endogenous opioid, nociceptin/orphanin FQ (NOC/oFQ), contributes to impairment of N-methyl-D-aspartate (NMDA)-induced cerebrovasodilation following fluid percussion brain injury (FPI) via a cyclooxygenase (COX)-dependent generation of superoxide anion (O(2)(-)). This study was designed to investigate the relationship between NOC/oFQ, another opioid, dynorphin, and activation of the COX-2 isoform of the enzyme in such impaired dilation to NMDA after FPI in piglets equipped with a closed cranial window. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O(-)(2) generation. Under non-brain injury conditions, NOC/oFQ (10(-10) M), the CSF concentration observed after FPI, increased CSF dynorphin, while the NOC/oFQ antagonist [F/G] NOC/oFQ (1-13) NH(2) attenuated the stimulated release of dynorphin following FPI (34 +/- 3 and 97 +/- 6 vs. 36 +/- 3 and 68 +/- 8 pg/mol for CSF dynorphin before and after FPI in untreated and NOC/oFQ antagonist-pretreated animals). FPI increased SOD-inhibitable NBT reduction, but pretreatment with norbinaltorphimine, a dynorphin antagonist, or NS398, a COX-2 inhibitor, blunted such reduction (1 +/- 1 vs. 19 +/- 3 vs. 4 +/- 1 vs. 4 +/- 1 pmol/mm(2) for control, FPI, FPI-norbinaltorphimine and FPI-NS398, respectively). Under non-brain injury conditions, dynorphin, in a concentration observed in CSF after FPI, also increased SOD-inhibitable NBT reduction, which was blunted by NS398. NMDA-induced pial artery dilation was reversed to vasoconstriction following FPI, but pretreatment with norbinaltorphimine or NS398 partially protected such responses (9 +/- 1 and 16 +/- 1, control; - 8 +/- 1 and - 13 +/- 2, FPI; 6 +/- 1 and 12 +/- 1% FPI-norbinaltorphimine for NMDA 10(-8), 10(-6) M, respectively). These data show that NOC/oFQ modulates the CSF release of dynorphin after FPI. These data also show that dynorphin contributes to O(2

  2. The characteristics of action potential and nonselec-tive cation current of cardiomyocytes in rabbit superior vena cava

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    As a special focus in initiating and maintaining atrial fibrillation (AF), cardiomyocytes in superior vena cava (SVC) have distinctive electrophysiological characters. In this study, we found that comparing with the right atrial (RA) cardiomyoctyes, the SVC cardiomyoctyes had longer APD90 at the different basic cycle lengths; the conduction block could be observed on both RA and SVC cardiomyoctyes. A few of SVC cardiomyoctyes showed slow response action potentials with automatic activity and some others showed early afterdepolarization (EAD) spontaneously. Further more, we found that there are nonselective cation current (INs) in both SVC and RA cardiomyocytes. The peak density of INs in SVC cardiomyocytes was smaller than that in RA cardiomyocytes. Removal of extracellular divalent cation and glucose could increase INs in SVC cardiomyocytes. The agonist or the antagonist of INs may in-crease or decrease APD. To sum up, some SVC cardiomyocytes possess the ability of spontaneous activity; the difference of transmembrane action potentials between SVC and RA cardiomyocytes is partly because of the different density of INs between them; the agonist or the antagonist of INs can in-crease or decrease APD leading to the enhancement or reduction of EAD genesis in SVC cardiomyo-cytes. INs in rabbit myocytes is fairly similar to TRPC3 current in electrophysiological property, which might play an important role in the mechanisms of AF.

  3. Safety of celecoxib and nonselective nonsteroidal anti-inflammatory drugs in juvenile idiopathic arthritis: results of the phase 4 registry

    Science.gov (United States)

    2014-01-01

    Background This study aimed to assess long-term safety and developmental data on juvenile idiopathic arthritis (JIA) patients treated in routine clinical practice with celecoxib or nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs). Methods Children aged ≥2 to nabumetone were the most frequently used nsNSAIDs. At baseline, the celecoxib group was older, had a numerically longer median time since diagnosis, and a numerically higher proportion of patients with a history of gastrointestinal-related NSAID intolerance. AEs reported were those frequently observed with NSAID treatment and were similar across groups (nsNSAIDs: 52.0%; celecoxib: 52.9%). Twelve unique patients experienced a total of 18 serious AEs; the most frequent were infections, and none was attributed to NSAID use. Conclusions The safety profile of celecoxib and nsNSAIDs appears similar overall. The results from this registry, ongoing pharmacovigilance, and the phase 3 trial that led to the approval of celecoxib for children with JIA provide evidence that the benefit-risk for celecoxib treatment in JIA remains positive. Trial registration ClinicalTrials.gov identifier NCT00688545. PMID:25057265

  4. The inhibitory effect of magnolol on cutaneous permeability in mice is probably mediated by a nonselective vascular hyporeactivity to mediators.

    Science.gov (United States)

    Wang, J P; Raung, S L; Chen, C C; Kuo, J S; Teng, C M

    1993-12-01

    In the present study, we demonstrated the inhibitory effect of magnolol on the plasma leakage in passive cutaneous anaphylactic (PCA) reaction, neurogenic inflammation, dorsal skin and ear edema in mice. Hind-paw skin plasma extravasation caused by antidromic stimulation of the saphenous nerve was reduced in mice pretreated with magnolol, diphenydramine or methysergide, but not with indomethacin. Ear edema formation in the PCA reaction was reduced by magnolol in dose-dependent manner. In addition, histamine-, serotonin-, compound 48/80-, bradykinin- and substance P-induced ear edema in mice was also suppressed by magnolol. A dose- and time-dependency of the inhibitory effect of magnolol was demonstrated in histamine- and compound 48/80-induced dorsal skin edema. The maximal inhibitory effect produced by a single dose of magnolol (10 mg/kg) persisted for 1 h, and significant suppression lasted for at least 3 h. In compound 48/80-pretreated mice, the histamine content of the ear was greatly reduced. Bradykinin- and substance P-induced ear edema in compound 48/80-pretreated mice was less severe than that seen in normal mice, but was still significantly reduced by magnolol pretreatment. Moreover, the inhibitory effect of magnolol was more marked than that of diphenhydramine combined with methysergide. These results suggest that the inhibitory effect of magnolol on local edema formation probably occurs through a nonselective inhibition on vascular tissue to prevent the permeability change caused by various mediators.

  5. The influence of piroxicam, a non-selective cyclooxygenase inhibitor, on autonomic nervous system activity in experimental cyclophosphamide-induced hemorrhagic cystitis and bladder outlet obstruction in rats.

    Science.gov (United States)

    Dobrek, Łukasz; Baranowska, Agnieszka; Skowron, Beata; Thor, Piotr J

    2014-01-01

    Signs and symptoms of secondary overactive bladder (OAB) are observed both in course of infravesical obstruction of urine outflow in patients with benign prostatic hyperplasia, and as a result of development of hemorrhagic cystitis (HC) following administration of cyclophosphamide (CP). Non-steroidal antiinflammatory drugs (NSAIDs) alleviate symptoms of bladder overactivity reducing local synthesis of prostaglandins (PGs), but precise effects of those agents on functions of the autonomic nervous system (ANS) in course of OAB remain unknown. The purpose of this study was to evaluate the effect of piroxicam-induced prostaglandins (PGs) synthesis block on activity of the ANS in two experimental models of secondary OAB: bladder outlet obstruction (BOO) and cyclophosphamide-induced HC (CP-HC), by heart rate variability analysis (HRV). The experiment was performed on a group of rats with surgically induced 2-week BOO, and on a group of rats that were administered CP five times, with corresponding control groups. Study animals were given piroxicam (PRX) i.p. in two doses: 2 and 10 mg/kg b.w. In the BOO model, PRX in both doses revealed a trend for reduction of value of all non-normalized components of HRV. The lower PRX dose caused an increased nHF value, and PRX administered in the dose of 10 mg/kg b.w. caused an increase of the nLF value. In the CP-HC model, the lower PRX dose caused a trend for an increase of values of all non-normalized components, and the higher dose--for their decrease. Both doses of PRX in that model caused increase of the nLF value. Inhibition of PGs synthesis caused changes of ANS function in both models of OAB. Both in BOO and in CP-HC, PGs seem to be ANS-activating factors, responsible for maintenance of a high parasympathetic activity. In both models, inhibition of PGs synthesis with PRX administered at the dose of 10 mg/kg b.w. lead to functional reconstruction of ANS, with marked sympathetic predominance. That may contribute to reduction of the bladder contractile action and improvement of its compliance in the filling period, which was demonstrated by other authors in urodynamic tests for NSAIDs.

  6. Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction

    DEFF Research Database (Denmark)

    Gislason, Gunnar H; Jacobsen, Søren; Rasmussen, Jeppe Nørgaard

    2006-01-01

    discharged alive and included in the study; 9773 experienced rehospitalization for MI, and 16 573 died. A total of 5.2% of patients received rofecoxib, 4.3% celecoxib, 17.5% ibuprofen, 10.6% diclofenac, and 12.7% other NSAIDs. For any use of rofecoxib, celecoxib, ibuprofen, diclofenac, and other NSAIDs......, the hazard ratios and 95% confidence intervals for death were 2.80 (2.41 to 3.25; for rofecoxib), 2.57 (2.15 to 3.08; for celecoxib), 1.50 (1.36 to 1.67; for ibuprofen), 2.40 (2.09 to 2.80; for diclofenac), and 1.29 (1.16 to 1.43; for other NSAIDS); there were dose-related increases in risk of death for all...

  7. PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-beta signaling during mammary tumorigenesis.

    Science.gov (United States)

    Tian, Maozhen; Schiemann, William P

    2010-04-01

    The molecular mechanisms that enable cyclooxygenase-2 (COX-2) and its mediator prostaglandin E2 (PGE2) to inhibit transforming growth factor-beta (TGF-beta) signaling during mammary tumorigenesis remain unknown. We show here that TGF-beta selectively stimulated the expression of the PGE2 receptor EP2, which increased normal and malignant mammary epithelial cell (MEC) invasion, anchorage-independent growth, and resistance to TGF-beta-induced cytostasis. Mechanistically, elevated EP2 expression in normal MECs inhibited the coupling of TGF-beta to Smad2/3 activation and plasminogen activator inhibitor-1 (PAI1) expression, while EP2 deficiency in these same MECs augmented Smad2/3 activation and PAI expression stimulated by TGF-beta. Along these lines, engineering malignant MECs to lack EP2 expression prevented their growth in soft agar, restored their cytostatic response to TGF-beta, decreased their invasiveness in response to TGF-beta, and potentiated their activation of Smad2/3 and expression of PAI stimulated by TGF-beta. More important, we show that COX-2 or EP2 deficiency both significantly decreased the growth, angiogenesis, and pulmonary metastasis of mammary tumors produced in mice. Collectively, this investigation establishes EP2 as a potent mediator of the anti-TGF-beta activities elicited by COX-2/PGE2 in normal and malignant MECs. Our findings also suggest that pharmacological targeting of EP2 receptors may provide new inroads to antagonize the oncogenic activities of TGF-beta during mammary tumorigenesis.-Tian, M., Schiemann, W. P. PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-beta signaling during mammary tumorigenesis.

  8. PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-β signaling during mammary tumorigenesis

    Science.gov (United States)

    Tian, Maozhen; Schiemann, William P.

    2010-01-01

    The molecular mechanisms that enable cyclooxygenase-2 (COX-2) and its mediator prostaglandin E2 (PGE2) to inhibit transforming growth factor-β (TGF-β) signaling during mammary tumorigenesis remain unknown. We show here that TGF-β selectively stimulated the expression of the PGE2 receptor EP2, which increased normal and malignant mammary epithelial cell (MEC) invasion, anchorage-independent growth, and resistance to TGF-β-induced cytostasis. Mechanistically, elevated EP2 expression in normal MECs inhibited the coupling of TGF-β to Smad2/3 activation and plasminogen activator inhibitor-1 (PAI1) expression, while EP2 deficiency in these same MECs augmented Smad2/3 activation and PAI expression stimulated by TGF-β. Along these lines, engineering malignant MECs to lack EP2 expression prevented their growth in soft agar, restored their cytostatic response to TGF-β, decreased their invasiveness in response to TGF-β, and potentiated their activation of Smad2/3 and expression of PAI stimulated by TGF-β. More important, we show that COX-2 or EP2 deficiency both significantly decreased the growth, angiogenesis, and pulmonary metastasis of mammary tumors produced in mice. Collectively, this investigation establishes EP2 as a potent mediator of the anti-TGF-β activities elicited by COX-2/PGE2 in normal and malignant MECs. Our findings also suggest that pharmacological targeting of EP2 receptors may provide new inroads to antagonize the oncogenic activities of TGF-β during mammary tumorigenesis.—Tian, M., Schiemann, W. P. PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-β signaling during mammary tumorigenesis. PMID:19897661

  9. LC-MS/MS confirms that COX-1 drives vascular prostacyclin whilst gene expression pattern reveals non-vascular sites of COX-2 expression.

    Directory of Open Access Journals (Sweden)

    Nicholas S Kirkby

    Full Text Available There are two schools of thought regarding the cyclooxygenase (COX isoform active in the vasculature. Using urinary prostacyclin markers some groups have proposed that vascular COX-2 drives prostacyclin release. In contrast, we and others have found that COX-1, not COX-2, is responsible for vascular prostacyclin production. Our experiments have relied on immunoassays to detect the prostacyclin breakdown product, 6-keto-PGF1α and antibodies to detect COX-2 protein. Whilst these are standard approaches, used by many laboratories, antibody-based techniques are inherently indirect and have been criticized as limiting the conclusions that can be drawn. To address this question, we measured production of prostanoids, including 6-keto-PGF1α, by isolated vessels and in the circulation in vivo using liquid chromatography tandem mass spectrometry and found values essentially identical to those obtained by immunoassay. In addition, we determined expression from the Cox2 gene using a knockin reporter mouse in which luciferase activity reflects Cox2 gene expression. Using this we confirm the aorta to be essentially devoid of Cox2 driven expression. In contrast, thymus, renal medulla, and regions of the brain and gut expressed substantial levels of luciferase activity, which correlated well with COX-2-dependent prostanoid production. These data are consistent with the conclusion that COX-1 drives vascular prostacyclin release and puts the sparse expression of Cox2 in the vasculature in the context of the rest of the body. In doing so, we have identified the thymus, gut, brain and other tissues as target organs for consideration in developing a new understanding of how COX-2 protects the cardiovascular system.

  10. Pro-inflammatory Signaling in a 3D Organotypic Skin Model after Low LET Irradiation—NF-κB, COX-2 Activation, and Impact on Cell Differentiation

    Science.gov (United States)

    Acheva, Anna; Schettino, Giuseppe; Prise, Kevin M.

    2017-01-01

    Nearly 85% of radiotherapy patients develop acute radiation dermatitis, which is an inflammatory reaction of the skin at the treatment field and in the surrounding area. The aims of this study were to unravel the mechanisms of radiation-induced inflammatory responses after localized irradiation in a human 3D organotypic skin culture model. This could provide possible inflammatory targets for reduction of skin side effects. 3D organotypic skin cultures were set up and locally irradiated with 225 kVp X-rays, using a combination of full exposure and partial shielding (50%) of the cultures. The secretion of pro-inflammatory cytokines, the phenotype, and the differentiation markers expression of the cultures were assessed up to 10 days postirradiation. The pro-inflammatory transcription factor nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (COX-2) pathways have been studied. The results showed fast activation of NF-κB, most likely triggered by DNA damage in the irradiated cells, followed by upregulation of p38 MAPK and COX-2 in the irradiated and surrounding, non-irradiated, areas of the 3D cultures. The application of the COX-2 inhibitor sc-236 was effective at reducing the COX-2 mRNA levels 4 h postirradiation. The same inhibitor also suppressed the PGE2 secretion significantly 72 h after the treatment. The expression of a pro-inflammatory phenotype and abnormal differentiation markers of the cultures were also reduced. However, the use of an NF-κB inhibitor (Bay 11-7085) did not have the predicted positive effect on the cultures phenotype postirradiation. Radiation-induced pro-inflammatory responses have been observed in the 3D skin model. The activated signaling pathways involved NF-κB transcription factor and its downstream target COX-2. Further experiments aiming to suppress the inflammatory response via specific inhibitors showed that COX-2 is a suitable target for reduction of the normal skin inflammatory responses at radiotherapy, while NF

  11. COX-2 gene expression in colon cancer tissue related to regulating factors and promoter methylation status

    Directory of Open Access Journals (Sweden)

    Lagerstedt Kristina

    2011-06-01

    Full Text Available Abstract Background Increased cyclooxygenase activity promotes progression of colorectal cancer, but the mechanisms behind COX-2 induction remain elusive. This study was therefore aimed to define external cell signaling and transcription factors relating to high COX-2 expression in colon cancer tissue. Method Tumor and normal colon tissue were collected at primary curative operation in 48 unselected patients. COX-2 expression in tumor and normal colon tissue was quantified including microarray analyses on tumor mRNA accounting for high and low tumor COX-2 expression. Cross hybridization was performed between tumor and normal colon tissue. Methylation status of up-stream COX-2 promoter region was evaluated. Results Tumors with high COX-2 expression displayed large differences in gene expression compared to normal colon. Numerous genes with altered expression appeared in tumors of high COX-2 expression compared to tumors of low COX-2. COX-2 expression in normal colon was increased in patients with tumors of high COX-2 compared to normal colon from patients with tumors of low COX-2. IL1β, IL6 and iNOS transcripts were up-regulated among external cell signaling factors; nine transcription factors (ATF3, C/EBP, c-Fos, Fos-B, JDP2, JunB, c-Maf, NF-κB, TCF4 showed increased expression and 5 (AP-2, CBP, Elk-1, p53, PEA3 were decreased in tumors with high COX-2. The promoter region of COX-2 gene did not show consistent methylation in tumor or normal colon tissue. Conclusions Transcription and external cell signaling factors are altered as covariates to COX-2 expression in colon cancer tissue, but DNA methylation of the COX-2 promoter region was not a significant factor behind COX-2 expression in tumor and normal colon tissue.

  12. Extended cox regression model: The choice of timefunction

    Science.gov (United States)

    Isik, Hatice; Tutkun, Nihal Ata; Karasoy, Durdu

    2017-07-01

    Cox regression model (CRM), which takes into account the effect of censored observations, is one the most applicative and usedmodels in survival analysis to evaluate the effects of covariates. Proportional hazard (PH), requires a constant hazard ratio over time, is the assumptionofCRM. Using extended CRM provides the test of including a time dependent covariate to assess the PH assumption or an alternative model in case of nonproportional hazards. In this study, the different types of real data sets are used to choose the time function and the differences between time functions are analyzed and discussed.

  13. COX-2 disruption leads to increased central vasopressin stores and impaired urine concentrating ability in mice

    DEFF Research Database (Denmark)

    Norregaard, Rikke; Madsen, Kirsten Morill; Hansen, Pernille Bl

    2011-01-01

    It was hypothesized that cyclooxygenase-2 (COX-2) activity promotes urine concentrating ability through stimulation of vasopressin (AVP) release after water deprivation (WD). COX-2-deficient (COX-2(-/-), C57BL/6) and wild-type (WT) mice were water deprived for 24 h, and water balance, central AVP...

  14. Secretory phospholipase A(2) induces delayed neuronal COX-2 expression compared with glutamate

    DEFF Research Database (Denmark)

    Nielsen, Marianne; Bazan, Nicolas G; Diemer, Nils H;

    2002-01-01

    and immunohistochemistry. An up-regulation of COX-2, c-fos, and c-jun, but not COX-1, was observed around the lesion as well as in the neocortex 4 hr after the injection. Hippocampal up-regulation of COX-2 was seen in dentate gyrus 8 hr after injection. When glutamate was injected, up-regulation of the early...

  15. OxLDL up-regulates Niemann-Pick type C1 expression through ERK1/2/COX-2/ PPARα-signaling pathway in macrophages

    Institute of Scientific and Technical Information of China (English)

    Xiaohua yu; Chaoke Tang; Xiaoxu Li; Guojun Zhao; Ji Xiao; Zhongcheng Mo; Kai Yin; Zhisheng Jiang; Yuchang Fu; Xiaohui Zha

    2012-01-01

    The Niemann-Pick type C1 (NPC1) is located mainly in the membranes of the late endosome/lysosome and controls the intracellular cholesterol trafficking from the late endosome/lysosome to the plasma membrane.It has been reported that oxidized low-density lipoprotein (oxLDL) can up-regulate NPC1 expression.However,the detailed mechanisms are not fully understood.In this study,we investigated the effect of oxLDL stimulation on NPC1 expression in THP-1 macrophages.Our results showed that oxLDL up-regulated NPC1 expression at both mRNA and protein levels in a dose-dependent and time-dependent manner.In addition,oxLDL also induced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2).Treatment with oxLDL significantly increased cyclooxygenase-2 (COX-2)mRNA and protein expression in the macrophages,and these increases were suppressed by the ERK1/2 inhibitor PD98059 or ERK1/2 small interfering RNA (siRNA) treatment.OxLDL up-regulated the expression of peroxisome proliferator-activated receptor α (PPARα) at the mRNA and protein levels,which could be abolished by COX-2 siRNA or COX-2 inhibitor NS398 treatment in these macrophages.OxLDL dramatically elevated cellular cholesterol efflux,which was abrogated by inhibiting ERK1/2 and/or COX-2.In addition,oxLDL-induced NPC1 expression and cellular cholesterol effiux were reversed by PPARα siRNA or GW6471,an antagonist of PPARα.Taken together,these results provide the evidence that oxLDL can up-regulate the expression of the NPC1 through ERK1/2/COX-2/PPARα-signaling pathway in macrophages.

  16. Flavonoids targeting of IκB phosphorylation abrogates carcinogen-induced MMP-9 and COX-2 expression in human brain endothelial cells

    Directory of Open Access Journals (Sweden)

    Tahanian E

    2011-05-01

    Full Text Available Elizabeth Tahanian¹, Luis Arguello Sanchez¹, Tze Chieh Shiao², René Roy², Borhane Annabi¹¹Centre de Recherche BioMED, ²Centre de Recherche PharmaQAM, Département de chimie, Université du Québec à Montréal, QC, CanadaAbstract: Brain endothelial cells play an essential role as structural and functional components of the blood–brain barrier (BBB. Increased BBB breakdown and brain injury are associated with neuroinflammation and are thought to trigger mechanisms involving matrix metalloproteinase upregulation. Emerging evidence also indicates that cyclooxygenase (COX inhibition limits BBB disruption, but the mechanisms linking metalloproteinase to COX remain unknown. In this study, we sought to investigate the nuclear factor-kappa B (NF-κB signaling pathway, a common pathway in both the regulation of matrix metalloproteinase-9 (MMP-9 and COX-2 expression, and the inhibitory properties of several chemopreventive flavonoids. Human brain microvascular endothelial cells were treated with a combination of phorbol 12-myristate 13-acetate (PMA, a carcinogen documented to increase MMP-9 and COX-2 through NF-κB, and several naturally occurring flavonoids. Among the molecules tested, we found that fisetin, apigenin, and luteolin specifically and dose-dependently antagonized PMA-induced COX-2 and MMP-9 gene and protein expressions as assessed by qRT-PCR, immunoblotting, and zymography respectively. We further demonstrate that flavonoids impact on IκK-mediated phosphorylation activity as demonstrated by the inhibition of PMA-induced IκB phosphorylation levels. Our results suggest that BBB disruption during neuroinflammation could be pharmacologically reduced by a specific class of flavonoids acting as NF-κB signal transduction inhibitors.Keywords: blood–brain barrier, flavonoids, neuroinflammation, NF-κB signal transduction inhibitors

  17. Non-selective regulation of peroxide and superoxide resistance genes by PerR in Campylobacter jejuni

    Directory of Open Access Journals (Sweden)

    Jong-Chul eKim

    2015-02-01

    Full Text Available Campylobacter jejuni is an important foodborne pathogen. The molecular mechanisms for the regulation of oxidative stress resistance have not yet been understood fully in this bacterium. In this study, we investigated how PerR (peroxide stress regulator modulates the transcriptional regulation of both peroxide and superoxide resistance genes in C. jejuni, particularly under oxidative stress conditions. The transcriptional levels of ahpC, katA, and sodB were substantially increased by aeration and oxidant exposure. Interestingly, a perR mutation completely abrogated the transcriptional response of ahpC, katA and sodB to oxidants. Furthermore, we demonstrated that perR transcription was reduced by aeration and oxidant exposure. In contrast to the unique role of PerR homologs in peroxide stress regulation in other bacteria, interestingly, C. jejuni PerR directly regulates the transcription of sodB, the most important gene in superoxide defense, as evidenced by the alteration of sodB transcription by the perR mutation and direct binding of rPerR to the sodB promoter. In addition, we also observed notable morphological changes in C. jejuni from spiral rods to coccoid morphology under aerobic conditions. Based on the intracellular ATP levels, C. jejuni entered a viable-but-non-culturable state under aerobic conditions. These findings clearly demonstrate that C. jejuni possesses a unique regulatory mechanism of oxidative stress defense that does not specifically distinguish between peroxide and superoxide defense, and PerR plays a pivotal role in this non-selective regulation of oxidative stress resistance in C. jejuni.

  18. The incentive amplifying effects of nicotine are reduced by selective and non-selective dopamine antagonists in rats.

    Science.gov (United States)

    Palmatier, Matthew I; Kellicut, Marissa R; Brianna Sheppard, A; Brown, Russell W; Robinson, Donita L

    2014-11-01

    Nicotine is a psychomotor stimulant with 'reinforcement enhancing' effects--the actions of nicotine in the brain increase responding for non-nicotine rewards. We hypothesized that this latter effect of nicotine depends on increased incentive properties of anticipatory cues; consistent with this hypothesis, multiple laboratories have reported that nicotine increases sign tracking, i.e. approach to a conditioned stimulus (CS), in Pavlovian conditioned-approach tasks. Incentive motivation and sign tracking are mediated by mesolimbic dopamine (DA) transmission and nicotine facilitates mesolimbic DA release. Therefore, we hypothesized that the incentive-promoting effects of nicotine would be impaired by DA antagonists. To test this hypothesis, separate groups of rats were injected with nicotine (0.4mg/kg base) or saline prior to Pavlovian conditioning sessions in which a CS (30s illumination of a light or presentation of a lever) was immediately followed by a sweet reward delivered in an adjacent location. Both saline and nicotine pretreated rats exhibited similar levels of conditioned approach to the reward location (goal tracking), but nicotine pretreatment significantly increased approach to the CS (sign tracking), regardless of type (lever or light). The DAD1 antagonist SCH-23390 and the DAD2/3 antagonist eticlopride reduced conditioned approach in all rats, but specifically reduced goal tracking in the saline pretreated rats and sign tracking in the nicotine pretreated rats. The non-selective DA antagonist flupenthixol reduced sign-tracking in nicotine rats at all doses tested; however, only the highest dose of flupenthixol reduced goal tracking in both nicotine and saline groups. The reductions in conditioned approach behavior, especially those by SCH-23390, were dissociated from simple motor suppressant effects of the antagonists. These experiments are the first to investigate the effects of dopaminergic drugs on the facilitation of sign-tracking engendered by

  19. Differential contribution of TRPM4 and TRPM5 nonselective cation channels to the slow afterdepolarization in mouse prefrontal cortex neurons

    Directory of Open Access Journals (Sweden)

    Ya-Ting eLei

    2014-09-01

    Full Text Available In certain neurons from different brain regions, a brief burst of action potentials can activate a slow afterdepolarization (sADP in the presence of muscarinic acetylcholine receptor agonists. The sADP, if suprathreshold, can contribute to persistent non-accommodating firing in some of these neurons. Previous studies have characterized a Ca2+-activated non-selective cation (CAN current (ICAN that is thought to underlie the sADP. ICAN depends on muscarinic receptor stimulation and exhibits a dependence on neuronal activity, membrane depolarization and Ca2+-influx similar to that observed for the sADP. Despite the widespread occurrence of sADPs in neurons throughout the brain, the molecular identity of the ion channels underlying these events, as well as ICAN, remains uncertain. Here we used a combination of genetic, pharmacological and electrophysiological approaches to characterize the molecular mechanisms underlying the muscarinic receptor-dependent sADP in layer 5 pyramidal neurons of mouse prefrontal cortex. First, we confirmed that in the presence of the cholinergic agonist carbachol a brief burst of action potentials triggers a prominent sADP in these neurons. Second, we confirmed that this sADP requires activation of a PLC signaling cascade and intracellular calcium signaling. Third, we obtained direct evidence that the transient receptor potential melastatin 5 channel (TRPM5, which is thought to function as a CAN channel in non-neural cells, contributes importantly to the sADP in the layer 5 neurons. In contrast, the closely related TRPM4 channel may play only a minor role in the sADP.

  20. Chronic Periprosthetic Hip Joint Infection. A Retrospective, Observational Study on the Treatment Strategy and Prognosis in 130 Non-Selected Patients

    DEFF Research Database (Denmark)

    Lange, Jeppe; Troelsen, Anders; Søballe, Kjeld

    2016-01-01

    INTRODUCTION: Limited information is available regarding the treatment strategy and prognosis of non-selected patients treated for chronic periprosthetic hip joint infection. Such information is important as no head-to-head studies on treatment strategies are available. The purpose of this study...... is to report on the treatment strategy and prognosis of a non-selected, consecutive patient population. METHODS: We identified 130 patients in the National Patient Registry, consecutively treated for a chronic periprosthetic hip joint infection between 2003-2008 at 11 departments of orthopaedic surgery. We.......00001). After adjusting for selected confounders, the mortality risk was no longer significantly different. The 5-year re-infection rate after re-implantation was 14.6% (95%CI 8.0-23.1). Re-infections occurred mainly within 3 years of follow-up. The overall 1-year survival rate was 92% (95%CI 86...

  1. COX-2 in Cancer: Gordian knot or Achilles heel?

    Directory of Open Access Journals (Sweden)

    Ioannis eStasinopoulos

    2013-03-01

    Full Text Available The networks of blood and lymphatic vessels and of the extracellular matrix and their cellular and structural components, that are collectively termed the tumor microenvironment, are frequently co-opted and shaped by cancer cells to survive, invade and form distant metastasis. With an enviable capacity to adapt to continually changing environments, cancer represents the epitome of functional chaos, a stark contrast to the hierarchical and organized differentiation processes that dictate the development and life of biological organisms. The consequences of changing landscapes such as hypoxia and acidic extracellular pH in and around tumors create a cascade of, or themselves are results of, changes in multiple pathways and networks that become apparent only several years later as recurrence and metastasis. These molecular and phenotypic changes approach the complexities of a ‘Gordian Knot’. We review evidence from our studies and from literature suggesting that COX-2 biology presents a nodal point in cancer biology and an ‘Achilles heel’ of COX-2-dependent tumors.

  2. Statistical Inference in Cox-Ingersoll-Ross Model%Cox-Ingersoll-Ross模型的统计推断

    Institute of Scientific and Technical Information of China (English)

    陈萍; 杨孝平

    2005-01-01

    本文研究了Cox-Ingersoll-Ross模型的统计推断问题.给出了CIR过程的平稳均值m与平稳方差v的矩估计,并利用m和v给出了CIR过程中尺度参数α与波动率β之间的关系,讨论了参数α的条件矩估计和渐近极大似然估计.并通过数值模拟对条件矩估计,渐近极大似然估计这两种方法作了比较.

  3. Imrecoxib:a novel and selective cyclooxygenase 2 inhibitor with anti-inflammatory effect

    Institute of Scientific and Technical Information of China (English)

    Xiao-hong CHEN; Jin-ye BAI; Fang SHEN; Ai-ping BAI; Zong-ru GUO; Gui-fang CHENG

    2004-01-01

    AIM: To investigate the inhibitory effect of imrecoxib, a synthetic compound of completely new structure, on cyclooxygenase 1 (COX-1) and 2 (COX-2) and its anti-inflammatory effect in vivo. METHODS: The inhibitory effects of imrecoxib on cyclooxygenase 1 and 2 were studied using whole cell assay with murine peritoneal macrophages induced by calcimycin and LPS. The inhibitory effects of imrecoxib on mRNA level of COX- 1 and COX2 in human macrophage cell line U937 were detected by reverse transcription polymerase chain reaction (RT-PCR)analysis. Effects of imrecoxib on acute and chronic inflammation were evaluated in rat carrageenan induced edema model and rat adjuvant-induced arthritis model, respectively. RESULTS: Imrecoxib was found to inhibit COX-1and COX-2 with IC50 value of 115+28 nmol/L and 18+4 nmol/L, respectively. Imrecoxib was shown to selectively and dose-dependently inhibit COX-2 mRNA level. Imrecoxib effectively inhibited carrageenan-induced acute inflammation at the doses of 5, 10, and 20 mg.kg-1 ig and adjuvant-induced chronic inflammation at the doses of 10and 20 rmg.kg-1.d-1 ig. CONCLUSION: Imrecoxib is a novel and moderately selective COX-2 inhibitor that possesses anti-inflammatory effect by inhibition of COX-2 mRNA expression.

  4. Cox26 is a novel stoichiometric subunit of the yeast cytochrome c oxidase.

    Science.gov (United States)

    Levchenko, Maria; Wuttke, Jan-Moritz; Römpler, Katharina; Schmidt, Bernhard; Neifer, Klaus; Juris, Lisa; Wissel, Mirjam; Rehling, Peter; Deckers, Markus

    2016-07-01

    The cytochrome c oxidase (COX) is the terminal enzyme of the respiratory chain. The complex accepts electrons from cytochrome c and passes them onto molecular oxygen. This process contributes to energy capture in the form of a membrane potential across the inner membrane. The enzyme complex assembles in a stepwise process from the three mitochondria-encoded core subunits Cox1, Cox2 and Cox3, which associate with nuclear-encoded subunits and cofactors. In the yeast Saccharomyces cerevisiae, the cytochrome c oxidase associates with the bc1-complex into supercomplexes, allowing efficient energy transduction. Here we report on Cox26 as a protein found in respiratory chain supercomplexes containing cytochrome c oxidase. Our analyses reveal Cox26 as a novel stoichiometric structural subunit of the cytochrome c oxidase. A loss of Cox26 affects cytochrome c oxidase activity and respirasome organization.

  5. Cyclooxygenases (COX-1 and COX-2) for tissue engineering of articular cartilage--from a developmental model to first results of tissue and scaffold expression.

    Science.gov (United States)

    Brochhausen, Christoph; Zehbe, Rolf; Gross, Ulrich; Libera, Jeanette; Schubert, Helmut; Nüsing, Rolf M; Klaus, Günter; Kirkpatrick, C James

    2008-01-01

    Tissue engineering of articular cartilage remains an ongoing challenge. Since tissue regeneration recapitulates ontogenetic processes the growth plate can be regarded as an innovative model to target suitable signalling molecules and growth factors for the tissue engineering of cartilage. In the present study we analysed the expression of cyclooxygenases (COX) in a short-term chondrocyte culture in gelatin-based scaffolds and in articular cartilage of rats and compared it with that in the growth plate. Our results demonstrate the strong cellular expression of COX-1 but only a focal weak expression of COX-2 in the seeded scaffolds. Articular cartilage of rats expresses homogeneously COX-1 and COX-2 with the exception of the apical cell layer. Our findings indicate a functional role of COX in the metabolism of articular chondrocytes. The expression of COX in articular cartilage and in the seeded scaffolds opens interesting perspectives to improve the proliferation and differentiation of chondrocytes in scaffold materials by addition of specific receptor ligands of the COX system.

  6. Sulforaphane inhibits IL-1β-induced proliferation of rheumatoid arthritis synovial fibroblasts and the production of MMPs, COX-2, and PGE2.

    Science.gov (United States)

    Choi, Yun Jung; Lee, Won-Seok; Lee, Eun-Gyeong; Sung, Myung-Soon; Yoo, Wan-Hee

    2014-10-01

    This study was performed to define the effects of sulforaphane on interleukin-1β (IL-1β)-induced proliferation of rheumatoid arthritis synovial fibroblasts (RASFs), the expression of matrix metalloproteinases (MMPs) and cyclooxygenase (COX), and the production of prostaglandin E2 (PGE2) by RASFs. The proliferation of RASFs was evaluated with CCK-8 reagent in the presence of IL-1β with/without sulforaphane. The expression of MMPs, tissue inhibitor of metalloproteinase-1, COXs, intracellular mitogen-activated protein kinase signalings, including p-ERK, p-p38, p-JNK, and nuclear factor-kappaB (NF-kB), and the production of PGE2 were examined by Western blotting or semi-quantitative RT-PCR and ELISA. Sulforaphane inhibits unstimulated and IL-1β-induced proliferation of RASFs; the expression of MMP-1, MMP-3, and COX-2 mRNA and protein; and the PGE2 production induced by IL-1β. Sulforaphane also inhibits the phosphorylation of ERK-1/2, p-38, and JNK and activation of NF-kB by IL-1β. These results indicate that sulforaphane inhibits the proliferation of synovial fibroblasts, the expression of MMPs and COX-2, and the production of PGE2, which are involved in synovitis and destruction of RA, and suggest that sulforaphane might be a new therapeutic agent for RA.

  7. Gaussian estimation for discretely observed Cox-Ingersoll-Ross model

    Science.gov (United States)

    Wei, Chao; Shu, Huisheng; Liu, Yurong

    2016-07-01

    This paper is concerned with the parameter estimation problem for Cox-Ingersoll-Ross model based on discrete observation. First, a new discretized process is built based on the Euler-Maruyama scheme. Then, the parameter estimators are obtained by employing the maximum likelihood method and the explicit expressions of the error of estimation are given. Subsequently, the consistency property of all parameter estimators are proved by applying the law of large numbers for martingales, Holder's inequality, B-D-G inequality and Cauchy-Schwarz inequality. Finally, a numerical simulation example for estimators and the absolute error between estimators and true values is presented to demonstrate the effectiveness of the estimation approach used in this paper.

  8. Random weighting method for Cox's proportional hazards model

    Institute of Scientific and Technical Information of China (English)

    CUI WenQuan; LI Kai; YANG YaNing; WU YueHua

    2008-01-01

    Variance of parameter estimate in Cox's proportional hazards model is based on asymptotic variance.When sample size is small,variance can be estimated by bootstrap method.However,if censoring rate in a survival data set is high,bootstrap method may fail to work properly.This is because bootstrap samples may be even more heavily censored due to repeated sampling of the censored observations.This paper proposes a random weighting method for variance estimation and confidence interval estimation for proportional hazards model.This method,unlike the bootstrap method,does not lead to more severe censoring than the original sample does.Its large sample properties are studied and the consistency and asymptotic normality are proved under mild conditions.Simulation studies show that the random weighting method is not as sensitive to heavy censoring as bootstrap method is and can produce good variance estimates or confidence intervals.

  9. Inverse probability weighted Cox regression for doubly truncated data.

    Science.gov (United States)

    Mandel, Micha; de Uña-Álvarez, Jacobo; Simon, David K; Betensky, Rebecca A

    2017-09-08

    Doubly truncated data arise when event times are observed only if they fall within subject-specific, possibly random, intervals. While non-parametric methods for survivor function estimation using doubly truncated data have been intensively studied, only a few methods for fitting regression models have been suggested, and only for a limited number of covariates. In this article, we present a method to fit the Cox regression model to doubly truncated data with multiple discrete and continuous covariates, and describe how to implement it using existing software. The approach is used to study the association between candidate single nucleotide polymorphisms and age of onset of Parkinson's disease. © 2017, The International Biometric Society.

  10. Regularization for Cox's Proportional Hazards Model With NP-Dimensionality

    CERN Document Server

    Bradic, Jelena; Jiang, Jiancheng

    2010-01-01

    High throughput genetic sequencing arrays with thousands of measurements per sample and a great amount of related censored clinical data have increased demanding need for better measurement specific model selection. In this paper we establish strong oracle properties of non-concave penalized methods for {\\it non-polynomial} (NP) dimensional data with censoring in the framework of Cox's proportional hazards model. A class of folded-concave penalties are employed and both LASSO and SCAD are discussed specifically. We unveil the question under which dimensionality and correlation restrictions can an oracle estimator be constructed and grasped. It is demonstrated that non-concave penalties lead to significant reduction of the "irrepresentable condition" needed for LASSO model selection consistency. The large deviation result for martingales, bearing interests of its own, is developed for characterizing the strong oracle property. Moreover, the non-concave regularized estimator, is shown to achieve asymptotically ...

  11. Clinical Profile of Cyclooxygenase-2 Inhibitors in Treating Non-Small Cell Lung Cancer: A Meta-Analysis of Nine Randomized Clinical Trials.

    Directory of Open Access Journals (Sweden)

    Yuan Yuan Zhou

    Full Text Available Evidence on the benefits of combining cyclooxygenase-2 inhibitor (COX-2 in treating non-small cell lung cancer (NSCLC is still controversial. We investigated the efficacy and safety profile of cyclooxygenase-2 inhibitors in treating NSCLC.The first meta-analysis of eligible studies was performed to assess the effect of COX-2 inhibitors for patients with NSCLC on the overall response rate (ORR, overall survival (OS, progression-free survival (PFS, one-year survival, and toxicities. The fixed-effects model was used to calculate the pooled RR and HR and between-study heterogeneity was assessed. Subgroup analyses were conducted according to the type of COX-2 inhibitors, treatment pattern, and treatment line.Nine randomized clinical trials, comprising 1679 patents with NSCLC, were included in the final meta-analysis. The pooled ORR of patients who have NSCLC with COX-2 inhibitors was significantly higher than that without COX-2 inhibitors. In subgroup analysis, significantly increased ORR results were found on celecoxib (RR = 1.29, 95% CI: 1.09, 1.51, rofecoxib (RR = 1.61, 95% CI: 1.14, 2.28, chemotherapy (RR = 1.40, 95% CI: 1.20, 1.63, and first-line treatment (RR = 1.39, 95% CI: 1.19, 1.63. However, COX-2 inhibitors had no effect on the one-year survival, OS, and PFS. Increased RR of leucopenia (RR = 1.21, 95% CI: 1.01, 1.45 and thrombocytopenia (RR = 1.36, 95% CI: 1.06, 1.76 suggested that COX-2 inhibitors increased hematologic toxicities (grade ≥ 3 of chemotherapy.COX-2 inhibitors increased ORR of advanced NSCLC and had no impact on survival indices, but it may increase the risk of hematologic toxicities associated with chemotherapy.

  12. Box-Cox Mixed Logit Model for Travel Behavior Analysis

    Science.gov (United States)

    Orro, Alfonso; Novales, Margarita; Benitez, Francisco G.

    2010-09-01

    To represent the behavior of travelers when they are deciding how they are going to get to their destination, discrete choice models, based on the random utility theory, have become one of the most widely used tools. The field in which these models were developed was halfway between econometrics and transport engineering, although the latter now constitutes one of their principal areas of application. In the transport field, they have mainly been applied to mode choice, but also to the selection of destination, route, and other important decisions such as the vehicle ownership. In usual practice, the most frequently employed discrete choice models implement a fixed coefficient utility function that is linear in the parameters. The principal aim of this paper is to present the viability of specifying utility functions with random coefficients that are nonlinear in the parameters, in applications of discrete choice models to transport. Nonlinear specifications in the parameters were present in discrete choice theory at its outset, although they have seldom been used in practice until recently. The specification of random coefficients, however, began with the probit and the hedonic models in the 1970s, and, after a period of apparent little practical interest, has burgeoned into a field of intense activity in recent years with the new generation of mixed logit models. In this communication, we present a Box-Cox mixed logit model, original of the authors. It includes the estimation of the Box-Cox exponents in addition to the parameters of the random coefficients distribution. Probability of choose an alternative is an integral that will be calculated by simulation. The estimation of the model is carried out by maximizing the simulated log-likelihood of a sample of observed individual choices between alternatives. The differences between the predictions yielded by models that are inconsistent with real behavior have been studied with simulation experiments.

  13. Prospective performance evaluation of selected common virtual screening tools. Case study: Cyclooxygenase (COX) 1 and 2.

    Science.gov (United States)

    Kaserer, Teresa; Temml, Veronika; Kutil, Zsofia; Vanek, Tomas; Landa, Premysl; Schuster, Daniela

    2015-01-01

    Computational methods can be applied in drug development for the identification of novel lead candidates, but also for the prediction of pharmacokinetic properties and potential adverse effects, thereby aiding to prioritize and identify the most promising compounds. In principle, several techniques are available for this purpose, however, which one is the most suitable for a specific research objective still requires further investigation. Within this study, the performance of several programs, representing common virtual screening methods, was compared in a prospective manner. First, we selected top-ranked virtual screening hits from the three methods pharmacophore modeling, shape-based modeling, and docking. For comparison, these hits were then additionally predicted by external pharmacophore- and 2D similarity-based bioactivity profiling tools. Subsequently, the biological activities of the selected hits were assessed in vitro, which allowed for evaluating and comparing the prospective performance of the applied tools. Although all methods performed well, considerable differences were observed concerning hit rates, true positive and true negative hits, and hitlist composition. Our results suggest that a rational selection of the applied method represents a powerful strategy to maximize the success of a research project, tightly linked to its aims. We employed cyclooxygenase as application example, however, the focus of this study lied on highlighting the differences in the virtual screening tool performances and not in the identification of novel COX-inhibitors.

  14. FGFR1-induced epithelial to mesenchymal transition through MAPK/PLCγ/COX-2-mediated mechanisms.

    Directory of Open Access Journals (Sweden)

    Darren C Tomlinson

    Full Text Available Tumour invasion and metastasis is the most common cause of death from cancer. For epithelial cells to invade surrounding tissues and metastasise, an epithelial-mesenchymal transition (EMT is required. We have demonstrated that FGFR1 expression is increased in bladder cancer and that activation of FGFR1 induces an EMT in urothelial carcinoma (UC cell lines. Here, we created an in vitro FGFR1-inducible model of EMT, and used this model to identify regulators of urothelial EMT. FGFR1 activation promoted EMT over a period of 72 hours. Initially a rapid increase in actin stress fibres occurred, followed by an increase in cell size, altered morphology and increased migration and invasion. By using site-directed mutagenesis and small molecule inhibitors we demonstrated that combined activation of the mitogen activated protein kinase (MAPK and phospholipase C gamma (PLCγ pathways regulated this EMT. Actin stress fibre formation was regulated by PLCγ activation, and was also important for the increase in cell size, migration and altered morphology. MAPK activation regulated migration and E-cadherin expression, indicating that combined activation of PLCγ and MAPK is required for a full EMT. We used expression microarrays to assess changes in gene expression downstream of these signalling cascades. COX-2 was transcriptionally upregulated by FGFR1 and caused increased intracellular prostaglandin E(2 levels, which promoted migration. In conclusion, we have demonstrated that FGFR1 activation in UC cells lines promotes EMT via coordinated activation of multiple signalling pathways and by promoting activation of prostaglandin synthesis.

  15. Synthesis of thio-heterocyclic analogues from Baylis-Hillman bromides as potent cyclooxygenase-2 inhibitors.

    Science.gov (United States)

    Santhoshi, Amlipur; Mahendar, Budde; Mattapally, Saidulu; Sadhu, Partha Sarathi; Banerjee, Sanjay Kumar; Jayathirtha Rao, Vaidya

    2014-04-15

    A series of thio-substituted pyrimidine, benzoxazole, benzothiazole and triazole analogues were synthesized from Baylis-Hillman bromides in a clean and efficient way. The synthesized twenty new compounds were subjected to in vitro COX-1 and COX-2 inhibitory activity. Majority of compounds found to be highly selective COX-2 inhibitor. Seven compounds (16e, 16f, 16k, 16l, 16m, 16r and 16s) displayed anti-inflammatory activity at micromolar concentrations with IC50 values for COX-2 inhibition ranging from 2.93 to 5.34 μM compared to reference drug whose IC50 is 2.66 μM. All these seven compounds had very little COX-1 inhibition property and thus are suitable candidates for anti-inflammatory drugs with less gastrointestinal side effect. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Vitual screening and binding mode elucidation of curcumin analogues on Cyclooxygenase-2 using AYO_COX2_V1.1 protocol

    Science.gov (United States)

    Mulatsari, E.; Mumpuni, E.; Herfian, A.

    2017-05-01

    Curcumin is yellow colored phenolic compounds contained in Curcuma longa. Curcumin is known to have biological activities as anti-inflammatory, antiviral, antioxidant, and anti-infective agent [1]. Synthesis of curcumin analogue compounds has been done and some of them had biological activity like curcumin. In this research, the virtual screening of curcumin analogue compounds has been conducted. The purpose of this research was to determine the activity of these compounds as selective Cyclooxygenase-2inhibitors in in-silico. Binding mode elucidation was made by active and inactive representative compounds to see the interaction of the amino acids in the binding site of the compounds. This research used AYO_COX2_V.1.1, a structure-based virtual screening protocol (SBVS) that has been validated by Mumpuni E et al, 2014 [2]. AYO_COX2_V.1.1 protocol using a variety of integrated applications such as SPORES, PLANTS, BKchem, OpenBabel and PyMOL. The results of virtual screening conducted on 49 curcumin analogue compounds obtained 8 compounds with 4 active amino acid residues (GLY340, ILE503, PHE343, and PHE367) that were considered active as COX-2 inhibitor.

  17. Endocrine side effects of broad-acting kinase inhibitors.

    Science.gov (United States)

    Lodish, Maya B; Stratakis, Constantine A

    2010-09-01

    Targeted therapy in oncology consists of drugs that specifically interfere with abnormal signaling pathways that are dysregulated in cancer cells. Tyrosine kinase inhibitors (TKIs) take advantage of unique oncogenes that are activated in certain types of cancer, and also target common mechanisms of growth, invasion, metastasis, and angiogenesis. However, many kinase inhibitors for cancer therapy are somewhat nonselective, and most have additional mechanisms of action at the cellular level, which are not completely understood. The use of these agents has increased our knowledge of important side effects, of which the practicing clinician must be aware. Recently, proposed endocrine-related side effects of these agents include alterations in thyroid function, bone metabolism, linear growth, gonadal function, fetal development, and glucose metabolism, and adrenal function. This review summarizes the most recent data on the endocrine side effects of TKIs.

  18. The adverse effect of selective cyclooxygenase-2 inhibitor on random skin flap survival in rats.

    Directory of Open Access Journals (Sweden)

    Haiyong Ren

    Full Text Available BACKGROUND: Cyclooxygenase-2(COX-2 inhibitors provide desired analgesic effects after injury or surgery, but evidences suggested they also attenuate wound healing. The study is to investigate the effect of COX-2 inhibitor on random skin flap survival. METHODS: The McFarlane flap model was established in 40 rats and evaluated within two groups, each group gave the same volume of Parecoxib and saline injection for 7 days. The necrotic area of the flap was measured, the specimens of the flap were stained with haematoxylin-eosin(HE for histologic analysis. Immunohistochemical staining was performed to analyse the level of VEGF and COX-2 . RESULTS: 7 days after operation, the flap necrotic area ratio in study group (66.65 ± 2.81% was significantly enlarged than that of the control group(48.81 ± 2.33%(P <0.01. Histological analysis demonstrated angiogenesis with mean vessel density per mm(2 being lower in study group (15.4 ± 4.4 than in control group (27.2 ± 4.1 (P <0.05. To evaluate the expression of COX-2 and VEGF protein in the intermediate area II in the two groups by immunohistochemistry test .The expression of COX-2 in study group was (1022.45 ± 153.1, and in control group was (2638.05 ± 132.2 (P <0.01. The expression of VEGF in the study and control groups were (2779.45 ± 472.0 vs (4938.05 ± 123.6(P <0.01.In the COX-2 inhibitor group, the expressions of COX-2 and VEGF protein were remarkably down-regulated as compared with the control group. CONCLUSION: Selective COX-2 inhibitor had adverse effect on random skin flap survival. Suppression of neovascularization induced by low level of VEGF was supposed to be the biological mechanism.

  19. Prognostic relevance of cyclooxygenase-2 (COX-2) expression in Chinese patients with prostate cancer.

    Science.gov (United States)

    Bin, Wu; He, Wang; Feng, Zhang; Xiangdong, Lu; Yong, Chen; Lele, Kou; Hongbin, Zhang; Honglin, Guo

    2011-02-01

    Cyclooxygenase-2 (COX-2), an inducible isoform of cyclooxygenase, has been reported to be correlated with tumorigenesis, tumor progression and metastasis. The present study was designed to investigate the clinicopathological and prognostic significance of COX-2 in Chinese patients with prostate cancer. Firstly, RT-PCR and Western blot assays were performed to detect the expression of COX-2 mRNA and protein in prostate cancer cell lines and 20 tissue samples (tumor or corresponding non-tumor). Next, immunohistochemistry was performed to detect the expression of COX-2 protein in 88 prostate cancer tissue samples. Finally, the correlation between COX-2 expression and clinicopathological factors and patient survival was evaluated. We found that the expression levels of COX-2 mRNA and protein showed significant difference among four prostate cancer cell lines. Moreover, the levels of COX-2 mRNA and protein were significantly higher in prostate cancer tissues than in corresponding non-tumor tissues. COX-2 staining was positive in the cytoplasm of prostate cancer cells. High-COX-2 expression was correlated with the Gleason score (P=0.009), tumor stage (P=0.012), and lymph-node status (P=0.036). Furthermore, patients with high-COX-2 expression showed lower disease-free (P=0.014) and overall survival (P=0.047) rates than those with low-COX-2 expression. Univariate and multivariate analyses suggested that the status of COX-2 protein expression was an independent prognostic indicator for patients' survival. Taken together, higher COX-2 protein expression might provide an independent prognostic marker for Chinese patients with prostate cancer who have undergone surgery.

  20. Ultraviolet C Irradiation Induces Different Expression of Cyclooxygenase 2 in NIH 3T3 Cells and A431 Cells: The Roles of COX-2 Are Different in Various Cell Lines

    Directory of Open Access Journals (Sweden)

    Ming-Hsiu Wu

    2012-04-01

    Full Text Available Ultraviolet C (UVC is a DNA damage inducer, and 20 J/m2 of UVC irradiation caused cell growth inhibition and induced cell death after exposure for 24–36 h. The growth of NIH 3T3 cells was significantly suppressed at 24 h after UVC irradiation whereas the proliferation of A431 cells was inhibited until 36 h after UVC irradiation. UVC irradiation increased COX-2 expression and such up-regulation reached a maximum during 3–6 h in NIH 3T3 cells. In contrast, UVC-induced COX-2 reached a maximum after 24–36 h in A431 cells. Measuring prostaglandin E2 (PGE2 level showed a biphasic profile that PGE2 release was rapidly elevated in 1–12 h after UVC irradiation and increased again at 24 h in both cell lines. Treatment with the selective COX-2 inhibitor, SC-791, during maximum expression of COX-2 induction, attenuated the UVC induced-growth inhibition in NIH 3T3 cells. In contrast, SC-791 treatment after UVC irradiation enhanced death of A431 cells. These data showed that the patterns of UVC-induced PGE2 secretion from NIH 3T3 cells and A431 cells were similar despite the differential profile in UVC-induced COX-2 up-regulation. Besides, COX-2 might play different roles in cellular response to UVC irradiation in various cell lines.

  1. miR-143 decreases COX-2 mRNA stability and expression in pancreatic cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Pham, Hung [Department of Surgery, UCLA Center of Excellence in Pancreatic Diseases, UCLA David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095 (United States); Department of Medicine, Veterans Affair Greater Los Angeles Healthcare System, Los Angeles, CA 90073 (United States); Ekaterina Rodriguez, C.; Donald, Graham W.; Hertzer, Kathleen M.; Jung, Xiaoman S.; Chang, Hui-Hua; Moro, Aune; Reber, Howard A.; Hines, O. Joe [Department of Surgery, UCLA Center of Excellence in Pancreatic Diseases, UCLA David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095 (United States); Eibl, Guido, E-mail: geibl@mednet.ucla.edu [Department of Surgery, UCLA Center of Excellence in Pancreatic Diseases, UCLA David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095 (United States)

    2013-09-13

    Highlights: •Pancreatic cancer cells express low miR-143 levels and elevated p-MEK, p-MAPK and RREB1. •MEK inhibitors U0126 and PD98059 increase miR-143 expression. •miR-143 decreases COX-2 mRNA stability and expression and PGE{sub 2}. •miR-143 decreases p-p38MAPK, p-MEK, p-MAPK and RREB1 expression. -- Abstract: Small non-coding RNAs, microRNAs (miRNA), inhibit the translation or accelerate the degradation of message RNA (mRNA) by targeting the 3′-untranslated region (3′-UTR) in regulating growth and survival through gene suppression. Deregulated miRNA expression contributes to disease progression in several cancers types, including pancreatic cancers (PaCa). PaCa tissues and cells exhibit decreased miRNA, elevated cyclooxygenase (COX)-2 and increased prostaglandin E{sub 2} (PGE{sub 2}) resulting in increased cancer growth and metastases. Human PaCa cell lines were used to demonstrate that restoration of miRNA-143 (miR-143) regulates COX-2 and inhibits cell proliferation. miR-143 were detected at fold levels of 0.41 ± 0.06 in AsPC-1, 0.20 ± 0.05 in Capan-2 and 0.10 ± 0.02 in MIA PaCa-2. miR-143 was not detected in BxPC-3, HPAF-II and Panc-1 which correlated with elevated mitogen-activated kinase (MAPK) and MAPK kinase (MEK) activation. Treatment with 10 μM of MEK inhibitor U0126 or PD98059 increased miR-143, respectively, by 187 ± 18 and 152 ± 26-fold in BxPC-3 and 182 ± 7 and 136 ± 9-fold in HPAF-II. miR-143 transfection diminished COX-2 mRNA stability at 60 min by 2.6 ± 0.3-fold in BxPC-3 and 2.5 ± 0.2-fold in HPAF-II. COX-2 expression and cellular proliferation in BxPC-3 and HPAF-II inversely correlated with increasing miR-143. PGE{sub 2} levels decreased by 39.3 ± 5.0% in BxPC-3 and 48.0 ± 3.0% in HPAF-II transfected with miR-143. Restoration of miR-143 in PaCa cells suppressed of COX-2, PGE{sub 2}, cellular proliferation and MEK/MAPK activation, implicating this pathway in regulating miR-143 expression.

  2. Discovery of a potent cyclooxygenase-2 inhibitor, S4, through docking-based pharmacophore screening, in vivo and in vitro estimations.

    Science.gov (United States)

    Tseng, Tien-Sheng; Chuang, Show-Mei; Hsiao, Nai-Wan; Chen, Yi-Wen; Lee, Yu-Ching; Lin, Chi-Chen; Huang, Cheng; Tsai, Keng-Chang

    2016-07-19

    Cyclooxygenase (COX; EC: 1.14.99.1), the key enzyme in prostaglandin production in the human body, is a major pharmacological target for developing anti-inflammatory agents. Nonsteroidal anti-inflammatory drugs exhibit anti-inflammatory and analgesic activities when inhibiting COX-2 but cause gastrointestinal toxicity and other side effects because of concurrent inhibition of COX-1. Thus, potent and safe inhibitors against COX-2 are urgently required. We constructed a novel docking-based pharmacophore model for screening selective COX-2 inhibitors and discovered compounds S1, S2, S3, and S4, which apparently inhibit COX-2. Particularly, S4 inhibits COX-2 in vitro and shows a potent anti-inflammatory effect in vivo without cytotoxicity. Molecular docking analyses revealed that S4 interacted satisfactorily with the active site of COX-2 but not with that of COX-1. This reveals that S4 more specifically inhibits COX-2 and has potential for application in developing anti-inflammatory and anticancer agents.

  3. Lineage-specific fragmentation and nuclear relocation of the mitochondrial cox2 gene in chlorophycean green algae (Chlorophyta).

    Science.gov (United States)

    Rodríguez-Salinas, Elizabeth; Riveros-Rosas, Héctor; Li, Zhongkui; Fucíková, Karolina; Brand, Jerry J; Lewis, Louise A; González-Halphen, Diego

    2012-07-01

    In most eukaryotes the subunit 2 of cytochrome c oxidase (COX2) is encoded in intact mitochondrial genes. Some green algae, however, exhibit split cox2 genes (cox2a and cox2b) encoding two polypeptides (COX2A and COX2B) that form a heterodimeric COX2 subunit. Here, we analyzed the distribution of intact and split cox2 gene sequences in 39 phylogenetically diverse green algae in phylum Chlorophyta obtained from databases (28 sequences from 22 taxa) and from new cox2 data generated in this work (23 sequences from 18 taxa). Our results support previous observations based on a smaller number of taxa, indicating that algae in classes Prasinophyceae, Ulvophyceae, and Trebouxiophyceae contain orthodox, intact mitochondrial cox2 genes. In contrast, all of the algae in Chlorophyceae that we examined exhibited split cox2 genes, and could be separated into two groups: one that has a mitochondrion-localized cox2a gene and a nucleus-localized cox2b gene ("Scenedesmus-like"), and another that has both cox2a and cox2b genes in the nucleus ("Chlamydomonas-like"). The location of the split cox2a and cox2b genes was inferred using five different criteria: differences in amino acid sequences, codon usage (mitochondrial vs. nuclear), codon preference (third position frequencies), presence of nucleotide sequences encoding mitochondrial targeting sequences and presence of spliceosomal introns. Distinct green algae could be grouped according to the form of cox2 gene they contain: intact or fragmented, mitochondrion- or nucleus-localized, and intron-containing or intron-less. We present a model describing the events that led to mitochondrial cox2 gene fragmentation and the independent and sequential migration of cox2a and cox2b genes to the nucleus in chlorophycean green algae. We also suggest that the distribution of the different forms of the cox2 gene provides important insights into the phylogenetic relationships among major groups of Chlorophyceae.

  4. Cox-Ingersoll-Ross模型的统计推断%Statistical Inference of Cox-Ingersoll-Ross Model

    Institute of Scientific and Technical Information of China (English)

    舒丽玲; 周占功

    2006-01-01

    该文在离散样本观察下,研究了Cox-Ingersoll-Ross模型的统计推问题,给出了CIR过程的平稳均值m与平稳方差ν的矩估计,并用-m和-ν给出了CIR过程中尺度参数α与β波动率之间的关系,基于CIR过程的平方变差,得到参数β的平方变差估计和参数α的估计.通过数值模拟的方法对平方变差估计与条件矩估计([9])方法作了比较,并选择1997-2006年的R007数据对这两种方法进行了实证分析.

  5. Regulation of COX-2 expression by miR-146a in lung cancer cells.

    Science.gov (United States)

    Cornett, Ashley L; Lutz, Carol S

    2014-09-01

    Prostaglandins are a class of molecules that mediate cellular inflammatory responses and control cell growth. The oxidative conversion of arachidonic acid to prostaglandin H2 is carried out by two isozymes of cyclooxygenase, COX-1 and COX-2. COX-1 is constitutively expressed, while COX-2 can be transiently induced by external stimuli, such as pro-inflammatory cytokines. Interestingly, COX-2 is overexpressed in numerous cancers, including lung cancer. MicroRNAs (miRNAs) are small RNA molecules that function to regulate gene expression. Previous studies have implicated an important role for miRNAs in human cancer. We demonstrate here that miR-146a expression levels are significantly lower in lung cancer cells as compared with normal lung cells. Conversely, lung cancer cells have higher levels of COX-2 protein and mRNA expression. Introduction of miR-146a can specifically ablate COX-2 protein and the biological activity of COX-2 as measured by prostaglandin production. The regulation of COX-2 by miR-146a is mediated through a single miRNA-binding site present in the 3' UTR. Therefore, we propose that decreased miR-146a expression contributes to the up-regulation and overexpression of COX-2 in lung cancer cells. Since potential miRNA-mediated regulation is a functional consequence of alternative polyadenylation site choice, understanding the molecular mechanisms that regulate COX-2 mRNA alternative polyadenylation and miRNA targeting will give us key insights into how COX-2 expression is involved in the development of a metastatic condition.

  6. Population death sequences and Cox processes driven by interacting Feller diffusions

    CERN Document Server

    Wei Gang; Feng Jian Feng

    2002-01-01

    We carry out a complete study on the relationship between Cox processes driven by interacting Feller diffusions and death sequences of immigration-emigration linked population networks. It is first proved that the Cox process driven by a Feller diffusion is equivalent to the death sequence of a birth and death process. The conclusion is then generalized to the case of Cox processes driven by interacting Feller diffusions and death sequences of interacting populations.

  7. The role of chemoprevention by selective cyclooxygenase-2 inhibitors in colorectal cancer patients - a population-based study

    Directory of Open Access Journals (Sweden)

    Yang Yi-Hsin

    2012-12-01

    Full Text Available Abstract Background There are limited population-based studies focusing on the chemopreventive effects of selective cyclooxygenase-2 (COX-2 inhibitors against colorectal cancer. The purpose of this study is to assess the trends and dose–response effects of various medication possession ratios (MPR of selective COX-2 inhibitor used for chemoprevention of colorectal cancer. Methods A population-based case–control study was conducted using the Taiwan Health Insurance Research Database (NHIRD. The study comprised 21,460 colorectal cancer patients and 79,331 controls. The conditional logistic regression was applied to estimate the odds ratios (ORs for COX-2 inhibitors used for several durations (5 years, 3 years, 1 year, 6 months and 3 months prior to the index date. Results In patients receiving selective COX-2 inhibitors, the OR was 0.51 (95% CI=0.29~0.90, p=0.021 for an estimated 5-year period in developing colorectal cancer. ORs showing significant protection effects were found in 10% of MPRs for 5-year, 3-year, and 1-year usage. Risk reduction against colorectal cancer by selective COX-2 inhibitors was observed as early as 6 months after usage. Conclusion Our results indicate that selective COX-2 inhibitors may reduce the development of colorectal cancer by at least 10% based on the MPRs evaluated. Given the limited number of clinical reports from general populations, our results add to the knowledge of chemopreventive effects of selective COX-2 inhibitors against cancer in individuals at no increased risk of colorectal cancer.

  8. Knipholone, a selective inhibitor of leukotriene metabolism.

    Science.gov (United States)

    Wube, A A; Bucar, F; Asres, K; Gibbons, S; Adams, M; Streit, B; Bodensieck, A; Bauer, R

    2006-06-01

    Inhibition of leukotriene formation is one of the approaches to the treatment of asthma and other inflammatory diseases. We have investigated knipholone, isolated from the roots of Kniphofia foliosa, Hochst (Asphodelaceae), for inhibition of leukotriene biosynthesis in an ex vivo bioassay using activated human neutrophile granulocytes. Moreover, activities on 12-lipoxygenase from human platelets and cycloxygenase (COX)-1 and -2 from sheep cotyledons and seminal vesicles, respectively, have been evaluated. Knipholone was found to be a selective inhibitor of leukotriene metabolism in a human blood assay with an IC(50) value of 4.2microM. However, at a concentration of 10microg/ml, the compound showed weak inhibition of 12(S)-HETE production in human platelets and at a concentration of 50microM it produced no inhibition of COX-1 and -2. In our attempt to explain the mechanism of inhibition, we examined the antioxidant activity of knipholone using various in vitro assay systems including free radical scavenging, non-enzymatic lipid peroxidation, and metal chelation. Knipholone was found to be a weak dose-independent free radical scavenger and lipid peroxidation inhibitor, but not a metal chelator. Therefore, the leukotriene biosynthesis inhibitory effect of knipholone was evident by its ability either to inhibit the 5-lipoxygenase activating protein (FLAP) or as a competitive (non-redox) inhibitor of the enzyme. Cytotoxicity results also provided evidence that knipholone exhibits less toxicity for a mammalian host cell.

  9. Structural insight into DNA binding and oligomerization of the multifunctional Cox protein of bacteriophage P2.

    Science.gov (United States)

    Berntsson, Ronnie P-A; Odegrip, Richard; Sehlén, Wilhelmina; Skaar, Karin; Svensson, Linda M; Massad, Tariq; Högbom, Martin; Haggård-Ljungquist, Elisabeth; Stenmark, Pål

    2014-02-01

    The Cox protein from bacteriophage P2 is a small multifunctional DNA-binding protein. It is involved in site-specific recombination leading to P2 prophage excision and functions as a transcriptional repressor of the P2 Pc promoter. Furthermore, it transcriptionally activates the unrelated, defective prophage P4 that depends on phage P2 late gene products for lytic growth. In this article, we have investigated the structural determinants to understand how P2 Cox performs these different functions. We have solved the structure of P2 Cox to 2.4 Å resolution. Interestingly, P2 Cox crystallized in a continuous oligomeric spiral with its DNA-binding helix and wing positioned outwards. The extended C-terminal part of P2 Cox is largely responsible for the oligomerization in the structure. The spacing between the repeating DNA-binding elements along the helical P2 Cox filament is consistent with DNA binding along the filament. Functional analyses of alanine mutants in P2 Cox argue for the importance of key residues for protein function. We here present the first structure from the Cox protein family and, together with previous biochemical observations, propose that P2 Cox achieves its various functions by specific binding of DNA while wrapping the DNA around its helical oligomer.

  10. Evaluating COX-2-765 G →C Genetic Polymorphism in Migraineurs

    Directory of Open Access Journals (Sweden)

    E Mozaffari

    2015-08-01

    Results: The study results revealed that the frequency of the COX-2-765CC and COX-2-765CG genotypes in migraine cases were significantly higher than those of controls. Conclusion: The study findings demonstrated that COX-2-765G→C polymorphism can increase the risk of migraine susceptibility. However, further studies are necessitated to be conducted on larger samples in different nations in other parts of the world in order to assess the role of COX-2 gene variants in the migraine development.

  11. Cox7a2 mediates steroidogenesis in TM3 mouse Leydig cells

    Institute of Scientific and Technical Information of China (English)

    Liang Chen; Zhong-Cheng Xin; Xin Li; Long Tian; Yi-Ming Yuan; Gang Liu; Xue-Jun Jiang; Ying-Lu Guo

    2006-01-01

    Aim: To investigate the regulatory function of Cox7a2 on steroidogenesis and the mechanism involved in TM3 mouse Leydig cells. Methods: The cDNA of Cox7a2 was cloned from TM3 mouse Leydig cells. It was subcloned to pDsRedExpress-N1 and transfected back into TM3 mouse Leydig cells for Cox7a2 overexpression by transient gene transfection.Steroidogenesis affected by overexpressed Cox7a2 was studied by ELISA. To elicit the mechanism of this effect,expression of steroidogenic acute regulatory (StAR) protein and reactive oxygen species (ROS) were examined by Western blot and fluorometer, respectively. Results: The cDNA of Cox7a2 (249 bp) was cloned from Leydig cells and confirmed by DNA sequencing. After constructed pDsRed-Express-Nl-Cox7a2 was transfected back into TM3 mouse Leydig cells, Cox7a2 inhibited not only luteinizing hormone (LH)-induced secretion of testosterone but also the expression of StAR protein. At the same time, Cox7a2 increased the activity of ROS in TM3 mouse Leydig cells. Conclusion:Cox7a2 inhibited LH-induced StAR protein expression, and consequent testosterone production, at least in part, by increasing ROS activity in TM3 mouse Leydig cells.

  12. Kaempferol inhibits IL-1β-induced proliferation of rheumatoid arthritis synovial fibroblasts and the production of COX-2, PGE2 and MMPs.

    Science.gov (United States)

    Yoon, Ha-Yong; Lee, Eun-Gyeong; Lee, Hyun; Cho, In Jin; Choi, Yun Jung; Sung, Myung-Soon; Yoo, Han-Gyul; Yoo, Wan-Hee

    2013-10-01

    Inflammatory cytokines, matrix metalloproteinases (MMPs) and cyclooxygenase (COX)-2 released from rheumatoid arthritis synovial fibroblasts (RASFs) are involved in the destruction of both articular bone and cartilage. Kaempferol has been reported to act as an antioxidant and anti-inflammatory agent by inhibiting nitric oxide synthase and COX enzymes. The aim of the present study was to determine the effects of kaempferol on the interleukin-1β (IL-1β)-induced proliferation of RASFs and the production of MMPs, COX and prostaglandin E2 (PGE2) by RASFs. The proliferation of the RASFs stimulated with IL-1β and treated with/without kaempferol was evaluated by CCK-8 assay. The expression of MMPs, TIMP metallopeptidase inhibitor-1 (TIMP-1), COXs, PGE2 and that of intracellular MAPK signaling molecules, including p-ERK, p-p38, p-JNK and nuclear factor-κB (NF-κB) was examined by immunoblotting or semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and ELISA under the conditions described above. Kaempferol inhibited the proliferation of both unstimulated and IL-1β‑stimulated RASFs, as well as the mRNA and protein expression of MMP-1, MMP-3, COX-2 and PGE2 induced by IL-1β. Kaempferol also inhibited the phosphorylation of ERK-1/2, p38 and JNK, as well as the activation of NF-κB induced by IL-1β. These results indicate that kaempferol inhibits synovial fibroblast proliferation, as well as the production of and MMPs, COX‑2 and PGE2, which is involved in articular inflammation and destruction in rheumatoid arthritis (RA). Our data suggest that kaempferol may be a novel therapeutic agent for the treatment of RA.

  13. Characterisation of PDO olive oil Chianti Classico by non-selective (UV-visible, NIR and MIR spectroscopy) and selective (fatty acid composition) analytical techniques

    Energy Technology Data Exchange (ETDEWEB)

    Casale, M., E-mail: monica@dictfa.unige.it [Universita degli Studi di Genova, Department of Chemistry and Food and Pharmaceutical Technologies, Via Brigata Salerno 13, I-16147, Genoa (Italy); Oliveri, P.; Casolino, C. [Universita degli Studi di Genova, Department of Chemistry and Food and Pharmaceutical Technologies, Via Brigata Salerno 13, I-16147, Genoa (Italy); Sinelli, N. [Universita degli Studi di Milano, Department of Food Science and Technology, Via Celoria, 2 - I-20133 Milan (Italy); Zunin, P.; Armanino, C.; Forina, M.; Lanteri, S. [Universita degli Studi di Genova, Department of Chemistry and Food and Pharmaceutical Technologies, Via Brigata Salerno 13, I-16147, Genoa (Italy)

    2012-01-27

    Highlights: Black-Right-Pointing-Pointer Characterisation of the Italian PDO extra virgin olive oil Chianti Classico. Black-Right-Pointing-Pointer Comparison between non-selective (UV-vis, NIR and MIR spectroscopy) and selective (fatty acid composition) analytical techniques. Black-Right-Pointing-Pointer Synergy among spectroscopic techniques, by the fusion of the respective spectra. Black-Right-Pointing-Pointer Prediction of the content of oleic and linoleic acids in the olive oils. - Abstract: An authentication study of the Italian PDO (protected designation of origin) extra virgin olive oil Chianti Classico was performed; UV-visible (UV-vis), Near-Infrared (NIR) and Mid-Infrared (MIR) spectroscopies were applied to a set of samples representative of the whole Chianti Classico production area. The non-selective signals (fingerprints) provided by the three spectroscopic techniques were utilised both individually and jointly, after fusion of the respective profile vectors, in order to build a model for the Chianti Classico PDO olive oil. Moreover, these results were compared with those obtained by the gas chromatographic determination of the fatty acids composition. In order to characterise the olive oils produced in the Chianti Classico PDO area, UNEQ (unequal class models) and SIMCA (soft independent modelling of class analogy) were employed both on the MIR, NIR and UV-vis spectra, individually and jointly, and on the fatty acid composition. Finally, PLS (partial least square) regression was applied on the UV-vis, NIR and MIR spectra, in order to predict the content of oleic and linoleic acids in the extra virgin olive oils. UNEQ, SIMCA and PLS were performed after selection of the relevant predictors, in order to increase the efficiency of both classification and regression models. The non-selective information obtained from UV-vis, NIR and MIR spectroscopy allowed to build reliable models for checking the authenticity of the Italian PDO extra virgin olive oil

  14. [Cost-effectiveness analysis of celecoxib versus non-selective non-steroidal anti-inflammatory drug therapy for the treatment of osteoarthritis in Spain: A current perspective].

    Science.gov (United States)

    De Lossada, A; Oteo-Álvaro, Á; Giménez, S; Oyagüez, I; Rejas, J

    2016-01-01

    To assess the cost-effectiveness of celecoxib and non-selective non-steroidal anti-inflammatory drugs for the treatment of osteoarthritis in clinical practice in Spain. A decision-tree model using distribution, doses, treatment duration and incidence of GI and CV events observed in the pragmatic PROBE-designed «GI-Reasons» trial was used for cost-effectiveness. Effectiveness was expressed in terms of event averted and quality-adjusted life-years (QALY) gained. QALY were calculated based on utility decrement in case of any adverse events reported in GI-Reasons trial. The National Health System perspective in Spain was applied; cost calculations included current prices of drugs plus cost of adverse events occurred. The analysis was expressed as an incremental cost-effectiveness ratio per QALY gained and per event averted. One-way and probabilistic analyses were performed. Compared with non-selective non-steroidal anti-inflammatory drugs, at current prices, celecoxib treatment had higher overall treatment costs €201 and €157, respectively. However, celecoxib was associated with a slight increase in QALY gain and significantly lower incidence of gastrointestinal events (pcost-effectiveness ratio of €13,286 per QALY gained and €4,471 per event averted. Sensitivity analyses were robust, and confirmed the results of the base case. Celecoxib at current price may be considered as a cost-effective alternative vs. non-selective non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis in daily practice in the Spanish NHS. Copyright © 2015 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

  15. Expression and significance of COX-2 and VEGF in osteosarcoma%骨肉瘤组织中COX-2、VEGF的表达及意义

    Institute of Scientific and Technical Information of China (English)

    马隽; 陈晓明; 钟艳平; 黎丹戎; 肖增明

    2011-01-01

    目的 观察骨肉瘤组织中环氧化酶2(COX-2)、血管内皮生长因子(VEGF)的表达情况,并探讨其意义.方法 对骨肉瘤患者45例行截肢术或瘤段切除假体置换术.术中分别切取骨肉瘤组织及对应癌旁(肿瘤组织边缘外5.0 cm处)组织标本.采用免疫组化SP法检测骨肉瘤组织及其癌旁组织中的COX-2、VEGF;以CD34为标记,计算微血管密度(MVD).结果 COX-2和VEGF阳性表达率及MVD在骨肉瘤组织中分别为80.0%、75.6%和(43.6±11.4)条/HP,均高于癌旁组织的22.2%、17.8%和(13.5±7.3)条/HP,且三者与骨肉瘤的外科分期有关(P均<0.05).COX-2与VEGF的表达呈正相关,COX-2和VEGF的表达均与MVD呈正相关(r分别为0.75、0.58和0.75,P均<0.05).COX-2和VEGF同时阳性表达时,MVD显著增高(P<0.05).结论 COX-2和VEGF在骨肉瘤组织中呈高表达,且与骨肉瘤外科分期呈正相关.二者共同参与了骨肉瘤的发生、发展,其机制可能是促进骨肉瘤组织中血管生成.%Objective To investigate the expression of cyclooxygenase 2 (COX-2) and vascular endothelial growth factor (VEGF) in osteosarcoma and explore the significance.Methods 45 patients with osteosarcoma were treated with amputation or prosthesis replacement.Osteosarcoma and corresponding adjacent ( > 5.0 cm at the outer edge of the tumor tissue) tissue samples were obtained during operation.The expression of COX-2, VEGF and MVD marked by CD34 of osteosarcoma and their adjacent tissues were detected by immuno histochemistry.Results The positive rates of COX-2, VEGF and MVD in osteosarcoma tissues were 80.0%, 75.6% and (43.6 ± 11.4) stripe/HP, respectively, which were higher than those in adjacent tissues(P all <0.05).In patients with osteosarcoma, the expression of COX-2, VEGF and MVD were associated with Enneking stage( P all <0.05).There was a positive relationship between the expression of COX-2 and VEGF,the expression of COX-2 and VEGF were positively correlated with MVD

  16. Further evidence for differences between non-selective and BZ-1 (omega 1) selective, benzodiazepine receptor ligands in murine models of "state" and "trait" anxiety.

    Science.gov (United States)

    Griebel, G; Sanger, D J; Perrault, G

    1996-01-01

    The behavioural effects of several BZ (omega) receptor ligands were compared in mice using the light/dark choice task, an animal model of "state" anxiety, and the free-exploration test, which has been proposed as an experimental model of "trait" anxiety. The drugs used included non-selective full (alprazolam, clorazepate, chlordiazepoxide and diazepam), partial agonists (bretazenil, imidazenil and Ro 19-8022) and BZ-1 (omega 1) selective receptor ligands (abecarnil, CL 218,872 and zolpidem). In the light/dark choice task, non-selective full agonists elicited clear anxiolytic-like effects increasing time spent in the lit box and simultaneously reducing attempts at entry into the illuminated cage followed by withdrawal responses, a measure of risk assessment. With the exception of abecarnil, both non-selective partial agonists and BZ-1 (omega 1) selective receptor ligands displayed reduced efficacy compared to the full agonists as they decreased risk assessment responses without altering time in the lit box. In addition, the weak anxiolytic-like actions displayed by selective BZ-1 (omega 1) agents were evident only at doses which reduced locomotor activity, indicating that this effect may be non-specific. In the free-exploration test, non-selective BZ (omega) receptor agonists markedly increased the percentage of time spent in the novel compartment and reduced the number of attempts to enter whereas selective BZ-1 (omega 1) receptor ligands displayed a weaker neophobia-reducing effect as they reduced risk assessment responses only. As was the case in the light/dark choice task, this latter effect was observed at locomotor depressant doses. These findings indicate that while both full and partial BZ (omega) receptor agonists are equally effective against "trait" anxiety, full agonists may be superior in reducing "state" anxiety. In addition, the lack of specific effects of selective BZ-1 (omega 1) receptor ligands in reducing both types of anxiety suggests that the BZ

  17. 沉默COX-2抑制A549细胞的恶性增殖%COX-2 silencing inhibits cell proliferation in A549 cell

    Institute of Scientific and Technical Information of China (English)

    Weiying Li; Wentao Yue; Lina Zhang; Xiaoting Zhao; Li Ma; Xuehui Yang; Chunyan Zhang; Yue Wang; Meng Gu

    2011-01-01

    Objective: The aim of this study was to explore the effects on malignant proliferation of A549 cell by silencing cyclooxygenase (COX)-2. Methods: In the present study, we constructed three siRNA vectors producing small interference RNA. The siRNA vectors and the vacant vectors were transfected into A549 cell with lipofectamine respectively and the transfected cell strains were constructed. The change of COX-2 expression levels was examined by Western blot and RT-PCR. The effects on the proliferation of lung cancer cells were studied by cell growth curve, clonogenic assay and xenograft assays. Results: The siRNA expression vectors produced marked effects in A549 cell but the inhibited effects were different. The effect of psi-10 was best and the mRNA and protein levels of COX-2 reduced 61.2% and 56.2% respectively in A549-si10 cell in contrast to the control.The growth of A549 cell slowed and the colony formation rate reduced after silencing COX-2. In xenograft assays, the growth speeds of tumor became slow and the numbers of tumor reduced after silencing COX-2. Conclusion: The si10 target of COX-2 has the best silencing effect in A549 cell and the best inhibition effect on malignant proliferation of A549 cell in vivo and in vitro.

  18. PARP inhibitors.

    Science.gov (United States)

    Anwar, Maheen; Aslam, Hafiz Muhammad; Anwar, Shahzad

    2015-01-01

    Poly (ADP-ribose) polymerases, abbreviated as PARPs, are a group of familiar proteins that play a central role in DNA repair employing the base excision repair (BER) pathway. There about 17 proteins in this family out of which the primary nuclear PARPs are PARP-1, PARP-2, PARP-3, and tankyrases 1 and 2 (PARP-5a and -5b) .The PARP family members are known to engage in a wide range of cellular activities, for example, DNA repair, transcription, cellular signaling, cell cycle regulation and mitosis amongst others. The chief functional units of PARP-1 are an amino terminal DNA binding domain (DBD), a central auto modification domain (AMD), and a carboxyl-terminal catalytic domain (CD). PARP inhibitors are currently undergoing clinical trials as targeted treatment modalities of breast, uterine, colorectal and ovarian cancer. This review summarizes current insights into the mechanism of action of PARP inhibitors, its recent clinical trials, and potential next steps in the evaluation of this promising class of anti-cancer drugs.

  19. Prognostic Significance and Clinicopathological Associations of COX-2 SNP in Patients with Nonsmall Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Peter P. Grimminger

    2009-01-01

    Full Text Available Background. To further improve the screening, diagnosis, and therapy of patients with nonsmall cell lung cancer (NSCLC additional diagnostic tools are urgently needed. Gene expression of Cyclooxygenase-2 (COX-2 has been linked to prognosis in patients with NSCLC. The role of the COX-2 926G>C Single Nucleotide Polymorphism (SNP in patients with NSCLC remains unclear. The aim of this study was to investigate the potential of the COX-2 926G>C SNP as a molecular marker in this disease. Methods. COX-2 926G>C SNP was analyzed in surgically resected tumor tissue of 85 patients with NSCLC using a PCR-based RFLP technique. Results. The COX-2 926G>C SNP genotypes were detected with the following frequencies: GG n=62 (73%, GC n=20 (23%, CC n=3 (4%. There were no associations between COX-2 SNP genotype and histology, grading or gender detectable. COX-2 SNP was significantly associated with tumor stage (P=.032 and lymph node status (P=.016, Chi-square test. With a median followup of 85.9 months, the median survival was 59.7 months. There were no associations seen between the COX-2 SNP genotype and patients prognosis. Conclusions. The COX-2 926G>C SNP is detectable at a high frequency in patients with NSCLC. The COX-2 926G>C SNP genotype is not a prognostic molecular marker in this disease. However, patients with the GC or CC genotype seem more susceptible to lymph node metastases and higher tumor stage than patients with the GG genotype. The results suggest COX-2 926G>C SNP as a molecular marker for lymph node involvement in this disease.

  20. Presenilin 1/gamma-secretase is associated with cadmium-induced E-cadherin cleavage and COX-2 gene expression in T47D breast cancer cells.

    Science.gov (United States)

    Park, Chang Seok; Kim, Ohn Soon; Yun, Sang-Moon; Jo, Sangmee A; Jo, Inho; Koh, Young Ho

    2008-12-01

    Cadmium is a heavy metal that has multiple toxic effects on human health and has been classified as a human carcinogen. E-cadherin is a major target of cadmium; however, the roles of E-cadherin and cadmium and the mechanisms of tumor progression remain to be defined. Here, we demonstrate that cadmium increases E-cadherin processing via a gamma-secretase in the T47D breast cancer cell lines. This presenilin 1 (PS1)/gamma-secretase-dependent cleavage of E-cadherin was accompanied by changes in reactive oxygen species or calcium. E-cadherin cleavage was blocked by a PS1 dominant-negative mutant, gamma-secretase inhibitors [N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) and L-685,486], antioxidants (N-acetylcysteine and Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride), or a calcium chelating drug 1,2-bis(o-Aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester. Immunofluorescence analysis confirmed the disappearance of E-cadherin staining at the cell surface. Those inhibitors attenuated cadmium-induced cytotoxicity. Additionally, cadmium treatment increased cell motility and invasion ability, which was abated by DAPT. Interestingly, cyclooxygenase-2 (COX-2) expression induced by cadmium was also inhibited by DAPT. The cadmium-induced cell motility and invasion ability were inhibited by a COX-2 inhibitor, NS398. Our data indicate a novel molecular mechanism that links cytotoxicity of cadmium and disrupted E-cadherin processing to adherens junctions; cadmium induces COX-2 expression via gamma-secretase, which increases cell motility and invasion ability. Understanding the downstream signaling cascades of cadmium that promote tumor progression might be a key to the development of novel therapeutic strategies.

  1. Synthesis and evaluation of radioiodinated cyclooxygenase-2 inhibitors as potential SPECT tracers for cyclooxygenase-2 expression

    Energy Technology Data Exchange (ETDEWEB)

    Kuge, Yuji [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan)]. E-mail: kuge@pharm.kyoto-u.ac.jp; Katada, Yumiko [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Shimonaka, Sayaka [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Temma, Takashi [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Kimura, Hiroyuki [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Kiyono, Yasushi [Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto 606-8507 (Japan); Yokota, Chiaki [Cerebrovascular Laboratory, National Cardiovascular Center Research Institute, Osaka 565-8565 (Japan); Minematsu, Kazuo [Cerebrovascular Division, Department of Medicine, National Cardiovascular Center Research Institute, Osaka 565-8565 (Japan); Seki, Koh-ichi [Central Institute of Isotope Science, Hokkaido University, Hokkaido 060-8638 (Japan); Tamaki, Nagara [Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Hokkaido 060-8638 (Japan); Ohkura, Kazue [Department of Radiopharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido 061-0293 (Japan); Saji, Hideo [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan)

    2006-01-15

    Although several COX-2 inhibitors have recently been radiolabeled, their potential for imaging COX-2 expression remains unclear. In particular, the sulfonamide moiety of COX-2 inhibitors may cause slow blood clearance of the radiotracer, due to its affinity for carbonic anhydrase (Canada) in erythrocytes. Thus, we designed a methyl sulfone-type analogue, 5-(4-iodophenyl)-1-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole (IMTP). In this study, the potential of radioiodinated IMTP was assessed in comparison with a {sup 125}I-labeled celecoxib analogue with a sulfonamide moiety ({sup 125}I-IATP). Methods: The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation by hydrogen peroxide. The biodistribution of {sup 125}I-IMTP and {sup 125}I-IATP was determined by the ex vivo tissue counting method in rats. Distribution of the labeled compounds to rat blood cells was measured. Results: The COX-2 inhibitory potency of IMTP (IC{sub 5}=5.16 {mu}M) and IATP (IC{sub 5}=8.20 {mu}M) was higher than that of meloxicam (IC{sub 5}=29.0 {mu}M) and comparable to that of SC-58125 (IC{sub 5}=1.36 {mu}M). The IC{sub 5} ratios (COX-1/COX-2) indicated the high isoform selectivity of IMTP and IATP for COX-2. Significant levels of {sup 125}I-IMTP and {sup 125}I-IATP were observed in the kidneys and the brain (organs known to express COX-2). The blood clearance of {sup 125}I-IMTP was much faster than that of {sup 125}I-IATP. Distribution of {sup 125}I-IATP to blood cells (88.0%) was markedly higher than that of {sup 125}I-IMTP (18.1%), which was decreased by CA inhibitors. Conclusions: Our results showed a high inhibitory potency and selectivity of IMTP for COX-2. The substitution of a sulfonamide moiety to a methyl sulfone moiety effectively improved the blood clearance of the compound, indicating the loss of the cross reactivity with CA in {sup 125}I-IMTP. {sup 123}I-IMTP may be a potential SPECT radiopharmaceutical for COX-2 expression.

  2. Characterisation of PDO olive oil Chianti Classico by non-selective (UV-visible, NIR and MIR spectroscopy) and selective (fatty acid composition) analytical techniques.

    Science.gov (United States)

    Casale, M; Oliveri, P; Casolino, C; Sinelli, N; Zunin, P; Armanino, C; Forina, M; Lanteri, S

    2012-01-27

    An authentication study of the Italian PDO (protected designation of origin) extra virgin olive oil Chianti Classico was performed; UV-visible (UV-vis), Near-Infrared (NIR) and Mid-Infrared (MIR) spectroscopies were applied to a set of samples representative of the whole Chianti Classico production area. The non-selective signals (fingerprints) provided by the three spectroscopic techniques were utilised both individually and jointly, after fusion of the respective profile vectors, in order to build a model for the Chianti Classico PDO olive oil. Moreover, these results were compared with those obtained by the gas chromatographic determination of the fatty acids composition. In order to characterise the olive oils produced in the Chianti Classico PDO area, UNEQ (unequal class models) and SIMCA (soft independent modelling of class analogy) were employed both on the MIR, NIR and UV-vis spectra, individually and jointly, and on the fatty acid composition. Finally, PLS (partial least square) regression was applied on the UV-vis, NIR and MIR spectra, in order to predict the content of oleic and linoleic acids in the extra virgin olive oils. UNEQ, SIMCA and PLS were performed after selection of the relevant predictors, in order to increase the efficiency of both classification and regression models. The non-selective information obtained from UV-vis, NIR and MIR spectroscopy allowed to build reliable models for checking the authenticity of the Italian PDO extra virgin olive oil Chianti Classico. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. Genomic, Lipidomic and Metabolomic Analysis of Cyclooxygenase-null Cells: Eicosanoid Storm, Cross Talk, and Compensation by COX-1.

    Science.gov (United States)

    Islam, Abul B M M K; Dave, Mandar; Amin, Sonia; Jensen, Roderick V; Amin, Ashok R

    2016-04-01

    The constitutively-expressed cyclooxygenase 1 (COX-1) and the inducible COX-2 are both involved in the conversion of arachidonic acid (AA) to prostaglandins (PGs). However, the functional roles of COX-1 at the cellular level remain unclear. We hypothesized that by comparing differential gene expression and eicosanoid metabolism in lung fibroblasts from wild-type (WT) mice and COX-2(-/-) or COX-1(-/-) mice may help address the functional roles of COX-1 in inflammation and other cellular functions. Compared to WT, the number of specifically-induced transcripts were altered descendingly as follows: COX-2(-/-)>COX-1(-/-)>WT+IL-1β. COX-1(-/-) or COX-2(-/-) cells shared about 50% of the induced transcripts with WT cells treated with IL-1β, respectively. An interactive "anti-inflammatory, proinflammatory, and redox-activated" signature in the protein-protein interactome map was observed in COX-2(-/-) cells. The augmented COX-1 mRNA (in COX-2(-/-) cells) was associated with the upregulation of mRNAs for glutathione S-transferase (GST), superoxide dismutase (SOD), NAD(P)H dehydrogenase quinone 1 (NQO1), aryl hydrocarbon receptor (AhR), peroxiredoxin, phospholipase, prostacyclin synthase, and prostaglandin E synthase, resulting in a significant increase in the levels of PGE2, PGD2, leukotriene B4 (LTB4), PGF1α, thromboxane B2 (TXB2), and PGF2α. The COX-1 plays a dominant role in shifting AA toward the LTB4 pathway and anti-inflammatory activities. Compared to WT, the upregulated COX-1 mRNA in COX-2(-/-) cells generated an "eicosanoid storm". The genomic characteristics of COX-2(-/-) is similar to that of proinflammatory cells as observed in IL-1β induced WT cells. COX-1(-/-) and COX-2(-/-) cells exhibited compensation of various eicosanoids at the genomic and metabolic levels.

  4. Genomic, Lipidomic and Metabolomic Analysis of Cyclooxygenase-null Cells: Eicosanoid Storm, Cross Talk, and Compensation by COX-1

    Directory of Open Access Journals (Sweden)

    Abul B.M.M.K. Islam

    2016-04-01

    Full Text Available The constitutively-expressed cyclooxygenase 1 (COX-1 and the inducible COX-2 are both involved in the conversion of arachidonic acid (AA to prostaglandins (PGs. However, the functional roles of COX-1 at the cellular level remain unclear. We hypothesized that by comparing differential gene expression and eicosanoid metabolism in lung fibroblasts from wild-type (WT mice and COX-2-/- or COX-1-/- mice may help address the functional roles of COX-1 in inflammation and other cellular functions. Compared to WT, the number of specifically-induced transcripts were altered descendingly as follows: COX-2-/- > COX-1-/- > WT + IL-1β. COX-1-/- or COX-2-/- cells shared about 50% of the induced transcripts with WT cells treated with IL-1β, respectively. An interactive “anti-inflammatory, proinflammatory, and redox-activated” signature in the protein–protein interactome map was observed in COX-2-/- cells. The augmented COX-1 mRNA (in COX-2-/- cells was associated with the upregulation of mRNAs for glutathione S-transferase (GST, superoxide dismutase (SOD, NAD(PH dehydrogenase quinone 1 (NQO1, aryl hydrocarbon receptor (AhR, peroxiredoxin, phospholipase, prostacyclin synthase, and prostaglandin E synthase, resulting in a significant increase in the levels of PGE2, PGD2, leukotriene B4 (LTB4, PGF1α, thromboxane B2 (TXB2, and PGF2α. The COX-1 plays a dominant role in shifting AA toward the LTB4 pathway and anti-inflammatory activities. Compared to WT, the upregulated COX-1 mRNA in COX-2-/- cells generated an “eicosanoid storm”. The genomic characteristics of COX-2-/- is similar to that of proinflammatory cells as observed in IL-1β induced WT cells. COX-1-/- and COX-2-/- cells exhibited compensation of various eicosanoids at the genomic and metabolic levels.

  5. Imaging of cyclooxygenase-2 (COX-2) expression : Potential use in diagnosis and drug evaluation

    NARCIS (Netherlands)

    de Vries, E. F. J.

    2006-01-01

    Cyclooxygenase is an enzyme that catalyzes the first two steps in the biosynthesis of prostanoids. The constitutively expressed isoform COX-1 is regarded as a housekeeping enzyme that is responsible for the normal production of prostanoids. The inducible isoform COX-2, on the other hand, is transien

  6. Correlation of VEGF and COX-2 Expression with VM in Malignant Melanomas

    Institute of Scientific and Technical Information of China (English)

    BaocunSun; ShiwuZhang; XiulanZhao; YanxueLiu; ChunshengNi; DanfangZhang; HongQi; ZhiyongLiu; XishanHao

    2004-01-01

    OBJECTIVE To investigate the relationship between vascular epithelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) in melanomas and the expressive difference of VEGF and COX-2 between melanomas with and without vasculogenic mimicry(VM).METHODS Sixty cases of malignant melanomas emoeaaea In paraffin were studied. The tumors were divided into a high-grade malignant group and a low-grade malignant group based on their tumor type, atypia and survival time of the patient. Then tissue microarrays were produced from these paraffin-embedded tumor tissues which were stained for VEGF, COX-2 and PAS. The difference in expression between VEGF and COX-2 in the malignant melanomas was compared using a grid-count. In addition, the tumors were also divided into mimicry and non-mimicry groups based on their PAS staining. Then the differences between the PAS positive and negative areas of the 2 groups were compared.RESULTS In malignant melanomas with VM, VEGF and COX-2 expression was less in tumors in which VM was absent, but VEGF, COX-2 expression in high-grade malignant melanomas was higher than that in low-grade grade malignant melanomas. Expression of VEGF was correlated with COX-2 expression.CONCLUSION VM exists in some high-grade malignant melanomas. The differences and relations between VEGF and COX-2 showed that some high-grade malignant melanomas possess a unique molecular-mechanism of tumor metastasis and blood supply.

  7. COX-2 and TGF-β expression in proliferative disorders of canine prostate

    OpenAIRE

    Marcela M.P. Rodrigues; Di Santis, Giovana W.; De Moura, Veridiana M.B.D.; Amorim, Renée Laufer [UNESP

    2010-01-01

    COX-2 and TGF-β expression was determined in order to correlate non-neoplastic lesions, preneoplastic lesions and carcinoma in the prostate of dogs. The results show that neoplastic and preneoplastic lesions express more COX-2 and TGF-β when compared to carcinomas, which suggests these proteins may cooperate in the process of prostate tumorigenesis.

  8. Protective effect of NSAIDs on cancer and influence of COX-2 C-765G genotype

    NARCIS (Netherlands)

    C. Siemes (Claire); L.E. Visser (Loes); J.W.W. Coebergh (Jan Willem); A. Hofman (Albert); A.G. Uitterlinden (André); B.H.Ch. Stricker (Bruno)

    2008-01-01

    textabstractPurpose: Inhibition of COX-2 enzymes is a frequently suggested mechanism for the beneficial effects of NSAIDs on carcinogenesis. The aim of this study was to explore the role of cumulative NSAID use on four common non-skin related cancers and modification by COX-2 G-765C genotype. Patien

  9. Predicting and Modelling of Survival Data when Cox's Regression Model does not hold

    DEFF Research Database (Denmark)

    Scheike, Thomas H.; Zhang, Mei-Jie

    2002-01-01

    Aalen model; additive risk model; counting processes; competing risk; Cox regression; flexible modeling; goodness of fit; prediction of survival; survival analysis; time-varying effects......Aalen model; additive risk model; counting processes; competing risk; Cox regression; flexible modeling; goodness of fit; prediction of survival; survival analysis; time-varying effects...

  10. Comparing treatment effects after adjustment with multivariable Cox proportional hazards regression and propensity score methods

    NARCIS (Netherlands)

    Martens, Edwin P|info:eu-repo/dai/nl/088859010; de Boer, Anthonius|info:eu-repo/dai/nl/075097346; Pestman, Wiebe R; Belitser, Svetlana V; Stricker, Bruno H Ch; Klungel, Olaf H|info:eu-repo/dai/nl/181447649

    PURPOSE: To compare adjusted effects of drug treatment for hypertension on the risk of stroke from propensity score (PS) methods with a multivariable Cox proportional hazards (Cox PH) regression in an observational study with censored data. METHODS: From two prospective population-based cohort

  11. Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease.

    Science.gov (United States)

    Indrieri, Alessia; van Rahden, Vanessa Alexandra; Tiranti, Valeria; Morleo, Manuela; Iaconis, Daniela; Tammaro, Roberta; D'Amato, Ilaria; Conte, Ivan; Maystadt, Isabelle; Demuth, Stephanie; Zvulunov, Alex; Kutsche, Kerstin; Zeviani, Massimo; Franco, Brunella

    2012-11-02

    Microphthalmia with linear skin lesions (MLS) is an X-linked dominant male-lethal disorder associated with mutations in holocytochrome c-type synthase (HCCS), which encodes a crucial player of the mitochondrial respiratory chain (MRC). Unlike other mitochondrial diseases, MLS is characterized by a well-recognizable neurodevelopmental phenotype. Interestingly, not all clinically diagnosed MLS cases have mutations in HCCS, thus suggesting genetic heterogeneity for this disorder. Among the possible candidates, we analyzed the X-linked COX7B and found deleterious de novo mutations in two simplex cases and a nonsense mutation, which segregates with the disease, in a familial case. COX7B encodes a poorly characterized structural subunit of cytochrome c oxidase (COX), the MRC complex IV. We demonstrated that COX7B is indispensable for COX assembly, COX activity, and mitochondrial respiration. Downregulation of the COX7B ortholog (cox7B) in medaka (Oryzias latipes) resulted in microcephaly and microphthalmia that recapitulated the MLS phenotype and demonstrated an essential function of complex IV activity in vertebrate CNS development. Our results indicate an evolutionary conserved role of the MRC complexes III and IV for the proper development of the CNS in vertebrates and uncover a group of mitochondrial diseases hallmarked by a developmental phenotype.

  12. Effect of uric acid on inflammatory COX-2 and ROS pathways in vascular smooth muscle cells.

    Science.gov (United States)

    Oğuz, Nurgül; Kırça, Mustafa; Çetin, Arzu; Yeşilkaya, Akın

    2017-10-01

    Hyperuricemia is thought to play a role in cardiovascular diseases (CVD), including hypertension, coronary artery disease and atherosclerosis. However, exactly how uric acid contributes to these pathologies is unknown. An underlying mechanism of inflammatory diseases, such as atherosclerosis, includes enhanced production of cyclooxygenase-2 (COX-2) and superoxide anion. Here, we aimed to examine the effect of uric acid on inflammatory COX-2 and superoxide anion production and to determine the role of losartan. Primarily cultured vascular smooth muscle cells (VSMCs) were time and dose-dependently induced by uric acid and COX-2 and superoxide anion levels were measured. COX-2 levels were determined by ELISA, and superoxide anion was measured by the superoxide dismutase (SOD)-inhibitable reduction of ferricytochrome c method. Uric acid elevated COX-2 levels in a time-dependent manner. Angiotensin-II receptor blocker, losartan, diminished uric-acid-induced COX-2 elevation. Uric acid also increased superoxide anion level in VSMCs. Uric acid plays an important role in CVD pathogenesis by inducing inflammatory COX-2 and ROS pathways. This is the first study demonstrating losartan's ability to reduce uric-acid-induced COX-2 elevation.

  13. Nucleobindin co-localizes and associates with cyclooxygenase (COX-2 in human neutrophils.

    Directory of Open Access Journals (Sweden)

    Patrick Leclerc

    Full Text Available The inducible cyclooxygenase isoform (COX-2 is associated with inflammation, tumorigenesis, as well as with physiological events. Despite efforts deployed in order to understand the biology of this multi-faceted enzyme, much remains to be understood. Nucleobindin (Nuc, a ubiquitous Ca(2+-binding protein, possesses a putative COX-binding domain. In this study, we investigated its expression and subcellular localization in human neutrophils, its affinity for COX-2 as well as its possible impact on PGE(2 biosynthesis. Complementary subcellular localization approaches including nitrogen cavitation coupled to Percoll fractionation, immunofluorescence, confocal and electron microscopy collectively placed Nuc, COX-2, and all of the main enzymes involved in prostanoid synthesis, in the Golgi apparatus and endoplasmic reticulum of human neutrophils. Immunoprecipitation experiments indicated a high affinity between Nuc and COX-2. Addition of human recombinant (hr Nuc to purified hrCOX-2 dose-dependently caused an increase in PGE(2 biosynthesis in response to arachidonic acid. Co-incubation of Nuc with COX-2-expressing neutrophil lysates also increased their capacity to produce PGE(2. Moreover, neutrophil transfection with hrNuc specifically enhanced PGE(2 biosynthesis. Together, these results identify a COX-2-associated protein which may have an impact in prostanoid biosynthesis.

  14. New Insights on COX-2 in Chronic Inflammation Driving Breast Cancer Growth and Metastasis.

    Science.gov (United States)

    Hugo, Honor J; Saunders, C; Ramsay, R G; Thompson, E W

    2015-12-01

    The medicinal use of aspirin stretches back to ancient times, before it was manufactured in its pure form in the late 19th century. Its accepted mechanistic target, cyclooxygenase (COX), was discovered in the 1970s and since this landmark discovery, the therapeutic application of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has increased dramatically. The most significant benefits of NSAIDs are in conditions involving chronic inflammation (CI). Given the recognized role of CI in cancer development, the use of long-term NSAID treatment in the prevention of cancer is an enticing possibility. COX-2 is a key driver of CI, and here we review COX-2 expression as a predictor of survival in various cancer types, including breast. Obesity and post-partum involution are natural inflammatory states that are associated with increased breast cancer risk. We outline the COX-2 mediated mechanisms contributing to the growth of cancers. We dissect the cellular mechanism of epithelial-mesenchymal transition (EMT) and how COX-2 may induce this to facilitate tumor progression. Finally we examine the potential regulation of COX-2 by c-Myb, and the possible interplay between c-Myb/COX-2 in proliferation, and hypoxia inducible factor-1 alpha (HIF1α)/COX-2 in invasive pathways in breast cancer.

  15. Glutathione selectively modulates the binding of platinum drugs to human copper chaperone Cox17.

    Science.gov (United States)

    Zhao, Linhong; Wang, Zhen; Wu, Han; Xi, Zhaoyong; Liu, Yangzhong

    2015-12-01

    The copper chaperone Cox17 (cytochrome c oxidase copper chaperone) has been shown to facilitate the delivery of cisplatin to mitochondria, which contributes to the overall cytotoxicity of the drug [Zhao et al. (2014) Chem. Commun. 50: , 2667-2669]. Kinetic data indicate that Cox17 has reactivity similar to glutathione (GSH), the most abundant thiol-rich molecule in the cytoplasm. In the present study, we found that GSH significantly modulates the reaction of platinum complexes with Cox17. GSH enhances the reactivity of three anti-cancer drugs (cisplatin, carboplatin and oxaliplatin) to Cox17, but suppresses the reaction of transplatin. Surprisingly, the pre-formed cisplatin-GSH adducts are highly reactive to Cox17; over 90% platinum transfers from GSH to Cox17. On the other hand, transplatin-GSH adducts are inert to Cox17. These different effects are consistent with the drug activity of these platinum complexes. In addition, GSH attenuates the protein aggregation of Cox17 induced by platination. These results indicate that the platinum-protein interactions could be substantially influenced by the cellular environment.

  16. Endomicroscopic Imaging of COX-2 Activity in Murine Sporadic and Colitis-Associated Colorectal Cancer.

    Science.gov (United States)

    Foersch, Sebastian; Neufert, Clemens; Neurath, Markus F; Waldner, Maximilian J

    2013-01-01

    Although several studies propose a chemopreventive effect of aspirin for colorectal cancer (CRC) development, the general use of aspirin cannot be recommended due to its adverse side effects. As the protective effect of aspirin has been associated with an increased expression of COX-2, molecular imaging of COX-2, for instance, during confocal endomicroscopy could enable the identification of patients who would possibly benefit from aspirin treatment. In this pilot trial, we used a COX-2-specific fluorescent probe for detection of colitis-associated and sporadic CRC in mice using confocal microscopy. Following the injection of the COX-2 probe into tumor-bearing APCmin mice or mice exposed to the AOM + DSS model of colitis-associated cancer, the tumor-specific upregulation of COX-2 could be validated with in vivo fluorescence imaging. Subsequent confocal imaging of tumor tissue showed an increased number of COX-2 expressing cells when compared to the normal mucosa of healthy controls. COX-2-expression was detectable with subcellular resolution in tumor cells and infiltrating stroma cells. These findings pose a proof of concept and suggest the use of CLE for the detection of COX-2 expression during colorectal cancer surveillance endoscopy. This could improve early detection and stratification of chemoprevention in patients with CRC.

  17. Endomicroscopic Imaging of COX-2 Activity in Murine Sporadic and Colitis-Associated Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Sebastian Foersch

    2013-01-01

    Full Text Available Although several studies propose a chemopreventive effect of aspirin for colorectal cancer (CRC development, the general use of aspirin cannot be recommended due to its adverse side effects. As the protective effect of aspirin has been associated with an increased expression of COX-2, molecular imaging of COX-2, for instance, during confocal endomicroscopy could enable the identification of patients who would possibly benefit from aspirin treatment. In this pilot trial, we used a COX-2-specific fluorescent probe for detection of colitis-associated and sporadic CRC in mice using confocal microscopy. Following the injection of the COX-2 probe into tumor-bearing APCmin mice or mice exposed to the AOM + DSS model of colitis-associated cancer, the tumor-specific upregulation of COX-2 could be validated with in vivo fluorescence imaging. Subsequent confocal imaging of tumor tissue showed an increased number of COX-2 expressing cells when compared to the normal mucosa of healthy controls. COX-2-expression was detectable with subcellular resolution in tumor cells and infiltrating stroma cells. These findings pose a proof of concept and suggest the use of CLE for the detection of COX-2 expression during colorectal cancer surveillance endoscopy. This could improve early detection and stratification of chemoprevention in patients with CRC.

  18. Cox-2 levels in canine mammary tumors, including inflammatory mammary carcinoma: clinicopathological features and prognostic significance.

    Science.gov (United States)

    Queiroga, Felisbina Luisa; Perez-Alenza, Maria Dolores; Silvan, Gema; Peña, Laura; Lopes, Carlos; Illera, Juan Carlos

    2005-01-01

    Cyclo-oxygenase (Cox-2) plays an important role in mammary carcinogenesis, nevertheless, its role in canine mammary tumors, and particularly in inflammatory mammary carcinoma (IMC), is unknown. Tumor Cox-2 levels were analyzed by enzyme immunoassay, in post-surgical tumor homogenates of 129 mammary tumors (62 dysplasias and benign tumors, 57 malignant non-IMC and 10 IMC) from 57 female dogs. The highest Cox-2 values were detected in the IMC group. In non-IMC malignant tumors, high values of Cox-2 were related to skin ulceration (p IMC cases could indicate a special role of Cox-2 in the inflammatory phenotype and open the possibility of additional new therapeutic approaches in this special type of mammary cancer in humans and dogs.

  19. Survival Prognostic Factors of Male Breast Cancer in Southern Iran: a LASSO-Cox Regression Approach.

    Science.gov (United States)

    Shahraki, Hadi Raeisi; Salehi, Alireza; Zare, Najaf

    2015-01-01

    We used to LASSO-Cox method for determining prognostic factors of male breast cancer survival and showed the superiority of this method compared to Cox proportional hazard model in low sample size setting. In order to identify and estimate exactly the relative hazard of the most important factors effective for the survival duration of male breast cancer, the LASSO-Cox method has been used. Our data includes the information of male breast cancer patients in Fars province, south of Iran, from 1989 to 2008. Cox proportional hazard and LASSO-Cox models were fitted for 20 classified variables. To reduce the impact of missing data, the multiple imputation method was used 20 times through the Markov chain Mont Carlo method and the results were combined with Rubin's rules. In 50 patients, the age at diagnosis was 59.6 (SD=12.8) years with a minimum of 34 and maximum of 84 years and the mean of survival time was 62 months. Three, 5 and 10 year survival were 92%, 77% and 26%, respectively. Using the LASSO-Cox method led to eliminating 8 low effect variables and also decreased the standard error by 2.5 to 7 times. The relative efficiency of LASSO-Cox method compared with the Cox proportional hazard method was calculated as 22.39. The19 years follow of male breast cancer patients show that the age, having a history of alcohol use, nipple discharge, laterality, histological grade and duration of symptoms were the most important variables that have played an effective role in the patient's survival. In such situations, estimating the coefficients by LASSO-Cox method will be more efficient than the Cox's proportional hazard method.

  20. Flavocoxid Inhibits Phospholipase A2, Peroxidase Moieties of the Cyclooxygenases (COX, and 5-Lipoxygenase, Modifies COX-2 Gene Expression, and Acts as an Antioxidant

    Directory of Open Access Journals (Sweden)

    Bruce P. Burnett

    2011-01-01

    Full Text Available The multiple mechanisms of action for flavocoxid relating to arachidonic acid (AA formation and metabolism were studied in vitro. Flavocoxid titrated into rat peritoneal macrophage cultures inhibited cellular phospholipase A2 (PLA2 (IC50 = 60 μg/mL. In in vitro enzyme assays, flavocoxid showed little anti-cyclooxygenase (CO activity on COX-1/-2 enzymes, but inhibited the COX-1 (IC50 = 12.3 and COX-2 (IC50 = 11.3 μg/mL peroxidase (PO moieties as well as 5-lipoxygenase (5-LOX (IC50 = 110 μg/mL. No detectable 5-LOX inhibition was found for multiple traditional and COX-2 selective NSAIDs. Flavocoxid also exhibited strong and varied antioxidant capacities in vitro and decreased nitrite levels (IC50 = 38 μg/mL in rat peritoneal macrophages. Finally, in contrast to celecoxib and ibuprofen, which upregulated the cox-2 gene, flavocoxid strongly decreased expression. This work suggests that clinically favourable effects of flavocoxid for management of osteoarthritis (OA are achieved by simultaneous modification of multiple molecular pathways relating to AA metabolism, oxidative induction of inflammation, and neutralization of reactive oxygen species (ROS.

  1. [Cyclooxygenase 2 inhibitors and urologic and gynaecologic cancers].

    Science.gov (United States)

    Eschwege, Pascal

    2004-05-01

    PGE2 is one of the most important prostaglandin involved in the oncogenesis. PGE2 is found at high concentration level in the most of epithelial cancer. Urologic and gynaecologic cancer express the enzyme which are at the origin of PGE2: cyclooxygenase 2. Cox2 inhibitors present anticancer properties demonstrated in wide varieties of cellular and animal models. Human applications are currently tested in many clinical trials for bladder, prostate and uterine carcinomas.

  2. Enrichment of Echinacea angustifolia with Bauer alkylamide 11 and Bauer ketone 23 increased anti-inflammatory potential through interfering with COX-2 enzyme activity

    Science.gov (United States)

    LaLone, Carlie A.; Huang, Nan; Rizshsky, Ludmila; Yum, Man-Yu; Singh, Navrozedeep; Hauck, Cathy; Nikolau, Basil J.; Wurtele, Eve S.; Kohut, Marian L.; Murphy, Patricia A.; Birt, Diane F.

    2013-01-01

    Bauer alkylamide 11 and ketone 23 were partially responsible for Echinacea angustifolia anti-inflammatory properties previously. This study further tested their importance using the inhibition of prostaglandin E2 (PGE2) and nitric oxide (NO) production by RAW264.7 mouse macrophages in the absence and presence of lipopolysaccharide (LPS) and E. angustifolia extracts, phytochemical enriched fractions, or pure synthesized standards. Molecular targets were probed using microarray, qRT-PCR, western blot, and enzyme assays. Fractions with these phytochemicals were more potent inhibitors of LPS induced PGE2 production than E. angustifolia extracts. Microarray did not detect changes in transcripts with phytochemical treatments; however qRT-PCR showed decrease in TNF-α and increase of iNOS transcripts. LPS induced COX-2 protein was increased by an E. angustifolia fraction containing Bauer ketone 23 and by pure phytochemical. COX-2 activity was decreased with all treatments. The phytochemical inhibition of PGE2 production by Echinacea may be due to the direct targeting of COX-2 enzyme. PMID:20681645

  3. Leukotriene B(4) BLT receptor signaling regulates the level and stability of cyclooxygenase-2 (COX-2) mRNA through restricted activation of Ras/Raf/ERK/p42 AUF1 pathway.

    Science.gov (United States)

    Zhai, Beibei; Yang, Huiqing; Mancini, Arturo; He, QingWen; Antoniou, John; Di Battista, John A

    2010-07-30

    Recent studies suggest that active resolution of the inflammatory response in animal models of arthritis may involve leukotriene B(4) (LTB(4))-dependent stimulation of "intermediate" prostaglandin production, which in turn favors the synthesis of "downstream" anti-inflammatory and pro-resolving lipoxins, resolvins, and protectins. We explored a putative mechanism involving LTB(4)-dependent control of cyclooxygenase-2 (COX-2) expression, the rate-limiting step in inflammatory prostaglandin biosynthesis. Indeed, LTB(4) potently up-regulated/stabilized interleukin-1beta-induced COX-2 mRNA and protein expression under conditions of COX-2 inhibitor-dependent blockade of PGE(2) release in human synovial fibroblasts (EC(50) = 16.5 + or - 1.7 nm for mRNA; 19 + or - 2.4 nm for protein, n = 4). The latter response was pertussis toxin-sensitive, and semi-quantitative reverse transcription-PCR confirmed the quantitative predominance of the BLT2 receptor. Transfection experiments, using human COX-2 promoter plasmids and chimeric luciferase-COX-2 mRNA 3'-untranslated region (3'-UTR) reporter constructs, revealed that LTB(4) exerted its stabilizing effect at the post-transcriptional level through a 116-bp adenylate/uridylate-rich sequence in the proximal region of the COX-2 3'-UTR. Using luciferase-COX-2 mRNA 3'-UTR reporter constructs and Ras/c-Raf expression and mutant constructs, we showed that the Ras/c-Raf/MEK1/2/ERK1/2 signaling pathway mediated LTB(4)-dependent COX-2 mRNA stabilization. Knockdown experiments with specific short hairpin RNAs confirmed that LTB(4) stabilization of COX-2 mRNA was apparently mediated through the RNA-binding protein, p42 AUF1. The nuclear export of p42 AUF1 was driven by c-Raf/MEK1/2/ERK1/2 signaling and sensitive to leptomycin B treatment, suggesting a CRM1-dependent mechanism. We conclude that LTB(4) may support the resolution phase of the inflammatory response by stabilizing COX-2, ensuring a reservoir of ambient pro-resolution lipid

  4. Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth.

    Science.gov (United States)

    Bergman, Joel A; Woan, Karrune; Perez-Villarroel, Patricio; Villagra, Alejandro; Sotomayor, Eduardo M; Kozikowski, Alan P

    2012-11-26

    The incidence of malignant melanoma has dramatically increased in recent years thus requiring the need for improved therapeutic strategies. In our efforts to design selective histone deactylase inhibitors (HDACI), we discovered that the aryl urea 1 is a modestly potent yet nonselective inhibitor. Structure-activity relationship studies revealed that adding substituents to the nitrogen atom of the urea so as to generate compounds bearing a branched linker group results in increased potency and selectivity for HDAC6. Compound 5 g shows low nanomolar inhibitory potency against HDAC6 and a selectivity of ∼600-fold relative to the inhibition of HDAC1. These HDACIs were evaluated for their ability to inhibit the growth of B16 melanoma cells with the most potent and selective HDAC6I being found to decrease tumor cell growth. To the best of our knowledge, this work constitutes the first report of HDAC6-selective inhibitors that possess antiproliferative effects against melanoma cells.

  5. Celecoxib offsets the negative renal influences of cyclosporine via modulation of the TGF-β1/IL-2/COX-2/endothelin ET{sub B} receptor cascade

    Energy Technology Data Exchange (ETDEWEB)

    El-Gowelli, Hanan M. [Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria (Egypt); Helmy, Maged W.; Ali, Rabab M. [Pharmacology and Toxicology, Faculty of Pharmacy, Pharos University, Alexandria (Egypt); El-Mas, Mahmoud M., E-mail: mahelm@hotmail.com [Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria (Egypt)

    2014-03-01

    Endothelin (ET) signaling provokes nephrotoxicity induced by the immunosuppressant drug cyclosporine A (CSA). We tested the hypotheses that (i): celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, counterbalances renal derangements caused by CSA in rats and (ii) the COX-2/endothelin ET{sub B} receptor signaling mediates the CSA-celecoxib interaction. Ten-day treatment with CSA (20 mg/kg/day) significantly increased biochemical indices of renal function (serum urea, creatinine), inflammation (interleukin-2, IL-2) and fibrosis (transforming growth factor-β{sub 1}, TGF-β{sub 1}). Histologically, CSA caused renal tubular atrophy along with interstitial fibrosis. These detrimental renal effects of CSA were largely reduced in rats treated concurrently with celecoxib (10 mg/kg/day). We also report that cortical glomerular and medullary tubular protein expressions of COX-2 and ET{sub B} receptors were reduced by CSA and restored to near-control values in rats treated simultaneously with celecoxib. The importance of ET{sub B} receptors in renal control and in the CSA-celecoxib interaction was further verified by the findings (i) most of the adverse biochemical, inflammatory, and histopathological profiles of CSA were replicated in rats treated with the endothelin ET{sub B} receptor antagonist BQ788 (0.1 mg/kg/day, 10 days), and (ii) the BQ788 effects, like those of CSA, were alleviated in rats treated concurrently with celecoxib. Together, the data suggest that the facilitation of the interplay between the TGF-β1/IL-2/COX-2 pathway and the endothelin ET{sub B} receptors constitutes the cellular mechanism by which celecoxib ameliorates the nephrotoxic manifestations of CSA in rats. - Highlights: • Celecoxib abolishes nephrotoxic manifestations of CSA in rats. • Blockade of ETB receptors by BQ788 mimicked the nephrotoxic effects of CSA. • CSA or BQ788 reduces renal protein expression of COX-2 and endothelin ETB receptors. • Enhanced TGFβ1/IL-2/COX2/ETB

  6. RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2 causes deficits in glucose metabolism.

    Directory of Open Access Journals (Sweden)

    Azamat Aslanukov

    2006-10-01

    Full Text Available The Ran-binding protein 2 (RanBP2 is a large multimodular and pleiotropic protein. Several molecular partners with distinct functions interacting specifically with selective modules of RanBP2 have been identified. Yet, the significance of these interactions with RanBP2 and the genetic and physiological role(s of RanBP2 in a whole-animal model remain elusive. Here, we report the identification of two novel partners of RanBP2 and a novel physiological role of RanBP2 in a mouse model. RanBP2 associates in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11, and the pacemaker of glycolysis, hexokinase type I (HKI via its leucine-rich domain. The leucine-rich domain of RanBP2 also exhibits strong chaperone activity toward intermediate and mature folding species of Cox11 supporting a chaperone role of RanBP2 in the cytosol during Cox11 biogenesis. Cox11 partially colocalizes with HKI, thus supporting additional and distinct roles in cell function. Cox11 is a strong inhibitor of HKI, and RanBP2 suppresses the inhibitory activity of Cox11 over HKI. To probe the physiological role of RanBP2 and its role in HKI function, a mouse model harboring a genetically disrupted RanBP2 locus was generated. RanBP2(-/- are embryonically lethal, and haploinsufficiency of RanBP2 in an inbred strain causes a pronounced decrease of HKI and ATP levels selectively in the central nervous system. Inbred RanBP2(+/- mice also exhibit deficits in growth rates and glucose catabolism without impairment of glucose uptake and gluconeogenesis. These phenotypes are accompanied by a decrease in the electrophysiological responses of photosensory and postreceptoral neurons. Hence, RanBP2 and its partners emerge as critical modulators of neuronal HKI, glucose catabolism, energy homeostasis, and targets for metabolic, aging disorders and allied neuropathies.

  7. A cyclooxygenase (COX) inhibitory biflavonoid from the seeds of Semecarpus anacardium.

    Science.gov (United States)

    Selvam, C; Jachak, Sanjay M

    2004-12-01

    Semecarpus anacardium Linn., Anacardiaceae, is being most commonly used in India for the treatment of rheumatoid arthritis and other inflammatory disorders. Bioactivity guided fractionation of ethyl acetate extract led to the isolation of major active principle, tetrahydroamentoflavone (THA), a biflavonoid. The in vitro cyclooxygenase (COX-1) catalyzed prostaglandin biosynthesis assay of THA gave an IC(50) value of 29.5 microM (COX-1) and 40.5% inhibition at 100 microg/mL (COX-2). The in vivo carrageenan induced paw edema assay resulted in dose dependent anti-inflammatory effect of THA and the activity was comparable to that of ibuprofen, one of the well known NSAIDs.

  8. The Distribution of the Interval between Events of a Cox Process with Shot Noise Intensity

    Directory of Open Access Journals (Sweden)

    Angelos Dassios

    2008-01-01

    Full Text Available Applying piecewise deterministic Markov processes theory, the probability generating function of a Cox process, incorporating with shot noise process as the claim intensity, is obtained. We also derive the Laplace transform of the distribution of the shot noise process at claim jump times, using stationary assumption of the shot noise process at any times. Based on this Laplace transform and from the probability generating function of a Cox process with shot noise intensity, we obtain the distribution of the interval of a Cox process with shot noise intensity for insurance claims and its moments, that is, mean and variance.

  9. Exogenous hydrogen sulfide promotes C6 glioma cell growth through activation of the p38 MAPK/ERK1/2-COX-2 pathways.

    Science.gov (United States)

    Zhen, Yulan; Zhang, Wei; Liu, Chujie; He, Jing; Lu, Yun; Guo, Ruixian; Feng, Jianqiang; Zhang, Ying; Chen, Jingfu

    2015-11-01

    Hydrogen sulfide (H2S) participates in multifarious physiological and pathophysiologic progresses of cancer both in vitro and in vivo. We have previously demonstrated that exogenous H2S promoted liver cancer cells proliferation/anti‑apoptosis/angiogenesis/migration effects via amplifying the activation of NF-κB pathway. However, the effects of H2S on cancer cell proliferation and apoptosis are controversial and remain unclear in C6 glioma cells. The present study investigated the effects of exogenous H2S on cancer cells growth via activating p38 MAPK/ERK1/2-COX-2 pathways in C6 glioma cells. C6 glioma cells were treated with 400 µmol/l NaHS (a donor of H2S) for 24 h. The expression levels of phosphorylated (p)-p38 MAPK, total (t)-p38 MAPK, p-ERK1/2, t-ERK1/2, cyclooxygenase-2 (COX-2) and caspase-3 were measured by western blotting assay. Cell viability was detected by Cell Counting Kit-8 (CCK-8). Apoptotic cells were observed by Hoechst 33258 staining assay. Cell proliferation was directly detected under fully automatic inverted microscope. Exposure of C6 glioma cells to NaHS resulted in cell proliferation, as evidenced by an increase in cell viability. In addition, NaHS treatment reduced apoptosis, as indicated by the decreased apoptotic percentage and the cleaved caspase-3 expression. Importantly, exposure of the cells to NaHS increased the expression levels of p-p38 MAPK, p-ERK1/2 and COX-2. Notably, co-treatment of C6 glioma cells with 400 µmol/l NaHS and AOAA (an inhibitor of CBS) largely suppressed the above NaHS-induced effects. Combined treatment with NaHS and SB203580 (an inhibitor of p38 MAPK) or PD-98059 (an inhibitor of ERK1/2) resulted in the synergistic reduction of COX-2 expression and increase of caspase-3 expression, a decreased number of apoptotic cells, along with decreased cell viability. Combined treatment with NS-398 (an inhibitor of COX-2) and NaHS also resulted in the synergistic increase of caspase-3, a decreased in the

  10. Comparison under a simulated sun of two black-nickel-coated flat-plate solar collectors with a nonselective black-paint-coated collector

    Science.gov (United States)

    Simon, F. F.

    1975-01-01

    A performance evaluation was made of two, black nickel coated, flat plate solar collectors. Collector performance was determined under a simulated sun for a wide range of inlet temperatures, including the temperature required for solar powered absorption air conditioning. For a basis of comparison a performance test was made on a traditional, two glass, nonselective, black paint coated, flat plate collector. Performance curves and performance parameters are presented to point out the importance of the design variables which determine an efficient collector. A black nickel coated collector was found to be a good performer at the conditions expected for solar powered absorption air conditioning. This collector attained a thermal efficiency of 50 percent at an inlet temperature of 366 K (200 F) and an incident flux of 946 watts/sq m (300 Btu/hr-sq ft).

  11. Melamine activates NFκB/COX-2/PGE2 pathway and increases NADPH oxidase-dependent ROS production in macrophages and human embryonic kidney cells.

    Science.gov (United States)

    Kuo, Fu-Chen; Tseng, Yu-Ting; Wu, Sing-Ru; Wu, Ming-Tsang; Lo, Yi-Ching

    2013-09-01

    Melamine is a wildly used compound in manufactures of plastics and resins. A variety of toxic effects from melamine, including nephrolithiasis, chronic kidney inflammation, and bladder carcinoma, have been mentioned. Oxidative stress is considered to be an important pathogenic mechanism of kidney disease which may develop from an increasing free radical production through inflammation. The aim of this study is to investigate melamine-induced oxidative stress and inflammation in macrophage-like cell line RAW 264.7 and human embryonic kidney cell line HEK293. Results indicated melamine activated nuclear factor (NF)-κB through increasing IκB-α degradation and NF-κB p65/p50 DNA-binding activity. In addition, melamine significantly increased COX-2 expression and prostaglandin E2 (PGE2) production. Moreover, melamine activated NADPH oxidase (NOX), including NOX1, NOX2 and NOX4, accompanied with an increase in reactive oxygen species (ROS) production. Furthermore, melamine-induced ROS production could be attenuated by apocynin, a NOX inhibitor. In conclusion, our findings suggest melamine increased inflammation and oxidative stress via activation of NF-κB/COX-2 and NOX/ROS pathway, and first revealed the critical role of NOX in melamine-induced ROS production, suggesting the potential of NOX inhibitor against melamine toxicity.

  12. Recollections on the early days of the Marcé Society for Perinatal Mental Health from Professor John Cox.

    Science.gov (United States)

    Cox, John L; Wisner, Katherine L

    2016-02-01

    Dr. Katherine Wisner interviewed Dr. John Cox, a founding member of the Marcé Society. Dr. Cox discussed the beginnings of the Marcé Society, his views about the current Society, and his vision for the future.

  13. Expression of COX-2 and p53 in juvenile polyposis coli and its correlation with adenomatous changes

    Directory of Open Access Journals (Sweden)

    Shatavisha Das Gupta

    2016-01-01

    Conclusion: We observed significantly higher COX-2 expression in JPC. Establishment of the role of COX-2 in JPC will help us formulate chemopreventive therapies as an adjunct to its surgical management.

  14. Enforced Expression of miR-101 Inhibits Prostate Cancer Cell Growth by Modulating the COX-2 Pathway In Vivo

    OpenAIRE

    Hao, Yubin; Gu, Xinbin; Zhao, Yuan; Greene, Stephen; Sha, Wei; Smoot, Duane T.; Califano, Joseph; Wu, T.-C.; Pang, Xiaowu

    2011-01-01

    It is commonly agreed that there is an association of chronic inflammation with tumorigenesis. COX-2, a key regulator of inflammation-producing prostaglandins, promotes cell proliferation and growth; thus, overexpression of COX-2 is often found in tumor tissues. Therefore, a better understanding of the regulatory mechanism(s) of COX-2 could lead to novel targeted cancer therapies. In this study, we investigated the mechanism of microRNA-101 (miR-101)-regulated COX-2 expression and the therape...

  15. Cyclooxygenases in human and mouse skin and cultured human keratinocytes: association of COX-2 expression with human keratinocyte differentiation

    Science.gov (United States)

    Leong, J.; Hughes-Fulford, M.; Rakhlin, N.; Habib, A.; Maclouf, J.; Goldyne, M. E.

    1996-01-01

    Epidermal expression of the two isoforms of the prostaglandin H-generating cyclooxygenase (COX-1 and COX-2) was evaluated both by immunohistochemistry performed on human and mouse skin biopsy sections and by Western blotting of protein extracts from cultured human neonatal foreskin keratinocytes. In normal human skin, COX-1 immunostaining is observed throughout the epidermis whereas COX-2 immunostaining increases in the more differentiated, suprabasilar keratinocytes. Basal cell carcinomas express little if any COX-1 or COX-2 immunostaining whereas both isozymes are strongly expressed in squamous cell carcinomas deriving from a more differentiated layer of the epidermis. In human keratinocyte cultures, raising the extracellular calcium concentration, a recognized stimulus for keratinocyte differentiation, leads to an increased expression of both COX-2 protein and mRNA; expression of COX-1 protein, however, shows no significant alteration in response to calcium. Because of a recent report that failed to show COX-2 in normal mouse epidermis, we also looked for COX-1 and COX-2 immunostaining in sections of normal and acetone-treated mouse skin. In agreement with a previous report, some COX-1, but no COX-2, immunostaining is seen in normal murine epidermis. However, following acetone treatment, there is a marked increase in COX-1 expression as well as the appearance of significant COX-2 immunostaining in the basal layer. These data suggest that in human epidermis as well as in human keratinocyte cultures, the expression of COX-2 occurs as a part of normal keratinocyte differentiation whereas in murine epidermis, its constitutive expression is absent, but inducible as previously published.

  16. Forecasts of non-Gaussian parameter spaces using Box-Cox transformations

    CERN Document Server

    Joachimi, B

    2011-01-01

    Forecasts of statistical constraints on model parameters using the Fisher matrix abound in many fields of astrophysics. The Fisher matrix formalism involves the assumption of Gaussianity in parameter space and hence fails to predict complex features of posterior probability distributions. Combining the standard Fisher matrix with Box-Cox transformations, we propose a novel method that accurately predicts arbitrary posterior shapes. The Box-Cox transformations are applied to parameter space to render it approximately multivariate Gaussian, performing the Fisher matrix calculation on the transformed parameters. We demonstrate that, after the Box-Cox parameters have been determined from an initial likelihood evaluation, the method correctly predicts changes in the posterior when varying various parameters of the experimental setup and the data analysis, with marginally higher computational cost than a standard Fisher matrix calculation. We apply the Box-Cox-Fisher formalism to forecast cosmological parameter con...

  17. COX assembly factor ccdc56 regulates mitochondrial morphology by affecting mitochondrial recruitment of Drp1.

    Science.gov (United States)

    Ban-Ishihara, Reiko; Tomohiro-Takamiya, Shiho; Tani, Motohiro; Baudier, Jacques; Ishihara, Naotada; Kuge, Osamu

    2015-10-07

    Mitochondria are dynamic organelles that alter their morphology in response to cellular signaling and differentiation through balanced fusion and fission. In this study, we found that the mitochondrial inner membrane ATPase ATAD3A interacted with ccdc56/MITRAC12/COA3, a subunit of the cytochrome oxidase (COX)-assembly complex. Overproduction of ccdc56 in HeLa cells resulted in fragmented mitochondrial morphology, while mitochondria were highly elongated in ccdc56-repressed cells by the defective recruitment of the fission factor Drp1. We also found that mild and chronic inhibition of COX led to mitochondrial elongation, as seen in ccdc56-repressed cells. These results indicate that ccdc56 positively regulates mitochondrial fission via regulation of COX activity and the mitochondrial recruitment of Drp1, and thus, suggest a novel relationship between COX assembly and mitochondrial morphology.

  18. a study of the slope of cox proportional hazard and weibull models

    African Journals Online (AJOL)

    Adejumo & Ahmadu

    the values of the unknown parameters. These include the ... semi parametric cox proportional hazard model when the parametric ... simulated and the real life data approach. ... greatest risk progression of TB infection to active disease. People.

  19. Neoplasms escape selective COX-2 inhibition in an animal model of breast cancer.

    LENUS (Irish Health Repository)

    Barry, M

    2009-06-01

    Cyclo-oxygenase-2 (COX-2) is up-regulated in malignant tumours rendering it an attractive target for cancer therapeutics. However, whether long-term antagonism maintains its initial efficacy on established tumours is unclear.

  20. Nebulizable colloidal nanoparticles co-encapsulating a COX-2 inhibitor and a herbal compound for treatment of lung cancer.

    Science.gov (United States)

    Said-Elbahr, Ramy; Nasr, Maha; Alhnan, Mohamed A; Taha, Ismail; Sammour, Omaima

    2016-06-01

    A challenging disease such as lung cancer requires the combination of different modalities to achieve beneficial therapeutic outcomes. In this work, PLGA nanoparticles were chosen as colloidal carrier for two drugs with reported anti-lung cancer activity: naringin and celecoxib. PLGA nanoparticles were prepared and characterized for their particle size, zeta potential, entrapment efficiency, in vitro release, stability, morphology, cytotoxicity, as well as aerosolization and nebulization behaviors. Their biodistribution pattern upon pulmonary aerosolization, and safety on healthy lung tissues were determined as well. Results showed that the described system displayed a particle size nanoparticles accompanied with high distribution to the bones, brain and liver which are common metastatic sites of lung cancer, proving their promising nature in the treatment of lung cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. A Controlled Trial of Chemoprevention Using COX-2 Inhibitors in an Avian Model of Spontaneous Ovarian Carcinogesis

    Science.gov (United States)

    2007-09-01

    ovarian cancer risk: collaborative analysis of seven US case control studies . Epithelial ovarian cancer in black women. JNCI 1993;85:142-147. 26...594- 598. 20 27. Franceschi S, Parazzini F, Negri, et al. Pooled analysis of 3 European case control studies of epithelial ovarian cancer. Oral...development of cancer or cause reversion of the malignant phenotype. To more directly address the potential preventive role of NSAIDs, case - control studies of

  2. The role of selective Cox-2 inhibitors on HIF-1 alpha gene in colorectal cancer: an in-vitro study

    Directory of Open Access Journals (Sweden)

    Sanaz Rismanchi

    2014-10-01

    Conclusion: Angiogenesis is a key factor in the carcinogenesis process and FDA today approved bevacizumab as a first-line treatment for patients with metastatic colorectal cancer. The results of this study showed one of the causes of angiogenesis reduction in celecoxib-treated colorectal cancer. According to clinical findings and basic studies, celecoxib will be hopefully used as a first-line therapy along with chemotherapy in the near future in colorectal cancer. The advantages of this treatment method include its low cost and low side effects.

  3. Effects of dexamethasone and cox inhibitors on intracranial pressure and cerebral perfusion in the lipopolysaccharide treated rats with hyperammonemia

    DEFF Research Database (Denmark)

    Rohde, Johan; Pedersen, Hans; Bjerring, Peter N

    2015-01-01

    with and without NH3 induced a similar increase in plasma 6-keto-prostaglandin-F1α (6-keto-PGF1α) concentration together with a concomitant rise in CBF and ICP. Indomethacin and diclofenac prevented the increase in ICP by LPS alone, and with the addition of NH3 the increase in both CBF and ICP, which...... was associated with a decrease in 6-keto-PGF1α. Dexamethasone only reduced the LPS induced increase in ICP but not CBF, and partly the 6-keto-PGF1α plasma concentration in the combined setup. CONCLUSION: These data indicate that activation of cycloooxygenases is of central importance for development of cerebral...

  4. Selective cyclooxygenase-2 inhibitor use and progression of renal function in patients with chronic kidney disease: a single-center retrospective cohort study

    Directory of Open Access Journals (Sweden)

    Kaewput W

    2016-11-01

    Full Text Available Wisit Kaewput,1,2 Preedee Disorn,2 Bancha Satirapoj2 1Department of Military and Community Medicine, Phramongkutklao College of Medicine, 2Department of Medicine, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand Background: The use of selective COX-2 (sCOX-2 inhibitors with acute kidney injury, salt water retention, and cardiovascular events have been correlated in subjects with normal kidney function, but sCOX-2 inhibitor use concerning the progression of chronic kidney disease (CKD remains uncertain. Objectives: To determine the progression of renal function and electrolyte abnormalities among CKD patients after using sCOX-2 inhibitors during short- and long-term periods. Methods: The study employed a retrospective cohort design comprising all types of CKD patients with and without sCOX-2 inhibitors (celecoxib and etoricoxib. Data collected included medical data, estimated glomerular filtration rate (eGFR, and serum electrolytes at 3 and 6 months between January 2009 and January 2014. Subjects attended the outpatient clinic and were then followed up until discontinuation of the drugs at years 1 and 2 until May 2016. Results: Ninety-two CKD patients on sCOX-2 inhibitors and 92 CKD patients without sCOX-2 inhibitors were included. The sCOX-2 inhibitor group showed more decline in eGFR than the control group at 3 and 6 months of follow-up (–8.27±9.75 vs –1.64±6.05 mL/min/1.73 m2, P<0.001 and –12.36±6.48 vs –4.31±5.11 mL/min/1.73 m2, P=0.001, respectively and at 1 and 2 years of follow-up after subjects discontinued sCOX-2 (–6.84±10.34 vs –1.61±8.93 mL/min/1.73 m2, P=0.004 and –10.26±10.19 vs –5.12±8.61 mL/min/1.73 m2, P=0.005, respectively. In addition, the sCOX-2 inhibitor group had significantly more increased serum potassium during the study follow-up than the control group. Conclusion: The sCOX-2 inhibitors are associated with an increased risk for rapid eGFR decline and hyperkalemia in both the

  5. Variations from Zn1-xCoxO Magnetic Semiconductor to Co-ZnCoO Granular Composite

    Institute of Scientific and Technical Information of China (English)

    CHEN Yan-Xue; YAN Shi-Shen; LIU Guo-Lei; MEI Liang-Mo; REN Miao-Juan

    2007-01-01

    @@ We investigate the variations from as-deposited Zn1-xCoxO magnetic semiconductors to the post-annealed CoZnCoO granular composite. The as-deposited Zn1-xCoxO magnetic semiconductor deposited under thermal nonequilibrium conditions is composed of Zn1-xCoxO nanograins of high Co concentration.

  6. Hypermethylation of the COX-2 gene is a potential prognostic marker for cervical cancer.

    Science.gov (United States)

    Jo, Hoenil; Kang, Sokbom; Kim, Jae W; Kang, Gyeong H; Park, Noh H; Song, Yong S; Park, Sang Y; Kang, Soon B; Lee, Hyo P

    2007-06-01

    The aim of the present study was to evaluate the DNA hypermethylation profiles of 14 genes known to be associated with tumor behavior and their clinical significance in cervical cancer. The clinical features of 82 patients with stage IB cervical cancer were analyzed in terms of DNA hypermethylation of 14 genes (hMLH1, p16, COX-2, CDH1, APC, DAPK, MGMT, p14, RASSF1A, RUNX3, TIMP3, FHIT, THBS1, and HLTF). Of 14 genes investigated, only hypermethylation of COX-2 showed significant association with poor disease-free survival (P = 0.001). To further investigate an alteration in COX-2 expression by DNA hypermethylation, immunohistochemistry for COX-2 protein was performed in the cervical cancer tissues. We found no significant association between hypermethylation and expression patterns of the COX-2 gene. The present results suggest that DNA hypermethylation of the COX-2 gene may be a potential prognostic marker in early stage cervical cancer, the underlying mechanism of which is independent of gene silencing.

  7. Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation.

    Science.gov (United States)

    Hermanson, Daniel J; Hartley, Nolan D; Gamble-George, Joyonna; Brown, Naoko; Shonesy, Brian C; Kingsley, Phillip J; Colbran, Roger J; Reese, Jeffrey; Marnett, Lawrence J; Patel, Sachin

    2013-09-01

    Augmentation of endogenous cannabinoid (eCB) signaling represents an emerging approach to the treatment of affective disorders. Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid to form prostaglandins, but also inactivates eCBs in vitro. However, the viability of COX-2 as a therapeutic target for in vivo eCB augmentation has not been explored. Using medicinal chemistry and in vivo analytical and behavioral pharmacological approaches, we found that COX-2 is important for the regulation of eCB levels in vivo. We used a pharmacological strategy involving substrate-selective inhibition of COX-2 to augment eCB signaling without affecting related non-eCB lipids or prostaglandin synthesis. Behaviorally, substrate-selective inhibition of COX-2 reduced anxiety-like behaviors in mice via increased eCB signaling. Our data suggest a key role for COX-2 in the regulation of eCB signaling and indicate that substrate-selective pharmacology represents a viable approach for eCB augmentation with broad therapeutic potential.

  8. Antiinflammatory and antinociceptive activities of gossypin and procumbentin--cyclooxygenase-2 (COX-2) inhibition studies.

    Science.gov (United States)

    Mada, Sripal Reddy; Metukuri, Mallikarjuna Reddy; Burugula, Laxminarayana; Reddanna, Pallu; Krishna, Devarakonda Rama

    2009-06-01

    In the present study the antiinflammatory and antinociceptive activities of a few selected flavonoids were investigated. Procumbentin, gossypin, chrysin and methylhespiridin were studied for antiinflammatory and antinociceptive activities using in vitro enzymatic assays and in animal models utilizing acetic acid-induced writhing in mice and hind paw edema in rats. In vitro studies were performed using TMPD (NNN'N'-tetramethyl-p-phenylene diamine) and oxygraphic methods for COX-1 (cyclooxygenase-1), COX-2, 5-LOX (5-lipoxygenase) and 15-LOX. Gossypin and procumbentin showed COX-2 inhibitory activity and exhibited IC(50) (COX-2/COX-1) ratios of 0.14 and 0.11, respectively. None of the flavonoids tested in this study showed LOX inhibitory activity. Four groups were studied for each test compound following intraperitoneal (i.p.) administration of doses of 10, 30 and 100 mg/kg. Antiinflammatory activity was measured by the carrageenin-induced rat hind paw edema model and antinociceptive activity by acetic acid-induced writhing. Procumbentin and gossypin showed antinociceptive activity at the 100 mg/kg dose. Gossypin showed antiinflammatory activity at doses of 10, 30, 100 mg/kg. Procumbentin and gossypin exhibited COX-2 inhibitory activity when tested by in vitro methods. Procumbentin and gossypin showed antinociceptive, and gossypin showed antiinflammatory, activities.

  9. Expression of COX-2 and bcl-2 in oral lichen planus lesions and lichenoid reactions

    Science.gov (United States)

    Arreaza, Alven J; Rivera, Helen; Correnti, María

    2014-01-01

    Oral lichen planus and lichenoid reactions are autoimmune type inflammatory conditions of the oral mucosa with similar clinical and histological characteristics. Recent data suggest that oral lichenoid reactions (OLR) present a greater percentage of malignant transformation than oral lichen planus (OLP). Objective To compare the expression of bcl-2 and COX-2 in OLP and OLR. Methods The study population consisted of 65 cases; 34 cases diagnosed as OLR and 31 as OLP. A retrospective study was done, and bcl-2 and COX-2 expression was semiquantitatively analysed. Results Fifty-three per cent (18/34) of the ORL samples tested positive for COX-2, whereas in the OLP group, 81% of the samples (25/31) immunostained positive for COX-2. The Fisher’s exact test for the expression of COX-2 revealed that there are significant differences between the two groups, P = 0.035. With respect to the expression of the bcl-2 protein, 76% (26/34) of the samples were positive in OLR, while 97% (30/31) were positive in the group with OLP. The Fisher’s exact test for the expression of bcl-2 revealed that there are significant statistical differences between the two groups, P = 0.028. Conclusions The expression of bcl-2 and COX-2 was more commonly expressed in OLP when compared with OLR. PMID:24834112

  10. Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, Ajit G.; Rojas, Camilo [Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Tanega, Cordelle; Shen, Min; Simeonov, Anton; Boxer, Matthew B.; Auld, Douglas S. [National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850 (United States); Ferraris, Dana V. [Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Tsukamoto, Takashi [Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Slusher, Barbara S., E-mail: bslusher@jhmi.edu [Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States)

    2013-08-23

    Highlights: •Ebselen, chelerythrine and apomorphine were identified as glutaminase inhibitors. •These had greater affinities and efficiency of inhibition than known prototypes. •Their previously reported biological activity could be due to glutaminase inhibition. -- Abstract: Glutaminase catalyzes the hydrolysis of glutamine to glutamate and plays a central role in the proliferation of neoplastic cells via glutaminolysis, as well as in the generation of excitotoxic glutamate in central nervous system disorders such as HIV-associated dementia (HAD) and multiple sclerosis. Both glutaminase siRNA and glutaminase inhibition have been shown to be effective in in vitro models of cancer and HAD, suggesting a potential role for small molecule glutaminase inhibitors. However, there are no potent, selective inhibitors of glutaminase currently available. The two prototypical glutaminase inhibitors, BPTES and DON, are either insoluble or non-specific. In a search for more drug-like glutaminase inhibitors, we conducted a screen of 1280 in vivo active drugs (Library of Pharmacologically Active Compounds (LOPAC{sup 1280})) and identified ebselen, chelerythrine and (R)-apomorphine. The newly identified inhibitors exhibited 10 to 1500-fold greater affinities than DON and BPTES and over 100-fold increased efficiency of inhibition. Although non-selective, it is noteworthy that the affinity of ebselen for glutaminase is more potent than any other activity yet described. It is possible that the previously reported biological activity seen with these compounds is due, in part, to glutaminase inhibition. Ebselen, chelerythrine and apomorphine complement the armamentarium of compounds to explore the role of glutaminase in disease.

  11. NS-398, Ibuprofen and COX-2 RNAi produce significantly different gene expression profiles in prostate cancer cells

    OpenAIRE

    John-Aryankalayil, Molykutty; Palayoor, Sanjeewani T.; Cerna, David; Falduto, Michael T.; Magnuson, Scott R.; Coleman, C. Norman

    2009-01-01

    Cyclooxygenase-2 (COX-2) plays a significant role in tumor development and progression. Nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit potent anticancer effects in vitro and in vivo by COX-2 dependent and independent mechanisms. In this study, we used microarray analysis to identify the change of expression profile regulated by a COX-2 specific NSAID NS-398 (0.01 and 0.1mM), a non-specific NSAID ibuprofen (0.1 and 1.5mM) and RNA interference-mediated COX-2 inhibition (COX-2 RNAi) in PC...

  12. CONVERGENT SYNTHESIS AND EVALUATION OF 18F-LABELED AZULENIC COX2 PROBES FOR CANCER IMAGING

    Directory of Open Access Journals (Sweden)

    Donald D. Nolting

    2013-01-01

    Full Text Available The overall objectives of this research are to (i develop azulene-based PET probes and (ii image COX2 as a potential biomarker of breast cancer. Several lines of research have demonstrated that COX2 is overexpressed in breast cancer and that its presence correlates with poor prognoses. While other studies have reported that COX2 inhibition can be modulated and used beneficially as a chemopreventive strategy in cancer, no viable mechanism for achieving that approach has yet been developed. This shortfall could be circumvented through in vivo imaging of COX2 activity, particularly using sensitive imaging techniques such as PET. Toward that goal, our laboratory focuses on the development of novel 18F-labled COX2 probes. We began the synthesis of the probes by transforming tropolone into a lactone, which was subjected to an [8+2] cycloaddition reaction to yield 2-methylazulene as the core ring of the probe. After exploring numerous synthetic routes, the final target molecule and precursor PET compounds were prepared successfully using convergent synthesis. Conventional 18F labeling methods caused precursor decomposition, which prompted us to hypothesize that the acidic protons of the methylene moiety between the azulene and thiazole rings were readily abstracted by a strong base such as potassium carbonate. Ultimately, this caused the precursors to disintegrate. This observation was supported after successfully using an 18F labeling strategy that employed a much milder phosphate buffer. The 18F-labeled COX2 probe was tested in a breast cancer xenograft mouse model. The data obtained via successive whole-body PET/CT scans indicated probe accumulation and retention in the tumor. Overall, the probe was stable in vivo and no defluorination was observed. A biodistribution study and Western blot analysis corroborate with the imaging data. In conclusion, this novel COX2 PET probe was shown to be a promising agent for cancer imaging and deserves further

  13. Different role of COX-2 and angiogenesis in canine inflammatory and non-inflammatory mammary cancer.

    Science.gov (United States)

    Clemente, Mónica; Sánchez-Archidona, Ana Rodríguez; Sardón, David; Díez, Lucía; Martín-Ruiz, Asunción; Caceres, Sara; Sassi, Francesco; Dolores Pérez-Alenza, M; Illera, Juan C; Dunner, Susana; Peña, Laura

    2013-08-01

    Human inflammatory breast cancer (IBC) and canine inflammatory mammary cancer (IMC) are the most aggressive and fatal types of mammary cancer, and both have a very poor prognosis and low survival rate. Human IBC is characterised by exacerbated angiogenesis, lymphangiogenesis, and lymphangiotropism. Lymphangiotropism is also characteristic of IMC, but microvascular density (MVD) and lymphangiogenesis have not been previously studied in canine IMC. In this study immunohistochemical expression of several angiogenesis-related factors (cyclooxygenase [COX]-2, vascular endothelial growth factors A and D [VEGF-A, VEGF-D], and vascular endothelial growth factor receptor 3 [VEGFR-3]), MVD, lymphatic proliferation index (LPI), and Ki-67 tumour proliferation index (PI) were studied in 21 canine IMC samples, 20 canine high-grade malignant non-IMC mammary tumours (MMTs), and four normal mammary gland samples (NMGs). All mammary neoplasms were histologically categorised as grade III. COX-2 values were also analysed by RT-PCR in seven IMCs, six MMTs and four NMGs. The expressions of COX-2, VEGF-A, and VEGF-D were significantly higher in IMC, MVD and LPI tumours, but not PI. In MMTs, COX-2 immunoexpression was significantly associated with VEGF-A, while in IMCs COX-2 was associated with VEGF-D (lymphangiogenic factor), its receptor VEGFR-3, and LPI. These results suggested that lymphangiogenic pathway stimulation isa specific role of COX-2 in IMC angiogenesis, which justifies the use of COX-2-based targeted palliative therapies in dogs. The exacerbated angiogenesis and lymphangiogenesis and the increased expression of angiogenesis-related factors further support canine IMC as a natural model for the study of human IBC.

  14. Overexpression of cyclooxygenase-2 in malignant peripheral nerve sheath tumor and selective cyclooxygenase-2 inhibitor-induced apoptosis by activating caspases in human malignant peripheral nerve sheath tumor cells.

    Directory of Open Access Journals (Sweden)

    Michiyuki Hakozaki

    Full Text Available BACKGROUND: Cyclooxygenase-2 (COX-2 is a key enzyme in the conversion of arachidonic acid to prostanoids, and its activation is associated with carcinogenesis as well as inflammation. The antitumor effect of selective COX-2 inhibitors has been noted in various malignancies. Malignant peripheral nerve sheath tumor (MPNST is a rare and aggressive soft tissue sarcoma for which effective treatments have not yet been established. The purpose of this study was to investigate a potential therapeutic role of COX-2 in MPNST. METHODS: We evaluated the expression of COX-2 in 44 cases of high-grade MPNST using immunohistochemical staining and compared the staining results with the characteristics and outcome of the patients. We also investigated the antitumor effect of etodolac, a selective COX-2 inhibitor, on MPNST cells in vitro using the MPNST cell line, FMS-1. RESULTS: Overexpression of COX-2 (≥50% positive cells was observed in 29 cases (65.9%, was significantly associated with a poor overall survival (P = 0.0495, and was considered an independent risk factor for a poor outcome by the results of both univariate and multivariate analysis. Etodolac induced apoptosis of FMS-1 cells through the activation of caspase-8, -9, and -3. Moreover, several caspase inhibitors significantly inhibited etodolac-induced apoptosis. CONCLUSIONS: Selective COX-2 inhibitors including etodolac had an antitumor effect on MPNST cells, and their use holds promise as a novel therapeutic strategy for patients with MPNST to improve their prognoses.

  15. EPA:DHA 6:1 prevents angiotensin II-induced hypertension and endothelial dysfunction in rats: role of NADPH oxidase- and COX-derived oxidative stress.

    Science.gov (United States)

    Niazi, Zahid Rasul; Silva, Grazielle C; Ribeiro, Thais Porto; León-González, Antonio J; Kassem, Mohamad; Mirajkar, Abdur; Alvi, Azhar; Abbas, Malak; Zgheel, Faraj; Schini-Kerth, Valérie B; Auger, Cyril

    2017-09-07

    Eicosapentaenoic acid:docosahexaenoic acid (EPA:DHA) 6:1, an omega-3 polyunsaturated fatty acid formulation, has been shown to induce a sustained formation of endothelial nitric oxide (NO) synthase-derived NO, a major vasoprotective factor. This study examined whether chronic intake of EPA:DHA 6:1 prevents hypertension and endothelial dysfunction induced by angiotensin II (Ang II) in rats. Male Wister rats received orally corn oil or EPA:DHA 6:1 (500 mg kg(-1) per day) before chronic infusion of Ang II (0.4 mg kg(-1) per day). Systolic blood pressure was determined by tail cuff sphingomanometry, vascular reactivity using a myograph, oxidative stress using dihydroethidium and protein expression by immunofluorescence and western blot analysis. Ang II-induced hypertension was associated with reduced acetylcholine-induced relaxations of secondary branch mesenteric artery rings affecting the endothelium-dependent hyperpolarization (EDH)- and the NO-mediated relaxations, both of which were improved by the NADPH oxidase inhibitor VAS-2870. The Ang II treatment induced also endothelium-dependent contractile responses (EDCFs), which were abolished by the cyclooxygenase (COX) inhibitor indomethacin. An increased level of vascular oxidative stress and expression of NADPH oxidase subunits (p47(phox) and p22(phox)), COX-1 and COX-2, endothelial NO synthase and Ang II type 1 receptors were observed in the Ang II group, whereas SKCa and connexin 37 were downregulated. Intake of EPA:DHA 6:1 prevented the Ang II-induced hypertension and endothelial dysfunction by improving both the NO- and EDH-mediated relaxations, and by reducing EDCFs and the expression of target proteins. The present findings indicate that chronic intake of EPA:DHA 6:1 prevented the Ang II-induced hypertension and endothelial dysfunction in rats, most likely by preventing NADPH oxidase- and COX-derived oxidative stress.Hypertension Research advance online publication, 7 September 2017; doi:10.1038/hr

  16. COX-2, MMP-7 expression in oral lichen planus and oral squamous cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    Tie-Jun Li; Jun Cui

    2013-01-01

    Objective:To observe cyclooxygenase (COX)-2 expression in normal oral mucosa (NOM), oral lichen planus (OLP) and oral squamous cell carcinoma (OSCC) and explore its significance in the incidence of oral cancer. Methods: The immunohistochemical method and RT-PCR method were applied to detect the expression of COX-2 and MMP-7 in 10 cases with NOM, 33 cases of with OLP and 38 cases with OSCC. Results: The expression of COX-2 mRNA in OSCC tissues (68.4%, 26/38) was significantly higher than in the OLP (24.2%, 8/33) and NOM (0.0%, 0/10) (P<0.01). The expression of MMP-7 mRNA in OSCC tissues (65.8%, 25/38) was significantly higher than in the OLP (30.3%, 10/33) and NOM (0.0%, 0/10) (P<0.01). The expression of MMP-7 in OLP was significantly higher than in the NOM (P<0.05). There was no significant expression of COX-2 protein in NOM, and the positive rate was 42.4% (14/33) and 89.5% (34/38) in OLP and OSCC group, respectively. The COX-2 expression in cancer tissues was significantly higher than in NOM and OLP (P<0.05). The MMP-7 protein expression in cancer tissues (84.2%, 32/38) was significantly higher than in NOM (10.0%, 1/10) and in OLP (42.4%, 14/33), and the positive rate in OLP was significantly higher than in NOM (P<0.01). The COX-2 expression was associated with clinical stage (P<0.05), the MMP-7 expression was associated with clinical stage and lymph node metastasis (P<0.05). The expressions of COX-2 and MMP-7 mRNA were positively correlated with OSCC. Conclusions:The abnormal expressions of COX-2 and MMP-7 are closely related to the biological behavior of OSCC, the MMP-7 may be induced by COX-2, and further lead to the invasion and metastasis of OSCC.

  17. TGF-β1 downregulates COX-2 expression leading to decrease of PGE2 production in human lung cancer A549 cells, which is involved in fibrotic response to TGF-β1.

    Directory of Open Access Journals (Sweden)

    Erina Takai

    Full Text Available Transforming growth factor-ß1 (TGF-β1 is a multifunctional cytokine that is involved in various pathophysiological processes, including cancer progression and fibrotic disorders. Here, we show that treatment with TGF-β1 (5 ng/mL induced downregulation of cyclooxygenase-2 (COX-2, leading to reduced synthesis of prostaglandin E2 (PGE2, in human lung cancer A549 cells. Treatment of cells with specific inhibitors of COX-2 or PGE2 receptor resulted in growth inhibition, indicating that the COX-2/PGE2 pathway contributes to proliferation in an autocrine manner. TGF-β1 treatment induced growth inhibition, which was attenuated by exogenous PGE2. TGF-β1 is also a potent inducer of epithelial mesenchymal transition (EMT, a phenotype change in which epithelial cells differentiate into fibroblastoid cells. Supplementation with PGE2 or PGE2 receptor EP4 agonist PGE1-alcohol, as compared with EP1/3 agonist sulprostone, inhibited TGF-β1-induced expression of fibronectin and collagen I (extracellular matrix components. Exogenous PGE2 or PGE2 receptor agonists also suppressed actin remodeling induced by TGF-β1. These results suggest that PGE2 has an anti-fibrotic effect. We conclude that TGF-β1-induced downregulation of COX-2/PGE2 signaling is involved in facilitation of fibrotic EMT response in A549 cells.

  18. TGF-β1 Downregulates COX-2 Expression Leading to Decrease of PGE2 Production in Human Lung Cancer A549 Cells, Which Is Involved in Fibrotic Response to TGF-β1

    Science.gov (United States)

    Takai, Erina; Tsukimoto, Mitsutoshi; Kojima, Shuji

    2013-01-01

    Transforming growth factor-ß1 (TGF-β1) is a multifunctional cytokine that is involved in various pathophysiological processes, including cancer progression and fibrotic disorders. Here, we show that treatment with TGF-β1 (5 ng/mL) induced downregulation of cyclooxygenase-2 (COX-2), leading to reduced synthesis of prostaglandin E2 (PGE2), in human lung cancer A549 cells. Treatment of cells with specific inhibitors of COX-2 or PGE2 receptor resulted in growth inhibition, indicating that the COX-2/PGE2 pathway contributes to proliferation in an autocrine manner. TGF-β1 treatment induced growth inhibition, which was attenuated by exogenous PGE2. TGF-β1 is also a potent inducer of epithelial mesenchymal transition (EMT), a phenotype change in which epithelial cells differentiate into fibroblastoid cells. Supplementation with PGE2 or PGE2 receptor EP4 agonist PGE1-alcohol, as compared with EP1/3 agonist sulprostone, inhibited TGF-β1-induced expression of fibronectin and collagen I (extracellular matrix components). Exogenous PGE2 or PGE2 receptor agonists also suppressed actin remodeling induced by TGF-β1. These results suggest that PGE2 has an anti-fibrotic effect. We conclude that TGF-β1-induced downregulation of COX-2/PGE2 signaling is involved in facilitation of fibrotic EMT response in A549 cells. PMID:24098479

  19. Inhibitors of cyclo-oxygenase-2 and secretory phospholipase A2 preserve bone architecture following ovariectomy in adult rats.

    Science.gov (United States)

    Gregory, Laura S; Kelly, Wendy L; Reid, Robert C; Fairlie, David P; Forwood, Mark R

    2006-07-01

    Epidemiological evidence and in vitro data suggest that COX-2 is a key regulator of accelerated remodeling. Accelerated states of osteoblast and osteoclast activity are regulated by prostaglandins in vitro, but experimental evidence for specific roles of cyclooxygenase-2 (COX-2) and secretory phospholipase A2 (sPLA2) in activated states of remodeling in vivo is lacking. The aim of this study was to determine the effect of specific inhibitors of sPLA2-IIa and COX-2 on bone remodeling activated by estrogen deficiency in adult female rats. One hundred and twenty-four adult female Wistar rats were ovariectomized (OVX) or sham-operated. Rats commenced treatment 14 days after surgery with either vehicle, a COX-2 inhibitor (DFU at 0.02 mg/kg/day and 2.0 mg/kg/day) or a sPLA2-group-IIa inhibitor (KH064 at 0.4 mg/kg/day and 4.0 mg/kg/day). Treatment continued daily until rats were sacrificed at 70 days or 98 days post-OVX. The right tibiae were harvested, fixed and embedded in methylmethacrylate for structural histomorphometric bone analysis at the proximal tibial metaphysis. The specific COX-2 or sPLA2 inhibitors prevented ovariectomy-induced (OVX-induced) decreases in trabecular connectivity (Pbone resorption; and maintained bone turnover at SHAM levels following OVX in the rat. The sPLA2 inhibitor significantly suppressed increases in osteoclast surface induced by OVX (Pbone loss in the adult rat by conserving trabecular bone mass and architecture through reduced bone remodeling and decreased resorptive activity. Moreover, we report an important role of sPLA2-IIa in osteoclastogenesis that may be independent of the COX-2 metabolic pathway in the OVX rat in vivo.

  20. Analysis of the cytochrome c oxidase subunit II (COX2) gene in giant panda, Ailuropoda melanoleuca.

    Science.gov (United States)

    Ling, S S; Zhu, Y; Lan, D; Li, D S; Pang, H Z; Wang, Y; Li, D Y; Wei, R P; Zhang, H M; Wang, C D; Hu, Y D

    2017-01-23

    The giant panda, Ailuropoda melanoleuca (Ursidae), has a unique bamboo-based diet; however, this low-energy intake has been sufficient to maintain the metabolic processes of this species since the fourth ice age. As mitochondria are the main sites for energy metabolism in animals, the protein-coding genes involved in mitochondrial respiratory chains, particularly cytochrome c oxidase subunit II (COX2), which is the rate-limiting enzyme in electron transfer, could play an important role in giant panda metabolism. Therefore, the present study aimed to isolate, sequence, and analyze the COX2 DNA from individuals kept at the Giant Panda Protection and Research Center, China, and compare these sequences with those of the other Ursidae family members. Multiple sequence alignment showed that the COX2 gene had three point mutations that defined three haplotypes, with 60% of the sequences corresponding to haplotype I. The neutrality tests revealed that the COX2 gene was conserved throughout evolution, and the maximum likelihood phylogenetic analysis, using homologous sequences from other Ursidae species, showed clustering of the COX2 sequences of giant pandas, suggesting that this gene evolved differently in them.

  1. Bond and CDS Pricing via the Stochastic Recovery Black-Cox Model

    Directory of Open Access Journals (Sweden)

    Albert Cohen

    2017-04-01

    Full Text Available Building on recent work incorporating recovery risk into structural models by Cohen & Costanzino (2015, we consider the Black-Cox model with an added recovery risk driver. The recovery risk driver arises naturally in the context of imperfect information implicit in the structural framework. This leads to a two-factor structural model we call the Stochastic Recovery Black-Cox model, whereby the asset risk driver At defines the default trigger and the recovery risk driver Rt defines the amount recovered in the event of default. We then price zero-coupon bonds and credit default swaps under the Stochastic Recovery Black-Cox model. Finally, we compare our results with the classic Black-Cox model, give explicit expressions for the recovery risk premium in the Stochastic Recovery Black-Cox model, and detail how the introduction of separate but correlated risk drivers leads to a decoupling of the default and recovery risk premiums in the credit spread. We conclude this work by computing the effect of adding coupons that are paid continuously until default, and price perpetual (consol bonds in our two-factor firm value model, extending calculations in the seminal paper by Leland (1994.

  2. Oms1 associates with cytochrome c oxidase assembly intermediates to stabilize newly synthesized Cox1.

    Science.gov (United States)

    Bareth, Bettina; Nikolov, Miroslav; Lorenzi, Isotta; Hildenbeutel, Markus; Mick, David U; Helbig, Christin; Urlaub, Henning; Ott, Martin; Rehling, Peter; Dennerlein, Sven

    2016-05-15

    The mitochondrial cytochrome c oxidase assembles in the inner membrane from subunits of dual genetic origin. The assembly process of the enzyme is initiated by membrane insertion of the mitochondria-encoded Cox1 subunit. During complex maturation, transient assembly intermediates, consisting of structural subunits and specialized chaperone-like assembly factors, are formed. In addition, cofactors such as heme and copper have to be inserted into the nascent complex. To regulate the assembly process, the availability of Cox1 is under control of a regulatory feedback cycle in which translation of COX1 mRNA is stalled when assembly intermediates of Cox1 accumulate through inactivation of the translational activator Mss51. Here we isolate a cytochrome c oxidase assembly intermediate in preparatory scale from coa1Δ mutant cells, using Mss51 as bait. We demonstrate that at this stage of assembly, the complex has not yet incorporated the heme a cofactors. Using quantitative mass spectrometry, we define the protein composition of the assembly intermediate and unexpectedly identify the putative methyltransferase Oms1 as a constituent. Our analyses show that Oms1 participates in cytochrome c oxidase assembly by stabilizing newly synthesized Cox1.

  3. The Characterization And Role of Zinc Binding in Yeast Cox4

    Energy Technology Data Exchange (ETDEWEB)

    Coyne, H.J., III; Ciofi-Baffoni, S.; Banci, L.; Bertini, I.; Zhang, L.; George, G.N.; Winge, D.R.; /Utah U. /Florence U. /Saskatchewan U.

    2007-07-09

    Yeast Cox4 is a zinc binding subunit of cytochrome c oxidase. Cox4 is the only cofactor-containing subunit that is not directly part of the catalytic core of the enzyme located in the mitochondrial inner membrane. The Zn(II) site is shown to be distinct from the bovine ortholog, as it results from the x-ray structure of the entire cytochrome c oxidase in having a single histidyl residue and three conserved cysteines residues in the coordination sphere. Substitutions at the Cys ligand positions result in non-functional Cox4 proteins that fail to lead to cytochrome oxidase assembly. Limited function exists in His-119 mutants when overexpressed. Zn(II) binding in Cox4 is, therefore, important for the stability of the complex. The solution structure of yeast Cox4 elucidated by multidimensional NMR reveals a C-terminal globular domain consisting of two {beta} sheets analogous to the bovine ortholog except the loop containing the coordinating His in the yeast protein and the fourth Cys in the bovine protein are in different positions in the two structures. The conformation of this loop is dictated by the different sequence position of the fourth coordinating zinc ligand. The Zn(II) ion is buried within the domain, consistent with its role in structural stability. Potential functions of this matrix-facing subunit are discussed.

  4. The flavouring phytochemical 2-pentanone reduces prostaglandin production and COX-2 expression in colon cancer cells.

    Science.gov (United States)

    Pettersson, Jenny; Karlsson, Pernilla Christina; Göransson, Ulf; Rafter, Joseph James; Bohlin, Lars

    2008-03-01

    Many phytochemicals found in the diet may prevent colon carcinogenesis by affecting biochemical processes in the colonic mucosa. Inflammation and subsequent elevation of the enzyme cyclooxygenase-2 (COX-2) are two such factors involved in the development of colon cancer, and inhibition of these processes could be important targets for chemoprevention. We have previously shown COX-2 inhibitory activity locally in the colon; e.g. in human fecal water from a group of vegetarians. In this study we focus on 2-pentanone, a frequently occurring compound in common foods such as banana and carrot. The aim was to study the inhibitory effects on prostaglandin production and COX-2 protein expression in tumour necrosis factor-alpha stimulated colon cancer cells (HT29) by radioimmunoassay and Western blotting. 2-Pentanone inhibited both prostaglandin production and COX-2 protein expression in human colon cancer cells. A concentration of 400 mumol/l 2-pentanone inhibited the prostaglandin production by 56.9+/-12.9% which is in the same range as the reference compound NS398 (59.8+/-7.6%). The two highest concentrations of 2-pentanone were further analyzed by Western blot, and 400 micromol/l and 200 micromol/l 2-pentanone resulted in a 53.3+/-9.6% and +/-27.1% reduction of the COX-2 protein levels respectively. Further studies on flavouring compounds, for example 2-pentanone, as colon cancer chemopreventives would be very valuable, and such results may contribute to future dietary recommendations.

  5. Renal and related cardiovascular effects of conventional and COX-2-specific NSAIDs and non-NSAID analgesics.

    Science.gov (United States)

    Whelton, A

    2000-03-01

    On a daily basis it appears that as many as one in five adults in the United States may consume an analgesic compound either on a prescription basis or by over-the-counter (OTC) purchase. This high profile of intermittent or repetitive analgesic use appears to be relatively similar throughout the developed world. Although analgesics generally have a good renal safety profile, the nonsteroidal anti-inflammatory drug (NSAID) analgesics may produce mild renal side effects, such as the generation of peripheral edema in up to 5% of the general population. Other more serious renal and related cardiovascular side effects tend to be more apparent in lesser numbers of clinically "at risk" NSAID analgesic users. In contrast, non-NSAID analgesics, such as paracetamol or tramadol, have essentially no renal or related cardiovascular side effects when used at recommended dosing schedules. This review characterizes the renal syndromes associated with the use of NSAID analgesics, identifies the risks inherent in the use of these compounds in treated patients with hypertension and congestive heart failure, summarizes the early comparable data available for the new COX-2-specific inhibitors, and profiles the scant acute and long-term clinical concerns attendant with the use of non-NSAID nonnarcotic analgesics. It is important that healthcare providers and practitioners are aware of the relative renal risks of different analgesics and that they use this knowledge to counsel the analgesic-consuming population appropriately.

  6. A comparison between the use of Cox regression and the use of partial least squares-Cox regression to predict the survival of kidney-transplant patients

    Science.gov (United States)

    Solimun

    2017-05-01

    The aim of this research is to model survival data from kidney-transplant patients using the partial least squares (PLS)-Cox regression, which can both meet and not meet the no-multicollinearity assumption. The secondary data were obtained from research entitled "Factors affecting the survival of kidney-transplant patients". The research subjects comprised 250 patients. The predictor variables consisted of: age (X1), sex (X2); two categories, prior hemodialysis duration (X3), diabetes (X4); two categories, prior transplantation number (X5), number of blood transfusions (X6), discrepancy score (X7), use of antilymphocyte globulin(ALG) (X8); two categories, while the response variable was patient survival time (in months). Partial least squares regression is a model that connects the predictor variables X and the response variable y and it initially aims to determine the relationship between them. Results of the above analyses suggest that the survival of kidney transplant recipients ranged from 0 to 55 months, with 62% of the patients surviving until they received treatment that lasted for 55 months. The PLS-Cox regression analysis results revealed that patients' age and the use of ALG significantly affected the survival time of patients. The factor of patients' age (X1) in the PLS-Cox regression model merely affected the failure probability by 1.201. This indicates that the probability of dying for elderly patients with a kidney transplant is 1.152 times higher than that for younger patients.

  7. Proton pump inhibitors

    Science.gov (United States)

    Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This ...

  8. Alkylamino derivatives of 4-aminomethylpyridine as inhibitors of copper-containing amine oxidases.

    Science.gov (United States)

    Bertini, Vincenzo; Buffoni, Franca; Ignesti, Giovanni; Picci, Nevio; Trombino, Sonia; Iemma, Francesca; Alfei, Silvana; Pocci, Marco; Lucchesini, Francesco; De Munno, Angela

    2005-02-10

    The first substratelike, reversible inhibitors of different copper amine oxidases (CAOs) with IC50 (M) as low as 2.0 x 10(-8) corresponding to derivatives of 4-aminomethylpyridine with alkoxy (1a-d), alkylthio (2a,b), and alkylamino (3a-e, 4a-j) groups in the positions 3 and 5 have been prepared and studied. The inhibitors 1a-d are active on benzylamine oxidase and semicarbazide-sensitive amine oxidase and are very selective with respect to diamine oxidase, lysyl oxidase, and monoamine oxidases. The inhibitors 2a,b are selective for benzylamine oxidase whereas 2a is also a new type of good substrate of diamine oxidase. The inhibitors 3a-e and 4a-j are substratelike, reversible, nonselective inhibitors of various CAOs including pea seedling amine oxidase and Hansenula polymorpha amine oxidase, whose enzymatic sites are known from X-ray structure determinations. The inhibitors 3b,c and 4b,c are excellent substratelike tools for studies correlating CAOs that afford crystals suitable for X-ray structure determinations with CAOs from mammals.

  9. A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors

    Science.gov (United States)

    Goracci, Laura; Deschamps, Nathalie; Randazzo, Giuseppe Marco; Petit, Charlotte; Dos Santos Passos, Carolina; Carrupt, Pierre-Alain; Simões-Pires, Claudia; Nurisso, Alessandra

    2016-07-01

    The human histone deacetylase isoform 6 (HDAC6) has been demonstrated to play a major role in cell motility and aggresome formation, being interesting for the treatment of multiple tumour types and neurodegenerative conditions. Currently, most HDAC inhibitors in preclinical or clinical evaluations are non-selective inhibitors, characterised by a hydroxamate zinc-binding group (ZBG) showing off-target effects and mutagenicity. The identification of selective HDAC6 inhibitors with novel chemical properties has not been successful yet, also because of the absence of crystallographic information that makes the rational design of HDAC6 selective inhibitors difficult. Using HDAC inhibitory data retrieved from the ChEMBL database and ligand-based computational strategies, we identified 8 original new non-hydroxamate HDAC6 inhibitors from the SPECS database, with activity in the low μM range. The most potent and selective compound, bearing a hydrazide ZBG, was shown to increase tubulin acetylation in human cells. No effects on histone H4 acetylation were observed. To the best of our knowledge, this is the first report of an HDAC6 selective inhibitor bearing a hydrazide ZBG. Its capability to passively cross the blood-brain barrier (BBB), as observed through PAMPA assays, and its low cytotoxicity in vitro, suggested its potential for drug development.

  10. Characterization of the Cytochrome C Oxidase Assembly Factor Cox19 of 'Saccharomyces Cerevisiae'

    Energy Technology Data Exchange (ETDEWEB)

    Rigby, K.; Zhang, L.; Cobine, P.A.; George, G.N.; Winge, D.R.; /Utah U. /Saskatchewan U.

    2007-07-12

    Cox19 is an important accessory protein in the assembly of cytochrome c oxidase in yeast. The protein is functional when tethered to the mitochondrial inner membrane, suggesting its functional role within the intermembrane space. Cox19 resembles Cox17 in having a twin CX{sub 9}C sequence motif that adopts a helical hairpin in Cox17. The function of Cox17 appears to be a Cu(I) donor protein in the assembly of the copper centers in cytochrome c oxidase. Cox19 also resembles Cox17 in its ability to coordinate Cu(I). Recombinant Cox19 binds 1 mol eq of Cu(I) per monomer and exists as a dimeric protein. Cox19 isolated from the mitochondrial intermembrane space contains variable quantities of copper, suggesting that Cu(I) binding may be a transient property. Cysteinyl residues important for Cu(I) binding are also shown to be important for the in vivo function of Cox19. Thus, a correlation exists in the ability to bind Cu(I) and in vivo function.

  11. The potential role of COX-2 in cancer stem cell-mediated canine mammary tumor initiation: an immunohistochemical study.

    Science.gov (United States)

    Huang, Jian; Zhang, Di; Xie, Fuqiang; Lin, Degui

    2015-01-01

    Increasing evidence suggests that cancer stem cells (CSCs) are responsible for tumor initiation and maintenance. Additionally, it is becoming apparent that cyclooxygenase (COX) signaling is associated with canine mammary tumor development. The goals of the present study were to investigate COX-2 expression patterns and their effect on CSC-mediated tumor initiation in primary canine mammary tissues and tumorsphere models using immunohistochemistry. Patterns of COX-2, CD44, octamer-binding transcription factor (Oct)-3/4, and epidermal growth factor receptor (EGFR) expression were examined in malignant mammary tumor (MMT) samples and analyzed in terms of clinicopathological characteristics. COX-2 and Oct-3/4 expression was higher in MMTs compared to other histological samples with heterogeneous patterns. In MMTs, COX-2 expression correlated with tumor malignancy features. Significant associations between COX-2, CD44, and EGFR were observed in low-differentiated MMTs. Comparative analysis showed that the levels of COX-2, CD44, and Oct-3/4 expression varied significantly among TSs of three histological grades. Enhanced COX-2 staining was consistently observed in TSs. Similar levels of staining intensity were found for CD44 and Oct-3/4, but EGFR expression was weak. Our findings indicate the potential role of COX-2 in CSC-mediated tumor initiation, and suggest that COX-2 inhibition may help treat canine mammary tumors by targeting CSCs.

  12. Selective CDK inhibitors:promising candidates for future clinical traumatic brain injury trials

    Institute of Scientific and Technical Information of China (English)

    Shruti V.Kabadi; Alan I.Faden

    2014-01-01

    Traumatic brain injury induces secondary injury that contributes to neuroinlfammation, neuronal loss, and neurological dysfunction. One important injury mechanism is cell cycle activation which causes neuronal apoptosis and glial activation. The neuroprotective effects of both non-selective (Flavopiridol) and selective (Roscovitine and CR-8) cyclin-dependent kinase inhibitors have been shown across multiple experimental traumatic brain injury models and species. Cyclin-depen-dent kinaseinhibitors, administered as a single systemic dose up to 24 hours after traumatic brain injury, provide strong neuroprotection-reducing neuronal cell death, neuroinflammation and neurological dysfunction. Given their effectiveness and long therapeutic window, cyclin-depen-dent kinase inhibitors appear to be promising candidates for clinical traumatic brain injury trials.

  13. Cyclopamine and jervine induce COX-2 overexpression in human erythroleukemia cells but only cyclopamine has a pro-apoptotic effect