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Sample records for 4-methylnitrosamino-1-3-pyridyl-1-butanone induce cyclooxygenase-2

  1. The regulation of 4-(methylnitrosamino-1-(3-pyridyl-1-butanone-induced lung tumor promotion by estradiol in female A/J mice.

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    Rong-Jane Chen

    Full Text Available Epidemiological studies indicate that women are at a higher risk developing lung cancer than men are. It is suggested that estrogen is one of the most important factors in lung cancer development in females. Additionally, cigarette smoke, and environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, may play salient roles in female lung carcinogenesis. However, the mechanisms responsible for the interaction of these factors in the promotion of lung cancer are still poorly understood. The present study was designed to explore two ideas: first, the synergistic lung tumorigenic effects of 4-(methylnitrosamino-1-(3-pyridyl-butanol (NNK combined with TCDD, 17β-estradiol (E2 or both through a long-term treatment experiment, and second, to identify early changes in the inflammatory and signaling pathways through short-term treatment experiments. The results indicate that A/J mice given E2 had strong effects in potentiating NNK-induced activation of MAPK signaling, NFκB, and COX-2 expression. In the long-term exposure model, E2 had a strong tumor promoting effect, whereas TCDD antagonized this effect in A/J mice. We conclude that treatment with NNK combined with either E2 or TCDD induces lung carcinogenesis and the promotion effects could be correlated with lung inflammation. E2 was shown to potentiate NNK-induced inflammation, cell proliferation, thereby leading to lung tumorigenesis.

  2. Phenotypic modification of human airway epithelial cells in air-liquid interface culture induced by exposure to the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

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    Carson, Johnny L; Brighton, Luisa E; Jaspers, Ilona

    2015-04-01

    The nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco-specific carcinogen. We used an air-liquid interface epithelial cell culture system to model changes associated with NNK exposure relative to pathologies documented in human tobacco-related illnesses. Although in vitro systems exhibit certain limitations, they often offer accentuation of subtle pathologies. While the distribution of cell types in control cultures typically favors the ciliated cell phenotype, NNK-exposed cultures transitioned to non-ciliated cell phenotypes as well as reflecting features consistent with squamous metaplasia. We conclude that NNK impacts normal growth and differentiation of human airway epithelium in a short interval of time in vitro.

  3. Synergism between 2,3,7,8-tetrachlorodibenzo-p-dioxin and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone on lung tumor incidence in mice

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    Wang Yingjan [Department of Environmental and Occupational Health, National Cheng Kung University, Medical College, Tainan, Taiwan (China); Chang Han [Department of Pathology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan (China); Kuo, Yu-Chun; Wang, Chien-Kai [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan (China); Siao, Shih-He [Department of Environmental and Occupational Health, National Cheng Kung University, Medical College, Tainan, Taiwan (China); Chang, Louis W. [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan (China); Lin Pinpin, E-mail: pplin@nhri.org.tw [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan (China)

    2011-02-15

    Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is classified as a human carcinogen, TCDD only induced oxidative DNA damages. In our present study, we combined TCDD with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to investigate their tumorigenic effects on lung tumor formation in A/J mice. Application of NNK at a tumorigenic dose (2 mg/mouse) induced lung adenoma in both male and female A/J mice. Neither application of NNK at a non-tumorigenic dose (1 mg/mouse) nor repeated application of TCDD alone increased tumor incidence. Following the single injection of NNK at a non-tumorigenic dose (1 mg/mouse), repeated application of TCDD significantly increased the lung tumor incidence in female, but not in male, A/J mice 24 weeks later. Utilizing the real-time RT-PCR array, we found that P16 mRNA was significantly reduced in female lung, but not male lung, of NNK/TCDD co-treated A/J mice. With immunohistochemical staining, we confirmed that nuclear P16 protein was reduced in the lungs of NNK/TCDD co-treated female mice. These data suggest that P16 reduction at least partially contributed to synergistic effects of TCDD in lung tumorigenesis.

  4. Synergism between 2,3,7,8-tetrachlorodibenzo-p-dioxin and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone on lung tumor incidence in mice

    International Nuclear Information System (INIS)

    Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is classified as a human carcinogen, TCDD only induced oxidative DNA damages. In our present study, we combined TCDD with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to investigate their tumorigenic effects on lung tumor formation in A/J mice. Application of NNK at a tumorigenic dose (2 mg/mouse) induced lung adenoma in both male and female A/J mice. Neither application of NNK at a non-tumorigenic dose (1 mg/mouse) nor repeated application of TCDD alone increased tumor incidence. Following the single injection of NNK at a non-tumorigenic dose (1 mg/mouse), repeated application of TCDD significantly increased the lung tumor incidence in female, but not in male, A/J mice 24 weeks later. Utilizing the real-time RT-PCR array, we found that P16 mRNA was significantly reduced in female lung, but not male lung, of NNK/TCDD co-treated A/J mice. With immunohistochemical staining, we confirmed that nuclear P16 protein was reduced in the lungs of NNK/TCDD co-treated female mice. These data suggest that P16 reduction at least partially contributed to synergistic effects of TCDD in lung tumorigenesis.

  5. Human cyt P450 mediated metabolic toxicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) evaluated using electrochemiluminescent arrays†

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    Krishnan, Sadagopan; Hvastkovs, Eli G.; Bajrami, Besnik; Schenkman, John B.; Rusling, James F.

    2008-01-01

    Electrochemiluminescent (ECL) arrays containing polymer ([Ru(bpy)2(PVP)10]2+, PVP = polyvinylpyridine), DNA, and selected enzymes were employed to elucidate cytochrome (cyt) P450 dependent metabolism of the tobacco specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Bioactivated NNK metabolites formed upon H2O2-enzymatic activation were captured as DNA adducts and detected simultaneously from 36 spot arrays by capturing and quantifying emitted ECL with an overhead CCD c...

  6. Induction of lung lesions in Wistar rats by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and its inhibition by aspirin and phenethyl isothiocyanate

    International Nuclear Information System (INIS)

    The development of effective chemopreventive agents against cigarette smoke-induced lung cancer could be greatly facilitated by suitable laboratory animal models, such as animals treated with the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In the current study, we established a novel lung cancer model in Wistar rats treated with NNK. Using this model, we assessed the effects of two chemopreventive agents, aspirin and phenethyl isothiocyanate (PEITC), on tumor progression. First, rats were treated with a single-dose of NNK by intratracheal instillation; control rats received iodized oil. The animals were then sacrificed on the indicated day after drug administration and examined for tumors in the target organs. PCNA, p63 and COX-2 expression were analyzed in the preneoplastic lung lesions. Second, rats were treated with a single-dose of NNK (25 mg/kg body weight) in the absence or presence of aspirin and/or PEITC in the daily diet. The control group received only the vehicle in the regular diet. The animals were sacrificed on day 91 after bronchial instillation of NNK. Lungs were collected and processed for histopathological and immunohistochemical assays. NNK induced preneoplastic lesions in lungs, including 33.3% alveolar hyperplasia and 55.6% alveolar atypical dysplasia. COX-2 expression increased similarly in alveolar hyperplasia and alveolar atypical dysplasia, while PCNA expression increased more significantly in the latter than the former. No p63 expression was detected in the preneoplastic lesions. In the second study, the incidences of alveolar atypical dysplasia were reduced to 10%, 10% and 0%, respectively, in the aspirin, PEITC and aspirin and PEITC groups, compared with 62.5% in the carcinogen-treated control group. COX-2 expression decreased after dietary aspirin or aspirin and PEITC treatment. PCNA expression was significantly reduced in the aspirin and PEITC group. (1) A single dose of 25 mg/kg body weight

  7. Human cyt P450 mediated metabolic toxicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) evaluated using electrochemiluminescent arrays†

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    Krishnan, Sadagopan; Hvastkovs, Eli G.; Bajrami, Besnik; Schenkman, John B.; Rusling, James F.

    2012-01-01

    Electrochemiluminescent (ECL) arrays containing polymer ([Ru(bpy)2(PVP)10]2+, PVP = polyvinylpyridine), DNA, and selected enzymes were employed to elucidate cytochrome (cyt) P450 dependent metabolism of the tobacco specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Bioactivated NNK metabolites formed upon H2O2-enzymatic activation were captured as DNA adducts and detected simultaneously from 36 spot arrays by capturing and quantifying emitted ECL with an overhead CCD camera. Increased ECL emission was dependent on NNK exposure time. Of the enzymes tested, the activity toward NNK bioactivation was cyt P450 1A2 > 2E1 > 1B1 ≈ chloroperoxidase (CPO) > myoglobin (Mb) in accordance with reported in vivo studies. Cyt P450/polyion films were also immobilized on 500 nm diameter silica nanospheres for product analysis by LC-MS. Analysis of the nanosphere film reaction media provided ECL array validation and quantitation of the bioactivated NNK hydrolysis product 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) confirming production of reactive metabolites in the films. Chemical screening in this fashion allows rapid clarification of enzymes responsible for genotoxic activation as well as offering insight into cyt P450-related toxicity and mechanisms. PMID:19156262

  8. Facile Synthesis of CeO2-LaFeO3 Perovskite Composite and Its Application for 4-(Methylnitrosamino-1-(3-Pyridyl-1-Butanone (NNK Degradation

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    Kaixuan Wang

    2016-04-01

    Full Text Available A facile and environmentally friendly surface-ion adsorption method using CeCO3OH@C as template was demonstrated to synthesize CeO2-LaFeO3 perovskite composite material. The obtained composite was characterized by X-ray diffraction (XRD, fourier transform infrared spectra (FT-IR, field-emission scanning electron microscopy (FE-SEM, transmission electron microscopy (TEM, thermo-gravimetric analysis and differential scanning calorimetry (TG-DSC, N2 adsorption/desorption isotherms and X-ray photoelectron spectra (XPS measurements. The catalytic degradation of nitrosamine 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK was tested to evaluate catalytic activity of the CeO2-LaFeO3 composite. Much better activity was observed for the CeO2-LaFeO3 composite comparing with CeO2 and LaFeO3. These results suggested that perovskite composite materials are a promising candidate for the degradation of tobacco-specific nitrosamines (TSNAs.

  9. Inhibition of pancreatic acinar mitochondrial thiamin pyrophosphate uptake by the cigarette smoke component 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

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    Srinivasan, Padmanabhan; Thrower, Edwin C; Gorelick, Fred S; Said, Hamid M

    2016-05-15

    Thiamin is essential for normal metabolism in pancreatic acinar cells (PAC) and is obtained from their microenvironment through specific plasma-membrane transporters, converted to thiamin pyrophosphate (TPP) in the cytoplasm, followed by uptake of TPP by mitochondria through the mitochondrial TPP (MTPP) transporter (MTPPT; product of SLC25A19 gene). TPP is essential for normal mitochondrial function. We examined the effect of long-term/chronic exposure of PAC in vitro (pancreatic acinar 266-6 cells) and in vivo (wild-type or transgenic mice carrying the SLC25A19 promoter) of the cigarette smoke toxin, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), on the MTPP uptake process. Our in vitro and in vivo findings demonstrate that NNK negatively affects MTPP uptake and reduced expression of MTPPT protein, MTPPT mRNA, and heterogenous nuclear RNA, as well as SLC25A19 promoter activity. The effect of NNK on Slc25a19 transcription was neither mediated by changes in expression of transcriptional factor NFY-1 (known to drive SLC25A19 transcription), nor due to changes in methylation profile of the Slc25a19 promoter. Rather, it appears to be due to changes in histone modifications that involve significant decreases in histone H3K4-trimethylation and H3K9-acetylation (activation markers). The effect of NNK on MTPPT function is mediated through the nonneuronal α7-nicotinic acetylcholine receptor (α7-nAChR), as indicated by both in vitro (using the nAChR antagonist mecamylamine) and in vivo (using an α7-nAchR(-/-) mouse model) studies. These findings demonstrate that chronic exposure of PAC to NNK negatively impacts PAC MTPP uptake. This effect appears to be exerted at the level of Slc25a19 transcription, involve epigenetic mechanism(s), and is mediated through the α7-nAchR. PMID:26999808

  10. Metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in the patas monkey: pharmacokinetics and characterization of glucuronide metabolites.

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    Hecht, S S; Trushin, N; Reid-Quinn, C A; Burak, E S; Jones, A B; Southers, J L; Gombar, C T; Carmella, S G; Anderson, L M; Rice, J M

    1993-02-01

    The metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was examined in the patas monkey, in order to provide further information about NNK metabolic pathways in primates. Female patas monkeys were given i.v. injections of [5-3H]NNK, and metabolites in serum and urine were analyzed by HPLC. Metabolism by alpha-hydroxylation of NNK was rapid and extensive, and the products of this pathway, 4-hydroxy-4-(3-pyridyl)butyric acid and 4-oxo-4-(3-pyridyl) butyric acid, accounted for a relatively large proportion of serum and urinary metabolites at all time points. This is significant because the formation of these products is associated with modification of DNA by NNK. The other major metabolic pathway was carbonyl reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which detected both unconjugated and diastereomeric O-glucuronides. One of these glucuronides had been previously identified in rat urine, but the other diastereomer, which was the more prevalent of the two in serum and urine, had not been observed in studies of NNK metabolism in rodents. It was characterized by its spectral properties, by enzymatic hydrolysis to NNAL, and by derivatization of the released NNAL enantiomer with (R)-(+)-alpha-methylbenzylisocyanate. The two NNAL glucuronides accounted for 15-20% of the urinary metabolites in monkeys given 0.1 micrograms/kg NNK, which is similar to a smoker's dose, suggesting their use as dosimeters of NNK exposure in humans. Pharmacokinetic parameters were consistent with those observed in previous studies of nitrosamines, and varied predictably with body weight of five species. The results of this study have provided new insights relevant to assessing human metabolism of NNK.

  11. Curcumin down regulates smokeless tobacco-induced NF-κB activation and COX-2 expression in human oral premalignant and cancer cells

    International Nuclear Information System (INIS)

    Smokeless tobacco (ST) consumption is a major cause of oral cancer in South East Asia including India. Recently, we showed that exposure to smokeless tobacco extract (STE) (khaini) results in increased expression and activation of nuclear factor-κB (NF-κB) and its downstream target cyclooxygenase-2 (COX-2) in human oral cell systems in vitro. The present study was designed to test the hypothesis that curcumin may inhibit the activation of NF-κB in ST exposed oral premalignant and cancer cells. Exposure of oral premalignant and cancer cells to curcumin resulted in significant decrease in cell viability and induced apoptosis. STE-induced nuclear translocation and DNA-binding activity of NF-κB were inhibited in curcumin pretreated oral premalignant and cancer cells in vitro. Curcumin treatment led to decreased expression of NF-κB and COX-2. The tobacco specific nitrosamine, 4-(methylnitrosamino-)-1-(3-pyridyl)-1-butanone (NNK), is one of the carcinogenic components of STE (khaini). We demonstrate that curcumin pretreatment abrogated NNK-induced activation of NF-κB and COX-2 expression, suggesting that NNK is one of the factors in STE (khaini) modulated by curcumin. In conclusion, our findings demonstrate for the first time that curcumin downregulates STE (khaini) or NNK-induced NF-κB and COX-2 in oral premalignant and cancer cells in vitro

  12. Bcl2 Family Functions as Signaling Target in Nicotine-/NNK-Induced Survival of Human Lung Cancer Cells

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    Xingming Deng

    2014-01-01

    Full Text Available Lung cancer is the leading cause of cancer death and has a strong etiological association with cigarette smoking. Nicotine and nitrosamine 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK are two major components in cigarette smoke that significantly contribute to the development of human lung cancer. Nicotine is able to stimulate survival of both normal human lung epithelial and lung cancer cells. In contrast to nicotine, NNK is a more potent carcinogen that not only induces single-strand DNA breaks and oxidative DNA damage but also stimulates survival and proliferation of normal lung epithelial and lung cancer cells. However, the molecular mechanism(s by which nicotine and NNK promote cell survival, proliferation, and lung tumor development remains elusive. The fate of cells (i.e., survival or death is largely decided by the Bcl2 family members. In the past several years, multiple signaling links between nicotine/NNK and Bcl2 family members have been identified that regulate survival and proliferation. This review provides a concise, systematic overview of the current understanding of the role of the pro- or antiapoptotic proteins in cigarette smoking, lung cancer development, and treatment resistance.

  13. Deficiency of CCAAT/enhancer binding protein family DNA binding prevents malignant conversion of adenoma to carcinoma in NNK-induced lung carcinogenesis in the mouse

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    Kimura Shioko

    2012-12-01

    Full Text Available Abstract Background The CCAAT/enhancer binding proteins (C/EBPs play important roles in carcinogenesis of many tumors including the lung. Since multiple C/EBPs are expressed in lung, the combinatorial expression of these C/EBPs on lung carcinogenesis is not known. Methods A transgenic mouse line expressing a dominant negative A-C/EBP under the promoter of lung epithelial Clara cell secretory protein (CCSP gene in doxycycline dependent fashion was subjected to 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK-induced lung carcinogenesis bioassay in the presence and absence of doxycycline, and the effect of abolition of DNA binding activities of C/EBPs on lung carcinogenesis was examined. Results A-C/EBP expression was found not to interfere with tumor development; however, it suppressed the malignant conversion of adenoma to carcinoma during NNK-induced lung carcinogenesis. The results suggested that Ki67 may be used as a marker for lung carcinomas in mouse. Conclusions The DNA binding of C/EBP family members can be used as a potential molecular target for lung cancer therapy.

  14. Early and delayed intervention with rapamycin prevents NNK-induced lung adenocarcinoma in A/J mice.

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    Patlolla, Jagan M R; Kopelovich, Levy; Qian, Li; Zhang, Yuting; Kumar, Gaurav; Madka, Venkateshwar; Mohammed, Altaf; Biddick, Laura; Sadeghi, Michael; Lightfoot, Stan; Rao, Chinthalapally V

    2015-12-01

    In tobacco-associated lung cancers, the protein kinase B/mammalian target of rapamycin (Akt/mTOR) pathway frequently is activated by nicotine and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The aim of the present study was to examine the effects of early or late intervention with rapamycin in NNK-induced lung adenoma and progression to adenocarcinoma in female A/J mice. At 7 weeks of age, 40 mice/each carcinogen group received one dose of 10 μmol NNK i.p. Three weeks later, the early intervention groups (25/group) were fed diets containing 0, 8 or 16 ppm rapamycin. The mice were sacrificed after 17 or 34 weeks of drug exposure and tumors were evaluated via histopathology. For late intervention (late adenoma and adenocarcinoma stage), groups of 15 mice were administered diets containing 8 or 16 ppm rapamycin starting 20 weeks after NNK treatment and continuing for 17 weeks before evaluation of tumor progression. Administration of 8 or 16 ppm rapamycin as an early or a late stage intervention significantly suppressed lung adenoma and adenocarcinoma formation (p50‑60% tumor inihibition; p2.10 to Lung tumors harvested from mice exposed to rapamycin showed a significant decrease in p-mTOR, p-S6K1, PCNA and Bcl-xL as compared with controls in the early and late stage intervention studies. These observations suggest that rapamycin is highly effective even with administration after dysplastic adenoma or early adenocarcinoma stages and is useful for high-risk lung cancer patients.

  15. Comparison of hepatocarcinogen-induced gene expression profiles in conventional primary rat hepatocytes with in vivo rat liver.

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    Doktorova, Tatyana Y; Ellinger-Ziegelbauer, Heidrun; Vinken, Mathieu; Vanhaecke, Tamara; van Delft, Joost; Kleinjans, Jos; Ahr, Hans-Juergen; Rogiers, Vera

    2012-09-01

    At present, substantial efforts are focused on the development of in vitro assays coupled with "omics" technologies for the identification of carcinogenic substances as an alternative to the classical 2-year rodent carcinogenicity bioassay. A prerequisite for the eventual regulatory acceptance of such assays, however, is the in vivo relevance of the observed in vitro findings. In the current study, hepatocarcinogen-induced gene expression profiles generated after the exposure of conventional cultures of primary rat hepatocytes to three non-genotoxic carcinogens (methapyrilene hydrochloride, piperonyl butoxide, and Wy-14643), three genotoxic carcinogens (aflatoxin B1, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and 2-nitrofluorene), and two non-carcinogens (nifedipine and clonidine) are compared with previously obtained in vivo data after oral administration for up to 14 days of the same hepatocarcinogens to rats. In addition to the comparison of deregulated genes and functions per compound between in vivo and in vitro models, the major discriminating cellular pathways found in vivo in livers of exposed rats were examined for deregulation in vitro. Further, in vivo-derived gene signatures for the identification of genotoxic versus non-genotoxic carcinogens are used to classify in vitro-tested hepatocarcinogens and non-carcinogens. In the primary hepatocyte cultures, two out of the three tested genotoxic carcinogens mimicked the in vivo-relevant DNA damage response and were correctly assessed. Exposure to the non-genotoxic hepatocarcinogens, however, triggered a relatively weak response in the in vitro system, with no clear similarities to in vivo. This study contributes to the further optimization of toxicogenomics predictive tools when applied in in vitro settings. PMID:22484513

  16. Chemopreventive Effects of the p53-Modulating Agents CP-31398 and Prima-1 in Tobacco Carcinogen-Induced Lung Tumorigenesis in A/J Mice

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    Chinthalapally V. Rao

    2013-09-01

    Full Text Available Lung cancer is the leading cause of cancer deaths worldwide. Expression of the p53 tumor suppressor protein is frequently altered in tobacco-associated lung cancers. We studied chemopreventive effects of p53-modulating agents, namely, CP-31398 and Prima-1, on 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK-induced lung adenoma and adenocarcinoma formation in female A/J mice. Seven-week-old mice were treated with a single dose of NNK (10 µmol/mouse by intraperitoneal injection and, 3 weeks later, were randomized to mice fed a control diet or experimental diets containing 50 or 100 ppm CP-31398 or 150 or 300 ppm Prima-1 for either 17 weeks (10 mice/group or 34 weeks (15 mice/group to assess the efficacy against lung adenoma and adenocarcinoma. Dietary feeding of 50 or 100 ppm CP-31398 significantly suppressed (P < .0001 lung adenocarcinoma by 64% and 73%, respectively, after 17 weeks and by 47% and 56%, respectively, after 34 weeks. Similarly, 150 or 300 ppm Prima-1 significantly suppressed (P < .0001 lung adenocarcinoma formation by 56% and 62%, respectively, after 17 weeks and 39% and 56%, respectively, after 34 weeks. Importantly, these results suggest that both p53 modulators cause a delay in the progression of adenoma to adenocarcinoma. Immunohistochemical analysis of lung tumors from mice exposed to p53-modulating agents showed a significantly reduced tumor cell proliferation and increased accumulation of wild-type p53 in the nucleus. An increase in p21- and apoptotic-positive cells was also observed in lung tumors of mice exposed to p53-modulating agents. These results support a chemopreventive role of p53-modulating agents in tobacco carcinogen-induced lung adenocarcinoma formation.

  17. Comparison of the expression profiles induced by genotoxic and nongenotoxic carcinogens in rat liver

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    Ellinger-Ziegelbauer, Heidrun [Bayer Healthcare AG, Department of Molecular and Genetic Toxicology, Aprather Weg 18a, 42096 Wuppertal (Germany)]. E-mail: heidrun.ellinger-ziegelbauer@bayerhealthcare.com; Stuart, Barry [Bayer Crop Science, Department of Toxicology, Stilwell, KS (United States); Wahle, Brad [Bayer Crop Science, Department of Toxicology, Stilwell, KS (United States); Bomann, Werner [Bayer Crop Science, Department of Toxicology, Stilwell, KS (United States); Ahr, Hans Juergen [Bayer Healthcare AG, Department of Molecular and Genetic Toxicology, Aprather Weg 18a, 42096 Wuppertal (Germany)

    2005-08-04

    Application of recently developed gene expression techniques using microarrays in toxicological studies (toxicogenomics) facilitate the interpretation of a toxic compound's mode of action and may also allow the prediction of selected toxic effects based on gene expression changes. In order to test this hypothesis, we investigated whether carcinogens at doses known to induce liver tumors in the 2-year rat bioassay deregulate characteristic sets of genes in a short term in vivo study and whether these deregulated genes represent defined biological pathways. Male Wistar rats were dosed with the four nongenotoxic hepatocarcinogens methapyrilene (MPy, 60 mg/kg/day), diethylstilbestrol (DES, 10 mg/kg/day), Wy-14643 (Wy, 60 mg/kg/day), and piperonylbutoxide (PBO, 1200 mg/kg/day). After 1, 3, 7, and 14 days, the livers were taken for histopathological evaluation and for analysis of the gene expression profiles on Affymetrix RG{sub U}34A arrays. The expression profile of the four nongenotoxic carcinogens were compared to the profiles of the four genotoxic carcinogens 2-nitrofluorene (2-NF), dimethylnitrosamine (DMN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and aflatoxin B1 (AB1) from a similar study reported previously. By using statistical and clustering tools characteristically deregulated genes were extracted and functionally classified. Distinct cellular pathways were affected by the nongenotoxic carcinogens compared to the genotoxic carcinogens which at least partly correlated with the two-stage model of carcinogenesis. Characteristic to genotoxic carcinogens were a DNA damage response and the activation of proliferative and survival signaling. Nongenotoxic carcinogens showed responses to oxidative DNA or protein damage, as well as cell cycle progression and signs of regeneration. Many of the gene alterations found with the nongenotoxic carcinogens imply compound-specific mechanisms. Although neither a single gene nor a single pathway will be

  18. The Effect of Celecoxib, a Cyclooxygenase-2 Inhibitor on Noise- Induced Hearing Loss

    OpenAIRE

    Akram Pourbakht

    2013-01-01

    Objective(s): Noise-induced hearing loss (NIHL) is the major cause of acquired hearing loss.  Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, is a non- steroidal anti- inflammatory drug (NSAID) with known antioxidant and antineoplastic activity. Therefore, we monitored the extent of temporary noise- induced threshold shifts (TTS) and cochlear damage caused by high level 4- kHz noise exposure to verify the differences with those pretreated with celecoxib. Materials and Methods: Ten male albin...

  19. Lithium induces microcysts and polyuria in adolescent rat kidney independent of cyclooxygenase-2

    DEFF Research Database (Denmark)

    Kjærsgaard, Gitte; Madsen, Kirsten; Marcussen, Niels;

    2014-01-01

    In patients, chronic treatment with lithium leads to renal microcysts and nephrogenic diabetes insipidus (NDI). It was hypothesized that renal cyclooxygenase-2 (COX-2) activity promotes microcyst formation and NDI. Kidney microcysts were induced in male adolescent rats by feeding dams with lithium...... was found in microcyst epithelium in rat kidney. A human nephrectomy specimen from a patient treated for 28 years with lithium displayed multiple, COX-1-immunopositive, microcysts. In chronic lithium-treated adolescent rats, COX-2 is not colocalized with microcystic epithelium, mitotic activity...

  20. Mechanisms of Cancer Induction by Tobacco-Specific NNK and NNN

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    Xue, Jiaping [Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612 (United States); Yang, Suping; Seng, Seyha, E-mail: sseng@bidmc.harvard.edu [Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 (United States)

    2014-05-14

    Tobacco use is a major public health problem worldwide. Tobacco-related cancers cause millions of deaths annually. Although several tobacco agents play a role in the development of tumors, the potent effects of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are unique. Metabolically activated NNK and NNN induce deleterious mutations in oncogenes and tumor suppression genes by forming DNA adducts, which could be considered as tumor initiation. Meanwhile, the binding of NNK and NNN to the nicotinic acetylcholine receptor promotes tumor growth by enhancing and deregulating cell proliferation, survival, migration, and invasion, thereby creating a microenvironment for tumor growth. These two unique aspects of NNK and NNN synergistically induce cancers in tobacco-exposed individuals. This review will discuss various types of tobacco products and tobacco-related cancers, as well as the molecular mechanisms by which nitrosamines, such as NNK and NNN, induce cancer.

  1. Novel effects of the cyclooxygenase-2-selective inhibitor NS-398 on IL-1β-induced cyclooxygenase-2 and IL-8 expression in human ovarian granulosa cells.

    Science.gov (United States)

    Ou, Hui-Ling; Sun, David; Peng, Yen-Chun; Wu, Yuh-Lin

    2016-08-01

    Ovulation is a critical inflammation-like event that is central to ovarian physiology. IL-1β is an immediate early pro-inflammatory cytokine that regulates production of several other inflammatory mediators, such as cyclooxygenase 2 (COX)-2 and IL-8. NS-398 is a selective inhibitor of COX-2 bioactivity and thus this drug is able to mitigate the COX-2-mediated production of downstream prostaglandins and the subsequent inflammatory response. Here we have investigated the action of NS-398 using a human ovarian granulosa cell line, KGN, by exploring IL-1β-regulated COX-2 and IL-8 expression. First, NS-398, instead of reducing inflammation, appeared to further enhance IL-1β-mediated COX-2 and IL-8 production. Using selective inhibitors targeting various signaling molecules, MAPK and NF-κB pathways both seemed to be involved in the impact of NS-398 on IL-1β-induced COX-2 and IL-8 expression. NS-398 also promoted IL-1β-mediated NF-κB p65 nuclear translocation but had no effect on IL-1β-activated MAPK phosphorylation. Flow cytometry analysis demonstrated that NS-398, in combination with IL-1β, significantly enhanced cell cycle progression involving IL-8. Our findings demonstrate a clear pro-inflammatory function for NS-398 in the IL-1β-mediated inflammatory response of granulosa cells, at least in part, owing to its augmenting effect on the IL-1β-induced activation of NF-κB. PMID:27312705

  2. 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.

  3. The Effect of Celecoxib, a Cyclooxygenase-2 Inhibitor on Noise- Induced Hearing Loss

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    Akram Pourbakht

    2013-05-01

    Full Text Available Objective(s: Noise-induced hearing loss (NIHL is the major cause of acquired hearing loss.  Celecoxib, a cyclooxygenase-2 (COX-2 inhibitor, is a non- steroidal anti- inflammatory drug (NSAID with known antioxidant and antineoplastic activity. Therefore, we monitored the extent of temporary noise- induced threshold shifts (TTS and cochlear damage caused by high level 4- kHz noise exposure to verify the differences with those pretreated with celecoxib. Materials and Methods: Ten male albino guinea pigs (300-350 g in weight were randomly allocated into two groups: the primal group was exposed to 4- kHz octave band noise at 102 dB SPL for 3 hrs (group 1, n=5;  the latter pretreated with 50 mg/ kg celecoxib for 3 days, then  exposed to noise (group 2, n=5.  Before exposure and one hr after noise exposure, threshold shifts were evaluated with auditory brainstem responses (ABR and finally the animals were euthanized for histological evaluation.  Results: Comparing the threshold shifts before/after noise exposure with those pretreated, we found out that TTS caused by noise exposure did not show significant mitigation by celecoxib.  By observing the organ of Corti at lower middle turn of cochlea in celecoxib pretreated group, considerable hair cell loss was discovered. Conclusion:The current study clearly confirmed that celecoxib had no attenuation against temporary noise-induced hearing loss.

  4. Curcumin-attenuated trinitrobenzene sulphonic acid induces chronic colitis by inhibiting expression of cyclooxygenase-2

    Institute of Scientific and Technical Information of China (English)

    Hua Jiang; Chang-Sheng Deng; Ming Zhang; Jian Xia

    2006-01-01

    AIM: To explore the possible mechanisms of curcumin in rat colitis induced by trinitrobenzene sulfonic (TNBS) acid. METHODS: Rats with TNBS acid-induced colitis were treated with curcumin (30 mg/kg or 60 mg/kg per day ip). Changes of body weight and histological scores as well as survival rate were evaluated. Leukocyte infiltration was detected by myeloperoxidase (MPO)activity assay. The expression of cyclooxygenase-2(COX-2) was detected by RT-PCR and Western blot.Inflammation cytokines were determined by RT-PCR.Local concentration of prostaglandin E2 (PGE2) in colon mucosa was determined by ELISA.RESULTS: Curcumin improved survival rate and histological image, decreased the macroscopic scores and MPO activity. Also curcumin reduced the expression of COX-2 and inflammation cytokines. In addition,treatment with curcumin increased the PGE2 level.CONCLUSION: Curcumin has therapeutic effects on TNBS acid-induced colitis, the mechanisms seem to be related to COX-2 inhibition and PGE2 improvement.

  5. Atorvastatin reduces lipopolysaccharide-induced expression of cyclooxygenase-2 in human pulmonary epithelial cells

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    Chen Ping

    2005-04-01

    Full Text Available Abstract Objective To explore the effects of atorvastatin on expression of cyclooxygenase-2 (COX-2 in human pulmonary epithelial cells (A549. Methods A549 cells were incubated in DMEM medium containing lipopolysaccharide (LPS in the presence or absence of atorvastatin. After incubation, the medium was collected and the amount of prostaglandin E2 (PGE2 was measured by enzyme-linked immunosorbent assay (ELISA. The cells were harvested, and COX-2 mRNA and protein were analyzed by RT-PCR and western-blot respectively. Results LPS increased the expression of COX-2 mRNA and production of PGE2 in a dose- and time-dependent manner in A549. Induction of COX-2 mRNA and protein by LPS were inhibited by atorvastatin in a dose-dependent manner. Atorvastatin also significantly decreased LPS-induced production of PGE2. There was a positive correlation between reduced of COX-2 mRNA and decreased of PGE2 (r = 0.947, P Conclusion Atorvastatin down-regulates LPS-induced expression of the COX-2 and consequently inhibits production of PGE2 in cultured A549 cells.

  6. Inhibition of cyclooxygenase-2 reduces hypothalamic excitation in rats with adriamycin-induced heart failure.

    Directory of Open Access Journals (Sweden)

    Min Zheng

    Full Text Available BACKGROUND: The paraventricular nucleus (PVN of the hypothalamus plays an important role in the progression of heart failure (HF. We investigated whether cyclooxygenase-2 (COX-2 inhibition in the PVN attenuates the activities of sympathetic nervous system (SNS and renin-angiotensin system (RAS in rats with adriamycin-induced heart failure. METHODOLOGY/PRINCIPAL FINDING: Heart failure was induced by intraperitoneal injection of adriamycin over a period of 2 weeks (cumulative dose of 15 mg/kg. On day 19, rats received intragastric administration daily with either COX-2 inhibitor celecoxib (CLB or normal saline. Treatment with CLB reduced mortality and attenuated both myocardial atrophy and pulmonary congestion in HF rats. Compared with the HF rats, ventricle to body weight (VW/BW and lung to body weight (LW/BW ratios, heart rate (HR, left ventricular end-diastolic pressure (LVEDP, left ventricular peak systolic pressure (LVPSP and maximum rate of change in left ventricular pressure (LV±dp/dtmax were improved in HF+CLB rats. Angiotensin II (ANG II, norepinephrine (NE, COX-2 and glutamate (Glu in the PVN were increased in HF rats. HF rats had higher levels of ANG II and NE in plasma, higher level of ANG II in myocardium, and lower levels of ANP in plasma and myocardium. Treatment with CLB attenuated these HF-induced changes. HF rats had more COX-2-positive neurons and more corticotropin releasing hormone (CRH positive neurons in the PVN than did control rats. Treatment with CLB decreased COX-2-positive neurons and CRH positive neurons in the PVN of HF rats. CONCLUSIONS: These results suggest that PVN COX-2 may be an intermediary step for PVN neuronal activation and excitatory neurotransmitter release, which further contributes to sympathoexcitation and RAS activation in adriamycin-induced heart failure. Treatment with COX-2 inhibitor attenuates sympathoexcitation and RAS activation in adriamycin-induced heart failure.

  7. Interferon-α and cyclooxygenase-2 inhibitor cooperatively mediates TRAIL-induced apoptosis in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zuo, Chaohui, E-mail: zuochaohui@vip.sina.com [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Department of Pathology, Immunology and Laboratory Medicine and Shands Cancer Center, University of Florida, Gainesville, FL (United States); Qiu, Xiaoxin [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Cancer Research Institute, University of South China, Hengyang, Hunan Province (China); Liu, Nianli; Yang, Darong [Cancer Research Institute, University of South China, Hengyang, Hunan Province (China); Xia, Man [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Department of Pathology, Immunology and Laboratory Medicine and Shands Cancer Center, University of Florida, Gainesville, FL (United States); Liu, Jingshi [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Wang, Xiaohong [Cancer Research Institute, University of South China, Hengyang, Hunan Province (China); and others

    2015-05-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-α) has recently been recognized to harbor therapeutic potential in the prevention and treatment of HCC, but it remains controversial as to whether IFN-α exerts direct cytotoxicity against HCC. Cyclooxygenase-2 (COX-2) is overexpressed in HCC and is considered to play a role in hepatocarcinogenesis. Therefore, we aimed to elucidate the combined effect of a COX-2 inhibitor, celecoxib, and IFN-α on in vitro growth suppression of HCC using the hepatoma cell line HLCZ01 and the in vivo nude mouse xenotransplantation model using HLCZ01 cells. Treatment with celecoxib and IFN-α synergistically inhibited cell proliferation in a dose- and time-dependent manner. Apoptosis was identified by 4',6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. IFN-α upregulated the expression of TRAIL, while celecoxib increased the expression of TRAIL receptors. The combined regimen with celecoxib and IFN-α reduced the growth of xenotransplanted HCCs in nude mice. The regulation of IFN-α- and COX-2 inhibitor-induced cell death is impaired in a subset of TRAIL-resistant cells. The molecular mechanisms of HCC cells resistant to TRAIL-induced apoptosis were explored using molecular biological and immunological methods. Interferon-α and the COX-2 inhibitor celecoxib synergistically increased TRAIL-induced apoptosis in hepatocellular carcinoma. These data suggest that IFN-α and celecoxib may offer a novel role with important implications in designing new therapeutics for TRAIL-resistant tumors. - Highlights: ●The cytotoxic effect of TRAIL on a developed HCC HLCZ01 cells infected with HBV. ●IFN-α and celecoxib induced apoptosis in HLCZ01 cells infected with HBV. ●The combined regime reduced the growth of xenotransplanted HCCs in nude mice model.

  8. Selective cyclooxygenase-2 inhibitor ameliorates cholecystokinin-octapeptide-induced acute pancreatitis in rats

    Institute of Scientific and Technical Information of China (English)

    Sang-Wan Seo; Won-Seok Jung; Tai-Guang Piao; Seung-Heon Hong; Ki-Jung Yun; Rae-Kil Park; Min-Kyo Shin; Ho-Joon Song; Sung-Joo Park

    2007-01-01

    AIM: To investigate the effect of selective Cyclooxygenase-2 (COX-2) inhibitor 4-[5-(4-Chloro-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide (SC-236), on the cholecystokinin (CCK)-octapeptideinduced acute pancreatitis (AP) in rats.METHODS: Wistar rat weighing 240 g to 260 g were divided into three groups. (1) Normal DNISO treated group, (2) SC-236 at 4 mg/kg treated group; SC-236 systemically administered via the intravenous (i.v.) catheter, followed by 75 μg/kg CCK octapeptide subcutaneously three times, after 1,3 and 5 h. This whole procedure was repeated for 5 d. (3) Dimethyl sulfoxide (DMSO) treated group: an identical protocol was used in this group as in the SC-236 cohort (see 2. above). Repeated CCK octapeptide treatment resulted in a typical experimentally induced pancreatitis in the Wistar rats.RESULTS: SC-236 improved the severity of CCK-octapeptide-induced AP as measured by laboratory criteria [the pancreatic weight/body weight (p.w/ b.w) ratio, the level of serum amylase and lipase]. The SC-236 treated group showed minimal histologic evidence of pancreatitis and a significant reduction in myeloperoxidase activity. SC-236 also increased heat shock protein (HSP)-60 and HSP72 compared with the DMSO-treated group in the CCK-octapeptide-induced AP and also reduced the pancreatic levels of COX-2. Furthermore, SC-236 reduced proinflammatory cytokine synthesis and inhibited NF-κB activation compared with the DMSO-treated group in the CCK-octapeptide-induced AP.CONCLUSION: Our results suggested that COX-2 plays pivotal role in the development of AP and COX-2 inhibitors may play a beneficial role in preventing AP.

  9. Selective Cyclooxygenase-2 Inhibitor Prevents Cisplatin-induced Tumorigenesis in A/J Mice

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    Okada,Toshiaki

    2012-06-01

    Full Text Available Cisplatin is used to treat lung cancer;however, it is also a known carcinogen. Cyclooxygenase-2 (COX-2 inhibitors have been shown to prevent carcinogen-induced experimental tumors. We investigated the effect of a COX-2 inhibitor, celecoxib, on cisplatin-induced lung tumors. One hundred twenty 4-week-old A/J mice were divided into 6 groups:group 1, no treatment;group 2, low-dose celecoxib (150mg/kg;group 3, high-dose celecoxib (1,500mg/kg;group 4, cisplatin alone;group 5, cisplatin plus low-dose celecoxib;and group 6, cisplatin plus high-dose celecoxib. Mice in groups 4-6 were administered cisplatin (1.62mg/kg, i.p. once a week for 10 weeks between 7 and 16 weeks of age. All mice were sacrificed at week 30. Tumor incidence was 15.8% in group 1, 25% in group 2, 26.3% in group 3, 60% in group 4, 50% in group 5, and 50% in group 6. Tumor multiplicity was 0.2, 0.3, 0.3, 1.3, 1.0, and 0.6 in groups 1-6, respectively. Tumor multiplicity in the cisplatin-treated mice was reduced by celecoxib treatment in a dose-dependent manner (p<0.05, group 4 vs. group 6. Celecoxib significantly reduced COX-2 expression in cisplatin-induced tumors (p<0.01, group 4 vs. group 6.

  10. Celecoxib Inhibits Proliferation and Induces Apoptosis via Cyclooxygen-ase-2 Pathway in Human Pancreatic Carcinoma Cells

    Institute of Scientific and Technical Information of China (English)

    WU Gaosong; YI Jilin; DI Fang; ZOU Shengquan; LI Xingrui

    2005-01-01

    In order to evaluate the effects and mechanisms of celecoxib in inhibiting proliferation and inducing apoptosis on human pancreatic carcinoma cells, the anti-proliferative effect was measured by using methabenzthiazuron (MTT) assay. Cell cycle and apoptosis were analyzed by using flow cytometry (FCM), and the PGE2 levels in the supernatant of cultured pancreatic carcinoma cells were quantitated by enzyme-linked immunoabsordent assay (ELISA). Our results showed that celecoxib suppressed the production of PGE2 and inhibited the growth of JF-305 cells, and the anti-proliferative effect of celecoxib could be abolished by addition of PGE2. FCM revealed that celecoxib could inhibit proliferation and induce apoptosis by G1-S cell cycle arrest. It was concluded that cyclooxygenase-2 specific inhibitor celecoxib could inhibit proliferation and induced apoptosis of human pancreatic carcinoma cells via suppression of PGE2 production in vitro.

  11. Progressive Metaplastic and Dysplastic Changes in Mouse Pancreas Induced by Cyclooxygenase-2 Overexpression

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    Jennifer K.L. Colby

    2008-08-01

    Full Text Available Cyclooxygenase-2 (COX-2 overexpression is an established factor linking chronic inflammation with metaplastic and neoplastic change in various tissues. We generated transgenic mice (BK5.COX-2 in which elevation of COX-2 and its effectors trigger a metaplasia-dysplasia sequence in exocrine pancreas. Histologic evaluation revealed a chronic pancreatitis-like state characterized by acinar-to-ductal metaplasia and a well-vascularized fibroinflammatory stroma that develops by 3 months. By 6 to 8 months, strongly dysplastic features suggestive of pancreatic ductal adenocarcinoma emerge in the metaplastic ducts. Increased proliferation, cellular atypia, and loss of normal cell/tissue organization are typical features in transgenic pancreata. Alterations in biomarkers associated with human inflammatory and neoplastic pancreatic disease were detected using immunohistochemistry. The abnormal pancreatic phenotype can be completely prevented by maintaining mice on a diet containing celecoxib, a well-characterized COX-2 inhibitor. Despite the high degree of atypia, only limited evidence of invasion to adjacent tissues was observed, with no evidence of distant metastases. However, cell lines derived from spontaneous lesions are aggressively tumorigenic when injected into syngeneic or nude mice. The progressive nature of the metaplastic/dysplastic changes observed in this model make it a valuable tool for examining the transition from chronic inflammation to neoplasia.

  12. Mercury induces proliferation and reduces cell size in vascular smooth muscle cells through MAPK, oxidative stress and cyclooxygenase-2 pathways

    International Nuclear Information System (INIS)

    Mercury exposure is known to increase cardiovascular risk but the underlying cellular mechanisms remain undetermined. We analyzed whether chronic exposure to HgCl2 affects vascular structure and the functional properties of vascular smooth muscle cells (VSMC) through oxidative stress/cyclooxygenase-2 dependent pathways. Mesenteric resistance arteries and aortas from Wistar rats treated with HgCl2 (first dose 4.6 mg kg−1, subsequent doses 0.07 mg kg−1 day−1, 30 days) and cultured aortic VSMC stimulated with HgCl2 (0.05–5 μg/ml) were used. Treatment of rats with HgCl2 decreased wall thickness of the resistance and conductance vasculature, increased the number of SMC within the media and decreased SMC nucleus size. In VSMCs, exposure to HgCl2: 1) induced a proliferative response and a reduction in cell size; 2) increased superoxide anion production, NADPH oxidase activity, gene and/or protein levels of the NADPH oxidase subunit NOX-1, the EC- and Mn-superoxide dismutases and cyclooxygenase-2 (COX-2); 3) induced activation of ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized the proliferative response and the altered cell size induced by HgCl2. Blockade of ERK1/2 and p38 signaling pathways abolished the HgCl2-induced Nox1 and COX-2 expression and normalized the alterations induced by mercury in cell proliferation and size. In conclusion, long exposure of VSMC to low doses of mercury activates MAPK signaling pathways that result in activation of inflammatory proteins such as NADPH oxidase and COX-2 that in turn induce proliferation of VSMC and changes in cell size. These findings offer further evidence that mercury might be considered an environmental risk factor for cardiovascular disease. - Highlights: ► Chronic HgCl2 exposure induces vascular remodeling. ► HgCl2 induces proliferation and decreased cell size in vascular smooth muscle cells. ► HgCl2 induces MAPK activation, oxidative stress and COX-2 expression. ► Inhibition of

  13. Mercury induces proliferation and reduces cell size in vascular smooth muscle cells through MAPK, oxidative stress and cyclooxygenase-2 pathways

    Energy Technology Data Exchange (ETDEWEB)

    Aguado, Andrea; Galán, María; Zhenyukh, Olha; Wiggers, Giulia A.; Roque, Fernanda R. [Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), 28029, Madrid (Spain); Redondo, Santiago [Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, 28040, Madrid (Spain); Peçanha, Franck [Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), 28029, Madrid (Spain); Martín, Angela [Departamento de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos, 28922, Alcorcón (Spain); Fortuño, Ana [Área de Ciencias Cardiovasculares, Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008, Pamplona (Spain); Cachofeiro, Victoria [Departamento de Fisiología, Facultad de Medicina, Universidad Complutense, 28040, Madrid (Spain); Tejerina, Teresa [Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, 28040, Madrid (Spain); Salaices, Mercedes, E-mail: mercedes.salaices@uam.es [Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), 28029, Madrid (Spain); and others

    2013-04-15

    Mercury exposure is known to increase cardiovascular risk but the underlying cellular mechanisms remain undetermined. We analyzed whether chronic exposure to HgCl{sub 2} affects vascular structure and the functional properties of vascular smooth muscle cells (VSMC) through oxidative stress/cyclooxygenase-2 dependent pathways. Mesenteric resistance arteries and aortas from Wistar rats treated with HgCl{sub 2} (first dose 4.6 mg kg{sup −1}, subsequent doses 0.07 mg kg{sup −1} day{sup −1}, 30 days) and cultured aortic VSMC stimulated with HgCl{sub 2} (0.05–5 μg/ml) were used. Treatment of rats with HgCl{sub 2} decreased wall thickness of the resistance and conductance vasculature, increased the number of SMC within the media and decreased SMC nucleus size. In VSMCs, exposure to HgCl{sub 2}: 1) induced a proliferative response and a reduction in cell size; 2) increased superoxide anion production, NADPH oxidase activity, gene and/or protein levels of the NADPH oxidase subunit NOX-1, the EC- and Mn-superoxide dismutases and cyclooxygenase-2 (COX-2); 3) induced activation of ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized the proliferative response and the altered cell size induced by HgCl{sub 2}. Blockade of ERK1/2 and p38 signaling pathways abolished the HgCl{sub 2}-induced Nox1 and COX-2 expression and normalized the alterations induced by mercury in cell proliferation and size. In conclusion, long exposure of VSMC to low doses of mercury activates MAPK signaling pathways that result in activation of inflammatory proteins such as NADPH oxidase and COX-2 that in turn induce proliferation of VSMC and changes in cell size. These findings offer further evidence that mercury might be considered an environmental risk factor for cardiovascular disease. - Highlights: ► Chronic HgCl{sub 2} exposure induces vascular remodeling. ► HgCl{sub 2} induces proliferation and decreased cell size in vascular smooth muscle cells. ► HgCl{sub 2} induces

  14. Increased cyclooxygenase-2 and thromboxane synthase expression is implicated in diosgenin-induced megakaryocytic differentiation in human erythroleukemia cells.

    Science.gov (United States)

    Cailleteau, C; Liagre, B; Battu, S; Jayat-Vignoles, C; Beneytout, J L

    2008-09-01

    Differentiation induction as a therapeutic strategy has, so far, the greatest impact in hematopoietic malignancies, most notably leukemia. Diosgenin is a very interesting natural product because, depending on the specific dose used, its biological effect is very different in HEL (human erythroleukemia) cells. For example, at 10 microM, diosgenin induced megakaryocytic differentiation, in contrast to 40 microM diosgenin, which induced apoptosis in HEL cells previously demonstrated using sedimentation field-flow fractionation (SdFFF). The goal of this work focused on the correlation between cyclooxygenase-2 (COX-2) and thromboxane synthase (TxS) and megakaryocytic differentiation induced by diosgenin in HEL cells. Furthermore, the technique of SdFFF, having been validated in our models, was used in this new study as an analytical tool that provided us with more or less enriched differentiated cell fractions that could then be used for further analyses of enzyme protein expression and activity for the first time. In our study, we showed the implication of COX-2 and TxS in diosgenin-induced megakaryocytic differentiation in HEL cells. Furthermore, we showed that the analytical technique of SdFFF may be used as a tool to confirm our results as a function of the degree of cell differentiation.

  15. 15-lipoxygenase-1 mediates cyclooxygenase-2 inhibitor induced apoptosis in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    It has been found that expression of 15-lipoxygenasc-1(15-LOX-1) and its main product,13-C-hydroxyoctadecadienoic acid (13-S-HODE),are decreased in human colorectal and esophageal cancers and that nonsteroidal anti-inflammatory drugs(NSAIDs) can therspeutically induce 15-LOC-1 expression to trigger apoptosis in those cancer cells independently COX-2.We found that a specific COX-2 inhibitor SC-236 similarly induce apoptosis in gastric cancer cells,although the mechanisms of these effects remain to be defined.In the present study,we tested whether SC-236 induced apoptosis through up-regulation of 15-LOX-1 in gastric cancer cells.We found that,(a) SC-236 inhibited growth of gastric cancer cells mainly by apoptosis induced;(b) SC-236 induced 15-LOX-1 expression and increased endogenous 13-S-HODE product,instead of 15-S-HETE during apoptosis in gastric cancer cells without 15-LOX-1 expression before treatment by SC-236;(c)sc-236 didn't effect expression of COX-1,COX-2,5-LOX and 12-LOX;and (d)15-LOX-1 inhibition suppressed SC-236 induced apoptosis.These findings demonstrated that SC-236 induced apoptosis in gastric cancer cells via up-regulation of 25-LOX-1.They also support the concept that the loss of the proapopotic role of 15-LOX-1 in epithelial cancers is not limited to human colorectal and esophageal cancers.

  16. Triptolide Inhibits Cyclooxygenase-2 and Inducible Nitric Oxide Synthase Expression in Human Colon Cancer and Leukemia Cells

    Institute of Scientific and Technical Information of China (English)

    Xiangmin TONG; Shui ZHENG; Jie JIN; Lifen ZHU; Yinjun LOU; Hangping YAO

    2007-01-01

    Triptolide (TP), a traditional Chinese medicine, has been reported to be effective in the treatment of autoimmune diseases and exerting antineoplastic activity in several human tumor cell lines. This study investigates the antitumor effect of TP in human colon cancer cells (SW114) and myelocytic leukemia (K562), and elucidates the possible molecular mechanism involved. SW114 and K562 cells were treated with different doses of TP (0, 5, 10, 20, or 50 ng/ml). The cell viability was assessed by 3-[4,5-dimethylthiazol2-yl]-2,5-diphenyltetrazolium bromide (MTT). Results demonstrated that TP inhibited the proliferation of both tumor cell lines in a dose-dependent manner. To further investigate its mechanisms, the products prostaglandin E2 (PGE2) and nitric oxide (NO) were measured by enzyme-linked immunosorbent assay (ELISA). Our data showed that TP strongly inhibited the production of NO and PGE2. Consistent with these results, the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) was up-regulated both at the mRNA level and the protein expression level, as shown by real-time RT-PCR and Western blotting. These results indicated that the inhibition of the inflammatory factor COX-2 and iNOS activity could be involved in the antitumor mechanisms of TP.

  17. Inhibitory effect of dihydroartemisinin against phorbol ester-induced cyclooxygenase-2 expression in macrophages.

    Science.gov (United States)

    Kim, Hyung Gyun; Yang, Ji Hye; Han, Eun Hee; Choi, Jae Ho; Khanal, Tilak; Jeong, Myung Ho; Jeong, Tae Cheon; Jeong, Hye Gwang

    2013-06-01

    Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin isolated from the traditional Chinese herb Artemisia annua L., has recently been shown to possess antitumor activity in various cancer cells. However, the effect of anti-inflammatory potentials of DHA in murine macrophage RAW 264.7 cells has not been studied. The present study investigated the effect of COX-2 and molecular mechanisms by DHA in PMA stimulated RAW 264.7 cells. DHA dose-dependently decreased PMA-induced COX-2 expression and PGE2 production, as well as COX-2 promoter-driven luciferase activity. Additionally, DHA decreased luciferase activity of COX-2 regulation-related transcription factors including NF-κB, AP-1, C/EBP and CREB. DHA also remarkably reduced PMA-induced p65, C/EBPβ, c-jun and CREB nuclear translocation. Furthermore, DHA evidently inhibited PMA-induced phosphorylation of AKT and the MAP Kinases, such as ERK, JNK and p38. Taken together, our data indicated that DHA effectively attenuates COX-2 production via down-regulation of AKT and MAPK pathway, revealing partial molecular basis for the anti-inflammatory properties of DHA. PMID:23429041

  18. Silkworm Thorn Stem Extract Targets RSK2 and Suppresses Solar UV-Induced Cyclooxygenase-2 Expression

    Directory of Open Access Journals (Sweden)

    Jong-Eun Kim

    2015-10-01

    Full Text Available Excessive exposure to solar UV (sUV is associated with numerous human skin disorders, such as carcinogenesis, skin photoaging and skin inflammation. Silkworm Thorn (Cudraniatricuspidata, SW is a plant belonging to the Moraceae family and widely present throughout Korea, China, and Japan. Most parts of the tree (including the fruit, leaf, stem, root, and bark is consumable as a functional food or tea. In this study, we found that SW extract (SWE inhibited the elevated expression of sUV-induced cyclooxygenase (COX-2 levels in both HaCaT and JB6 cells. Levels of nuclear factor-κB and activator protein-1, two crucial transcription factors involved in COX-2 expression, were elevated by sUV treatment. Treatment with SWE abolished this activation. SWE also inhibited sUV-induced histone H3 phosphorylation. However, sUV-induced phosphorylation of Akt, c-Jun N-terminal kinase and p38 kinase remained unchanged in the presence of SWE. SWE inhibited RSK2 activity, and pull-down assays using SWE-Sepharose beads revealed that SWE binds directly with RSK2 in an ATP-competitive manner. These results suggest a potential for SWE to be developed as a cosmeceutical material and functional food constituent for the promotion of skin health.

  19. Silkworm Thorn Stem Extract Targets RSK2 and Suppresses Solar UV-Induced Cyclooxygenase-2 Expression.

    Science.gov (United States)

    Kim, Jong-Eun; Lee, Ki Won

    2015-01-01

    Excessive exposure to solar UV (sUV) is associated with numerous human skin disorders, such as carcinogenesis, skin photoaging and skin inflammation. Silkworm Thorn (Cudraniatricuspidata, SW) is a plant belonging to the Moraceae family and widely present throughout Korea, China, and Japan. Most parts of the tree (including the fruit, leaf, stem, root, and bark) is consumable as a functional food or tea. In this study, we found that SW extract (SWE) inhibited the elevated expression of sUV-induced cyclooxygenase (COX)-2 levels in both HaCaT and JB6 cells. Levels of nuclear factor-κB and activator protein-1, two crucial transcription factors involved in COX-2 expression, were elevated by sUV treatment. Treatment with SWE abolished this activation. SWE also inhibited sUV-induced histone H3 phosphorylation. However, sUV-induced phosphorylation of Akt, c-Jun N-terminal kinase and p38 kinase remained unchanged in the presence of SWE. SWE inhibited RSK2 activity, and pull-down assays using SWE-Sepharose beads revealed that SWE binds directly with RSK2 in an ATP-competitive manner. These results suggest a potential for SWE to be developed as a cosmeceutical material and functional food constituent for the promotion of skin health.

  20. The role of cyclooxygenase-2/prostanoid pathway in visceral pain induced liver stress response in rats

    Institute of Scientific and Technical Information of China (English)

    PISTON Donald; WANG Shan; FENG Yi; YE Ying-jiang; ZHOU Jing; JIANG Ke-wei; XU Feng; ZHAO Yong; CUI Zhi-rong

    2007-01-01

    Background Cyclooxygenase (COX) is the rate-limiting enzyme in the production of prostanoids from arachidonic acid.COX-2 is the inducible enzyme in the COX family, together with the prostanoids forms the COX-2/prostanoid pathway.Research showed that the COX-2/prostanoid pathway is activated in hepatic diseases and liver stress reaction, such as fibrogenesis, portal hypertension, carcinogenesis, and ischemic/reperfusion injury. But there was no report on visceral pain induced liver stress. This study was to investigate the role of the COX-2/prostanoid pathway in liver stress response in rat acute colitis visceral pain liver stress model.Methods Fifty-three male SD rats were randomly divided into Naive, Model, NS398 treatment, and Morphine treatment groups. The rat acute colitis visceral pain liver stress model was established under anesthesia by the colonic administration of 0.5 ml of 6% acetic acid using a urethral catheter. NS398 and morphine were administrated 30 minutes prior to model establishment in NS398 and Morphine treatment groups respectively. Spontaneous activities and pain behavior were counted and the extent of colonic inflammation was assessed histologically. Liver tissue levels of Glutathione-S-Transferase (GST) activity, COX-2 mRNA, prostaglandin E2 (PGE2), thromboxane B2 (TXB2) and 6-Ketone-prostaglandin F1α (6-K-PGF1α) contents were assessed.Results Thirty minutes after the colonic administration of acetic acid, a significant decrease in spontaneous activities and an increase in pain behaviors were observed in Model group (P<0.01 and P<0.05 respectively), accompanied by colonic inflammation. Liver GST activity levels significantly dropped (P<0.05). Liver COX-2 mRNA expression significantly increased, accompanied by an increase in liver concentrations of PGE2 and TXB2, but no obvious change in 6-K-PGF1α concentrations. NS398 and morphine both ameliorated post-stress liver GST activity (P<0.05 and P<0.01respectively), decreased stress-induced

  1. Roles of cyclooxygenase-2 in microvascular endothelial cell proliferation induced by basic fibroblast growth factor

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Background The level of basic fibroblast growth factor (bFGF) increases rapidly after cerebral ischemia. However, the molecular mechanisms for the effects of bFGF on cerebral microvascular endothelial cells (cMVECs) have not yet been fully elucidated. In this study, a murine cMVEC line, bend.3, was employed to study the effects of bFGF on cyclooxygenase (COX) expression and its downstream effects in cMVECs. Methods After treatment with bFGF, RT-PCR and Western blotting analyses were carried out to evaluate the changes in COX-2 mRNA and protein expression, respectively. Ml-r assays were performed to measure cell proliferation. The prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) concentrations in the culture medium were measured by enzyme-linked immunosorbent assay (ELISA). Results COX-2 mRNA and protein expressions in bEnd.3 cells were induced by bFGF in time- and dose-dependent manners. The bFGF-induced COX-2 upregulation led to enhanced PGE2 production by bEnd.3 cells, and this effect was abolished by the selective COX-2 inhibitor NS-398. bFGF also increased VEGF production by bend.3 cells, and this effect was blocked by NS-398 and the EP1/2 (PGE2 receptors) antagonist AH6809. Furthermore, exogenous PGE2 increased VEGF production in bend.3 cells, and AH6809 blocked this effect. Conclusion bFGF increases VEGF production in an autocrine manner by increasing COX-2-generated PGE2 in cMVECs and subsequently stimulates MVEC proliferation and angiogenesis.

  2. Viscum album exerts anti-inflammatory effect by selectively inhibiting cytokine-induced expression of cyclooxygenase-2.

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    Pushpa Hegde

    Full Text Available Viscum album (VA preparations are extensively used as complementary therapy in cancer and are shown to exert anti-tumor activities which involve the cytotoxic properties, induction of apoptosis, inhibition of angiogenesis and several other immunomodulatory mechanisms. In addition to their application in cancer therapy, VA preparations have also been successfully utilized in the treatment of several inflammatory pathologies. Owing to the intricate association of inflammation and cancer and in view of the fact that several anti-tumor phytotherapeutics also exert a potent anti-inflammatory effect, we hypothesized that VA exerts an anti-inflammatory effect that is responsible for its therapeutic benefit. Since, inflammatory cytokine-induced cyclo-oxygenase-2 (COX-2 and prostaglandin E2 (PGE2 play a critical role in the pathogenesis of inflammatory diseases, we investigated the anti-inflammatory effect of VA on regulation of cyclo-oxygenase expression and PGE2 biosynthesis by using human lung adenocarcinoma cells (A549 cells as a model. A549 cells were stimulated with IL-1β and treated with VA preparation (VA Qu Spez for 18 hours. PGE2 was analysed in the culture supernatants by enzyme immunoassay. Expression of COX-2 and COX-1 proteins was analyzed by immunoblotting and the expression of COX-2 mRNA was assessed by semi-quantitative RT-PCR. We found that VA Qu Spez inhibit the secretion of IL-1β-induced PGE2 in a dose-dependent manner. Further, we also show that this inhibitory action was associated with a reduced expression of COX-2 without modulating the COX-1 expression. Together these results demonstrate a novel anti-inflammatory mechanism of action of VA preparations wherein VA exerts an anti-inflammatory effect by inhibiting cytokine-induced PGE2 via selective inhibition of COX-2.

  3. Induction of heme oxygenase-1 attenuates lipopolysaccharide-induced cyclooxygenase-2 expression in mouse brain endothelial cells

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    Yang Chuen-Mao

    2010-11-01

    Full Text Available Abstract Background Prostaglandin E2 (PGE2, an arachidonic acid metabolite converted by cyclooxygenase-2 (COX-2, plays important roles in the regulation of endothelial functions in response to bacterial infection. The enzymatic activity of COX-2 can be down-regulated by heme oxygenase-1 (HO-1 induction. However, the mechanisms underlying HO-1 modulating COX-2 protein expression are not known. Objective The aim of the present study was to investigate whether the up-regulation of HO-1 regulates COX-2 expression induced by lipopolysaccharide (LPS, an endotoxin produced by Gram negative bacteria, in mouse brain endothelial cells (bEnd.3 Methods Cultured bEnd.3 cells were used to investigate LPS-induced COX-2 expression and PGE2 production. Cobalt protoporphyrin IX (CoPP, an HO-1 inducer, infection with a recombinant adenovirus carried with HO-1 gene (Adv-HO-1, or zinc protoporphyrin (ZnPP, an HO-1 inhibitor was used to stimulate HO-1 induction or inhibit HO-1 activity. The expressions of COX-2 and HO-1 were evaluated by western blotting. PGE2 levels were detected by an enzyme-linked immunoassay. Hemoglobin (a chelator of carbon monoxide, CO, one of metabolites of HO-1 and CO-RM2 (a CO releasing molecule were used to investigate the mechanisms of HO-1 regulating COX-2 expression. Results We found that LPS-induced COX-2 expression and PGE2 production were mediated through NF-κB (p65 via activation of Toll-like receptor 4 (TLR4. LPS-induced COX-2 expression was inhibited by HO-1 induction by pretreatment with CoPP or infection with Adv-HO-1. This inhibitory effect of HO-1 was reversed by pretreatment with either ZnPP or hemoglobin. Pretreatment with CO-RM2 also inhibited TLR4/MyD88 complex formation, NF-κB (p65 activation, COX-2 expression, and PGE2 production induced by LPS. Conclusions We show here a novel inhibition of HO-1 on LPS-induced COX-2/PGE2 production in bEnd.3. Our results reinforce the emerging role of cerebral endothelium-derived HO-1

  4. Cyclooxygenase 2,pS2,inducible nitric oxide synthase and transforming growth factor alpha in gastric adaptation to stress

    Institute of Scientific and Technical Information of China (English)

    Shi-Nan Nie; Hai-Chen Sun; Xue-Hao Wu; Xiao-Ming Qian

    2004-01-01

    AIM: To determine the role of mucosal gene expression of cyclooxygenase 2 (COX-2), pS2 (belongs to trefoil peptides),inducible nitric oxide synthase (iNOS) and transforming growth factor alpha (TGFα) in gastric adaptation to water immersion and restraint stress (WRS) in rats.METHODS: Wistar rats were exposed to single or repeated WRS for 4 h every other day for up to 6 d. Gastric mucosal blood flow (GMBF) was measured by laser Doppler fiowmeter3. The extent of gastric mucosal lesions were evaluated grossly and histologically and expressions of COX-2, pS2,iNOS and TGFα were determined by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot.RESULTS: The damage to the surface of gastric epithelium with focal areas of deep haemorrhagic necrosis was induced by repeated WRS.The adaptative cytoprotection against stress was developed with activation of cell proliferation in the neck regions of gastric glands. The ulcer index (UI) in groups Ⅱ, Ⅲ and Ⅳ was markedly reduced as compared with group Ⅰ (Ⅰ: 47.23±1.20; Ⅳ: 10.39±1.18,P<0.01). GMBF significantly decreased after first exposure to WRS with an adaptive increasement of GMBF in experimental groups after repetitive challenges with WRS. After the 4th WRS,the value of GMBF almost restored to normal level (Ⅰ:321.87±8.85; Ⅳ: 455.95±11.81,P<0.01). First WRS significantly decreased the expression of pS2 and significantly increased the expressions of COX-2, iNOS and TGFα. After repeated WRS, pS2 and TGFα expressions gradually increased (pS2: Ⅰ: 0.37±0.02; Ⅳ: 0.77±0.01; TGFα: Ⅰ:0.86±0.01; Ⅳ: 0.93±0.03, P<0.05) with a decrease in the expressions of COX-2 and iNOS (COX-2: Ⅰ: 0.45±0.02; Ⅳ:0.22±0.01; iNOS: Ⅰ: 0.93±0.01; Ⅳ: 0.56±0.01, P<0.01).Expressions of pS2, COX-2, iNOS and TGFα showed regular changes with a good relationship among them.CONCLUSION: Gastric adaptation to WRS injury involves enhanced cell proliferation, increased expression of pS2 and

  5. TCDD promotes lung tumors via attenuation of apoptosis through activation of the Akt and ERK1/2 signaling pathways.

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    Rong-Jane Chen

    Full Text Available 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD is a multiple-site, multiple-species carcinogen that induces cancer in multiple organs. The molecular mechanisms underlying TCDD-induced lung tumorigenesis remain unclear. In the present study, a two-stage lung tumorigenesis model was established by administrating a single low dose of 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK combined with TCDD to female A/J mice. The results indicated that TCDD combined with low-dose NNK has a significant tumor-promoting effect compared with TCDD or low-dose NNK alone. Resistance to apoptosis is a hallmark of cancer and is thought to be one of the tumor-promoting mechanisms regulated by TCDD. We performed an additional series of experiments in the normal human bronchial epithelial cell line Beas2B cells, in which TCDD was combined with the apoptosis inducer staurosporine. Our in vitro results confirmed that TCDD could rescue cells from apoptosis induced by staurosporine. The inhibition of apoptosis is likely mediated by the activation of the Akt and ERK1/2 pathways, as determined by the effectiveness of pathway-specific inhibitors in abrogating the anti-apoptotic activity of TCDD. In conclusion, we demonstrated that TCDD promoted NNK-induced lung tumorigenesis and revealed that TCDD inhibits staurosporine-induced apoptosis, at least in part, through the Akt and ERK1/2 signaling pathways.

  6. Tobacco specific N-nitrosamines: occurrence and bioassays

    Energy Technology Data Exchange (ETDEWEB)

    Hoffmann, D.; Adams, J.D.; Brunnemann, K.D.; Rivenson, A.; Hecht, S.S.

    1982-01-01

    A new GC-TEA method for the analysis of tobacco-specific N-nitrosamines (TSNA) has been developed. Four TSNA have thus far been identified; these are N'-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N'-nitrosoanatabine (NAT) and N'-nitrosoanabasine (NAB). The method is currently being applied to the development of cigarette filter-tips which will selectively remove these carcinogens from cigarette smoke. Since recent epidemiological studies have established a correlation between snuff dipping and oral cancer, we have analysed leading snuff brands for TSNA. Snuff products from Sweden, Denmark, Bavaria and the USA contained 5-106 mg/kg of the TSNA and the saliva of snuff dippers had TSNA levels of 20-890 micrograms/kg. NNN, NNK and NAB induce benign and malignant tumours of the respiratory tract of mice and rats. We have shown that NNN and NNK induce tumours in the upper respiratory tract of hamsters and that NNK is the most active carcinogen of the TSNA, also inducing adenoma and adenocarcinoma in the hamster lung. The reported chemical analyses and bioassay results support the epidemiological findings on the causal association of tobacco use and cancer in man.

  7. Inhibition of lipopolysaccharide-induced inducible nitric oxide synthase and cyclooxygenase-2 expression by xanthanolides isolated from Xanthium strumarium.

    Science.gov (United States)

    Yoon, Jeong Hoon; Lim, Hyo Jin; Lee, Hwa Jin; Kim, Hee-Doo; Jeon, Raok; Ryu, Jae-Ha

    2008-03-15

    Three sesquiterpenoids, xanthatin (1), xanthinosin (2), and 4-oxo-bedfordia acid (3) were isolated from Xanthium strumarium as inhibitors of nitric oxide synthesis in activated microglia (IC(50) values: 0.47, 11.2, 136.5 microM, respectively). Compounds 1 and 2 suppressed the expression of iNOS and COX-2 and the activity of NF-kappaB through the inhibition of LPS-induced I-kappaB-alpha degradation in microglia. PMID:18276135

  8. Gq protein mediates UVB-induced cyclooxygenase-2 expression by stimulating HB-EGF secretion from HaCaT human keratinocytes

    Energy Technology Data Exchange (ETDEWEB)

    Seo, MiRan [Department of Biochemistry and Molecular Biology and Cancer Research Institute, Seoul National University College of Medicine, Seoul (Korea, Republic of); Juhnn, Yong-Sung, E-mail: juhnn@snu.ac.kr [Department of Biochemistry and Molecular Biology and Cancer Research Institute, Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2010-03-05

    Ultraviolet (UV) radiation induces cyclooxygenase-2 expression to produce cellular responses including aging and carcinogenesis in skin. We hypothesised that heterotrimeric G proteins mediate UV-induced COX-2 expression by stimulating secretion of soluble HB-EGF (sHB-EGF). In this study, we aimed to elucidate the role and underlying mechanism of the {alpha} subunit of Gq protein (G{alpha}q) in UVB-induced HB-EGF secretion and COX-2 induction. We found that expression of constitutively active G{alpha}q (G{alpha}qQL) augmented UVB-induced HB-EGF secretion, which was abolished by knockdown of G{alpha}q with shRNA in HaCaT human keratinocytes. G{alpha}q was found to mediate the UVB-induced HB-EGF secretion by sequential activation of phospholipase C (PLC), protein kinase C{delta} (PKC{delta}), and matrix metaloprotease-2 (MMP-2). Moreover, G{alpha}qQL mediated UVB-induced COX-2 expression in an HB-EGF-, EGFR-, and p38-dependent manner. From these results, we concluded that G{alpha}q mediates UV-induced COX-2 expression through activation of EGFR by HB-EGF, of which ectodomain shedding was stimulated through sequential activation of PLC, PKC{delta} and MMP-2 in HaCaT cells.

  9. Lysophosphatidic acid transactivates both c-Met and epidermal growth factor receptor, and induces cyclooxygenase-2 expression in human colon cancer LoVo cells

    Institute of Scientific and Technical Information of China (English)

    Dai Shida; Joji Kitayama; Hironori Yamaguchi; Hiroharu Yamashita; Ken Mori; Toshiaki Watanabe; Hirokazu Nagawa

    2005-01-01

    AIM: To examine whether lysophosphatidic acid (LPA)induces phosphorylation of c-Met and epidermal growth factor receptor (EGFR), both of which have been proposed as prognostic markers of colorectal cancer, and whether LPA induces cyclooxygenase-2 (COX-2) expression in human colon cancer cells.METHODS: Using a human colon cancer cell line, LoVo cells, we performed immunoprecipitation analysis,followed by Western blot analysis. We also examined whether LPA induced COX-2 expression, by Western blot analysis.RESULTS: Immunoprecipitation analysis revealed that 10 μmol/L LPA induced tyrosine phosphorylation of c-Met and EGFR in LoVo cells within a few minutes. We found that c-Met tyrosine phosphorylation induced by LPA was not attenuated by pertussis toxin or a matrix metalloproteinase inhibitor, in marked contrast to the results for EGFR. In addition, 0.2-40 μmol/L LPA induced COX-2 expression in a dose-dependent manner.CONCLUSION: Our results suggest that LPA acts upstream of various receptor tyrosine kinases (RTKs) and COX-2,and thus may act as a potent stimulator of colorectal cancer.

  10. Aqueous extract of the edible Gracilaria tenuistipitata inhibits hepatitis C viral replication via cyclooxygenase-2 suppression and reduces virus-induced inflammation.

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    Kuan-Jen Chen

    Full Text Available Hepatitis C virus (HCV is an important human pathogen leading to hepatocellular carcinoma. Using an in vitro cell-based HCV replicon and JFH-1 infection system, we demonstrated that an aqueous extract of the seaweed Gracilaria tenuistipitata (AEGT concentration-dependently inhibited HCV replication at nontoxic concentrations. AEGT synergistically enhanced interferon-α (IFN-α anti-HCV activity in a combination treatment. We found that AEGT also significantly suppressed virus-induced cyclooxygenase-2 (COX-2 expression at promoter transactivation and protein levels. Notably, addition of exogenous COX-2 expression in AEGT-treated HCV replicon cells gradually abolished AEGT anti-HCV activity, suggesting that COX-2 down-regulation was responsible for AEGT antiviral effects. Furthermore, we highlighted the inhibitory effect of AEGT in HCV-induced pro-inflammatory gene expression such as the expression of tumour necrosis factor-α, interleukin-1β, inducible nitrite oxide synthase and COX-2 in a concentration-dependent manner to evaluate the potential therapeutic supplement in the management of patients with chronic HCV infections.

  11. Aqueous extract of the edible Gracilaria tenuistipitata inhibits hepatitis C viral replication via cyclooxygenase-2 suppression and reduces virus-induced inflammation.

    Science.gov (United States)

    Chen, Kuan-Jen; Tseng, Chin-Kai; Chang, Fang-Rong; Yang, Jin-Iong; Yeh, Chi-Chen; Chen, Wei-Chun; Wu, Shou-Fang; Chang, Hsueh-Wei; Lee, Jin-Ching

    2013-01-01

    Hepatitis C virus (HCV) is an important human pathogen leading to hepatocellular carcinoma. Using an in vitro cell-based HCV replicon and JFH-1 infection system, we demonstrated that an aqueous extract of the seaweed Gracilaria tenuistipitata (AEGT) concentration-dependently inhibited HCV replication at nontoxic concentrations. AEGT synergistically enhanced interferon-α (IFN-α) anti-HCV activity in a combination treatment. We found that AEGT also significantly suppressed virus-induced cyclooxygenase-2 (COX-2) expression at promoter transactivation and protein levels. Notably, addition of exogenous COX-2 expression in AEGT-treated HCV replicon cells gradually abolished AEGT anti-HCV activity, suggesting that COX-2 down-regulation was responsible for AEGT antiviral effects. Furthermore, we highlighted the inhibitory effect of AEGT in HCV-induced pro-inflammatory gene expression such as the expression of tumour necrosis factor-α, interleukin-1β, inducible nitrite oxide synthase and COX-2 in a concentration-dependent manner to evaluate the potential therapeutic supplement in the management of patients with chronic HCV infections.

  12. Leptin potentiates IFN-γ-induced expression of nitric oxide synthase and cyclo-oxygenase-2 in murine macrophage J774A.1

    Science.gov (United States)

    Raso, Giuseppina Mattace; Pacilio, Maria; Esposito, Emanuela; Coppola, Anna; Di Carlo, Raffaele; Meli, Rosaria

    2002-01-01

    Leptin, a pleiotropic hormone believed to regulate body weight, has recently been associated with inflammatory states and immune activity. Here we have studied the effect of leptin on expression of IFN-γ-induced nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2), both prominent markers of macrophage activation, using the murine macrophage J774A.1 cell line. After 24 h of incubation, leptin (1–10 μg ml−1) potently synergized with IFN-γ (100 U ml−1) in nitric oxide (NO) release, evaluated as nitrite and nitrate (NOx), and prostaglandin E2 (PGE2) production in culture medium. The observed increase of NO and PGE2 was related to enhanced expression of the respective inducible enzyme isoforms, measured in mRNA and protein by RT–PCR and Western blot analysis, respectively. When cells were stimulated only with leptin, a weak induction of NO and PGE2 release and of the expression of related inducible enzymes was observed. Moreover IFN-γ increased the expression of the functional form of leptin receptor (Ob-Rb) and this effect was potentiated by leptin in a concentration-dependent manner. These data suggest that macrophages, among the peripheral immune cells, represent a target for leptin and confirm the relevance of this hormone in the pathophysiology of inflammation. PMID:12411410

  13. Acanthopanax koreanum roots inhibit the expression of pro-inflammatory cytokines, inducible nitric oxide synthase, and cyclooxygenase-2 in RAW 264.7 macrophages

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    Eun-Jin Yang

    2016-03-01

    Full Text Available Acanthopanax koreanum is a popular plant found on Jeju Island, Korea and is commonly used to prevent the side effects of consumption of alcoholic beverages. However, this plant has not been properly utilized as a medicinal material. In this study, we investigated the anti-inflammatory effects of the 70% ethanol extract of A. koreanum roots (AKR-E. The results indicated that the AKR-E (200 μg/mL inhibited the lipopolysaccharide (LPS-induced production of nitric oxide (NO and prostaglandin E2 (PGE2 in RAW 264.7 macrophages by 41.2% and 78.9%, respectively. These effects were accompanied by concentration-dependent decreases in the expression levels of inducible NO synthase (iNOS and cyclooxygenase-2 (COX-2 proteins. Additionally, the AKR-E inhibited the expression of pro-inflammatory cytokines, including interleukin (IL-6 (22.7% and IL-1β (74%. These data showed that the AKR-E had protective effects against the induction of LPS-induced inflammation in RAW 264.7 macrophages.

  14. Cyclooxygenase-2 level and culture conditions influence NS398-induced apoptosis and caspase activation in lung cancer cells.

    Science.gov (United States)

    Chang, H C; Weng, C F

    2001-01-01

    Cyclooxygenases (COXs) catalyze the synthesis of prostaglandins (PGs) from arachidonic acid. Overexpression of COX-2 is frequently found in human cancers and is suggested to play an important role in tumorigenesis. Recent studies indicated that COX-2 inhibitors exert potent anti-cancer effects on a number of cancers. Interestingly, some COX-2 inhibitors potently induce apoptosis, while other COX-2 inhibitors primarily induce growth inhibition. Therefore, there is a variability in the effects that different COX-2 inhibitors have on cancer cells. In this study, we demonstrated that induction of apoptosis of high COX-2-expressing A549 lung cancer cells by a specific COX-2 inhibitor NS398 was observed in cells cultured under serum-free condition. However, this drug induced G1 growth arrest rather than apoptosis in A549 cells maintained in 10% serum medium. Conversely, low COX-2-expressing H226 lung cancer cells were resistant to NS398-induced apoptosis under both serum-free and serum-containing conditions. Moreover, our results showed that NS398-induced apoptosis is associated with activation of caspase-3, a cysteine protease that plays a crucial role in the execution phase of apoptosis. These results suggest that the cytotoxic effect of COX-2 inhibitors on cancer cells may be influenced by extracellular environments and the anti-cancer action of these inhibitors in vivo needs careful evaluation. Additionally, a correlation between the level of COX-2 expression and the extent of apoptosis induced by COX-2 inhibitors was found. PMID:11605058

  15. Involvement of hypothalamic cyclooxygenase-2, interleukin-1β and melanocortin in the development of docetaxel-induced anorexia in rats.

    Science.gov (United States)

    Yamamoto, Kouichi; Asano, Keiko; Ito, Yui; Matsukawa, Naoki; Kim, Seikou; Yamatodani, Atsushi

    2012-12-16

    Docetaxel, a taxane derivative, is frequently used for the treatment of advanced breast cancer, non-small cell lung cancer, and metastatic prostate cancer. Clinical reports demonstrated that docetaxel-based chemotherapy often induces anorexia, but the etiology is not completely understood. To elucidate possible mechanisms, we investigated the involvement of central interleukin (IL)-1β, cyclooxygenase (COX)-2, and pro-opiomelanocortin (POMC) in the development of docetaxel-induced anorexia in rats. Rats received docetaxel (10mg/kg, i.p.) with or without pretreatment with selective COX-2 inhibitors, NS-398 (10 and 30 mg/kg, i.g.) or celecoxib (10 and 30 mg/kg, i.g.), and a non-selective COX inhibitor, indomethacin (10mg/kg, i.g.), then food intake was monitored for 24h after administration. We also examined expression of IL-1β, COX-2, and POMC mRNA in hypothalamus of docetaxel-treated rats and the effect of a COX-2 inhibitor on docetaxel-induced POMC mRNA expression. Food consumption in rats was significantly decreased 24h after administration of docetaxel and anorexia was partially reversed by all COX inhibitors. Administration of docetaxel increased IL-1β, COX-2, and POMC mRNA expression in the hypothalamus of rats. The time required to increase these gene expressions was comparable to the latency period of docetaxel-induced anorexia in rats. In addition, pretreatment with COX-2 inhibitors suppressed docetaxel-induced expression of POMC mRNA. These results suggest that IL-1β and COX-2 mRNA expression and subsequent activation of POMC in the hypothalamus may contribute to the development of docetaxel-induced anorexia in rats.

  16. Lipopolysaccharide Enhances the Production of Nicotine-Induced Prostaglandin E2 by an Increase in Cyclooxygenase-2 Expression in Osteoblasts

    Institute of Scientific and Technical Information of China (English)

    Maiko SHOJI; Natsuko TANABE; Narihiro MITSUI; Naoto SUZUKI; Osamu TAKEICHI; Tomoko KATONO; Akira MOROZUMI; Masao MAENO

    2007-01-01

    Previous studies have indicated that lipopolysaccharide (LPS) from Gram-negative bacteria in plaque induces the release of prostaglandin E2 (PGE2),which promotes alveolar bone resorption in periodontitis,and that tobacco smoking might be an important risk factor for the development and severity of periodontitis.We determined the effect of nicotine and LPS on alkaline phosphatase (ALPase)activity,PGE2 production,and the expression of cyclooxygenase (COX-1,COX-2),PGE2 receptors Ep1-4,and macrophage colony stimulating factor(M-CSF)in human osteoblastic Saos-2 cells.The cells were cultured with 10-3 M nicotine in the presence of 0,1,or 10 μg/ml LPS,or with LPS alone.ALPase activity decreased in cells cultured with nicotine or LPS alone,and decreased further in those cultured with both nicotine and LPS,whereas PGE2 production significantly increased in the former and increased further in the latter.By itself,nicotine did not affect expression of COX-1,COX-2,any of the PGE2 receptors,or M-CSF,but when both nicotine and LPS were present,expression of COX-2,Ep3,Ep4,and M-CSF increased significantly.Simultaneous addition of 10-4 M indomethacin eliminated the effects of nicotine and LPS on ALPase activity,PGE2 production,and MCSF expression.Phosphorylation of protein kinase A was high in cells cultured with nicotine and LPS.These results suggest that LPS enhances the production of nicotine-induced PGE2 by an increase in COX-2 expression in osteoblasts,that nicotine-LPS-induced PGE2 interacts with the osteoblast Ep4 receptor primarily in autocrine or paracrine mode,and that the nicotine-LPS-induced PGE2 then decreases ALPase activity and increases M-CSF expression.

  17. Quercetin induces apoptosis by activating caspase-3 and regulating Bcl-2 and cyclooxygenase-2 pathways in human HL-60 cells

    Institute of Scientific and Technical Information of China (English)

    Guomin Niu; Songmei Yin; Shuangfeng Xie; Yiqing Li; Danian Nie; Liping Ma; Xiuju Wang; Yudan Wu

    2011-01-01

    Quercetin is one of the naturally occurring dietary flavo-nol compounds. It is present abundantly in plants and has chemopreventive and anticancer effects. To investigate its anticancer mechanism, we examined the activity of quercetin against acute leukemia cell line, HL-60. Our results showed that quercetin inhibited cell proliferation and induced apoptosis in a time- and dose-dependent manner. Furthermore, quercetin down-regulated the expression of anti-apoptosis protein Bcl-2 and up-regulated the expression of pro-apoptosis protein Bax. Caspase-3 was also activated by quercetin, which started a caspase-3-depended mitochodrial pathway to induce apoptosis. It was also found that quercetin inhibited the expression of the cycloocygenase-2 (Cox-2) mRNA and Cox-2 protein. Taken together, these findings suggested that quercetin induces apoptosis in a caspase-3-dependent pathway by inhibiting Cox-2 expression and regulates the expression of downstream apoptotic components, including Bcl-2 and Bax. Quercetin can be a potent and promising medicine which might be safely used in leukemia therapy.

  18. Role of the cyclooxygenase 2-thromboxane pathway in 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced decrease in mesencephalic vein blood flow in the zebrafish embryo

    International Nuclear Information System (INIS)

    Previously, we reported that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) evoked developmental toxicity required activation of aryl hydrocarbon receptor type 2 (AHR2), using zebrafish embryos. However, the downstream molecular targets of AHR2 activation are largely unknown and are the focus of the present investigation. TCDD induces cyclooxygenase 2 (COX2), a rate-limiting enzyme for prostaglandin synthesis in certain cells. In the present study, we investigated the role of the COX2-thromboxane pathway in causing a specific endpoint of TCDD developmental toxicity in the zebrafish embryo, namely, a decrease in regional blood flow in the dorsal midbrain. It was found that the TCDD-induced reduction in mesencephalic vein blood flow was markedly inhibited by selective COX2 inhibitors, NS-398 and SC-236, and by a general COX inhibitor, indomethacin, but not by a selective COX1 inhibitor, SC-560. Gene knock-down of COX2 by two different types of morpholino antisense oligonucleotides, but not by their negative homologs, also protected the zebrafish embryos from mesencephalic vein circulation failure caused by TCDD. This inhibitory effect of TCDD on regional blood flow in the dorsal midbrain was also blocked by selective antagonists of the thromboxane receptor (TP). Treatment of control zebrafish embryos with a TP agonist also caused a reduction in mesencephalic vein blood flow and it too was blocked by a TP antagonist, without any effect on trunk circulation. Finally, gene knock-down of thromboxane A synthase 1 (TBXS) with morpholinos but not by the morpholinos' negative homologs provided significant protection against TCDD-induced mesencephalic circulation failure. Taken together, these results point to a role of the prostanoid synthesis pathway via COX2-TBXS-TP in the local circulation failure induced by TCDD in the dorsal midbrain of the zebrafish embryo

  19. Expression of inducible nitric oxide synthase and cyclooxygenase-2 in pancreatic adenocarcinoma:Correlation with microvessel density

    Institute of Scientific and Technical Information of China (English)

    Hans U. Kasper; Hella Wolf; Uta Drebber; Helmut K. Wolf; Michael A. Kern

    2004-01-01

    AIM: Cyclooxygenases (COX) are key enzymes for conversion of arachidonic acid to prostaglandins. Nitric oxide synthase (NOS) is the enzyme responsible for formation of nitric oxide.Both have constitutive and inducible isoforms. The inducible isoforms (iNOS and COX-2) are of great interest as regulators of tumor angiogenesis, tumorigenesis and inflammatory processes. This study was to clarify their role in pancreatic adenocarcinomas.METHODS: We investigated the immunohistochemical iNOS and COX-2 expression in 40 pancreatic ducal adenocarcinomas of different grade and stage. The results were compared with microvessel density and clinicopathological data.RESULTS: Twenty-one (52.5%) of the cases showed iNOS expression, 15 (37.5%) of the cases were positive for COX-2.The immunoreaction was heterogeneously distributed within the tumors. Staining intensity was different between the tumors. No correlation between iNOS and COX-2 expression was seen. There was no relationship with microvessel density.However, iNOS positive tumors developed more often distant metastases and the more malignant tumors showed a higher COX-2 expression. There was no correlation with other clinicopathological data.CONCLUSION: Approximately half of the cases expressed iNOS and COX-2. These two enzymes do not seem to be the key step in angiogenesis or carcinogenesis of pancreatic adenocarcinomas. Due to a low prevalence of COX-2expression, chemoprevention of pancreatic carcinomas by COX-2 inhibitors can only achieve a limited success.

  20. Selective cyclooxygenase-2 inhibitors show a differential ability to inhibit proliferation and induce apoptosis of colon adenocarcinoma cells.

    Science.gov (United States)

    Yamazaki, Ryuta; Kusunoki, Natsuko; Matsuzaki, Takeshi; Hashimoto, Shusuke; Kawai, Shinichi

    2002-11-01

    Although the influence of selective cyclooxygenase (COX)-2 inhibitors on the proliferation of colon adenocarcinoma cells have been the subject of much investigation, relatively little research has compared the effects of different COX-2 inhibitors. Celecoxib strongly suppressed the proliferation of COX-2 expressing HT-29 cells at 10-40 microM. NS-398 and nimesulide also inhibited cell proliferation, whereas rofecoxib, meloxicam, and etodolac did not. Only celecoxib induced apoptosis of HT-29 cells, as detected on the basis of DNA fragmentation, TUNEL positivity, and caspase-3/7 activation. DNA fragmentation was also increasd in COX-2 non-expressing cell lines (SW-480 and HCT-116) by exposure to celecoxib for 6-24 h. All six COX-2 inhibitors suppressed the production of prostaglandin E(2) by HT-29 cells, suggesting that the pro-apoptotic effect of celecoxib was unrelated to inhibition of COX-2. Inactivation of Akt might explain the differential pro-apoptotic effect of these selective COX-2 inhibitors on colon adenocarcinoma cells. PMID:12417326

  1. VEGF gene expression in adult human thymus fat: a correlative study with hypoxic induced factor and cyclooxygenase-2.

    Directory of Open Access Journals (Sweden)

    Francisco Tinahones

    Full Text Available UNLABELLED: It is well known that the adult human thymus degenerates into fat tissue; however, it has never been considered as a potential source of angiogenic factors. Recently, we have described that this fat (TAT produces angiogenic factors and induces human endothelial cell proliferation and migration, indicating its potential angiogenic properties. DESIGN: Adult thymus fat and subcutaneous adipose tissue specimens were obtained from 28 patients undergoing cardiac surgery, making this tissue readily available as a prime source of adipose tissue. We focused our investigation on determining VEGF gene expression and characterizing the different genes, mediators of inflammation and adipogenesis, and which are known to play a relevant role in angiogenesis regulation. RESULTS: We found that VEGF-A was the isoform most expressed in TAT. This expression was accompanied by an upregulation of HIF-1alpha, COX-2 and HO-1 proteins, and by increased HIF-1 DNA binding activity, compared to SAT. Furthermore, we observed that TAT contains a high percentage of mature adipocytes, 0.25% of macrophage cells, 15% of endothelial cells and a very low percentage of thymocyte cells, suggesting the cellular variability of TAT, which could explain the differences in gene expression observed in TAT. Subsequently, we showed that the expression of genes known as adipogenic mediators, including PPARgamma1/gamma2, FABP-4 and adiponectin was similar in both TAT and SAT. Moreover the expression of these latter genes presented a significantly positive correlation with VEGF, suggesting the potential association between VEGF and the generation of adipose tissue in adult thymus. CONCLUSION: Here we suggest that this fat has a potential angiogenic function related to ongoing adipogenesis, which substitutes immune functions within the adult thymus. The expression of VEGF seems to be associated with COX-2, HO-1 and adipogenesis related genes, suggesting the importance that this new

  2. New Inducible Nitric Oxide Synthase and Cyclooxygenase-2 Inhibitors, Nalidixic Acid Linked to Isatin Schiff Bases via Certain l-Amino Acid Bridges

    Directory of Open Access Journals (Sweden)

    Ahmed M. Naglah

    2016-04-01

    Full Text Available A series of new Schiff bases were synthesized by condensation of isatins with the nalidixic acid-l-amino acid hydrazides. Prior to hydrazide formation, a peptide linkage has been prepared via coupling of nalidixic acid with appropriate l-amino acid methyl esters to yield 3a–c. The chemical structures of the new Schiff bases (5b and 5d–h were confirmed by means of IR, NMR, mass spectroscopic, and elemental analyses. The anti-inflammatory activity of these Schiff bases was evaluated via measurement of the expressed inducible nitric oxide synthase (iNOS and cyclooxygenase-2 (COX-2 in the lipopolysaccharide (LPS-stimulated RAW264.7 macrophage cells model. The Schiff bases exhibited significant dual inhibitory effect against the induction of the pro-inflammatory iNOS and COX-2 proteins with variable potencies. However, they strongly down-regulated the iNOS expression to the level of 16.5% ± 7.4%–42.2% ± 19.6% compared to the effect on COX-2 expression (<56.4% ± 3.1% inhibition at the same concentration (10 μM. The higher iNOS inhibition activity of the tested Schiff bases, relative to that of COX-2, seems to be a reflection of the combined suppressive effects exerted by their nalidixic acid, isatins (4a–c, and l-amino acid moieties against iNOS expression. These synthesized nalidixic acid-l-amino acid-isatin conjugates can be regarded as a novel class of anti-inflammatory antibacterial agents.

  3. Small interfering RNA of cyclooxygenase-2 induces growth inhibition and apoptosis independently of Bcl-2 in human myeloma RPMI8226 cells

    Institute of Scientific and Technical Information of China (English)

    Qiu-bai LI; Zhi-chao CHEN; Yong YOU; Ping ZOU

    2007-01-01

    Aim: To investigate the effects of small interfering RNA of cyclooxygenase-2 (COX-2) on the proliferation and apoptosis of human multiple myeloma RPMI8226 cells and its relation with the Bcl-2 family in vitro. Methods: Transcription and expression of COX-2 in human myeloma RPMI8226 cells were checked by RT-PCR and Western blot analysis, respectively. The COX-2 siRNA fragment targeting exon 5 of COX-2 gene was transfected into the cells with the Amaxa nucleofection technique. The inhibition of cell growth was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium (MTT) assay. Apoptosis was estimated by Annexin-V/propidium iodide double-labeled cytometry and confirmed by termi-nal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. Bcl-2 and Bax expression was evaluated by Western blot analysis. Results: The COX-2 siRNA fragment could be successfully transfected into RPMI8226 cells, which resulted in the significant inhibition of transcription and expression of COX-2 in the myeloma cells. Proliferation of the transfected cells was inhibited and apoptosis was induced (6.52%±0.32%, 12.53%±2.52%, 24.39%±3.51% and 36.48%±4.96% for 0, 12, 24, and 48 h, respectively) in a time-dependent manner (P<0.01), However, the expression of Bcl-2 and Bax in the RPMI8226 cells had no significant changes after nucleofection. Conclusion: COX-2 siRNA transfection can suppress COX-2 expression in human myeloma RPMI8226 cells, which leads to growth inhibition and apoptosis independent of Bcl-2.

  4. Chronic exposure to combined carcinogens enhances breast cell carcinogenesis with mesenchymal and stem-like cell properties.

    Directory of Open Access Journals (Sweden)

    Lenora Ann Pluchino

    Full Text Available Breast cancer is the most common type of cancer affecting women in North America and Europe. More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcinogenesis, we studied the activity of environmental carcinogens 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK and benzo[a]pyrene (B[a]P, and dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP using our breast cell carcinogenesis model. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells. Co-exposure was more potent than sequential exposure to combined NNK and B[a]P followed by PhIP in inducing carcinogenesis. Initiation of carcinogenesis was measured by transient endpoints induced in a single exposure, while progression of carcinogenesis was measured by acquisition of constitutive endpoints in cumulative exposures. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species elevation, and increased cellular proliferation. Constitutive endpoints included various cancer-associated properties and signaling modulators, as well as enrichment of cancer stem-like cell population and activation of the epithelial-to-mesenchymal transition program. Using transient and constitutive endpoints as targets, we detected that a combination of the green tea catechins ECG and EGCG, at non-cytotoxic levels, was more effective than individual agents in intervention of cellular carcinogenesis induced by combined NNK, B[a]P, and PhIP. Thus, use of combined ECG and EGCG should be seriously considered for early intervention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens.

  5. Naturally occurring variants of human Α9 nicotinic receptor differentially affect bronchial cell proliferation and transformation.

    Directory of Open Access Journals (Sweden)

    Anna Chikova

    Full Text Available Isolation of polyadenilated mRNA from human immortalized bronchial epithelial cell line BEP2D revealed the presence of multiple isoforms of RNA coded by the CHRNA9 gene for α9 nicotinic acetylcholine receptor (nAChR. BEP2D cells were homozygous for the rs10009228 polymorphism encoding for N442S amino acid substitution, and also contained mRNA coding for several truncated isoforms of α9 protein. To elucidate the biologic significance of the naturally occurring variants of α9 nAChR, we compared the biologic effects of overexpression of full-length α9 N442 and S442 proteins, and the truncated α9 variant occurring due to a loss of the exon 4 sequence that causes frame shift and early termination of the translation. These as well as control vector were overexpressed in the BEP2D cells that were used in the assays of proliferation rate, spontaneous vs. tobacco nitrosamine 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK-induced cellular transformation, and tumorigenicity in cell culture and mice. Overexpression of the S442 variant significantly increased cellular proliferation, and spontaneous and NNK-induced transformation. The N442 variant significantly decreased cellular transformation, without affecting proliferation rate. Overexpression of the truncated α9 significantly decreased proliferation and suppressed cellular transformation. These results suggested that α9 nAChR plays important roles in regulation of bronchial cell growth by endogenous acetylcholine and exogenous nicotine, and susceptibility to NNK-induced carcinogenic transformation. The biologic activities of α9 nAChR may be regulated at the splicing level, and genetic polymorphisms in CHRNA9 affecting protein levels, amino acid sequence and RNA splicing may influence the risk for lung cancer.

  6. Cardiovascular effects of selective cyclooxygenase-2 inhibitors.

    Science.gov (United States)

    Krum, Henry; Liew, Danny; Aw, Juan; Haas, Steven

    2004-03-01

    Selective cyclooxygenase-2 inhibitors represent a significant advance in the management of inflammatory disorders. They have similar efficacy to nonselective 'conventional' nonsteroidal anti-inflammatory drugs, but a superior gastrointestinal safety profile. However, a significant caveat is the perceived potential of cyclooxygenase-2 inhibitors to cause adverse cardiovascular effects, an issue first raised by the Vioxx Gastrointestinal Outcomes Research (VIGOR) study of rofecoxib (Vioxx, Merck & Co. Inc.). Mechanisms by which cyclooxygenase-2 inhibitors may increase cardiovascular risk are selective inhibition of prostaglandin I2 over thromboxane A2 within the eicosanoid pathway, which promotes thrombosis, and inhibition of prostaglandins E2 and I2 within the kidney, which leads to sodium and water retention and blood pressure elevation. In spite of this, the cardiovascular findings from VIGOR are not firmly supported by observations from large cohort studies and other clinical trials of selective cyclooxygenase-2 inhibitors, including the Celecoxib Long-term Arthritis Safety Study. The two main theories that explain the VIGOR findings are that the comparator used (naproxen; Naprosyn, Roche) is cardioprotective and that very high doses of rofecoxib were used, but at present neither is backed by firm evidence. Indeed, there is now early evidence that selective cyclooxygenase-2 inhibition with celecoxib may even protect against the progression of cardiovascular disease, on the basis that cyclooxygenase-2 mediates key processes in atherothrombosis. Currently, it is not clear what the net cardiovascular effects of cyclooxygenase-2 inhibitors are. The data are inconsistent and at best, speculative. It may be also that celecoxib and rofecoxib differ in their cardiovascular effects. Clarification of these issues is of vital importance given the vast number of patients presently taking both types of cyclooxygenase-2 inhibitors. Therefore, what is clear in this situation is

  7. Expression of the α7 nicotinic acetylcholine receptor in human lung cells

    OpenAIRE

    Schuller Hildegard M; Dhar Madhu; Plummer Howard K

    2005-01-01

    Abstract Background We and others have shown that one of the mechanisms of growth regulation of small cell lung cancer cell lines and cultured pulmonary neuroendocrine cells is by the binding of agonists to the α7 neuronal nicotinic acetylcholine receptor. In addition, we have shown that the nicotine-derived carcinogenic nitrosamine, 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is a high affinity agonist for the α7 nicotinic acetylcholine receptor. In the present study, our goal was t...

  8. An Asp49 Phospholipase A2 from Snake Venom Induces Cyclooxygenase-2 Expression and Prostaglandin E2 Production via Activation of NF-κB, p38MAPK, and PKC in Macrophages

    Directory of Open Access Journals (Sweden)

    Vanessa Moreira

    2014-01-01

    Full Text Available Phospholipases A2 (PLA2 are key enzymes for production of lipid mediators. We previously demonstrated that a snake venom sPLA2 named MT-III leads to prostaglandin (PGE2 biosynthesis in macrophages by inducing the expression of cyclooxygenase-2 (COX-2. Herein, we explored the molecular mechanisms and signaling pathways leading to these MT-III-induced effects. Results demonstrated that MT-III induced activation of the transcription factor NF-κB in isolated macrophages. By using NF-κB selective inhibitors, the involvement of this factor in MT-III-induced COX-2 expression and PGE2 production was demonstrated. Moreover, MT-III-induced COX-2 protein expression and PGE2 release were attenuated by pretreatment of macrophages with SB202190, and Ly294002, and H-7-dihydro compounds, indicating the involvement of p38MAPK, PI3K, and PKC pathways, respectively. Consistent with this, MT-III triggered early phosphorylation of p38MAPK, PI3K, and PKC. Furthermore, SB202190, H-7-dihydro, but not Ly294002 treatment, abrogated activation of NF-κB induced by MT-III. Altogether, these results show for the first time that the induction of COX-2 protein expression and PGE2 release, which occur via NF-κB activation induced by the sPLA2-MT-III in macrophages, are modulated by p38MAPK and PKC, but not by PI3K signaling proteins.

  9. Tongxinluo Inhibits Cyclooxygenase-2, Inducible Nitric Oxide Synthase, Hypoxia-inducible Factor-2α/Vascular Endothelial Growth Factor to Antagonize Injury in Hypoxia-stimulated Cardiac Microvascular Endothelial Cells

    Institute of Scientific and Technical Information of China (English)

    Yan-Ning Li; Xiu-Juan Wang; Bin Li; Kun Liu; Jin-Sheng Qi; Bing-Hui Liu; Ye Tian

    2015-01-01

    Background:Endothelial dysfunction is considered as the initiating process and pathological basis of cardiovascular disease.Cyclooxygenase-2 (COX-2) and prostacyclin synthase (PGIS),inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS)are key enzymes with opposing actions in inflammation and oxidative stress,which are believed to be the major driver of endothelial dysfunction.And in hypoxia (Hx),Hx-inducible factor (HIF)-1 α and HIF-2α are predominantly induced to activate vascular endothelial growth factor (VEGF),resulting in abnormal proliferation.Whether and how Tongxinluo (TXL) modulates COX-2,PGIS,iNOS,eNOS,HIF-1 α,HIF-2α,and VEGF in Hx-stimulated human cardiac microvascular endothelial cells (HCMECs) have not been clarified.Methods:HCMEC were treated with CoCl2 to mimic Hx and the mRNA expressions of COX-2,PGIS,iNOS,eNOS,HIF-1α,HIF-2α,and VEGF were first confirmed,and then their mRNA expression and protein content as well as the cell pathological alterations were evaluated for TXL treatment with different concentrations.In addition,the effector molecular of inflammation prostaglandin E2 (PGE2)and the oxidative marker nitrotyrosine (NT) was adopted to reflect HCMEC injury.Results:Hx could induce time-dependent increase of COX-2,iNOS,HIF-2α,and VEGF in HCMEC.Based on the Hx-induced increase,TXL could mainly decrease COX-2,iNOS,HIF-2α,and VEGF in a concentration-dependent manner,with limited effect on the increase of PGIS and eNOS.Their protein contents verified the mRNA expression changes,which was consistent with the cell morphological alterations.Furthermore,high dose TXL could inhibit the Hx-induced increase of PGE2 and NT contents,attenuating the inflammatory and oxidative injury.Conclusions:TXL could inhibit inflammation-related COX-2,oxidative stress-related iNOS,and HIF-2α/VEGF to antagonize Hx-induced HCMEC injury.

  10. Melatonin-mediated Bim up-regulation and cyclooxygenase-2 (COX-2) down-regulation enhances tunicamycin-induced apoptosis in MDA-MB-231 cells.

    Science.gov (United States)

    Woo, Seon Min; Min, Kyoung-jin; Kwon, Taeg Kyu

    2015-04-01

    Melatonin is involved in many physiological functions, and it has differential effects on apoptosis in normal and cancer cells. However, the mechanism of its antitumor roles is not well understood. In this study, we show that melatonin enhances tunicamycin-induced apoptosis in human breast carcinoma MDA-MB-231 cells. Melatonin up-regulates pro-apoptotic protein Bim expression at the transcriptional levels in the presence of tunicamycin. Melatonin inhibits tunicamycin-induced COX-2 expression in MDA-MB-231 cells. Furthermore, inhibition of COX-2 activity using the COX-2 inhibitor, NS398, increases tunicamycin-induced apoptosis. Interestingly, these effects were not associated with melatonin receptor signal pathways. Pertussis toxin (a general Gi protein inhibitor) or luzindole (a nonspecific melatonin receptor antagonist) did not reverse the effect of melatonin. In addition, melatonin blocked tunicamycin-induced NF-κB transcriptional activity, p65 nuclear translocation, and p38 MAPK activation. Melatonin-mediated p38 MAPK inhibition contributed to decreased COX-2 mRNA stability. Taken together, our results suggest that melatonin enhances antitumor function through up-regulation of Bim expression and down-regulation of COX-2 expression in tunicamycin-treated MDA-MB-231 cells. PMID:25711465

  11. Ethanol enhances arsenic-induced cyclooxygenase-2 expression via both NFAT and NF-κB signalings in colorectal cancer cells.

    Science.gov (United States)

    Wang, Lei; Hitron, John Andrew; Wise, James T F; Son, Young-Ok; Roy, Ram Vinod; Kim, Donghern; Dai, Jin; Pratheeshkumar, Poyil; Zhang, Zhuo; Xu, Mei; Luo, Jia; Shi, Xianglin

    2015-10-15

    Arsenic is a known carcinogen to humans, and chronic exposure to environmental arsenic is a worldwide health concern. As a dietary factor, ethanol carries a well-established risk for malignancies, but the effects of co-exposure to arsenic and ethanol on tumor development are not well understood. In the present study, we hypothesized that ethanol would enhance the function of an environmental carcinogen such as arsenic through increase in COX-2 expression. Our in vitro results show that ethanol enhanced arsenic-induced COX-2 expression. We also show that the increased COX-2 expression associates with intracellular ROS generation, up-regulated AKT signaling, with activation of both NFAT and NF-κB pathways. We demonstrate that antioxidant enzymes have an inhibitory effect on arsenic/ethanol-induced COX-2 expression, indicating that the responsive signaling pathways from co-exposure to arsenic and ethanol relate to ROS generation. In vivo results also show that co-exposure to arsenic and ethanol increased COX-2 expression in mice. We conclude that ethanol enhances arsenic-induced COX-2 expression in colorectal cancer cells via both the NFAT and NF-κB pathways. These results imply that, as a common dietary factor, ethanol ingestion may be a compounding risk factor for arsenic-induced carcinogenesis/cancer development.

  12. Advanced glycation end-products induce apoptosis in pancreatic islet endothelial cells via NF-κB-activated cyclooxygenase-2/prostaglandin E2 up-regulation.

    Directory of Open Access Journals (Sweden)

    Kuo-Cheng Lan

    Full Text Available Microvascular complications eventually affect nearly all patients with diabetes. Advanced glycation end-products (AGEs resulting from hyperglycemia are a complex and heterogeneous group of compounds that accumulate in the plasma and tissues in diabetic patients. They are responsible for both endothelial dysfunction and diabetic vasculopathy. The aim of this study was to investigate the cytotoxicity of AGEs on pancreatic islet microvascular endothelial cells. The mechanism underlying the apoptotic effect of AGEs in pancreatic islet endothelial cell line MS1 was explored. The results showed that AGEs significantly decreased MS1 cell viability and induced MS1 cell apoptosis in a dose-dependent manner. AGEs dose-dependently increased the expressions of cleaved caspase-3, and cleaved poly (ADP-ribose polymerase in MS1 cells. Treatment of MS1 cells with AGEs also resulted in increased nuclear factor (NF-κB-p65 phosphorylation and cyclooxygenase (COX-2 expression. However, AGEs did not affect the expressions of endoplasmic reticulum (ER stress-related molecules in MS1 cells. Pretreatment with NS398 (a COX-2 inhibitor to inhibit prostaglandin E2 (PGE2 production reversed the induction of cleaved caspase-3, cleaved PARP, and MS1 cell viability. Moreover, AGEs significantly increased the receptor for AGEs (RAGE protein expression in MS1 cells, which could be reversed by RAGE neutralizing antibody. RAGE Neutralizing antibody could also reverse the induction of cleaved caspase-3 and cleaved PARP and decreased cell viability induced by AGEs. These results implicate the involvement of NF-κB-activated COX-2/PGE2 up-regulation in AGEs/RAGE-induced islet endothelial cell apoptosis and cytotoxicity. These findings may provide insight into the pathological processes within the pancreatic islet microvasculature induced by AGEs accumulation.

  13. Oxidized low-density lipoprotein-induced periodontal inflammation is associated with the up-regulation of cyclooxygenase-2 and microsomal prostaglandin synthase 1 in human gingival epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Nagahama, Yu [Department of Periodontology, School of Dentistry, Showa University Dental Hospital, Tokyo (Japan); Department of Biological Chemistry, Showa University School of Pharmacy, Tokyo (Japan); Obama, Takashi [Department of Biological Chemistry, Showa University School of Pharmacy, Tokyo (Japan); Usui, Michihiko [Department of Periodontology, School of Dentistry, Showa University Dental Hospital, Tokyo (Japan); Kanazawa, Yukari [Department of Biological Chemistry, Showa University School of Pharmacy, Tokyo (Japan); Iwamoto, Sanju [Department of Biochemistry, Showa University School of Medicine, Tokyo (Japan); Suzuki, Kazushige [Department of Periodontology, School of Dentistry, Showa University Dental Hospital, Tokyo (Japan); Miyazaki, Akira [Department of Biochemistry, Showa University School of Medicine, Tokyo (Japan); Yamaguchi, Tomohiro [Department of Biological Chemistry, Showa University School of Pharmacy, Tokyo (Japan); Yamamoto, Matsuo [Department of Periodontology, School of Dentistry, Showa University Dental Hospital, Tokyo (Japan); Itabe, Hiroyuki, E-mail: h-itabe@pharm.showa-u.ac.jp [Department of Biological Chemistry, Showa University School of Pharmacy, Tokyo (Japan)

    2011-10-07

    Highlights: {yields} OxLDL-induced responses in human gingival epithelial cells were studied. {yields} OxLDL enhanced the production of IL-8, IL-1{beta} and PGE{sub 2} in Ca9-22 cells. {yields} An NF-{kappa}B inhibitor suppressed the expression of COX-2 and mPGES1 induced by oxLDL. {yields} Unlike the case in macrophages, oxLDL did not increase the CD36 level. -- Abstract: Periodontitis is characterized by chronic gingival tissue inflammation, and inflammatory mediators such as IL-8 and prostaglandin E{sub 2} (PGE{sub 2}) are associated with disease progression. Previously we showed that oxidatively modified low-density lipoprotein (oxLDL) was present in gingival crevicular fluid. In this study, the role of oxLDL in the gingival epithelial cell inflammatory response was further investigated using Ca9-22 cells and primary human oral keratinocytes (HOK). Treatment of Ca9-22 cells and HOK with oxLDL induced an up-regulation of IL-8 and the PGE{sub 2}-producing enzymes, cyclooxygenase-2 and microsomal PGE{sub 2} synthase-1. These responses induced by oxLDL were significantly suppressed by a nuclear factor-kappa B (NF-{kappa}B) inhibitor. However, unlike the result in macrophages, oxLDL did not lead to an increase in CD36 expression in these two cells. These results suggest that oxLDL elicits gingival epithelial cell inflammatory responses through an activation of the NF-{kappa}B pathway. These data suggest a mechanistic link between periodontal disease and lipid metabolism-related disorders, including atherosclerosis.

  14. Safrole oxide induces human umbilical vein endothelial cell transdifferentiation to 5-hydroxytryptaminergic neuron-like cells through tropomyosin receptor kinase A/cyclooxygenase 2/nuclear factor-kappa B/interleukin 8 signaling.

    Science.gov (United States)

    Su, Le; Zhao, Jing; Zhao, Bao Xiang; Zhang, Shang Li; Miao, Jun Ying

    2011-10-01

    The phenomenon of endothelial-neural transdifferentiation has been observed for a long time, but the mechanism is not clear. We previously found that safrole oxide induced human umbilical vein endothelial cell transdifferentiation into neuron-like cells. In this study, we first validated that these cells induced by safrole oxide were functional 5-hydroxytryptaminergic neuron-like cells. Then, we performed microarray analysis of safrole oxide-treated and -untreated human umbilical vein endothelial cells. Safrole oxide elevated the levels of cyclooxygenase 2 (COX-2), interleukin-8 (IL-8) and reactive oxygen species (ROS), which was accompanied by nuclear factor-kappa B (NF-κB) nuclear translocation during the transdifferentiation. Blockade of tropomyosin receptor kinase A (TrkA) by an inhibitor or short hairpin RNA inhibited the levels of COX-2/IL-8 and the nuclear translocation of NF-κB but did not suppress the increased ROS level. As a result, cells underwent apoptosis. Therefore, via TrkA, safrole oxide may induce endothelial cell transdifferentiation into functional neuron-like cells. During this process, the increased levels of COX-2/IL-8 and the subsequent elevation of ROS production induced NF-κB nuclear translocation and IL-8 secretion. With the activity of TrkA inhibited, the inactive NF-κB regulated the ROS level in a negative feedback manner. Finally, the transdifferentiation pathway was blocked and cells became apoptotic. The TrkA/COX-2/IL-8 signal pathway may have an important role in endothelial-neural transdifferentiation, and safrole oxide may trigger this process by activating TrkA.

  15. Translocation of NF-κB and expression of cyclooxygenase-2 are enhanced by ketamine-induced ulcerative cystitis in rat bladder.

    Science.gov (United States)

    Juan, Yung-Shun; Lee, Yi-Lun; Long, Cheng-Yu; Wong, Jhen-Hong; Jang, Mei-Yu; Lu, Jian-He; Wu, Wen-Jeng; Huang, Yen-Shun; Chang, Wei-Chiao; Chuang, Shu-Mien

    2015-08-01

    The number of ketamine abusers has increased significantly recently. Ketamine abusers exhibit urinary frequency, urgency, and at times urinary incontinence. Our aim was to investigate the role of transcription factor NF-κB and cyclooxygenase (COX)-2 in ketamine-induced cystitis. Sprague-Dawley rats were distributed into three groups, which received saline or treatment with ketamine or ketamine combined with a Cox-2 inhibitor (parecoxib). In addition, the toxic effect of ketamine and its metabolites were examined by primary urothelial cell culture. The ketamine-treated group displayed bladder hyperactivity and decreased bladder capacity. Treatment with ketamine + COX-2 inhibitor prevented these bladder dysfunctions. These bladder dysfunctions were accompanied by increases in the expression of NF-κB and COX-2 at the protein and mRNA levels. Ketamine treatment also enhanced bladder interstitial fibrosis, whereas ketamine + Cox-2 inhibitor decreased the intensity of fibrosis. Treatment of primary urothelial cells in vitro with ketamine or urine obtained from ketamine-treated rats stimulated the expression of NF-κB p65 and COX-2. Ketamine also initiated NF-κB translocation from cell cytoplasm to nucleus. Treatment with NF-κB inhibitor suppressed Cox-2 mRNA expression. Promoter-deletion analysis revealed that NF-κB was a necessary transcription factor for COX-2 gene (Ptgs2) activation. These results demonstrate that the regulation of COX-2 via the NF-κB pathway is involved in the inflammatory signaling of ketamine-induced cystitis in rat urinary bladder. PMID:26073037

  16. Induction of apoptosis in renal cell carcinoma by reactive oxygen species: involvement of extracellular signal-regulated kinase 1/2, p38delta/gamma, cyclooxygenase-2 down-regulation, and translocation of apoptosis-inducing factor.

    LENUS (Irish Health Repository)

    Ambrose, Monica

    2012-02-03

    Renal cell carcinoma (RCC) is the most common malignancy of the kidney. Unfortunately, RCCs are highly refractory to conventional chemotherapy, radiation therapy, and even immunotherapy. Thus, novel therapeutic targets need to be sought for the successful treatment of RCCs. We now report that 6-anilino-5,8-quinolinequinone (LY83583), an inhibitor of cyclic GMP production, induced growth arrest and apoptosis of the RCC cell line 786-0. It did not prove deleterious to normal renal epithelial cells, an important aspect of chemotherapy. To address the cellular mechanism(s), we used both genetic and pharmacological approaches. LY83583 induced a time- and dose-dependent increase in RCC apoptosis through dephosphorylation of mitogen-activated protein kinase kinase 1\\/2 and its downstream extracellular signal-regulated kinases (ERK) 1 and -2. In addition, we observed a decrease in Elk-1 phosphorylation and cyclooxygenase-2 (COX-2) down-regulation. We were surprised that we failed to observe an increase in either c-Jun NH(2)-terminal kinase or p38alpha and -beta mitogen-activated protein kinase activation. In contradiction, reintroduction of p38delta by stable transfection or overexpression of p38gamma dominant negative abrogated the apoptotic effect. Cell death was associated with a decrease and increase in Bcl-x(L) and Bax expression, respectively, as well as release of cytochrome c and translocation of apoptosis-inducing factor. These events were associated with an increase in reactive oxygen species formation. The antioxidant N-acetyl l-cysteine, however, opposed LY83583-mediated mitochondrial dysfunction, ERK1\\/2 inactivation, COX-2 down-regulation, and apoptosis. In conclusion, our results suggest that LY83583 may represent a novel therapeutic agent for the treatment of RCC, which remains highly refractory to antineoplastic agents. Our data provide a molecular basis for the anticancer activity of LY83583.

  17. Cyclooxygenase-2 immunoreactivity in collagenous colitis

    DEFF Research Database (Denmark)

    Wildt, Signe; Rumessen, Jüri J; Csillag, Claudio;

    2009-01-01

    Collagenous colitis (CC) is an inflammatory bowel disease of unknown aetiology and pathogenesis. In ulcerative colitis and Crohn's disease, prostaglandins may be involved in the pathogenesis of inflammation, and increased expression of cyclo-oxygenase-2 (COX-2) has been detected. The purpose...... with samples from eight normal controls, and samples from eight patients with ulcerative colitis or Crohn's disease. Specimens from patients with CC expressed COX-2 protein in increased amounts compared with controls, but similar to patients with ulcerative colitis and Crohn's disease. COX-2 expression...

  18. Deletion of Protein Tyrosine Phosphatase 1B (PTP1B Enhances Endothelial Cyclooxygenase 2 Expression and Protects Mice from Type 1 Diabetes-Induced Endothelial Dysfunction.

    Directory of Open Access Journals (Sweden)

    David J Herren

    Full Text Available Protein tyrosine phosphatase 1B (PTP1B dephosphorylates receptors tyrosine kinase and acts as a molecular brake on insulin signaling pathway. Conditions of metabolic dysfunction increase PTP1B, when deletion of PTP1B protects against metabolic disorders by increasing insulin signaling. Although vascular insulin signaling contributes to the control of glucose disposal, little is known regarding the direct role of PTP1B in the control of endothelial function. We hypothesized that metabolic dysfunctions increase PTP1B expression in endothelial cells and that PTP1B deletion prevents endothelial dysfunction in situation of diminished insulin secretion. Type I diabetes (T1DM was induced in wild-type (WT and PTP1B-deficient mice (KO with streptozotocin (STZ injection. After 28 days of T1DM, KO mice exhibited a similar reduction in body weight and plasma insulin levels and a comparable increase in glycemia (WT: 384 ± 20 vs. Ko: 432 ± 29 mg/dL, cholesterol and triglycerides, as WT mice. T1DM increased PTP1B expression and impaired endothelial NO-dependent relaxation, in mouse aorta. PTP1B deletion did not affect baseline endothelial function, but preserved endothelium-dependent relaxation, in T1DM mice. NO synthase inhibition with L-NAME abolished endothelial relaxation in control and T1DM WT mice, whereas L-NAME and the cyclooxygenases inhibitor indomethacin were required to abolish endothelium relaxation in T1DM KO mice. PTP1B deletion increased COX-2 expression and PGI2 levels, in mouse aorta and plasma respectively, in T1DM mice. In parallel, simulation of diabetic conditions increased PTP1B expression and knockdown of PTP1B increased COX-2 but not COX-1 expression, in primary human aortic endothelial cells. Taken together these data indicate that deletion of PTP1B protected endothelial function by compensating the reduction in NO bioavailability by increasing COX-2-mediated release of the vasodilator prostanoid PGI2, in T1DM mice.

  19. o,p'-DDT induces cyclooxygenase-2 gene expression in murine macrophages: Role of AP-1 and CRE promoter elements and PI3-kinase/Akt/MAPK signaling pathways

    International Nuclear Information System (INIS)

    Dichlorodiphenyltrichloroethane (DDT) has been used as an insecticide to prevent the devastation of malaria in tropical zones. However, many reports suggest that DDT may act as an endocrine disruptor and may have possible carcinogenic effects. Cyclooxygenase-2 (COX-2) acts as a link between inflammation and carcinogenesis through its involvement in tumor promotion. In the present study, we examined the effect of o,p'-DDT on COX-2 gene expression and analyzed the molecular mechanism of its activity in murine RAW 264.7 macrophages. Exposure to o,p'-DDT markedly enhanced the production of prostaglandin E2 (PGE2), a major COX-2 metabolite, in murine macrophages. Furthermore, o,p'-DDT dose-dependently increased the levels of COX-2 protein and mRNA. Transfection with human COX-2 promoter construct, electrophoretic mobility shift assays and DNA-affinity protein-binding assay experiments revealed that o,p'-DDT activated the activator protein 1 (AP-1) and cyclic AMP response element (CRE) sites, but not the NF-κB site. Phosphatidylinositol 3 (PI3)-kinase, its downstream signaling molecule, Akt, and mitogen-activated protein kinases (MAPK) were also significantly activated by the o,p'-DDT-induced AP-1 and CRE activation. These results demonstrate that o,p'-DDT induced COX-2 expression via AP-1 and CRE activation through the PI3-K/Akt/ERK, JNK, and p38 MAP kinase pathways. These findings provide further insight into the signal transduction pathways involved in the carcinogenic effects of o,p'-DDT

  20. ETORICOXIB IS A NEW SELECTIVE CYCLOOXYGENASE-2 INHIBITOR

    Directory of Open Access Journals (Sweden)

    A E Karateev

    2009-01-01

    Full Text Available The paper provides the clinical characteristics of etoricoxib (Arcoxia, a new selective cyclooxygenase-2 inhibitor having unique properties, which permits it to be distinguished among other nonsteroidal anti-inflammatory agents.

  1. ETORICOXIB IS A NEW SELECTIVE CYCLOOXYGENASE-2 INHIBITOR

    Directory of Open Access Journals (Sweden)

    A E Karateev

    2009-06-01

    Full Text Available The paper provides the clinical characteristics of etoricoxib (Arcoxia, a new selective cyclooxygenase-2 inhibitor having unique properties, which permits it to be distinguished among other nonsteroidal anti-inflammatory agents.

  2. Pathologic Cellular Events in Smoking-Related Pancreatitis

    Energy Technology Data Exchange (ETDEWEB)

    Thrower, Edwin [Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520 (United States); Veterans Affairs Connecticut Healthcare, West Haven, CT 06516 (United States)

    2015-04-29

    Pancreatitis, a debilitating inflammatory disorder, results from pancreatic injury. Alcohol abuse is the foremost cause, although cigarette smoking has recently surfaced as a distinct risk factor. The mechanisms by which cigarette smoke and its toxins initiate pathological cellular events leading to pancreatitis, have not been clearly defined. Although cigarette smoke is composed of more than 4000 compounds, it is mainly nicotine and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which have been extensively studied with respect to pancreatic diseases. This review summarizes these research findings and highlights cellular pathways which may be of relevance in initiation and progression of smoking-related pancreatitis.

  3. Adiponectin Promotes Revascularization of Ischemic Muscle through a Cyclooxygenase 2-Dependent Mechanism ▿ †

    OpenAIRE

    Ohashi, Koji; Ouchi, Noriyuki; Sato, Kaori; Higuchi, Akiko; Ishikawa, Tomo-o; Herschman, Harvey R.; Kihara, Shinji; Walsh, Kenneth

    2009-01-01

    Adiponectin is a fat-derived plasma protein that has cardioprotective roles in obesity-linked diseases. Because cyclooxygenase 2 (COX-2) is an important modulator of endothelial function, we investigated the possible contribution of COX-2 to adiponectin-mediated vascular responses in a mouse hind limb model of vascular insufficiency. Ischemic insult increased COX-2 expression in endothelial cells of wild-type mice, but this induction was attenuated in adiponectin knockout mice. Ischemia-induc...

  4. The effect of risedronate on osteogenic lineage is mediated by cyclooxygenase-2 gene upregulation

    OpenAIRE

    Valenti, Maria Teresa; Giannini, Sandro; Donatelli, Luca; Zanatta, Mirko; Bertoldo, Francesco; Sella, Stefania; Vilei, Maria Teresa; Ossi, Elena; Realdi, Giuseppe; Lo Cascio, Vincenzo; Dalle Carbonare, Luca

    2010-01-01

    Introduction The purpose of this study was to evaluate the effects of risedronate (Ris) in the modulation of bone formation in rats with glucocorticoid (GC)-induced osteoporosis by histomorphometric, immunohistochemical and gene expression analyses. Methods We analyzed structure, turnover and microarchitecture, cyclooxygenase 2 (COX-2) levels and osteocyte apoptosis in 40 female rats divided as follows: 1) vehicle of methylprednisolone (vGC) + vehicle of risedronate (vRis); 2) Ris 5 μg/Kg + v...

  5. Inhibition of Cyclooxygenase-2 Prevents Chronic and Recurrent Cystitis

    Directory of Open Access Journals (Sweden)

    Thomas J. Hannan

    2014-11-01

    Full Text Available The spread of multidrug-resistant microorganisms globally has created an urgent need for novel therapeutic strategies to combat urinary tract infections (UTIs. Immunomodulatory therapy may provide benefit, as treatment of mice with dexamethasone during acute UTI improved outcome by reducing the development of chronic cystitis, which predisposes to recurrent infection. Here we discovered soluble biomarkers engaged in myeloid cell development and chemotaxis that were predictive of future UTI recurrence when elevated in the sera of young women with UTI. Translation of these findings revealed that temperance of the neutrophil response early during UTI, and specifically disruption of bladder epithelial transmigration of neutrophils by inhibition of cyclooxygenase-2, protected mice against chronic and recurrent cystitis. Further, proteomics identified bladder epithelial remodeling consequent to chronic infection that enhances sensitivity to neutrophil damage. Thus, cyclooxygenase-2 expression during acute UTI is a critical molecular trigger determining disease outcome and drugs targeting cyclooxygenase-2 could prevent recurrent UTI.

  6. Endoglin regulates cyclooxygenase-2 expression and activity.

    Science.gov (United States)

    Jerkic, Mirjana; Rivas-Elena, Juan V; Santibanez, Juan F; Prieto, Marta; Rodríguez-Barbero, Alicia; Perez-Barriocanal, Fernando; Pericacho, Miguel; Arévalo, Miguel; Vary, Calvin P H; Letarte, Michelle; Bernabeu, Carmelo; López-Novoa, Jose M

    2006-08-01

    The endoglin heterozygous (Eng(+/-)) mouse, which serves as a model of hereditary hemorrhagic telangiectasia (HHT), was shown to express reduced levels of endothelial NO synthase (eNOS) with impaired activity. Because of intricate changes in vasomotor function in the Eng(+/-) mice and the potential interactions between the NO- and prostaglandin-producing pathways, we assessed the expression and function of cyclooxygenase (COX) isoforms. A specific upregulation of COX-2 in the vascular endothelium and increased urinary excretion of prostaglandin E(2) were observed in the Eng(+/-) mice. Specific COX-2 inhibition with parecoxib transiently increased arterial pressure in Eng(+/-) but not in Eng(+/+) mice. Transfection of endoglin in L6E9 myoblasts, shown previously to stimulate eNOS expression, led to downregulation of COX-2 with no change in COX-1. In addition, COX-2 promoter activity and protein levels were inversely correlated with endoglin levels, in doxycyclin-inducible endothelial cells. Chronic NO synthesis inhibition with N(omega)-nitro-l-arginine methyl ester induced a marked increase in COX-2 only in the normal Eng(+/+) mice. N(omega)-nitro-l-arginine methyl ester also increased COX-2 expression and promoter activity in doxycyclin-inducible endoglin expressing endothelial cells, but not in control cells. The level of COX-2 expression following transforming growth factor-beta1 treatment was less in endoglin than in mock transfected L6E9 myoblasts and was higher in human endothelial cells silenced for endoglin expression. Our results indicate that endoglin is involved in the regulation of COX-2 activity. Furthermore, reduced endoglin levels and associated impaired NO production may be responsible, at least in part, for augmented COX-2 expression and activity in the Eng(+/-) mice. PMID:16840721

  7. Crystallization of recombinant cyclo-oxygenase-2

    Science.gov (United States)

    Stevens, Anna M.; Pawlitz, Jennifer L.; Kurumbail, Ravi G.; Gierse, James K.; Moreland, Kirby T.; Stegeman, Roderick A.; Loduca, Jina Y.; Stallings, William C.

    1999-01-01

    The integral membrane protein, prostaglandin H 2 synthase, or cyclo-oxygenase (COX), catalyses the first step in the conversion of arachidonic acid to prostaglandins (PGs) and is the target of nonsteroidal anti-inflammatory drugs (NSAIDs). Two isoforms are known. The constitutive enzyme, COX-1, is present in most tissues and is responsible for the physiological production of PGs. The isoform responsible for the elevated production of PGs during inflammation is COX-2 which is induced specifically at inflammatory sites. Three-dimensional structures of inhibitor complexes of COX-2, and of site variants of COX-2 which mimic COX-1, provide insight into the structural basis for selective inhibition of COX-2. Additionally, structures of COX-2 mutants and complexes with the substrate can provide a clearer understanding of the catalytic mechanism of the reaction. A crystallization protocol has been developed for COX-2 which reproducibly yields diffraction quality crystals. Polyethyleneglycol 550 monomethylether (MMP550) and MgCl 2 were systematically varied and used in conjunction with the detergent β- D-octylglucopyranoside ( β-OG). As a result of many crystallization trials, we determined that the initial β-OG concentration should be held constant, allowing the salt concentration to modulate the critical micelle concentration (CMC) of the detergent. Over 25 crystal structures have been solved using crystals generated from this system. Most crystals belong to the space group P2 12 12, with lattice constants of a=180, b=134, c=120 Å in a pseudo body-centered lattice.

  8. Cyclooxygenase-2 expression in oligodendrocytes increases sensitivity to excitotoxic death

    Directory of Open Access Journals (Sweden)

    Rojas Monica A

    2010-04-01

    Full Text Available Abstract Background We previously found that cyclooxygenase 2 (COX-2 was expressed in dying oligodendrocytes at the onset of demyelination in the Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD model of multiple sclerosis (MS (Carlson et al. J.Neuroimmunology 2006, 149:40. This suggests that COX-2 may contribute to death of oligodendrocytes. Objective The goal of this study was to examine whether COX-2 contributes to excitotoxic death of oligodendrocytes and potentially contributes to demyelination. Methods The potential link between COX-2 and oligodendrocyte death was approached using histopathology of MS lesions to examine whether COX-2 was expressed in dying oligodendrocytes. COX-2 inhibitors were examined for their ability to limit demyelination in the TMEV-IDD model of MS and to limit excitotoxic death of oligodendrocytes in vitro. Genetic manipulation of COX-2 expression was used to determine whether COX-2 contributes to excitotoxic death of oligodendrocytes. A transgenic mouse line was generated that overexpressed COX-2 in oligodendrocytes. Oligodendrocyte cultures derived from these transgenic mice were used to examine whether increased expression of COX-2 enhanced the vulnerability of oligodendrocytes to excitotoxic death. Oligodendrocytes derived from COX-2 knockout mice were evaluated to determine if decreased COX-2 expression promotes a greater resistance to excitotoxic death. Results COX-2 was expressed in dying oligodendrocytes in MS lesions. COX-2 inhibitors limited demyelination in the TMEV-IDD model of MS and protected oligodendrocytes against excitotoxic death in vitro. COX-2 expression was increased in wild-type oligodendrocytes following treatment with Kainic acid (KA. Overexpression of COX-2 in oligodendrocytes increased the sensitivity of oligodendrocytes to KA-induced excitotoxic death eight-fold compared to wild-type. Conversely, oligodendrocytes prepared from COX-2 knockout mice showed a

  9. Expression of Cyclooxygenase-2 in Ovarian Cancer Cell Lines

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    To investigate the expression of cyclooxygenase-2 (COX-2) in ovarian cancer cell lines,RT-PCR and immunocytochemistry were used to detect the expression of COX-2 in 5 ovarian cancer cell lines. The expression of COX-2 mRNA and protein was detected in all 5 cell lines. It is suggested that COX-2 is expressed in ovarian cancer cell lines, which provides a basis for the chemoprevention of ovarian cancer.

  10. Transcriptional activation of cyclooxygenase-2 by tumor suppressor p53 requires nuclear factor-kappaB

    OpenAIRE

    Benoit, Valérie; Moraes, E.; Dar, N A; Taranchon, E.; Bours, Vincent; Hautefeuille, A.; Taniere, P; Chariot, Alain; Scoazec, J Y; Gallo, C. V. D.; Merville, Marie-Paule; Hainaut, Pierre

    2006-01-01

    Overexpression of cyclooxygenase-2 (Cox-2) is thought to exert antiapoptotic effects in cancer. Here we show that the tumor suppressor p53 upregulated Cox-2 in esophageal and colon cancer cell lines by inducing the binding of nuclear factor-kappaB (NF-kappaB) to its response element in the COX-2 promoter. Inhibition of NF-kappaB prevented p53 induction of Cox-2 expression. Cooperation between p53 and NF-kappaB was required for activation of COX-2 promoter in response to daunomycin, a DNA-dama...

  11. Analysis of angiogenic factors and cyclooxygenase-2 expression in cartilaginous tumors: clinical and histological correlation

    Directory of Open Access Journals (Sweden)

    Francisco Fontes Cintra

    2011-01-01

    Full Text Available OBJECTIVES: To study the role of angiogenesis and cyclooxygenase-2 expression in cartilaginous tumors and correlate these factors with prognosis. INTRODUCTION: For chondrosarcoma, the histological grade is the current standard for predicting tumor outcome. However, a low-grade chondrosarcoma can follow an aggressive course-as monitored by sequential imaging techniques-even when it is histologically indistinguishable from an enchondroma. Therefore, additional tools are needed to help identify the biological potential of these tumors. The degree of angiogenesis that is induced by the tumor could assist in this task. Angiogenesis can be quantified by measuring the expression of vascular endothelial growth factor and CD34, and cyclooxygenase-2 can induce angiogenesis by stimulating the production of proangiogenic factors. METHODS: In total, 21 enchondromas and 58 conventional chondrosarcomas were studied by examining the clinical and histopathological findings in conjunction with the immunostaining markers of angiogenesis and cyclooxygenase- 2 expression. RESULTS: The significant variables that were associated with poor outcome were 1 higher-grade chondrosarcomas, 2 tumors that developed in flat bones, and 3 over-expression of CD34 (with a median count that was higher than 5.9 vessels in 5 high power fields. Moreover, CD34 expression (measured using the Chalkley method revealed significantly higher microvessel density in flat bone chondrosarcomas. DISCUSSION: Previous studies have shown a positive correlation between Chalkley microvessel density and histological grade; however, in our sample, we found that the former is predictive of the outcome. Chondrosarcomas in flat bones have been shown to correlate with a poor prognosis. We also found that CD34 microvessel density values were significantly higher in flat-bone chondrosarcomas. This could explain-at least in part-the more aggressive biological course that is taken by these tumors. CONCLUSIONS

  12. Effect of etoricoxib, a cyclooxygenase-2 selective inhibitor on aberrant crypt formation and apoptosis in 1,2 dimethyl hydrazine induced colon carcinogenesis in rat model Efecto del etoricoxib, un inhibidor selectivo de la ciclooxigenasa-2, sobre la formación de criptas aberrantes y la apoptosis en un modelo murino de carcinogénesis de colon inducidad por 1,2-dimetilhidracina

    OpenAIRE

    Sharma, P.; J Kaur; S. N. Sanyal

    2010-01-01

    Etoricoxib, a second generation selective cyclooxygenase-2 (COX-2) inhibitor had been studied for the chemopreventive response at its therapeutic anti-inflammatory dose in 1,2-dimethylhydrazine (DMH) induced colon carcinogenesis in rat model. Eight to ten weeks old male rats of Sprague-Dawley strain were divided into four groups. While group 1 served as control and received the vehicle of the drugs, group 2 and 3 were administered freshly prepared DMH in 1mM EDTA-saline (pH 7.0) (30 mg/kg bod...

  13. Mechanism underlying the reversal of contractility dysfunction in experimental colitis by cyclooxygenase-2 inhibition.

    Science.gov (United States)

    Khan, I; Oriowo, M A

    2006-03-01

    Inflammatory bowel diseases are associated with reduced colonic contractility and induction of cyclooxygenase-2. In this study a possible role of cyclooxygenase-2 in and the underlying mechanism of the reduced contractility were investigated in experimental colitis. The effects of meloxicam, a cyclooxygenase-2 selective inhibitor were examined on colonic contractility and MAP kinase p38 and ERK(1/2) expression. Colitis was induced in Sprague-Dawley male rats by intra-colonic instillation of trinitrobenzenesulphonic acid (TNBS; 40 mg/rat in 50 ethanol). The animals were divided into three groups. Group 1 (n=9) received meloxicam (3 mg/kg-day) gavage 1 h before and 1 day (Group 2) after induction of colitis. Group 3 (n=9) received phosphate buffered saline (PBS) in a similar manner and served as colitic control. The non colitic control animals received meloxicam in a similar manner. The animals were sacrificed after 5 days of treatment, colon was cleaned with PBS and colonic smooth muscle was obtained which was used in this study. Meloxicam treatment given 1 h before or 1 day after administration of colitis restored the reduced colonic contractility without affecting the sensitivity to carbachol. The levels of colonic smooth muscle IL-1beta mRNA, PGE(2), ERK(1/2), p38, malondialdehyde, myeloperoxidase activity and colonic mass were increased, whereas the body weight was decreased due to TNBS. The changes except colonic muscle mass and p38 expression were reversed by meloxicam treatment. These findings indicate that restoration of reduced colonic contractility by meloxicam is mediated by ERK(1/2), and that ERK(1/2) may serve as an important anti inflammatory target for treatment of colitis. PMID:16835710

  14. 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.

  15. Expression of cyclooxygenase-2 in human esophageal squamous cell carcinomas

    Institute of Scientific and Technical Information of China (English)

    Jian-Gang Jiang; Dao-Wen Wang; Jiang-Bo Tang; Chun-Lian Chen; Bao-Xing Liu; Xiang-Ning Fu; Zhi-Hui Zhu; Wei Qu; Katherine Cianflone; Michael P. Waalkes

    2004-01-01

    AIM: To determine whether cyclooxygenase-2 (COX-2) was expressed in human esophageal squamous cell carcinoma.METHODS: Quantitative reverse transcription-polymerase chain reaction (RT-PCR), western blotting, immunohistochemistry and immunofluorescence were used to assess the expression level of COX-2 in esophageal tissue.RESULTS: COX-2 mRNA levels were increased by >80-fold in esophageal squamous cell carcinoma when compared to adjacent noncancerous tissue. COX-2 protein was present in 21 of 30 cases of esophageal squamous cell carcinoma tissues, but was undetectable in noncancerous tissue. Immunohistochemistry was performed to directly show expression of COX-2 in tumor tissue.CONCLUSION: These results suggest that COX-2 may be an important factor for esophageal cancer and inhibition of COX-2 may be helpful for prevention and possibly treatment of this cancer.

  16. Targeting cyclooxygenase-2 in hematological malignancies: rationale and promise.

    Science.gov (United States)

    Bernard, M P; Bancos, S; Sime, P J; Phipps, R P

    2008-01-01

    There is much interest in the potential use of Cox-2 selective inhibitors in combination with other cancer therapeutics. Malignancies of hematopoietic and non-hematopoietic origin often have increased expression of cyclooxygenase-2 (Cox-2), a key modulator of inflammation. For example, hematological malignancies such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma and multiple myeloma often highly express Cox-2, which correlates with poor patient prognosis. Expression of Cox-2 enhances survival and proliferation of malignant cells, while negatively influencing anti-tumor immunity. Hematological malignancies expressing elevated levels of Cox-2 potentially avoid immune responses by producing factors that enhance angiogenesis and metastasis. Cellular immune responses regulated by natural killer cells, cytotoxic T lymphocytes, and T regulatory cells are also influenced by Cox-2 expression. Therefore, Cox-2 selective inhibitors have promising therapeutic potential in patients suffering from certain hematological malignancies.

  17. 环氧化酶2抑制剂对大鼠机械通气所致肺损伤肺水代谢的影响%Effect of cyclooxygenase 2 inhibitor on pulmonary water metabolism of ventilator-induced lung injury in rats

    Institute of Scientific and Technical Information of China (English)

    金立达; 王良荣; 熊响清; 林丽娜; 单鸳露

    2013-01-01

    Objective: To investigate the effect of cyclooxygenase 2 inhibitor on pulmonary water metabolism of ventilator-induced lung injury in rats. Methods: Thirty healthy adult male SD rats weighing 300-350 g were randomly divided into 3 groups (n =10 each): group TV (traditional tidal volume VT=8 mL/kg); group HV (high tidal volume VT=40 mL/kg) and group HV+NS398 (pretreated with NS398 8 mg/kg before ventilation). The animals were anesthe-tized with intraperitoneal 20% urethane 8 mL/kg, tracheotomized, intubated and mechanically ventilated for 4 h. Group HV+NS398 8 mg/kg was intraperitoneally injected at 30 min before mechanical ventilation. The animals were sacrificed at 4 h after mechanical ventilation. The lungs were removed for determination the concentration of protein in bronchoalveolar lavage fluid (BALF), TNF- a concentration, lung permeability index (LPI) and wet to dry weight ratio (W/D). Expression of aquaporin 1 (AQP1) and aquaporin 5 (AQP5) was analyzed with Western blot. Results: The BALF concentration of TNF-a and expression of AQP1 and AQP5 decreased significantly in group HV than that in group TV. The LPI and W/D were higher in group HV than that in group TV. Cyclooxygenase-2 inhibitor significantly attenuated the HV-induced changes listed above in group HV+NS398. Conclusion: Cyclooxygenase 2 inhibitor attenuates ventilation-induced lung injury in rats. Its mechanism may relate to upregulate expression of aquaporin 1 and aquaporin 5, strengthen the active reabsorption and exchange of fluid between alveolar space and alveolar epithelium barrier during edema in VILI.%目的:探讨环氧化酶2 (COX-2)抑制剂对大鼠机械通气所致肺损伤(VILI)肺水代谢的影响.方法:健康成年雄性SD大鼠30只,体质量300~ 350 g,随机分为3组(n=10),对照组(TV组,潮气量8 mL/kg)、机械通气肺损伤组(HV组,潮气量40 mL/kg)、NS398预处理组(HV+NS398组).NS398预处理组于机械通气前30 min腹腔注射COX-2抑制剂NS398 8 mg

  18. TTF-1 action on the transcriptional regulation of cyclooxygenase-2 gene in the rat brain.

    Directory of Open Access Journals (Sweden)

    Chang Ho Yun

    Full Text Available We have recently found that thyroid transcription factor-1 (TTF-1, a homeodomain-containing transcription factor, is postnatally expressed in discrete areas of the hypothalamus and closely involved in neuroendocrine functions. We now report that transcription of cyclooxygenase-2 (COX-2, the rate limiting enzyme in prostaglandin biosynthesis, was inhibited by TTF-1. Double immunohistochemistry demonstrated that TTF-1 was expressed in the astrocytes and endothelial cells of blood vessel in the hypothalamus. Promoter assays and electrophoretic mobility shift assays showed that TTF-1 inhibited COX-2 transcription by binding to specific binding domains in the COX-2 promoter. Furthermore, blocking TTF-1 synthesis by intracerebroventricular injection of an antisense oligomer induced an increase of COX-2 synthesis in non-neuronal cells of the rat hypothalamus, and resulted in animals' hyperthermia. These results suggest that TTF-1 is physiologically involved in the control of thermogenesis by regulating COX-2 transcription in the brain.

  19. Crystal structure of rofecoxib bound to human cyclooxygenase-2

    Energy Technology Data Exchange (ETDEWEB)

    Orlando, Benjamin J.; Malkowski, Michael G. (Buffalo)

    2016-10-26

    Rofecoxib (Vioxx) was one of the first selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) to be approved for use in humans. Within five years after its release to the public, Vioxx was withdrawn from the market owing to the adverse cardiovascular effects of the drug. Despite the widespread knowledge of the development and withdrawal of Vioxx, relatively little is known at the molecular level about how the inhibitor binds to COX-2. Vioxx is unique in that the inhibitor contains a methyl sulfone moiety in place of the sulfonamide moiety found in other coxibs such as celecoxib and valdecoxib. Here, new crystallization conditions were identified that allowed the structural determination of human COX-2 in complex with Vioxx and the structure was subsequently determined to 2.7- Å resolution. The crystal structure provides the first atomic level details of the binding of Vioxx to COX-2. As anticipated, Vioxx binds with its methyl sulfone moiety located in the side pocket of the cyclooxygenase channel, providing support for the isoform selectivity of this drug.

  20. 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.

  1. Cobalt Protoporphyrin Upregulates Cyclooxygenase-2 Expression Through a Heme Oxygenase-Independent Mechanism.

    Science.gov (United States)

    Lin, Hsiao-Yun; Tsai, Chon-Haw; Lin, Chingju; Yeh, Wei-Lan; Tsai, Cheng-Fang; Chang, Pei-Chun; Wu, Ling-Hsuan; Lu, Dah-Yuu

    2016-09-01

    Cobalt protoporphyrin (CoPP) is a potent HO-1 inducer and generally known to be an antioxidant in various cell types. Little is known about the CoPP-induced cyclooxygenase-2 (COX-2) expression and its downstream signaling in microglial cells. In current study, CoPP caused concentration- and time-dependent increases in COX-2 expression in microglial cells. Furthermore, activation of apoptosis signal-regulating kinase (ASK) 1/MAP kinase involved in CoPP-induced COX-2 expression in microglia. CoPP also induced P2X7 receptor activation, and treatment of P2X7 inhibitors effectively reduced CoPP-induced COX-2 expression. Protein inhibitor of activated STAT (PIAS) 1 is reported to be involved in modulating anti-inflammatory response through negative regulation of transcription factors. Interestingly, treatment with CoPP markedly induced PIAS1 degradation which is regulated by PI3K, Akt, and glycogen synthase kinase 3α/β (GSK3α/β) signaling pathways. These results suggest that CoPP induces COX-2 expression through activating P2X7 receptors and ASK1/MAP kinases as well as PIAS1 degradation signaling pathways. Our study provides a new insight into the regulatory effect of CoPP on neuroinflammation in microglial cells. PMID:26255181

  2. 低氧诱导因子-1α和环氧合酶-2在豚鼠银屑病样模型皮损中的表达及意义%Expression of hypoxia-inducible factor-1α and cyclooxygenase-2 in epidermis of guinea pig psoriasis-like animal model

    Institute of Scientific and Technical Information of China (English)

    于春水; 苏江维; 胡珍; 邓利丽; 熊芬

    2012-01-01

    Objective To study hypoxia-inducible factor-lα( HIF-1 ) and cyclooxygenase-2 ( Cox-2 ) expression in epidermis of guinea pig psoriasis-like animal model and their roles in the pathogenesis of psoriasis. Methods Psoriasis-like animal model was established by topical treatment with 5% propranolol emulsion on ear's back of guinea pig. We detected HIF-lα and Cox-2 in normal epidermal tissues from 20 normal guinea pig and the lesions of ear's back from guinea pig psoriasis-like animal model by in immunohistochemistry. Results Expression of HIF-1α and Cox-2 in lesions of treated group were significantly increased, while in normal epidermis there were no positive staining expression. Compared with the normal epidermis, the positive rate and the mean expression level of HIF-1α and Cox-2 in epidermis of guinea pig psoriasis-like animal model were significantly higher than those in the normal epidermal( P < 0. 05 ). Conclusions The expression of HIF-1α and Cox-2 in the epidermis of guinea pig psoriasis-like animal model were higher than normal epidermal. It has high concordance with human psoriatic lesions not only in histopathology, but also at molecular level.%目的 研究低氧诱导因子-1α(HIF-1α)和环氧合酶-2(COX-2)在豚鼠银屑病样动物模型皮损表皮中的表达,探讨其在银屑病发病机制的作用.方法 用5%普萘洛尔乳剂外涂豚鼠耳背部皮肤诱导银屑病样动物模型,应用免疫组化法检测正常豚鼠表皮和豚鼠银屑病样动物模型皮损表皮中HIF-1α和COX-2表达.结果 5%普萘洛尔外涂所致豚鼠银屑病样动物模型皮损中HIF-1α和COX-2表达水平较正常对照组明显增高,有显著性差异(P均<0.05).结论 HIF-1α和COX-2在豚鼠银屑病样动物模型皮损的表皮中表达明显增高,不仅在组织病理学而且在分子水平上与人类银屑病皮损基本一致.

  3. Induction of cyclooxygenase-2 by insulin in cultured rat vascular smooth muscle cells

    Institute of Scientific and Technical Information of China (English)

    LI Hong-tao; PAN Xiao-ming; FAN Min; WU Zong-gui; LU Hui-qi; TU Xiao-qing; GAO Chun-fang

    2004-01-01

    To evaluate cyclooxygenase-2 (COX-2) expression induced by insulin in cultured rat vascularmuscle smooth cells (VSMCs). Methods: The rat VSMCs were isolated and cultured in 60 mm plates, pre-treated with in-sulin 10, 100, 500, 1 000 mU/L for 6 h, and 100 mU/L for 3, 6, 12, and 24 h, respectively. RT-PCR was performed tomeasure COX-2 mRNA induction, and Western-blot was used to measure protein expression. In regard to the COX-2 enzymeactivity, after stimulation for a specified duration, the culture medium was collected; Prostaglandin E2 (PGE2) released byVSMCs was measured with an EIA kit. Results: Three hours after insulin (100 mU/L) stimulation, the induction of COX-2mRNA was detectable and increased with the time and dosage of insulin. Insulin induced COX-2 protein expression occurredin a time- and dose-dependent manner. In rat VSMCs, COX-2 induced by insulin resulted in PGE2 production, which wasincreased with insulin action. Conclusion: Insulin could induce COX-2 expression and PGE2 production in VSMCs in time-and dose-dependent manners.

  4. Novel anti-inflammatory chalcone derivatives inhibit the induction of nitric oxide synthase and cyclooxygenase-2 in mouse peritoneal macrophages.

    Science.gov (United States)

    Herencia, F; Ferrándiz, M L; Ubeda, A; Guillén, I; Dominguez, J N; Charris, J E; Lobo, G M; Alcaraz, M J

    1999-06-18

    In a previous work, we tested a series of chalcone derivatives as possible anti-inflammatory compounds. We now investigate the effects of three of those compounds, CHI, CH8 and CH12, on nitric oxide and prostanoid generation in mouse peritoneal macrophages stimulated with lipopolysaccharide and in the mouse air pouch injected with zymosan, where they showed a dose-dependent inhibition with inhibitory concentration 50% values in the microM range. This effect was not the consequence of a direct inhibitory action on enzyme activities. Our results demonstrated that chalcone derivatives inhibited de novo inducible nitric oxide synthase and cyclooxygenase-2 synthesis, being a novel therapeutic approach for inflammatory diseases.

  5. Cyclooxygenase-2 and Ki67 Expression in Oral Leukoplakia: a Clinicopathological Study

    OpenAIRE

    Alper Sinanoglu; Merva Soluk-Tekkesin; Vakur Olgac

    2015-01-01

    ABSTRACT Objectives Oral leukoplakia is a precancerous lesion of the oral mucosa. The upregulation of Ki67 and cyclooxygenase-2 has been reported in both dysplastic and non-dysplastic tissues. The aim of this clinicopathological study was to investigate the prognostic value of Ki67 and cyclooxygenase-2 expression for oral leukoplakia. Material and Methods A total of 50 samples were investigated and the study group consisted of 30 oral leukoplakia samples. Samples of 10 intact oral mucosa and ...

  6. Influenza A viruses suppress cyclooxygenase-2 expression by affecting its mRNA stability

    Science.gov (United States)

    Dudek, Sabine Eva; Nitzsche, Katja; Ludwig, Stephan; Ehrhardt, Christina

    2016-01-01

    Infection with influenza A viruses (IAV) provokes activation of cellular defence mechanisms contributing to the innate immune and inflammatory response. In this process the cyclooxygenase-2 (COX-2) plays an important role in the induction of prostaglandin-dependent inflammation. While it has been reported that COX-2 is induced upon IAV infection, in the present study we observed a down-regulation at later stages of infection suggesting a tight regulation of COX-2 by IAV. Our data indicate the pattern-recognition receptor RIG-I as mediator of the initial IAV-induced COX-2 synthesis. Nonetheless, during on-going IAV replication substantial suppression of COX-2 mRNA and protein synthesis could be detected, accompanied by a decrease in mRNA half-life. Interestingly, COX-2 mRNA stability was not only imbalanced by IAV replication but also by stimulation of cells with viral RNA. Our results reveal tristetraprolin (TTP), which is known to bind COX-2 mRNA and promote its rapid degradation, as regulator of COX-2 expression in IAV infection. During IAV replication and viral RNA accumulation TTP mRNA synthesis was induced, resulting in reduced COX-2 levels. Accordingly, the down-regulation of TTP resulted in increased COX-2 protein expression after IAV infection. These findings indicate a novel IAV-regulated cellular mechanism, contributing to the repression of host defence and therefore facilitating viral replication. PMID:27265729

  7. Exposure and Metabolic Activation Biomarkers of Carcinogenic Tobacco-Specific Nitrosamines.

    Science.gov (United States)

    Hecht, Stephen S; Stepanov, Irina; Carmella, Steven G

    2016-01-19

    Lung cancer is the leading cause of cancer death in the world, and cigarette smoking is its main cause. Oral cavity cancer is another debilitating and often fatal cancer closely linked to tobacco product use. While great strides have been made in decreasing tobacco use in the United States and some other countries, there are still an estimated 1 billion men and 250 million women in the world who are cigarette smokers and there are hundreds of millions of smokeless tobacco users, all at risk for cancer. Worldwide, lung cancer kills about three people per minute. This Account focuses on metabolites and biomarkers of two powerful tobacco-specific nitrosamine carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN), considered to be among the main causes of lung cancer and oral cavity cancer in people who use tobacco products. Three properties of NNK and NNN are critical for successful biomarker studies: they are present in all tobacco products, they are tobacco-specific and are not found in any other product, and they are strong carcinogens. NNK and NNN are converted in humans to urinary metabolites that can be quantified by mass spectrometry as biomarkers of exposure to these carcinogens. They are also metabolized to diazonium ions and related electrophiles that react with DNA to form addition products that can be detected and quantified by mass spectrometry. These urinary metabolites and DNA addition products can serve as biomarkers of exposure and metabolic activation, respectively. The biomarkers of exposure, in particular the urinary NNK metabolites 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides, have been extensively applied to document tobacco-specific lung carcinogen uptake in smokers and nonsmokers exposed to secondhand tobacco smoke. Highly sensitive mass spectrometric methods have been developed for quantitative analysis of these NNK metabolites as well as metabolites of NNN in human urine

  8. Exposure and Metabolic Activation Biomarkers of Carcinogenic Tobacco-Specific Nitrosamines.

    Science.gov (United States)

    Hecht, Stephen S; Stepanov, Irina; Carmella, Steven G

    2016-01-19

    Lung cancer is the leading cause of cancer death in the world, and cigarette smoking is its main cause. Oral cavity cancer is another debilitating and often fatal cancer closely linked to tobacco product use. While great strides have been made in decreasing tobacco use in the United States and some other countries, there are still an estimated 1 billion men and 250 million women in the world who are cigarette smokers and there are hundreds of millions of smokeless tobacco users, all at risk for cancer. Worldwide, lung cancer kills about three people per minute. This Account focuses on metabolites and biomarkers of two powerful tobacco-specific nitrosamine carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN), considered to be among the main causes of lung cancer and oral cavity cancer in people who use tobacco products. Three properties of NNK and NNN are critical for successful biomarker studies: they are present in all tobacco products, they are tobacco-specific and are not found in any other product, and they are strong carcinogens. NNK and NNN are converted in humans to urinary metabolites that can be quantified by mass spectrometry as biomarkers of exposure to these carcinogens. They are also metabolized to diazonium ions and related electrophiles that react with DNA to form addition products that can be detected and quantified by mass spectrometry. These urinary metabolites and DNA addition products can serve as biomarkers of exposure and metabolic activation, respectively. The biomarkers of exposure, in particular the urinary NNK metabolites 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides, have been extensively applied to document tobacco-specific lung carcinogen uptake in smokers and nonsmokers exposed to secondhand tobacco smoke. Highly sensitive mass spectrometric methods have been developed for quantitative analysis of these NNK metabolites as well as metabolites of NNN in human urine

  9. Exploring effect of cyclooxygenase-2 inhibitor on serum lipid profiles in collagen-induced arthritis model using shotgun lipidomics%基于鸟枪法脂质组学研究环氧酶-2抑制剂对关节炎模型血清脂代谢的干预作用

    Institute of Scientific and Technical Information of China (English)

    潘洁莉; 胡长锋; 韦双双; 陈娇; 周佳

    2016-01-01

    Rheumatoid arthritis( RA)is an inflammatory disease leading to joint swollen,pain and even deformity. Cardiovascular disease( CVD)is regarded as a major cause of morbidity in patients. Chronic systemic inflammation in patients is an independent CVD risk factor. Cycloox-ygenase-2( COX-2)inhibitor,a commonly used drug in the treatment of RA,can increase the risk of CVD. Lipid metabolic disorder is highly correlated with the occurrence of CVD,thus we investigated the serum lipid changes caused by RA and drug treatment to help to elucidate the mechanism of CVD in RA. Collagen-induced arthritis( CIA)is employed as a model of RA. After modeling,COX-2 inhibitor-meloxicam was orally administrated for three weeks,and the serum lipid profiles were analyzed by the multi-dimensional mass spectrometry-based shotgun lipido-mics(MDMS-SL). Totally 105 lipids were detected in serum,including 35 phosphatidylcholines ( PCs),18 lysophosphatidylcholines( LysoPCs),15 phosphatidyl inositols( PIs),3 phosphati-dyl glycerols( PGs),19 sphingomyelins( SMs)and 15 ceramides( Cers). In the principle com-ponent analysis,it was observed that the lipid profiles of CIA model rats were very different from those of the control rats,and the COX-2 inhibitor can improve the lipid metabolism partly. Further,ANOVA analysis revealed that 39 of the 105 identified lipids were up-regulated in CIA rats,including 7 PIs,15 SMs,5 Cers,10 PCs and 2 LysoPCs. Most of these lipids were down-regulated under the treatment of COX-2 inhibitor. In addition,the five PCs and one LysoPC were abnormally regulated by the drug. The MDMS-SL discovered lipid disturbance in CIA mod-el rats that might be related to risk factors of atherosclerosis;the COX-2 inhibitor can greatly repair the lipid disorder caused by modeling,while induce abnormal changes of some PCs and LysoPC which may cause side-effect.%心血管疾病( CVD)是类风湿关节炎( RA)患者死亡的重要原因之一,脂代谢紊乱与 CVD 发生有密

  10. The Impact of Clean Indoor Air Exemptions and Preemption Policies on the Prevalence of a Tobacco-Specific Lung Carcinogen Among Nonsmoking Bar and Restaurant Workers

    Science.gov (United States)

    Stark, Michael J.; Rohde, Kristen; Maher, Julie E.; Pizacani, Barbara A.; Dent, Clyde W.; Bard, Ronda; Carmella, Steven G.; Benoit, Adam R.; Thomson, Nicole M.; Hecht, Stephen S.

    2007-01-01

    Objectives. We studied the impact of clean indoor air law exemptions and preemption policies on the prevalence of a tobacco-specific lung carcinogen—4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)—among nonsmoking bar and restaurant workers. Methods.secondhand smoke were compared with results from participants who were exposed to it. Results. Participants exposed to workplace secondhand smoke were more likely to have any detectable level of NNAL (P=.005) and higher mean levels of NNAL (P < .001) compared with nonexposed participants. Increased levels of NNAL were also associated with hours of a single workplace exposure (P=.005). Conclusions. Nonsmoking employees left unprotected from workplace secondhand smoke exposure had elevated levels of a tobacco-specific carcinogen in their bodies. All workers—including bar and restaurant workers—should be protected from indoor workplace exposure to cancer-causing secondhand smoke. PMID:17600262

  11. Cyclooxygenase-2 inhibitor, celecoxib, inhibits leiomyoma cell proliferation through the nuclear factor κB pathway.

    Science.gov (United States)

    Park, Seung Bin; Jee, Byung Chul; Kim, Seok Hyun; Cho, Yeon Jean; Han, Myoungseok

    2014-09-01

    Our aim was to investigate whether celecoxib, a cyclooxygenase 2 (COX-2) inhibitor, decreases the in vitro proliferation of leiomyoma cells if the inflammatory pathway is blocked. Menstruation is an inflammation of uterus that produces cytokines and prostanoids, but the inflammatory mechanism underlying the growth of leiomyoma remains unexplained. Using in vitro cultures of leiomyoma cells obtained from 5 patients who underwent hysterectomy, cell proliferation, inflammatory signaling, transcription factors, growth factors, and extracellular matrix were examined by (4,5-dimethylthiaxol-2-yi)-2,5-diphenyltetraxolium bromide assay, immunoblotting, and quantitative polymerase chain reaction. Prostaglandin E2 was used to induce menstruation-like condition in the cells. We found that celecoxib inhibited COX-2 through the expression of nuclear factor κB in the cells. Celcoxib also decreased the gene expression of interleukin 6, tumor necrosis factor α, collagen A, fibronectin, platelet-derived growth factor, epidermal growth factor, and transforming growth factor β. In conclusion, the present study indicated that celecoxib could inhibit leiomyoma cell proliferation through blocking the inflammatory pathway that is probably one of the mechanisms underlying its pathogenesis.

  12. Transcriptional activation of cyclooxygenase-2 by tumor suppressor p53 requires nuclear factor-kappaB.

    Science.gov (United States)

    Benoit, V; de Moraes, E; Dar, N A; Taranchon, E; Bours, V; Hautefeuille, A; Tanière, P; Chariot, A; Scoazec, J-Y; de Moura Gallo, C V; Merville, M-P; Hainaut, P

    2006-09-21

    Overexpression of cyclooxygenase-2 (Cox-2) is thought to exert antiapoptotic effects in cancer. Here we show that the tumor suppressor p53 upregulated Cox-2 in esophageal and colon cancer cell lines by inducing the binding of nuclear factor-kappaB (NF-kappaB) to its response element in the COX-2 promoter. Inhibition of NF-kappaB prevented p53 induction of Cox-2 expression. Cooperation between p53 and NF-kappaB was required for activation of COX-2 promoter in response to daunomycin, a DNA-damaging agent. Pharmacological inhibition of Cox-2 enhanced apoptosis in response to daunomycin, in particular in cells containing active p53. In esophageal cancer, there was a correlation between Cox-2 expression and wild-type TP53 in Barrett's esophagus (BE) and in adenocarcinoma, but not in squamous cell carcinoma (P<0.01). These results suggest that p53 and NF-kappaB cooperate in upregulating Cox-2 expression, promoting cell survival in inflammatory precursor lesions such as BE. PMID:16682957

  13. Eugenol suppresses cyclooxygenase-2 expression in lipopolysaccharide-stimulated mouse macrophage RAW264.7 cells.

    Science.gov (United States)

    Kim, Sun Suk; Oh, O-Jin; Min, Hye-Young; Park, Eun-Jung; Kim, Youngleem; Park, Hyen Joo; Nam Han, Yong; Lee, Sang Kook

    2003-06-01

    Inducible cyclooxygenase (COX-2) has been implicated in the processes of inflammation and carcinogenesis. Thus, the potential COX-2 inhibitors have been considered as anti-inflammatory or cancer chemopreventive agents. In this study, the methanolic extract of the cortex of Eugenia caryophyllata Thunberg (Myrtaceae) was found to potently inhibit the prostaglandin E(2) production in lipopolysaccharide (LPS)-activated mouse macrophage RAW264.7 cells (98.3% inhibition at the test concentration of 10 microg/ml). Further, hexane-soluble layer was the most active partition compared to ethyl acetate, n-butanol, and water-soluble parts. By bioassay-guided fractionation of hexane-soluble partition, eugenol was isolated and exhibited a significant inhibition of PGE(2) production (IC(50) = 0.37 microM). In addition, eugenol suppressed the cyclooxygenase-2 (COX-2) gene expression in LPS-stimulated mouse macrophage cells. On the line of COX-2 playing an important role in colon carcinogenesis further study was designed to investigate the effect of eugenol on the growth and COX-2 expression in HT-29 human colon cancer cells. Eugenol inhibited the proliferation of HT-29 cells and the mRNA expression of COX-2, but not COX-1. This result suggests that eugenol might be a plausible lead candidate for further developing the COX-2 inhibitor as an anti-inflammatory or cancer chemopreventive agent.

  14. Elevated cyclooxygenase-2 expression correlates with diminished survival in carcinoma of the cervix treated with radiotherapy

    International Nuclear Information System (INIS)

    Purpose: The purpose of this study was to examine the relationship between overall survival and prognostic factors in carcinoma of the cervix treated with radiation therapy. A clinicopathologic study was performed on 24 patients. Methods and Materials: Formalin-fixed, paraffin-embedded tumor biopsies were stained for Cyclooxygenase-2 (COX-2), Topoisomerase I, Topoisomerase II, and p53. Clinical factors such as stage, grade, tumor size, pre- and post-treatment hemoglobin level, and radiotherapy dose were also evaluated. Results: Median follow-up was 75 months for living patients. The only immunohistochemical or clinical factor that was associated with improved survival was decreased COX-2 distribution staining. High COX-2 distribution staining was associated with decreased overall survival (p=0.021) and decreased disease-free survival (p=0.015) by log-rank comparison of Kaplan-Meier survival curves. The 5-year overall survival rates for tumors with low vs. high COX-2 distribution values were 75% and 35%, respectively. COX-2 staining intensity was found to correlate positively with tumor size (p=0.022). Conclusion: These findings indicate that increased expression of COX-2 portends a diminished survival in patients with invasive carcinoma of the cervix treated with radiotherapy. Because COX-2 is an early-response gene involved in angiogenesis and inducible by different stimuli, these data may indicate opportunity to intervene with specific inhibitors of COX-2 in carcinoma of the cervix

  15. 环氧化酶-2抑制剂帕瑞昔布对急性芬太尼诱导的大鼠痛觉过敏的抑制作用%The Inhibitant Effects Of Parecoxib, A Cyclooxygenase-2 Inhibitor, in Acute Fentanyl Induced Hyperalgesia in Rats

    Institute of Scientific and Technical Information of China (English)

    舒海华; 李桥波; 叶芳; 黄文起

    2015-01-01

    Objective To investigate the inhibitant effects of parecoxib, a cyclooxygenase-2 (COX-2) inhibitor, in acute fentanyl induced hyperalgesia in rats. Methods (1) Thirty SD rats (n=6 for each group) were subcutaneously injected with fentanyl (40 μg/kg × 4 times with a 15 min-interval) or saline to establish acute fentanyl induced hyperalgesia model, andparecoxib (5, 10 mg/kg) was administrated intraperitoneally in parecoxib group. Mechanical nociceptive thresholds were measured by the tail pressure test every hour during 1~4 hours and once a day during 1~5 days. (2) 24 SD rats (n = 6 foreach group) were subcutaneously injected with fentanyl as above described and randomly administrated intraperitoneally with parecoxib in 10 mg/kg in 15 min before and at the 4th hour and the 1st day after fentanyl injection except rats in the control group, mechanical nociceptive thresholds were measured by the tail pressure test at time points as above described. Results (1)Acute high dose fentanyl injection induced mechanical hyperalgesia and parecoxib (at 5 or 10 mg/kg)inhibited fentanyl induced hyperalgesia in rats. (2)Parecoxib inhibited fentanyl induced hyperalgesia at 15 min before and at the 4th hour after, but not on the 1st day after fentanyl injection. Conclusions This study provides the first evidence that subanalgesia doses of parecoxib had inhibitory effects on acute fentanyl induced hyperalgesia in time-dependent manners in rats.%目的:了解不同剂量和给药时间点下环氧化酶-2抑制剂帕瑞昔布对急性芬太尼诱导的大鼠机械痛觉过敏的作用。方法:(1)30只SD大鼠随机分为5组(n =6):生理盐水组、芬太尼组、芬太尼对照组、帕瑞昔布低剂量组和高剂量组,分别于皮下注射芬太尼或生理盐水,并在之前15 min腹腔内注射生理盐水或帕瑞昔布5或10 mg/kg,在芬太尼注射前、注射后第1~4小时每小时和第1~5天每天进行压尾测试

  16. A novel gliotic P2 receptor mediating cyclooxygenase-2 induction in rat and human astrocytes.

    Science.gov (United States)

    Brambilla, R; Ceruti, S; Malorni, W; Cattabeni, F; Abbracchio, M P

    2000-07-01

    In astrocytic cultures maintained in vitro, a brief challenge with the ATP analog alpha,beta methyleneATP (alpha,betameATP) results, 3 days later, in marked elongation of astrocytic processes, an event that resembles the astrocytic hypertrophy known to occur in vivo during reactive astrogliosis. alpha,beta meATP-induced effects were observed in primary astrocytes obtained from both rat striatum and cortex (a brain area highly involved in chronic neurodegenerative pathologies), as well as in human astrocytoma cells (ADF cells). Purine-induced gliosis could be reversed by the non-selective P2X/P2Y receptor antagonist pyridoxalphosphate-6-azophenyl-2', 4'-disulphonic acid (PPADS), but not by oxidized ATP (an antagonist of the P2X(7) receptor), in line with previous studies of our laboratory suggesting the involvement of a P2Y receptor subtype. Induction of reactive gliosis was preceded by increased expression of cyclooxygenase-2 (COX-2), an enzyme whose excessive activation has been implicated in both acute and chronic neurodegenerative diseases. The selective COX-2 inhibitor NS-398 prevented both purine-induced astrogliosis and the associated COX-2 induction, suggesting that inhibition of the transcription of the COX-2 gene may also contribute to the anti-inflammatory properties of this agent. Significant blockade of both alpha,beta meATP-mediated reactive gliosis and COX-2 induction was also observed with PPADS. These data suggest that COX-2 mediates P2Y receptor-induced reactive astrogliosis, and that antagonists selective for this receptor subtype may represent a novel class of anti-inflammatory agents of potential interest in acute and chronic neurological disorders characterized by an inflammatory component and reactive gliosis.

  17. Cyclooxygenase-2 expression in the normal human eye and its expression pattern in selected eye tumours

    DEFF Research Database (Denmark)

    Wang, Jinmei; Wu, Yazhen; Heegaard, Steffen;

    2011-01-01

    Purpose: Cyclooxygenase-2 (COX-2) is an enzyme involved in neoplastic processes. The purpose of the present study is to investigate COX-2 expression in the normal human eye and the expression pattern in selected eye tumours involving COX-2 expressing cells. Methods: Immunohistochemical staining...... using antibodies against COX-2 was performed on paraffin sections of normal human eyes and selected eye tumours arising from cells expressing COX-2. Results: Cyclooxygenase-2 expression was found in various structures of the normal eye. Abundant expression was seen in the cornea, iris, ciliary body...... and retina. The COX-2 expression was less in tumours deriving from the ciliary epithelium and also in retinoblastoma. Conclusion: Cyclooxygenase-2 is constitutively expressed in normal human eyes. The expression of COX-2 is much lower in selected eye tumours involving COX-2 expressing cells....

  18. Experimental observation of sodium arsenite induced cyclooxygenase 2 and prostaglandin E2 expression in non-tumorigenic human urothelial cells%亚砷酸钠诱导人膀胱上皮细胞环氧化酶2和前列腺素E2表达的实验观察

    Institute of Scientific and Technical Information of China (English)

    王惠惠; 席淑华; 王菲; 郑怡; 张强; 王达; 刘博莹; 刘盛男; 孙贵范

    2013-01-01

    目的 观察不同浓度亚砷酸钠(NaAsO2)对人膀胱上皮细胞(SV-HUC-1)环氧化酶2(COX-2)和前列腺素E2(PGE2)表达的诱导作用.方法 不同浓度NaAsO2[0(对照)、1、2、4、8、10 μmol/L]作用于SV-HUC-1细胞24h后,应用实时定量(RT)-PCR法检测SV-HUC-1细胞内COX-2 mRNA表达水平,酶联免疫吸附试验(ELISA)测定细胞培养液中PGE2含量.结果 与对照组(1.00±0.00)比较,2、4、8、10μmol/L NaAsO2 组SV-HUC-1细胞内COX-2 mRNA表达(1.73±0.25、245±0.23、1.94±0.71、1.75±0.43)明显升高(P均<0.05),并且4μmol/L NaAsO2组SV-HUC-1细胞内COX-2 mRNA表达达到最高;随NaAsO2浓度的增高,细胞培养液中PGE2含量呈升高趋势,表现为剂量反应关系,其中4、8、10 μmol/L NaAsO2组细胞培养液中PGE2含量[(9.59±1.27)、(10.40±2.19)、(12.93±1.33)ng/g]明显高于对照组[(6.64±1.46)ng/g,P均<0.05].结论 NaAsO2能够诱导SV-HUC-1细胞COX-2 mRNA表达和PGE2分泌.%Objective To study the expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2)induced by sodium arsenite(NaAsO2) in non-tumorigenic human urothelial cells(SV-HUC-1).Methods SV-HUC-1 cells were treated with different dose of NaAsO2[0(control),1,2,4,8,10 umol/L] and cultured for 24 h.The mRNA level of COX-2 in SV-HUC-1 cells was detected by RT-PCR.The PGE2 concentrations in cell-culture medium were analyzed by enzyme-linked immunosorbent assay(ELISA) kit.Results Compared with control group (1.00 + 0.00),COX-2 mRNA levels significantly increased in SV-HUC-1 cells in 2,4,8,10 μmol/L NaAsO2 exposed groups(1.73 ± 0.25,2.45 ± 0.23,1.94 ± 0.71,1.75 + 0.43,all P < 0.05).With NaAsO2 concentration increased,the level of PGE2 in the cell culture medium tended to increase,and it showed a significant doseresponse relationship.Compared with the control group[(6.64 ± 1.46)ng/g],PGE2 levels in culture medium of SV-HUC-1 cells significantly increased in 4,8,10 μmol/L NaAsO2 exposed groups [(9.59 ± 1.27),(10.40 ± 2

  19. Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice.

    Science.gov (United States)

    Motiño, Omar; Agra, Noelia; Brea Contreras, Rocío; Domínguez-Moreno, Marina; García-Monzón, Carmelo; Vargas-Castrillón, Javier; Carnovale, Cristina E; Boscá, Lisardo; Casado, Marta; Mayoral, Rafael; Valdecantos, M Pilar; Valverde, Ángela M; Francés, Daniel E; Martín-Sanz, Paloma

    2016-09-01

    Cyclooxygenase-2 (COX-2) is involved in different liver diseases but little is known about the significance of COX-2 in the development and progression of non-alcoholic steatohepatitis (NASH). This study was designed to elucidate the role of COX-2 expression in hepatocytes in the pathogenesis of steatohepatitis and hepatic fibrosis. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were either fed methionine-and-choline deficient (MCD) diet to establish an experimental non-alcoholic steatohepatitis (NASH) model or injected with carbon tetrachloride (CCl4) to induce liver fibrosis. In our animal model, hCOX-2-Tg mice fed MCD diet showed lower grades of steatosis, ballooning and inflammation than Wt mice, in part by reduced recruitment and infiltration of hepatic macrophages, with a corresponding decrease in serum levels of pro-inflammatory cytokines. Furthermore, hCOX-2-Tg mice showed a significant attenuation of the MCD diet-induced increase in oxidative stress and hepatic apoptosis observed in Wt mice. Even more, hCOX-2-Tg mice treated with CCl4 had significantly lower stages of fibrosis and less hepatic content of collagen, hydroxyproline and pro-fibrogenic markers than Wt controls. Collectively, our data indicates that constitutive hepatocyte COX-2 expression ameliorates NASH and liver fibrosis development in mice by reducing inflammation, oxidative stress and apoptosis and by modulating activation of hepatic stellate cells, respectively, suggesting a possible protective role for COX-2 induction in NASH/NAFLD progression. PMID:27321932

  20. Effects of cyclooxygenase-2 on sinusoidal capillarization in cirrhotic rats induced by carbon tetrachloride%环氧合酶-2在四氯化碳诱导肝硬化大鼠肝窦毛细血管化形成中的作用

    Institute of Scientific and Technical Information of China (English)

    涂传涛; 王吉耀; 郭津生

    2009-01-01

    目的 观察环氧合酶-2(COX-2)在实验性肝硬化大鼠肝窦毛细血管化形成中的作用.方法 腹腔注射CCl4每周2次共8周诱导雄性SD大鼠肝硬化模型.将SD大鼠分成3组:正常对照组(n=10)、模型对照组(n=15)和罗非昔布治疗组(10 mg·kg-1·d-1,n=15).光镜下观察肝组织标本,电镜观察肝窦超微结构改变.用Western印迹和免疫组化法检测基底膜蛋白主要成分层粘连蛋白(LN)和Ⅳ型胶原,同时通过Ⅷ因子相关抗原(vWF)免疫组化标记微血管牛成密度.结果 与模型对照组相比,罗非昔布干预治疗能减少肝纤维化面积(分别为30.7±8.9和23.5±6.5,P<0.05).光镜及电镜提示,在模型对照组可见肝窦内皮细胞窗孔减少、缩小,有完整的基底膜形成,Disse腔隙内有大量的胶原纤维沉积,罗非昔布组上述病变有所减轻.随着肝硬化的形成,肝组织微血管密度明显升高,罗非昔布组肝组织微血管密度(6.4±0.7)较模型对照组(11.3±1.6)明显降低(P<0.01).肝硬化时肝组织表达Ⅳ型胶原和LN蛋白明显增加(分别为3.8±0.4和3.7±0.5),罗非昔布能降低Ⅳ犁胶原和LN的表达(分别为3.0±0.5和3.0±0.5;与模型对照组相比两者均为Pcyclooxygenase-2 (COX-2) in sinusoidal capillarization in liver cirrhotic rats. Methods The SD rats were intraperitoneally injected with carbon tetrachloride (CCl4) twice a week for 8 weeks to induce liver cirrhosis. The rats were randomly divided into three groups: normal control group (n= 10), model control group (n= 15) and rofecoxib treated group (received 10 mg/kg of rofecoxib daily, n = 15). Liver histopathology was examined by light microscopy, and sinusoidal ultrastructure was observed by transmission electron microscopy. Furthermore, the level of basement membrane proteins (collagen type

  1. 薯蓣皂苷对胶原性关节炎模型大鼠环氧合酶2及NF-κB的抑制作用%Inhibitory effect of dioscin on cyclooxygenase-2 and NF-κB in collagen-induced arthritis rats

    Institute of Scientific and Technical Information of China (English)

    褚春民; 张洪泉; 卜平

    2013-01-01

    OBJECTIVE To investigate the inhibitory effects on cyclooxygenase-2 (COX-2) and NF-κB in collagen-induced arthritis (CIA) rats by dioscin.METHODS The CIA model rats were established by intradermal injecting chicken type Ⅱ collagen on the left hind toes of rats.The booster injection was carried out at the seventh day.Then each group was ig given dioscin 30,60 and 120 mg·kg-1 or indometacin 8 mg·kg-1 on the 12th day,for 14 d,respectively.The right hind paw volume of rats was examined just before medicine given and every 4 d after medicine given.The right hind paws of sacrified rats were taken to examine the change in histomorphology,and thymus and spleen indexes of CIA rats were measured.At the same time,the expressions of NF-κB p65 and COX-2 in synovium of ankle joints were examined by Western blotting,and the contents of tumor necrosis factor-α(TNF-α) and prostaglandin E2 (PGE2) in claws were detected by the radioimmunoassay.RESULTS Compared with normal control group,the tumefaction of right hind toes in CIA rats were significantly increased (P < 0.01),and infiltration of inflammatory cells and proliferation of the synovial cells were remarkably increased through pathological section analysis.The thymus index (TI) and spleen index (SI),the expression levels of NF-κB p65 and COX-2 in synovium of ankle joints and the contents of TNF-α and PGE2 in CIA rats were significantly increased (P < 0.01) compared with normal control group.Dioscin 60 and 120 mg·kg-1 could inhibit the tumefaction of digitipedis,ameliorate the pathological changes of the lesion significantly,lower the TI,decrease the expression levels of NF-κB p65 and COX-2 in synovium of ankle joints and the contents of TNF-α and PGE2 compared with CIA model group.CONCLUSION Dioscin can inhibit the inflammatoryreaction of CIA rats and decrease the expression of NF-κB p65 and COX-2,indicating that NF-κB p65 and COX-2 may be involved in the mechanism of dioscin.%目的 研究薯蓣皂苷对大

  2. 透骨消痛颗粒干预膝骨性关节炎早期环氧合酶2和诱导型一氧化氮合酶的表达%Expression of cyclooxygenase-2 and inducible nitric oxide synthase in primary knee osteoarthritis interfered by Tougu Xiaotong granules

    Institute of Scientific and Technical Information of China (English)

    刘伯龄; 梁珪清; 刘献祥; 吴广文; 李西海

    2011-01-01

    BACKGROUND: Mornda root, radix paeoniae alba from Hangzhou of China, zhongjiefeng, szechwan lovage rhizome composed of Tougu Xiaotong granule can effectively improve the symptoms of knee osteoarthritis (KOA), but the mechanism of it remains unclear.OBJECTIVE: To observe the effect of Tougu Xiaotong granule on primary knee osteoarthritis cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression.METHODS: A total of 90 New Zealand White rabbits were randomly divided into 6 groups: normal group, model group, Tougu Xiaotong granule low-dosage group, Tougu Xiaotong granule midst-dose group, Tougu Xiaotong granule high-dose group, and Zhuangguguanjie pill group. In addition to the normal group, osteoarthritis model was established by improved Hulth method in the other groups. Tougu Xiaotong granule low-dosage group, Tougu Xiaotong granule midst-dose group, Tougu Xiaotong granule high-dose group, and Zhuangguguanjie pill group was based on modeling treated with containing 5, 10, 20 g Tougu Xiaotong granule or Zhuangguguanjie aqueous solution of 10 g pill at every day, respectively. After 4 weeks, the level of nitrogen monoxidum (NO), NOS, and prostaglandin E2 (PGE2) in rabbit synovial fluid, articular cartilage, iNOS and COX-2 in synovium tissue was detected.RESULTS AND CONCLUSION: In the early stage of osteoarthritis, the level of NO, NOS, PGE2, and the expression of COX-2,iNOS in synovium and cartilage were higher than that in normal group. Tougu Xiaotong granule and Zhuangguguanjie pill can reduce the expression of NO, NOS, PGE2, and expression of COX-2 and iNOS in synovium and cartilage. Tougu Xiaotong granule midst-dose group and high-dose group have the most significant effects. It is indicated that Tougu Xiaotong granule can inhibit degradation of cartilage, release clinical sym ptoms to protect articular cartilage, prevent and cu re osteoarthritis by COX-2 and iNOS expression.%背景:由巴戟天、杭白芍、肿节风、川芎等组成的

  3. Cyclooxygenase-2 expression in the normal human eye and its expression pattern in selected eye tumours

    DEFF Research Database (Denmark)

    Wang, Jinmei; Wu, Yazhen; Heegaard, Steffen;

    2011-01-01

    and retina. The COX-2 expression was less in tumours deriving from the ciliary epithelium and also in retinoblastoma. Conclusion: Cyclooxygenase-2 is constitutively expressed in normal human eyes. The expression of COX-2 is much lower in selected eye tumours involving COX-2 expressing cells....

  4. Quercetin suppresses cyclooxygenase-2 expression and angiogenesis through inactivation of P300 signaling.

    Directory of Open Access Journals (Sweden)

    Xiangsheng Xiao

    Full Text Available Quercetin, a polyphenolic bioflavonoid, possesses multiple pharmacological actions including anti-inflammatory and antitumor properties. However, the precise action mechanisms of quercetin remain unclear. Here, we reported the regulatory actions of quercetin on cyclooxygenase-2 (COX-2, an important mediator in inflammation and tumor promotion, and revealed the underlying mechanisms. Quercetin significantly suppressed COX-2 mRNA and protein expression and prostaglandin (PG E(2 production, as well as COX-2 promoter activation in breast cancer cells. Quercetin also significantly inhibited COX-2-mediated angiogenesis in human endothelial cells in a dose-dependent manner. The in vitro streptavidin-agarose pulldown assay and in vivo chromatin immunoprecipitation assay showed that quercetin considerably inhibited the binding of the transactivators CREB2, C-Jun, C/EBPβ and NF-κB and blocked the recruitment of the coactivator p300 to COX-2 promoter. Moreover, quercetin effectively inhibited p300 histone acetyltransferase (HAT activity, thereby attenuating the p300-mediated acetylation of NF-κB. Treatment of cells with p300 HAT inhibitor roscovitine was as effective as quercetin at inhibiting p300 HAT activity. Addition of quercetin to roscovitine-treated cells did not change the roscovitine-induced inhibition of p300 HAT activity. Conversely, gene delivery of constitutively active p300 significantly reversed the quercetin-mediated inhibition of endogenous HAT activity. These results indicate that quercetin suppresses COX-2 expression by inhibiting the p300 signaling and blocking the binding of multiple transactivators to COX-2 promoter. Our findings therefore reveal a novel mechanism of action of quercetin and suggest a potential use for quercetin in the treatment of COX-2-mediated diseases such as breast cancers.

  5. The adverse effect of selective cyclooxygenase-2 inhibitor on random skin flap survival in rats.

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    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.

  6. Guggulsterone of Commiphora mukul resin reverses drug resistance in imatinib-resistant leukemic cells by inhibiting cyclooxygenase-2 and P-glycoprotein.

    Science.gov (United States)

    Xu, Hong-Bin; Xu, Lu-Zhong; Mao, Xia-Ping; Fu, Jun

    2014-06-15

    The purpose of this study was to investigate the effects of guggulsterone on cyclooxygenase-2 and P-glycoprotein mediated drug resistance in imatinib-resistant K562 cells (K562/IMA). MTT cytotoxicity assay, flow cytometry, western blot analysis, and ELISA were performed to investigate the anti-proliferative effect, the reversal action of drug resistance, and the inhibitory effect on cyclooxygenase-2, P-glycoprotein, BCR/ABL kinase, and PGE2 release in K562/IMA cells by guggulsterone. The results showed that co-administration of guggulsterone resulted in a significant increase in chemo-sensitivity of K562/IMA cells to imatinib, compared with imatinib treatment alone. Rhodamine123 accumulation in K562/IMA cells was significantly enhanced after incubation with guggulsterone (60, 120 μM), compared with untreated K562/IMA cells (pP-glycoprotein and prostaglandin E2. However, guggulsterone had little inhibitory effect on the activity of BCR/ABL kinase. The present study indicates guggulsterone induces apoptosis by inhibiting cyclooxygenase-2 and down-regulating P-glycoprotein expression in K562/IMA cells.

  7. Entamoeba histolytica: inflammatory process during amoebic liver abscess formation involves cyclooxygenase-2 expression in macrophages and trophozoites.

    Science.gov (United States)

    Gutiérrez-Alarcón, A; Moguel-Torres, M; Mata-Leyva, O; Cuellar-Nevárez, G; Siqueiros-Cendón, T; Erosa, G; Ramos-Martínez, E; Talamás-Rohana, P; Sánchez-Ramírez, B

    2006-11-01

    It has been demonstrated that expression of cyclooxygenase-2 (COX-2) isoform is induced by Entamoeba histolytica in macrophages and polymorphonuclear cells during amoebic liver abscess (ALA) formation in hamsters. Trophozoites present in the lesion were also positive for COX-2 signal. However, no cross reactivity of the anti-COX-2 antibody with protein extract of cultivated trophozoites was found. To clarify if trophozoites are involved in PGE(2) production during ALA development, COX-2 expression was detected by in situ hybridization and RT-PCR in liver tissue from intrahepatically infected hamsters. COX-2 mRNA was in polymorphonuclear cells since 4h postinfection, and subsequently, local macrophages expressed COX-2 mRNA in a similar way. Additionally, a positive signal for COX-2 mRNA expression was detected in E. histolytica trophozoites, suggesting that, in vivo, parasite COX expression may be an important mechanism to promote inflammation.

  8. Effects of cyclooxygenase-2 on human esophageal squamous cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    Li Zhang; Yong-Dong Wu; Peng Li; Jun Tu; Ying-Lin Niu; Cai-Min Xu; Shu-Tian Zhang

    2011-01-01

    AIM: To study the relationship between the cyclooxygenase (COX)-2 gene and the proliferation and apoptosis of esophageal squamous carcinoma EC109 cells.METHODS: The techniques of RNA interference (RNAi) and cell transfection, as well as the levels of oncogenicity in nude mice, were used to study the role of COX-2 in the esophageal squamous carcinoma cell (ESCC) line EC109. Following RNAi and transfection, Western blotting analysis was used to determine the expression of the COX-2 protein. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction assay was used to evaluate cell growth, and flow cytometry was used to detect cell apoptosis.RESULTS: Western blotting analysis demonstrated that COX-2 expression was significantly reduced in EC109 cells treated with COX-2-specific short interfering RNA (siRNA) but was increased in EC109 cells transfected with COX-2. Furthermore, COX-2 siRNA treatment inhibited cell proliferation (P < 0.01) and induced apoptosis in EC109 cells, as determined by an MTT assay and by flow cytometry, respectively. In contrast, transfected COX-2 led to increased cell proliferation (P < 0.05) and decreased apoptosis in EC109 cells. In addition, combination treatment of cells with COX-2 siRNA and aspirin had a synergistic effect (P < 0.01). For experiments measuring tumorigenicity, xenograft tumors of a greater volume and weight were found in the COX-2 group compared with other groups (P < 0.05). A large dose of aspirin inhibited tumor growth in nude mice effectively (P < 0.05), and the rate of tumor suppression was 51.8% in the high-dose aspirin group.CONCLUSION: COX-2 plays a very critical role in ESCC carcinogenesis, and COX-2 siRNA combined with aspirin has the potential to be an anticancer therapy for the treatment of ESCC.

  9. Comparative analysis of clinicopathological correlations of cyclooxygenase-2 expression in resectable pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Marketa; Hermanova; Petr; Karasek; Jiri; Tomasek; Jiri; Lenz; Jiri; Jarkovsky; Petr; Dite

    2010-01-01

    AIM:To perform a comparative analysis of clinicopathological correlations of cyclooxygenase2 (COX2) expression in pancreatic cancer, examined by monoclonal and polyclonal antibodies.METHODS: The COX2 expression in 85 resection specimens of pancreatic ductal adenocarcinoma was immunohistochemically examined using both monoclonal and polyclonal antibodies. The final immunoscores were obtained by multiplying the percentage of positive cells with the numeric score reflecting the staining intensity.COX2 expressi...

  10. Cyclooxygenase-2 Inhibition Restored Endothelium-Mediated Relaxation in Old Obese Zucker Rat Mesenteric Arteries

    OpenAIRE

    EricJ Belin De Chantemèle; Anne-LaureGuihot; DanielHenrion

    2010-01-01

    Metabolic syndrome is associated with reduced endothelial vasodilator function. It is also associated with the induction of cyclooxygenase-2 (COX2), which produces vasoactive prostanoids. The frequency of metabolic syndrome increases with age and aging per se is a risk factor associated with reduced endothelium-mediated relaxation. Nevertheless, the combined effect of aging and metabolic syndrome on the endothelium is less known. We hypothesized that COX2 derived prostanoids may affect endoth...

  11. Inhibition of Bacterial Multidrug Resistance by Celecoxib, a Cyclooxygenase-2 Inhibitor▿

    OpenAIRE

    Kalle, Arunasree M.; Rizvi, Arshad

    2010-01-01

    Multidrug resistance (MDR) is a major problem in the treatment of infectious diseases and cancer. Accumulating evidence suggests that the cyclooxygenase-2 (COX-2)-specific inhibitor celecoxib would not only inhibit COX-2 but also help in the reversal of drug resistance in cancers by inhibiting the MDR1 efflux pump. Here, we demonstrate that celecoxib increases the sensitivity of bacteria to the antibiotics ampicillin, kanamycin, chloramphenicol, and ciprofloxacin by accumulating the drugs ins...

  12. Cyclooxygenase-2 Expression in Non-Small Cell Lung Cancer Correlates With Hypertrophic Osteoarthropathy.

    Science.gov (United States)

    Rotas, Ioannis; Cito, Giovanni; Letovanec, Igor; Christodoulou, Michel; Perentes, Jean Y

    2016-02-01

    Hypertrophic osteoarthrpathy (HO) is a rare paraneoplasic syndrome associated with non-small cell lung cancer (NSCLC). The pathophysiology of HO is unknown but was recently related to enhanced levels of urine prostaglandin E2 (PGE2). Here, we report the case of a patient that presented HO in association with a resectable left upper lobe NSCLC. Following surgery and adjuvant chemotherapy, HO resolved and did not recur with development of a brain metastasis 1 year later. Interestingly, tumor cyclooxygenase-2, an enzyme responsible the synthesis of PGE2, was expressed in the primary tumor but not in the resected metastasis. PMID:26777972

  13. Anti-inflammatory effects of essential oils from Chamaecyparis obtusa via the cyclooxygenase-2 pathway in rats.

    Science.gov (United States)

    An, Beum-Soo; Kang, Ji-Houn; Yang, Hyun; Jung, Eui-Man; Kang, Hong-Seok; Choi, In-Gyu; Park, Mi-Jin; Jeung, Eui-Bae

    2013-07-01

    Essential oils are concentrated hydrophobic liquids containing volatile aromatic compounds from plants. In the present study, the essential oil of Chamaecyparis obtusa (C. obtusa), which is commercially used in soap, toothpaste and cosmetics, was extracted. Essential oil extracted from C. obtusa contains several types of terpenes, which have been shown to have anti-oxidative and anti-inflammatory effects. In the present study, we examined the anti-inflammatory effects of C. obtusa essential oil in vivo and in vitro following the induction of inflammation by lipopolysaccharides (LPS) in rats. While LPS induced an inflammatory response through the production of prostaglandin E2 (PGE2) in the blood and peripheral blood mononuclear cells (PMNCs), these levels were reduced when essential oil was pre-administered. Additionally, the mechanism of action underlying the anti-inflammatory effects of C. obtusa essential oil was investigated by measuring the mRNA expression of inflammation‑associated genes. LPS treatment significantly induced the expression of transforming growth factor α (TNFα) and cyclooxygenase-2 (COX-2) in rats, while C. obtusa essential oil inhibited this effect. Taken together, our results demonstrate that C. obtusa essential oil exerts anti‑inflammatory effects by regulating the production of PGE2 and TNFα gene expression through the COX-2 pathway. These findings suggest that C. obtusa essential oil may constitute a novel source of anti-inflammatory drugs.

  14. Uteroplacental insufficiency alters nephrogenesis and downregulates cyclooxygenase-2 expression in a model of IUGR with adult-onset hypertension.

    Science.gov (United States)

    Baserga, Mariana; Hale, Merica A; Wang, Zheng Ming; Yu, Xing; Callaway, Christopher W; McKnight, Robert A; Lane, Robert H

    2007-05-01

    Clinical and animal studies indicate that intrauterine growth restriction (IUGR) following uteroplacental insufficiency (UPI) reduces nephron number and predisposes toward renal insufficiency early in life and increased risk of adult-onset hypertension. In this study, we hypothesized that the inducible enzyme cyclooxygenase-2 (COX-2), a pivotal protein in nephrogenesis, constitutes a mechanism through which UPI and subsequent glucocorticoid overexposure can decrease nephron number. We further hypothesized that UPI downregulates the key enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which converts corticosterone to inert 11-dehydrocorticosterone, thereby protecting both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) from the actions of corticosterone. Following bilateral uterine ligation on the pregnant rat, UPI significantly decreased renal COX-2, 11beta-HSD2, and GR mRNA and protein levels, but upregulated expression of MR at birth. At day 21 of life, 11beta-HSD2, GR, and also MR mRNA and protein levels were downregulated. UPI did not affect blood pressures (BP) at day 21 of life but significantly increased systolic BP in both genders at day 140. We conclude that in our animal model, UPI decreases fetal COX-2 expression during a period of active nephrogenesis in the IUGR rat, which is also characterized by decreased nephron number and adult-onset hypertension. PMID:17272666

  15. Suppression of cyclooxygenase-2 gene transcription by humulon of beer hop extract studied with reference to glucocorticoid.

    Science.gov (United States)

    Yamamoto, K; Wang, J; Yamamoto, S; Tobe, H

    2000-01-14

    In murine osteoblastic MC3T3-E1 cells which produced prostaglandin E2 as a bone resorption factor, the cyclooxygenase-2 induction by tumor necrosis factor alpha (TNFalpha) was suppressed by dexamethasone with an IC(50) of 1 nM. Humulon isolated from hop extract for beer brewing was reported previously as an inhibitor of bone resorption [Tobe, H. et al. (1997) Biosci. Biotech. Biochem. 61, 158-159]. We showed that the compound suppressed the TNFalpha-dependent cyclooxygenase-2 induction with an IC(50) of as low as about 30 nM as demonstrated experimentally by catalytic activity assay, Northern blot analysis and promoter analysis. Reporter gene experiments suggested that humulon blocked the cyclooxygenase-2 expression mediated by NFkappaB and NF-IL6, but the intracellular glucocorticoid receptor was not involved. The catalytic activity of cyclooxygenase-2 was inhibited by humulon with an IC(50) of as high as 1.6 microM. These results showed that humulon suppressed cyclooxygenase-2 induction at the step of transcription.

  16. Regulation of cyclooxygenase-2 expression by heat: a novel aspect of heat shock factor 1 function in human cells.

    Directory of Open Access Journals (Sweden)

    Antonio Rossi

    Full Text Available The heat-shock response, a fundamental defense mechanism against proteotoxic stress, is regulated by a family of heat-shock transcription factors (HSF. In humans HSF1 is considered the central regulator of heat-induced transcriptional responses. The main targets for HSF1 are specific promoter elements (HSE located upstream of heat-shock genes encoding cytoprotective heat-shock proteins (HSP with chaperone function. In addition to its cytoprotective function, HSF1 was recently hypothesized to play a more complex role, regulating the expression of non-HSP genes; however, the non-canonical role of HSF1 is still poorly understood. Herein we report that heat-stress promotes the expression of cyclooxygenase-2 (COX-2, a key regulator of inflammation controlling prostanoid and thromboxane synthesis, resulting in the production of high levels of prostaglandin-E(2 in human cells. We show that heat-induced COX-2 expression is regulated at the transcriptional level via HSF1-mediated signaling and identify, by in-vitro reporter gene activity assay and deletion-mutant constructs analysis, the COX-2 heat-responsive promoter region and a new distal cis-acting HSE located at position -2495 from the transcription start site. As shown by ChIP analysis, HSF1 is recruited to the COX-2 promoter rapidly after heat treatment; by using shRNA-mediated HSF1 suppression and HSE-deletion from the COX-2 promoter, we demonstrate that HSF1 plays a central role in the transcriptional control of COX-2 by heat. Finally, COX-2 transcription is also induced at febrile temperatures in endothelial cells, suggesting that HSF1-dependent COX-2 expression could contribute to increasing blood prostaglandin levels during fever. The results identify COX-2 as a human non-classical heat-responsive gene, unveiling a new aspect of HSF1 function.

  17. Immunoexpression of cyclooxygenase-2 in primary gastric carcinomas and lymph node metastases

    Institute of Scientific and Technical Information of China (English)

    Paulo RC Almeida; Francisco VA Ferreira; Cássio C Santos; Francisco D Rocha-Filho; Raul RP Feitosa; Esther AA Falc(a)o; Belise K Cavada; Roberto CP Lima-Júnior; Ronaldo A Ribeiro

    2012-01-01

    AIM:To evaluate immunoexpression of cyclooxygenase-2 (COX-2) in primary gastric carcinomas and respective lymph node metastases.METHODS:Immunohistochemistry to analyze COX-2 expression was performed on tissue microarray slices obtained from 36 specimens of gastrectomy and satellite lymph nodes from patients with gastric carcinoma.RESULTS:Immunostaining was seen in most cases,and COX-2 expression was higher in lymph node metastases than in corresponding primary gastric tumors of intestinal,diffuse and mixed carcinomas,with a statistically significant difference in the diffuse histotype (P=0.0108).CONCLUSION:COX-2 immunoexpression occurs frequently in primary gastric carcinomas,but higher expression of this enzyme is observed in lymph node metastases of the diffuse histotype.

  18. UP-REGULATION OF CYCLOOXYGENASE-2 GENE EXPRESSION CORRELATES WITH TUMOR ANGIOGENESIS IN HUMAN BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    代志军; 王西京; 刘小旭; 康华峰; 姜建涛; 管海涛; 张淑群; 薛兴欢; 薛锋杰

    2003-01-01

    Objective: To study the relationship between cyclooxygenase-2 (COX-2) expression and tumor angiogenesis in human breast cancer. Methods: Archival primary breast carcinomas (n = 62), adjacent ductal carcinoma in situ (DCIS, n = 13) and DCIS alone (n = 5) were analyzed for COX-2 and VEGF expression by immunohistochemistry using specific monoclonal antibodies. Microvessel density (MVD) was also examined the using CD34 staining. Results: A significant correlation was found between COX-2 and VEGF expression (P<0.01). Both COX-2 and VEGF were significantly correlated with MVD (P<0.05) and P<0.01, respectively). COX-2 and VEGF genes were overexpressed in tumor specimens as compared with normal epithelia. Conclusion: COX-2 is related to tumor angiogenesis in breast cancer. It is likely that VEGF is one of the most important mediators of the COX-2 angiogenic pathway.

  19. O-desmethylquinine as a cyclooxygenase-2 (COX-2) inhibitors using AutoDock Vina

    Science.gov (United States)

    Damayanti, Sophi; Mahardhika, Andhika Bintang; Ibrahim, Slamet; Chong, Wei Lim; Lee, Vannajan Sanghiran; Tjahjono, Daryono Hadi

    2014-10-01

    Computational approach was employed to evaluate the biological activity of novel cyclooxygenase-2 COX-2 inhibitor, O-desmethylquinine, in comparison to quinine as common inhibitor which can also be used an agent of antipyretic, antimalaria, analgesic and antiinflamation. The molecular models of the compound were constructed and optimized with the density function theory with at the B3LYP/6-31G (d,p) level using Gaussian 09 program. Molecular docking studies of the compounds were done to obtain the COX-2 complex structures and their binding energies were analyzed using the AutoDock Vina. The results of docking of the two ligands were comparable and cannot be differentiated from the energy scoring function with AutoDock Vina.

  20. Premedication with cyclooxygenase-2 inhibitor meloxicam reduced postoperative pain in patients after oral surgery.

    Science.gov (United States)

    Aoki, T; Yamaguchi, H; Naito, H; Shiiki, K; Izawa, K; Ota, Y; Sakamoto, H; Kaneko, A

    2006-07-01

    The efficacy of the selective cyclooxygenase-2 (COX-2) inhibitor meloxicam for treatment of postoperative oral surgical pain was assessed in a randomized controlled trial. Patients undergoing unilateral mandibular 3rd molar extraction surgery were allocated to 3 groups, A, B and C. After oral premedication of meloxicam 10 mg in group A, ampiroxicam 27 mg in group B and placebo in group C, surgery was completed within 30 min under local anaesthesia using 2% lidocaine. For postoperative pain relief the patients were allowed to take oral loxoprofen (60 mg per tablet). Postoperative pain was evaluated at the clinic on the 1st, 7th and 14th postoperative day (POD) using a visual analogue scale (VAS), as was the number of loxoprofen tablets consumed, and the results were compared among the 3 groups with statistical significance of Psurgery and 1 POD was significantly lower in group A than in group C (Psurgery. PMID:16540287

  1. Antitumor activity of the selective cyclooxygenase-2 inhibitor, celecoxib, on breast cancer in Vitro and in Vivo

    Directory of Open Access Journals (Sweden)

    Dai Zhi-Jun

    2012-12-01

    Full Text Available Abstract Background Cyclooxygenase-2(COX-2 promotes carcinogenesis, tumor proliferation, angiogenesis, prevention of apoptosis, and immunosuppression. Meanwhile, COX-2 over-expression has been associated with tumor behavior and prognosis in several cancers. This study investigated the antitumor effects of the selective COX-2 inhibitor, Celecoxib, on breast cancer in vitro and in vivo. Methods Human breast cancer MCF-7 and MDA-MB-231 cells were cultured with different concentration (10, 20, 40 μmol/L of celecoxib after 0-96 hours in vitro. MTT assay was used to determine the growth inhibition of breast cancer cells in vitro. The expression of COX-2 on mRNA was measured by real-time quantitive PCR analysis. Flow cytometry was performed to analyze the cell cycle of MCF-7 cells. Levels of PGE2 were measured by ELISA method. The in vivo therapeutic effects of celecoxib were determined using rat breast cancer chemically induced by 7,12-dimethylben anthracene (DMBA. Results The inhibition of proliferation of both MCF-7 and MDA-MB-231 cells in vitro by celecoxib was observerd in time and dose dependent manner. Celecoxib effectively down-regulated the expression of COX-2. The cell cycle was arrested at G0/G1, and rate of cells in S phase was obviously decreased. Levels of PGE2 were inhibited by Celecoxib. The tumor incidence rate of the celecoxib group was lower than that of the control group. In addition, the tumor latency period of the celecoxib group was longer than that of the control group. Conclusions Celecoxib inhibited the proliferation of breast cancer cell lines in vitro, and prevented the occurrence of rat breast cancer chemically induced by DMBA. Therefore, celecoxib exhibits an antitumor activity and seems to be effective in anti-tumor therapy.

  2. Vascular endothelial growth factor and not cyclooxygenase 2 promotes endothelial cell viability in the pancreatic tumor microenvironment.

    LENUS (Irish Health Repository)

    Toomey, Desmond P

    2010-07-01

    Cyclooxygenase 2 (COX-2) and vascular endothelial growth factor (VEGF), often coexpressed in cancer, are associated with poor prognosis. However, results from pancreatic cancer trials of their inhibitors were disappointing. This study delineated the role of COX-2 and nonsteroidal anti-inflammatory drugs in angiogenesis and VEGF regulation.

  3. Exacerbation of inflammatory bowel disease by nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors:Fact or fiction?

    Institute of Scientific and Technical Information of China (English)

    Mario Guslandi

    2006-01-01

    The existence of a possible link between inflammatory bowel disease (IBD) and nonsteroidal anti-inflammatory drugs (NSAIDs) has been repeatedly suggested. Recently, a few studies have addressed the issue of a possible,similar effect by selective cyclooxygenase-2 inhibitors (COXIBs). The present article reviews the available scientific evidence for this controversial subject.

  4. Cyclooxygenase 2 and neuronal nitric oxide synthase expression in the renal cortex are not interdependent in states of salt deficiency

    DEFF Research Database (Denmark)

    Castrop, H; Kammerl, M; Mann, Birgitte;

    2000-01-01

    Neuronal nitric oxide synthase (nNOS) and cyclooxygenase-2 (COX-2) expression in the kidney are localized to the cortical thick ascending limb of the loop of Henle (cTALH), including the macula region, and increase after salt restriction. Because of the similar localization and regulation of n...

  5. 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

  6. Expression of Cyclooxygenase 2 and p-53 and their Relation with 5 Years Survival in Hodgkin's Lymphoma

    Directory of Open Access Journals (Sweden)

    E. Abdoli

    2012-07-01

    Full Text Available Introduction & Objective: Hodgkin lymphoma accounts for about 1% of all cancers. Cyclooxygenase 2 (COX2 is a cytoplasmic enzyme. Oncogene, and growth factor induce over expression of COX2. COX2 is apoptotic inhibitor. Mutation of the p53 tumor suppressor gene represents the most common genetic alternation in human tumors. This study aimed to evaluate the expression of COX2 and p53 in subtypes of Hodgkin's lymphoma.Materials & Methods: In this cross- sectional study,62 Hodgkin's lymphomas were studied in admitted samples of pathology departments of Hamadan hospitals before 2005.Age,sex and type of HL were recorded in each case. p53 and COX2 expression was investigated immunohistochemically and expression intensity. The comparison of p53 and COX2 between subtypes of HL was evaluated with SPSS v13 soft ware and chi-square test.Results: The mean age of the patients of HL was 41±16 and 79% if HL immunoreactive for p53. In this study the mean age of the patients of HL who died was more than the mean age of the patients of HL who survived which is statistically considered significant (P<0.003. 24% of the patients of HL were immunoreactive for COX2.Conclusion: Regarding to p53 and COX2 in subtypes of HL and insignificant difference in p53 and COX2 expression between subtypes of HL. We concluded that p53 and COX2 have not an important role in the prognosis of HL, but it is recommended to do more universal studies in the immunohistochemical level of P53 and COX2 to attain perfect results.(Sci J Hamadan Univ Med Sci 2012;19(2:34-38

  7. Expression of cyclooxygenase-2 and its pathogenic effects in nonalcoholic fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    Mingbo Cao; Lei Dong; Xiaolan Lu; Jinyan Luo

    2008-01-01

    Objective:To investigate the expression of cyclooxygenase-2 and its pathological effect in the experimental nonalcoholic fatty fiver of rats, and to explore its possible mechanism. Methods:The rat NAFLD model was established by giving a fat-enriched diet. The blood samples were obtained form abdominal aorta and the levels of serum ALT, AST and IL-1, changes in the hepatic tissue 6-k-PGF1 α TXB2 were measured. The expression level of COX-2 in rats livers were assayed by immunohistochemistry, RT-PCR and Western-blot. Results: Light microscope analysis revealed that hepatocytes were injured in the model group and slightly in the treatment group. The levels of serum TXB2 and IL-1 in the fatty liver rats were increased. Compared with the model group, the IL-] and TXB2 increased significantly(P<0.05), on the contrary, compared with the normal group, the hepatic tissue 6-Keto-prostagland decreased significantly in the model group(P<0.05), the treatment group also increased but P>0.05. There was no positive expression of COX-2 in hepatic tissue of normal rats. In the model group, there was positive expression of COX-2 antigen and the number of COX positive cells progressively increased at 4, 8, 12 wks. The intensity of expression of COX-2 had significantly increased(P<0.05) and the intensity of COX-2 expression in the treated group decreased remarkably compared with the model group(P < 0.05). The expression of COX-2 mRNA and the level of COX-2 protein were significantly stronger in the liver of model rats compared with normal rats, and significantly weaker in treated rats, than in 8W and 12W model rats(P<0.05). Conclusion:The increase of COX-2 expression in NAFLD is closely associated with the severity of liver inflammation and damage. COX-2 may play an important role in the progression of rat NAFLD, and the expression of COX-2 mRNA is downregulated by cyclooxygenase-2 inhibitor, which can depress the oxidative stress and control inflammatory response

  8. Effect of etoricoxib, a cyclooxygenase-2 selective inhibitor on aberrant crypt formation and apoptosis in 1,2 dimethyl hydrazine induced colon carcinogenesis in rat model Efecto del etoricoxib, un inhibidor selectivo de la ciclooxigenasa-2, sobre la formación de criptas aberrantes y la apoptosis en un modelo murino de carcinogénesis de colon inducidad por 1,2-dimetilhidracina

    Directory of Open Access Journals (Sweden)

    P. Sharma

    2010-02-01

    Full Text Available Etoricoxib, a second generation selective cyclooxygenase-2 (COX-2 inhibitor had been studied for the chemopreventive response at its therapeutic anti-inflammatory dose in 1,2-dimethylhydrazine (DMH induced colon carcinogenesis in rat model. Eight to ten weeks old male rats of Sprague-Dawley strain were divided into four groups. While group 1 served as control and received the vehicle of the drugs, group 2 and 3 were administered freshly prepared DMH in 1mM EDTA-saline (pH 7.0 (30 mg/kg body wt/week, subcutaneously. Group 3 was also given a daily treatment of etoricoxib (0.6 mg/kg body wt orally while the group 4 received the same amount of etoricoxib only, prepared in 0.5% carboxymethyl cellulose. Animals were sacrificed at the end of 6 weeks, body weight recorded and the colons were subjected to macroscopic and histopathological studies. The maximum number of raised mucosal lesions called the multiple plaque lesions (MPL were found in the DMH group which significantly reverted back in the DMH + etoricoxib group, while very few MPLs were recorded in the control and etoricoxib only group. Similarly, the number of aberrant crypt foci (ACF, the point of future carcinogenic growth, was recorded more in the DMH group and significantly less in the DMH + etoricoxib group. The histopathological analysis showed the presence of severe hyperplasia, occasional dysplasia and aggregates of lymphoid cells in the localized regions. Etoricoxib group showed near normal histological features with the crypt architecture and the surrounding stromal tissue remaining intact. To ascertain the molecular mechanism of such anti-carcinogenic features the colonocytes were isolated and studied in primary culture for the evidence of apoptosis by fluorescent staining and genotoxic changes by single cell gel electrophoresis assay (comet assay which shows that the DMH treated animals produced much less apoptotic nuclei but more comet producing cell, while these features were

  9. MAPK pathway activation by chronic lead-exposure increases vascular reactivity through oxidative stress/cyclooxygenase-2-dependent pathways

    Energy Technology Data Exchange (ETDEWEB)

    Simões, Maylla Ronacher, E-mail: yllars@hotmail.com [Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091 (Brazil); Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain); Aguado, Andrea [Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain); Fiorim, Jonaína; Silveira, Edna Aparecida; Azevedo, Bruna Fernandes; Toscano, Cindy Medice [Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091 (Brazil); Zhenyukh, Olha; Briones, Ana María [Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain); Alonso, María Jesús [Dept. of Biochemistry, Physiology and Molecular Genetics, Universidad Rey Juan Carlos, Alcorcón (Spain); Vassallo, Dalton Valentim [Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091 (Brazil); Health Science Center of Vitória-EMESCAM, Vitória, ES CEP 29045-402 (Brazil); Salaices, Mercedes, E-mail: mercedes.salaices@uam.es [Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain)

    2015-03-01

    Chronic exposure to low lead concentration produces hypertension; however, the underlying mechanisms remain unclear. We analyzed the role of oxidative stress, cyclooxygenase-2-dependent pathways and MAPK in the vascular alterations induced by chronic lead exposure. Aortas from lead-treated Wistar rats (1st dose: 10 μg/100 g; subsequent doses: 0.125 μg/100 g, intramuscular, 30 days) and cultured aortic vascular smooth muscle cells (VSMCs) from Sprague Dawley rats stimulated with lead (20 μg/dL) were used. Lead blood levels of treated rats attained 21.7 ± 2.38 μg/dL. Lead exposure increased systolic blood pressure and aortic ring contractile response to phenylephrine, reduced acetylcholine-induced relaxation and did not affect sodium nitroprusside relaxation. Endothelium removal and L-NAME left-shifted the response to phenylephrine more in untreated than in lead-treated rats. Apocynin and indomethacin decreased more the response to phenylephrine in treated than in untreated rats. Aortic protein expression of gp91(phox), Cu/Zn-SOD, Mn-SOD and COX-2 increased after lead exposure. In cultured VSMCs lead 1) increased superoxide anion production, NADPH oxidase activity and gene and/or protein levels of NOX-1, NOX-4, Mn-SOD, EC-SOD and COX-2 and 2) activated ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized superoxide anion production, NADPH oxidase activity and mRNA levels of NOX-1, NOX-4 and COX-2. Blockade of the ERK1/2 and p38 signaling pathways abolished lead-induced NOX-1, NOX-4 and COX-2 expression. Results show that lead activation of the MAPK signaling pathways activates inflammatory proteins such as NADPH oxidase and COX-2, suggesting a reciprocal interplay and contribution to vascular dysfunction as an underlying mechanisms for lead-induced hypertension. - Highlights: • Lead-exposure increases oxidative stress, COX-2 expression and vascular reactivity. • Lead exposure activates MAPK signaling pathway. • ROS and COX-2 activation by

  10. Cyclooxygenase-2 polymorphisms and the risk of esophageal adeno- or squamous cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    Jón O Kristinsson; Paul van Westerveld; Rene HM te Morsche; Hennie MJ Roelofs; T Wobbes; Ben JM Witteman; Adriaan CITL Tan; Martijn GH van Oijen; Jan BMJ Jansen; Wilbert HM Peters

    2009-01-01

    AIM: To determine whether - 1195 A→ G and/or - 765 G→ C polymorphisms in Cyclooxygenase-2 ( COX-2) may have a risk modifying effect on the development of esophageal carcinoma in a Dutch Caucasian population. METHODS: Two study groups were recruited, 252 patients with esophageal carcinoma and 240 healthy controls, matched for race, age, gender and recruiting area. DNA was isolated from whole blood and used for genotyping. PCR products were digested with restriction enzymes and products were analyzed by agarose gel electrophoresis. Odds ratios (OR) and 95% confidence intervals (CI) were estimated. RESULTS: The dist r ibut ion of the - 1195 A→ G polymorphism was significantly different in esophageal cancer patients compared to controls. The - 1195 GG genotype resulted in a higher risk of developing esophageal adenocarcinoma (OR = 3.85, 95% CI: 1.45-10.3) compared with the - 1195 AA genotype as a reference. The - 765 G→ C genotype distribution was not different between the two groups. The GG/ GG haplotype was present more often in esophageal adenocarcinoma patients than in controls (OR = 3.45, 95% CI: 1.24-9.58; with AG/AG as a reference). The same trends were observed in patients with squamous cell carcinomas, however, the results did not reach statistical significance. CONCLUSION: Presence of the COX-2 -1195 GG genotype and of the GG/GG haplotype may result in a higher risk of developing esophageal carcinoma.

  11. Tumor cyclooxygenase-2 levels correlate with tumor invasiveness in human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Terence C. Tang; Ronnie T. Poon; Cecilia P. Lau; Dan Xie; Sheung Tat Fan

    2005-01-01

    AIM: Recent studies suggested that cyclooxygenase-2(COX-2) enhances tumor angiogenesis via upregulationof vascular endothelial growth factor (VEGF). AlthoughCOX-2 expression has been demonstrated in hepatocellularcarcinoma (HCC), the significance of COX-2 in progressionof HCC remains unclear. This study evaluated the clinico-pathological correlation of COX-2 level and its relationshipwith VEGF level in HCC.METHODS: Fresh tumor tissues were obtained from 100patients who underwent resection of HCC. COX-2 proteinexpression was examined by immunohistochemistry, andquantitatively by an enzyme immunometric assay (EIA)of tumor cytosolic COX-2 levels. Tumor cytosolic VEGFlevels were measured by an ELISA.RESULTS: Immunostaining showed expression of COX-2in tumor cells. Tumor cytosolic COX-2 levels correlatedwith VEGF levels (r = 0.469, P<0.001). Correlation withclinicopathological features showed significantly highertumor cytosolic COX-2 levels in the presence of multipletumors (P = 0.027), venous invasion (P = 0.030),microsatellite lesions (P = 0.037) and advanced tumorstage (P = 0.008). Higher tumor cytosolic COX-2 levelswere associated with worse patient survival.CONCLUSION: This study shows that elevated tumorCOX-2 levels correlate with elevated VEGF levels andinvasiveness in HCC, suggesting that COX-2 plays a significantrole in the progression of HCC.

  12. EXPRESSION OF CYCLOOXYGENASE-2 IN MALIGNANT PHEOCHROMOCYTOMAS AND ITS RELATIONSHIP WITH MICROVESSEL DENSITY

    Institute of Scientific and Technical Information of China (English)

    ZHU Yu; JIN Xiao-long; HE Hong-chao; RUI Wen-bin; WU Yu-xuan; ZHANG Chong-yu; SHEN Zhou-jun

    2009-01-01

    Objective To investigate the expression of cyclooxygenase-2 (Cox-2) and microvessel density (MVD) in benign and malignant pheochromocytomas, and the relationship between Cox-2 and MVD. Methods Specimens and clinical data from 38 patients (21 benign and 17 malignant pheochromocytomas) were studied. Slides of normal adrenal glands in nephrectomy specimens from another 20 patients with benign renal tumors were used as control. Immunohistochemical technology was performed to detect the Cox-2 and MVD in all specimens. Results Expression of Cox-2 was observed in 5 of the 21 benign pheochromocytomas (23.8%), and in 14 of the 17 malignant (82.4%). No expression of Cox-2 was observed in control slides. There were significant differences of Cox-2 expression between benign and malignant pheochromocytomas, as well as between malignant pheochromocytomas and control (P<0.05). Expressions of MVD were 36.41±13.00, 21.43±8.05, and 13.36±4.34 in malignant, benign pheochromocytomas, and in control, respectively. Conclusion Cox-2 may contribute to the invasive characteristics of malignant pheochromocytomas and be used as a marker to distinguish malignant from benign pheochromocytomas. Expression of MVD in malignant pheochromocytomas was directly correlated with Cox-2.

  13. Cyclooxygenase-2 Inhibitor Reduces Hepatic Stiffness in Pediatric Chronic Liver Disease Patients Following Kasai Portoenterostomy

    Science.gov (United States)

    Chang, Hye Kyung; Chang, Eun Young; Ryu, Seonae

    2016-01-01

    Purpose The purpose of this study was to define the role of cyclooxygenase-2 inhibitors (COX-2i) in reducing hepatic fibrosis in pediatric patients with chronic liver disease. Materials and Methods From September 2009 to September 2010, patients over 2 years old who visited our outpatient clinic for follow-up to manage their chronic liver disease after Kasai portoenterostomy for biliary atresia, were included in this study. Volunteers were assigned to the study or control groups, according to their preference. A COX-2i was given to only the study group after obtaining consent. The degree of hepatic fibrosis (liver stiffness score, LSS) was prospectively measured using FibroScan, and liver function was examined using serum analysis before and after treatment. After 1 year, changes in LSSs and liver function were compared between the two groups. Results Twenty-five patients (18 females and 7 males) were enrolled in the study group. The control group included 44 patients (26 females and 18 males). After 1 year, the least square mean values for the LSSs were significantly decreased by 3.91±0.98 kPa (p=0.004) only in the study group. Serum total bilirubin did not decrease significantly in either group. Conclusion COX-2i treatment improved the LSS in patients with chronic liver disease after Kasai portoenterostomy for biliary atresia. PMID:27189282

  14. The prognostic importance of cyclooxygenase 2 and HER2 expression in epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Dahl Steffensen, Karina; Waldstrøm, M; Jeppesen, U;

    2007-01-01

    Both cyclooxygenase 2 (COX2) and human epidermal growth factor receptor 2 (HER2, also called c-erbB-2) overexpression have been related to a worse prognosis in epithelial ovarian cancer (EOC), but the data are conflicting and the percentage of tumors with overexpression varies widely in different......) and immunohistochemistry (IHC) for evaluation of the HER2 status in EOC. Immunostaining was performed for COX2/HER2 together with FISH analysis for HER2 gene amplification in 160 patients with EOC, FIGO stages IIB-IV. Follow-up was more than 10 years. COX2 overexpression was found in 20.0% of the tumors. With HER2...... staining, 64.4% were scored as 0, 24.4% as 1+, 6.9% as 2+, and 4.4% as 3+. Median survival time for COX2-negative tumors was 21.6 versus 36 months for COX2-positive tumors. The longer survival for COX2 positive was significant by both univariate analysis (P= 0.015) and multivariate analysis (P= 0...

  15. Study of Osteoarthritis Treatment with Anti-Inflammatory Drugs: Cyclooxygenase-2 Inhibitor and Steroids

    Directory of Open Access Journals (Sweden)

    Hongsik Cho

    2015-01-01

    Full Text Available Patients with osteoarthritis (OA, a condition characterized by cartilage degradation, are often treated with steroids, nonsteroidal anti-inflammatory drugs (NSAIDs, and cyclooxygenase-2 (COX-2 selective NSAIDs. Due to their inhibition of the inflammatory cascade, the drugs affect the balance of matrix metalloproteinases (MMPs and inflammatory cytokines, resulting in preservation of extracellular matrix (ECM. To compare the effects of these treatments on chondrocyte metabolism, TNF-α was incubated with cultured chondrocytes to mimic a proinflammatory environment with increasing production of MMP-1 and prostaglandin E2 (PGE2. The chondrocytes were then treated with either a steroid (prednisone, a nonspecific COX inhibitor NSAID (piroxicam, or a COX-2 selective NSAID (celecoxib. Both prednisone and celecoxib decreased MMP-1 and PGE-2 production while the nonspecific piroxicam decreased only the latter. Both prednisone and celecoxib decreased gene expression of MMP-1 and increased expression of aggrecan. Increased gene expression of type II collagen was also noted with celecoxib. The nonspecific piroxicam did not show these effects. The efficacy of celecoxib in vivo was investigated using a posttraumatic OA (PTOA mouse model. In vivo, celecoxib increases aggrecan synthesis and suppresses MMP-1. In conclusion, this study demonstrates that celecoxib and steroids exert similar effects on MMP-1 and PGE2 production in vitro and that celecoxib may demonstrate beneficial effects on anabolic metabolism in vivo.

  16. Chronic inhibition of cyclooxygenase-2 attenuates antibody responses against vaccinia infection.

    Science.gov (United States)

    Bernard, Matthew P; Bancos, Simona; Chapman, Timothy J; Ryan, Elizabeth P; Treanor, John J; Rose, Robert C; Topham, David J; Phipps, Richard P

    2010-02-01

    Generation of optimal humoral immunity to vaccination is essential to protect against devastating infectious agents such as the variola virus that causes smallpox. Vaccinia virus (VV), employed as a vaccine against smallpox, provides an important model of infection. Herein, we evaluated the importance cyclooxygenase-2 (Cox-2) in immunity to VV using Cox-2 deficient mice and Cox-2 selective inhibitory drugs. The effects of Cox-2 inhibition on antibody responses to live viruses such as vaccinia have not been previously described. Here, we used VV infection in Cox-2 deficient mice and in mice chronically treated with Cox-2 selective inhibitors and show that the frequency of VV-specific B cells was reduced, as well as the production of neutralizing IgG. VV titers were approximately 70 times higher in mice treated with a Cox-2 selective inhibitor. Interestingly, Cox-2 inhibition also reduced the frequency of IFN-gamma producing CD4(+) T helper cells, important for class switching. The significance of these results is that the chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), and other drugs that inhibit Cox-2 activity or expression, blunt the ability of B cells to produce anti-viral antibodies, thereby making vaccines less effective and possibly increasing susceptibility to viral infection. These new findings support an essential role for Cox-2 in regulating humoral immunity.

  17. Expression of p63 and Cyclooxygenase-2 and Their Correlation in Skin Tumors

    Institute of Scientific and Technical Information of China (English)

    WU Yan; LIU Houjun; LI Jiawen

    2007-01-01

    To study the expression of p63 and cyclooxygenase-2 (cox-2) in skin tumors and evaluate the correlation between p63 and cox-2, the expressions of cox-2 and p63 were measured by streptavidin-peroxidase complex immunohistochemical technique in 17 cases of skin squamous cell carcinoma (SCC), 19 cases of Bowen's disease(Bowen), 11 cases of actinic keratosis(AK), 12 cases of seborreic keratosis(SK) and 13 specimens of normal skin. Our results showed that the expression of p63 in skin squamous cell carcinoma, Bowen's disease and actinic keratosis were significantly higher than that in seborreic keratosis, while the expression of p63 in seborreic keratosis was significantly higher than that in normal skin. The expression of cox-2 in skin squamous cell carcinoma,Bowen's disease and actinic keratosis were significantly higher than that in seborreic keratosis, while no statistical difference was noted in the expression of cox-2 between seborreic keratosis and normal skin. Cox-2 expression was positively correlated with the high p63 expression in malignant skin tumors. The increased expression of cox-2 and p63 may play an important role in the development of skin tumors and work synergetically in malignant skin tumors.

  18. Altered mRNA editing and expression of ionotropic glutamate receptors after kainic acid exposure in cyclooxygenase-2 deficient mice.

    Directory of Open Access Journals (Sweden)

    Luca Caracciolo

    Full Text Available Kainic acid (KA binds to the AMPA/KA receptors and induces seizures that result in inflammation, oxidative damage and neuronal death. We previously showed that cyclooxygenase-2 deficient (COX-2(-/- mice are more vulnerable to KA-induced excitotoxicity. Here, we investigated whether the increased susceptibility of COX-2(-/- mice to KA is associated with altered mRNA expression and editing of glutamate receptors. The expression of AMPA GluR2, GluR3 and KA GluR6 was increased in vehicle-injected COX-2(-/- mice compared to wild type (WT mice in hippocampus and cortex, whereas gene expression of NMDA receptors was decreased. KA treatment decreased the expression of AMPA, KA and NMDA receptors in the hippocampus, with a significant effect in COX-2(-/- mice. Furthermore, we analyzed RNA editing levels and found that the level of GluR3 R/G editing site was selectively increased in the hippocampus and decreased in the cortex in COX-2(-/- compared with WT mice. After KA, GluR4 R/G editing site, flip form, was increased in the hippocampus of COX-2(-/- mice. Treatment of WT mice with the COX-2 inhibitor celecoxib for two weeks decreased the expression of AMPA/KA and NMDAR subunits after KA, as observed in COX-2(-/- mice. After KA exposure, COX-2(-/- mice showed increased mRNA expression of markers of inflammation and oxidative stress, such as cytokines (TNF-α, IL-1β and IL-6, inducible nitric oxide synthase (iNOS, microglia (CD11b and astrocyte (GFAP. Thus, COX-2 gene deletion can exacerbate the inflammatory response to KA. We suggest that COX-2 plays a role in attenuating glutamate excitotoxicity by modulating RNA editing of AMPA/KA and mRNA expression of all ionotropic glutamate receptor subunits and, in turn, neuronal excitability. These changes may contribute to the increased vulnerability of COX-2(-/- mice to KA. The overstimulation of glutamate receptors as a consequence of COX-2 gene deletion suggests a functional coupling between COX-2 and the

  19. Neuroprotective effects of cyclooxygenase-2 inhibitor celecoxib against toxicity of LPS-stimulated macrophages toward motor neurons

    Institute of Scientific and Technical Information of China (English)

    Yong HUANG; Jing LIU; Li-zhen WANG; Wei-yu ZHANG; Xing-zu ZHU

    2005-01-01

    Aim: To establish an in vitro injured motor neuronal model and investigate the neuroprotective effects and possible mechanism of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on this model. Methods: After macrophages were stimulated with lipopolysaccharide (LPS)+interferon-γ (IFN-γ) in the presence or absence of celecoxib for 24 h, the cell-free supernatant of LPS-stimulated macrophages was transferred to the culture of NSC34 cells. Viability of NSC34cells was assessed by MTT assay after a further 24 h and 72 h incubation. After macrophages were stimulated by LPS+IFN-γ for 12 h or 24 h, the release of prostaglandin E2 (PGE2), nitric oxide (NO), reactive oxygen species (ROS), tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1 β) from macrophages was measured by radioimmunoassay, Griess assay, fluorescence assay and enzyme-linked immunosorbent assay, respectively. The mRNA levels of COX-2, inducible nitric oxide synthase (iNOS), TNF-α and IL-1 β in macrophages were determined by reverse transcription-polymerase chain reaction after macrophages were stimulated for 6 h and 12 h. Results: The supernatant of LPS-stimulated mouse macrophages induced the death of NSC34 cells and celecoxib protected the NSC34cells against this toxicity. The LPS-induced increases in the release of PGE2, NO,TNF-o and IL-1 β from macrophages were attenuated by pre-treatment with celecoxib. However, celecoxib showed no effect on the ROS levels upregulated by LPS+IFN-γin the macrophage supernatant. The mRNA levels of COX-2, iNOS,TNF-α and IL-1β were increased in LPS-activated macrophages and, except COX-2,reduced by pre-treatment with celecoxib. Conclusion: An in vitro injured motor neuronal model was established by using the toxicity of LPS-stimulated mouse macrophages toward motor neuronal NSC34 cells. In this model, celecoxib exerted neuroprotective effects on motor neurons via an inhibition of the neurotoxic secretions from activated macrophages.

  20. Zoledronic acid cooperates with a cyclooxygenase-2 inhibitor and gefitinib in inhibiting breast and prostate cancer.

    Science.gov (United States)

    Melisi, Davide; Caputo, Rosa; Damiano, Vincenzo; Bianco, Roberto; Veneziani, Bianca Maria; Bianco, A Raffaele; De Placido, Sabino; Ciardiello, Fortunato; Tortora, Giampaolo

    2005-12-01

    Biphosphonates (BPs) are widely used to inhibit osteoclastic activity in malignant diseases such as bone metastatic breast and prostate carcinoma. Recent studies reported that BPs could also cause a direct antitumor effect, probably due to their ability to interfere with several intracellular signalling molecules. The enzyme cyclooxygenase-2 (COX-2) and the epidermal growth factor receptor (EGFR) play an important role in the control of cancer cell growth and inhibitors of COX-2 and EGFR have shown antitumor activity in vitro and in vivo in several tumor types. We, and others, have previously shown that EGFR and COX-2 may be directly related to each other and that their selective inhibitors may have a cooperative effect. In the present study we have evaluated the combined effect of zoledronic acid, the most potent nitrogen-containing BP, with the COX-2 inhibitor SC-236 and the selective EGFR-tyrosine kinase inhibitor gefitinib, on breast and prostate cancer models in vitro and in xenografted nude mice. We show that combination of zoledronic acid with SC-236 and gefitinib causes a cooperative antitumor effect accompanied by induction of apoptosis and regulation of the expression of mitogenic factors, proangiogenic factors and cell cycle controllers both in vitro and in xenografted nude mice. The modulatory effect on protein expression and the inhibitory effect on tumor growth is much more potent when the three agents are used together. Since studies are ongoing to explore the antitumor effect of zoledronic acid, our results provide new insights into the mechanism of action of these agents and a novel rationale to translate this feasible combination treatment strategy into a clinical setting.

  1. Effects of adenovirus-mediated human cyclooxygenase-2 antisense RNA on the growth of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Xiao-Hu Wang; Sheng-Bao Li; Qiang Tong; Guo-Jian Xie; Qing-Ming Wu

    2005-01-01

    AIM: To investigate the relation between the expression of cyclooxygenase-2 (COX-2) and liver cancer, to construct the recombinant adenovirus encoding human COX-2antisense RNA, and to explore its effects on liver cancer cell proliferation.METHODS: We studied the expression of COX-2 in 34cases of hepatocellular carcinoma (HCC) and SMMC7402and SMMC7721 by immunohistochemical technique.Recombinant adenovirus Ad-AShcox-2 was constructed and transfected into human HCC cell lines SMMC7402and SMMC7721, and its effects on COX-2 expression, cell apoptosis and cell cycle were analyzed by flow cytometry.Cell proliferation was determined by colony-forming efficiency.RESULTS: We observed COX-2 expression in 82.4% of HCC and SMMC7402 cells, but no COX-2 expression in SMMC7721 cells. In addition, recombinant adenovirus encoding antisense COX-2 fragment Ad-AShcox-2 was obtained with the titer of 1.06× 1012 PFU/mL. Ad-AShcox-2 could reduce the expression of COX-2 and enhance the percentage of cells in G1/G0 phase in SMMC7402 cell line.The difference of apoptotic index between the Ad-AShcox2 group and control group was statistically significant(tcontrol group= 32.62 and tAd-LacZ= 10.93, P<0.001) in SMMC7402 but not in SMMC7721. Similarly, colony-forming rates of SMMC7402 and SMMC7721 cell lines, after the transfer of Ad-AShcox-2, were (2.7±0.94)% and(33.6±4.24)%, respectively.CONCLUSION: Reduction in the expression of COX-2 can inhibit COX-2 expressing HCC cells.

  2. Immunohistochemical Expression of Cyclooxygenase-2 in Urinary Bladder Transitional Cell Carcinomas

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    F Niki

    2012-07-01

    Full Text Available Background: Transitional Cell Carcinoma (TCC is the most common type of urinary bladder cancer. Cyclooxygenase-2 (COX-2, a key enzyme in prostaglandins biosynthesis, has been introduced as a new candidate for targeted therapy in this cancer. In this study, we investigated the expression of COX-2 in urinary bladder TCCs and its relationship with clinicopathological parameters such as tumor grade and stage. Methods: This cross-sectional study was performed in the Pathology department of Sina Hospital in Tehran, Iran during 2006-2011. Pathology reports of patients with definite diagnosis of urinary bladder TCCs who had undergone Transurethral Resection (TUR were reviewed and 40 cases were selected. Subsequently, COX-2 expression was assessed immunohistochemically by the examination of paraffin embedded tissue blocks. Staining in more than 5% of tumor cells was considered as positive expression. Results: COX-2 was expressed in 52.5% of the patients. High-grade tumors revealed a higher (87.5% COX-2 expression versus other grades of the lesions and there was a statistically significant difference in COX-2 expression between them (P<0.001. Patients age was also related to the expression of this marker (P=0.03. In contrast, this marker did not correlate with other characteristics including gender, lymphatic invasion or tumor stage. In addition, perineurial or vascular invasions were not detected in any of the patients. Conclusion: COX-2 expression was seen in more than half of our patients and it had a marked relation to tumor differentiation. Accordingly, this molecule may be a useful tumor marker in the assessment of urinary bladder cancers.

  3. Quantitative analysis of cyclooxygenase 2 in the posterior longitudinal ligament of cervical spondylotic myelopathy

    Institute of Scientific and Technical Information of China (English)

    SONG Hong-xing; Michael Scarpatetti; Wolfgang Kreil; SHEN Hui-liang; Koppany Bodo; Birgit Ebner; Heribert Schr(o)ttner; Michael Mokry

    2011-01-01

    Background Cervical spondylotic myelopathy (CSM), in part, results from degeneration of the posterior longitudinal ligament (PLL), which mechanically compresses the spinal cord. Much research was done on the ossification of PLL, but not concerning the non-ossifying degeneration of cervical PLL. The degeneration of cervical PLL may be related to inflammation. The aim of this study was to elucidate the pathological features of the PLL and the role of cyclooxygenase 2 (COX-2) in the degeneration of the PLL in CSM.Methods A total of 23 PLL specimens were collected during surgery from patients with CSM for the histological and immunohistochemical (type Ⅱ collagen and Ki-67) study. For the control group 14 cervical PLL autopsy specimens were investigated in the same manner. mRNA expression of COX-2 was quantitatively measured by real-time reverse transcription-polymerase chain reaction (RT-PCR) from 18 PLL specimens of patients with CSM and 18 PLL specimens of autopsy cases. Immunohistochemistry was used to evaluate the cellular location of COX-2 in PLL.Results A distinct amount of fibrotic area, chondrometaplastic tissue and calcification were found in the PLL of the patient group, compared with the control group. Type Ⅱ collagen was apparent around chondrometaplastic cells. Ki-67 positive reaction was less than 5%. A COX-2 positive reaction was found in 9 of the patient specimens (39.1%) in which the COX-2 was released from vascular endothelial cells in the PLL. However, such reactions were not found in the control group. Real-time PCR showed that the mRNA expression level of COX-2 in the patient group was significantly higher than that in the control group (P <0.01).Conclusions Chondrometaplastic tissue producing type Ⅱ collagen was identified as the most predominant pathological feature in the degenerative PLL. The higher expression of COX-2 might be related to degeneration of the PLL in CSM.

  4. Effects of aspirin on atherosclerosis and the cyclooxygenase-2 expression in atherosclerotic rabbits

    Institute of Scientific and Technical Information of China (English)

    GUO Yi; WANG Qi-zhang; TANG Bing-shan; ZUO Yan-fang; LI Fang-ming; JIANG Xin; WANG Ling; MA Ke-fu

    2006-01-01

    Background Atherosclerosis is a complex vascular inflammatory disease. Aspirin is a mainstay in the prevention of vascular complications of atherosclerosis. In this study, the effectiveness of aspirin in suppressing atherosclerosis and the inflammation process was evaluated in rabbits fed with a high fat diet.Methods Eighteen male New Zealand rabbits were randomly divided into 3 groups: control group, untreated cholesterol-fed group, aspirin treated cholesterol-fed group, which were fed for 12 weeks. After 12 weeks, the aorta was harvested for pathologic morphology observation. Immunohistochemical analysis of cyclooxygenase-2 (COX-2), macrophage and vascular smooth muscle cell (VSMC) was performed. The statistical analysis was performed by the statistical program SPSS 10.0.Results The aorta plaque/intima size (P/I) by pathologic morphology observation was 0%, (59.6± 13.7)% and (36.3± 16.5)% in the control, untreated cholesterol-fed group and aspirin treated group, respectively. The maximum plaque thickness, the degree of artery stenosis and the proportion of the intimal circumference occupied by atheroma of the 3 groups were significantly different from each other (P<0.01). The expression of COX-2 and macrophage in plaque of the aspirin treated group were decreased compared with that in untreated cholesterol-fed group. However, no difference was found in the expression of VSMC between the aspirin treated and the untreated cholesterol-fed group.Conclusion The mechanism of atherosclerosis suppression by aspirin in cholesterol-fed rabbits is related to the inhibition of COX-2 expression together with the reduced inflammation followed by, but not related to the hypolipidemic effects.

  5. Association of cyclooxygenase-2 expression with Hp-cagA infection in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Xiao-Lin Guo; Li-Er Wang; Shu-Yan Du; Chen-Ling Fan; Li Li; Peng Wang; Yuan Yuan

    2003-01-01

    AIM: To observe the expression of cyclooxygenase-2 (COX-2) and to investigate the association between COX-2expression and infection with cytotoxic-associated gene A( cagA) positive strair Helicobacter pylori ( Hp) in humangastric cancer, and subsequently to provide fresh ideas forthe early prevention of gastric cancer.METHODS: 32 Specimens of gastric cancer andcorresponding adjacent normal gastric mucosa were obtainedfrom patients who had undergone surgical operations ofgastric cancer. All the samples including 1 case of stomachmalignant lymphoma and 31 cases of gastric adenocarcinomawere confirmed by pathology diagnosis. The expression ofCOX-2 in 32 specimens of gastric cancer and correspondingadjacent normal gastric mucosa was quantitativelydetermined and analyzed with Flow Cytometry, and the levelsof COX-2 protein were compared between specimens withcagA+ Hp infection and those without cagA+ Hp infection.The cagA gene in 32 specimens of gastric cancer wasdetected bypolymerase chain reaction (PCR) method.RESULTS: Twenty-seven of 32 (84 %) specimens of gastriccancer showed over-expression of COX-2, compared withthe adjacent normal gastric mucosa. cagA+ gene weredetected from 19 specimens of gastric cancer, but not fromthe other 13 specimens. The levels of COX-2 protein in 19specimens of gastric cancer with cagA+ Hp infection (thenumber of positive cells was 73.82±18.2) were significantlyhigher than those in the 13 specimens without cagA+ Hpinfection (the number of positive cells was 35.92±22.1).CONCLUSION: COX-2 is overexpressed in gastric cancerand cagA+Hp infection could up-regulate the expression ofCOX-2 in gastric cancer in human. There may also existanother way or channel to regulate the expression of COX-2 in gastric cancer in addition to cagA+Hp infection.Therefore, applying COX-2 selective inhibitors could be aneffective and promising way to prevent gastric cancer.

  6. 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.

  7. Cyclooxygenase-2 suppresses the anabolic response to PTH infusion in mice.

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    Shilpa Choudhary

    Full Text Available We previously reported that the ability of continuously elevated PTH to stimulate osteoblastic differentiation in bone marrow stromal cell cultures was abrogated by an osteoclastic factor secreted in response to cyclooxygenase-2 (Cox2-produced prostaglandin E2. We now examine the impact of Cox2 (Ptgs2 knockout (KO on the anabolic response to continuously elevated PTH in vivo. PTH (40 μg/kg/d or vehicle was infused for 12 or 21 days in 3-mo-old male wild type (WT and KO mice in the outbred CD-1 background. Changes in bone phenotype were assessed by bone mineral density (BMD, μCT and histomorphometry. PTH infusion for both 12 and 21 days increased femoral BMD in Cox2 KO mice and decreased BMD in WT mice. Femoral and vertebral trabecular bone volume fractions were increased in KO mice, but not in WT mice, by PTH infusion. In the femoral diaphysis, PTH infusion increased cortical area in Cox2 KO, but not WT, femurs. PTH infusion markedly increased trabecular bone formation rate in the femur, serum markers of bone formation, and expression of bone formation-related genes, growth factors, and Wnt target genes in KO mice relative to WT mice, and decreased gene expression of Wnt antagonists only in KO mice. In contrast to the differential effects of PTH on anabolic factors in WT and KO mice, PTH infusion increased serum markers of resorption, expression of resorption-related genes, and the percent bone surface covered by osteoclasts similarly in both WT and KO mice. We conclude that Cox2 inhibits the anabolic, but not the catabolic, effects of continuous PTH. These data suggest that the bone loss with continuously infused PTH in mice is due largely to suppression of bone formation and that this suppression is mediated by Cox2.

  8. EFFECTS OF CYCLOOXYGENASE-2 ANTISENSE VECTOR ON PROLIFERATION OF HUMAN CHOLANGIOCARCINOMA CELLS

    Institute of Scientific and Technical Information of China (English)

    Gao-song Wu; Sheng-quan Zou; Xiao-yong Wu; Fa-zu Qiu

    2004-01-01

    Objective To transfect antisense vector of human cyclooxygenase-2 (COX-2) gene into COX-2 highly expressing cholangiocarcinoma cell line QBC939 and explore its biological activities and role in carcinogenesis.Methods QBC939 cells were transfected with antisense vector of human COX-2 gene using LipoVecTM transfecting technique. Transfected cells were selected with G418; COX-2 mRNA was examined using reverse transcription polymerase chain reaction (RT-PCR) and COX-2 protein expression was detected by immunocytochemistry using isozyme selective antibodies. The proliferative status of transfected cells was measured by using methabenzthiazuron (MTT) assay; Cell cycle and apoptosis were analyzed by using flow cytometry.Results RT-PCR showed a lower COX-2 mRNA level in antisense vector transfected cells and immunocytochemistry showed a weaker COX-2 protein expression in antisense vector transfected cells. The antisense vector transfected cells proliferative index decreased significantly (P< 0.01), the percentage of S phase decreased remarkably (P< 0.05) in antisense vector transfected cells (9.27% ± 1.91%) compared with that in QBC939 cells without transfection(16.35% ± 2.87%), and the percentage of G0/G 1 phase increased remarkably (P < 0.05) in antisense vector transfected cells (75.16%±4.13%) compared with that in QBC939 cells without transfection (57.31%± 10.16%). Transfection with antisense vector of human COX-2 gene had no significant influence on the apoptosis in QBC939 cells (P > 0.05).Conclusion Transfection with antisense vector of human COX-2 gene could inhibit the proliferation of human cholangiocarcinoma QBC939 cells.

  9. Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis.

    Science.gov (United States)

    Evans, Iona C; Barnes, Josephine L; Garner, Ian M; Pearce, David R; Maher, Toby M; Shiwen, Xu; Renzoni, Elisabetta A; Wells, Athol U; Denton, Christopher P; Laurent, Geoffrey J; Abraham, David J; McAnulty, Robin J

    2016-04-01

    Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc) produce low levels of prostaglandin (PG) E2, due to a limited capacity to up-regulate cyclooxygenase-2 (COX-2). This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood. In the present study, we examined whether the reduced level of COX-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5-aza-2'-deoxycytidine (5AZA) restored COX-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of PGE2 production, collagen mRNA expression and sensitivity to apoptosis. COX-2 methylation assessed by bisulfite sequencing and methylation microarrays was not different in fibrotic fibroblasts compared with controls. However, further analysis of the methylation array data identified a transcriptional regulator, chromosome 8 open reading frame 4 (thyroid cancer protein 1, TC-1) (c8orf4), which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knockdown of c8orf4 in control fibroblasts down-regulated COX-2 and PGE2 production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates COX-2 expression in lung fibroblasts through binding of the proximal promoter. We conclude that the decreased capacity of fibrotic lung fibroblasts to up-regulate COX-2 expression and COX-2-derived PGE2 synthesis is due to an indirect epigenetic mechanism involving hypermethylation of the transcriptional regulator, c8orf4.

  10. Cyclooxygenase-2 (COX-2) Polymorphisms and Risk of Inflammatory Bowel Disease in a Scottish and Danish Case–Control Study

    DEFF Research Database (Denmark)

    Andersen, Vibeke; Nimmo, Elaine; Krarup, Henrik B.;

    2011-01-01

    Background: Inflammatory bowel diseases (IBDs) are a result of interactions between luminal pathogens and the intestinal immune response. Cyclooxygenase-2 (COX-2) plays a key role in the regulation of the inflammatory response upon stimulation by luminal pathogens via Toll-like receptors. Methods...... among never-smokers, suggesting that low activity of COX-2 may predispose to UC. Our results suggest that inclusion of smoking status may be essential for the evaluation of the role of genetic predisposition to IBD....

  11. Analgesic Efficacy of Firocoxib, a Selective Inhibitor of Cyclooxygenase 2, in a Mouse Model of Incisional Pain

    OpenAIRE

    Reddyjarugu, Balagangadharreddy; Pavek, Todd; Southard, Teresa; Barry, Jason; Singh, Bhupinder

    2015-01-01

    Pain management in laboratory animals is generally accomplished by using opioids and NSAIDs. However, opioid use is hindered by controlled substance requirements and a relatively short duration of action. In this study, we compared the analgesic efficacy of firocoxib (a cyclooxygenase-2-selective NSAID) with that of buprenorphine in the mouse model of plantar incisional pain by objective measurement of mechanical allodynia and thermal hyperalgesia using von Frey and Hargreaves equipment, resp...

  12. Aspirin inhibits the proliferation of tobacco-related esophageal squamous carcinomas cell lines through cyclooxygenase 2 pathway

    Institute of Scientific and Technical Information of China (English)

    ZHOU Qiao-Zhi; LIU Hai-bo; DING Xin-chun; LI Peng; ZHANG Shu-tian; YU Zhong-lin

    2007-01-01

    Background Cigarette smoking has been verified as the risk factor of esophageal squamous cell carcinoma(ESCC).Overexpression of cyclooxygenase 2(COX-2)is shown in ESCC.The objective of this study was to investigate the effects of cigarette smoking ethanol extract(EE)on the proliferation of the human ESCC cell Iines,and to explore the correlation between the proliferation rate of human ESCC cell lines and the expression pattern of COX-2.Whether aspirin can inhibit the proliferation of the ESCC cell lines pretreated with EE.and regulate the mRNA expression levels of COX-2 are also examined.Methods Two human ESCC cell Iines were selected.EC109 was poorly differentiated and EC9706 was highly differentiated.EC109 and EC9706 were treated with EE and aspirin for different time course.The cell growth of ESCC was measured by MTT reduction assay and the expression of COX-2 was measured by RT-PCR and Western blot analysis.Results EE promoted the proliferation of EC109 and EC9706 in dose- and time-dependent manners.In the concentration range (10-100 μg/ml for EE)and in the time range(24-72 hours)after addition of EE,the cell proliferation was prominent in an up-scaled manner respectively.Aspirin could inhibit the proliferation of cell lines EC109 and EC9706.pretreated with EE for 5 hours,in a dose-dependent manner.In the concentration range (0.5-8.0 mmol/L for aspirin),the cell growth inhibition was prominent in an up-scaled manner accordingly (P<0.05).The effect of EE on cell proliferation was correlated with the up-regulation of COX-2 gene.However,the cell growth inhibition of aspirin was correlated with the down-regulation of COX-2 gene.Conclusions EE can stimulate the proliferation of human ESCC cell lines EC109 and EC9706,most likely through up-regulating the expression of COX-2.Aspirin can inhibit the proliferation of ESCC cell lines induced by EE,which suggests it may be advantageous in the chemoprevention and therapy of human tobacco-related ESCC.And its effect is

  13. Alterations in Lipoxygenase and Cyclooxygenase-2 Catalytic Activity and mRNA Expression in Prostate Carcinoma

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    Scott B. Shappell

    2001-01-01

    Full Text Available Recent studies in prostate tissues and especially cell lines have suggested roles for arachidonic acid (AA metabolizing enzymes in prostate adenocarcinoma (Pca development or progression. The goal of this study was to more fully characterize lipoxygenase (LOX and cyclooxygenase-2 (COX-2 gene expression and AA metabolism in benign and malignant prostate using snap-frozen tissues obtained intraoperatively and mRNA analyses and enzyme assays. Formation of 15-hydroxyeicosatetraenoic acid (15-HETE was detected in 23/29 benign samples and 15-LOX-2 mRNA was detected in 21/25 benign samples. In pairs of pure benign and Pca from the same patients, 15-HETE production and 15-LOX-2 mRNA were reduced in Pca versus benign in 9/14 (P=.04 and 14/17 (P=.002, respectively. Under the same conditions, neither 5HETE nor 12-HETE formation was detectable in 29 benign and 24 tumor samples; with a more sensitive assay, traces were detected in some samples, but there was no clear association with tumor tissue. COX-2 mRNA was detected by nuclease protection assay in 7/16 benign samples and 5/16 tumors. In benign and tumor pairs from 10 patients, COX-2 was higher in tumor versus benign in only 2, with similar results by in situ hybridization. Paraffin immunoperoxidase for COX2 was performed in whole mount sections from 87 additional radical prostatectomy specimens, with strong expression in ejaculatory duct as a positive control and corroboration with in situ hybridization. No immunostaining was detected in benign prostate or tumor in 45% of cases. Greater immunostaining in tumor versus benign was present in only 17% of cases, and correlated with high tumor grade (Gleason score 8 and 9 vs. 5 to 7. In conclusion, reduced 15-LOX-2 expression and 15-HETE formation is the most characteristic alteration of AA metabolism in Pca. Increased 12-HETE and 5-HETE formation in Pca were not discernible. Increased COX-2 expression is not a typical abnormality in Pca in general, but

  14. Role of cyclooxygenase-2 signaling pathway dysfunction in unexplained recurrent spontaneous abortion

    Institute of Scientific and Technical Information of China (English)

    WANG Yu; ZHAO Ai-min; LIN Qi-de

    2010-01-01

    Background Experimental evidence indicates that cyclooxygenase-2 (COX-2) plays a critical role in blastocyst implantation; however, little is known of the role of COX-2 in unexplained recurrent spontaneous abortion (URSA).Methods We evaluated the expression level and potential signaling pathway of COX-2 in 30 cases of URSA who were excluded the abnormality of chromosomes, anatomy, endocrine, infectious, autoimmune diseases and in 30 normal pregnancies.Results The mRNA and the protein expression level of COX-2 in the URSA group (-0.238±0.848, 0.368±0.089,respectively) were significantly lower than that in the control group (1.943±3.845, 1.046±0.108, respectively) (both, P<0.01). The expression of prostaglandins PGF2a, PGD2, PGE2, and PGI2, in the URSA group ((2326.0±295.6) pg/ml,(2164.0±240.5) pg/ml, (238.7±26.4) pg/ml, (2337.0±263.0) pg/ml, respectively) were significantly lower than that in the control group ((3450.0±421.7) pg/ml, (3174.0±415.6) pg/ml, (323.5±43.8) pg/ml, (3623.0±460.4) pg/ml, respectively) (P<0.05). The mRNA expression level of PPARβ and RXRa (0.859±0.653, -0.172±0.752, respectively) in URSA group was significantly lower than that in the control group (1.554±1.735, 0.777±2.482, respectively) (both P <0.05). The mRNA and protein expression levels of vascular endothelial growth factor-A (VEGF-A) in the URSA group (2.010±1.522, 0.35±0.46)was significantly lower than that in the control group (4.569±2.430, 0.750±0.350) (both P <0.05).Conclusions COX-2 and the COX-2-derived PGI2 signaling pathway possibly play an important role in successful embryo implantation, and their decreased expression may result in URSA. The decreased expression may influence the expression of VEGF-A which interferes with placental angiogenesis causing failure of embryo implantation, leading to spontaneous abortion.

  15. Cyclooxygenase-2 inhibitor is a robust enhancer of anticancer agents against hepatocellular carcinoma multicellular spheroids

    Directory of Open Access Journals (Sweden)

    Cui J

    2014-02-01

    Full Text Available Jie Cui,1,2 Ya-Huan Guo,3 Hong-Yi Zhang,4 Li-Li Jiang,1 Jie-Qun Ma,1 Wen-Juan Wang,1 Min-Cong Wang,1 Cheng-Cheng Yang,1 Ke-Jun Nan,1 Li-Ping Song5 1Department of Oncology, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, 2Department of Oncology, Yan'an University Affiliated Hospital, Yan'an, 3Department of Oncology, Shaanxi Province Cancer Hospital, Xi'an, 4Department of Urology, Yan'an University Affiliated Hospital, Yan'an, 5Department of Radiotherapy, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, People's Republic of China Purpose: Celecoxib, an inhibitor of cyclooxygenase-2 (COX2, was investigated for enhancement of chemotherapeutic efficacy in cancer clinical trials. This study aimed to determine whether celecoxib combined with 5-fluorouracil or sorafenib or gefitinib is beneficial in HepG2 multicellular spheroids (MCSs, as well as elucidate the underlying mechanisms. Methods: The human hepatocellular carcinoma cell line HepG2 MCSs were used as in vitro models to investigate the effects of celecoxib combined with 5-fluorouracil or sorafenib or gefitinib treatment on cell growth, apoptosis, and signaling pathway. Results: MCSs showed resistance to drugs compared with monolayer cells. Celecoxib combined with 5-fluorouracil or sorafenib exhibited a synergistic action. Exposure to celecoxib (21.8 µmol/L plus 5-fluorouracil (8.1 × 10-3 g/L or sorafenib (4.4 µmol/L increased apoptosis but exerted no effect on COX2, phosphorylated epidermal growth-factor receptor (p-EGFR and phosphorylated (p-AKT expression. Gefitinib (5 µmol/L, which exhibits no growth-inhibition activity as a single agent, increased the inhibitory effect of celecoxib. Gefitinib (5 µmol/L plus celecoxib (21.8 µmol/L increased apoptosis. COX2, p-EGFR, and p-AKT were inhibited. Conclusion: Celecoxib combined with 5-fluorouracil or sorafenib or gefitinib may be superior to single-agent therapy in HepG2

  16. Regulation of cyclooxygenase-2 expression by cAMP response element and mRNA stability in a human airway epithelial cell line exposed to zinc

    Science.gov (United States)

    Exposure to zinc-laden particulate matter in ambient and occupational settings has been associated with proinflammatory responses in the lung. Cyclooxygenase 2-derived eicosanoids are important modulators of airway inflammation. In this study, we characterized the transcriptional...

  17. Radiation Therapy Overcomes Adverse Prognostic Role of Cyclooxygenase-2 Expression on Reed-Sternberg Cells in Early Hodgkin Lymphoma

    International Nuclear Information System (INIS)

    Purpose: To analyze the role of radiation therapy (RT) on the adverse prognostic influence of cyclooxygenase-2 (COX-2) expression on Reed-Sternberg (RS) cells, in the setting of early Hodgkin lymphoma (HL) treated with ABVD (adriamycin, vinblastine, bleomycin, dacarbazine). Methods and Materials: In the present study we retrospectively investigated the prognostic value of COX-2 expression in a large (n=143), uniformly treated early HL population from the Spanish Network of HL using tissue microarrays. Univariate and multivariate analyses were done, including the most recognized clinical variables and the potential role of administration of adjuvant RT. Results: Median age was 31 years; the expression of COX-2 defined a subgroup with significantly worse prognosis. Considering COX-2+ patients, those who received RT had significantly better 5-year progression-free survival (PFS) (80% vs 54% if no RT; P=.008). In contrast, COX-2− patients only had a modest, nonsignificant benefit from RT in terms of 5-year PFS (90% vs 79%; P=.13). When we compared the outcome of patients receiving RT considering the expression of COX-2 on RS cells, we found a nonsignificant 10% difference in terms of PFS between COX-2+ and COX-2− patients (P=.09), whereas the difference between the 2 groups was important (25%) in patients not receiving RT (P=.04). Conclusions: Cyclooxygenase-2 RS cell expression is an adverse independent prognostic factor in early HL. Radiation therapy overcomes the worse prognosis associated with COX-2 expression on RS cells, acting in a chemotherapy-independent way. Cyclooxygenase-2 RS cell expression may be useful for determining patient candidates with early HL to receive consolidation with RT

  18. Radiation Therapy Overcomes Adverse Prognostic Role of Cyclooxygenase-2 Expression on Reed-Sternberg Cells in Early Hodgkin Lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Mestre, Francisco [Service of Radiation Therapy, University Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca (Spain); Gutiérrez, Antonio, E-mail: antoniom.gutierrez@ssib.es [Service of Hematology, University Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca (Spain); Rodriguez, Jose [MD Anderson Cancer Center, Madrid (Spain); Ramos, Rafael [Service of Pathology, University Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca (Spain); Garcia, Juan Fernando [Spanish National Cancer Research Centre, Madrid (Spain); Martinez-Serra, Jordi [Service of Hematology, University Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca (Spain); Casasus, Marta; Nicolau, Cristina [Service of Radiation Therapy, Policlinica Miramar, Palma de Mallorca (Spain); Bento, Leyre; Herraez, Ines [Service of Hematology, University Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca (Spain); Lopez-Perezagua, Paloma [Service of Radiology, IDISPA, Palma de Mallorca (Spain); Daumal, Jaime [Service of Nuclear Medicine, IDISPA, Palma de Mallorca (Spain); Besalduch, Joan [Service of Hematology, University Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca (Spain)

    2015-05-01

    Purpose: To analyze the role of radiation therapy (RT) on the adverse prognostic influence of cyclooxygenase-2 (COX-2) expression on Reed-Sternberg (RS) cells, in the setting of early Hodgkin lymphoma (HL) treated with ABVD (adriamycin, vinblastine, bleomycin, dacarbazine). Methods and Materials: In the present study we retrospectively investigated the prognostic value of COX-2 expression in a large (n=143), uniformly treated early HL population from the Spanish Network of HL using tissue microarrays. Univariate and multivariate analyses were done, including the most recognized clinical variables and the potential role of administration of adjuvant RT. Results: Median age was 31 years; the expression of COX-2 defined a subgroup with significantly worse prognosis. Considering COX-2{sup +} patients, those who received RT had significantly better 5-year progression-free survival (PFS) (80% vs 54% if no RT; P=.008). In contrast, COX-2{sup −} patients only had a modest, nonsignificant benefit from RT in terms of 5-year PFS (90% vs 79%; P=.13). When we compared the outcome of patients receiving RT considering the expression of COX-2 on RS cells, we found a nonsignificant 10% difference in terms of PFS between COX-2{sup +} and COX-2{sup −} patients (P=.09), whereas the difference between the 2 groups was important (25%) in patients not receiving RT (P=.04). Conclusions: Cyclooxygenase-2 RS cell expression is an adverse independent prognostic factor in early HL. Radiation therapy overcomes the worse prognosis associated with COX-2 expression on RS cells, acting in a chemotherapy-independent way. Cyclooxygenase-2 RS cell expression may be useful for determining patient candidates with early HL to receive consolidation with RT.

  19. Clinical Implication of Cyclooxygenase-2 Expression for Rectal Cancer Patients with Lymph Node Involvement

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hyung Sik; Choi, Young Min; Hur, Won Joo; Kim, Su Jin; Kim, Dae Cheol; Roh, Mee Sook; Hong, Young Seoub; Park, Ki Jae [Dona-A University School of Medicine, Busan (Korea, Republic of)

    2009-12-15

    To assess the influence of cyclooxygenase-2 (COX-2) expression on the survival of patients with a combination of rectal cancer and lymph node metastasis. The study included rectal cancer patients treated by radical surgery and postoperative radiotherapy at the Dong-A university hospital from 1998 to 2004. A retrospective analysis was performed on a subset of patients that also had lymph node metastasis. After excluding eight of 86 patients, due to missing tissue samples in three, malignant melanoma in one, treatment of gastric cancer around one year before diagnosis in one, detection of lung cancer after one year of diagnosis in one, liver metastasis in one, and refusal of radiotherapy after 720 cGy in one, 78 patients were analyzed. The immunohistochemistry for COX-2 was conducted with an autostainer (BenchMark; Ventana, Tucson, AZ, USA). An image analyzer (TissueMine; Bioimagene, Cupertino, CA, USA) was used for analysis after scanning (ScanScope; Aperio, Vista, CA, USA). A survival analysis was performed using the Kaplan Meier method and significance was evaluated using the log rank test. COX-2 was stained positively in 62 patients (79.5%) and negatively in 16 (20.5%). A total of 6 (7.7%), 15 (19.2%), and 41 (52.6%) patients were of grades 1, 2, and 3, respectively for COX-2 expression. No correlation was found between being positive of COX-2 patient characteristics, which include age (<60-year old vs. {>=}60), sex, operation methods (abdominoperineal resection vs. lower anterior resection), degrees of differentiation, tumor size (<5 cm vs. {>=}5 cm), T stages, N stages, and stages (IIIa, IIIb, IIIc). The 5-year overall and 5-year disease free survival rates for the entire patient population were 57.0% and 51.6%, respectively. The 5-year overall survival rates for the COX-2 positive and negative patients were 53.0% and 72.9%, respectively (p=0.146). Further, the 5-year disease free survival rates for the COX-2 positive and negative patients were 46.3% and 72

  20. Cyclooxygenase-2 and epithelial growth factor receptor up-regulation during progression of Barrett's esophagus to adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Yan Li; John M Wo; Mukunda B Ray; Whitney Jones; Ruifeng R Su; Susan Ellis; Robert C G Martin

    2006-01-01

    AIM: To investigate the expression of cyclooxygenase-2(COX-2) and epithelial growth factor receptor (EGFR)throughout the progression of Barrett's esophagus (BE).METHODS: COX-2 and EGFR protein expressions were detected by using immunohistochemical method. A detailed cytomorphological changes were determined.Areas of COX-2 and EGFR expression were quantified by using computer Imaging System.RESULTS: The expressions of both COX-2 and EGFR increased along with the progression from BE to esophagus adenocarcinoma (EAC). A positive correlation was found between COX-2 expression and EGFR expression.CONCLUSION: COX-2 and EGFR may be cooperative in the stepwise progression from BE to EAC, thereby leading to carcinogenesis.

  1. Induction of cyclooxygenase-2 mRNA and protein expression by epoxy resin and zinc oxide-eugenol based root canal sealers in human osteoblastic cells.

    Science.gov (United States)

    Huang, Fu-Mei; Chou, Ming-Yung; Chang, Yu-Chao

    2003-05-01

    An ideal root canal sealer should be nonirritating to the surrounding tissues. Unfortunately, all histological investigation demonstrated that all types of root canal sealer can induce mild to severe inflammatory alternations. However, there is little information on the precise mechanisms about root canal sealers-induced inflammatory reaction. Cyclooxygenase-2 (COX-2) is an inducible enzyme believed to be responsible for prostaglandin synthesis at site of inflammation. The aim of the present study was to investigate the effects of epoxy resin (AH26) and zinc oxide-eugenol based (Endomethansone and N2) root canal sealers on the expression of COX-2 mRNA gene and protein in cultured human osteoblastic cells. Investigations of the time dependence of COX-2 mRNA expression in root canal sealer-treated human osteoblastic cells revealed a rapid accumulation of the transcript, a significant signal first detectable within 2h and diminished to control level after 24h. In addition, all root canal sealers also induced COX-2 protein expression in human osteoblastic cells. Furthermore, to elucidate whether induction of COX-2 is associated with cytotoxicity, NS-398 (a selective COX-2 inhibitor), was added to test its protective effects. NS-398 at non-cytotoxic dose is not able to prevent root canal sealers-induced cytotoxicity. Taken together, the activation of COX-2 expression may be one of the pathogenesis of root canal sealers-induced periapical inflammation. In addition, root canal sealers-induced cytotoxicity is not directly via the induction of COX-2 expression.

  2. NO2 inhalation promotes Alzheimer’s disease-like progression: cyclooxygenase-2-derived prostaglandin E2 modulation and monoacylglycerol lipase inhibition-targeted medication

    Science.gov (United States)

    Yan, Wei; Yun, Yang; Ku, Tingting; Li, Guangke; Sang, Nan

    2016-03-01

    Air pollution has been reported to be associated with increased risks of cognitive impairment and neurodegenerative diseases. Because NO2 is a typical primary air pollutant and an important contributor to secondary aerosols, NO2-induced neuronal functional abnormalities have attracted greater attention, but the available experimental evidence, modulating mechanisms, and targeting medications remain ambiguous. In this study, we exposed C57BL/6J and APP/PS1 mice to dynamic NO2 inhalation and found for the first time that NO2 inhalation caused deterioration of spatial learning and memory, aggravated amyloid β42 (Aβ42) accumulation, and promoted pathological abnormalities and cognitive defects related to Alzheimer’s disease (AD). The microarray and bioinformation data showed that the cyclooxygenase-2 (COX-2)-mediated arachidonic acid (AA) metabolism of prostaglandin E2 (PGE2) played a key role in modulating this aggravation. Furthermore, increasing endocannabinoid 2-arachidonoylglycerol (2-AG) by inhibiting monoacylglycerol lipase (MAGL) prevented PGE2 production, neuroinflammation-associated Aβ42 accumulation, and neurodegeneration, indicating a therapeutic target for relieving cognitive impairment caused by NO2 exposure.

  3. Date syrup-derived polyphenols attenuate angiogenic responses and exhibits anti-inflammatory activity mediated by vascular endothelial growth factor and cyclooxygenase-2 expression in endothelial cells.

    Science.gov (United States)

    Taleb, Hajer; Morris, R Keith; Withycombe, Cathryn E; Maddocks, Sarah E; Kanekanian, Ara D

    2016-07-01

    Bioactive components such as polyphenols, present in many plants, are purported to have anti-inflammatory and antiangiogenic properties. Date syrup, produced from date fruit of the date palm tree, has traditionally been used to treat a wide range of diseases with etiologies involving angiogenesis and inflammation. It was hypothesized that polyphenols in date syrup reduce angiogenic responses such as cell migration, tube formation, and matrix metalloproteinase activity in an inflammatory model by exhibiting anti-inflammatory activity mediated by vascular endothelial growth factor (VEGF) and the prostaglandin enzyme cyclooxygenase-2 (COX-2) in endothelial cells. Date syrup polyphenols at 60 and 600μg/mL reduced inflammation and suppressed several stages of angiogenesis, including endothelial cell migration, invasion, matrix metalloproteinase activity, and tube formation, without evidence of cytotoxicity. VEGF and COX-2 expression induced by tumor necrosis factor-alpha at both gene expression and protein level was significantly reduced by date syrup polyphenols in comparison to untreated cells. In conclusion, polyphenols in date syrup attenuated angiogenic responses and exhibited anti-inflammatory activity mediated by VEGF and COX-2 expression in endothelial cells. PMID:27333954

  4. Tobacco-specific N-nitrosamines NNN and NNK levels in cigarette brands between 2000 and 2014.

    Science.gov (United States)

    Gunduz, I; Kondylis, A; Jaccard, G; Renaud, J-M; Hofer, R; Ruffieux, L; Gadani, F

    2016-04-01

    The evolution of the levels of tobacco-specific N-nitrosamines (TSNA), N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mainstream (MS) cigarette smoke is investigated based on smoke and tobacco chemistry data of cigarette brands sold by Philip Morris International (PMI) between 2000 and 2014. A total of 315 cigarette samples representing a wide range of product and design characteristics manufactured by PMI between 2008 and 2014 were analyzed and compared to a previously published dataset of PMI brands manufactured in 2000. The data indicate that there is a substantial reduction of NNN and NNK levels in tobacco fillers and MS cigarette smoke per mg of tar and per mg of nicotine using Health Canada Intense (HCI) machine-smoking regime. This observed reduction in NNN and NNK levels in MS cigarette smoke is also supported by the downward trend observed on NNN and NNK levels in USA flue-cured Virginia and Burley tobacco lots from 2000 to 2014 crops, reflecting effectiveness of measures taken on curing and agricultural practices designed to minimize TSNA formation in tobacco. PMID:26806560

  5. The chemical composition of smokeless tobacco: a survey of products sold in the United States in 2006 and 2007.

    Science.gov (United States)

    Borgerding, M F; Bodnar, J A; Curtin, G M; Swauger, J E

    2012-12-01

    Selected toxicant concentrations and other chemical measures have been determined for 43 U.S. smokeless tobacco products sold in 2006 and 2007. Products evaluated included moist snuff, dry snuff, loose leaf, plug, dissolvable and snus tobacco brands. Reference products available for scientific research purposes and eleven Swedish products were also evaluated and compared to the commercial products studied. Chemical endpoints determined included benzo[a]pyrene (B[a]P), N'-nitrosonornicotine (NNN), N'-nitrosoanatabine (NAT), N'-nitrosoanabasine (NAB), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-Nitrosodimethylamine (NDMA), nitrite, cadmium, lead, arsenic, nickel, chromium, chloride, water, pH and nicotine. Different toxicant profiles were observed for the products studied, with snus tobacco brands generally containing relatively low concentrations of B[a]P and tobacco specific nitrosamines (TSNAs) compared to other moist snuffs. Smokeless tobacco reference product toxicant profiles were similar to corresponding commercial products, with the exception of the TSNA content of the dry snuff reference material. TSNA concentrations observed for all commercial products were lower than historically reported values, likely reflecting changes in product shelf life, tobacco curing practices and, possibly, product blend formulations during the last 20-30 years. The survey results summarized provide a temporal point of comparison with future data anticipated from FDA "harmful and potentially harmful constituents in tobacco products" reporting.

  6. Expression of a constitutively active nitrate reductase variant in tobacco reduces tobacco-specific nitrosamine accumulation in cured leaves and cigarette smoke.

    Science.gov (United States)

    Lu, Jianli; Zhang, Leichen; Lewis, Ramsey S; Bovet, Lucien; Goepfert, Simon; Jack, Anne M; Crutchfield, James D; Ji, Huihua; Dewey, Ralph E

    2016-07-01

    Burley tobaccos (Nicotiana tabacum) display a nitrogen-use-deficiency phenotype that is associated with the accumulation of high levels of nitrate within the leaf, a trait correlated with production of a class of compounds referred to as tobacco-specific nitrosamines (TSNAs). Two TSNA species, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN), have been shown to be strong carcinogens in numerous animal studies. We investigated the potential of molecular genetic strategies to lower nitrate levels in burley tobaccos by overexpressing genes encoding key enzymes of the nitrogen-assimilation pathway. Of the various constructs tested, only the expression of a constitutively active nitrate reductase (NR) dramatically decreased free nitrate levels in the leaves. Field-grown tobacco plants expressing this NR variant exhibited greatly reduced levels of TSNAs in both cured leaves and mainstream smoke of cigarettes made from these materials. Decreasing leaf nitrate levels via expression of a constitutively active NR enzyme represents an exceptionally promising means for reducing the production of NNN and NNK, two of the most well-documented animal carcinogens found in tobacco products. PMID:26800860

  7. A randomized, controlled exposure study in adult smokers of full flavor Marlboro cigarettes switching to Marlboro Lights or Marlboro Ultra Lights cigarettes.

    Science.gov (United States)

    Mendes, Paul; Kapur, Sunil; Wang, Jingzhu; Feng, Shixia; Roethig, Hans

    2008-08-01

    Rationale. To date no state-of-the-art clinical study has been conducted to address the question as to whether switching to lower tar cigarettes reduces exposure to smoke constituents in humans. Methods. Randomized, controlled, forced switching study in 225 adult smokers of full flavor Marlboro (MFF) cigarettes for 8 days with a 24-week follow-up. Subjects smoked MFF (a 15-mg Federal Trade Commission (FTC) tar cigarette) at baseline and were randomized to smoke 11-mg Marlboro Lights (ML) or 6-mg Marlboro Ultra Lights (MUL) cigarettes. Biomarkers of exposure to nicotine, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), pyrene, CO, benzene, acrolein, and mutagenic substances were measured. Results. In the short-term phase, switching from MFF to ML showed statistically significant decreases in nicotine exposure (-13%) and non-significant increases in CO exposure (+6%), while switching from MFF to MUL showed statistically significant decreases in nicotine (-27%) and CO (-13%) exposure. Both nicotine and CO biomarkers trended similarly in the 24-week follow-up as in the short-term phase. The other biomarkers of cigarette smoke constituents followed the same trend as nicotine at the end of the 24-week follow-up. Conclusions. Switching smokers to lower FTC tar yield cigarettes, on average, reduces nicotine and other biomarkers considered surrogates of tar exposure. PMID:18565634

  8. Synergistic Induction of Cyclooxygenase-2 by Transforming Growth Factor-β1 and Epidermal Growth Factor Inhibits Apoptosis in Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Debabrata Saha

    1999-12-01

    Full Text Available Increased expression of cyclooxygenase-2 (COX-2 expression has been observed in several human tumor types and in selected animal and cell culture models of carcinogenesis, including lung cancer. Increased expression of COX-2 and production of prostaglandins appear to provide a survival advantage to transformed cells through the inhibition of apoptosis, increased attachment to extracellular matrix, increased invasiveness, the stimulation of angiogenesis. In the present studies, we found that transforming growth factor β1 (TGF-β1 and epidermal growth factor (EGF synergistically induced the expression of COX-2 and prostaglandin E2 (PGE2 production in mink lung epithelial (Mvi Lu cells. EGF, but not PDGF or IGF-1, was able to inhibit TGF-β1-induced apoptosis in Mvi Lu cells and this effect was blocked by NS-398, a selective inhibitor of COX-2 activity, suggesting a possible role for COX-2 in the anti-apoptosic effect of EGF receptor ligands. The combination of TGF-β1 and EGF also significantly induced COX-2 expression in rat intestinal epithelial (RIE-1 cells and completely prevented sodium butyrate (NaBu-induced apoptosis. The synergistic induction of COX-2 by TGF-β1 and EGF was not observed in R1B-L17 cells, a line derived from Mvi Lu cells that lacks the TGF-β type-I receptor. AG1478, a selective inhibitor of EGF receptor tyrosine kinase activity, completely suppressed the induction of COX-2 expression by either EGF or TGF-β1+EGF. Also, PD98059, a specific inhibitor of MEK/ERK pathway, SB203580, a specific inhibitor of p38 MAPK activity, significantly inhibited the induction of COX-2 in response to combined EGF and TGF-β1. These results suggest an important collaborative interaction of TGF-β1 and EGF signaling in the induction of COX-2 and prostaglandin production in Mv1Lu cells.

  9. Vascular endothelial growth factor, matrix metalloproteinases, and cyclooxygenase-2 influence prognosis of uterine cervical cancer in young women.

    Science.gov (United States)

    Noriyuki, Maiko; Sumi, Toshiyuki; Zhi, Xu; Misugi, Fumiko; Nobeyama, Hiroyuki; Yoshida, Hiroyuki; Matsumoto, Yoshinari; Yasui, Tomoyo; Honda, Ken-Ichi; Ishiko, Osamu

    2007-09-01

    Recent changes in the lifestyle of young women have led to an increase in the rate of uterine cervical cancer. We investigated the clinicopathological characteristics of uterine cervical cancer in young women, and examined the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). Tumor samples from 439 patients with uterine cervical cancer, who were initially treated at Osaka City University Medical School Hospital, Japan between 1995 and 2004, were stained immunohistochemically. The patients were classified into two groups according to age at onset: group Y included women aged or =36 years. Group Y had more cases of squamous cell carcinoma, while group O had more advanced cases (Pcervical cancer in young women.

  10. Temporal and topographic profiles of cyclooxygenase-2 expression during 24 h of focal brain ishemia in rats.

    Science.gov (United States)

    Yokota, Chiaki; Kaji, Tomohito; Kuge, Yuji; Inoue, Hiroyasu; Tamaki, Nagara; Minematsu, Kazuo

    2004-03-11

    Substantial increases in cyclooxygenase-2 (COX-2) mRNA and protein levels were demonstrated in the peri-infarct and focal ischemic areas after 3-24 and 12-24 h, respectively, in rats. In the ischemic core, significant increases in COX-2 mRNA followed 6 h of ischemia, though the peak level was about one-third of that in the peri-infarct area. Increases in COX-2 protein in the ischemic core were not observed during ischemic periods. Diffuse, neuronal COX-2 staining was found in peri-infarct areas as well as in discrete, immunoreactive neurons in the ischemic core. Robust increases in prostaglandin E2 levels in the peri-infarct area were demonstrated following 24 h of ischemia. Prostaglandin production as well as COX-2 expression in ischemic tissues depended on the degree and duration of the reduction in cerebral blood flow.

  11. Effects of Acute and Chronic Cold Stress on Expression of Cyclooxygenase-2 and Prostaglandin E Synthase mRNA in Quail Intestine

    Directory of Open Access Journals (Sweden)

    J Fu, CP Liu1, ZW Zhang1, W Liao2 and SW Xu1,*

    2013-07-01

    Full Text Available The cold temperature, a common environmental stress, reduces the immunity and re-production activities of the poultry. This study aims to investigate the role of acute and chronic cold exposure in the regulation of cyclooxygenase-2 (COX-2 and prostaglandin E synthase (PTGES expression in the duodenum, jejunum, and ileum of quail. A total of 96 quail with 15 days of age were randomly allocated into 12 groups (8 each group for exposure to acute (up to 12 h and chronic (up to 20 days cold temperature (12±1°C. After that, different segments of the intestine were harvested and subjected to morphology observations under the light and electronic microscopes. qRT-PCR was performed to analyze expression of COX-2 and PTGES, and DNA sequencing was performed to analyze PCR products. The data showed that under acute cold stress, expression of COX-2 and PTGES mRNA was first decreased and then increased in the duodenum, jejunum, and ileum of quail. However, chronic cold stress induced expression of COX-2 and PTGES mRNA in the duodenum, jejunum and ileum of quail, which was then reduced after 20 days of cold exposure. Morphologically, significant changes were also observed in the duodenum, jejunum and ileum after both acute and chronic cold stresses to the animals. The data from the current study indicated that both acute and chronic cold stresses were able to induce inflammation responses in the duodenum, jejunum and ileum, which might be due to the cold-damaged intestinal morphology.

  12. The bitter barricading of prostaglandin biosynthesis pathway: understanding the molecular mechanism of selective cyclooxygenase-2 inhibition by amarogentin, a secoiridoid glycoside from Swertia chirayita.

    Directory of Open Access Journals (Sweden)

    Shantanu Shukla

    Full Text Available Swertia chirayita, a medicinal herb inhabiting the challenging terrains and high altitudes of the Himalayas, is a rich source of essential phytochemical isolates. Amarogentin, a bitter secoiridoid glycoside from S. chirayita, shows varied activity in several patho-physiological conditions, predominantly in leishmaniasis and carcinogenesis. Experimental analysis has revealed that amarogentin downregulates the cyclooxygenase-2 (COX-2 activity and helps to curtail skin carcinogenesis in mouse models; however, there exists no account on selective inhibition of the inducible cyclooxygenase (COX isoform by amarogentin. Hence the computer-aided drug discovery methods were used to unravel the COX-2 inhibitory mechanism of amarogentin and to check its selectivity for the inducible isoform over the constitutive one. The generated theoretical models of both isoforms were subjected to molecular docking analysis with amarogentin and twenty-one other Food and Drug Authority (FDA approved lead molecules. The post-docking binding energy profile of amarogentin was comparable to the binding energy profiles of the FDA approved selective COX-2 inhibitors. Subsequent molecular dynamics simulation analysis delineated the difference in the stability of both complexes, with amarogentin-COX-2 complex being more stable after 40ns simulation. The total binding free energy calculated by MMGBSA for the amarogentin-COX-2 complex was -52.35 KCal/mol against a binding free energy of -8.57 KCal/mol for amarogentin-COX-1 complex, suggesting a possible selective inhibition of the COX-2 protein by the natural inhibitor. Amarogentin achieves this potential selectivity by small, yet significant, structural differences inherent to the binding cavities of the two isoforms. Hypothetically, it might block the entry of the natural substrates in the hydrophobic binding channel of the COX-2, inhibiting the cyclooxygenation step. To sum up briefly, this work highlights the mechanism of the

  13. 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.

  14. 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

  15. 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...

  16. Nicotine impairs cyclooxygenase-2-dependent kinin-receptor-mediated murine airway relaxations

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Yuan, E-mail: yuan.xu@ki.se; Cardell, Lars-Olaf

    2014-02-15

    Introduction: Cigarette smoke induces local inflammation and airway hyperreactivity. In asthmatics, it worsens the symptoms and increases the risk for exacerbation. The present study investigates the effects of nicotine on airway relaxations in isolated murine tracheal segments. Methods: Segments were cultured for 24 h in the presence of vehicle, nicotine (10 μM) and/or dexamethasone (1 μM). Airway relaxations were assessed in myographs after pre-contraction with carbachol (1 μM). Kinin receptors, cyclooxygenase (COX) and inflammatory mediator expressions were assessed by real-time PCR and confocal-microscopy-based immunohistochemistry. Results: The organ culture procedure markedly increased bradykinin- (selective B{sub 2} receptor agonist) and des-Arg{sup 9}-bradykinin- (selective B{sub 1} receptor agonist) induced relaxations, and slightly increased relaxation induced by isoprenaline, but not that induced by PGE{sub 2}. The kinin receptor mediated relaxations were epithelium-, COX-2- and EP2-receptor-dependent and accompanied by drastically enhanced mRNA levels of kinin receptors, as well as inflammatory mediators MCP-1 and iNOS. Increase in COX-2 and mPGES-1 was verified both at mRNA and protein levels. Nicotine selectively suppressed the organ-culture-enhanced relaxations induced by des-Arg{sup 9}-bradykinin and bradykinin, at the same time reducing mPGES-1 mRNA and protein expressions. α7-nicotinic acetylcholine receptor inhibitors α-bungarotoxin and MG624 both blocked the nicotine effects on kinin B{sub 2} receptors, but not those on B{sub 1}. Dexamethasone completely abolished kinin-induced relaxations. Conclusion: It is tempting to conclude that a local inflammatory process per se could have a bronchoprotective component by increasing COX-2 mediated airway relaxations and that nicotine could impede this safety mechanism. Dexamethasone further reduced airway inflammation together with relaxations. This might contribute to the steroid resistance seen in

  17. Effects of nimesulide, acetylsalicylic acid, ibuprofen and nabumetone on cyclooxygenase-1- and cyclooxygenase-2-mediated prostanoid production in healthy volunteers ex vivo.

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    Kerola, Markku; Vuolteenaho, Katriina; Kosonen, Outi; Kankaanranta, Hannu; Sarna, Seppo; Moilanen, Eeva

    2009-01-01

    : The beneficial actions of non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with inhibition of cyclooxygenase-2 (COX-2), whereas some of their adverse effects are associated mainly with inhibition of COX-1. Selective COX-2 inhibitors reduce the risk of gastrointestinal adverse events, but increase the risk of thromboembolic events pointing to importance of optimal COX-1/COX-2 inhibition in drug safety. We compared the effects of acetylsalicylic acid, ibuprofen, nabumetone and nimesulide on COX-1 and COX-2 pathways in healthy volunteers in an ex vivo set-up using single oral doses commonly used to treat acute pain. In a randomized, double-blind four-phase cross-over study, 15 healthy volunteers were given orally a single dose of either acetylsalicylic acid 500 mg, ibuprofen 400 mg, nabumetone 1 g or nimesulide 100 mg. Blood samples were drawn before and 1, 3, 6, 24 and 48 hr after the drug for the assessment of COX-1 and COX-2 activity. COX-1 activity was measured as thromboxane(2) production during blood clotting and COX-2 activity as endotoxin-induced prostaglandin E(2) synthesis in blood leucocytes. The data show that after a single oral dose these four NSAIDs have different profiles of action on COX-1 and COX-2. As expected, acetylsalicylic acid appeared to be COX-1-selective and ibuprofen effectively inhibited both COX-1 and COX-2. Nabumetone showed only a slight inhibitory effect on COX-1 and COX-2. Nimesulide caused almost complete suppression of COX-2 activity and a partial reduction of COX-1 activity. This confirms the relative COX-2 selectivity of nimesulide.

  18. Helicobacter pylori, cyclooxygenase-2 and evolution of gastric lesions: results from an intervention trial in China.

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    Zhang, Yang; Pan, Kai-Feng; Zhang, Lian; Ma, Jun-Ling; Zhou, Tong; Li, Ji-You; Shen, Lin; You, Wei-Cheng

    2015-12-01

    To investigate the role of cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) in the process of Helicobacter pylori-induced gastric carcinogenesis, a prospective study based on an intervention trial was conducted in Linqu County, China. A total of 1401 subjects with histopathologic diagnosis were investigated at baseline, among those, 919 completed subsequent interventions (anti-H.pylori and/or celecoxib treatment). Expressions of COX-2 and Ki-67 were assessed by immunohistochemistry, and PGE2 levels were measured by enzyme immunoassay before and after interventions, respectively. We found a grade-response relationship between COX-2 expression level and risk of advanced gastric lesions at baseline. Stratified analysis indicated an additive interaction between COX-2 expression and H.pylori infection on the elevated risk of advanced gastric lesions. The odds ratios (ORs) for both factors combined were 9.31 [95% confidence interval (CI): 4.13-20.95] for chronic atrophic gastritis, 16.26 (95% CI: 7.29-36.24) for intestinal metaplasia and 21.13 (95% CI: 7.87-56.75) for dysplasia, respectively. After interventions, COX-2 expression and Ki-67 labeling index (LI) were decreased in anti-H.pylori group (OR: 1.65, 95% CI: 1.36-1.99 for COX-2; OR: 1.78, 95% CI: 1.49-2.12 for Ki-67) or anti-H.pylori followed by celecoxib group (OR: 1.41, 95% CI: 1.17-1.70 for COX-2; OR: 1.63, 95% CI: 1.37-1.94 for Ki-67). PGE2 levels were decreased in all treatment groups. Furthermore, the regression of gastric lesions was associated with the decrease of COX-2 expression or Ki-67 LI after interventions. Our findings indicate that H.pylori-induced COX-2/PGE2 pathways play an important role on the progression of precancerous gastric lesions in a Chinese population. PMID:26449252

  19. Requirement of cyclooxygenase-2 expression and prostaglandins for human prostate cancer cell invasion.

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    Nithipatikom, Kasem; Isbell, Marilyn A; Lindholm, Paul F; Kajdacsy-Balla, Andre; Kaul, Sushma; Campell, William B

    2002-01-01

    The PC-3 Low Invasive cells and the PC-3 High Invasive cells were used to investigate the correlation of the COX-2 expression and its arachidonic acid metabolites, prostaglandins, with their invasiveness through Matrigel using a Boyden chamber assay. The COX-2 expression in PC-3 High Invasive cells was approximately 3-fold higher than in PC-3 Low Invasive cells while the COX-1 expression was similar in both cell sublines. When incubated with arachidonic acid, PGE2 was the major prostaglandin produced by these cells. PC-3 High Invasive cells produced PGE2 approximately 2.5-fold higher than PC-3 Low Invasive cells. PGD2 was the second most abundant prostaglandin produced by these cells. Both indomethacin (a nonspecific COX inhibitor) and NS-398 (a specific COX-2 inhibitor) inhibited the production of prostaglandins and the cell invasion. PGE2 alone did not induce the cell invasion of PC-3 Low Invasive cells. However, PGE2 reversed the inhibition of cell invasion by NS-398 and enhanced the cell invasion of the PC-3 High Invasive cells. In contrast, PGD2 slightly inhibited the cell invasion. These results suggest that in the PC-3 Low Invasive cells, COX-2-derived PGE2 may not be sufficient to induce cell invasion while in the PC-3 High Invasive cells, PGE2 may be sufficient to act as an enhancer for the cell invasion. Further, PGD2 may represent a weak inhibitor and counteracts the effect of PGE2 in the cell invasion. PMID:12498388

  20. Evaluation of 2 celecoxib derivatives: analgesic effect and selectivity to cyclooxygenase-2/1

    Institute of Scientific and Technical Information of China (English)

    Zhi-hong LU; Xiao-yun XIONG; Bang-le ZHANG; Guo-cheng LIN; Yu-xiang SHI; Zhen-guo LIU; Jing-ru MENG; Yu-mei ZHOU; Qi-bing MEI

    2005-01-01

    Aim: To evaluate the analgesic effects of 2 celecoxib derivatives and their inhibitory effects on cyclooxygenase (COX). Methods: Four antinociceptive assays were used: the acetic acid-induced writhing test, hot plate test, hot tail-flick test and formalin test. Three doses were used in the analgesic assays and ED50 values were calculated. For the selectivity assay, macrophages were incubated with test compounds at various concentrations and then stimulated with calcimycin or lipopolysaccharide (LPS). The amounts of 6-keto-prostaglandin F1α (6-keto-PGF1α)and prostaglandin E2 (PGE2) in the supernatant were examined by radioimmunoassay (RIA). The selectivity of the test compounds was expressed as the IC50,COX-1/IC50,COX-2 value. Results: Celecoxib and its 2 derivatives had a significant analgesic effect. The ED50 values of celecoxib, PC-406 and PC-407 were 94.2, 67.9, and 63.3mg/kg, respectively, for the acetic acid-induced writhing test; 104.7, 89.1, and 30.0mg/kg, respectively, for the hot tail-flick response test; 60.7, 56.7, and 86.2 mg/kg,respectively, for the hot plate response test; 67.1,55.8, and 68.8 mg/kg, respectively,for the formalin-induced response. That is, the ED50 of PC-406 was the lowest for the formalin and hot plate tests, which focus on changes above the spinal cord level; however, the ED50 of PC-407 was lowest for the tail-flick and writhing tests,which focus on changes at the spinal cord level. Celecoxib and PC-407 inhibited COX-1 with IC50 values of 39.8 and 27.5 nmol/L, respectively. PC-406 inhibited COX-1 with an IC50 value of more than 1000 nmol/L. The IC50 values for the effect of celecoxib, PC-406 and PC-407 on COX-2 were 4.8, 8.9, and 1.9 nmol/L respectively.The IC50,COX-1/IC50,COX-2 ratios for celecoxib and PC-407 were 8.3 and 14.4, respectively. For PC-406, the ratio was greater than 112.2. Conclusion: Derivatives of celecoxib via substitution with an isopropyl or naphthyl group at the 5 position in the pyrazole ring still have

  1. Interleukin-6 and Cyclooxygenase-2 downregulation by fatty-acid fractions of Ranunculus constantinopolitanus

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    Al-Saghir Jamal A

    2009-11-01

    (1:5:8:1 ratio, reduced ET-induced IL-6 levels in SCp2 cells without affecting cell viability or morphology. When compared to fish oil, conjugated linoleic acid (CLA and to individual FAs as palmitic, linoleic, oleic and stearic acid or to a mix of these FAs (1:5:8:1 ratio, Y2+3 exhibited higher potency in reducing ET-induced IL-6 levels within a shorter period of time. Y2+3 also reduced COX-2 expression in IL-1-treated Mode-K cells. Conclusion Our studies demonstrate the existence of potential anti-inflammatory bioactivities in R. constantinopolitanus and attribute them to a FA mix in this plant.

  2. Effects of IL-4 on cyclooxygenase-2 and platelet-derived growth factor in the lungs of COPD rats

    Institute of Scientific and Technical Information of China (English)

    Yan Li; Shengdao Xiong; Weining Xiong; Yongjian Xu

    2007-01-01

    Objective: To explore the role of interleukin 4 (IL-4), expressions of cyclooxygenase-2 (COX-2) and platelet-derived growth factor (PDGF) in the model of chronic obstructive pulmonary disease (COPD), in the lungs of rats. Methods: Male Wistar rats were used to build up the model of COPD. Rats were randomly divided into the control group and model group, the IL-4 group and the dexamethasone group. The expressions of COX-2, PDGF-A and PDGF-B in the lung tissue were detected by western blotting and RT-PCR. Results: The expressions of COX-2, PDGF-A and PDGF-B in the model group were increased significantly.Those expressions in the IL-4 and dexamethasone group were notably decreased. Conclusion: IL-4 and dexamethasone could interfere in the establishment of COPD. The expressions of COX-2 and PDGF in the lung tissue of COPD were increased significantly and IL-4 and dexamethasone could decrease those expressions.

  3. The Expression of Cyclooxygenase-2 in Cervical Cancers and Hela Cells Was Regulated by Estrogen/Progestogen

    Institute of Scientific and Technical Information of China (English)

    LI Yunguang; PU Demin; LI Yanli

    2007-01-01

    To investigate the relationship between the expression of cyclooxygenase-2 (COX-2) and menstrual cycle, the regulatory effects of 17-β-estradiol (E2) and medroxyprogesterone acetate (MPA) on the expression of COX-2 in cervical cancer Hela cells were examined. Cervical cancer specimens were obtained from 47 pre-menopausal patients. The phase of menstrual cycle was determined by case history and HE staining of uterine endometrium. COX-2 was immunohistochemically stained by SABC staining and the staining intensity was determined with computerized image analysis system.Hela cells were incubated with alcohol, E2, E2+MPA, MPA for 12, 24 and 48 h respectively. The expression of COX-2 in Hela cells was detected by Western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR). Our results showed that the expression of COX-2 was significantly higher during proliferative phase than secretory phase (P<0.05), but there was no difference in the positive rate between proliferative phase and secretory phase (P>0.05). Incubation with E2 could significantly enhance the expression of COX-2 continually. On the contrary, E2+MPA and MPA alone could decrease the expression of COX-2 as compared with the control and E2 group (P<0.05 and P<0.01 respectively). It is concluded that the expression of COX-2 in cervical cancer of pre-menopausal patients and Hela cells was regulated by estrogen/progestogen.

  4. Targeting the prostaglandin E2 EP1 receptor and cyclooxygenase-2 in the amygdala kindling model in mice.

    Science.gov (United States)

    Fischborn, Sarah Verena; Soerensen, Jonna; Potschka, Heidrun

    2010-09-01

    The prostaglandin E2 EP1 receptor as well as the inflammatory enzyme cyclooxygenase-2 have been suggested as targets for disease modulation, improvement of therapeutic response, and restoration of pharmacosensitivity in epilepsies. Translational development of respective add-on approaches requires careful analysis of putative effects on ictogenesis. Therefore we evaluated the impact of the EP1 receptor antagonist SC-51089, the EP1 receptor agonist misoprostol and the COX-2 inhibitors celecoxib and NS-398 in the mouse amygdala kindling model of temporal lobe epilepsy. Neither celecoxib nor NS-398 affected the generation, spread and termination of seizure activity. Whereas SC-51089 did not affect the seizure threshold, the highest dose (30mg/kg) significantly decreased the seizure severity when administered 60min before stimulation. Moreover, SC-51089 significantly prolonged seizure duration at the highest dose. The EP1 receptor agonist misoprostol exerted contrasting effects on seizure duration with a significant decrease in the duration of motor seizure activity. The data suggest that doses of COX-2 inhibitors and EP1 receptor antagonists which exert disease modulating or antiepileptic drug potentiating effects do not negatively affect seizure control in temporal lobe epilepsy. The contrasting impact of the EP1 receptor antagonist and agonist suggests that EP1 receptors can influence endogenous mechanisms involved in termination of seizure activity.

  5. Isomeric iodinated analogs of nimesulide: Synthesis, physicochemical characterization, cyclooxygenase-2 inhibitory activity, and transport across Caco-2 cells.

    Science.gov (United States)

    Yamamoto, Yumi; Arai, Jun; Hisa, Takuya; Saito, Yohei; Mukai, Takahiro; Ohshima, Takashi; Maeda, Minoru; Yamamoto, Fumihiko

    2016-08-15

    Isomeric iodinated derivatives of nimesulide, with an iodine substituent on the phenoxy ring, were prepared with the aim of identifying potential candidate compounds for the development of imaging agents targeting cyclooxygenase-2 (COX-2) in the brain. Both the experimental logP7.4 and pKa values for these iodinated analogs were in the acceptable range for passive brain penetration. The para-iodo-substituted analog was a more potent and selective COX-2 inhibitor than nimesulide, with a potency that was comparable to the reference drug, celecoxib. Iodination at the ortho- or meta-position of the phenoxy ring was associated with a substantial loss of COX-2 inhibitory activity. Transport studies across Caco-2 cell monolayers in the presence and absence of a P-glycoprotein (P-gp) inhibitor, verapamil, indicated that the para-iodo-substituted analog was not a P-gp transport substrate; this feature is a prerequisite for potential in vivo brain imaging compounds. The para-iodo-substituted analog of nimesulide appears to be an attractive candidate for the development of radioiodine-labeled tracers for in vivo brain imaging of COX-2 levels. PMID:27325447

  6. Quantitative assessment of the association of COX-2 (Cyclooxygenase-2 immunoexpression with prognosis in human osteosarcoma: a meta-analysis.

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    Zhe Wang

    Full Text Available BACKGROUND: Numerous studies examining the relationship between Cyclooxygenase-2 (COX-2 immunoexpression and clinical outcome in osteosarcoma patients have yielded inconclusive results. METHODS: We accordingly conducted a meta-analysis of 9 studies (442 patients that evaluated the correlation between COX-2 immunoexpression and clinical prognosis (death. Pooled odds ratios (OR and risk ratios (RR with 95% confidence intervals (95% CI were calculated using the random-effects or fixed-effects model. RESULTS: Meta-analysis showed no significant association between COX-2 positivity and age, gender, tumor location, histology, stage, metastasis or 90% necrosis. Conversely, COX-2 immunoexpression was associated with overall survival rate (RR=2.12; 95% CI: 1.10-3.74; P=0.009 and disease-free survival rate (RR=1.63; 95% CI: 1.17-2.28; P=0.004 at 2 years. Sensitivity analysis performed by omitting low quality studies showed that the pooled results were stable. CONCLUSIONS: COX-2 positivity was associated with a lower 2-year overall survival rate and disease-free survival rate. COX-2 expression change is an independent prognostic factor in patients with osteosarcoma.

  7. CYCLO-OXYGENASE 2 IS PRESENT IN THE MAJORITY OF LESIONAL SKIN FROM PATIENTS WITH AUTOINMUNE BLISTERING DISEASES

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    Ana Maria Abreu Velez

    2013-10-01

    Full Text Available Introduction: The in situ immune response within skin biopsies from patients affected by autoimmune skin blistering diseases (ABDs is not well characterized. Aim: Based on the fact that the ABD immune response is considered an adaptive immune response, both an innate immune response and inflammation would be expected in these diseases. Our investigation investigates the presence of cyclo-oxygenase-2 (COX-2, since this enzyme is commonly involved in innate immune responses. Methods: We utilized immunohistochemistry (IHC to evaluate the presence of COX-2 in lesional skin biopsies of patients affected by ABDs. We tested 30 patients with endemic pemphigus foliaceus (EPF, 15 controls from the endemic area, and 15 biopsies from healthy controls from the USA. We also tested archival biopsies from patients with selected ABDs, including 20 patients with bullous pemphigoid, 20 with pemphigus vulgaris, 8 with pemphigus foliaceus and 12 with dermatitis herpetiformis. Results: Most ABD biopsies stained positive for COX-2 in the lesional blister and/or the dermal inflammatory infiltrate, accentuated in the upper neurovascular plexus. In BP and EPF, the COX-2 staining was also seen in the sweat glands. All controls were negative. Conclusions: We document that COX-2 is expressed in lesional skin of patients with ABDs.

  8. Design and synthesis of [(125)I]Pyricoxib: A novel (125)I-labeled cyclooxygenase-2 (COX-2) inhibitors.

    Science.gov (United States)

    Tietz, Ole; Dzandzi, James; Bhardwaj, Atul; Valliant, John F; Wuest, Frank

    2016-03-15

    Cyclooxygenase-2 (COX-2) is the key enzyme in the prostaglandin synthesis pathway which is involved in various pathophysiological conditions. The enzyme is membrane bound and located inside of the endoplasmic reticulum and nuclear membrane. Effective perfusion of inhibitors to the active site requires lipophilic drugs, which consequently display high unspecific background accumulation, for example, in fatty tissues. The objective of this work was the development of a small molecule radiolabeled with a long-lived iodine radioisotope to enable longer imaging times and better target-to-background ratios. A group of iodinated compounds (8-10) was synthesized and identified as selective COX-2 inhibitors (COX-2 IC50=0.85-13 μM). Molecular docking results provided the theoretical support for the experimental COX-2 inhibition data. Furthermore, a novel (125)I-containing trifluoro-pyrimidine compound ([(125)I]Pyricoxib) was prepared via radioiododestannylation reaction as potent and selective COX-2 inhibitor. Radiosynthesis of [(125)I]Pyricoxib was accomplished with innovative fluorous chemistry using fluorous chloroamine-T (F-CAT) as novel oxidizing agent in high radiochemical yields of 91 ± 4%. PMID:26898334

  9. Expression of Vascular Endothelial Growth Factor and Cyclooxygenase-2 in Laryngeal Squamous Cell Carcinoma and Its significance

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    In order to study the expressions of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) in human laryngeal squamous cell carcinoma (LSCC) and its significance,the expression of VEGF mRNA and COX-2 mRNA in 62 cases of LSCC and 54 adjacent noncancerous laryngeal tissues and 9 normal human laryngeal mucous tissues was detected by using techniques of semi-quantitative RT-PCR. It was found that the expression level of VEGF and COX-2 mRNA was significantly increased in LSCC as compared with that in the normal human laryngeal mucous tissues (both P<0.01), and the expression level of VEGF and COX-2 mRNA were significantly increased in stage Ⅲ + Ⅳ tissues of LSCC as compared with the stage Ⅰ + Ⅱ tissues of LSCC (P <0. 01). There was a high positive correlation between VEGF and COX-2 expression in LSCC (r=0. 756,P<0.01). These data raise the possibility that VEGF and COX-2 may play key roles in the growth, invasion and metastasis of LSCC.

  10. Misoprostol Reverse Hippocampal Neuron Cyclooxygenase-2 Downstream Signaling Imbalance in Aluminum-Overload Rats

    Science.gov (United States)

    Guo, Yuanxin; Lei, Wenjuan; Wang, Jianfeng; Hu, Xinyue; Wei, Yuling; Ji, Chaonan; Yang, Junqing

    2016-01-01

    Although COX-2 inhibition in animal models of neurodegenerative diseases has shown neuroprotection, recent studies have revealed some serious side effects (ulcers, bleeding, fatal cerebrovascular diseases etc.) and the limited benefits of COX-2 inhibitors. A more focused approach is necessary to explore the therapeutic effect of the COX downstream signaling pathway in neurological research. The aim of this study was to explore the alterations of the PGES-PGE2-EP signal pathway and the effect of misoprostol on neurodegeneration by chronic aluminum-overload in rats. Adult rats were treated by intragastric administration of aluminum gluconate. The PGE2 content and expression of PGES and EPs in the hippocampi of rats were detected using ELISA, q-PCR and Western blot analysis, respectively. The content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in the rat hippocampi were also detected. The misoprostol treatment dose-dependently improved spatial learning and memory function as well as healing after hippocampal neuron damage induced by chronic aluminum-overload in rats. Meanwhile, the administration of misoprostol resulted in a decrease in the PGE2 level and down-regulation of the mPGES-1, EP2 and EP4 expression levels, while there was a dose-dependent up-regulation of EP3 expression. These results suggest that misoprostol possesses a neuroprotective property, and the mechanism involves affecting the EP3 level and reducing the endogenous production of PGE2 through a negative feedback mechanism, increasing the EP3 expression level, decreasing the EP2 and EP4 expression levels, and rebuilding the mPGES-1-PGE2-EP1-4 signal pathway balance. In this way, misoprostol has a counteractive effect on oxidant stress and inflammation in the central nervous system. The PGES-PGE2-EPs signaling pathway is a potential therapeutic strategy for treating neurodegeneration in patients. PMID:27033056

  11. Cell cycle regulation and apoptotic cell death in experimental colon carcinogenesis: intervening with cyclooxygenase-2 inhibitors.

    Science.gov (United States)

    Saini, Manpreet Kaur; Sanyal, Sankar Nath

    2015-01-01

    Relative imbalance in the pathways regulating cell cycle, cell proliferation, or cell death marks a prerequisite for neoplasm. C-phycocyanin, a biliprotein from Spirulina platensis and a selective COX-2 inhibitor along with piroxicam, a traditional nonsteroidal antiinflammatory drug was used to investigate the role of cell cycle regulatory proteins and proinflammatory transcription factor NFκB in 1,2-dimethylhydrazine dihydrochloride (DMH)-induced rat colon carcinogenesis. Cell cycle regulators [cyclin D1, cyclin E, cyclin dependent kinase 2 (CDK2), CDK4, and p53], NFκB (p65) pathway, and proliferating cell nuclear antigen (PCNA) were evaluated by gene and protein expression, whereas apoptosis was studied by terminal deoxynucleotidyl transferase dUTP nick end labeling and apoptotic bleb assay. Molecular docking of ligand protein interaction was done to validate the in vivo results. Cyclin D1, cyclin E, CDK2, and CDK4 were overexpressed in DMH, whereas piroxicam and c-phycocyanin promoted the cell cycle arrest by downregulating them. Both drugs mediated apoptosis through p53 activation. Piroxicam and c-phycocyanin also stimulated antiproliferation by restraining PCNA expression and reduced cell survival via inhibiting NFκB (p65) pathway. Molecular docking revealed that phycocyanobilin (a chromophore of c-phycocyanin) interact with DNA binding site of NFκB. Inhibition of cyclin/CDK complex by piroxicam and c-phycocyanin affects the expression of p53 in colon cancer followed by downregulation of NFκB and PCNA levels, thus substantiating the antineoplastic role of these agents. PMID:25825916

  12. Selective cyclooxygenase-2 inhibition prevents bone resorption Inibidor seletivo de cicloxigenase-2 prevenindo reabsorção óssea

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    Carlos Augusto Nassar

    2005-03-01

    Full Text Available The aim of the present work was to evaluate the effect of a selective cyclooxygenase-2 (COX-2 inhibitor (meloxicam on the alveolar bone loss progression in experimentally induced periodontitis. Forty (40 Wistar rats were separated into 8 experimental groups (n = 5. Cotton ligatures were placed at the gingival margin level of the lower right first molars of some rats. Four groups were treated for 5 or 15 days with an oral dose of 15 mg/kg of body weight/day of the selective COX-2 inhibitor. The other groups were used as positive control (sham or negative control in each experimental period. Standardized digital radiographs were taken after sacrifice at 5 and 15 days to measure the amount of bone loss at the mesial root surface of the first molar tooth in each rat. The treatment with meloxicam did not induce weight alteration or other visible systemic manifestations. One way analysis of variance (ANOVA indicated that groups treated with meloxicam, after 5 days, had significantly less alveolar bone loss (p O objetivo deste trabalho foi avaliar o efeito de um inibidor seletivo da cicloxigenase-2 (COX-2 (meloxicam na progressão da perda óssea alveolar durante o desenvolvimento da doença periodontal experimental induzida. Quarenta (40 ratos Wistar foram separados em 8 grupos experimentais (n = 5. Ligaduras de fio de algodão foram colocadas na margem gengival do primeiro molar inferior direito de alguns ratos. Quatro grupos foram tratados por 5 ou 15 dias com uma dose oral de 15 mg/kg de peso corporal/dia do inibidor seletivo de COX-2. Os outros grupos foram usados como controle positivo (sham e controle negativo dentro de cada período experimental. Radiografias digitais padronizadas foram realizadas para medir a perda óssea na região mesial do primeiro molar inferior de cada rato. O efeito do tratamento com meloxicam não induziu alteração de peso ou outras manifestações sistêmicas visíveis. A Análise de Variância (ANOVA indicou que os

  13. Cyclooxygenase/lipoxygenase shunting lowers the anti-cancer effect of cyclooxygenase-2 inhibition in colorectal cancer cells

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    Ganesh Radhakrishnan

    2012-09-01

    Full Text Available Abstract Background Arachidonic acid metabolite, generated by cyclooxygenase (COX, is implicated in the colorectal cancer (CRC pathogenesis. Inhibiting COX may therefore have anti-carcinogenic effects. Results from use of non-steroidal anti-inflammatory drugs inhibiting only COX have been conflicting. It has been postulated that this might result from the shunting of arachidonic acid metabolism to the 5-lipoxygenase (5-LOX pathway. Cancer cell viability is promoted by 5-LOX through several mechanisms that are similar to those of cyclooxygenase-2 (COX-2. Expression of 5-LOX is upregulated in colorectal adenoma and cancer. The aim of this study was to investigate the shunting of arachidonic acid metabolism to the 5-LOX pathway by cyclooxygenase inhibition and to determine if this process antagonizes the anti-cancer effect in colorectal cancer cells. Methods Three colorectal cancer cell lines (HCA7, HT-29 & LoVo expressing 5-LOX and different levels of COX-2 expression were used. The effects of aspirin (a non-selective COX inhibitor and rofecoxib (COX-2 selective on prostaglandin E2 (PGE2 and leukotriene B4 (LTB4 secretion were quantified by ELISA. Proliferation and viability were studied by quantifying double-stranded DNA (dsDNA content and metabolic activity. Apoptosis was determined by annexin V and propidium iodide staining using confocal microscopy, and caspase-3/7 activity by fluorescent substrate assay. Results COX inhibitors suppressed PGE2 production but enhanced LTB4 secretion in COX-2 expressing cell lines (P  Conclusions This study provides evidence of shunting between COX and 5-LOX pathways in the presence of unilateral inhibition, and may explain the conflicting anti-carcinogenic effects reported with use of COX inhibitors.

  14. Cyclooxygenase 2 polymorphism and colorectal cancer: -765G>C variant modifies risk associated with smoking and body mass index

    Institute of Scientific and Technical Information of China (English)

    Li-Li Xing; Zhen-Ning Wang; Li Jiang; Yong Zhang; Ying-Ying Xu; Juan Li; Yang Luo; Xue Zhang

    2008-01-01

    AIM: To explore whether cyclooxygenase 2 (COX-2) -765G>C polymorphism is associated with susceptibility of colorectal cancer (CRC) and to evaluate the risk of colorectal cancer in relation to environmental exposures and polymorphism.METHODS: We conducted a case-control study of 137 patients with colorectal cancer and 199 cancer-free controls in northeast China. Multivariate logistic regression analysis was performed to calculate the adjusted odds ratio (OR) and 95% confidence interval (95% CI).RESULTS: The -765G>C polymorphism was not independently associated with CRC risk. However, risk associated with the polymorphism differed by smoking and body mass index (BMI). Smoking and BMI associated risks were stronger among those with -765GG genotype, showing that smokers had a 2.682-fold greater risk of CRC than nonsmokers (51/43 vs 68/126, P = 0.006). Compared to those with a normal body mass index (BMI 18.5-22.9), those with overweight (BMI 23-24.9) had a 3.909-fold higher risk of CRC (OR = 3.909, 95% CI = 2.081-7.344; P < 0.001), while those with obesity (BMI > 25) had a 2.031- fold higher risk of CRC (OR = 1.107, 95% CI = 1.107-3.726; P = 0.022).CONCLUSION: Although COX-2 -765G>C polymorphism is not associated with an increased risk of CRC, -765GG genotype appears to be related to an increased risk in the presence of smoking and higher BMI.

  15. No association between cyclooxygenase-2 and uridine diphosphate glucuronosyltransferase 1A6 genetic polymorphisms and colon cancer risk

    Institute of Scientific and Technical Information of China (English)

    Cheryl L Thompson; Sarah J Plummer; Alona Merkulova; Iona Cheng; Thomas C Tucker; Graham Casey; Li Li

    2009-01-01

    AIM: To investigate the association of variations in the cyclooxygenase-2 (COX2) and uridine diphosphate glucuronosyltransferase 1A6 (UGT1A6) genes and nonsteroidal anti-inflammatory drugs (NSAIDs) use with risk of colon cancer. METHODS: NSAIDs, which are known to reduce the risk of colon cancer, act directly on COX2 and reduce its activity. Epidemiological studies have associated variations in the COX2 gene with colon cancer risk, but others were unable to replicate this finding. Similarly, enzymes in the UGT1A6 gene have been demonstrated to modify the therapeutic effect of NSAIDs on colon adenomas. Polymorphisms in the UGT1A6 gene have been statistically shown to interact with NSAID intake to influence risk of developing colon adenomas, but not colon cancer. Here we examined the association of tagging single nucleotide polymorphisms (SNPs) in the COX2 and UGT1A6 genes, and their interaction with NSAID consumption, on risk of colon cancer in a population of 422 colon cancer cases and 481 population controls. RESULTS: No SNP in either gene was individually statistically significantly associated with colon cancer, nor did they statistically significantly change the protective effect of NSAID consumption in our sample. Like others, we were unable to replicate the association of variants in the COX2 gene with colon cancer risk ( P > 0.05), and we did not observe that these variants modify the protective effect of NSAIDs ( P > 0.05). We were able to confirm the lack of association of variants in UGT1A6 with colon cancer risk, although further studies will have to be conducted to confirm the association of these variants with colon adenomas. CONCLUSION: Our study does not support a role of COX2 and UGT1A6 genetic variations in the development of colon cancer.

  16. 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.

  17. Analgesic Efficacy of Firocoxib, a Selective Inhibitor of Cyclooxygenase 2, in a Mouse Model of Incisional Pain.

    Science.gov (United States)

    Reddyjarugu, Balagangadharreddy; Pavek, Todd; Southard, Teresa; Barry, Jason; Singh, Bhupinder

    2015-07-01

    Pain management in laboratory animals is generally accomplished by using opioids and NSAIDs. However, opioid use is hindered by controlled substance requirements and a relatively short duration of action. In this study, we compared the analgesic efficacy of firocoxib (a cyclooxygenase-2-selective NSAID) with that of buprenorphine in the mouse model of plantar incisional pain by objective measurement of mechanical allodynia and thermal hyperalgesia using von Frey and Hargreaves equipment, respectively. Our experimental design included 5 treatment groups: firocoxib at 10 mg/kg IP every 24 h (F10 group); firocoxib at 20 mg/kg IP every 24 h (F20); buprenorphine at 0.2 mg/kg SC every 8 h; intraperitoneal normal saline every 24 h; and sham group (anesthesia, no incision) treated with firocoxib at 20 mg/kg IP every 24 h (sham+F20). All mice underwent nociceptive assays at 24 h before and 4, 24, 48, and 72 h after surgery. Buprenorphine alleviated allodynia at all time points after incision. The F10 treatment alleviated allodynia at 4, 24, and 48 h, whereas F20 alleviated allodynia at 24, 48, and 72 h. None of the treatments alleviated thermal hyperalgesia at 4h. Except for F10 and buprenorphine at 24 h, all treatments alleviated thermal hyperalgesia at 24, 48, and 72 h. No significant differences were noted between the 2 doses of firocoxib and buprenorphine regarding mechanical allodynia and thermal hyperalgesia at all time points. In conclusion, the analgesic efficacy of firocoxib is comparable to that of buprenorphine in this mouse pain model. PMID:26224441

  18. Simultaneous inhibition of EGFR/VEGFR and cyclooxygenase-2 targets stemness-related pathways in colorectal cancer cells.

    Directory of Open Access Journals (Sweden)

    Araceli Valverde

    Full Text Available Despite the demonstrated benefits of anti-EGFR/VEGF targeted therapies in metastatic colorectal cancer (mCRC, many patients initially respond, but then show evidence of disease progression. New therapeutic strategies are needed to make the action of available drugs more efficient. Our study aimed to explore whether simultaneous targeting of EGFR/VEGF and cyclooxygenase-2 (COX-2 may aid the treatment and management of mCRC patients. The dual tyrosine kinase inhibitor AEE788 and celecoxib were used to inhibit EGFR/VEGFR and COX-2, respectively, in colorectal cancer cells. COX-2 inhibition with celecoxib augmented the antitumoral and antiangiogenic efficacy of AEE788, as indicated by the inhibition of cell proliferation, induction of apoptosis and G1 cell cycle arrest, down-regulation of VEGF production by cancer cells and reduction of cell migration. These effects were related with a blockade in the EGFR/VEGFR signaling axis. Notably, the combined AEE788/celecoxib treatment prevented β-catenin nuclear accumulation in tumor cells. This effect was associated with a significant downregulation of FOXM1 protein levels and an impairment in the interaction of this transcription factor with β-catenin, which is required for its nuclear localization. Furthermore, the combined treatment also reduced the expression of the stem cell markers Oct 3/4, Nanog, Sox-2 and Snail in cancer cells, and contributed to the diminution of the CSC subpopulation, as indicated by colonosphere formation assays. In conclusion, the combined treatment of AEE788 and celecoxib not only demonstrated enhanced anti-tumoral efficacy in colorectal cancer cells, but also reduced colon CSCs subpopulation by targeting stemness-related pathways. Therefore, the simultaneous targeting of EGFR/VEGF and COX-2 may aid in blocking mCRC progression and improve the efficacy of existing therapies in colorectal cancer.

  19. Simultaneous Inhibition of EGFR/VEGFR and Cyclooxygenase-2 Targets Stemness-Related Pathways in Colorectal Cancer Cells

    Science.gov (United States)

    Valverde, Araceli; Peñarando, Jon; Cañas, Amanda; López-Sánchez, Laura M.; Conde, Francisco; Hernández, Vanessa; Peralbo, Esther; López-Pedrera, Chary; de la Haba-Rodríguez, Juan; Aranda, Enrique; Rodríguez-Ariza, Antonio

    2015-01-01

    Despite the demonstrated benefits of anti-EGFR/VEGF targeted therapies in metastatic colorectal cancer (mCRC), many patients initially respond, but then show evidence of disease progression. New therapeutic strategies are needed to make the action of available drugs more efficient. Our study aimed to explore whether simultaneous targeting of EGFR/VEGF and cyclooxygenase-2 (COX-2) may aid the treatment and management of mCRC patients. The dual tyrosine kinase inhibitor AEE788 and celecoxib were used to inhibit EGFR/VEGFR and COX-2, respectively, in colorectal cancer cells. COX-2 inhibition with celecoxib augmented the antitumoral and antiangiogenic efficacy of AEE788, as indicated by the inhibition of cell proliferation, induction of apoptosis and G1 cell cycle arrest, down-regulation of VEGF production by cancer cells and reduction of cell migration. These effects were related with a blockade in the EGFR/VEGFR signaling axis. Notably, the combined AEE788/celecoxib treatment prevented β-catenin nuclear accumulation in tumor cells. This effect was associated with a significant downregulation of FOXM1 protein levels and an impairment in the interaction of this transcription factor with β-catenin, which is required for its nuclear localization. Furthermore, the combined treatment also reduced the expression of the stem cell markers Oct 3/4, Nanog, Sox-2 and Snail in cancer cells, and contributed to the diminution of the CSC subpopulation, as indicated by colonosphere formation assays. In conclusion, the combined treatment of AEE788 and celecoxib not only demonstrated enhanced anti-tumoral efficacy in colorectal cancer cells, but also reduced colon CSCs subpopulation by targeting stemness-related pathways. Therefore, the simultaneous targeting of EGFR/VEGF and COX-2 may aid in blocking mCRC progression and improve the efficacy of existing therapies in colorectal cancer. PMID:26107817

  20. Cyclooxygenase-2, a Potential Therapeutic Target, Is Regulated by miR-101 in Esophageal Squamous Cell Carcinoma.

    Directory of Open Access Journals (Sweden)

    Ying Shao

    Full Text Available Cyclooxygenase-2 (COX-2 is known to promote the carcinogenesis of esophageal squamous cell carcinoma (ESCC. There are no reports on whether microRNAs (miRNAs regulate COX-2 expression in ESCC. This study investigated the effect of miR-101 on ESCC through modulating COX-2 expression in ESCC.Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR was used to quantify miR-101 expression in ESCC clinical tissues and cell lines. The effects of miR-101 on ESCC progression were evaluated by cell counting kit-8 (CCK8, transwell migration and invasion assays, as well as by flow cytometry. The COX-2 and PEG2 levels were determined by western blot and enzyme-linked immunosorbent assays (ELISA. The luciferase reporter assay was used to verify COX-2 as a direct target of miR-101. The anti-tumor activity of miR-101 in vivo was investigated in a xenograft nude mouse model of ESCC.Downregulation of miR-101 was confirmed through comparison of 30 pairs of ESCC tumor and adjacent normal tissues (P < 0.001, as well as in 11 ESCC cell lines and a human immortalized esophageal cell line (P < 0.001. Transfection of miR-101 in ESCC cell lines significantly suppressed cell proliferation, migration, and invasion (all P < 0.001. The antitumor effect of miR-101 was verified in a xenograft model. Furthermore, COX-2 was shown to be a target of miR-101.Overexpression of miR-101 in ESCC inhibits proliferation and metastasis. Therefore, the miR-101/COX-2 pathway might be a therapeutic target in ESCC.

  1. Epithelium-specific Ets transcription factor-1 acts as a negative regulator of cyclooxygenase-2 in human rheumatoid arthritis synovial fibroblasts

    OpenAIRE

    Lee, Chan-Mi; Gupta, Sahil; Wang, Jiafeng; Johnson, Elizabeth M.; Crofford, Leslie J.; Marshall, John C.; Kapoor, Mohit; Hu, Jim

    2016-01-01

    Background Rheumatoid arthritis (RA) is characterized by excessive synovial inflammation. Cyclooxygenase-2 (COX-2) is an enzyme that catalyzes the conversion of arachidonic acid (AA) into prostaglandins. Epithelium-specific Ets transcription factor-1 (ESE-1) was previously demonstrated to upregulate COX-2 in co-operation with nuclear factor kappa B (NFκB) in macrophages and chondrocytes. However, the role of ESE-1 in RA pathology has remained unclear. In this study, we aimed to elucidate the ...

  2. Sequential expression of cyclooxygenase-2, glutamate receptor-2, and platelet activating factor receptor in rat hippocampal neurons after fluid percussion injury

    Institute of Scientific and Technical Information of China (English)

    Zhiqiang Li; Qingming Shu; Lingzhi Li; Maolin Ge; Yongliang Zhang

    2014-01-01

    Traumatic brain injury causes gene expression changes in different brain regions. Occurrence and development of traumatic brain injury are closely related, involving expression of three factors, namely cyclooxygenase-2, glutamate receptor-2, and platelet activating factor receptor. However, little is known about the correlation of these three factors and brain neuronal injury. In this study, primary cultured rat hippocampal neurons were subjected to fluid percussion injury according to Scott’s method, with some modifications. RT-PCR and semi-quantitative immunocytochemical staining was used to measure the expression levels of cyclooxygenase-2, glutamate receptor-2, and platelet activating factor receptor. Our results found that cycloox-ygenase-2 expression were firstly increased post-injury, and then decreased. Both mRNA and protein expression levels reached peaks at 8 and 12 hours post-injury, respectively. Similar sequential changes in glutamate receptor 2 were observed, with highest levels mRNA and pro-tein expression at 8 and 12 hours post-injury respectively. On the contrary, the expressions of platelet activating factor receptor were firstly decreased post-injury, and then increased. Both mRNA and protein expression levels reached the lowest levels at 8 and 12 hours post-injury, respectively. Totally, our findings suggest that these three factors are involved in occurrence and development of hippocampal neuronal injury.

  3. Characterization of the effects of cyclooxygenase-2 inhibition in the regulation of apoptosis in human small and non-small cell lung cancer cell lines.

    LENUS (Irish Health Repository)

    Alam, Mahmood

    2012-02-03

    BACKGROUND: Cyclooxygenase-2 enzyme (COX-2) is overexpressed in human non-small cell lung cancer (NSCLC) but is not expressed in small cell lung cancer. Selective COX-2 inhibitors have been shown to induce apoptosis in NSCLC cells, an effect which is associated with the regulation of intracellular MAP kinase (MAPK) signal pathways. Our aims were to characterize the effects of COX-2 inhibition by rofecoxib on apoptosis in human NSCLC and small cell lung cancer cell lines. METHODS: The human NSCLC cell line NCI-H2126 and small cell lung cancer cell line DMS-79 were used. Constitutive COX-2 protein levels were first determined by Western blot test. Levels of apoptosis were evaluated by using propidium iodide staining on FACScan analysis after incubation of NCI-H2126 and DMS-79 with p38 MAPK inhibitor SB202190 (25 ?microM), NF-kappaB inhibitor SN50 (75 microg\\/mL), and rofecoxib at 100 and 250 microM. All statistical analysis was performed by analysis of variance. RESULTS: Western blot test confirmed the presence of COX-2 enzyme in NCI-H2126 and absence in DMS-79. Interestingly, rofecoxib treatment demonstrated a dose-dependent increase in apoptosis in both cell lines. Given this finding, the effect of rofecoxib on NF-kappaB and p38 MAPK pathways was also examined. Apoptosis in both cell lines was unaltered by SN50, either alone or in combination with rofecoxib. A similar phenomenon was observed in NCI-H2126 cells treated with SB202190, either alone or in combination with rofecoxib. In contrast, p38 MAPK inhibition greatly upregulated DMS-79 apoptosis in a manner that was unaltered by the addition of rofecoxib. CONCLUSIONS: Rofecoxib led to a dose-dependent increase in apoptosis in both tumor cell lines. This effect occurred independently of COX-2, NF-kappaB, and p38 MAPK pathways in DMS-79 cells. As such, rofecoxib must act on alternative pathways to regulate apoptosis in human small cell lung cancer cells.

  4. Experimental study on selective cyclooxygenase-2 inhibitor combined with radiotherapy for human prostate carcinoma xenografts in nude mice

    International Nuclear Information System (INIS)

    Objective: To investigate the anti-tumor and radiation-enhancement effects and observe a coordinate repression of celecoxib, a selected cyclooxygenase -2 inhibitor in prostate carcinoma. Methods: An animal model of human prostate carcinoma in BALC/C male nude mice was establised by injecting suspension of PC-3 cells and the mice were randomly divided into 4 groups which were interfered with celecoxib, radiation, and both celecoxib and radiation respectively, with 6 rats in each group. The effect of treatment was assessed by tumor growth delay (TGD) and radiosensitization enhancement effector (EF); the tumor tissues were collected and assessed for the detection of cyclooxygense-2 mRNA and prostaglandin E2 by RT-PCR and ELISA, and histopathological changes of transplanted mouse's important organs were observed. Results: The time that the longest diameters of all tumors growing from 8.0mm to 12.0mm for the control group and the celecoxib group was(6.18 ± 0.72)d and(7.87 ± 0.76)d, respectively ,while the time for the radiation group and celecoxib + radiation group was (9.16 ± 0.89)d and (12.62 ± 1.28)d respectively. The growth of tumors was significantly different among these groups (P2 levels between the control group and other groups (P2 levels between the radiation group and celecoxib + radiation group (P>0.05). Significant correlations were found between the growth delayed by celecoxib and the drop of prostaglandin E2 levels (r=0.807); Analysis of variance showed that there was no significant difference in cyclooxygense-2 mRNA among these four groups (P > 0.05). No significant toxic pathological changes of transplanted mouse's important organs were observed. Conclusion: Our results suggest a coordinative repression between celecoxib and radiation in inhibiting human prostate carcinoma xenografts by the anti-tumor and radiation-enhancement, which is safe and effective in some extent and may contribute to enlighten the future study and clinical therapy of

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Cyclo-oxygenase-2 selective inhibitors and nonsteroidal anti-inflammatory drugs: balancing gastrointestinal and cardiovascular risk

    Directory of Open Access Journals (Sweden)

    McQuay Henry J

    2007-08-01

    Full Text Available Abstract Background Differences between gastrointestinal and cardiovascular effects of traditional NSAID or cyclooxygenase-2 selective inhibitor (coxib are affected by drug, dose, duration, outcome definition, and patient gastrointestinal and cardiovascular risk factors. We calculated the absolute risk for each effect. Methods We sought studies with large amounts of information to calculate annualised rates for clearly defined gastrointestinal (complicated upper gastrointestinal perforations, ulcers, or bleeds, but not symptomatic or endoscopic ulcers and serious cardiovascular outcomes (antiplatelet trial collaborators – APTC – outcome of fatal or nonfatal myocardial infarction or stroke, or vascular death. Results Meta-analyses and large randomised trials specifically analysing serious gastrointestinal bleeding or cardiovascular events occurring with five different coxibs had appropriate data. In total there were 439 complicated upper gastrointestinal events in 49,006 patient years of exposure and 948 serious cardiovascular events in 99,400 patient years of exposure. Complicated gastrointestinal events occurred less frequently with coxibs than NSAIDs; serious cardiovascular events occurred at approximately equal rates. For each coxib, the reduction in complicated upper gastrointestinal events was numerically greater than any increase in APTC events. In the overall comparison, for every 1000 patients treated for a year with coxib rather than NSAID, there would be eight fewer complicated upper gastrointestinal events, but one more fatal or nonfatal heart attack or stroke. Three coxib-NSAID comparisons had sufficient numbers of events for individual comparisons. For every 1000 patients treated for a year with celecoxib rather than an NSAID there would be 12 fewer upper gastrointestinal complications, and two fewer fatal or nonfatal heart attacks or strokes. For rofecoxib there would be six fewer upper gastrointestinal complications, but three

  7. Downregulation of survivin expression and concomitant induction of apoptosis by celecoxib and its non-cyclooxygenase-2-inhibitory analog, dimethyl-celecoxib (DMC, in tumor cells in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Hofman Florence M

    2006-05-01

    Full Text Available Abstract Background 2,5-Dimethyl-celecoxib (DMC is a close structural analog of the selective cyclooxygenase-2 (COX-2 inhibitor celecoxib (Celebrex® that lacks COX-2-inhibitory function. However, despite its inability to block COX-2 activity, DMC is able to potently mimic the anti-tumor effects of celecoxib in vitro and in vivo, indicating that both of these drugs are able to involve targets other than COX-2 to exert their recognized cytotoxic effects. However, the molecular components that are involved in mediating these drugs' apoptosis-stimulatory consequences are incompletely understood. Results We present evidence that celecoxib and DMC are able to down-regulate the expression of survivin, an anti-apoptotic protein that is highly expressed in tumor cells and known to confer resistance of such cells to anti-cancer treatments. Suppression of survivin is specific to these two drugs, as other coxibs (valdecoxib, rofecoxib or traditional NSAIDs (flurbiprofen, indomethacin, sulindac do not affect survivin expression at similar concentrations. The extent of survivin down-regulation by celecoxib and DMC in different tumor cell lines is somewhat variable, but closely correlates with the degree of drug-induced growth inhibition and apoptosis. When combined with irinotecan, a widely used anticancer drug, celecoxib and DMC greatly enhance the cytotoxic effects of this drug, in keeping with a model that suppression of survivin may be beneficial to sensitize cancer cells to chemotherapy. Remarkably, these effects are not restricted to in vitro conditions, but also take place in tumors from drug-treated animals, where both drugs similarly repress survivin, induce apoptosis, and inhibit tumor growth in vivo. Conclusion In consideration of survivin's recognized role as a custodian of tumor cell survival, our results suggest that celecoxib and DMC might exert their cytotoxic anti-tumor effects at least in part via the down-regulation of survivin – in a

  8. Pioglitazone ameliorates nonalcoholic steatohepatitis by down-regulating hepatic nuclear factor-kappa B and cyclooxygenases-2 expression in rats

    Institute of Scientific and Technical Information of China (English)

    ZHAO Jia-sheng; ZHU Feng-shang; LIU Su; YANG Chang-qing; CHEN Xi-mei

    2012-01-01

    Background Pioglitazone is effective in nonalcoholic steatohepatitis (NASH),but the mechanisms of action are not completely understood.This study was designed to investigate the effects of pioglitazone on hepatic nuclear factor-kappa B (NF-κB) and cyclooxygenases-2 (COX-2) expression in NASH rats.Methods Thirty Sprague-Dawley male rats were randomly assigned to a control group (n=10),NASH group (n=10),and pioglitazone treatment group (n=10).Liver tissues were processed for histology by hematoxylin & eosin and Masson stained.Serum alanine aminotransferase (ALT),cholesterol,triglyceride,fasting blood glucose (FBG),fasting insulin (FINS) levels and biochemical parameters of antioxidant enzyme activities,tumor necrosis factor alpha (TNF-α),prostaglandin E2 (PGE2) levels in serum and liver were measured.The mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARy),NF-κB and COX-2 were determined by real-time polymerase chain reaction,Westem blotting and immunohistochemistry.One-way analysis of variance (ANOVA) and Wilcoxon's signed-rank test was used for the statistical analysis.Results There were severe steatosis,moderate inflammatory cellular infiltration and fibrosis in NASH rats.After pioglitazone treatment,steatosis,inflammation and fibrosis were significantly improved compared with the NASH group(X2=20.40,P <0.001; )X2=20.17,P <0.001; X2=13.98,P=0.002).Serum ALT,cholesterol,triglyceride,FBG,FINS levelswere significantly elevated in the NASH group (P <0.05).In the NASH group,total anti-oxidation competence (T-AOC),superoxide dismutase (SOD),catalase (CAT),glutathione peroxidase (GSH-PX) and malondialdehyde (MDA) levels inserum and liver were conspicuous disordered than those parameters in the control group.Meanwhile,TNF-α and PGE2levels in serum and liver were significantly increased compared with the control group.Immunohistochemistry showedNF-KB and COX-2 expression in liver was significantly elevated.However,PPARy level

  9. Helicobacter pylori VacA enhances prostaglandin E2 production through induction of cyclooxygenase 2 expression via a p38 mitogen-activated protein kinase/activating transcription factor 2 cascade in AZ-521 cells

    DEFF Research Database (Denmark)

    Hisatsune, Junzo; Yamasaki, Eiki; Nakayama, Masaaki;

    2007-01-01

    Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase 2 (COX-2) mRNA in a time- and dose-dependent manner. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erk1/2 cascade......A-induced COX-2 expression. In parallel with COX-2 expression, VacA increased prostaglandin E(2) (PGE(2)) production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE(2) production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription...... promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-small interfering RNA duplexes resulted in suppression of COX-2 expression. Thus, VacA enhances PGE(2) production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading...

  10. Development, validation, and application of a liquid chromatography-tandem mass spectrometry method for the determination of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in human hair.

    Science.gov (United States)

    Yao, Li; Yang, Jun; Guan, Ya-feng; Liu, Bai-zhan; Zheng, Sai-jing; Wang, Wei-miao; Zhu, Xiao-lan; Zhang, Zhi-dan

    2012-11-01

    The tobacco-specific nitrosamine metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a valuable biomarker for human exposure to the carcinogenic nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in tobacco and tobacco smoke. In this work, an efficient and sensitive method for the analysis of NNAL in human hair was developed and validated. The hair sample was extracted by NaOH solution digestion, purified by C(18) solid-phase extraction (SPE) and molecularly imprinted solid-phase extraction, further enriched by reverse-phase ultrasound-assisted dispersive liquid-liquid microextraction (USA-DLLME) into 1.0 % aqueous formic acid, and finally analyzed by liquid chromatography-electrospray ionization tandem mass spectrometry. Good linearity was obtained in the range of 0.24-10.0 pg/mg hair with a correlation coefficient of 0.9982, when 150 mg hair was analyzed. The limit of detection and lower limit of quantification were 0.08 and 0.24 pg/mg hair, respectively. Accuracies determined from hair samples spiked with three different levels of NNAL ranged between 87.3 and 107.7 %. Intra- and inter-day relative standard deviations varied from 4.1 to 8.5 % and from 6.9 to 11.3 %, respectively. Under the optimized conditions, an enrichment factor of 20 was obtained. Finally, the developed method was applied for the analysis of NNAL in smokers' hair. The proposed sample preparation procedure combining selectivity of two-step SPE and enrichment of DLLME significantly improves the purification and enrichment of the analyte and should be useful to analyze NNAL in hair samples for cancer risk evaluation and cancer prevention in relation to exposure to the tobacco-specific carcinogen NNK. PMID:22926132

  11. Tobacco-Specific Nitrosamines in Electronic Cigarettes: Comparison between Liquid and Aerosol Levels

    Directory of Open Access Journals (Sweden)

    Konstantinos E. Farsalinos

    2015-07-01

    Full Text Available Introduction: Although electronic cigarette (EC liquids contain low levels of tobacco-specific nitrosamines (TSNAs, studies evaluating the levels emitted to the aerosol are scarce. The purpose of this study was to compare the levels of TSNAs between liquids and generated aerosol. Methods: Three EC liquids were obtained from the market. An additional (spiked sample was prepared by adding known amounts of standard TSNAs solutions to one of the obtained liquids. N-nitrosonornicotine (NNN, N-nitrosoanatabine (NAT, N-nitrosoanabasine (NAB and 4-(methylnitrosamino1-(3-pyridyl-1-butanone (NNK were measured. Three 100-puff sets from each liquid were trapped in filter pads and were subsequently analyzed for the presence of TSNAs. The expected levels of TSNAs (calculated based on the liquid consumption were compared with the measured levels in the aerosol. Results: Only NAB was found at trace levels in two commercial liquids (1.2 and 2.3 ng/g, while the third contained 1.5 ng/g NAB and 7.7 ng/g NNN. The 100-puff sets resulted in 336–515 mg liquid consumption, with no TSNAs being detected in the aerosol. The spiked sample contained 42.0–53.9 ng/g of each of the TSNAs. All TSNAs were detected in the aerosol with the measured levels being statistically similar to the expected amounts. A significant correlation between expected and measured levels of TSNAs in the aerosol was found (r = 0.83, p < 0.001. Conclusion: The findings of this study show that exposure of EC users to TSNAs can be accurately assessed based on the levels present in the liquid, without the need to analyze the aerosol.

  12. Tobacco alkaloids and tobacco-specific nitrosamines in dust from homes of smokeless tobacco users, active smokers, and nontobacco users.

    Science.gov (United States)

    Whitehead, Todd P; Havel, Christopher; Metayer, Catherine; Benowitz, Neal L; Jacob, Peyton

    2015-05-18

    Smokeless tobacco products, such as moist snuff or chewing tobacco, contain many of the same carcinogens as tobacco smoke; however, the impact on children of indirect exposure to tobacco constituents via parental smokeless tobacco use is unknown. As part of the California Childhood Leukemia Study, dust samples were collected from 6 homes occupied by smokeless tobacco users, 6 homes occupied by active smokers, and 20 tobacco-free homes. To assess children's potential for exposure to tobacco constituents, vacuum-dust concentrations of five tobacco-specific nitrosamines, including N'-nitrosonornicotine [NNN] and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK], as well as six tobacco alkaloids, including nicotine and myosmine, were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We used generalized estimating equations derived from a multivariable marginal model to compare levels of tobacco constituents between groups, after adjusting for a history of parental smoking, income, home construction date, and mother's age and race/ethnicity. The ratio of myosmine/nicotine was used as a novel indicator of the source of tobacco contamination, distinguishing between smokeless tobacco products and tobacco smoke. Median dust concentrations of NNN and NNK were significantly greater in homes with smokeless tobacco users compared to tobacco-free homes. In multivariable models, concentrations of NNN and NNK were 4.8- and 6.9-fold higher, respectively, in homes with smokeless tobacco users compared to tobacco-free homes. Median myosmine/nicotine ratios were lower in homes with smokeless tobacco users (1.8%) compared to homes of active smokers (7.7%), confirming that cigarette smoke was not the predominant source of tobacco constituents in homes with smokeless tobacco users. Children living with smokeless tobacco users may be exposed to carcinogenic tobacco-specific nitrosamines via contact with contaminated dust and household surfaces.

  13. Urinary tobacco smoke-constituent biomarkers for assessing risk of lung cancer.

    Science.gov (United States)

    Yuan, Jian-Min; Butler, Lesley M; Stepanov, Irina; Hecht, Stephen S

    2014-01-15

    Tobacco-constituent biomarkers are metabolites of specific compounds present in tobacco or tobacco smoke. Highly reliable analytic methods, based mainly on mass spectrometry, have been developed for quantitation of these biomarkers in both urine and blood specimens. There is substantial interindividual variation in smoking-related lung cancer risk that is determined in part by individual variability in the uptake and metabolism of tobacco smoke carcinogens. Thus, by incorporating these biomarkers in epidemiologic studies, we can potentially obtain a more valid and precise measure of in vivo carcinogen dose than by using self-reported smoking history, ultimately improving the estimation of smoking-related lung cancer risk. Indeed, we have demonstrated this by using a prospective study design comparing biomarker levels in urine samples collected from smokers many years before their development of cancer versus those in their smoking counterparts without a cancer diagnosis. The following urinary metabolites were associated with lung cancer risk, independent of smoking intensity and duration: cotinine plus its glucuronide, a biomarker of nicotine uptake; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), a biomarker of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); and r-1-,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), a biomarker of polycyclic aromatic hydrocarbons (PAH). These results provide several possible new directions for using tobacco smoke-constituent biomarkers in lung cancer prevention, including improved lung cancer risk assessment, intermediate outcome determination in prevention trials, and regulation of tobacco products.

  14. DNA Sequence Variants in the Five Prime Untranslated Region of the Cyclooxygenase-2 Gene Are Commonly Found in Healthy Dogs and Gray Wolves.

    Directory of Open Access Journals (Sweden)

    Noa Safra

    Full Text Available The aim of this study was to investigate the frequency of regional DNA variants upstream to the translation initiation site of the canine Cyclooxygenase-2 (Cox-2 gene in healthy dogs. Cox-2 plays a role in various disease conditions such as acute and chronic inflammation, osteoarthritis and malignancy. A role for Cox-2 DNA variants in genetic predisposition to canine renal dysplasia has been proposed and dog breeders have been encouraged to select against these DNA variants. We sequenced 272-422 bases in 152 dogs unaffected by renal dysplasia and found 19 different haplotypes including 11 genetic variants which had not been described previously. We genotyped 7 gray wolves to ascertain the wildtype variant and found that the wolves we analyzed had predominantly the second most common DNA variant found in dogs. Our results demonstrate an elevated level of regional polymorphism that appears to be a feature of healthy domesticated dogs.

  15. Activated hepatic stellate cells promote liver cancer by induction of myeloid-derived suppressor cells through cyclooxygenase-2

    Science.gov (United States)

    Xu, Jianfeng; Li, Jie; Hong, Zaifa; Yin, Zhenyu; Wang, Xiaomin

    2016-01-01

    Hepatic stellate cells (HSCs) are critical mediators of immunosuppression and the pathogenesis of hepatocellular carcinoma (HCC). Our previous work indicates that HSCs promote HCC progression by enhancing immunosuppressive cell populations including myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). MDSCs are induced by inflammatory cytokines (e.g., prostaglandins) and are important in immune suppression. However, how HSCs mediate expansion of MDSCs is uncertain. Thus, we studied activated HSCs that could induce MDSCs from bone marrow cells and noted that HSC-induced MDSCs up-regulated immunosuppressive activity via iNOS, Arg-1, and IL-4Rα. After treating cells with a COX-2 inhibitor or an EP4 antagonist, we established that HSC-induced MDSC accumulation was mediated by the COX2-PGE2-EP4 signaling. Furthermore, in vivo animal studies confirmed that inhibition of HSC-derived PGE2 could inhibit HSC-induced MDSC accumulation and HCC growth. Thus, our data show that HSCs are required for MDSC accumulation mediated by the COX2-PGE2-EP4 pathway, and these data are the first to link HSC and MDSC subsets in HCC immune microenvironment and provide a rationale for targeting PGE2 signaling for HCC therapy. PMID:26758420

  16. Interventional effect of flunarizine on the expression of cyclooxygenase-2 and plasminogen activator inhibitor type-1 during experimental Cerebral ischemia/reperfusion in gerbils

    Institute of Scientific and Technical Information of China (English)

    Wensheng Zhou; Zhiping Hu; Yan Hong

    2006-01-01

    BACKGROUND:Some researches suggest that induced cyclooxygenase-2 (COX-2) can cause brain injury through a series of ways at the phase of cerebral ischemia/hypoxia.Plasminogen activator inhibitor type-1(PAI-1)is a kind of inhibitor of serine stretch protein enzyme and is able to protect cell surface and microvascular basement membrane from degradation of protease and also protect contact surface among cells so as to maintain integrality of tissue structure.However,correlation of protective effect of flunarizine on brain with COX-2 and PAI-1 should be studied further.OBJECTIVE:To observe the effect of flunadzine on expressions of COX-2 and PAI-1 protein in forebrain and degree of brain injury among gerbils after cerebral ischemia.DESIGN:A randomized controlled animal study.SEITING:Department of Neurology,the Second Xiangya Hospital of Central South University;Department of Neurology,Mawangdui Hospital of Hunan Province.MATERIALS:A total of 40 healthy gerbils,of both genders,aged 9 months,weighing(90±10)g,were selected in this study.Anti-COX-2 multi-antibody,anti-PAI-1 multi-antibody,SABC immunohistochemical kit and DAB kit were provided by Wuhan Boster Biological Engineering Co.,Ltd.;and flunarizine capsule was provided by Xi'an Yangsen Pharmaceutical Company(batch number:041018726,dosage:5 mg/pill).METHODS:The experiment was Carried out in Laboratory of Mental Disease,Hunan Provincial Gedatdcs Institute affiliated by Hunan Provincial Mawangdui Hospital from January 2004 to March 2005.① All gerbils were randomly divided into cerebral ischemia group,flunarizine intervention group,sham operation group and normal control group with 10 in each group.Gerbils in normal control group were only cut off their heads.Gerbils in sham operation group were only dissected their bilateral common carotid arteries and sacdficad 1 day later.Gerbils in cerebral ischemia group and flunanzine intervention group were anesthetized,centrally cut open skin of neck,bluntly dissected

  17. Interventional effect of flunarizine on the expression of cyclooxygenase-2 and plasminogen activator inhibitor type-1 during experimental Cerebral ischemia/reperfusion in gerbils

    Institute of Scientific and Technical Information of China (English)

    Wensheng Zhou; Zhiping Hu; Yan Hong

    2006-01-01

    BACKGROUND:Some researches suggest that induced cyclooxygenase-2 (COX-2) can cause brain injury through a series of ways at the phase of cerebral ischemia/hypoxia.Plasminogen activator inhibitor type-1(PAI-1)is a kind of inhibitor of serine stretch protein enzyme and is able to protect cell surface and microvascular basement membrane from degradation of protease and also protect contact surface among cells so as to maintain integrality of tissue structure.However,correlation of protective effect of flunarizine on brain with COX-2 and PAI-1 should be studied further.OBJECTIVE:To observe the effect of flunadzine on expressions of COX-2 and PAI-1 protein in forebrain and degree of brain injury among gerbils after cerebral ischemia.DESIGN:A randomized controlled animal study.SEITING:Department of Neurology,the Second Xiangya Hospital of Central South University;Department of Neurology,Mawangdui Hospital of Hunan Province.MATERIALS:A total of 40 healthy gerbils,of both genders,aged 9 months,weighing(90±10)g,were selected in this study.Anti-COX-2 multi-antibody,anti-PAI-1 multi-antibody,SABC immunohistochemical kit and DAB kit were provided by Wuhan Boster Biological Engineering Co.,Ltd.;and flunarizine capsule was provided by Xi'an Yangsen Pharmaceutical Company(batch number:041018726,dosage:5 mg/pill).METHODS:The experiment was Carried out in Laboratory of Mental Disease,Hunan Provincial Gedatdcs Institute affiliated by Hunan Provincial Mawangdui Hospital from January 2004 to March 2005.① All gerbils were randomly divided into cerebral ischemia group,flunarizine intervention group,sham operation group and normal control group with 10 in each group.Gerbils in normal control group were only cut off their heads.Gerbils in sham operation group were only dissected their bilateral common carotid arteries and sacdficad 1 day later.Gerbils in cerebral ischemia group and flunanzine intervention group were anesthetized,centrally cut open skin of neck,bluntly dissected

  18. Relative Expression of Vitamin D Hydroxylases, CYP27B1 and CYP24A1, and of Cyclooxygenase-2 and Heterogeneity of Human Colorectal Cancer in Relation to Age, Gender, Tumor Location, and Malignancy: Results from Factor and Cluster Analysis

    International Nuclear Information System (INIS)

    Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1,25-(OH)2D3 and prostaglandin cellular signaling networks. The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases, i.e., CYP27B1-encoded 25-hydroxyvitamin D-1α-hydroxylase and CYP24A1-encoded 25-hydroxyvitamin D-24-hydroxylase, and inflammation-induced cyclooxygenase-2 (COX-2). Data from 105 cancer patients on CYP27B1, VDR, CYP24A1, and COX-2 mRNA expression in relation to tumor grade, anatomical location, gender and age were fit into a multivariate model of exploratory factor analysis. Nearly identical results were obtained by the principal factor and the maximum likelihood method, and these were confirmed by hierarchical cluster analysis: Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis: (i) Escape of COX-2 activity from restraints by the CYP27B1/VDR system can initiate cancer growth anywhere in the colorectum regardless of age and gender; (ii) variations in COX-2 expression are mainly responsible for differences in cancer incidence in relation to tumor location; (iii) advancing age has a strong gender-specific influence on cancer incidence; (iv) progression from well differentiated to undifferentiated cancer is solely associated with a rise in CYP24A1 expression

  19. Relative Expression of Vitamin D Hydroxylases, CYP27B1 and CYP24A1, and of Cyclooxygenase-2 and Heterogeneity of Human Colorectal Cancer in Relation to Age, Gender, Tumor Location, and Malignancy: Results from Factor and Cluster Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Brozek, Wolfgang, E-mail: wolfgang.brozek@gmx.at; Manhardt, Teresa; Kállay, Enikö; Peterlik, Meinrad; Cross, Heide S. [Department of Pathophysiology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna (Austria)

    2012-07-26

    Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1,25-(OH){sub 2}D{sub 3} and prostaglandin cellular signaling networks. The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases, i.e., CYP27B1-encoded 25-hydroxyvitamin D-1α-hydroxylase and CYP24A1-encoded 25-hydroxyvitamin D-24-hydroxylase, and inflammation-induced cyclooxygenase-2 (COX-2). Data from 105 cancer patients on CYP27B1, VDR, CYP24A1, and COX-2 mRNA expression in relation to tumor grade, anatomical location, gender and age were fit into a multivariate model of exploratory factor analysis. Nearly identical results were obtained by the principal factor and the maximum likelihood method, and these were confirmed by hierarchical cluster analysis: Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis: (i) Escape of COX-2 activity from restraints by the CYP27B1/VDR system can initiate cancer growth anywhere in the colorectum regardless of age and gender; (ii) variations in COX-2 expression are mainly responsible for differences in cancer incidence in relation to tumor location; (iii) advancing age has a strong gender-specific influence on cancer incidence; (iv) progression from well differentiated to undifferentiated cancer is solely associated with a rise in CYP24A1 expression.

  20. Increase of carcinogenic risk via enhancement of cyclooxygenase-2 expression and hydroxyestradiol accumulation in human lung cells as a result of interaction between BaP and 17-beta estradiol.

    Science.gov (United States)

    Chang, Louis W; Chang, Yun-Ching; Ho, Chia-Chi; Tsai, Ming-Hsien; Lin, Pinpin

    2007-07-01

    Animal studies demonstrated that females are more susceptible than males to benzo[a]pyrene (BaP)-induced toxicities, including lung carcinogenesis. Elevation of cyclooxygenase-2 (COX-2) expression has been shown to increase the risk of cancer development. BaP induces COX-2 expression, and an interaction between BaP and estrogen in relation to COX-2 expression is suspected. In the present study, 10 muM BaP alone only slightly increased COX-2 mRNA expression and 10 nM 17-beta estradiol (E(2)) alone slightly increased prostaglandin E2 (PGE2) secretion in human bronchial epithelial cells. However, co-treatment with BaP and E(2) potentiated COX-2 mRNA expression and significantly elevated PGE2 secretion. Utilizing specific inhibitors and reporter assays, we further investigated the potentiation mechanisms of E(2) on BaP-induced COX-2 expression. First, E(2) activated estrogen receptor to increase PGE2 secretion, which directly increased COX-2 expression. Second, E(2) potentiated BaP-induced nuclear factor-kappaB (NF-kappaB) activation, which regulates COX-2 expression. Third, although the aryl hydrocarbon receptor (AhR) did not play a role in BaP-induced COX-2 expression, the potentiation effect of E(2) itself was AhR dependent. We further demonstrated that BaP induced the production of genotoxic E(2) metabolites (2- and 4-hydroxyestradiols) via AhR-up-regulated cytochromes P450 1A1 and 1B1. These metabolites could directly activate NF-kappaB to further promote COX-2 mRNA expression in human lung epithelial cells. These findings were further supported by increased PGE2 secretion in rat lung slice cultures. Our findings that the BaP-E(2) interaction enhanced COX-2 expression and hydroxyestradiol accumulation in the media of cultivated lung cells and tissues provide the needed scientific basis for higher risk of BaP-associated lung cancer in females.

  1. Mechanisms underlying aspirin-mediated growth inhibition and apoptosis induction of cyclooxygenase-2 negative colon cancer cell line SW480

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    AIM: To investigate the effects of aspirin (acetylsalicylic acid) on proliferation and apoptosis of colorectal can- cer cell line $W480 and its mechanism. METHODS: Cyclooxygenase (COX)-2 negative colorec- tal cancer cell line SW480 was treated with aspirin at concentrations of 2.5 retool/L, 5.0 retool/L, 10.0 mmol/L for different periods in vitro. Anti-proliferation effect of aspirin on SW480 was detected by 3-(4,5-dimeth- ylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle and apoptosis were observed by flow cytometry (FCM). Transmission electron microscope (TEM) was used for morphological study. Apoptosis-as- sociated genes were detected by immunohistochemical staining and Western blotting. RESULTS: Aspirin inhibited SW480 proliferation and induced apoptosis in a dose- and time-dependent manner. Treatment with different concentrations of aspirin significantly increased the proportions of cells at the G0/G1 phase and decreased the proportions of cells at the S- and G2/M phases in a concentration- dependent manner. Aspirin not only induced apoptosis but also caused cell necrosis at a high concentration as well. After treatment with aspirin, SW480 cells displayed typically morphological features of apoptosis and necrosis under TEM, and increased the Bcl-2 expression in cells, but the expression of Bax was down regulated. CONCLUSION: Aspirin inhibits proliferation and induces apoptosis of SW480 cells. Its anti-tumor mechanism may arrest cell cycle and shift Bax/Bcl-2 balance in cells.

  2. Targeting angiogenic pathway for chemoprevention of experimental colon cancer using C-phycocyanin as cyclooxygenase-2 inhibitor.

    Science.gov (United States)

    Saini, Manpreet Kaur; Sanyal, Sankar Nath

    2014-06-01

    An angiogenic pathway was studied that involved stromal tissue degradation with matrix metalloproteinases (MMPs), vesicular endothelial growth factor-A (VEGF-A), and hypoxia inducible factor-1α (HIF-1α) mediated growth regulation in a complex interaction with chemokines, such as monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β). Gene and protein expression was studied with real-time PCR, Western immunoblot, and immunofluorescence. Morphological and histopathological analysis of tumor was done, as also the activity of MMPs and HIF-1α by gelatin zymography and ELISA. Binding interactions of proteins were studied by molecular docking. Piroxicam, a traditional NSAID and C-phycocyanin, a biliprotein from Spirulina platensis, were utilized in the chemoprevention of DMH-induced rat colon cancer. A significant number of tumors was evident in DMH treated animals, while with piroxicam and C-phycocyanin, the number and size of tumors/lesions were reduced. Colonic tissues showed severe dysplasia, tubular adenoma, and adenocarcinoma from DMH, with invasive features along with signet ring cell carcinoma. No occurrence of carcinoma was detected in either of the drug treatments or in a combination regimen. An elevated VEGF-A, MMP-2, and MMP-9 level was observed, which is required for metastasis and invasion into surrounding tissues. Drugs induced chemoprevention by down-regulating these proteins. Piroxicam docked in VEGF-A binding site of VEGF-A receptors i.e., VEGFR1 and VEGFR2, while phycocyanobilin (a chromophore of C-phycocyanin) docked with VEGFR1 alone. HIF-1α is up-regulated which is associated with increased oxygen demand and angiogenesis. MCP-1 and MIP-1β expression was also found altered in DMH and regulated by the drugs. Anti-angiogenic role of piroxicam and C-phycocyanin is well demonstrated. PMID:24861078

  3. Inhibition of cyclooxygenase-2 activity by celecoxib does not lead to radiosensitization of human prostate cancer cells in vitro

    International Nuclear Information System (INIS)

    Purpose: To evaluate the potential radiosensitizing effect of the specific COX-2 inhibitor celecoxib (Celebrex[reg]) on prostate carcinoma cells in vitro. Materials and methods: The influence of celecoxib (concentration range 5 to 75 μM) on radiation-induced cellular and clonogenic survival was investigated in prostate carcinoma cell lines PC-3, DU145, LNCaP and normal prostate epithelial cells (PrEC). Western blot analysis and ELISA were used to determine the impact of radiation alone or radiation combined with celecoxib treatment on COX-2 expression and prostaglandin E2 synthesis. To evaluate induction of celecoxib-induced apoptosis cell cycle analysis has been performed. Results: Celecoxib (5, 10 and 25 μM) in combination with single-dose irradiation of 2 Gy induced a significant radiosensitization in normal prostate epithelial cells which could not be observed for any of the prostate carcinoma cell lines investigated. Increased COX-2 protein expression in PC-3 cells was obvious only after IR with 15 Gy, while PGE2 production was elevated following irradiation (2-15 Gy) in a dose-dependent manner. Treatment with celecoxib alone or in combination with IR led to a dose-dependent increase in COX-2 protein expression. Nevertheless pre-treatment with celecoxib caused a marked reduction of radiation-induced enzyme activity as tested at the level of PGE2 production, both in PC-3 and DU145 cells. Following fractionated irradiation with single doses of 2 Gy, elevated COX-2 protein expression as well as enhanced PGE2 production was observed already after the second fraction in PC-3 cells. Pre-treatment with celecoxib reduced the amount of PGE2 significantly, but not of COX-2 protein. Conclusions: Our data obtained for the human prostate cancer cell lines do not indicate that a marked inhibition of prostaglandin E2 synthesis by celecoxib leads to enhanced radiosensitization. Thus, in terms of radiosensitization the analysed prostate cancer cells can be classified as non

  4. Research Advances in Cyclooxygenase-2 and Gastric Carcinoma%环氧合酶-2在胃癌中的研究进展

    Institute of Scientific and Technical Information of China (English)

    王璟; 韩晓鹏; 李洪涛; 于建平; 刘宏斌

    2015-01-01

    我国胃癌发病人数居全球首位,其发生机制及安全有效的治疗是研究重点.大量研究结果表明,环氧化酶-2(Cyclooxygenase-2,COX-2)过度表达促进肿瘤细胞增殖和抑制细胞凋亡,并与胃癌的发生发展、淋巴转移、分化程度、病理分期及预后密切相关.随着COX-2与胃癌关系的研究的深入,COX-2已逐渐成为胃癌治疗的新的靶点.近年来,针对细胞受体、信号传导、细胞周期和血管生成等靶点的抗肿瘤治疗已成为肿瘤治疗研究的新方向.因此,以COX-2为特异靶点的治疗策略有望为胃癌治疗提供新的思路.%The population of patients with gastric carcinoma in China ranks first in the world.A safe and effective treatment of gastric carcinoma is the key point in the research.Several studies have shown that Cyclooxygenase-2 (COX-2) overexpression promotes tumor cell proliferation and inhibition of apoptosis.COX-2 is closely associated with the development of gastric carcinoma,lymph node metastasis,differentiation,pathological staging and prognosis.COX-2 has become a new target for cancer therapy with COX-2 and gastric carcinoma in-depth study.In recent years,along with the molecular biology of cancer occurrence and development mechanism of the deepening of the research,directed cell receptor,signal transduction,cell cycle and angiogenesis targeted anti tumor therapy has become a new research direction in tumor therapy.Therefore,COX-2,as a specific target for therapeutic strategies for the treatment of gastric carcinoma,is expected to provide new ideas.

  5. Cytosolic phospholipase A2 alpha amplifies early cyclooxygenase-2 expression, oxidative stress and MAP kinase phosphorylation after cerebral ischemia in mice

    Directory of Open Access Journals (Sweden)

    Koehler Raymond C

    2010-07-01

    Full Text Available Abstract Background The enzyme cytosolic phospholipase A2 alpha (cPLA2α has been implicated in the progression of cerebral injury following ischemia and reperfusion. Previous studies in rodents suggest that cPLA2α enhances delayed injury extension and disruption of the blood brain barrier many hours after reperfusion. In this study we investigated the role of cPLA2α in early ischemic cerebral injury. Methods Middle cerebral artery occlusion (MCAO was performed on cPLA2α+/+ and cPLA2α-/- mice for 2 hours followed by 0, 2, or 6 hours of reperfusion. The levels of cPLA2α, cyclooxygenase-2, neuronal morphology and reactive oxygen species in the ischemic and contralateral hemispheres were evaluated by light and fluorescent microscopy. PGE2 content was compared between genotypes and hemispheres after MCAO and MCAO and 6 hours reperfusion. Regional cerebral blood flow was measured during MCAO and phosphorylation of relevant MAPKs in brain protein homogenates was measured by Western analysis after 6 hours of reperfusion. Results Neuronal cPLA2α protein increased by 2-fold immediately after MCAO and returned to pre-MCAO levels after 2 hours reperfusion. Neuronal cyclooxygenase-2 induction and PGE2 concentration were greater in cPLA2α+/+ compared to cPLA2α-/- ischemic cortex. Neuronal swelling in ischemic regions was significantly greater in the cPLA2α+/+ than in cPLA2α-/- brains (+/+: 2.2 ± 0.3 fold vs. -/-: 1.7 ± 0.4 fold increase; P 2α+/+ ischemic core than in cPLA2α-/- (+/+: 7.12 ± 1.2 fold vs. -/-: 3.1 ± 1.4 fold; P 2α+/+, but not cPLA2α-/-, had disruption of neuron morphology and decreased PGE2 content. Phosphorylation of the MAPKs-p38, ERK 1/2, and MEK 1/2-was significantly greater in cPLA2a+/+ than in cPLA2α-/- ischemic cortex 6 hours after reperfusion. Conclusions These results indicate that cPLA2α modulates the earliest molecular and injury responses after cerebral ischemia and have implications for the potential clinical

  6. Induction of cyclo-oxygenase-2 mRNA by prostaglandin E2 in human prostatic carcinoma cells

    Science.gov (United States)

    Tjandrawinata, R. R.; Dahiya, R.; Hughes-Fulford, M.

    1997-01-01

    Prostaglandins are synthesized from arachidonic acid by the enzyme cyclo-oxygenase. There are two isoforms of cyclooxygenases: COX-1 (a constitutive form) and COX-2 (an inducible form). COX-2 has recently been categorized as an immediate-early gene and is associated with cellular growth and differentiation. The purpose of this study was to investigate the effects of exogenous dimethylprostaglandin E2 (dmPGE2) on prostate cancer cell growth. Results of these experiments demonstrate that administration of dmPGE2 to growing PC-3 cells significantly increased cellular proliferation (as measured by the cell number), total DNA content and endogenous PGE2 concentration. DmPGE2 also increased the steady-state mRNA levels of its own inducible synthesizing enzyme, COX-2, as well as cellular growth to levels similar to those seen with fetal calf serum and phorbol ester. The same results were observed in other human cancer cell types, such as the androgen-dependent LNCaP cells, breast cancer MDA-MB-134 cells and human colorectal carcinoma DiFi cells. In PC-3 cells, the dmPGE2 regulation of the COX-2 mRNA levels was both time dependent, with maximum stimulation seen 2 h after addition, and dose dependent on dmPGE2 concentration, with maximum stimulation seen at 5 microg ml(-1). The non-steroidal anti-inflammatory drug flurbiprofen (5 microM), in the presence of exogenous dmPGE2, inhibited the up-regulation of COX-2 mRNA and PC-3 cell growth. Taken together, these data suggest that PGE2 has a specific role in the maintenance of human cancer cell growth and that the activation of COX-2 expression depends primarily upon newly synthesized PGE2, perhaps resulting from changes in local cellular PGE2 concentrations.

  7. Key role for constitutive cyclooxygenase-2 of MDCK cells in basal signaling and response to released ATP.

    Science.gov (United States)

    Ostrom, R S; Gregorian, C; Drenan, R M; Gabot, K; Rana, B K; Insel, P A

    2001-08-01

    Madin-Darby canine kidney (MDCK) cells release ATP upon mechanical or biochemical activation, initiating P2Y receptor signaling that regulates basal levels of multiple second messengers, including cAMP (J Biol Chem 275: 11735--11739, 2000). Data shown here document inhibition of cAMP formation by Gd(3+) and niflumic acid, channel inhibitors that block ATP release. cAMP production is stimulated via Ca(2+)-dependent activation of cytosolic phospholipase A(2), release of arachidonic acid (AA), and cyclooxygenase (COX)-dependent production of prostaglandins, which activate prostanoid receptors coupled to G(s) and adenylyl cyclase. In the current investigation, we assessed the expression and functional role of the two known isoforms of COX, COX-1 and COX-2. Treatment of cells with either a COX-1-selective inhibitor, SC-560, or COX-2-selective inhibitors, SC-58125 or NS-398, inhibited basal and UTP-stimulated cAMP levels. COX inhibitors also decreased forskolin-stimulated cAMP formation, implying this response is in part attributable to an action of AA metabolites. These findings imply an important role for the inducible form of COX, COX-2, under basal conditions. Indeed, COX-2 expression was readily detectable by immunoblot, and treatments that induce or reduce COX-2 expression in other cells (interleukin-1beta, tumor necrosis factor-alpha, phorbol ester, or dexamethasone) had minimal or no effect on the levels of COX-2 immunoreactivity. RT-PCR using isoform-specific primers detected COX-2 mRNA. We conclude that COX-2 is constitutively expressed in MDCK-D(1) cells and participates in basal and P2Y(2)-mediated signaling, implying a key role for COX-2 in regulation of epithelial cell function. PMID:11443051

  8. Curcumin improves prostanoid ratio in diabetic mesenteric arteries associated with cyclooxygenase-2 and NF-κB suppression

    Directory of Open Access Journals (Sweden)

    Sirada Rungseesantivanon

    2010-12-01

    Full Text Available Sirada Rungseesantivanon1, Naris Thengchaisri4, Preecha Ruangvejvorachai2, Suthiluk Patumraj31Interdepartment of Physiology, Graduate School, 2Department of Pathology, 3Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 4Department of Companion Animal Clinical Sciences, Faculty of Veterinary Medicine, Kasetsart University, Bangkok, ThailandBackground: Curcumin, the active ingredient from turmeric rhizomes, has been shown to have a wide range of pharmacological properties including antioxidant and anti-inflammatory effects. Curcumin has been reviewed for its multiple molecular action on inhibiting tumor angiogenesis via its mechanisms of cyclooxygenase (COX-2, and vascular endothelial growth factor (VEGF inhibition. In this present study, we aimed to assess the effects of curcumin on preventing diabetes-induced vascular dysfunction in association with COX-2, nuclear factor-κB (NF-κB expression, and prostanoid production.Methods: Twelve-week-old male Wistar rats were separated into five groups: 1 diabetes with 0.9% normal saline (DM-NSS; n = 10, 2 diabetes treated with curcumin 30 mg/kg (n = 10, 3 diabetes treated with curcumin 300 mg/kg (n = 10, 4 the control with 0.9% normal saline (n = 10, and 5 the control treated with 300 mg/kg (n = 10. Daily oral feeding of curcumin was started at 6 weeks after the streptozotocin injection. Levels of 6-keto prostaglandin (PG F1α and thromboxane (TX B2 were determined from mesenteric perfusates using enzyme immunoassay kits. Protein kinase C (PKC-ßII and COX-2 with NF-κB levels were analyzed in the mesenteric arteries by immunofluorescent staining and immunohistochemistry, respectively.Results: The ratio of 6-keto-PGF1α and TXB2 was significantly decreased in DM-NSS compared with the control (P < 0.05. Double-immunofluorescent staining with specific antibodies for PKC-βII and a-smooth muscle actins showed that the diabetic mesenteric arteries contained increased

  9. Dehydrodiisoeugenol, an isoeugenol dimer, inhibits lipopolysaccharide-stimulated nuclear factor kappa B activation and cyclooxygenase-2 expression in macrophages.

    Science.gov (United States)

    Murakami, Yukio; Shoji, Masao; Hirata, Atsushi; Tanaka, Shoji; Yokoe, Ichiro; Fujisawa, Seiichiro

    2005-02-15

    o-Methoxyphenols such as eugenol and isoeugenol exhibit anti-oxidant and anti-inflammatory activities, but at higher concentrations act as oxidants and potent allergens. We recently demonstrated the eugenol dimer bis-eugenol to be an efficient inhibitor of lipopolysaccharide (LPS)-induced inflammatory cytokine expression in macrophages without cytotoxicity. This result suggested that dimer compound of o-methoxyphenols may possess anti-inflammatory activity. Thus, we further synthesized dehydrodiisoeugenol and alpha-diisoeugenol from isoeugenols, and investigated whether these dimers could inhibit LPS-stimulated nuclear factor kappa B (NF-kappaB) activation and cyclooxygenase (COX)-2 gene expression, both of which are closely involved in inflammation and mutagenesis. The expression of the COX-2 gene was strongly inhibited by dehydrodiisoeugenol in RAW264.7 murine macrophages stimulated with LPS. In contrast, isoeugenol and alpha-diisoeugenol did not inhibit it. Dehydrodiisoeugenol also significantly inhibited LPS-stimulated phosphorylation-dependent proteolysis of inhibitor kappaB-alpha and transcriptional activity of NF-kappaB in the cells. These findings suggest that dehydrodiisoeugenol acts as a potent anti-inflammatory agent.

  10. Effect of the major glycosides of Harpagophytum procumbens (Devil's Claw) on epidermal cyclooxygenase-2 (COX-2) in vitro.

    Science.gov (United States)

    Abdelouahab, Nassima; Heard, Charles

    2008-05-01

    Harpagophytum procumbens, commonly known as Devil's Claw, is indigenous to southern Africa, and extracts of the tubers have been used for centuries in the treatment of a variety of inflammatory disorders. Its major active components, harpagoside (1), harpagide (2), 8-coumaroylharpagide (3), and verbascoside (4), are believed to interact either synergistically or antagonistically in modulating the enzymes responsible for inducing inflammation, although this has not been probed hitherto. In the current work, the ability of these compounds to inhibit the expression of COX-2 following administration to freshly excised porcine skin has been investigated. An ethanol-soluble extract of H. procumbens tubers and two of the pure compounds tested showed promising activity in Western blotting and immunocytochemical assays, with harpagoside (1) and 8-coumaroylharpagide (3) exhibiting greater reductions in COX-2 expression than verbascoside (4). Harpagide (2) caused a significant increase in the levels of COX-2 expression after 6 h of topical application. The data suggest that the efficacy of H. procumbens is dependent upon the ratios of compounds 1-4 present, which is inconsistent with some current official monograph specifications based solely on harpagoside (1) content. PMID:18412394

  11. Expression of Cyclooxygenase-2 mRNA and Identification of Its Splice Variant in Human Myometrium Obtained from Women in Labor

    Institute of Scientific and Technical Information of China (English)

    HUANG Yinping; WAN Jingyuan; YE Duyun; WU Ping; HUANG Yanjun; ZHANG Li; ZHOU Xiaoyan; HUANG Yunfeng; YUAN Ping; ZHANG Daijuan

    2005-01-01

    In order to investigate the expression of cyclooxygenase-2 (COX-2) in human lower segments of myometrium obtained from women in labor and those not in labor and identify the splicing variant of COX-2, reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect the expression of COX-2. The primers were designed and synthesized according to the sequence of rat COX-2 splice variant which was discovered firstly by us. Then the splicing variant of COX-2 in human myometrium from woman in labor was identified, cloned into vector and sequenced. The results showed that the expression of COX-2 mRNA was lower in human myometrium obtained from women who were not in labor than that in labor women and a new band of COX-2 was obtained in myometrium from labor woman. The fragment included an unspliced intron, which pitched between exons 7 and 8. It was suggested that COX-2 gene was not only expressed highly in human myometrium from woman in labor, but also produced splicing variant by alternative splicing.

  12. Cervical changes in estrogen receptor alpha, oxytocin receptor, LH receptor, and cyclooxygenase-2 depending on the histologic compartment, longitudinal axis, and day of the ovine estrous cycle.

    Science.gov (United States)

    Rodríguez-Piñón, M; Gonzalez, R; Tasende, C; Bielli, A; Genovese, P; Garófalo, E G

    2014-04-01

    The aim was to investigate the histologic distribution of estrogen receptor α (ERα), oxytocin receptor (OxR), LH receptor (LHR), and cyclooxygenase-2 (COX-2) in the cervix of the ewe during the estrous cycle. Immunohistochemistry was performed in the cranial and caudal cervix of Corriedale ewes on Day 1 (n = 6), 6 (n = 5), or 13 (n = 6) after estrous detection (Day 0). The ERα proportional score (%ERα nuclei) was lower in the cranial cervix than in the caudal cervix, whereas the OxR and COX-2 immunostaining areas (%areas) were greater in the cranial cervix than in the caudal cervix (P epithelia, but increased from Days 1 to 6 or remained unchanged in stromata (P glandular epithelium, and increased from Days 1 to 13 in the deep glandular epithelium (P epithelia and fold stroma (P epithelia, and it was lower on Day 1 than on Days 6 and 13 in luminal epithelia (P epithelia, in contrast to little or no variations in the stroma, suggest a hormone-responsive driving role of epithelia in cervical function. PMID:24485556

  13. 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.

  14. Single subject pharmacological-MRI (phMRI study: Modulation of brain activity of psoriatic arthritis pain by cyclooxygenase-2 inhibitor

    Directory of Open Access Journals (Sweden)

    Chialvo DR

    2005-11-01

    Full Text Available Abstract We use fMRI to examine brain activity for pain elicited by palpating joints in a single patient suffering from psoriatic arthritis. Changes in these responses are documented when the patient ingested a single dose of a selective cyclooxygenase-2 inhibitor (COX-2i. We show that mechanical stimulation of the painful joints exhibited a cortical activity pattern similar to that reported for acute pain, with activity primarily localized to the thalamus, insular, primary and secondary somatosensory cortices and the mid anterior cingulum. COX-2i resulted in significant decreased in reported pain intensity and in brain activity after 1 hour of administration. The anterior insula and SII correlated with pain intensity, however no central activation site for the drug was detected. We demonstrate the similarity of the activation pattern for palpating painful joints to brain activity in normal subjects in response to thermal painful stimuli, by performing a spatial conjunction analysis between these maps, where overlap is observed in the insula, thalamus, secondary somatosensory cortex, and anterior cingulate. The results demonstrate that one can study effects of pharmacological manipulations in a single subject where the brain activity for a clinical condition is delineated and its modulation by COX-2i demonstrated. This approach may have diagnostic and prognostic utility.

  15. Design, Synthesis, and Evaluation of an (18)F-Labeled Radiotracer Based on Celecoxib-NBD for Positron Emission Tomography (PET) Imaging of Cyclooxygenase-2 (COX-2).

    Science.gov (United States)

    Kaur, Jatinder; Tietz, Ole; Bhardwaj, Atul; Marshall, Alison; Way, Jenilee; Wuest, Melinda; Wuest, Frank

    2015-10-01

    A series of novel fluorine-containing cyclooxygenase-2 (COX-2) inhibitors was designed and synthesized based on the previously reported fluorescent COX-2 imaging agent celecoxib-NBD (3; NBD=7-nitrobenzofurazan). In vitro COX-1/COX-2 inhibitory data show that N-(4-fluorobenzyl)-4-(5-p-tolyl-3-trifluoromethylpyrazol-1-yl)benzenesulfonamide (5; IC50 =0.36 μM, SI>277) and N-fluoromethyl-4-(5-p-tolyl-3-trifluoromethylpyrazol-1-yl)benzenesulfonamide (6; IC50 =0.24 μM, SI>416) are potent and selective COX-2 inhibitors. Compound 5 was selected for radiolabeling with the short-lived positron emitter fluorine-18 ((18) F) and evaluated as a positron emission tomography (PET) imaging agent. Radiotracer [(18) F]5 was analyzed in vitro and in vivo using human colorectal cancer model HCA-7. Although radiotracer uptake into COX-2-expressing HCA-7 cells was high, no evidence for COX-2-specific binding was found. Radiotracer uptake into HCA-7 tumors in vivo was low and similar to that of muscle, used as reference tissue. PMID:26287271

  16. Antineoplastic effect of a novel chemopreventive agent, neokestose, on the Caco-2 cell line via inhibition of expression of nuclear factor-κB and cyclooxygenase-2.

    Science.gov (United States)

    Lee, Shun-Mei; Chang, Jan-Yi; Wu, Jiann-Shing; Sheu, Dey-Chyi

    2015-07-01

    Neokestose is a 6G-fructooligosaccharide (FOS) and an important prebiotic. When FOS are ingested by patients with colorectal cancer, they may come into contact with cancer cells prior to being fermented by bifidobacteria in the colon. In the present study, the effects of neokestose on cell proliferation, cell cycle and apoptosis of the colorectal cancer cell line Caco-2 were investigated to evaluate its anti-cancer effect. An MTT assay showed that neokestose-treated Caco-2 cells exhibited a significant and dose-dependent loss of viability. Flow cytometric analysis indicated that the sub-G1 population of Caco-2 cells was significantly increased following treatment with neokestose, and the percentage of Caco-2 cells in the stage of late apoptosis was also significantly increased in a dose-dependent manner. Western blot analysis showed that the overexpression of nuclear factor-κB, a central molecule responsible for the transition from inflammation to cancer, and cyclooxygenase-2, an important enzyme in colorectal tumorigenesis, in colorectal carcinoma cells was inhibited by neokestose. Accordingly, the present study provided in vitro evidence that neokestose may be used as a dietary chemopreventive agent, whose application is more rational than that of COX-2 inhibitors or aspirin for preventing colorectal cancer. PMID:25815878

  17. Memory B cells from older people express normal levels of cyclooxygenase-2 and produce higher levels of IL-6 and IL-10 upon in vitro activation.

    Science.gov (United States)

    Bancos, Simona; Phipps, Richard P

    2010-01-01

    Worldwide the elderly population is increasing. The elderly show deficiencies in immune function. B lymphocytes are essential elements of the immune system responsible for antibody production. This laboratory previously showed that activated human B cells isolated from young adults express cyclooxygenase-2 (Cox-2) and that Cox-2 is essential for optimal antibody responses. Recent data suggests that Cox-2 expression decreases with age in mouse bone tissue. There is no information regarding Cox-2 expression in B cells from older human subjects. We investigated the expression and activity of Cox-2 in naïve and memory B cells from older people. We show that B cells from older subjects show similar Cox-2 protein expression and activity, antibody production and proliferation compared to younger people. However, we found that activated memory B cells from older people produce higher levels of IL-6 and IL-10 compared to young adults. Therefore, the dysregulated cytokine production could contribute to immune senescence in the elderly.

  18. USP22 acts as an oncogene by regulating the stability of cyclooxygenase-2 in non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Xiao, Haibo [Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092 (China); Tian, Yue [Institute of Orthopaedics, Chinese PLA General Hospital, Beijing 100853 (China); Yang, Yang; Hu, Fengqing; Xie, Xiao; Mei, Ju [Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092 (China); Ding, Fangbao, E-mail: drnail@sina.com [Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092 (China)

    2015-05-08

    The histone ubiquitin hydrolase ubiquitin-specific protease 22 (USP22) is an epigenetic modifier and an oncogene that is upregulated in many types of cancer. In non-small cell lung cancer (NSCLC), aberrant expression of USP22 is a predictor of poor survival, as is high expression of cyclooxygenase-2 (COX-2). Despite its oncogenic role, few substrates of USP22 have been identified and its mechanism of action in cancer remains unclear. Here, we identified COX-2 as a direct substrate of USP22 and showed that its levels are modulated by USP22 mediated deubiquitination. Silencing of USP22 downregulated COX-2, decreased its half-life, and inhibited lung carcinoma cell proliferation by directly interacting with and modulating the stability and activity of COX-2 through the regulation of its ubiquitination status. The findings of the present study suggest a potential mechanism underlying the oncogenic role of USP22 mediated by the modulation of the stability and activity of COX-2. - Highlights: • USP22 interacts with COX-2. • USP22 deubiquitinates and stabilizes COX-2. • USP22 is required for COX-2-mediated upregulation of prostaglandin E2.

  19. STUDY ON THE EXPRESSION OF CYCLOOXYGENASE-2 IN HEPATOCELLULAR CARCINOMA CELL LINES AND ON THE GROWTH INHIBITION EFFECT OF NS-398

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective: To investigate the expression of cyclooxygenase -2 (COX-2) in hepatocellular carcinoma cell lines and to explore the effect of NS-398, a selective inhibitor for COX-2, on HepG-2 cell line. Methods: Immunohistochemistry and RT-PCR were used to investigate COX-2 expression in 6 HCC cell lines. MTT and Flowcytometry were used to evaluate the effect of the selective inhibitor of COX-2, NS-398, on HepG-2 cell lines. Results: All six HCC cell lines showed COX-2 expression at protein level. Five out of 6 cell lines showed COX-2 expression at mRNA level. NS-398 could suppress the growth of HepG-2 cell line, in a time and dose dependant manner. Conclusion: NS-398, a selective inhibitor of COX-2, showed inhibition effect on HepG-2 HCC cell line. The efficacy of inhibition was time and dose dependent, providing a new evidence for chemoprovention of hepatocellular carcinorma with COX-2 selective inhibitors.

  20. Evaluation of [{sup 11}C]rofecoxib as PET tracer for cyclooxygenase 2 overexpression in rat models of inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Vries, Erik F.J. de [Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen (Netherlands)], E-mail: e.f.j.de.vries@ngmb.umcg.nl; Doorduin, Janine; Dierckx, Rudi A.; Waarde, Aren van [Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen (Netherlands)

    2008-01-15

    Background: Overexpression of cyclooxygenase type 2 (COX-2) is triggered by inflammatory stimuli, but it also plays a prominent role in the initiation and progression of various diseases. This study aims to investigate [{sup 11}C]rofecoxib as a positron emission tomography (PET) tracer for COX-2 expression. Methods: [{sup 11}C]Rofecoxib was prepared by methylation of its sulphinate precursor. Regional brain distribution and specific binding of [{sup 11}C]rofecoxib in healthy rats was studied by ex vivo biodistribution and autoradiography. Regional brain distribution and PET imaging studies were also performed on rats with severe encephalitis, caused by nasal infection with herpes simplex virus (HSV). Finally, ex vivo biodistribution and blocking studies were carried in rats with a sterile inflammation, induced by intramuscular turpentine injection. Results: [{sup 11}C]rofecoxib brain uptake in control animals corresponded with the known distribution of COX-2. Pretreatment with NS398 significantly reduced tracer uptake in the cingulate/frontopolar cortex, whereas the reduction in hippocampus approached significance. Ex vivo autoradiography also revealed preferential tracer uptake in hippocampus and cortical areas that could be blocked by NS398. In HSV-infected animals, [{sup 11}C]rofecoxib uptake was moderately increased in all brain regions, but it could not be blocked with indomethacin. Yet, some PET images revealed increased tracer uptake in brain areas with microglia activation. In turpentine-injected animals, [{sup 11}C]rofecoxib uptake in inflamed muscle was not higher than in control muscle and could not be blocked with NS398. Indomethacin caused a slight reduction in muscle uptake. Conclusions: Despite the apparent correlation between [{sup 11}C]rofecoxib uptake and COX-2 distribution in healthy rats, [{sup 11}C]rofecoxib could not unambiguously detect COX-2 overexpression in two rat models of inflammation.

  1. Lung Myofibroblasts Are Characterized by Down-Regulated Cyclooxygenase-2 and Its Main Metabolite, Prostaglandin E2

    Science.gov (United States)

    Gabasa, Marta; Royo, Dolores; Molina-Molina, Maria; Roca-Ferrer, Jordi; Pujols, Laura; Picado, Cesar

    2013-01-01

    Background Prostaglandin E2 (PGE2), the main metabolite of cyclooxygenase (COX), is a well-known anti-fibrotic agent. Moreover, myofibroblasts expressing α-smooth muscle actin (α-SMA), fibroblast expansion and epithelial-mesenchymal transition (EMT) are critical to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our aim was to investigate the expression of COX-2 and PGE2 in human lung myofibroblasts and establish whether fibroblast-myofibroblast transition (FMT) and EMT are associated with COX-2 and PGE2 down-regulation. Methods Fibroblasts obtained from IPF patients (n = 6) and patients undergoing spontaneous pneumothorax (control, n = 6) and alveolar epithelial cell line A549 were incubated with TGF-β1 and FMT and EMT markers were evaluated. COX-2 and α-SMA expression, PGE2 secretion and cell proliferation were measured after IL-1β and PGE2 incubation. Results Myofibroblasts from both control and IPF fibroblast cultures stimulated with IL-1β showed no COX-2 expression. IPF fibroblasts showed increased myofibroblast population and reduced COX-2 expression in response to IL-1β. TGF-β1 increased the number of myofibroblasts in a time-dependent manner. In contrast, TGF-β1 induced slight COX-2 expression at 4 h (without increase in myofibroblasts) and 24 h, but not at 72 h. Both IPF and control cultures incubated with TGF-β1 for 72 h showed diminished COX-2 induction, PGE2 secretion and α-SMA expression after IL-1β addition. The latter decreased proliferation in fibroblasts but not in myofibroblasts. A549 cells incubated with TGF-β1 for 72 h showed down-regulated COX-2 expression and low basal PGE2 secretion in response to IL-1β. Immuno-histochemical analysis of IPF lung tissue showed no COX-2 immuno-reactivity in myofibroblast foci. Conclusions Myofibroblasts are associated with COX-2 down-regulation and reduced PGE2 production, which could be crucial in IPF development and progression. PMID:23755232

  2. Progress of Cyclooxygenase-2 Expression in Tumors and Its Inhibitors Application in Anti-tumor%环氧合酶-2在肿瘤中的表达及其抑制剂在肿瘤中的应用进展

    Institute of Scientific and Technical Information of China (English)

    李巨仕; 汤恢焕

    2011-01-01

    环氧合酶-2(Cyclooxygenase-2,COX-2)是前列腺素合成过程中一重要的限速酶,COX-2的过度表达及其前列腺素产物与多种肿瘤的发生、发展关系密切,COX-2抑制剂通过抑制肿瘤细胞增殖,诱导肿瘤细胞凋亡,阻断致癌物的代谢,减弱肿瘤介导的免疫抑制,调节抑制血管生成,抑制肿瘤细胞侵袭,环氧合酶非依赖抑癌途径,对原癌基因及抑癌基因的影响等途径影响肿瘤的发生发展,这方面的研究为针对COX-2的抗肿瘤策略打开新的视野,提供新的线索.%Cyclooxygenase-2 (COX-2) is the process of prostaglandin synthesis is an important rate-limiting enzyme, COX-2 over-expression of prostaglandin products with a variety of tumors, the development of close.COX-2 inhibiting tumor cell added induce tumor cell apoptosis,blocking the metabolism of carcinogens, decreased tumor-mediated immunosuppression, inhibition of angiogenesis regulation, inhibition of tumor cell invasion, cyclooxygenase-independent tumor suppressor pathway, and suppression of oncogene the impact of cancer genes affect the tumor development pathway, esearch in this area is for COX-2 anti-tumor strategy to open new horizons and provide new clues.

  3. Non-steroidal anti-inflammatory drugs, Cyclooxygenase-2 inhibitors and paracetamol use in Queensland and in the whole of Australia

    Directory of Open Access Journals (Sweden)

    Tett Susan E

    2008-09-01

    Full Text Available Abstract Background Cross national drug utilization studies can provide information about different influences on physician prescribing. This is important for medicines with issues around safety and quality of use, like non selective non-steroidal anti-inflammatory drugs (ns-NSAIDs and cyclo-oxygenase-2 (COX-2 inhibitors. To enable comparison of prescription medicine use across different jurisdictions with a range of population sizes, data first need to be compared within Australia to understand whether use in a smaller sub-population may be considered as representative of the total use within Australia. The aim of this study was to compare the utilization of non selective NSAID, COX-2 inhibitors and paracetamol between Queensland and Australia. Method Dispensing data were obtained for concession beneficiaries for Australia for ns-NSAIDs, COX-2 inhibitors and paracetamol subsidized by the PBS over the period 1997–2003. The same data were purchased for Queensland. Data were converted to Defined Daily Dose (DDD/1000 beneficiaries/day (World Health Organization anatomical therapeutic chemical classification, 2005. Results Total NSAID and paracetamol consumption were similar in Australia and Queensland. Ns-NSAID use decreased sharply with the introduction of COX-2 inhibitors (from approximately 80 to 40 DDD/1000 beneficiaries/day. Paracetamol was constant (approximately 45 DDD/1000 beneficiaries/day. COX-2 inhibitors consumption was initially higher in Queensland than in the whole of Australia. Conclusion Despite initial divergence in celecoxib use between Queensland and Australia, the use of ns-NSAIDs, COX-2 inhibitors and paracetamol overall, in concession beneficiaries, was comparable in Australia and Queensland.

  4. Cyclooxygenase-2 overexpression is common in serrated and non-serrated colorectal adenoma, but uncommon in hyperplastic polyp and sessile serrated polyp/adenoma

    Directory of Open Access Journals (Sweden)

    Kirkner Gregory J

    2008-01-01

    Full Text Available Abstract Background Cyclooxygenase-2 (COX-2, PTGS2 plays an important role in colorectal carcinogenesis. COX-2 overexpression in colorectal cancer is inversely associated with microsatellite instability (MSI and the CpG island methylator phenotype (CIMP. Evidence suggests that MSI/CIMP+ colorectal cancer may arise through the serrated tumorigenic pathway through various forms of serrated neoplasias. Therefore, we hypothesized that COX-2 may play a less important role in the serrated pathway. Methods By immunohistochemistry, we assessed COX-2 expression in 24 hyperplastic polyps, 7 sessile serrated polyp/adenomas (SSA, 5 mixed polyps with SSA and adenoma, 27 traditional serrated adenomas, 515 non-serrated adenomas (tubular adenoma, tubulovillous adenoma and villous adenoma, 33 adenomas with intramucosal carcinomas, 96 adenocarcinomas with serration (corkscrew gland and 111 adenocarcinomas without serration. Results Strong (2+ COX-2 overexpression was more common in non-serrated adenomas (28% = 143/515 than in hyperplastic polyps (4.2% = 1/24, p = 0.008 and serrated polyps (7 SSAs and 5 mixed polyps (0% = 0/12, p = 0.04. Furthermore, any (1+/2+ COX-2 overexpression was more frequent in non-serrated adenomas (60% = 307/515 than in hyperplastic polyps (13% = 3/24, p Conclusion COX-2 overexpression is infrequent in hyperplastic polyp, SSA and mixed polyp with SSA and adenoma, compared to non-serrated and serrated adenoma. COX-2 overexpression becomes more frequent as tumors progress to higher grade neoplasias. Our observations suggest that COX-2 may play a less significant role in the serrated pathway of tumorigenesis; however, COX-2 may still play a role in later stage of the serrated pathway.

  5. Effect of phytic acid from rice and corn on morphology, cell proliferation, apoptosis and cyclooxygenase-2 expression in swine jejunal explants

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    Elisângela Olegário da Silva

    2014-06-01

    Full Text Available Phytic acid (IP6 is a potent antioxidant present in several natural foods. Beneficial effects on colon cancer and inflammation have been associated to IP6 in several studies, however, scarce data about the effect on small intestine are available. The aim of the present study was to evaluate the effect of different doses of IP6 from rice and corn on intestinal morphology, cellular proliferation, apoptosis and cyclooxygenase-2 (Cox-2 expression using swine jejunal explants as experimental model. This report demonstrated that explants treated with 0.5 mM, 2.5 mM and 5 mM of IP6 from rice and 2.5 mM and 5 mM from corn showed higher villi height compared to control. Explants treated with 2.5 mM and 5 mM IP6 from rice exhibited a significant reduction on intestinal histological changes (villi atrophy and fusion, edema, lymphatic vessel dilation, loss of apical enterocytes, cell vacuolation, necrotic debris, morphology of enterocytes and microvilli and number of villi. The cellular proliferation decreased in the explants treated with the dosages of 2.5 mM and 5 mM from rice and a significant decrease in cell apoptosis was observed in the treatments with 2.5 mM IP6 from rice and 5 mM IP6 from corn compared to the control. The explants treated with 2.5 mM and 5 mM IP6 from rice and corn showed a significant reduction of the Cox-2 expression. Higher dosages of IP6 from rice and corn used in this experiment increased the viability and preservation of intestinal tissue as evidenced by morphological and immunohistochemical assays.

  6. Soy Saponins Meditate the Progression of Colon Cancer in Rats by Inhibiting the Activity of β-Glucuronidase and the Number of Aberrant Crypt Foci but Not Cyclooxygenase-2 Activity

    OpenAIRE

    Yu-Wei Guo; Yue-Hwa Chen; Wan-Chun Chiu; Hsiang Liao; Shyh-Hsiang Lin

    2013-01-01

    Objective. The effect of extracted crude soybean saponins on preneoplastic lesions, aberrant crypt foci (ACF), and the related mechanism were investigated. Research Methods and Procedures. Rats were assigned into five groups according to different doses of extracted crude soybean saponins and received 1,2-dimethylhydrazine (DMH) injection in week 5. In week 15, all rats were sacrificed. The number of ACFs, the cyclooxygenase-2 (COX-2) protein expression, the level of prostaglandins E2 (PGE2),...

  7. 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

  8. Cyclooxygenase-2 inhibition in colon experimental carcinogenesis Inhibición de la ciclooxigenasa-2 en la carcinogénesis cólica experimental

    Directory of Open Access Journals (Sweden)

    J. F. Noguera Aguilar

    2005-09-01

    Full Text Available Background: an overexpression of cyclooxygenase-2 (COX-2 has been seen in colon tumors; therefore, COX-2 specific inhibitors may be used as preventive agents. The aim of this study was to investigate the effect of both selective and non-selective COX-2 inhibitors on the incidence of colonic tumors in a model of chemical carcinogenesis in the rat. Design: experimental study with 65 male Sprague-Dawley rats randomly assigned to one of four groups: (a control (n = 20, with chemical carcinogenesis using 1-2 dimethylhydrazine (1-2 DMH; (b acetylsalicylic acid (ASA (n = 15, with chemical carcinogenesis and the addition of ASA at 30 mg/kg; (c low-dose rofecoxib (n = 15, with chemical carcinogenesis and the addition of rofecoxib at a dose of 1.2 mg/kg; (d high-dose rofecoxib (n = 15, with carcinogenesis and the addition of rofecoxib at 3 mg/kg. Carcinogenic induction was performed with 1-2 DMH at a weekly dose of 25 mg/kg for 18 weeks. The main parameter evaluated was percentage of neoplastic colonic tissue, which relates tumor surface area to colon surface area. Results: rofecoxib at a dose of 3 mg/kg significantly reduced chemical colon carcinogenesis in rats (p Introducción: se ha comprobado a nivel clínico y experimental la existencia de sobreexpresión de la ciclooxigenasa-2 (COX-2 en los tumores de colon, por lo que los inhibidores de dicha enzima podrían tener un efecto preventivo. El objetivo del estudio es investigar el efecto de la inhibición de la ciclooxigenasa en un modelo de carcinogénesis cólica farmacológica en la rata. Material y métodos: estudio experimental en 65 ratas Sprague-Dawley macho, asignadas a uno de los grupos: control (n = 20, con carcinogénesis farmacológica con 1-2 dimetilhidrazina; grupo ácido acetilsalicílico (n = 15, con carcinogénesis y adición de AAS, grupo Inhibidores COX-2 a bajas dosis (n = 15, con carcinogénesis y adición de rofecoxib a dosis de 1,2 mg/kg, y grupo Inhibidores COX-2 a altas dosis

  9. 环氧合酶-2在低分子肝素干预大鼠酒精性肝病中的作用机制研究%Effect of cyclooxygenase-2 in alcoholic liver disease rats intervened with low molecular weight heparin

    Institute of Scientific and Technical Information of China (English)

    阎春英; 石军; 杨艳; 郝菁华; 任万华; 张捷

    2012-01-01

    目的 研究低分子肝素干预大鼠酒精性肝病模型的作用机制.方法 56% (V/v)的白酒平均以8 g/kg的剂量2次/d灌胃10周,初步制备大鼠酒精性肝病模型,成模后部分大鼠低分子肝素(100 IU/kg)皮下注射进行干预,4周后观察低分子肝素对大鼠的血清生物化学指标、肝组织中丙二醛及环氧化酶-2的影响.结果 与模型组比较,低分子肝素治疗组大鼠血清转氨酶、血脂及丙二醛含量明显下降(P<0.05);光学显微镜观察HE染色见脂肪变性、炎症反应程度明显减轻(P<0.01),免疫组织化学染色及逆转录聚合酶链反应显示环氧化酶-2的表达均明显降低(P<0.05).结论 低分子肝素通过改善脂肪代谢、抑制氧化应激及降低环氧化酶-2的表达而对酒精性肝病大鼠起到一定的保护治疗作用.%Objective To study the effect of low molecular weight heparin on alcohol-fed rats. Methods The model of alcoholic liver disease rats was made by alcohol gavage (infused with 56% of ethanol twice a day with a dose of 8 g/kg body weight for 10 weeks) , and then parts were treated with low molecular weight heparin (100 IU/kg). After 4 weeks, the effect of low molecular weight heparin on serum biochemical index, malondialdehyde and cyclooxygenase-2 in liver tissue was observed. Results Compared with model group, the levels of Iransaminases, lipids and malondialdehyde significantly decreased in low molecular weight heparin therapy group ( P <0. 05 ). Under the observation of optical microscope, the degree of liver steatosis, inflammation reaction were significantly reduced ( P < 0.01 ) . The levels of cyclooxygenase-2 in liver tissue were significantly lowered by immunohistochemical staining and semiquantitative reverse transcription-polymerase chain reaction. Conclusion Low molecular weight heparin has therapeutic effect on alcohol-induced liver disease rats by improving fat metabolism, reducing oxidative stress and decreasing the

  10. Synthesis and crystal structure of N-[(dimethylamino)methylidene]-4-[1-(4-nitrophenyl)-1H-tetrazol-5-yl]-benzenesulfonamide: Molecular docking and bioassay studies as cyclooxygenase-2 inhibitor

    Science.gov (United States)

    Jawabrah Al-Hourani, Baker; El-Barghouthi, Musa I.; McDonald, Robert; Al-Awaida, Wajdy; Sharma, Sai Kiran; Wuest, Frank

    2016-09-01

    The synthesis of N-[(dimethylamino)methylidene]-4-[1-(4-nitrophenyl)-1H-tetrazol-5-yl]benzenesulfonamide (3) has been easily approached and the structure has been determined by X-ray crystallography. Tetrazole 3 crystallizes in the monoclinic space group C2/c, with the cell parameters determined as a = 35.5408 (18) Å, b = 7.6972 (4) Å, c = 13.0700 (7) Å3, β = 96.8598 (6)°, V = 3549.9 (3) Å3, and Z = 8. Its structure refines to R1 = 0.0341 (for 2986 observed reflections [I ≥ 2σ(I)]) and wR2 = 0.0990 (for all 3637 unique reflections). The aryl rings at the 1- and 5-positions show no conjugation to the tetrazole group, and the [(Dimethylamino)methylene]aminosulfonyl (Me2NCHNSO2) group is disordered, with the two disorder conformers being related by a pseudo mirror plane. In the crystal, intermolecular interactions between adjacent molecule of 3 are dominated by weak (2.4-2.7 Å) CeH…O and CeH…N hydrogen bonds. The molecular docking studies were carried out to understand the interaction of compound 3 within the active site of the cyclooxygenase-2 enzyme, followed by a comparison study with the celecoxib drug as a reference compound. The in vitro bioassay studies of tetrazole 3 toward cyclooxygenase-1 and cyclooxygenase-2 enzymes showed that compound 3 has no inhibition potency for either enzyme.

  11. Retraction: "Concurrent inhibition of NF-κB, cyclooxygenase-2, and epidermal growth factor receptor leads to greater anti-tumor activity in pancreatic cancer" by Ali et al.

    Science.gov (United States)

    2016-08-01

    The above article, published online on March 8, 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the first author and the corresponding author that found Figures 2A, 4, 6A, and 6C to be inappropriately manipulated. REFERENCE Ali S, Banerjee S, Schaffert JM, El-Rayes BF, Philip PA, Sarkar FH. 2010. Concurrent inhibition of NF-κB, cyclooxygenase-2, and epidermal growth factor receptor leads to greater anti-tumor activity in pancreatic cancer. J Cell Biochem 110:171-181; doi: 10.1002/jcb.22523.

  12. Retraction: "Concurrent inhibition of NF-κB, cyclooxygenase-2, and epidermal growth factor receptor leads to greater anti-tumor activity in pancreatic cancer" by Ali et al.

    Science.gov (United States)

    2016-08-01

    The above article, published online on March 8, 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the first author and the corresponding author that found Figures 2A, 4, 6A, and 6C to be inappropriately manipulated. REFERENCE Ali S, Banerjee S, Schaffert JM, El-Rayes BF, Philip PA, Sarkar FH. 2010. Concurrent inhibition of NF-κB, cyclooxygenase-2, and epidermal growth factor receptor leads to greater anti-tumor activity in pancreatic cancer. J Cell Biochem 110:171-181; doi: 10.1002/jcb.22523. PMID:27301888

  13. Effects of Smoking Cessation on Eight Urinary Tobacco Carcinogen and Toxicant Biomarkers

    Science.gov (United States)

    Carmella, Steven G.; Chen, Menglan; Han, Shaomei; Briggs, Anna; Jensen, Joni; Hatsukami, Dorothy K.; Hecht, Stephen S.

    2009-01-01

    We determined the persistence at various times (3, 7, 14, 21, 28, 42 and 56 days) of eight tobacco smoke carcinogen and toxicant biomarkers in the urine of 17 smokers who stopped smoking. The biomarkers were 1-hydroxy-2-(N-acetylcysteinyl)-3-butene (1) and 1-(N-acetylcysteinyl)-2-hydroxy-3-butene (2) [collectively called MHBMA for monohydroxybutyl mercapturic acid] and 1,2-dihydroxy-4-(N-acetylcysteinyl)butane (3) [DHBMA for dihydroxybutyl mercapturic acid], metabolites of 1,3-butadiene; 1-(N-acetylcysteinyl)-propan-3-ol (4, HPMA for 3-hydroxypropyl mercapturic acid), a metabolite of acrolein; 2-(N-acetylcysteinyl)butan-4-ol (5, HBMA for 4-hydroxybut-2-yl mercapturic acid), a metabolite of crotonaldehyde; (N-acetylcysteinyl)benzene (6, SPMA for S-phenyl mercapturic acid), a metabolite of benzene; (N-acetylcysteinyl)ethanol (7, HEMA for 2-hydroxyethyl mercapturic acid), a metabolite of ethylene oxide; 1-hydroxypyrene (8) and its glucuronides (1-HOP), metabolites of pyrene; and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (9) and its glucuronides (total NNAL), a biomarker of exposure to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These biomarkers represent some of the major carcinogens and toxicants in cigarette smoke: 1,3-butadiene, acrolein, crotonaldehyde, benzene, ethylene oxide, polycyclic aromatic hydrocarbons (PAH), and NNK. With the exception of DHBMA, levels of which did not change after cessation of smoking, all other biomarkers decreased significantly after 3 days of cessation (P<0.001). The decreases in MHBMA, HPMA, HBMA, SPMA, and HEMA were rapid, nearly reaching their ultimate levels (81 – 91% reduction) after 3 days. The decrease in total NNAL was gradual, reaching 92% after 42 days, while reduction in 1-HOP was variable among subjects to about 50% of baseline. Since DHBMA did not change upon smoking cessation, there appear to be sources of this metabolite other than 1,3-butadiene. The results of this study demonstrate that the tobacco

  14. Assessing exposure to tobacco-specific carcinogen NNK using its urinary metabolite NNAL measured in US population: 2011-2012.

    Science.gov (United States)

    Wei, Binnian; Blount, Benjamin C; Xia, Baoyun; Wang, Lanqing

    2016-01-01

    Carcinogenic tobacco-specific nitrosamines (TSNAs) such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are found only in tobacco and derived products. Food and Drug Administration of the United States (US FDA) lists NNK as one of the 93 harmful and potentially harmful constituents (HPHCs) found in tobacco products and tobacco smoke. The aim of this study was to use the urinary concentration of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a major metabolite of NNK, to quantitatively estimate exposure to NNK in the US general population. In 2011-2012, the Centers for Disease Control and Prevention's National Health and Nutrition Examination Survey (NHANES) collected urine and serum samples from a representative sample of US residents. We used a serum cotinine cutoff of 10 ng/ml with combination of questionnaire data to select non-users from cigarette users and used self-reported data to determine different tobacco product user groups. We estimated the absorbed total daily dose of NNK using a probabilistic method based on a two-compartment model. The geometric mean (GM) for the daily dose of NNK among smokers aged 12-16 years was significantly higher than that for non-users at the same age stage exposed to second-hand smoke (SHS) (P<0.001). Among those exposed to SHS, the GM for daily dose of NNK in young children (6-11 years) was nearly three times of those for adults in the age range 21-59 years. Among cigarette users, non-Hispanic Whites had the highest NNK daily dose and Mexican Americans had the lowest levels. Exclusive snuff or chewing product users had significantly higher daily dose of NNK than did cigarette smokers. Our study found that the maximum daily dose of NNK for children aged from 6 to 11 years and that for a significant percentage of cigarette users, chewing product and snuff users were higher than an estimated provisional "reference" risk level.

  15. Multiclass Carcinogenic DNA Adduct Quantification in Formalin-Fixed Paraffin-Embedded Tissues by Ultraperformance Liquid Chromatography-Tandem Mass Spectrometry.

    Science.gov (United States)

    Guo, Jingshu; Yun, Byeong Hwa; Upadhyaya, Pramod; Yao, Lihua; Krishnamachari, Sesha; Rosenquist, Thomas A; Grollman, Arthur P; Turesky, Robert J

    2016-05-01

    DNA adducts are a measure of internal exposure to genotoxicants and an important biomarker for human risk assessment. However, the employment of DNA adducts as biomarkers in human studies is often restricted because fresh-frozen tissues are not available. In contrast, formalin-fixed paraffin-embedded (FFPE) tissues with clinical diagnosis are readily accessible. Recently, our laboratory reported that DNA adducts of aristolochic acid, a carcinogenic component of Aristolochia herbs used in traditional Chinese medicines worldwide, can be recovered quantitatively from FFPE tissues. In this study, we have evaluated the efficacy of our method for retrieval of DNA adducts from archived tissue by measuring DNA adducts derived from four other classes of human carcinogens: polycyclic aromatic hydrocarbons (PAHs), aromatic amines, heterocyclic aromatic amines (HAAs), and N-nitroso compounds (NOCs). Deoxyguanosine (dG) adducts of the PAH benzo[a]pyrene (B[a]P), 10-(deoxyguanosin-N(2)-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (dG-N(2)-B[a]PDE); the aromatic amine 4-aminobiphenyl (4-ABP), N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-4-ABP); the HAA 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), N-(deoxyguanosin-8-yl)-PhIP (dG-C8-PhIP); and the dG adducts of the NOC 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), O(6)-methyl-dG (O(6)-Me-dG) and O(6)-pyridyloxobutyl-dG (O(6)-POB-dG), formed in liver, lung, bladder, pancreas, or colon were recovered in comparable yields from fresh-frozen and FFPE preserved tissues of rodents treated with the procarcinogens. Quantification was achieved by ultraperformance liquid chromatography coupled with electrospray ionization ion-trap multistage mass spectrometry (UPLC/ESI-IT-MS(3)). These advancements in the technology of DNA adduct retrieval from FFPE tissue clear the way for use of archived pathology samples in molecular epidemiology studies designed to assess the causal role of exposure to hazardous chemicals

  16. Expression of inwardly rectifying potassium channels (GIRKs and beta-adrenergic regulation of breast cancer cell lines

    Directory of Open Access Journals (Sweden)

    Cakir Yavuz

    2004-12-01

    Full Text Available Abstract Background Previous research has indicated that at various organ sites there is a subset of adenocarcinomas that is regulated by beta-adrenergic and arachidonic acid-mediated signal transduction pathways. We wished to determine if this regulation exists in breast adenocarcinomas. Expression of mRNA that encodes a G-protein coupled inwardly rectifying potassium channel (GIRK1 has been shown in tissue samples from approximately 40% of primary human breast cancers. Previously, GIRK channels have been associated with beta-adrenergic signaling. Methods Breast cancer cell lines were screened for GIRK channels by RT-PCR. Cell cultures of breast cancer cells were treated with beta-adrenergic agonists and antagonists, and changes in gene expression were determined by both relative competitive and real time PCR. Potassium flux was determined by flow cytometry and cell signaling was determined by western blotting. Results Breast cancer cell lines MCF-7, MDA-MB-361 MDA-MB 453, and ZR-75-1 expressed mRNA for the GIRK1 channel, while MDA-MB-468 and MDA-MB-435S did not. GIRK4 was expressed in all six breast cancer cell lines, and GIRK2 was expressed in all but ZR-75-1 and MDA-MB-435. Exposure of MDA-MB-453 cells for 6 days to the beta-blocker propranolol (1 μM increased the GIRK1 mRNA levels and decreased beta2-adrenergic mRNA levels, while treatment for 30 minutes daily for 7 days had no effect. Exposure to a beta-adrenergic agonist and antagonist for 24 hours had no effect on gene expression. The beta adrenergic agonist, formoterol hemifumarate, led to increases in K+ flux into MDA-MB-453 cells, and this increase was inhibited by the GIRK channel inhibitor clozapine. The tobacco carcinogen 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK, a high affinity agonist for beta-adrenergic receptors stimulated activation of Erk 1/2 in MDA-MB-453 cells. Conclusions Our data suggests β-adrenergic receptors and GIRK channels may play a role in breast cancer.

  17. Expression of the α7 nicotinic acetylcholine receptor in human lung cells

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    Schuller Hildegard M

    2005-04-01

    Full Text Available Abstract Background We and others have shown that one of the mechanisms of growth regulation of small cell lung cancer cell lines and cultured pulmonary neuroendocrine cells is by the binding of agonists to the α7 neuronal nicotinic acetylcholine receptor. In addition, we have shown that the nicotine-derived carcinogenic nitrosamine, 4(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK, is a high affinity agonist for the α7 nicotinic acetylcholine receptor. In the present study, our goal was to determine the extent of α7 mRNA and protein expression in the human lung. Methods Experiments were done using reverse transcription polymerase chain reaction (RT-PCR, a nuclease protection assay and western blotting using membrane proteins. Results We detected mRNA for the neuronal nicotinic acetylcholine receptor α7 receptor in seven small cell lung cancer (SCLC cell lines, in two pulmonary adenocarcinoma cell lines, in cultured normal human small airway epithelial cells (SAEC, one carcinoid cell line, three squamous cell lines and tissue samples from nine patients with various types of lung cancer. A nuclease protection assay showed prominent levels of α7 in the NCI-H82 SCLC cell line while α7 was not detected in SAEC, suggesting that α7 mRNA levels may be higher in SCLC compared to normal cells. Using a specific antibody to the α7 nicotinic receptor, protein expression of α7 was determined. All SCLC cell lines except NCI-H187 expressed protein for the α7 receptor. In the non-SCLC cells and normal cells that express the α7 nAChR mRNA, only in SAEC, A549 and NCI-H226 was expression of the α7 nicotinic receptor protein shown. When NCI-H69 SCLC cell line was exposed to 100 pm NNK, protein expression of the α7 receptor was increased at 60 and 150 min. Conclusion Expression of mRNA for the neuronal nicotinic acetylcholine receptor α7 seems to be ubiquitously expressed in all human lung cancer cell lines tested (except for NCI-H441 as well as normal

  18. Regulation of cyclooxygenase-2 expression in rat oviductal epithelial cells: Evidence for involvement of GPR30/Src kinase-mediated EGFR signaling.

    Science.gov (United States)

    Popli, Pooja; Sirohi, Vijay Kumar; Manohar, Murli; Shukla, Vinay; Kaushal, Jyoti Bala; Gupta, Kanchan; Dwivedi, Anila

    2015-11-01

    The oviduct plays a crucial role in female reproduction by regulating gamete transport, providing a specific microenvironment for fertilization and early embryonic development. Cyclooxygenase (COX)-derived prostaglandins play essential role in carrying out these oviduct-specific functions. Estrogen upregulates COX-2 expression in rat oviduct; however, the mechanisms responsible for regulation of COX-2 expression in rat oviductal epithelial cells (OECs) remain unclear. In the present study, we proposed that estrogen induces COX-2 expression via G-protein coupled receptor i.e., GPR30 in OECs. To investigate this hypothesis, we examined the effects of E2-BSA, ICI 182,780, GPR30 agonist and GPR30 antagonist on COX-2 expression and explored potential signaling pathway leading to COX-2 expression. Co-localization experiments revealed GPR30 to be primarily located in the peri-nuclear space, which was also the site of E2-BSA-fluorescein isothiocyanate (E2-BSA-FITC) binding. The E2-BSA induced-COX-2 and prostaglandin release were subjected to regulation by both EGFR and PI3K signaling as inhibitors of c-Src kinase (PP2), EGFR (EGFR inhibitor) and PI-3 kinase (LY294002) attenuated E2-BSA mediated effect. These results suggest that EGFR transactivation leading to activation of PI-3K/Akt pathway participates in COX-2 expression in rat OECs. Interestingly, E2-BSA induced COX-2 expression and subsequent prostaglandin release were abolished by NF-κB inhibitor. In addition, E2-BSA induced the nuclear translocation of p65-NF-κB and up-regulated the NF-κB promoter activity in rat OECs. Taken together, results demonstrated that E2-BSA induced the COX-2 expression and consequent PGE2 and PGF2α release in rat OECs. These effects are mediated through GPR30-derived EGFR transactivation and PI-3K/Akt cascade leading to NF-κB activation.

  19. Bisgma stimulates prostaglandin E2 production in macrophages via cyclooxygenase-2, cytosolic phospholipase A2, and mitogen-activated protein kinases family.

    Directory of Open Access Journals (Sweden)

    Yu-Hsiang Kuan

    Full Text Available BACKGROUND: Bisphenol A-glycidyl-methacrylate (BisGMA employs as a monomer in dental resins. The leakage of BisGMA from composite resins into the peripheral environment can result in inflammation via macrophage activation. Prostaglandin E2 (PGE2 is a key regulator of immunopathology in inflammatory reactions. Little is known about the mechanisms of BisGMA-induced PGE2 expression in macrophage. The aim of this study was to evaluate the signal transduction pathways of BisGMA-induced PGE2 production in murine RAW264.7 macrophages. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we demonstrate that BisGMA can exhibit cytotoxicity to RAW264.7 macrophages in a dose- and time-dependent manner (p<0.05. In addition, PGE2 production, COX-2 expression, and cPLA2 phosphorylation were induced by BisGMA on RAW264.7 macrophages in a dose- and time-dependent manner (p<0.05. Moreover, BisGMA could induce the phosphorylation of ERK1/2 pathway (MEK1/2, ERK1/2, and Elk, p38 pathway (MEK3/6, p38, and MAPKAPK2, and JNK pathway (MEK4, JNK, and c-Jun in a dose- and time-dependent manner (p<0.05. Pretreatment with AACOCF3, U0126, SB203580, and SP600125 significantly diminished the phosphorylation of cPLA2, ERK1/2, p38, and JNK stimulated by BisGMA, respectively (p<0.05. BisGMA-induced cytotoxicity, cPLA2 phosphorylation, PGE2 generation, and caspases activation were reduced by AACOCF3, U0126, SB203580, and SP600125, respectively (p<0.05. CONCLUSIONS: These results suggest that BisGMA induced-PGE2 production may be via COX-2 expression, cPLA2 phosphorylation, and the phosphorylation of MAPK family. Cytotoxicity mediated by BisGMA may be due to caspases activation through the phosphorylation of cPLA2 and MAPKs family.

  20. Positive correlation between patency and mRNA levels for cyclooxygenase-2 and prostaglandin E synthase in the uterine cervix of bitches with pyometra

    OpenAIRE

    Tamada, Hiromichi; ADACHI, Nahoko; KAWATE, Noritoshi; Inaba, Toshio; HATOYA, Shingo; Sawada, Tsutomu

    2015-01-01

    Factors involved in patency of uterine cervices in the bitch with pyometra remain to be clarified. This study examined relationship between patency and mRNA levels for inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-1, COX-2 and prostaglandin E synthase (PGES) in the uterine cervix of bitches with pyometra. Cervical patency was measured by inserting the stainless steel rods with different diameter into cervical canals. Levels of mRNA expression were determined by semi-quantitativ...

  1. Effect of Sphingosine 1-Phosphate on Cyclo-Oxygenase-2 Expression, Prostaglandin E2 Secretion, and β2-Adrenergic Receptor Desensitization.

    Science.gov (United States)

    Rumzhum, Nowshin N; Rahman, M Mostafizur; Oliver, Brian G; Ammit, Alaina J

    2016-01-01

    Tachyphylaxis of the β2-adrenergic receptor limits the efficacy of bronchodilatory β2-agonists in respiratory disease. Cellular studies in airway smooth muscle (ASM) have shown that inflammatory mediators and infectious stimuli reduce β2-adrenergic responsiveness in a cyclo-oxygenase (COX)-2-mediated, prostaglandin E2 (PGE2)-dependant manner. Herein, we show that sphingosine 1-phosphate (S1P), a bioactive sphingolipid that plays an important role in pathophysiology of asthma, also induces β2-adrenergic receptor desensitization in bronchial ASM cells and exerts hyporesponsiveness to β2-agonists. We treated ASM cells with S1P (1 μM) for up to 24 hours and then examined the temporal kinetics of COX-2 mRNA expression, protein up-regulation, and PGE2 secretion. S1P significantly enhanced COX-2 expression and PGE2 secretion, and this was repressed by the selective COX-2 inhibitor celecoxib, the corticosteroid dexamethasone, or small interfering RNA (siRNA) knockdown of COX-2 expression. In combination with another proinflammatory mediator found elevated in asthmatic airways, the cytokine TNF-α, we observed that S1P-induced COX-2 mRNA expression and protein up-regulation and PGE2 secretion from ASM cells were significantly enhanced. Notably, S1P induced heterologous β2-adrenergic desensitization, as measured by inhibition of cyclic adenosine monophosphate production in response to the short-acting β2-agonist, salbutamol, and the long-acting β2-agonist, formoterol. Taken together, these data indicate that S1P represses β2-adrenergic activity in ASM cells by increasing COX-2-mediated PGE2 production, and suggest that this bioactive sphingolipid found elevated in asthma may contribute to β2-adrenergic desensitization. PMID:26098693

  2. Analyzing the Interaction of Andrographolide and Neoandrographolide, Diterpenoid Compounds From Andrographis Paniculata (Burm.F) Nees, to Cyclooxygenase-2 Enzyme by Docking Simulation

    OpenAIRE

    Jutti Levita; Enade P. Istyastono; As’ari Nawawi; Abdul Mutholib; de Esch, Iwan J. P.; Slamet Ibrahim Surantaatmadja

    2009-01-01

    Cyclooxygenase (COX), an enzyme involved in the conversion of arachidonic acid to prostaglandins, exists in two isoforms, which are COX-1 and COX-2. Despite the similarities of COX-1 and COX-2, the two isoforms show subtle differences in amino acid composition at the active sites. Since COX-1 has isoleucine, a bulkier amino acid at position 523 than COX-2’s valine, it allows COX-2 to have a larger space in its active site. Andrographolide reduces COX-2 expression induced by PAF and fMLP in...

  3. 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

    2016-07-01

    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. PMID:27226548

  4. Positive correlation between patency and mRNA levels for cyclooxygenase-2 and prostaglandin E synthase in the uterine cervix of bitches with pyometra.

    Science.gov (United States)

    Tamada, Hiromichi; Adachi, Nahoko; Kawate, Noritoshi; Inaba, Toshio; Hatoya, Shingo; Sawada, Tsutomu

    2016-03-01

    Factors involved in patency of uterine cervices in the bitch with pyometra remain to be clarified. This study examined relationship between patency and mRNA levels for inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-1, COX-2 and prostaglandin E synthase (PGES) in the uterine cervix of bitches with pyometra. Cervical patency was measured by inserting the stainless steel rods with different diameter into cervical canals. Levels of mRNA expression were determined by semi-quantitative reverse transcription-polymerase chain reaction. The cervical patency was positively correlated with mRNA levels for COX-2 and PGES, but not those for iNOS and COX-1. The results suggest that gene expression of COX-2 and PGES may be involved in the regulation of patency in the uterine cervix of bitches with pyometra. PMID:26596635

  5. Analyzing the Interaction of Andrographolide and Neoandrographolide, Diterpenoid Compounds From Andrographis Paniculata (Burm.F Nees, to Cyclooxygenase-2 Enzyme by Docking Simulation

    Directory of Open Access Journals (Sweden)

    Jutti Levita

    2009-09-01

    Full Text Available Cyclooxygenase (COX, an enzyme involved in the conversion of arachidonic acid to prostaglandins, exists in two isoforms, which are COX-1 and COX-2. Despite the similarities of COX-1 and COX-2, the two isoforms show subtle differences in amino acid composition at the active sites. Since COX-1 has isoleucine, a bulkier amino acid at position 523 than COX-2’s valine, it allows COX-2 to have a larger space in its active site. Andrographolide reduces COX-2 expression induced by PAF and fMLP in HL60/neutrophils. Neoandrographolide inhibits COX-2 expression at the translational level. The purpose of this study is to examine the binding modes of andrographolide and neoandrographolide against COX-1 and COX-2 in terms of hydrogen bonds and docking energy, to understand their antiinflammatory property. The docking study indicates that both andrographolide and neoandrographolide are able to be located in the COX-2’s binding pocket but not in the COX-1’s. It confirms that COX-1’s binding pocket is smaller than COX-2’s. Based on this study, both andrographolide and neoandrographolide show selective inhibitory property to COX-2. Their selectivity are due to their specific interaction with Arg 513 in the binding pocket of COX-2, which is also shown by SC-558, a COX-2 selective inhibitor.

  6. Manassantin B isolated from Saururus chinensis inhibits cyclooxygenase-2-dependent prostaglandin D2 generation by blocking Fyn-mediated nuclear factor-kappaB and mitogen activated protein kinase pathways in bone marrow derived-mast cells.

    Science.gov (United States)

    Lu, Yue; Hwang, Seung-Lark; Son, Jong Keun; Chang, Hyeun Wook

    2013-01-01

    The authors investigated the effect of manassantin B (Man B) isolated from Saururus chinensis (S. chinensis) on cyclooxygenase-2 (COX-2)-dependent prostaglandin D2 (PGD2) generation in mouse bone marrow derived-mast cells (BMMCs). Man B inhibited the generation of PGD2 dose-dependently by inhibiting COX-2 expression in immunoglobulin E (IgE)/Ag-stimulated BMMCs. To elucidate the mechanism responsible for the inhibition of COX-2 expression by Man B, the effects of Man B on the activation of nuclear factor-kappaB (NF-κB), a transcription factor essential and mitogen-activated protein kinases (MAPKs) for COX-2 induction, were examined. Man B attenuated the nuclear translocation of NF-κB p65 and its DNA-binding activity by inhibiting inhibitors of kappa Bα (IκBα) degradation and concomitantly suppressing IκB kinase (IKK) phosphorylation. In addition, Man B suppressed phosphorylation of MAPKs including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH2-terminal kinase (JNK) and p38. It was also found that Man B suppressed Fyn kinase activation and consequent downstream signaling processes, including those involving Syk, Gab2, and Akt. Taken together, the present results suggest that Man B suppresses COX-2 dependent PGD2 generation by primarily inhibiting Fyn kinase in FcεRI-mediated mast cells.

  7. Association of the Three Common SNPs of Cyclooxygenase-2 Gene (rs20417, rs689466, and rs5275 with the Susceptibility of Breast Cancer: An Updated Meta-Analysis Involving 34,590 Subjects

    Directory of Open Access Journals (Sweden)

    Zhi-Jun Dai

    2014-01-01

    Full Text Available Several single nucleotide polymorphisms have been identified in cyclooxygenase-2 (COX-2 genes (e.g., −765 G>C (rs20417, −1195G>A (rs689466, and 8473 C>T (rs5275. The association of these SNPs with the risk of different cancer types is still controversial. This study aims to evaluate the correlation between these SNPs and breast cancer risk in different ethnic groups. We have searched PubMed, Web of Knowledge, and Embase for relevant studies. Odds ratios (ORs with 95% confidence intervals (CIs were used to estimate the strength of the associations. A total of 13 studies (15,330 cases and 19,260 controls were eligible for meta-analysis. This meta-analysis showed that COX-2 rs20417 polymorphism was correlated with an increased risk of breast cancer in Caucasians, while rs689466 was associated with a decreased risk of breast cancer in Caucasians. The rs5275 polymorphism had no association with breast cancer risk.

  8. Gene expression of ornithine decarboxylase, cyclooxygenase-2, and gastrin in atrophic gastric mucosa infected with Helicobacter pylori before and after eradication therapy.

    Science.gov (United States)

    Konturek, Peter C; Rembiasz, Kazimierz; Konturek, Stanislaw J; Stachura, Jerzy; Bielanski, Wladyslaw; Galuschka, K; Karcz, Danuta; Hahn, Eckhart G

    2003-01-01

    H. pylori (Hp) -induced atrophic gastritis is a well-known risk factor for the development of gastric cancer. Whether Hp eradication can prevent or retard the progress of atrophy and metaplasia has been the topic of numerous studies but the subject remains controversial. Recently, the increased expression of ornithine decarboxylase (ODC), gastrin and cyclooxygenase (COX)-2 has been shown to be increased in premalignant lesions in gastric mucosa and to play an essential role in the malignant transformation. The aim of the study is to assess the effect of eradication therapy on atrophic gastritis and analyze the gene expression for ODC, COX-2 and gastrin in gastric mucosa after succesful eradication in patients with atrophic gastritis. Twenty patients with chronic atrophic gastritis including both corpus and antrum of the stomach were included in this study. Four antral mucosal biopsy specimens were obtained from antrum and four from corpus. The histopathologic evaluation of gastritis was based on Sydney classification of gastritis. All patients were Hp positive based on the [13C] urea breath test (UBT) and the presence of anti-Hp IgG and anti-CagA-antibodies detected by ELISA. The patients were then eradicated with triple therapy consiting of omeprazol (2 x 20 mg), amoxycillin (2 x 1 g) and clarithromycin (2 x 500 mg) for seven days and vitamin C 1 g/day for three months. In gastric mucosal samples obtained from the antrum and corpus before and after eradication, the mRNA expression for ODC, COX-2, and gastrin was assessed by reverse-transcription polymerase chain reaction (RT-PCR). In all patients the gastric secretory analysis was performed by measuring gastric acid output and serum gastrin levels. After triple therapy the successful eradication assessed by UBT was observed in 95% of patients. In 45% of patients the infection with CagA-positive Hp strain was observed. Three months after eradication a significant reduction in the gastric activity (neutrophilic

  9. 环氧合酶-2在子宫肌瘤组织中的表达及其意义%The expression and pathogenetic roles of cyclooxygenase-2 in uterine fibroids

    Institute of Scientific and Technical Information of China (English)

    柯小平; 程忠平; 窦芳芳; 戴虹; 张文超; 谢彦; 左晓明

    2012-01-01

    Objective To detect the expression of cyclooxygenase - 2 (COX-2) in uterine fibroids and normal uterine smooth muscles thus to investigate its roles in the pathogenesis of uterine fibroids. Methods To detect the expression of cyclooxygenase - 2 in uterine fibroids and normal uterine smooth muscle thus to investigate its roles in the pathogenesis of uterine fibroids. Results the COX - 2 positive index in smooth muscle cells (11. 90) was much lower than that in uterine fibroids cells (46. 50, P<0. 05). At protein level, the COX- 2 expression in uterine fibroids was significantly higher than in smooth muscle (0. 872 ± 0. 035 vs 0. 202 ± 0. 056). Similarly, at mR NA level, COX- 2 expression in uterine fibriods (0. 122 ± 0. 062) was higher than in normal smooth muscle tissue (0. 025 ± 0. 009)、(P<0. 05). Conclusion COX- 2 expression in uterine fibroids was significantly higher than u-terine smooth muscles, suggesting an important role of COX - 2 in the pathogenesis of uterine fibroids.%目的 观察环氧合酶-2(cyclooxygenase,COX-2)在子宫肌瘤与子宫平滑肌组织中的表达,探讨COX-2与子宫肌瘤发病机制的相关性.方法 选择2010年1月至2010年8月在上海市杨浦区中心医院行腹腔镜下子宫肌瘤切除术的30例患者的子宫肌瘤组织为实验组,并取其邻近的正常平滑肌组织为对照组,采用免疫组化方法检测COX-2的表达;并采用蛋白印迹法及实时荧光定量逆转录聚合酶链反应分别在蛋白水平和基因转录水平检测标本中COX-2的表达.结果 免疫组化检测实验组和对照组均有COX-2蛋白表达,平滑肌细胞阳性指数(MP1)为11.90,子宫肌瘤细胞阳性指数(FPI)为46.50,两者比较,差异有统计学意义(P<0.05).蛋白印迹法结果显示,COX-2在实验组(0.872±0.035)中的表达明显高于对照组(0.202±0.056),两者比较,差异有统计学意义(P<0.05).COX-2 mRNA在实验组(0.122±0.062)中的表达也高于对照组(0.025士0.009),两者

  10. Cyclooxygenase-2 expression in cervical cancer

    Directory of Open Access Journals (Sweden)

    Mandić Aljoša

    2014-01-01

    Full Text Available Background/Aim. Cyclooxygenase (COX or prostaglandin H2 synthase is the first enzyme that catalyzes the first two steps in the biosynthesis of prostaglandins from arachidonic acid. The aim of the study was to determine the expression level of COX-2 in patients with cervical cancer and compare it with that in the control group with no cervical pathology. Methods. The study included 76 patients divided into two groups: the control group - 30 patients without histopathological changes and the group A - 46 patients with cervical cancer, FIGO stage IB-IIA. Histopathological and immunohistochemical analyses were performed in these two groups of patients. Results. In the control group, the expression of COX-2 was not confirmed compared to the group A of 26 (56.52% patients. The expression of COX-2 showed a statistically significant difference in the presence of lymphocytic stromal infiltration (p = 0.0053. The expression of COX-2 was more pronounced in the stromal tissue without lymphocytic infiltration (80% vs 20%. Conclusion. A higher expression of COX-2 in cervical carcinoma without stromal lymphocytic infiltration suggests a possible paradoxical effect of COX-2 in immunosuppression. Frequent COX- 2 expression in the subgroup with poor prognostic histological parameters in the group A indicates the importance of COX-2 expression in the carcinogenesis of cervical cancer.

  11. [Recent development of selective cyclooxygenase-2 inhibitors].

    Science.gov (United States)

    Kawai, Shinichi

    2002-12-01

    Nonsteroidal anti-inflammatory drugs(NSAIDs) are clinically effective against the inflammatory symptoms of rheumatoid arthritis. Recent attention has been focused on selective cyclooxygenase(COX)-2 inhibitors, a type of NSAID that inhibits a subtype of COX. Because of the different actions of COX-1 and COX-2, selective COX-2 inhibitors were expected to reduce adverse reactions such as gastrointestinal disorders. Various clinical studies have confirmed that the efficacy of COX-2 inhibitors for RA is similar to that of conventional NSAIDs, but they cause fewer severe gastrointestinal disorders. The incidence of complications related to renal dysfunction, such as edema and hypertension, is not different. Patients using selective COX-2 inhibitors have recently been reported to show an increase in thrombotic complications such as myocardial infarction. Therefore, more data on adverse events should be collected in the future from large-scale clinical studies to further clarify the actual value of selective COX-2 inhibitors. PMID:12510364

  12. Cyclooxygenase-2 inhibitors in ginger (Zingiber officinale)

    Science.gov (United States)

    van Breemen, Richard B.; Tao, Yi; Li, Wenkui

    2010-01-01

    Ginger roots have been used to treat inflammation and have been reported to inhibit cyclooxygenase (COX). Ultrafiltration liquid chromatography mass spectrometry was used to screen a chloroform partition of a methanol extract of ginger roots for COX-2 ligands, and 10-gingerol, 12-gingerol, 8-shogaol, 10-shogaol, 6-gingerdione, 8-gingerdione, 10-gingerdione, 6-dehydro-10-gingerol, 6-paradol, and 8-paradol bound to the enzyme active site. Purified 10-gingerol, 8-shogaol and 10-shogaol inhibited COX-2 with IC50 values of 32 μM, 17.5 μM and 7.5 μM, respectively. No inhibition of COX-1 was detected. Therefore, 10-gingerol, 8-shogaol and 10-shogaol inhibit COX-2 but not COX-1, which can explain, in part, anti-inflammatory properties of ginger. PMID:20837112

  13. Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabinoid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain.

    Science.gov (United States)

    Jhaveri, Maulik D; Richardson, Denise; Robinson, Ian; Garle, Michael J; Patel, Annie; Sun, Yan; Sagar, Devi R; Bennett, Andrew J; Alexander, Stephen P H; Kendall, David A; Barrett, David A; Chapman, Victoria

    2008-07-01

    The antinociceptive effects of the endocannabinoids (ECs) are enhanced by inhibiting catabolic enzymes such as fatty acid amide hydrolase (FAAH). The physiological relevance of the metabolism of ECs by other pathways, such as cyclooxygenase-2 (COX2) is less clear. To address this question we compared the effects of local inhibition of FAAH versus COX2 (URB597 and nimesulide, respectively) on inflammatory hyperalgesia and levels of endocannabinoids and related molecules in the hindpaw. Inflammatory hyperalgesia was measured following intraplantar injection of carrageenan. Effects of intraplantar injection of URB597 (25 microg and 100 microg) or nimesulide (50 microg) on hyperalgesia and hindpaw levels of anandamide (AEA), 2-arachidonoylglycerol (2AG) and N-palmitoylethanolamine (PEA) were determined. Although both doses of URB597 increased levels of AEA and 2AG in the carrageenan inflamed hindpaw, only the lower dose of URB597 attenuated hyperalgesia (P<0.05). Nimesulide attenuated both hyperalgesia and hindpaw oedema (P<0.001, P<0.01, respectively) and increased levels of PEA (P<0.05) in the hindpaw. Since both AEA and PEA are ligands for peroxisome proliferator-activated receptor-alpha (PPARalpha), the effects of the PPARalpha antagonist GW6471 on nimesulide- and URB597-mediated effects were studied. GW6471, but not a PPARgamma antagonist, blocked the inhibitory effects of nimesulide and URB597 on hyperalgesia. Our data suggest that both COX2 and FAAH play a role in the metabolism of endocannabinoids and related molecules. The finding that PPARalpha antagonism blocked the inhibitory effects of nimesulide and URB597 suggests that PPARalpha contributes to their antinociceptive effects in the carrageenan model of inflammatory hyperalgesia.

  14. Expressin of cyclooxygenase-2 in human transitional cell carcinoma of bladder%膀胱移行细胞癌COX-2的表达及其意义

    Institute of Scientific and Technical Information of China (English)

    陈合群; 张向阳; 黄振国; 齐范

    2005-01-01

    目的研究环氧合酶-2(cyclooxygenase-2,COX-2)在膀胱移行细胞癌(transitional cell carcino--ma,TCC)组织中的表达及其意义.方法采用免疫组化技术,对49例膀胱TCC石蜡切片和18例正常膀胱黏膜组织进行COX-2蛋白检测,对阳性表达率与肿瘤分级及侵袭性间的相关性与TCC分级及侵袭性进行分析.结果COX-2蛋白在膀胱TCC中表达率为63.2%,正常膀胱黏膜无表达(P<0.01).低分级TCC阳性率36.4%,高分级为92.8%(P<0.05).表浅TCC阳性表达率38.9%,浸润TCC为77.4%(P<0.05).结论COX-2在高分级和侵袭性膀胱TCC中阳性表达率显著上升,可能会成为膀胱肿瘤患者恶性度和判断预后的重要生物学指标,并有可能成为治疗人类TCC的作用靶点.

  15. COX-2和P53在炎症应激和肿瘤发生中相互作用的研究进展%Advance in Research on Relations between Cyclooxygenase-2 and P53 during Inflammatory Stress and Carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    马晓丽; 许士国; 孙海基

    2009-01-01

    Over expression of Cyclooxygenase-2 (COX-2) is observed in most tumor types.Increased COX-2 activity and synthesis of prostaglandins stimulates proliferation,angiogenesis,and invasion,and inhibits apoptosis.Many stress and proinfiammatory signals induce COX-2 and P53 expression,including oxyradicals or DNA-damaging agents.P53,a transcription factor,is often inactivated by mutation in cancer.Several studies have identified complex cross-talks between P53 and COX-2,whereby P53 can either up-regulate or down-regulate the expression of COX-2,which in turn controls p53 transcriptional activity.However,the molecular bases of these effects are open to debate.In this review,we summarize the relationship and molecular mechanisms between COX-2 and P53 during inflammatory stress and carcinogenesis.%COX-2在多种肿瘤组织中过量表达,COX-2活性和前列腺素合成的增加促进细胞增殖、血管新生、肿瘤细胞浸润及抑制细胞凋亡.许多应激和前炎症信号,如氧自由基和DNA损伤剂,可诱导COX-2和P53的表达,而P53作为一种转录因子在肿瘤中常因突变而失活.已有研究表明,P53和COX-2存在复杂的交叉作用,P53能上调或下调COX-2的表达,而COX-2也可以调控p53转录活性,但两者相互作用的分子依据一直存在着争论.本文综述了炎症应激和肿瘤发生中COX-2和P53相互作用及其机制的研究进展.

  16. Direct lentiviral-cyclooxygenase 2 application to the tendon-bone interface promotes osteointegration and enhances return of the pull-out tensile strength of the tendon graft in a rat model of biceps tenodesis.

    Directory of Open Access Journals (Sweden)

    Charles H Rundle

    Full Text Available This study sought to determine if direct application of the lentiviral (LV-cyclooxygenase 2 (COX2 vector to the tendon-bone interface would promote osteointegration of the tendon graft in a rat model of biceps tenodesis. The LV-COX2 gene transfer strategy was chosen for investigation because a similar COX2 gene transfer strategy promoted bony bridging of the fracture gap during bone repair, which involves similar histologic transitions that occur in osteointegration. Briefly, a 1.14-mm diameter tunnel was drilled in the mid-groove of the humerus of adult Fischer 344 rats. The LV-COX2 or βgal control vector was applied directly into the bone tunnel and onto the end of the tendon graft, which was then pulled into the bone tunnel. A poly-L-lactide pin was press-fitted into the tunnel as interference fixation. Animals were sacrificed at 3, 5, or 8 weeks for histology analysis of osteointegration. The LV-COX2 gene transfer strategy enhanced neo-chondrogenesis at the tendon-bone interface but with only marginal effect on de novo bone formation. The tendon-bone interface of the LV-COX2-treated tenodesis showed the well-defined tendon-to-fibrocartilage-to-bone histologic transitions that are indicative of osteointegration of the tendon graft. The LV-COX2 in vivo gene transfer strategy also significantly enhanced angiogenesis at the tendon-bone interface. To determine if the increased osteointegration was translated into an improved pull-out mechanical strength property, the pull-out tensile strength of the LV-COX2-treated tendon grafts was determined with a pull-out mechanical testing assay. The LV-COX2 strategy yielded a significant improvement in the return of the pull-out strength of the tendon graft after 8 weeks. In conclusion, the COX2-based in vivo gene transfer strategy enhanced angiogenesis, osteointegration and improved return of the pull-out strength of the tendon graft. Thus, this strategy has great potential to be developed into an

  17. A Phase II Clinical Trial of Celecoxib Combined with Platinum-Based Regimen as First-Line Chemotherapy for Advanced Non-Small Cell Lung Cancer Patients with Cyclooxygenase-2 Positive Expression

    Institute of Scientific and Technical Information of China (English)

    Jun Zhao; Mei-na Wu; Xu-yi Liu; Jie Wang; Zhi-jie Wang; Jian-chun Duan; Qing-zhi Guo; Hua Bai; Lu Yang; Tong-tong An; Xin Wang; Yu-yan Wang

    2009-01-01

    Objective: To evaluate the efficacy and safety of celecoxib plus platinum-doublet as first-line chemotherapy in treatment of advanced non-small cell lung cancer (NSCLC), and to determine the subgroup benefiting from celecoxib combined therapy by molecular analysis. Methods: A total of 44 treatment-naive patients of advanced NSCLC with positive cyclooxygenase-2 (COX-2) expression confirmed by immunohistochemical (IHC) staining were designed to receive celecoxib plus platinum-doublet chemotherapy (cisplatin plus gemcitabine, novelbine or docetaxol) from February 2005 to May 2007. On 5(7 day before chemotherapy, 400 mg celecoxib was administered twice a day orally until obvious evidence of disease progression or intolerable toxicity was found. Adverse events were recorded according to NCI-CTC criteria. The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), 1-year survival rate, response rate (RR) and safety. Additionally, we detected epithelial growth factor receptor (EGFR) status including EGFR gene amplification by real-time PCR and gene mutations by DHPLC followed by sequencing. Results: The response rate was 45% (20/44), and the disease control rate (DCR) was 59% (26/44). The median progression-free survival time and median survival time were 6 m and 18 m, respectively. The 1-year survival rate was 68%. Chemotherapy cycle numbers and best response were found to be the predictive factors for PFS by COX model analysis (P=0.023 and P=0.000, respectively). No factor was found to affect OS. The most common toxicities included neutropenia and nausea/vomit. EGFR gene amplification was an independent prognostic factor influencing OS (P=0.0002). Patients with EGFR mutations (exon 21) had a tendency of disease progression (P=0.041). Conclusion: Encouraging activities of celecoxib combined with platinum-doublet chemotherapy were demonstrated in treatment-naive patients with advanced NSCLC, with good tolerances. For

  18. Utilización de coxibs: una estrategia de intervención en la atención primaria Prescription of cyclooxygenase-2 inhibitors: an intervention strategy in primary care

    Directory of Open Access Journals (Sweden)

    Isabel Rosich

    2005-06-01

    Full Text Available Objetivo: Evaluar una intervención dirigida a mejorar la prescripción de antiinflamatorios no esteroideos (AINE, fundamentalmente del grupo de los inhibidores de la ciclooxigenenasa-2 (coxibs. Sujetos y métodos: Estudio de intervención antes-después individual para médicos altamente prescriptores y grupal para el resto. Los datos sobre prescripción se obtuvieron del aplicativo de farmacia del Institut Català de la Salut. El período preintervención se comparó con el postintervención inmediato (que coincidió con la publicación de una alerta farmacológica sobre los efectos secundarios de los coxibs y tardío. Se controlaron el gasto de coxibs, la dosis diaria definida (DDD por 1.000 habitantes/día (DHD, el porcentaje DHD coxibs/total AINE, el porcentaje de AINE recomendados/total AINE, y el coste medio diario de la DDD de AINE. Resultados: La reducción media mensual del gasto en coxibs fue de 19.480 €/mes en el período postintervención inmediato y de 18.555 e/mes en el tardío. La disminución de la DHD de coxibs fue del 35,4% (p Objective: To evaluate an intervention designed to rationalize prescription of nonsteroidal anti-inflammatory drugs (NSAIDs, especially cyclooxygenase-2 inhibitors (COXIBs. Subjects and methods: We performed a before-after intervention study. Face-to-face educational outreach visits were conducted in general practitioners who were heavy prescribers and group intervention for the remaining. Data on prescribing habits were obtained from the pharmacy database of the Catalan Health Institute. The pre-intervention period (period 1 was compared with the immediate postintervention period (period 2, which coincided with the publication of a safety alert on the adverse effects of COXIBs and the late postintervention period (period 3. The data monitored were: a expenditure due to COXIBs; b consumption in daily defined doses (DDD per 1,000 habitants/day (DHD; c the percentage of COXIBs/total NSAIDs and the

  19. Role of aspirin on regulating the expression of cyclooxygenase-2 in the kidney of diabetic rats%阿司匹林对糖尿病大鼠肾脏COX-2表达的影响

    Institute of Scientific and Technical Information of China (English)

    叶林; 夏芳珍; 陆颖理; 施超; 郭明皓

    2012-01-01

    Objective To observe the expression of cyclooxygenase-2 and pathological change in the kidney of diabetic rats, and study how aspirin influences on the kidney and its possible mechanisms. Methods 24 Sprague Dawley (SD)rats were randomly divided into 3 groups t Control group (C), Diabetes group (D) : received peritoneal injection of streptozocin (STZ,60mg/kg), Aspirin treatment group(DT) received aspirin (lmg. Kg-1. D-l)from the fourth day after treatment as in group D. At the end of 8 weeks, the pathological changes in the kidney were observed under light microscope and electron microscope. Moreover, immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were used to examine the expression of COX-2 in the kidney. Results There was no prominent pathological change in C group. The renal pathological and lesions of rats in D group were obvious. The kidney of D group shows extra cellular matrix increasing and basilar membrane thickening. We can also see inflammatory cell infiltrating in the kidney interstitial under light microscope. The kidney glomerulus basilar membranes are uneven thickening and the structure is obscure, the close together foot processes are mainly coalition or losing under electron microscope. Compare with C group, the expression of COX-2 in renal tissue increased in D group. (P<0. 01) However, aspirin treatment could significantly decrease the expression Of COX-2(P<0. 01) and lessen the pathological lesions in comparison with those in D group. Conclusion Aspirin has a reno-protective effect on diabetic rats, it may be mediated by suppressing the expression of COX-2 and attenuating pathological change.%目的 探讨阿司匹林对糖尿病大鼠肾脏COX-2表达和病理的影响及其可能的作用机制.方法 将24只SD大鼠随机分成3组,分别为正常对照(C)组、糖尿病(D)组[腹腔注射链酶佐菌素(STZ) 60mg/kg]和糖尿病阿司匹林治疗(DT)组(先腹腔注射STZ 60mg/kg,第4天起给予0.9%氯

  20. Expression of cyclooxygenase-2 mRNA alternative splice variant in human cervical carcinoma tissues%人宫颈癌组织环加氧酶2mRNA剪接异构体的表达

    Institute of Scientific and Technical Information of China (English)

    龚霞; 万敬员; 叶笃筠; 吴萍; 张力; 周歧新

    2005-01-01

    BACKGROUND:Cervical cancer is one of the most frequent malignancies in women worldwide, and its occurrence and development is closely related to cyclooxygenase-2 (COX-2).OBJECTIVE: To examine the expression of COX-2 alternative splicing variants in human cervical carcinoma tissue and understand its possible implications.DESIGN: Non-randomized controlled experiment.SETTING: Key Laboratory of Biochemistry and Molecular Pharmacology,Department of Obstetrics and Gynecology, First Affiliated Hospital,Chongqing Medical University.PARTICIPANTS: Carcinoma tissue and normal tissue were obtained from 13 cervical carcinoma patients admitted during March 2002 to April 2002in the Department of Obstetrics and Gynecology, First Affiliated Hospital,Chongqing Medical University.METHODS: A pair of specific primers were designed for reverse transcription-polymerase chain reaction (RT-PCR) to obtain the mRNA of COX-2 in human cervical carcinoma tissues. The resultant band on electrophoresis was cloned, sequenced and analyzed.MAIN OUTCOME MEASURES: ① Agarose gel electrophoresis result of the PCR product of carcinoma and normal tissues; ② Sequencing result of the electrophoresis band from carcinoma and normal tissues.RESULTS: No COX-2 band (252 bp) was found in electrophoresis for normal tissues, while 2 bands appeared for cervical carcinoma tissues, including a new electrophoresis band of 534bp besides the COX-2 band. Cloning and sequencing revealed that this new band contained not only exons 7and 8 of COX-2 gene but also a reserved intron of 282 bp intron between exons 7 and 8. Analysis of the predicted amino acid sequence indicated that an in-frame stop codon occurred in the 48-50 bp of the intron retained in the mRNA.CONCLUSION: The presence of COX-2 alternative splicing mRNA variant (Genbank accession number:BU493602)is confirmed in human cervical carcinoma tissue, which codes for a protein possibly smaller than COX-2.%背景:宫颈癌是女性最常见的恶性肿瘤之一,

  1. 环氧化酶-2/前列腺素E2与磷脂酰肌醇-3激酶/Akt信号通路在腱骨连接处作用的相关研究%Signal Pathway of Cyclooxygenase-2/Prostaglandin E2 and Phosphoinositide-3 Kinase/Akt in Osteotendinous Junction (review)

    Institute of Scientific and Technical Information of China (English)

    王静; 王国祥

    2014-01-01

    Osteotendinous junction (OTJ) is the main structure of tendinopathy. Cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) and phosphoinositide-3 kinase (PI3K)/Akt is active under the stress, and expresses in OTJ. This article summarized the role of these two signal-ing pathways in OTJ.%腱骨连接是末端区的主要结构。环氧化酶-2/前列腺素E2与磷脂酰肌醇-3激酶/Akt在应力作用下反应活跃,并在腱骨连接各区都有相应表达,已有研究提示其与腱骨连接相关部位发病机理有着重要联系。

  2. Acute and subacute effects of tobacco alkaloids, tobacco-specific nitrosamines and phenethyl isothiocyanate on N'-nitrosonornicotine metabolism in rats

    International Nuclear Information System (INIS)

    N'-Nitrosonornicotine (NNN) was the first tobacco-specific nitrosamine (TSNA) identified as carcinogen in tobacco smoke, but no data exist on in vivo interactions between NNN and other tobacco alkaloids, TSNA or phenethyl isothiocyanate (PEITC) which have been demonstrated in various studies on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Acute effects on NNN metabolism were tested in male Fischer F344 rats injected s.c. with 30 nmol/kg body weight (bw) [5-3H]NNN either alone or simultaneously with 15 μmol/kg bw nicotine, nornicotine, anatabine, or anabasine, 150 μmol/kg bw cotinine, 3 μmol/kg bw myosmine, or 300 nmol/kg bw of either N'-nitrosoanatabine or N'-nitrosoanabasine. Another group of rats was fed a diet supplemented with PEITC at 1 μmol/g diet starting 24 h before NNN treatment. Within 24 h more than 80% and about 10% of the radioactivity was excreted with urine and feces, respectively. Urinary metabolites were separated by reversed-phase radio-HPLC and identified by co-chromatography with UV standards. In two sets of experiments with control rats treated with NNN only, 4-hydroxy-4-(3-pyridyl)butanoic acid (hydroxy acid, 44.4/44.8%), 4-oxo-4-(3-pyridyl)butanoic acid (keto acid, 32.4/31.5%), NNN-N-oxide (5.0/3.8%), 4-(3-pyridyl)butane-1,4-diol (diol, 1.1/1.0%) and norcotinine (2.3/1.0%) were consistently detected besides unmetabolised NNN (4.7/3.3%). Co-treatment with nicotine, cotinine, nornicotine and PEITC shifted the contribution of the two major metabolites significantly in favor of hydroxy acid (108-113% of control) as compared to keto acid (86-90% of control). The same treatments also increased norcotinine (135-170% of control). These changes are consistent with a decreased metabolic activation of NNN. In subacute studies rats received NNN in drinking water for 4 weeks at a daily dose of 30 nmol/kg bw with or without nornicotine at 15 μmol/kg bw or myosmine at 3 μmol/kg bw. On the last day of the experiment all rats received [5-3H

  3. Effects of cyclooxygenase-2 selective inhibitor Celecoxib on the expression of P-glycoprotein in rat with status epilepticus%环氧化酶-2选择性抑制剂塞来考昔对癫(癎)持续状态大鼠脑组织P-糖蛋白表达的影响

    Institute of Scientific and Technical Information of China (English)

    王雪莹; 黄绍平; 宋婷婷; 李丹; 杨琳

    2015-01-01

    目的 研究环氧化酶-2(COX-2)选择性抑制剂塞来考昔对癫(癎)持续状态大鼠脑组织中P-糖蛋白(P-gp)表达的影响,为寻找治疗难治性癫(癎)的新药物提供理论依据.方法 健康成年雄性SD大鼠60只按随机数字表法随机分为空白对照组、癫(癎)模型组和塞来考昔干预组.氯化锂-毛果芸香碱诱发SD大鼠癫(癎)持续状态,48只纳入实验,每组16只.各实验组均采用免疫组织化学法和Western blot法检测鼠额叶皮质区及海马区P-gp的表达情况.结果 免疫组织化学结果显示:与空白对照组比较,癫(癎)模型组中P-gp的表达显著增高,差异有统计学意义(P<0.01);塞来考昔干预后的大鼠脑组织P-gp较癫(癎)模型组显著下降,差异有统计学意义(P<0.01).Western blot法检测结果提示:各组额叶皮层和海马中均有P-gp的表达.与空白对照组比较,癫(癎)模型组中P-gp的表达量显著增高,差异有统计学意义(P<0.01);塞来考昔干预组大鼠脑组织P-gp的表达量较癫(癎)模型组显著下降,差异有统计学意义(P<0.05).结论 COX-2抑制剂塞来考昔可降低P-gp在癫(癎)持续状态大鼠脑组织中的表达,有望成为治疗难治性癫(癎)的新方法.%Objective To study the effect of cyclooxygenase-2 (COX-2)selective inhibitor Celecoxib on the expression of P-glycoprotein(P-gp)in the brain of rats with status epilepficus,in order to assess the therapeutic value of intractable epilepsy.Methods Sixty adult male SD rats were randomly divided into blank control group,the epilepsy model group and Celecoxib intervention group.The status epilepticus was induced in rats by injecting Lithium pilocarpine.Forty-eight rats were included in the experiment.There were 16 rats in each of the blank control group,epilepsy model group and Celecoxib intervention group,respectively.Immunohistochemical method and Western blot method were used to detect the expression of P-gp in experimental group in the

  4. Ethanol extract of Synurus deltoides (Aiton) Nakai suppresses in vitro LPS-induced cytokine production in RAW 264.7 macrophages and in vivo acute inflammatory symptoms

    OpenAIRE

    Jiang, Yunyao; Wang, Myeong-Hyeon

    2014-01-01

    Synurus deltoides (Aiton) Nakai, belonging to the Compositae family, is an edible plant widely distributed in Northeast Asia. In this study, we examined the mechanisms underlying the immunomodulative effects of the ethanol extract of S. deltoides (SDE). The SDE extract strongly down-regulated the mRNA expression of the inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and tumour necrosis factor (TNF)-α, thereby inhibiting the production of nitric oxide (NO), prostaglandin E2 (...

  5. Nimesulide, a cyclooxygenase-2 selective inhibitor, suppresses obesity-related non-alcoholic fatty liver disease and hepatic insulin resistance through the regulation of peroxisome proliferator-activated receptor γ

    Science.gov (United States)

    Tsujimoto, Shunsuke; Kishina, Manabu; Koda, Masahiko; Yamamoto, Yasutaka; Tanaka, Kohei; Harada, Yusuke; Yoshida, Akio; Hisatome, Ichiro

    2016-01-01

    Cyclooxygenase (COX)-2 selective inhibitors suppress non-alcoholic fatty liver disease (NAFLD); however, the precise mechanism of action remains unknown. The aim of this study was to examine how the COX-2 selective inhibitor nimesulide suppresses NAFLD in a murine model of high-fat diet (HFD)-induced obesity. Mice were fed either a normal chow diet (NC), an HFD, or HFD plus nimesulide (HFD-nime) for 12 weeks. Body weight, hepatic COX-2 mRNA expression and triglyceride accumulation were significantly increased in the HFD group. Triglyceride accumulation was suppressed in the HFD-nime group. The mRNA expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ) and the natural PPARγ agonist 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) were significantly increased in the HFD group and significantly suppressed in the HFD-nime group. Glucose metabolism was impaired in the HFD group compared with the NC group, and it was significantly improved in the HFD-nime group. In addition, the plasma insulin levels in the HFD group were increased compared with those in the NC group, and were decreased in the HFD-nime group. These results indicate that HFD-induced NAFLD is mediated by the increased hepatic expression of COX-2. We suggest that the production of 15d-PGJ2, which is mediated by COX-2, induces NAFLD and hepatic insulin resistance by activating PPARγ. Furthermore, the mRNA expression of tissue inhibitor of metalloproteinases-1 (TIMP-1), procollagen-1 and monocyte chemoattractant protein-1 (MCP-1), as well as the number of F4/80-positive hepatic (Kupffer) cells, were significantly increased in the HFD group compared with the NC group, and they were reduced by nimesulide. In conclusion, COX-2 may emerge as a molecular target for preventing the development of NAFLD and insulin resistance in diet-related obesity. PMID:27431935

  6. Celecoxib-induced cholestatic liver failure requiring orthotopic liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Ihab I El Hajj; Shahid M Malik; Hany R Alwakeel; Obaid S Shaikh; Eizaburo Sasatomi; Hossam M Kandil

    2009-01-01

    Selective cyclooxygenase-2 (COX-2) inhibitors are widely used due to their efficacy and good safety profile.However, recent case reports have described varying degrees of liver injuries associated with the use of COX-2 inhibitors. We report the case of a patient who developed acute cholestatic hepatitis progressing to hepatic failure requiring liver transplantation, following a 3-d course of celecoxib for treatment of generalized muscle aches and pains. The clinical presentation, the laboratory data, as well as the liver histopathology were supportive of the putative diagnosis of drug induced liver injury.

  7. Overexpression of cyclooxygenase-2 in NCI-H292 human alveolar epithelial carcinoma cells: roles of p38 MAPK, ERK-1/2, and PI3K/PKB signaling proteins.

    Science.gov (United States)

    Sung, Suhaeng; Park, Yukyoung; Jo, Jeong-Rang; Jung, Nak-Kyun; Song, Dae-Kyu; Bae, Jaehoon; Keum, Dong-Yun; Kim, Jae-Bum; Park, Gy-Young; Jang, Byeong-Churl; Park, Jong-Wook

    2011-10-01

    Evidence suggests overexpression of COX-2 and its role in many human cancers, including lung. However, the regulatory mechanism underlying COX-2 overexpression in lung cancer is not fully understood. We herein investigated whether COX-2 is overexpressed in human airway cancer cell lines, including A549 (lung), Hep-2 (bronchial), and NCI-H292 (alveolar). When grown in cell culture medium containing 10% FBS (serum), of note, there was strong and transient induction of COX-2 protein and mRNA in NCI-H292 cells, but little or low COX-2 expression is seen in A549 or Hep-2 cells. Interestingly, strong and sustained activities of ERK-1/2, JNK-1/2, p38 MAPK, and PKB were also shown in NCI-H292 cells grown in presence of serum. Profoundly, results of pharmacological inhibition studies demonstrated that the serum-dependent COX-2 up-regulation in NCI-H292 cells is attributed to not only the p38 MAPK-, PI3K/PKB-, and ERK-1/2-mediated COX-2 transcriptional up-regulation but also the p38 MAPK- and ERK-1/2-mediated post-transcriptional COX-2 mRNA stabilization. Of further note, it was shown that the ERK-1/2 and PI3K/PKB (but not COX-2, p38 MAPK, and JNK-1/2) activities are necessary for growth of NCI-H292 cells. These findings collectively demonstrate for the first time that COX-2 expression is transiently up-regulated by serum addition in NCI-H292 cells and the serum-induced COX-2 expression is closely linked to the p38 MAPK-, ERK-1/2-, and PI3K/PKB-mediated COX-2 transcriptional and post-transcriptional up-regulation.

  8. Effect of cyclooxygenase-2 on vascular endothelial cell apoptosis and proliferation%环氧合酶2对血管内皮细胞增殖和凋亡的影响

    Institute of Scientific and Technical Information of China (English)

    裴艳芳; 陈平

    2009-01-01

    环氧合酶(cyclooxygenase,COX)是以花生四烯酸为底物合成前列腺素的首要限速酶,COX-2作为其亚型之一,主要受细胞内外的各种刺激因素诱导表达.大量的研究表明,COX-2与血管的发生密切相关,它能够通过其衍生的各种前列腺素来影响血管内皮细胞的增殖与凋亡,并由此来参与各种慢性炎症性疾病和肿瘤的发生.弄清COX-2对血管内皮细胞增殖与凋亡的影响,及其相关的作用机制,有助于我们更好的认识其在疾病发生中的作用,从而避弊取利,为临床治疗提供更多更好的方案.%Cyclooxygenase (COX) is the rate-limiting enzyme of arachidonie acid synthesis prostaglandin,COX-2 is the subtype, whose expression can be induced expression by many stumilating factors. Many researches dedicated that COX-2 plays a very important role in angiogenesis,it could affect the vascular endothelial cell's apoptosis and proliferation through prostaglandins derived from it,then participate in the chronic inflammation and tumorigenisis. Understanding the influence of COX-2 to endothelial apoptosis and mechanism of action related,could help us to know what role it plays in the development of the disease, and make rational proposal for the clinical therapy.

  9. Effect of bone marrow stromal cells transplantation on expressions of cyclooxygenase-2 and vascular endothelial growth factor in rats following spinal cord injury%骨髓基质细胞移植对大鼠脊髓损伤后环氧化酶-2和血管内皮生长因子表达的影响

    Institute of Scientific and Technical Information of China (English)

    于德水; 曹阳; 梅晰凡; 王岩松; 闫鹏; 吕刚

    2013-01-01

    目的:观察骨髓基质细胞(bone marrow stromal cells,BMSCs)移植对大鼠脊髓损伤后环氧化酶-2(cyclooxygenase-2, COX-2)和血管内皮生长因子(vascular endothelial growth factor,VEGF)蛋白表达的影响。方法大鼠随机分为3组:A为假手术组,B为细胞培养基(DMEM)对照组,C为BMSCs移植组。B组和C组大鼠进行脊髓压迫损伤模型制作。脊髓损伤后, B组和C组大鼠分别给予DMEM培养液或BMSCs脊髓损伤周围区注射。术后应用Western Blot方法检测COX-2、VEGF蛋白在损伤脊髓组织中的表达变化。结果 COX-2、VEGF蛋白在A组大鼠未损伤脊髓组织中均低水平表达。B组与A组相比,脊髓损伤后COX-2蛋白表达水平明显增加(P<0.01),VEGF蛋白表达水平则短暂显著增加(P<0.05)。C组与B组相比, COX-2和VEGF蛋白表达水平均显著增加。结论 BMSCs移植能够增加脊髓损伤后COX-2、VEGF蛋白的表达。%Objective To observe the effect of bone marrow stromal cells (BMSCs) transplantation on expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) protein in rats following spinal cord injury (SCI). Methods Adult rats were randomly divided into group A (sham operation group), group B (DMEM control group), and group C (BMSCs transplantation group). A rat spinal cord compression injury model was established. Rats in groups B and C were injected with BMSCs or DMEM after SCI. Expression of COX-2 and VEGF protein in rats following SCI was detected by Western blot. Results The expression level of COX-2 and VEGF protein was low in group A. The expression level of COX-2 and VEGF protein was significantly higher in group B than in group A and in group C than in group B (P<0.01, P<0.05). Conclusion BMSCs transplantation can up-regulate the expression of COX-2 and VEGF protein in rats following SCI.

  10. Effects of No.2 Renal Failure Recipe on expressions of cyclooxygenase-2 and -1 mRNAs in rats with chronic renal failure%肾衰2号方对慢性肾衰大鼠肾皮质环氧化酶2及环氧化酶1 mRNA表达的影响

    Institute of Scientific and Technical Information of China (English)

    蒲冠军; 王琛; 郑平东; 何立群

    2009-01-01

    Objective: To observe the effects of No.2 Renal Failure Recipe (No.2RFR), a compound traditional Chinese herbal medicine, on expressions of cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) mRNAs in rats with chronic renal failure (CRF).Methods: A rat model of CRF was successfully established by infarction of approximately two-thirds of the left kidney and removal of the right kidney (ablation/infarction, A/I). Thirty A/I rats were randomly divided into untreated group, celebrex group and No.2RFR group. Another 10 SD rats were selected as normal control group. After 2-month treatment, the pathology of the nephridial tissue was observed with hematoxylin and eosin straining under a light microscope. Renal function including serum creatinine (SCr) and blood urea nitrogen (BUN) was determined by using an automatic biochemical analyzer. Expressions of COX-2 and COX-1 mRNAs in nephridial tissues were detected by reverse transcription-polymerase chain reaction (RT-PCR).Results: No.2RFR could significantly decrease the levels of SCr and BUN. Renal function and morphology of CRF rats were ameliorated and the expressions of COX-2 mRNA were decreased significantly in the No.2RFR group and the celebrex group, but the expressions of COX-1 mRNA had no differences among the four groups.Conclusion: No.2RFR can improve renal function and reduce glomerular sclerosis and renal fibrosis by inhibiting the over-expression of the COX-2 mRNA.%目的:观察肾衰2号方对慢性肾衰(chronic renal failure,CRF)大鼠肾皮质环氧化酶2(cyclooxygenase-2,COX-2)及环氧化酶1(cyclooxygenase-1,COX-1)mRNA表达的影响.方法:采用左肾动脉的2/3分支结扎,右肾摘除(ablation/infarction, A/I)法制作大鼠CRF模型.造模成功后,将造模大鼠随机分为模型组、西乐葆(塞来昔布)组、肾衰2号方组.选用10只正常大鼠作为正常对照组.治疗2个月后,苏木精和伊红染色观察大鼠肾组织形态学改变,检测治

  11. Furosemide stimulates macula densa cyclooxygenase-2 expression in rats

    DEFF Research Database (Denmark)

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

    2001-01-01

    of the loop diuretic furosemide (12 mg/day) or were fed with the diuretic hydrochlorothiazide (30 mg/kg day) for seven days each. To compensate for their salt and water loss, the animals had free access to normal water and to salt water (0.9% NaCl, 0.1% KCl). COX-2 expression in kidney cortex was assessed...

  12. Cyclooxygenase-2 expression and its association with thyroid lesions

    OpenAIRE

    Krawczyk-Rusiecka, Kinga; Lewiński, Andrzej

    2010-01-01

    Cyclooxygenase (COX), also known as prostaglandin H synthase, catalyses the formation of prostaglandins from arachidonic acid. It can be expressed in response to various stimuli, such as hormones, mitogens, cytokines, other inflammatory mediators and growth factors. The product of COX-2 activity has been implicated in carcinogenesis by promoting angiogenesis, inhibiting apoptosis, increasing cell invasion and stimulating cell proliferation. It has also been proved that the regular intake of n...

  13. Increased Cyclooxygenase-2 Expression in Juvenile Polyposis Syndrome

    NARCIS (Netherlands)

    W.A. van Hattem; L.A.A. Brosens; S.Y. Marks; A.N.A. Milne; S. van Eeden; C.A. Iacobuzio-Donahue; A. Ristimäki; F.M. Giardiello; G.J.A. Offerhaus

    2009-01-01

    Background & Aims: Gastrointestinal juvenile polyps may occur in juvenile polyposis syndrome (JPS) or sporadically. JPS is an autosomal-dominant condition caused by a germline defect in SMAD4 or BMPR1A in 50% to 60% of cases, and is characterized by multiple juvenile polyps, predominantly in the col

  14. Targeted deletions of cyclooxygenase-2 and atherogenesis in mice

    DEFF Research Database (Denmark)

    Hui, Yiqun; Ricciotti, Emanuela; Crichton, Irene;

    2010-01-01

    -2 in macrophages and T cells (TCs) to atherogenesis. METHODS AND RESULTS: Deletion of macrophage-COX-2 (Mac-COX-2KOs) was attained with LysMCre mice and completely suppressed lipopolysaccharide-stimulated macrophage prostaglandin (PG) formation and lipopolysaccharide-evoked systemic PG biosynthesis...... by approximately 30%. Lipopolysaccharide-stimulated COX-2 expression was suppressed in polymorphonuclear leukocytes isolated from MacKOs, but PG formation was not even detected in polymorphonuclear leukocyte supernatants from control mice. Atherogenesis was attenuated when MacKOs were crossed into hyperlipidemic...

  15. Ethanol extracts of Scutellaria baicalensis protect against lipopolysaccharide-induced acute liver injury in mice

    Institute of Scientific and Technical Information of China (English)

    Hai Nguyen Thanh; Hue Pham Thi Minh; Tuan Anh Le; Huong Duong Thi Ly; Tung Nguyen Huu; Loi Vu Duc; Thu Dang Kim; Tung Bui Thanh

    2015-01-01

    To investigated the protective potential of ethanol extracts of Scutellaria baicalensis (S. baicalensis ) against lipopolysaccharide (LPS)-induced liver injury. Methods: Dried roots of S. baicalensis were extracted with ethanol and concentrated to yield a dry residue. Mice were administered 200 mg/kg of the ethanol extracts orally once daily for one week. Animals were subsequently administered a single dose of LPS (5 mg/kg of body weight, intraperitoneal injection). Both protein and mRNA levels of cytokines, such as tumor necrosis factor alpha, interleukin-1β, and interleukin-6 in liver tissues were evaluated by ELISA assay and quantitative PCR. Cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor-κB protein levels in liver tissues were analyzed by western blotting. Results: Liver injury induced by LPS significantly increased necrosis factor alpha, interleukin-1β, interleukin-6, cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor-κB in liver tissues. Treatment with ethanol extracts of S. baicalensis prevented all of these observed changes associated with LPS-induced injury in liver mice. Conclusions: Our study showed that S. baicalensis is potentially protective against LPS-induced liver injury in mice.

  16. Azadirachtin interacts with the tumor necrosis factor (TNF) binding domain of its receptors and inhibits TNF-induced biological responses.

    OpenAIRE

    Thoh, Maikho; Kumar, Pankaj; Nagarajaram, Hampathalu A.; Manna, Sunil K

    2013-01-01

    The role of azadirachtin, an active component of a medicinal plant Neem (Azadirachta indica), on TNF-induced cell signaling in human cell lines was investigated. Azadirachtin blocks TNF-induced activation of nuclear factor κB (NF-κB) and also expression of NF-κB-dependent genes such as adhesion molecules and cyclooxygenase 2. Azadirachtin inhibits the inhibitory subunit of NF-κB (IκBα) phosphorylation and thereby its degradation and RelA (p65) nuclear translocation. It blocks IκBα kinase (IKK...

  17. 环氧合酶-2和血管内皮细胞生长因子与慢性乙型肝炎肝窦毛细血管化的关系%Relationship between cyclooxygenase-2 and vascular endothelial growth factor with liver sinusoidal capillarization of chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    于莉; 许建明; 严家春; 马勇; 徐长江

    2009-01-01

    Objective To study the relationship between expression of cyclooxygenase-2 (COX-2) and vas-culax endothelial growth factor (VEGF) with liver sinusnidal capillarization (LSC) of chronic hepatitis B (CHB). Methods We studied liver biopsies from 200 patients with CHB COX-2 ,VEGF immunohistochemical stain were ob-served to accomplish relationship between expression of COX-2,VEGF and LSC. Results LSC occupy above 80% in the group. There were manifestation in mild-LSC (focal) , middle-LSC (sheet-shape) and severe-LSC (widespread). Electron microscope shown the laceration in the endothelium of sinuses and formation of basal lamina and budding for-mation lumen of blood vessel and fat-storing cell convert myofibroblast. Expression of COX-2, VEGF, Co-Ⅳ and retic-ulum, collagen and elastic fibers with mild or severe in LSC is manifest locking relate. Conclusion Increased ex-pression of COX-2 ,VEGF in liver tissue of CHB may facilitate LSC and hepatic fibrosis.%目的 探讨环氧合酶-2(COX-2)和血管内皮细胞生长因子(VEGF)表达与慢性乙型肝炎(CHB)肝窦毛细血管化(LSC)的关系.方法 对200例CHB肝样本作COX-2、VEGF免疫组织化学染色,就其表达变化与LSC的关系进行观察.结果 LSC占该组病例80%以上,有轻(灶性)、中(片状)、重度(弥漫)表现.电镜示肝窦内皮撕裂,基膜形成,窦内皮细胞出芽形成血管腔,贮脂细胞转化肌成纤维细胞,COX-2、VEGF、Ⅳ型胶原(Co-Ⅳ)及网状、胶原、弹力纤维表达与LSC的轻重程度呈同步关系.结论 肝组织COX-2、VEGF表达增强可促进LSC及肝纤维化.

  18. The inhibitory effect of nimesulide and aspirin on esophageal squamous cell carcinoma cell lines with or without cyclooxygenase-2 expression%尼美舒利、阿司匹林对COX-2不同表达水平的食管鳞癌细胞株的抑制作用

    Institute of Scientific and Technical Information of China (English)

    周巧直; 孟欣颖; 朱圣韬; 张澍田

    2011-01-01

    Objective To investigate the inhibitory effect of nimesulide and aspiiin on esophageal squamous cell carcinoma( ESCC )cell lines with or without cyclooxygenase-2 expression. Methods The human ESCC cell lines ECl09 and TE-1 were used in this study.Cox-2 expression was detected by Western blotting. After 72 hours treatment with nimesulide and aspirin, the cell growth inhibition was determined by MTT assay, the cell cycle arrest and apoptosis detected by flow cytometry. Results Cox-2 protein expression was observed in ECl09, but not in TE-1. Nimesulide suppressed proliferation of ECl09 from 0.05 mmol/L to 0.4 mmol/L in a dose-dependent manner, while only 0.4 mmol/L nimesulide showed this effect in TE-1. Nimesulide exerted cell cycle arrest in the Go/G1 phase with induction of apoptosis, but had no effect on TE-1. Aspirin suppressed proliferation of ECl09 as well as TE-1 in a dose-dependent manner and promoted apoptosis in both cell lines. Conclusion The inhibitory effect on ESCC cell lines may be influenced by COX-2 expression for nimesulide, but not for aspirin. Non - selective COX-2 inhibitor may exert inhibitory effect on tumor proliferation via COX-2 independent pathway.%目的 比较选择性和非选择性环氧合酶-2(cyclooxygenase-2,COX-2)抑制剂对不同COX-2表达水平的食管鳞癌细胞的抑制作用.方法 选取食管鳞癌细胞株EC109和TE-1,采用Western blotting法测定COX-2蛋白表达、MTT法检测细胞增生以及流式细胞术检测细胞周期和细胞凋亡(PI标记),观察阿司匹林及尼美舒利对2株细胞增生、凋亡的作用.结果 Western blotting结果显示,EC109细胞表达COX-2,TE-1细胞不表达COX-2.选择性COX-2抑制剂--尼美舒利可抑制EC109细胞的增生,抑制率为(17.5±3.3)%~(80.1±3.9)%.尼美舒利仅在0.4 mmol/L时对TE-1细胞有抑制作用,抑制率为(16.2±7.0)%.尼美舒利可使EC109细胞的细胞周期阻滞于G0/G1期,并诱导细胞凋亡,但对TE-1细胞

  19. 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

  20. 人前列腺癌细胞转移潜能与环氧化酶-2的表达及患者预后的相关性%Expression of cyclooxygenase-2 in human prostate cancer cell with different metastatic potential

    Institute of Scientific and Technical Information of China (English)

    陈臻; 秦大山; 岳中瑾; 王志平; 傅生军

    2003-01-01

    目的: 探讨人前列腺癌细胞转移潜能与其环氧化酶-2( COX-2)表达之间的关系,及环氧化酶-2与前列腺癌患者预后的关系. 方法 : 用运免疫组化及反转录聚合酶链式反应( RT-PCR)检测两种不同转移潜能人前列腺癌细胞 PC3及 PC3M中 COX-2 mRNA及其蛋白的表达以及在肿瘤坏死因子-α( TNF-α)刺激下两者的表达是否有所变化. 结果 : PC3细胞在无 TNF-α刺激时,检测不到 COX-2 mRNA 的表达,其蛋白表达也为阴性,而在 TNF-α刺激 4 h后, COX-2 mRNA及其蛋白的表达均为阳性.而在 PC3M细胞中无 TNF-α刺激时, COX-2 mRNA及其蛋白的表达已为阳性,在 TNF-α刺激 4 h后, COX-2 mRNA及其蛋白的表达均有增强. 结论 : COX-2可能在前列腺癌的发生发展中起着重要的作用,抑制 COX-2的表达,或许能够降低前列腺癌的恶性程度甚至能够阻止其发生.这对前列腺癌患者生存期内创造良好的生活质量及前列腺癌的防治提供有力的理论依据.%AIM:To investigate the relationship between human prostate cancer cells with different metastatic potential and expression of COX-2. METHODS: Expression of cyclooxygenase-2 and it's regulation by tumor necrosis factor-α in PC3 and PC3M were detected by reverse transcription-PCR and immunohistochemistry. RESULTS:We observed that the COX-2 mRNA level and COX-2 protein were undetectable in PC3 cells but it was positive at 4 h after stimulation with TNF-α .In PC3M, there were a gradual increase in COX-2 expression up to 4 h after stimulation with TNF-α compared with the beginning. CONCLUSION: The result of the current study demonstrate that the human prostate carcinoma cells generated COX-2 and regulated by TNF-α ,and that COX-2 might play an important role in the proliferation of prostate carcinoma cells.These findings suggest that inhibition of COX-2 development may lead to inhibition of the proliferation and metastasis of prostate carcinoma but also to the

  1. 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。

  2. 尼美舒利对不同COX-2表达水平的食管鳞癌细胞的抑制作用%Inhibitory effect of Nimesulide on esophageal squamous cell carcinoma cell lines with different level of Cyclooxygenase-2 expression

    Institute of Scientific and Technical Information of China (English)

    孟欣颖; 赵燕; 朱圣韬; 张澍田

    2011-01-01

    Objective : To investigate the inhibitory effect of Nimesulide, a selective Cyclooxygenase - 2 ( COX 2 ) inhibitor, on esophageal squamous cell carcinoma ( ESCC ) cell lines with or without COX - 2 expression. Methods :The human ESCC cell lines EC 109 , KYSE 150 and TE - 1 were selected in this study. COX -2 expression was detected by Western blot. After 72 hours treatment with Nimesulide, the cell growth inhibition was determined by MTT assay, the cell cycle arrest and apoptosis were detected by flow cytometry. Results : COX - 2 protein expression was observed in EC 109 with high level and in KYSE 150 with moderate level, but not in TE - 1. Inhibitory effect of Nimesulide was observed in EC 109 and KYSE 150. Nimesulide suppressed proliferation of EC 109 and KYSE 150 from 50μ mol/L to 400lμmol/L in a dose - dependent manner ( P < 0. 05 ) . while only 400 μmol/L Nimesulide showed this effect in TE - 1. The IC50 of Nimesulide was low in EC 109 , moderate in KYSE 150 and high in TE - 1. Nimesulide exerted cell cycle arrest in the G0/G1 phase with induction of apoptosis in EC 109 and KYSE 150, but had no such effect in TE - 1. Conclusion :The inhibitory effect of Nimesulide on ESCC cell lines may be influenced by the level of COX - 2 expression.%目的:比较选择性环氧合酶-2(COX-2)抑制剂尼美舒利对不同COX-2表达水平的食管鳞癌细胞的抑制作用.方法:选取食管鳞癌细胞株EC 109、KYSE 150和TE-1,采用Western blot方法测定COX-2蛋白表达、MTT法检测细胞增殖抑制,流式细胞术检测细胞周期和细胞凋亡,观察尼美舒利对各组细胞的增殖抑制和促凋亡作用.结果:COX-2蛋白在EC 109细胞中呈高表达,KYSE 150细胞中呈中等度表达,TE-1细胞不表达COX-2蛋白.尼美舒利在50μmol/L-400μmol/L浓度区间可抑制EC 109、KYSE 150细胞的增殖(P<0.05),并呈剂量依赖性,在400μmol/L时对TE-1细胞有抑制作用.EC 109细胞尼美舒利的IC50值最低,KYSE150次之,TE-1

  3. Effect of promoter methylation on lower expressed cyclooxygenase-2 esophageal squamous cell carcinoma xenograft%启动子甲基化调节在低表达环氧合酶-2的食管鳞癌移植模型中的作用

    Institute of Scientific and Technical Information of China (English)

    王青釭; 孟莹; 朱圣韬; 施海韵; 张澍田

    2014-01-01

    目的:环氧合酶-2(cyclooxygenase-2,COX-2)参与食管鳞癌(esophageal squamous cell carcinoma,ESCC)的发生发展过程,但在部分 ESCC 细胞株中 COX-2呈低表达。选择低表达 COX-2基因的 ESCC 进行裸鼠移植。探讨 COX-2基因甲基化与基因表达的关系,观察联合 COX-2选择性抑制剂和去甲基化药物干预对移植瘤生长的影响。方法选择 KYSE 150细胞进行裸鼠移植,采用数字表法随机分为4组:0.9%(质量分数)氯化钠注射液对照检查组7只。分别给予①尼美舒利(nimesulide,NIM)+5-氮杂脱氧胞苷(5-Aza-deoxycytidine,5-Aza)干预②尼美舒利干预③5-Aza 干预。5周后处死动物,比较各组移植瘤的直径,计算移植瘤体积,绘制生长曲线。反转录-聚合酶链反应(reverse transcription-polymerase chain reaction,RT-PCR)测定组织中 COX-2 mRNA 表达;免疫组织化学方法测定 COX-2蛋白的表达;亚硫酸氢盐测序方法测定移植瘤中 COX-2启动子的甲基化状态。酶联免疫吸附测定(enzyme-linked immunosorbent assay,ELISA)法检测各组移植瘤中前列腺素 E2(prostaglandin E2,PGE2)的浓度。结果各组动物体质量增长差异无统计学意义,组间具有可比性。联合干预组移植瘤明显小于其他各组,差异具有统计学意义(P0. 05). Xenograft volumes were different between groups with that of the sodium chloride group smaller than other groups, and the difference was significant(P<0. 01). It was showed that methylation degree of COX-2 gene promoter was higher in NIM group and sodium choloride group than that in NIM combining 5-Aza group and 5-Aza group. For 10 CpG sites, methylation degrees were 30% and 58. 3% in group 3 and group 4, respectively. The expressions of COX-2 mRNA and protein were coincidently low in group 1 and high in group 3. PGE2 values were 0. 37, 0. 91 and 1. 22 in group 1, 2 and 3 compared with group 4, respectively. Conclusion Promoter methylation of COX-2 gene is one of the

  4. Effect of Human Interferon Alfa-2b and Cyclooxygenase-2 Inhibitor on Cells of Hepatocarcinoma%联合应用干扰素α-2b及选择性环氧化酶2抑制剂对肝癌细胞抑制作用的研究

    Institute of Scientific and Technical Information of China (English)

    孙忠志; 陈剑群

    2011-01-01

    目的 观察干扰素α-2b(IFN-α-2b),选择性环氧化酶2(COX-2)抑制剂非甾体类消炎药塞来昔布单用以及两者联合应用时,对人肝癌细胞株HepG2的生长抑制作用及同时检测药物作用后COX-2和血管内皮生长因子(VEGF)及Bcl-2表达的情况,探讨药物作用的机制.方法 HepG2细胞根据所加药物不同分为不同浓度的IFN-α-2b组(1250、2500、5000、10 000、20 000、40 000 U/mL)、塞来昔布组(25、50、100、200 μmol/L)、联合用药组(IFN-α-2b 5000 U/mL+塞来昔布 50 μmol/L、IFN-α-2b 5000 U/mL+选择性COX-2 100 μmol/L).MTT法检测不同时间(24、48 h)各组细胞增殖抑制率,流式细胞术检测细胞凋亡率,Western blot检测用药前后COX-2、VEGF、Bcl-2蛋白在HepG2细胞中的表达变化.结果 不同浓度的塞来昔布和干扰素对HepG2细胞均有抑制作用,且联合效果明显优于单用,各组与对照组差异有统计学意义(P<0.05);流式细胞术分析:塞来昔布50 μmol/L组、塞来昔布100 μmol/L组、IFN-α-2b 5000 U/mL组、IFN-α-2b 5000 U/mL+塞来昔布50 μmol/L组、IFN-α-2b 5000 U/mL+塞来昔布100 μmol/L组细胞凋亡率分别为(14.93±0.79)%、(25.43±0.89)%、(20.52±1.46)%、(27.12±3.34)%、(48.17±2.04)%,与阴性对照组(8.73±0.83)%比较差异均有统计学意义(P<0.05);塞来昔布单用及联合IFN-α-2b作用48 h后,各组COX-2、VEGF、Bcl-2蛋白的表达下调,呈剂量依赖性,联合用药组较单药组作用明显.结论 干扰素α-2b和塞来昔布均有抑制肝癌细胞HepG2增殖的作用,同时对细胞具有凋亡诱导作用,亦能抑制细胞中COX-2、VEGF、Bcl-2的表达.上述抑制作用随药物浓度的增加、作用时间的延长而增强,联合作用更强.%Objective To investigate the growth inhibition and its molecular mechanism on human hepatoma cell line HepG2 through application of celecoxib, cyclooxygenase-2 inhibitor, interferon alfa-2b alone or in combination with each other,and test

  5. Harpagoside suppresses lipopolysaccharide-induced iNOS and COX-2 expression through inhibition of NF-kappa B activation.

    Science.gov (United States)

    Huang, Tom Hsun-Wei; Tran, Van H; Duke, Rujee K; Tan, Sharon; Chrubasik, Sigrun; Roufogalis, Basil D; Duke, Colin C

    2006-03-01

    Preparations of Harpagophytum procumbens, known as devil's claw, are used as an adjunctive therapy for the treatment of pain and osteoarthritis. Pharmacological evaluations have proven the effectiveness of this herbal drug as an anti-inflammatory and analgesic agent. The present study has investigated the mechanism of action of harpagoside, one of the major components of Harpagophytum procumbens, using human HepG2 hepatocarcinoma and RAW 264.7 macrophage cell lines. Harpagoside inhibited lipopolysaccharide-induced mRNA levels and protein expression of cyclooxygenase-2 and inducible nitric oxide in HepG2 cells. These inhibitions appeared to correlate with the suppression of NF-kappaB activation by harpagoside, as pre-treating cells with harpagoside blocked the translocation of NF-kappaB into the nuclear compartments and degradation of the inhibitory subunit IkappaB-alpha. Furthermore, harpagoside dose-dependently inhibited LPS-stimulated NF-kappaB promoter activity in a gene reporter assay in RAW 264.7 cells, indicating that harpagoside interfered with the activation of gene transcription. These results suggest that the inhibition of the expression of cyclooxygenase-2 and inducible nitric oxide by harpagoside involves suppression of NF-kappaB activation, thereby inhibiting downstream inflammation and subsequent pain events. PMID:16203115

  6. Correlation of ultrasound features with the expression of vascular endothelial growth factor, cyclooxygenase-2, metalloprotease-9 in breast cancer%血管内皮生长因子、环氧化酶-2和基质金属蛋白酶-9在乳腺癌中的表达与超声征象的相关性研究

    Institute of Scientific and Technical Information of China (English)

    冉张申; 王克强; 李湘奇

    2015-01-01

    Objective By comparing with the relationship between important signs on ultrasound in breast cancer and the protein expression of vascular endothelial growth factor (VEGF),cyclooxygenase-2 (COX-2),metalloprotease-9 (MMP-9) biology,the relationship between molecular pathology and ultrasound features were studied,which provided a certain theoretical basis for the early diagnosis,treatment and prognosis of breast cancer patients.Methods 89 cases of breast lesions were confirmed by ultrasonic examination,operation and pathology.By using double-blind method,ultrasound features were grouped into burr,calcification,abnormal vascular,lymph node by physicians with rich breast diagnosis experience based on BI-RADS classification method.In each case,the expression of VEGF,COX-2,MMP-9 were detected by immunohistochemical SP method,then the relationship between the expression of VEGF,COX-2,MMP-9 and breast ultrasound features were analyzed.Results positive rate of protein expression of VEGF,COX-2,MMP-9 in burr syndrome group were higher than that of no-burr syndrome group (P < 0.05),no obvious difference(P > 0.05) between the calcification group and no calcification group,higher in abnormal breast cancer group than that of no-abnormal blood vessels (P < 0.05),higher in lymph node metastasis group than that of no-lymph node metastasis (P < 0.05).Conclusions The high expression of VEGF,COX-2,MMP-9 could have an influence on burr syndrome,abnormal blood vessels,lymph node metastasis in breast cancer ultrasound features,which could be used as a biological basis of malignant signs in ultrasound of breast cancer.And at the same time,it's prompted that the breast cancer patients with ultrasound features is high in malignant degree and with poor prognosis.%目的 通过比较乳腺癌组织中血管内皮生长因子(VEGF)、环氧化酶-2(COX-2)、基质金属蛋白酶-9(MMP-9)三种蛋白的表达与乳腺癌超声重要征象的关系,初步探讨乳腺癌超声征象与分

  7. Expression and clinical significance of cyclooxygenase-2 and prostaglandin E2 in lumbar disc herniation%环氧合酶-2、前列腺素 E2在突出腰椎间盘中的表达及其意义

    Institute of Scientific and Technical Information of China (English)

    姜志钊; 李毅中

    2014-01-01

    Objective To investigate the expression of cyclooxygenase-2 ( COX-2 ) and prostaglandin E2 ( PGE2 ) in lumbar disc herniation and explore their significance in the pathogenesis of sciatica. Methods 42 discs from patients with lumbar disc herniation (12 inflation type, 15 extrusion type, 15 sequestration type) and had the sciatic nerve ra-dioactive pain symptoms went to surgery were collected. The disc herniation was obtained from two zones of disc:Zone A was hernia tissue or separate fragment, Zone B was the remainder nucleus pulpous of lumbar intervetebral disc. In control group, 5 normal discs were harvested from 1 young fresh specimen obtained from two zone of disc. Zone A was the margin of lumbar intervetebral disc, Zone B was the center nucleus pulpous of lumbar intervetebral disc. Before the operation of all such patients in sciatica severity score for visual analogue scale ( VAS) . The content of COX-2 and PGE2 were evaluated with enzyme linked immunosorbent assay ( ELISA ) . Results The content of COX-2 and PGE2 in lumbar intervetebral disc tissue was obviously higher than that of the normal control grorp. The content of COX-2 and PGE2 gradually raised from inflation,extrasion to sequestration type at Zone A in LDH group( P<0. 01). The content of COX-2 and PGE2 were higher at Zone A than at Zone B in LDH group(P<0. 01). A posi-tive correlation was found between the content of COX-2 and PGE2 in LDH group(r=0. 863,P<0. 01). At the same time,the content of PGE2 and VAS also had a positive correlation in LDH group(r=0. 848,P<0. 01). Conclusions COX-2 and PGE2 are involved in the pathogenesis of lumbar disc degeneration and lumbar disc herniation. COX-2 and PGE2 play critical role in the development of lumbar disc herniation and herniation. COX-2 participate in the reg-ulation of the expression of PGE2 . The content of PGE2 have a closely relationship with the degree of sciatica.%目的:探讨环氧合酶-2(COX-2)、前列腺素E2(PGE2)在突出腰椎间盘

  8. Low salt induces the expression of cyclooxygenase-2 in a mouse macula densa cells through the activation of ERK、AP-1 pathways%低盐通过激活ERK和AP-1通路诱导小鼠致密斑细胞系COX-2的表达

    Institute of Scientific and Technical Information of China (English)

    刘冬妍; 李学旺; 李航; 李雪梅

    2007-01-01

    目的 探讨低盐培养对小鼠致密斑(mouse macula densa derived cells,MMDD1)细胞环氧化酶-2(cyclooxygenase,COX-2)表达和p44/42 激酶(ERK)、 AP-1活性的影响.方法 经脂质体转染含AP-1的报告质粒,采用瞬时表达方法检测AP-1转录活性;RT-PCR检测MMDD1细胞COX-2的表达;免疫印迹方法检测细胞内p-p44/42、C-JUN、C-FOS和COX-2蛋白的表达.用ELISA法检测上清液PGE2的含量.结果 低盐(LS)培养促进MMDD1细胞COX-2 mRNA和蛋白表达.培养后ERK的磷酸化程度显著上调,180 min达到高峰;ERK抑制剂PD-98059降低LS诱导的COX-2表达和PGE2分泌;LS培养促进C-JUN、C-FOS蛋白表达,激活AP-1的转录活性.AP-1抑制剂curcumin (20 μmol/L)下调LS诱导的AP-1活性、COX-2 mRNA和蛋白表达.结论 LS促进MMDD1细胞COX-2的表达,其作用可能与促进ERK的磷酸化、增加AP-1的活性有关.

  9. 前列腺素E2在环氧合酶-2促胰腺癌新生血管生成中的介导作用%Cyclooxygenase-2 inducing angiogenesis in pancreatic carcinoma is mediated by prostaglandin E2

    Institute of Scientific and Technical Information of China (English)

    王兴鹏; 谢传高; 董育玮; 张汝玲; 吴丽颖; 吴凯

    2003-01-01

    目的探讨环氧合酶-2(COX-2)促进胰腺癌新生血管生成过程中前列腺素E2(PGE2)的介导作用,进一步揭示COX-2促进胰腺癌生长的机制.方法体外培养胰腺癌细胞株PC-3,分别应用酶联免疫吸附(ELISA)和放射免疫(RIA)等方法,检测选择性COX-2抑制剂Celebrex对胰腺癌PC-3细胞血管内皮生长因子(VEGF)和PGE2表达的调节作用,并观察外源性PGE2对Celebrex调节VEGF表达的干预.建立裸鼠PC-3细胞移植瘤,Western印迹检测Celebrex对胰腺癌组织VEGF表达的影响,RIA测定Celebrex对胰腺癌组织PGE2变化的调节.结果随着Celebrex作用浓度的提高以及作用时间的延长,PC-3细胞分泌的VEGF和PGE2受到抑制,呈时间和剂量依赖性.外源性PGE2显著上调Cele-brex作用后PC-3细胞VEGF蛋白表达,呈剂量依赖性,体内实验表明,Celebrex可显著抑制移植瘤组织VEGF和PGE2的表达.结论COX-2参与了PC-3细胞VEGF分泌的调节,进而促进胰腺癌新生血管形成,而PGE2则在该过程中起着重要的介导作用.

  10. Co-administration of α-lipoic acid and cyclosporine aggravates colon ulceration of acetic acid-induced ulcerative colitis via facilitation of NO/COX-2/miR-210 cascade.

    Science.gov (United States)

    El-Gowelli, Hanan M; Saad, Evan I; Abdel-Galil, Abdel-Galil A; Ibrahim, Einas R

    2015-11-01

    In this work, α-lipoic acid and cyclosporine demonstrated significant protection against acetic acid-induced ulcerative colitis in rats. We proposed that α-lipoic acid and cyclosporine co-administration might modulate their individual effects. Induction of ulcerative colitis in rats was performed by intra-rectal acetic acid (5% v/v) administration for 3 consecutive days. Effects of individual or combined used of α-lipoic acid (35 mg/kg ip) or cyclosporine (5mg/kg sc) for 6 days starting 2 days prior to acetic acid were assessed. Acetic acid caused colon ulceration, bloody diarrhea and weight loss. Histologically, there was mucosal atrophy and inflammatory cells infiltration in submucosa, associated with depletion of colon reduced glutathione, superoxide dismutase and catalase activities and elevated colon malondialdehyde, serum C-reactive protein (C-RP) and tumor necrosis factor-α (TNF-α). Colon gene expression of cyclooxygenase-2 and miR-210 was also elevated. These devastating effects of acetic acid were abolished upon concurrent administration of α-lipoic acid. Alternatively, cyclosporine caused partial protection against acetic acid-induced ulcerative colitis. Cyclosporine did not restore colon reduced glutathione, catalase activity, serum C-RP or TNF-α. Unexpectedly, co-administration of α-lipoic acid and cyclosporine aggravated colon ulceration. Concomitant use of α-lipoic acid and cyclosporine significantly increased nitric oxide production, cyclooxygenase-2 and miR-210 gene expression compared to all other studied groups. The current findings suggest that facilitation of nitric oxide/cyclooxygenase-2/miR-210 cascade constitutes, at least partially, the cellular mechanism by which concurrent use of α-lipoic acid and cyclosporine aggravates colon damage. Collectively, the present work highlights the probable risk of using α-lipoic acid/cyclosporine combination in ulcerative colitis patients.

  11. Androgen deprivation modulates the inflammatory response induced by irradiation

    International Nuclear Information System (INIS)

    The aim of this study was to determine whether radiation (RT)-induced inflammatory responses and organ damage might be modulated by androgen deprivation therapies. The mRNA and tissue sections obtained from the lungs, intestines and livers of irradiated mice with or without androgen deprivation were analyzed by real-time PCR and histological analysis. Activation of NF-kappa B was examined by measuring nuclear protein levels in the intestine and lung 24 h after irradiation. We also examined the levels of cyclooxygenase-2 (COX-2), TGF-β1 and p-AKT to elucidate the related pathway responsible to irradiation (RT) -induced fibrosis. We found androgen deprivation by castration significantly augmented RT-induced inflammation, associated with the increase NF-κB activation and COX-2 expression. However, administration of flutamide had no obvious effect on the radiation-induced inflammation response in the lung and intestine. These different responses were probably due to the increase of RT-induced NF-κB activation and COX-2 expression by castration or lupron treatment. In addition, our data suggest that TGF-β1 and the induced epithelial-mesenchymal transition (EMT) via the PI3K/Akt signaling pathway may contribute to RT-induced fibrosis. When irradiation was given to patients with total androgen deprivation, the augmenting effects on the RT-induced inflammation and fibrosis should take into consideration for complications associated with radiotherapy

  12. Androgen deprivation modulates the inflammatory response induced by irradiation

    Directory of Open Access Journals (Sweden)

    Lin Paul-Yang

    2009-03-01

    Full Text Available Abstract Background The aim of this study was to determine whether radiation (RT-induced inflammatory responses and organ damage might be modulated by androgen deprivation therapies. Methods The mRNA and tissue sections obtained from the lungs, intestines and livers of irradiated mice with or without androgen deprivation were analyzed by real-time PCR and histological analysis. Activation of NF-kappa B was examined by measuring nuclear protein levels in the intestine and lung 24 h after irradiation. We also examined the levels of cyclooxygenase-2 (COX-2, TGF-β1 and p-AKT to elucidate the related pathway responsible to irradiation (RT -induced fibrosis. Results We found androgen deprivation by castration significantly augmented RT-induced inflammation, associated with the increase NF-κB activation and COX-2 expression. However, administration of flutamide had no obvious effect on the radiation-induced inflammation response in the lung and intestine. These different responses were probably due to the increase of RT-induced NF-κB activation and COX-2 expression by castration or lupron treatment. In addition, our data suggest that TGF-β1 and the induced epithelial-mesenchymal transition (EMT via the PI3K/Akt signaling pathway may contribute to RT-induced fibrosis. Conclusion When irradiation was given to patients with total androgen deprivation, the augmenting effects on the RT-induced inflammation and fibrosis should take into consideration for complications associated with radiotherapy.

  13. The therapeutic effect of recombinant human trefoil factor 3 on hypoxia-induced necrotizing enterocolitis in immature rat.

    Science.gov (United States)

    Zhang, Bing-Hong; Yu, Hong-Gang; Sheng, Zhi-Xiang; Luo, He-Sheng; Yu, Jie-Ping

    2003-11-15

    Trefoil peptides are a new class of regulatory peptides involved in mucosal protection and repair in the gastrointestinal tract. Among them, trefoil factor 3 (TFF3) (intestinal trefoil factor) is known to be cytoprotective in the gut. The aim of this study was to determine the effect of recombinant human trefoil factor 3 (rhTFF3) on hypoxia-induced necrotizing enterocolitis (NEC) in immature rats. In the present study, thirty-two 1-day-old Wistar rat pups were randomly divided into four groups. Group 1 served as nonhypoxic controls. Group 2 rats were subjected to hypoxia reoxygenation (H/O) and then were returned to their mothers. Groups 3 and 4 rats were subjected to H/O, were returned to their mothers, and were treated with rhTFF3 intraperitoneally (0.5 mg) and subcutaneously (0.2 mg), respectively, for the next 3 days. All animals were killed on day 4, and intestine specimens were obtained to determine the histological changes, tissue level of interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), malondialdehyde (MDA), prostaglandin E2 (PGE2), tromboxane B2 (TXB2), and nitric oxide (NO). In addition, the effects of rhTFF3 on abundance of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) were also investigated. In neonatal NEC (group 2), necrosis of villi and crypts and, in some cases, transmural necrosis was observed under light microscopy. Tissue level of interleukin-8, tumor necrosis factor-alpha, malondialdehyde, prostaglandin E2, tromboxane B2, and nitric oxide were significantly higher than group 1. In addition, abundance of inducible nitric oxide synthase and cyclooxygenase 2 was markedly increased. In groups 3 and 4, only very slight intestinal injury was observed. The tissue level of interleukin-8, tumor necrosis factor-alpha, malondialdehyde, prostaglandin E2, tromboxane B2, and nitric oxide were significantly decreased in comparison to the group 2. Meanwhile, the abundance of inducible nitric oxide synthase and cyclooxygenase

  14. 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.

  15. The Sarin-like Organophosphorus Agent bis (isopropyl methyl)phosphonate Induces Apoptotic Cell Death and COX-2 Expression in SK-N-SH Cells.

    Science.gov (United States)

    Arima, Yosuke; Yoshimoto, Kanji; Namera, Akira; Makita, Ryosuke; Murata, Kazuhiro; Nagao, Masataka

    2016-03-01

    Organophosphorus compounds, such as sarin, are highly toxic nerve agents that inhibit acetylcholinesterase (AChE), but not cholinesterase, via multiple mechanisms. Recent studies have shown that organophosphorus compounds increase cyclooxygenase-2 (COX-2) expression and induce neurotoxicity. In this study, we examined the toxicity of the sarin-like organophosphorus agent bis(isopropyl methyl)phosphonate (BIMP) and the effects of BIMP on COX-2 expression in SK-N-SH human neuroblastoma cells. Exposure to BIMP changed cell morphology and induced caspase-dependent apoptotic cell death accompanied by cleavage of caspase 3, caspase 9, and poly (ADP-ribose) polymerase (PARP). It also increased COX-2 expression, while pretreatment with a COX inhibitor, ibuprofen, decreased BIMP-dependent cell death and COX-2 expression in SK-N-SH cells. Thus, our findings suggest that BIMP induces apoptotic cell death and upregulates COX-2 expression. PMID:27348899

  16. Protective effect of Justicia gendarussa Burm.f. on carrageenan-induced inflammation.

    Science.gov (United States)

    Kavitha, S K; Viji, V; Kripa, K; Helen, A

    2011-07-01

    The present study focuses on the anti-inflammatory activity of Justicia gendarussa Burm.f. on an acute model of inflammation: the carrageenan-induced paw edema assay. Methanolic extract of J. gendarussa (JRM) roots at a dose of 100 mg/kg significantly inhibited edema formation 5 h after carrageenan induction. JRM inhibited carrageenan-elicited total cycloxygenase activity, 5-lipoxygenase and 15-lipoxygenase activities in blood mononuclear cells of rats, decreased neutrophil infiltration in paw tissue as shown by low myeloperoxidase activity, and also caused a 53% inhibition in cyclooxygenase-2 activity in paw tissue. Purification of JRM by liquid-liquid partitioning yielded an ethyl acetate fraction of JRM that showed interleukin-6 downregulation potential and the ability to inhibit prostaglandin E2 production in vivo. The present investigation provides pharmacological evidence to support the folklore claim that J. gendarussa is an anti-inflammatory agent. PMID:21416126

  17. Preliminary study on inhibitory effect of matrine on bladdercancer via regulation of cyclooxygenase-2 expression in rats%苦参碱调控环氧化酶-2的表达及对大鼠膀胱癌抑制作用的初步研究

    Institute of Scientific and Technical Information of China (English)

    邓宁; 高华; 国亚芳; 邱晓峰; 冯军; 郑萍; 戴贵东

    2012-01-01

    目的 研究苦参碱(matrine)对膀胱癌形成和发展的抑制作用及其对大鼠膀胱环氧化酶-2(COX-2)表达的影响.方法 采用N-丁基-N-(4-羟丁基)亚硝基胺(BBN)诱发大鼠膀胱癌,苦参碱50、100和200 mg·kg-1灌胃给药35周后,分别以病理和免疫组织化学法观察苦参碱抑制膀胱癌的作用和对膀胱组织COX-2蛋白表达的影响.结果 苦参碱对BBN诱导的大鼠膀胱癌变率无影响(P>0.05),但可抑制膀胱癌的生长(P 0. 05 ), however, the frequency of invasive tumors in matrine( 50,100 mg ? Kg"1 ? D"1 ) treated rats were significantly lower ( 15. 4% , 9% ) than in those given BBN alone( 50% )( P < 0. 05 ). Bladder weight and protein expression of COX-2 in matrine ( 50, 100 and 200 mg ? Kg"1 ? D"1 ) group were also significantly lower than in BBN rats( P < 0. 05 ). Conclusions The results shows that matrine has no anti-carcinogenic effect, but inhibits tumor growth and invasion in BBN-induced bladder cancer in rats, through the inhibition of COX-2 protein expression.

  18. Transduced PEP-1-ribosomal protein S3 (rpS3) ameliorates 12-O-tetradecanoylphorbol-13-acetate-induced inflammation in mice

    International Nuclear Information System (INIS)

    This study investigated the preventive effect of ribosomal protein S3 (rpS3) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema in mice. A cell permeable expression vector PEP-1-rpS3 was constructed. Topical application of the vector markedly inhibited TPA-induced expression levels of cyclooxygenase-2 (COX-2) and pro-inflammatory cytokines. Application of PEP-1-rpS3 also resulted in a significant reduction in the activation of nuclear factor-kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) in TPA-treated ears. These results indicate that PEP-1-rpS3 inhibits inflammatory response cytokines and enzymes by blocking NF-kB and MAPK, prompting the suggestion that PEP-1-rpS3 can be used as a therapeutic agent against skin inflammation.

  19. Analgésicos inibidores específicos da ciclooxigenase-2: avanços terapêuticos Analgésicos inhibidores específicos de la ciclooxigenase-2: avanzos terapéuticos Specific cyclooxygenase-2 inhibitor analgesics: therapeutic advances

    Directory of Open Access Journals (Sweden)

    Wilson Andrade Carvalho

    2004-06-01

    ón principalmente a través de la inhibición de la ciclooxigenasis (COX, la enzima clave que catalisa la conversión de ácido araquidónico en prostaglandinas y tromboxanos. Por lo menos dos isoformas de la COX ya fueron identificadas, la COX-1, que es constitutivamente expresa en la mayoría de los tejidos, y la COX-2, que es una forma inducible de la enzima localizada principalmente en células y tejidos envueltos en procesos inflamatorios. Con la descubierta de la COX-2 y la determinación de su estructura, fue posible desenvolver drogas más selectivas que reducen la inflamación sin afectar la COX-1, protectora del estomago y riñones, dando origen a una nueva generación de compuestos antiinflamatorios denominados de inhibidores específicos de la COX-2. CONCLUSIONES: No entanto estos compuestos de última generación presenten menor toxicidad para el trato gastrointestinal, otros efectos adversos graves han sido observados, incluyendo insuficiencia renal y efectos cardiovasculares, como el infarto del miocardio y la trombosis. A despecho de estos efectos colaterales, estos nuevos fármacos están siendo testados en otras condiciones clínicas, principalmente en el tratamiento preventivo del cáncer y de la enfermedad de Alzheimer.BACKGROUND AND OBJECTIVES: Nonsteroidal Anti-inflammatory Drugs (NSAIDs are among the most widely prescribed drugs, including for Anesthesiology. This review aimed at discussing some current cycloxygenase biochemical aspects, which have provided the basis for the development of new analgesic and anti-inflammatory drugs. CONTENTS: These drugs primarily act by inhibiting cycloxygenase (COX, which is the key-enzyme catalyzing the conversion of arachidonic acid into prostaglandins and thromboxane. At least two COX isoforms have already been identified: COX-1, which is constitutively expressed in most tissues, and the inducible enzyme COX-2, which is primarily found in inflammatory cells and tissues. The discovery of COX-2 has enabled the development

  20. Inibição da expressão de ciclooxigenase 2 em feridas cutâneas de camundongos NOD submetidos à terapia a laser de baixa intensidade Inhibition of cyclooxygenase 2 expression in NOD mice cutaneous wound by low-level laser therapy

    Directory of Open Access Journals (Sweden)

    Carolina de Lourdes Julião Vieira Rocha

    2012-09-01

    Full Text Available CONTEXTO: A terapia a laser de baixa intensidade (LLLT tem sido relatada como importante moduladora da cicatrização de feridas cutâneas aumentando a proliferação fibroblástica associada ao aumento da expressão da citocina fator transformador de crescimento- β2 (TGF-βB2. OBJETIVO: No presente estudo foram avaliados os efeitos da LLLT sobre a expressão da enzima ciclooxigenase 2 (COX2 no sítio do reparo tecidual utilizando o modelo experimental com camundongos diabéticos não obesos (NOD para estudar a cicatrização de feridas cutâneas. MÉTODOS: Foram utilizados 30 camundongos NOD, destes 14 ficaram diabéticos e foram divididos em dois grupos: o grupo I (n=7 foi submetido a um procedimento cirúrgico de feridas cutâneas e o grupo II (n=7 foi submetido a um procedimento cirúrgico de feridas cutâneas e tratados com LLLT. O grupo II foi submetido à LLLT nos seguintes parâmetros: 15 mW de potência, dose de 3,8 J/cm² e tempo de aplicação de 20 segundos. Após sete dias do ato cirúrgico e após aplicação do laser, os animais foram eutanasiados com sobredose de anestesia e amostras das feridas foram colhidas para posterior análise histopatológica, histomorfométrica e imuno-histoquímica. RESULTADOS: A LLLT promoveu a inibição da expressão da COX2 em feridas cutâneas de camundongos diabéticos. CONCLUSÃO: Em conjunto, os resultados sugeriram que a LLLT é capaz de modular negativamente a expressão da enzima COX2 contribuindo para o controle da resposta inflamatória em feridas cutâneas de camundongos NOD.BACKGROUND: Low-level laser therapy (LLLT has been reported to modulate the healing of wounds by inducing an increase in fibroblast number associated with increased expression of the cytokine transforming growth factor-β2 (TGF-β2. OBJECTIVE: In the present study, the effect of LLLT on expression of COX2 at the site of tissue repair was evaluated, using an experimental model with non obese diabetic mice (NOD to study

  1. Expression and Clinical Significance of Cyclooxygenase-2 and Microsomal Prostaglandin E2 Synthase-1 in Clear Cell Renal Cell Carcinoma%COX-2与mPGES-1在肾透明细胞癌中的表达及临床意义

    Institute of Scientific and Technical Information of China (English)

    滕皓; 周荣祥; 张钢; 张宗亮; 王鹏; 赵凯

    2012-01-01

    Objective:To study the feasibility of lightwand tracheal intubation in emergency process, compare the cardiovascular response between lightwand and direct laryngoscope tracheal intubation. Methods: 80 patients getting emergency treatment were randomly classified into lightwand or laryngoscope group. We recorded intubation time, success rate of first intubation, SBP, DBP, MAP, HR and SPO2 at period of "before intubation", "during intubation", "after intubation lmin " and "after intubation 3mins" for 2 groups. Results: Contrast to laryngoscope, lightwand completed tracheal intubation with shorter time (lightwand: 31.23 9.94s, laryngoscope: 48.15 8.67s) and better success rate in the first intubation (lightwand: 97.5%, laryngoscope:80.0%). The result of repeated measurement variance analysis showed that the tendency of SBP, DBP, MAP and HR at different period was lower among lightwand group, compared with laryngoscope group. Conclusion: During tracheal intubation process, contrast to laryngoscope tracheal intubation, lightwand induced less cardiovascular response and were associated with better intubation time and success rate. Thus, it was a suitable technology to be used in Emergency setting.%目的:探讨环氧合酶-2(COX-2)和膜结合型前列腺素E2合成酶1(mPGES-1)在肾透明细胞癌组织中的表达及临床意义.方法:采用免疫组化SP法分别检测49例肾透明细胞癌组织标本和21例正常肾组织标本中COX-2和mPGES-1的表达.结果:COX-2在正常肾组织中的阳性表达率为4.8%,在肾透明细胞癌组织中的阳性表达率为53.1%(P<0.05);mPGES-1在正常肾组织中的阳性表达率为4.8%,在肾透明细胞癌组织中的阳性表达率为40.8%( P<0,05);COX-2和mPGES-1的高表达均与肾透明细胞癌的病理分级和临床分期无相关性(P>0.05);COX-2和mPGES-1在肾透明细胞癌中的表达呈正相关(P<0.05),r=0.5.结论:COX-2和mPGES-1在肾透明细胞癌发生及发展过程中

  2. Burn injury enhances brain prostaglandin E2 production through induction of cyclooxygenase2 and microsomal prostaglandin E synthase in cerebral vascular endothelial cells in rats%前列腺素E2(PGE2)在烧伤后大鼠血管内皮细胞分泌的机制研究

    Institute of Scientific and Technical Information of China (English)

    刘永林; 陈能彬

    2012-01-01

    prostaglandin E2 concentration in the ccrcbrospinal fluid was significantly elevated in the injured rats,and this elevation was suppressed by a cyclo-oxygcnasc-2-spccific inhibitor, NS398. Only in the injured rats,cyclooxygcnasc-2 and microsomal-typc prostaglandin E synthasc proteins were detected in vascular cndothelial cells throughout the central nervous system with no regional difference. A double-immunofluorcsccncc study revealed that cyclooxygcnasc-2 and microsomal-typc prostaglandin E synthasc were coexpresscd in the pcrinuclcar region of the cndothclial cells. Conclusion These results indicate that peripheral burn injury induces cyclooxygcnasc-2 and microsomal-typc prostaglandin E synthasc in cndothclial cells of the central nervous system. These enzymes likely elevate the ccrcbrospinal fluid concentration of prostaglandin E2,a prostanoid that,in turn,activates prostaglandin E2 receptors on the central nervous system neurons involved in the general symptoms following burn injury.

  3. 煤焦沥青烟提取物对 BEAS-2 B细胞环氧化酶-2 mRNA 表达的影响%Effect of coal tar pitch smoke extract on cyclooxygenase-2 mRNA expres-sion in human bronchial epithelial cells

    Institute of Scientific and Technical Information of China (English)

    杨维超; 逯洋; 李娟; 晋乐飞; 刘文佳; 燕贞; 吴卫东

    2014-01-01

    To examine the effect of coal tar pitch smoke extract (CTPE) on COX-2 gene expression in human bronchial epithelial cells .Methods:The human bronchial epithelial cell line ( BEAS-2B) was used as an in vitro model . CTPE induced COX-2 mRNA expression were measured by RT-PCR.Actinomycin D,a transcription inhibitor, was applied to test the effect of CTPE on COX-2 gene transcription .mRNA decay assay was used to observe the effect of CTPE on COX-2 mRNA stability at post transcriptional level .Results:CTPE stimulation increased COX-2 mRNA expression in BEAS-2B cells(Fgroup =71.750,Ftime =93.120,Finteraction =17.300,all P<0.001).Pretreatment of BEAS-2B cells with Actinomycin D (1 mg/L),for 30 min could significantly reduce the effect of CTPE on COX-2 mRNA expression (FAct D =174.203, FCTPE =260.312,Finteraction =188.521,P<0.001).Actinomycin D was used to terminate COX-2 mRNA synthesis elevated by zinc sulfate.At different time points (0, 2, 4 h) COX-2 mRNA levels were higher in CTPE group than those in control group(Fgroup =365.700,Ftime =37.780,Finteraction =6.240,all P<0.05).Conclusion: CTPE stimulation can significantly increase COX-2 mRNA expression levels in BEAS-2B cells.%目的:探讨煤焦沥青烟提取物( CTPE)对人支气管上皮细胞环氧化酶-2( COX-2) mRNA表达的影响。方法:应用RT-PCR方法测定不同质量浓度(2、4、8 mg/L)CTPE作用不同时间(2、4、8 h)对人支气管上皮BEAS-2B细胞COX-2 mRNA表达水平影响。使用放线菌素(Act)D(1 mg/L)作用于BEAS-2B细胞,观察其对2 mg/L CTPE作用30 min后的BEAS-2B细胞COX-2基因转录的影响。利用ZnSO4溶液刺激BEAS-2B细胞COX-2 mRNA表达,去除ZnSO4后,加入1 mg/L的Act D 30 min,检测CTPE 作用不同时间点(0、2、4 h)的COX-2 mRNA表达的变化。结果:2、4、8 mg/L CTPE刺激均可以使BEAS-2B细胞COX-2 mRNA表达水平升高( F组间=71.750,F时间=93.120, F交互=17.300,P<0.001),2 mg

  4. Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice.

    Directory of Open Access Journals (Sweden)

    Seung Jun Lee

    Full Text Available Radiation-induced lung injury (RILI is a common and unavoidable complication of thoracic radiotherapy. The current study was conducted to evaluate the ability of clarithromycin (CLA to prevent radiation-induced pneumonitis, oxidative stress, and lung fibrosis in an animal model. C57BL/6J mice were assigned to control, irradiation only, irradiation plus CLA, and CLA only groups. Test mice received single thoracic exposures to radiation and/or oral CLA (100 mg/kg/day. Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group. On a microscopic level, CLA inhibited macrophage influx, alveolar fibrosis, parenchymal collapse, consolidation, and epithelial cell changes. The concentration of collagen in lung tissue was lower in irradiation plus CLA mice. Radiation-induced expression of tumor necrosis factor (TNF-α, TNF receptor 1, acetylated nuclear factor kappa B, cyclooxygenase 2, vascular cell adhesion molecule 1, and matrix metallopeptidase 9 were also attenuated by CLA. Expression levels of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, transforming growth factor-β1, connective tissue growth factor, and type I collagen in radiation-treated lungs were also attenuated by CLA. These findings indicate that CLA ameliorates the deleterious effects of thoracic irradiation in mice by reducing pulmonary inflammation, oxidative damage, and fibrosis.

  5. Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice.

    Science.gov (United States)

    Lee, Seung Jun; Yi, Chin-ok; Heo, Rok Won; Song, Dae Hyun; Cho, Yu Ji; Jeong, Yi Yeong; Kang, Ki Mun; Roh, Gu Seob; Lee, Jong Deog

    2015-01-01

    Radiation-induced lung injury (RILI) is a common and unavoidable complication of thoracic radiotherapy. The current study was conducted to evaluate the ability of clarithromycin (CLA) to prevent radiation-induced pneumonitis, oxidative stress, and lung fibrosis in an animal model. C57BL/6J mice were assigned to control, irradiation only, irradiation plus CLA, and CLA only groups. Test mice received single thoracic exposures to radiation and/or oral CLA (100 mg/kg/day). Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group. On a microscopic level, CLA inhibited macrophage influx, alveolar fibrosis, parenchymal collapse, consolidation, and epithelial cell changes. The concentration of collagen in lung tissue was lower in irradiation plus CLA mice. Radiation-induced expression of tumor necrosis factor (TNF)-α, TNF receptor 1, acetylated nuclear factor kappa B, cyclooxygenase 2, vascular cell adhesion molecule 1, and matrix metallopeptidase 9 were also attenuated by CLA. Expression levels of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, transforming growth factor-β1, connective tissue growth factor, and type I collagen in radiation-treated lungs were also attenuated by CLA. These findings indicate that CLA ameliorates the deleterious effects of thoracic irradiation in mice by reducing pulmonary inflammation, oxidative damage, and fibrosis. PMID:26114656

  6. Ethanol extracts of Scutellaria baicalensis protect against lipopolysaccharide-induced acute liver injury in mice

    Institute of Scientific and Technical Information of China (English)

    Hai; Nguyen; Thanh; Hue; Pham; Thi; Minh; Tuan; Anh; Le; Huong; Duong; Thi; Ly; Tung; Nguyen; Huu; Loi; Vu; Duc; Thu; Dang; Kim; Tung; Bui; Thanh

    2015-01-01

    Objective: To investigated the protective potential of ethanol extracts of Scutellaria baicalensis(S. baicalensis) against lipopolysaccharide(LPS)-induced liver injury. Methods: Dried roots of S. baicalensis were extracted with ethanol and concentrated to yield a dry residue. Mice were administered 200 mg/kg of the ethanol extracts orally once daily for one week. Animals were subsequently administered a single dose of LPS(5 mg/kg of body weight, intraperitoneal injection). Both protein and m RNA levels of cytokines, such as tumor necrosis factor alpha, interleukin-1β, and interleukin-6 in liver tissues were evaluated by ELISA assay and quantitative PCR. C yclooxygenase-2, inducible nitric oxide synthase, and nuclear factor-κB protein levels in liver tissues were analyzed by western blotting. Results: Liver injury induced by LPS signifi cantly increased necrosis factor alpha, interleukin-1β, interleukin-6, cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor-κB in liver tissues. Treatment with ethanol extracts of S. baicalensis prevented all of these observed changes associated with LPS-induced injury in liver mice.Conclusions: Our study showed that S. baicalensis is potentially protective against LPS-induced liver injury in mice.

  7. Cyclooxygenase-2-dependent prostacyclin formation and blood pressure homeostasis: targeted exchange of cyclooxygenase isoforms in mice

    DEFF Research Database (Denmark)

    Yu, Ying; Stubbe, Jane; Ibrahim, Salam;

    2010-01-01

    pressure. OBJECTIVE: To elucidate the role of COX-2 in blood pressure homeostasis using COX-1>COX-2 mice, in which the COX-1 expression is controlled by COX-2 regulatory elements. METHODS AND RESULTS: COX-1>COX-2 mice developed systolic hypertension relative to wild types (WTs) on a high-salt diet (HSD......RATIONALE: Cyclooxygenase (COX)-derived prostanoids (PGs) are involved in blood pressure homeostasis. Both traditional nonsteroidal antiinflammatory drugs (NSAIDs) that inhibit COX-1 and COX-2 and NSAIDs designed to be selective for inhibition of COX-2 cause sodium retention and elevate blood...

  8. Local osteogenic expression of cyclooxygenase-2 and systemic response in porcine models of osteomyelitis

    DEFF Research Database (Denmark)

    Johansen, Louise K.; Iburg, Tine M.; Nielsen, Ole L.;

    2012-01-01

    phosphatase and haptoglobin were measured. Extensive COX-2 expression by osteoblasts was present 2 days after inoculation together with many activated osteoclasts. Simultaneously, the serum concentration of alkaline phosphatase decreased whereas the haptoglobin concentration increased. This is the first...... aureus and groups of animals were euthanized following 6h, 12h, 24h, 2 days, 5 days, 11 days and 15 days, respectively. Expression of COX-2 was evaluated immunohistochemically and combined with characterization of morphological changes in bone tissue. Furthermore, the serum concentrations of alkaline...

  9. Expression of cyclooxygenase-2 in intestine of pigs of different ages and hygiene status

    DEFF Research Database (Denmark)

    Lauridsen, Charlotte; Whiting, C; Lewis, M;

    2010-01-01

    arachidonic acid. The hypothesis of the present study was that expression of COX-2 in porcine intestine was dependent on the microbial load and the age of piglets. Piglets were obtained from sows raised either on outdoor free-range farms or on indoor commercial farms, and littermates were divided into three...... treatments: One group of piglets suckled the sow, a second group was put into an isolator and fed a milk formula, and a third group was put into the isolator fed milk formula and injected with broad spectrum antibiotics. Samples were collected from the 75% level of the small intestine at day 5, 28 and 56...... of age. Tissue section from four piglets from each of these six treatment groups was analysed by immunofluorescence for COX-2 and type-IV collagen (basement membrane, defining lamina propria (LP)). Image analysis was used to determine the number of positive pixels expressing LP and epithelial COX-2. COX...

  10. Haplotype of prostaglandin synthase 2/cyclooxygenase 2 is involved in the susceptibility to inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    David G Cox; J Bart A Crusius; Petra HM Peeters; H Bas Bueno-de-Mesquita; A Salvador Pe(~n)a; Federico Canzian

    2005-01-01

    AIM: Prostaglandin G/H synthase 2 (PTGS2 or COX2) is one of the key factors in the cellular response to inflammation.PTGS2 is expressed in the affected intestinal segments of patients with inflammatory bowel diseases (IBD). In IBD patients, non-steroidal anti-inflammatory drugs, which have been shown to reduce both the production and activity of PTGS2, may activate IBD and aggravate the symptoms.We aimed at examining genetic variants of PTGS2 that may be risk factors for IBD.METHODS: We genotyped 291 individuals diagnosed with IBD and 367 controls from the Dutch population for the five most frequent polymorphisms of the PTGS2 gene.Clinical data were collected on all patients. DNA was extracted via normal laboratory methods. Genotyping was carried out using multiplex PCR followed by the Invader Assay and the 5' exonuclease assay (TaqMan). New polymorphism screening was performed by pre-screening with denaturing high-performance liquid chromatography,followed by fluorescent sequencing.RESULTS: Allele 5209G was weakly associated with Crohn's disease (odds ratio [OR] 1.63, 95% confidence interval [CI] 1.03-2.57), and allele 8473T with ulcerative colitis (OR 1.50, 95%CI 1.00-2.27). The haplotype including both alleles showed a strong association with IBD (OR 13.15, 95%CI 3.17-116.15). This haplotype, while rare (-0.3%) in the general population, is found more frequently in patients (3.5%).CONCLUSION: Our data suggest that this haplotype of PTGS2 contributes to the susceptibility of IBD.

  11. Hemicrania continua changed to chronic paroxysmal hemicrania after treatment with cyclooxygenase-2 inhibitor.

    Science.gov (United States)

    Müller, Kai Ivar; Bekkelund, Svein Ivar

    2011-02-01

    Remission of hemicrania continua (HC) and transformation from HC to chronic paroxysmal hemicrania (CPH) are unusual. We report a patient with left-sided HC who, after a period of remission, presented as CPH. The continuous HC headache disappeared completely after initiating treatment with cyclooxygenase (COX)-2 inhibitor, but reappeared on the same side after 14 months remission with paroxysmal, frequent, intense and short-lasting headache attacks accompanied by ipsilateral cranial autonomic symptoms. This happened shortly after the treatment was discontinued because of withdrawal of the COX-2 inhibitor from the market. The response to indomethacin was prompt, and the patient became completely free from her paroxysmal headache with a dose of 50 mg 2 times daily. This case questions a possible modification effect on the course of HC by use of COX-2 inhibitor, as well as further supporting that some aspects of the pathophysiology of HC may resemble those of CPH, and may argue for common biological mechanisms in HC and CPH.

  12. Cyclooxygenase-2 contributes to elevated renin in the early postnatal period in rats

    DEFF Research Database (Denmark)

    Stubbe, Jane; Jensen, Boye L; Bachmann, Sebastian;

    2003-01-01

    We asked whether cyclooxygenase (COX) activity controls the renin-angiotensin system in the postnatal period. During kidney development, renin peaked at postnatal days 0-1 at the mRNA, tissue protein [renal renin concentration (RRC)], and plasma renin concentration (PRC) levels and was widely...

  13. Role of the Slug Transcription Factor in Chemically-Induced Skin Cancer

    Directory of Open Access Journals (Sweden)

    Kristine von Maltzan

    2016-02-01

    Full Text Available The Slug transcription factor plays an important role in ultraviolet radiation (UVR-induced skin carcinogenesis, particularly in the epithelial-mesenchymal transition (EMT occurring during tumor progression. In the present studies, we investigated the role of Slug in two-stage chemical skin carcinogenesis. Slug and the related transcription factor Snail were expressed at high levels in skin tumors induced by 7,12-dimethylbenz[α]anthracene application followed by 12-O-tetradecanoylphorbol-13-acetate (TPA treatment. TPA-induced transient elevation of Slug and Snail proteins in normal mouse epidermis and studies in Slug transgenic mice indicated that Slug modulates TPA-induced epidermal hyperplasia and cutaneous inflammation. Although Snail family factors have been linked to inflammation via interactions with the cyclooxygenase-2 (COX-2 pathway, a pathway that also plays an important role in skin carcinogenesis, transient TPA induction of Slug and Snail appeared unrelated to COX-2 expression. In cultured human keratinocytes, TPA induced Snail mRNA expression while suppressing Slug expression, and this differential regulation was due specifically to activation of the TPA receptor. These studies show that Slug and Snail exhibit similar patterns of expression during both UVR and chemical skin carcinogenesis, that Slug and Snail can be differentially regulated under some conditions and that in vitro findings may not recapitulate in vivo results.

  14. Pycnogenol attenuates the inflammatory and nitrosative stress on joint inflammation induced by urate crystals.

    Science.gov (United States)

    Peng, Yi-Jen; Lee, Chian-Her; Wang, Chih-Chien; Salter, Donald M; Lee, Herng-Sheng

    2012-02-15

    Acute gouty arthritis results from monosodium urate (MSU) crystal deposition in joint tissues. Deposited MSU crystals induce an acute inflammatory response which leads to damage of joint tissue. Pycnogenol (PYC), an extract from the bark of Pinus maritime, has documented antiinflammatory and antioxidant properties. The present study aimed to investigate whether PYC had protective effects on MSU-induced inflammatory and nitrosative stress in joint tissues both in vitro and in vivo. MSU crystals upregulated cyclooxygenase 2 (COX-2), interleukin 8 (IL-8) and inducible nitric oxide synthase (iNOS) gene expression in human articular chondrocytes, but only COX-2 and IL-8 in synovial fibroblasts. PYC inhibited the up-regulation of COX-2, and IL-8 in both articular chondrocytes and synovial fibroblasts. PYC attenuated MSU crystal induced iNOS gene expression and NO production in chondrocytes. Activation of NF-κB and SAPK/JNK, ERK1/2 and p38 MAP kinases by MSU crystals in articular chondrocytes and synovial fibroblasts in vitro was attenuated by treatment with PYC. The acute inflammatory cell infiltration and increased expression of COX-2 and iNOS in synovial tissue and articular cartilage following intra-articular injection of MSU crystals in a rat model was inhibited by coadministration of PYC. Collectively, this study demonstrates that PYC may be of value in treatment of MSU crystal-induced arthritis through its anti-inflammatory and anti-nitrosative activities. PMID:22198264

  15. Coptisine Prevented IL-β-Induced Expression of Inflammatory Mediators in Chondrocytes.

    Science.gov (United States)

    Zhou, Kai; Hu, Li; Liao, Wenjun; Yin, Defeng; Rui, Feng

    2016-08-01

    Interleukin 1β (IL-1β) is a pleiotropic pro-inflammatory cytokine that plays a critical role in the development of osteoarthritis (OA). Coptisine is an isoquinoline alkaloid extracted from Coptidis rhizome and has been reported to possess anti-inflammatory activity. However, the anti-inflammatory effects of coptisine on interleukin-1 beta (IL-1β)-stimulated chondrocytes have not been reported. Therefore, the aim of this study was to investigate the effects of coptisine on IL-1β-induced inflammation in human articular chondrocytes. Our results showed that coptisine greatly inhibited the production of nitric oxide (NO) and prostaglandin E2 (PGE2), as well as suppressed the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in human OA chondrocytes induced by IL-1β. It also inhibited the expression of matrix metalloproteinase-3 (MMP-3) and MMP-13 in IL-1β-stimulated human OA chondrocytes. Furthermore, coptisine significantly inhibited the IL-1β-induced NF-kB activation in human OA chondrocytes. Taken together, these data suggest that coptisine inhibits the IL-1β-induced inflammatory response by suppressing the NF-kB signaling pathway. Thus, coptisine may be a potential agent in the treatment of OA. PMID:27294276

  16. Protective Effect of Isorhamnetin on Lipopolysaccharide-Induced Acute Lung Injury in Mice.

    Science.gov (United States)

    Yang, Bo; Li, Xiao-Ping; Ni, Yun-Feng; Du, Hong-Yin; Wang, Rong; Li, Ming-Jiang; Wang, Wen-Chen; Li, Ming-Ming; Wang, Xu-Hui; Li, Lei; Zhang, Wei-Dong; Jiang, Tao

    2016-02-01

    Isorhamnetin has been reported to have anti-inflammatory, anti-oxidative, and anti-proliferative effects. The aim of this study was to investigate the protective effect of isorhamnetin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice by inhibiting the expression of cyclooxygenase-2 (COX-2). The effects of isorhamnetin on LPS-induced lung pathological damage, wet/dry ratios and the total protein level in bronchoalveolar lavage fluid (BALF), inflammatory cytokine release, myeloperoxidase (MPO) and superoxide dismutase (SOD) activities, and malondialdehyde (MDA) level were examined. In addition, the COX-2 activation in lung tissues was detected by Western blot. Isorhamnetin pretreatment improved the mice survival rates. Moreover, isorhamnetin pretreatment significantly attenuated edema and the pathological changes in the lung and inhibited protein extravasation in BALF. Isorhamnetin also significantly decreased the levels of inflammatory cytokines in BALF. In addition, isorhamnetin markedly prevented LPS-induced oxidative stress. Furthermore, isorhamnetin pretreatment significantly suppressed LPS-induced activation of COX-2. Isorhamnetin has been demonstrated to protect mice from LPS-induced ALI by inhibiting the expression of COX-2. PMID:26276127

  17. Effects of Parecoxib and Fentanyl on nociception-induced cortical activity

    Directory of Open Access Journals (Sweden)

    Wang Ying-Wei

    2010-01-01

    Full Text Available Abstract Background Analgesics, including opioids and non-steroid anti-inflammatory drugs reduce postoperative pain. However, little is known about the quantitative effects of these drugs on cortical activity induced by nociceptive stimulation. The aim of the present study was to determine the neural activity in response to a nociceptive stimulus and to investigate the effects of fentanyl (an opioid agonist and parecoxib (a selective cyclooxygenase-2 inhibitor on this nociception-induced cortical activity evoked by tail pinch. Extracellular recordings (electroencephalogram and multi-unit signals were performed in the area of the anterior cingulate cortex while intracellular recordings were made in the primary somatosensory cortex. The effects of parecoxib and fentanyl on induced cortical activity were compared. Results Peripheral nociceptive stimulation in anesthetized rats produced an immediate electroencephalogram (EEG desynchronization resembling the cortical arousal (low-amplitude, fast-wave activity, while the membrane potential switched into a persistent depolarization state. The induced cortical activity was abolished by fentanyl, and the fentanyl's effect was reversed by the opioid receptor antagonist, naloxone. Parecoxib, on the other hand, did not significantly affect the neural activity. Conclusion Cortical activity was modulated by nociceptive stimulation in anesthetized rats. Fentanyl showed a strong inhibitory effect on the nociceptive-stimulus induced cortical activity while parecoxib had no significant effect.

  18. Caffeine prevents LPS-induced inflammatory responses in RAW264.7 cells and zebrafish.

    Science.gov (United States)

    Hwang, Ji-Hyun; Kim, Kui-Jin; Ryu, Su-Jung; Lee, Boo-Yong

    2016-03-25

    Caffeine is a white crystalline xanthine alkaloid found in the seeds of coffee plants and leaves of the tea bush. In this study, we evaluated whether caffeine exerts anti-inflammatory effects on lipopolysaccharide (LPS)-induced inflammation both in vitro and in vivo. RAW264.7 cells were treated with various concentrations of caffeine in the presence or absence of LPS. Caffeine decreased the LPS-induced inflammatory mediator, nitric oxide (NO). Caffeine treatment also reduced the expression of pro-inflammatory genes, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-3, IL-6 and IL-12, and decreased both IL-6 secretion and phosphorylated p38MAPK expression in LPS-treated RAW264.7 cells. Caffeine inhibited nuclear translocation of nuclear factor κB (NF-κB) via IκBα phosphorylation. In addition, caffeine inhibited LPS-induced NO production in zebrafish. These results suggest that caffeine may suppress LPS-induced inflammatory responses in RAW264.7 cells by regulating NF-κB activation and MAPK phosphorylation.

  19. Red Bean Extract Inhibits Lipopolysaccharide-Induced Inflammation and H₂O₂-Induced Oxidative Stress in RAW 264.7 Macrophages.

    Science.gov (United States)

    Chao, Wen-Wan; Chung, Yun-Chin; Shih, I-Ping; Wang, Hsun-Yen; Chou, Su-Tze; Hsu, Cheng-Kuang

    2015-07-01

    Red bean (Phaseolus radiatus L. var. Aurea) is a leguminous seed and mainly used as one of the popular ingredients in oriental desserts. The objective of this study was to evaluate the anti-inflammatory activity of 50 g/kg ethanolic extract of red bean (RBE) by measuring lipopolysaccharide (LPS)-induced expressions of nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in RAW 264.7 macrophages. On the other hand, the antioxidant activity of RBE was determined by thiobarbituric acid reactive substances method and comet assay using H2O2-induced macrophages. The results showed that RBE at the concentrations of 50-200 μg/mL can significantly suppress the inflammatory responses in LPS-stimulated macrophages through the reduction of cellular NO and downregulation of the gene expressions of iNOS, COX-2, TNF-α, and IL-6 in a dose-dependent manner. Furthermore, RBE can diminish H2O2-induced oxidative damage in RAW 264.7 macrophage. Phenolic compounds and cyanidin-3-O-glucoside from BRE may have efficacy as overall in vitro anti-inflammatory and antioxidant agents. Red bean exerts an anti-inflammatory response and has potential as a health-promoting ingredient. PMID:25871313

  20. Thymoquinone inhibits phorbol ester-induced activation of NF-κB and expression of COX-2, and induces expression of cytoprotective enzymes in mouse skin in vivo.

    Science.gov (United States)

    Kundu, Joydeb Kumar; Liu, Lijia; Shin, Jun-Wan; Surh, Young-Joon

    2013-09-01

    Thymoquinone (TQ), the active ingredient of Nigella sativa, has been reported to possess anti-inflammatory and chemopreventive properties. The present study was aimed at elucidating the molecular mechanisms of anti-inflammatory and antioxidative activities of thymoquinone in mouse skin. Pretreatment of female HR-1 hairless mouse skin with TQ attenuated 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of cyclooxygenase-2 (COX-2). TQ diminished nuclear translocation and the DNA binding of nuclear factor-kappaB (NF-κB) via the blockade of phosphorylation and subsequent degradation of IκBα in TPA-treated mouse skin. Pretreatment with TQ attenuated the phosphorylation of Akt, c-Jun-N-terminal kinase and p38 mitogen-activated protein kinase, but not that of extracellular signal-regulated kinase-1/2. Moreover, topical application of TQ induced the expression of heme oxygenase-1, NAD(P)H-quinoneoxidoreductase-1, glutathione-S-transferase and glutamate cysteine ligase in mouse skin. Taken together, the inhibitory effects of TQ on TPA-induced COX-2 expression and NF-κB activation, and its ability to induce the expression of cytoprotective proteins provide a mechanistic basis of anti-inflammatory and antioxidative effects of TQ in hairless mouse skin.

  1. The gastroprotective effect of pogostone from Pogostemonis Herba against indomethacin-induced gastric ulcer in rats.

    Science.gov (United States)

    Chen, Xiao-Ying; Chen, Hai-Ming; Liu, Yu-Hong; Zhang, Zhen-Biao; Zheng, Yi-Feng; Su, Zu-Qing; Zhang, Xie; Xie, Jian-Hui; Liang, Yong-Zhuo; Fu, Lu-Di; Lai, Xiao-Ping; Su, Zi-Ren; Huang, Xiao-Qi

    2016-01-01

    Pogostemonis Herba, known as "Guang-Huo-Xiang" in Chinese, has been widely used in the treatment of gastrointestinal dysfunction. Pogostone is one of the major constituents of Pogostemonis Herba. The aim was to scientifically evaluate the possible gastroprotective effect and the underlying mechanisms of pogostone against indomethacin-induced gastric ulcer in rats. Rats were orally treated with vehicle, lansoprazole (30 mg/kg) or pogostone (10, 20 and 40 mg/kg) and subsequently exposed to acute gastric lesions induced by indomethacin. Gross evaluation, histological observation, gastric mucosal superoxide dismutase activity, glutathione content, catalase activity, malonaldehyde level and prostaglandin E2 production were performed. Immunohistochemistry and reverse transcription polymerase chain reaction for cyclooxygenase-1 and cyclooxygenase-2, as well as terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay, immunohistochemistry for heat-shock protein 70, B-cell lymphoma-2 and Bax were conducted. Results indicated that rats pretreated with pogostone showed remarkable protection from the gastric mucosa damage compared to vehicle-treated rats based on the ulcer index and inhibition percentage. Histologically, oral administration of pogostone resulted in observable improvement of gastric injury, characterized by reduction of necrotic lesion, flattening of gastric mucosa and alleviation of submucosal edema with hemorrhage. Pogostone pretreatment significantly raised the depressed activities of superoxide dismutase, glutathione and catalase, while reduced the elevated malonaldehyde level compared with indomethacin-induced group. Pogostone-pretreated group induced a significant increase in gastric mucosal prostaglandin E2 level and obvious up-regulation of protein levels and mRNA expressions of cyclooxygenase-1 and cyclooxygenase-2. Furthermore, antiapoptotic effect of pogostone was verified by terminal deoxynucleotidyltransferase-mediated d

  2. Ethyl linoleate from garlic attenuates lipopolysaccharide-induced pro-inflammatory cytokine production by inducing heme oxygenase-1 in RAW264.7 cells.

    Science.gov (United States)

    Park, Sun Young; Seetharaman, Rajasekar; Ko, Min Jung; Kim, Do Yeon; Kim, Tae Hoon; Yoon, Moo Kyoung; Kwak, Jung Ho; Lee, Sang Joon; Bae, Yoe Sik; Choi, Young Whan

    2014-04-01

    In the present study, an essential fatty acid, ethyl linoleate (ELA), was isolated from the cloves of Allium sativum, and its structure was elucidated by NMR and GC-MS analyses. In vitro systems were used to evaluate the anti-inflammatory activity of ELA. Our results indicate that ELA down-regulates inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and thereby reduces nitric oxide (NO) and prostaglandin E2 production in lipopolysaccharide (LPS)-activated RAW 264.7 cells. Immunofluorescent microscopy and western blot analyses revealed that these effects were mediated by impaired translocation of nuclear factor (NF)-κB and inhibition of phosphorylation of mitogen activated protein kinases. Furthermore, ELA exerted its anti-inflammatory activity by inducing heme oxygenase-1 (HO-1) expression, as determined by HO-1 small interfering (Si) RNA system. Si RNA-mediated knock-down of HO-1 abrogated the inhibitory effects of ELA on the production of NO, TNF-α, IL-1β, and IL-6 in LPS-induced macrophages. These findings indicate the potential therapeutic use of ELA as an anti-inflammatory agent.

  3. Zoledronic acid induces apoptosis and autophagy in cervical cancer cells.

    Science.gov (United States)

    Wang, I-Te; Chou, Shou-Chu; Lin, Ying-Chin

    2014-12-01

    Cervical cancer is one of the most common gynecological cancers in association with high mortality and morbidity. The present study was aimed to investigate the in vitro effects of zoledronic acid (ZA) on viability and induction of apoptosis and autophagy as well as inflammatory effects in three human cervical cancer cell lines (HeLa, SiHa, and CaSki). Cell viability was measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay. Induction of apoptosis was determined by quantitation of expression level of B cell lymphoma 2 (Bcl-2) and Bax messenger RNA (mRNA) and identification of the proteolytic cleavage of poly (ADP)-ribose polymerase (PARP) and caspase-3. Autophagic effects were examined by quantitation of mRNA expression of autophagy protein 5 (ATG5) and beclin1 and identifying accumulation of microtubule-associated protein 1 light chain 3 (LC3)-II. Inflammatory effect was determined by measuring expression and production of IL-6 and cyclooxygenase-2 (Cox-2). The results showed ZA significantly inhibited cell viability of cervical cancer cells. ZA-induced cell death displayed features characteristic to both apoptosis and autophagy and was associated with different changes in the levels of Bcl-2 and Bax in the various cervical cancer lines. Expression of metastatic cytokines, IL-6 and Cox-2, was upregulated in the presence of ZA at low concentration. Our data revealed that ZA inhibits cervical cancer cells through the synergistic effect of apoptosis induction and autophagy activation.

  4. Protection of MPTP-induced neuroinflammation and neurodegeneration by Pycnogenol.

    Science.gov (United States)

    Khan, Mohammad Moshahid; Kempuraj, Duraisamy; Thangavel, Ramasamy; Zaheer, Asgar

    2013-03-01

    Oxidative stress and inflammation play a crucial role in Parkinson's disease (PD) pathogenesis and may represent a target for treatment. Current PD drugs provide only symptomatic relief and have limitations in terms of adverse effects and inability to prevent neurodegeneration. Flavonoids have been suggested to exert human health benefits by its anti-oxidant and anti-inflammatory properties. Therefore, in the present study, using 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP)-induced mouse model of Parkinsonism, we investigated the neuroprotective potential of bioflavonoid compound Pycnogenol® (PYC), an extract of Pinus maritime bark. MPTP injected mice developed significantly severe oxidative stress and impaired motor coordination at day 1 and day 7 postinjection. This was associated with significantly increased inflammatory responses of astrocyte and microglia as assessed by ionized calcium binding adaptor molecule 1 (Iba 1) and glial fibrillary acidic protein (GFAP) immunohistochemistry, and nuclear transcription factor-κB (NF-κB), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in the striata by Western blot. Additionally, there was significant upregulation of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) expression in the striata of MPTP injected mice compared to saline controls. The MPTP-induced neuroinflammation, neurodegeneration and behavioral impairments were markedly repudiated by treatment with PYC. These results suggest that PYC protects dopaminergic neurons from MPTP-induced toxicity in the mouse model of PD. Thus, the present finding of PYC-induced adaptation to oxidative stress and inflammation could suggest a novel avenue for clinical intervention in neurodegenerative diseases including PD. PMID:23391521

  5. Stress-induced neuroinflammation: mechanisms and new pharmacological targets

    Directory of Open Access Journals (Sweden)

    C.D. Munhoz

    2008-12-01

    Full Text Available Stress is triggered by numerous unexpected environmental, social or pathological stimuli occurring during the life of animals, including humans, which determine changes in all of their systems. Although acute stress is essential for survival, chronic, long-lasting stress can be detrimental. In this review, we present data supporting the hypothesis that stress-related events are characterized by modifications of oxidative/nitrosative pathways in the brain in response to the activation of inflammatory mediators. Recent findings indicate a key role for nitric oxide (NO and an excess of pro-oxidants in various brain areas as responsible for both neuronal functional impairment and structural damage. Similarly, cyclooxygenase-2 (COX-2, another known source of oxidants, may account for stress-induced brain damage. Interestingly, some of the COX-2-derived mediators, such as the prostaglandin 15d-PGJ2 and its peroxisome proliferator-activated nuclear receptor PPARγ, are activated in the brain in response to stress, constituting a possible endogenous anti-inflammatory mechanism of defense against excessive inflammation. The stress-induced activation of both biochemical pathways depends on the activation of the N-methyl-D-aspartate (NMDA glutamate receptor and on the activation of the transcription factor nuclear factor kappa B (NFκB. In the case of inducible NO synthase (iNOS, release of the cytokine TNF-α also accounts for its expression. Different pharmacological strategies directed towards different sites in iNOS or COX-2 pathways have been shown to be neuroprotective in stress-induced brain damage: NMDA receptor blockers, inhibitors of TNF-α activation and release, inhibitors of NFκB, specific inhibitors of iNOS and COX-2 activities and PPARγ agonists. This article reviews recent contributions to this area addressing possible new pharmacological targets for the treatment of stress-induced neuropsychiatric disorders.

  6. Mulberry fruit prevents LPS-induced NF-κB/pERK/MAPK signals in macrophages and suppresses acute colitis and colorectal tumorigenesis in mice.

    Science.gov (United States)

    Qian, Zhengjiang; Wu, Zhiqin; Huang, Lian; Qiu, Huiling; Wang, Liyan; Li, Li; Yao, Lijun; Kang, Kang; Qu, Junle; Wu, Yonghou; Luo, Jun; Liu, Johnson J; Yang, Yi; Yang, Wancai; Gou, Deming

    2015-11-30

    Here, we investigated the impact of mulberry fruit (MBF) extracts on lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 macrophages, and the therapeutic efficacy of MBF diet in mice with dextran sulfate sodium (DSS)-induced acute colitis and MUC2(-/-) mice with colorectal cancer. In vitro, LPS-induced nitric oxide (NO) production was significantly inhibited by MBF extracts via suppressing the expression of proinflammatory molecules, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-β) and IL-6. Particularly, a dose-dependent inhibition on LPS-induced inflammatory responses was observed following treatment with MBF dichloromethane extract (MBF-DE), in which linoleic acid and ethyl linolenate were identified as two active compounds. Moreover, we elucidated that MBF-DE attenuated LPS-induced inflammatory responses by blocking activation of both NF-κB/p65 and pERK/MAPK pathways. In vivo, DSS-induced acute colitis was significantly ameliorated in MBF-fed mice as gauged by weight loss, colon morphology and histological damage. In addition, MBF-fed MUC2(-/-) mice displayed significant decrease in intestinal tumor and inflammation incidence compared to control diet-fed group. Overall, our results demonstrated that MBF suppressed the development of intestinal inflammation and tumorgenesis both in vitro and in vivo, and supports the potential of MBF as a therapeutic functional food for testing in human clinical trials.

  7. Hepatoprotective effect of pinoresinol on carbon tetrachloride-induced hepatic damage in mice.

    Science.gov (United States)

    Kim, Hyo-Yeon; Kim, Joon-Ki; Choi, Jun-Ho; Jung, Joo-Yeon; Oh, Woo-Yong; Kim, Dong Chun; Lee, Hee Sang; Kim, Yeong Shik; Kang, Sam Sik; Lee, Seung-Ho; Lee, Sun-Mee

    2010-01-01

    Forsythiae Fructus is known to have diuretic, anti-bacterial, and anti-inflammatory activities. This study examined the hepatoprotective effects of pinoresinol, a lignan isolated from Forsythiae Fructus, against carbon tetrachloride (CCl(4))-induced liver injury. Mice were treated intraperitoneally with vehicle or pinoresinol (25, 50, 100, and 200 mg/kg) 30 min before and 2 h after CCl4 (20 microl/kg) injection. In the vehicle-treated CCl(4 )group, serum aminotransferase activities were significantly increased 24 h after CCl4 injection, and these increases were attenuated by pinoresinol at all doses. Hepatic glutathione contents were significantly decreased and lipid peroxidation was increased after CCl4 treatment. These changes were attenuated by 50 and 100 mg/kg of pinoresinol. The levels of protein and mRNA expression of inflammatory mediators, including tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclooxygenase-2, were significantly increased after CCl4 injection; and these increases were attenuated by pinoresinol. Nuclear translocation of nuclear factor-kappaB (NF-kappaB) and phosphorylation of c-Jun, one of the components of activating protein 1 (AP-1), were inhibited by pinoresinol. Our results suggest that pinoresinol ameliorates CCl4)-induced acute liver injury, and this protection is likely due to anti-oxidative activity and down-regulation of inflammatory mediators through inhibition of NF-kappaB and AP-1.

  8. MicroRNAs Constitute a Negative Feedback Loop in Streptococcus pneumoniae-Induced Macrophage Activation.

    Science.gov (United States)

    Griss, Kathrin; Bertrams, Wilhelm; Sittka-Stark, Alexandra; Seidel, Kerstin; Stielow, Christina; Hippenstiel, Stefan; Suttorp, Norbert; Eberhardt, Martin; Wilhelm, Jochen; Vera, Julio; Schmeck, Bernd

    2016-07-15

    Streptococcus pneumoniae causes high mortality as a major pneumonia-inducing pathogen. In pneumonia, control of innate immunity is necessary to prevent organ damage. We assessed the role of microRNAs (miRNAs) as regulators in pneumococcal infection of human macrophages. Exposure of primary blood-derived human macrophages with pneumococci resulted in transcriptional changes in several gene clusters and a significant deregulation of 10 microRNAs. Computational network analysis retrieved miRNA-146a as one putatively important regulator of pneumococci-induced host cell activation. Its induction depended on bacterial structural integrity and was completely inhibited by blocking Toll-like receptor 2 (TLR-2) or depleting its mediator MyD88. Furthermore, induction of miRNA-146a release did not require the autocrine feedback of interleukin 1β and tumor necrosis factor α released from infected macrophages, and it repressed the TLR-2 downstream mediators IRAK-1 and TRAF-6, as well as the inflammatory factors cyclooxygenase 2 and interleukin 1β. In summary, pneumococci recognition induces a negative feedback loop, preventing excessive inflammation via miR-146a and potentially other miRNAs. PMID:26984146

  9. Suppression of LPS-induced inflammatory activities by Rosmarinus officinalis L.

    Science.gov (United States)

    Yu, Mi-Hee; Choi, Jun-Hyeok; Chae, In-Gyeong; Im, Hyo-Gwon; Yang, Seun-Ah; More, Kunal; Lee, In-Seon; Lee, Jinho

    2013-01-15

    Rosemary (Rosmarinus officinalis L.) has been used in folk medicine to treat headaches, epilepsy, poor circulation, and many other ailments. It was found that rosemary could act as a stimulant and mild analgesic and could reduce inflammation. However, the mechanisms underlying the anti-inflammatory effects of rosemary need more study to be established. Therefore, in this study, the effects of rosemary on the activation of nuclear factor kappa beta (NF-kB) and mitogen-activated protein kinases (MAPKs), the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and the production of nitric oxide (NO), prostaglandin E(2) (PGE(2)), and cytokine in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells were investigated. A methanol extract of rosemary and its hexane fraction reduced NO generation with an IC(50) of 2.75 and 2.83 μg/ml, respectively. Also, the methanol extract and the hexane fraction inhibited LPS-induced MAPKs and NF-kB activation associated with the inhibition of iNOS or COX-2 expression. LPS-induced production of PGE(2) and tumour necrosis factor-alpha (TNF-α) were blocked by rosemary. Rosemary extract and its hexane fraction are important for the prevention of phosphorylation of MAPKs, thereby blocking NF-kB activation, which in turn leads to decreased expression of iNOS and COX-2, thus preventing inflammation. PMID:23122161

  10. Synergic Effect of Genistein and Daidzein on UVB-Induced DNA Damage: An Effective Photoprotective Combination

    Directory of Open Access Journals (Sweden)

    Barbara Iovine

    2011-01-01

    Full Text Available The anti-inflammatory effects and antioxidant activities of individual isoflavones are well established although little is known about the photoprotective effect of their combination. The aim of this study was to investigate the photoprotective effects of different concentrations of genistein and daidzein individually or combined. We measured the expression levels of the cyclo-oxygenase-2 (COX-2 and growth arrest and DNA-damage inducible (Gadd45 genes, which are involved in inflammation and DNA repair, respectively, in BJ-5ta human skin fibroblasts irradiated with 60 mJ/cm2 UVB. We also determined the cellular response to UVB-induced DNA damage by Comet assay. We report that genistein and daidzein when administered combined, and at a specific concentration and ratio, exerted a synergistic photoprotective effect that was greater than the effect obtained with each isoflavone alone. The results reported herein suggest that low concentrations of genistein and daidzein combined may be good candidate ingredients for protective agents against UV-induced photodamage.

  11. Derinat Protects Skin against Ultraviolet-B (UVB-Induced Cellular Damage

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    Wen-Li Hsu

    2015-11-01

    Full Text Available Ultraviolet-B (UVB is one of the most cytotoxic and mutagenic stresses that contribute to skin damage and aging through increasing intracellular Ca2+ and reactive oxygen species (ROS. Derinat (sodium deoxyribonucleate has been utilized as an immunomodulator for the treatment of ROS-associated diseases in clinics. However, the molecular mechanism by which Derinat protects skin cells from UVB-induced damage is poorly understood. Here, we show that Derinat significantly attenuated UVB-induced intracellular ROS production and decreased DNA damage in primary skin cells. Furthermore, Derinat reduced intracellular ROS, cyclooxygenase-2 (COX-2 expression and DNA damage in the skin of the BALB/c-nu mice exposed to UVB for seven days in vivo. Importantly, Derinat blocked the transient receptor potential canonical (TRPC channels (TRPCs, as demonstrated by calcium imaging. Together, our results indicate that Derinat acts as a TRPCs blocker to reduce intracellular ROS production and DNA damage upon UVB irradiation. This mechanism provides a potential new application of Derinat for the protection against UVB-induced skin damage and aging.

  12. Protective effects of polydatin from Polygonum cuspidatum against carbon tetrachloride-induced liver injury in mice.

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    Hong Zhang

    Full Text Available Polydatin is one of main compounds in Polygonum cuspidatum, a plant with both medicinal and nutritional value. The possible hepatoprotective effects of polydatin on acute liver injury mice induced by carbon tetrachloride (CCl(4 and the mechanisms involved were investigated. Intraperitoneal injection of CCl(4 (50 µl/kg resulted in a significant increase in the levels of serum aspartate aminotransferase (AST, alanine aminotransferase (ALT and hepatic malondialdehyde (MDA, also a marked enhancement in the expression of hepatic tumor necrosis factor-alpha (TNF-α, interleukin-1 beta (IL-1β, cyclooxygenase-2 (COX-2, inducible nitric oxide synthase (iNOS and nuclearfactor-kappa B (NF-κB. On the other hand, decreased glutathione (GSH content and activities of glutathione transferase (GST, superoxide dismutase (SOD, catalase (CAT and glutathione peroxidase (GPx were observed following CCl(4 exposure. Nevertheless, all of these phenotypes were evidently reversed by preadministration of polydatin for 5 continuous days. The mRNA and protein expression levels of hepatic growth factor-beta1 (TGF-β(1 were enhanced further by polydatin. These results suggest that polydatin protects mice against CCl(4-induced liver injury through antioxidant stress and antiinflammatory effects. Polydatin may be an effective hepatoprotective agent and a promising candidate for the treatment of oxidative stress- and inflammation-related diseases.

  13. TGF-β in jaw tumor fluids induces RANKL expression in stromal fibroblasts

    Science.gov (United States)

    Yamada, Chiaki; Aikawa, Tomonao; Okuno, Emi; Miyagawa, Kazuaki; Amano, Katsuhiko; Takahata, Sosuke; Kimata, Masaaki; Okura, Masaya; Iida, Seiji; Kogo, Mikihiko

    2016-01-01

    Odontogenic tumors and cysts, arising in the jawbones, grow by resorption and destruction of the jawbones. However, mechanisms underlying bone resorption by odontogenic tumors/cysts remain unclear. Odontogenic tumors/cysts comprise odontogenic epithelial cells and stromal fibroblasts, which originate from the developing tooth germ. It has been demonstrated that odontogenic epithelial cells of the developing tooth germ induce osteoclastogenesis to prevent the tooth germ from invading the developing bone to maintain its structure in developing bones. Thus, we hypothesized that odontogenic epithelial cells of odontogenic tumors/cysts induce osteoclast formation, which plays potential roles in tumor/cyst outgrowth into the jawbone. The purpose of this study was to examine osteoclastogenesis by cytokines, focusing on transforming growth factor-β (TGF-β), produced by odontogenic epithelial cells. We observed two pathways for receptor activator of NF-κB ligand (RANKL) induction by keratocystic odontogenic tumor fluid: the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway through interleukin-1α (IL-1α) signaling and non-COX-2/PGE2 pathway through TGF-β receptor signaling. TGF-β1 and IL-1α produced by odontogenic tumors/cysts induced osteoclastogenesis directly in the osteoclast precursor cells and indirectly via increased RANKL induction in the stroma. PMID:27279422

  14. Luteolin supplementation adjacent to aspirin treatment reduced dimethylhydrazine-induced experimental colon carcinogenesis in rats.

    Science.gov (United States)

    Osman, Neamt H A; Said, Usama Z; El-Waseef, Ahmed M; Ahmed, Esraa S A

    2015-02-01

    Previous studies have shown that aspirin is used in colon cancer treatment. However, long-term of Aspirin usage is limited to gastric and renal toxicity. Luteolin (LUT) has cancer prevention and anti-inflammatory effects. The present study was designed to investigate the effect of LUT supplementation and Aspirin treatment in dimethylhydrazine (DMH)-induced carcinogenesis in rats. DMH (20 mg/kg BW/week) treated rats received gavages with Aspirin (50 mg/kg BW/week) and LUT (0.2 mg/kg BW/day) for 15 weeks. DMH injections induce colon polyps and renal bleeding, significantly increasing carcinoembryonic antigen (CEA), cyclooxygenase-2 (COX-2), oxidative stress, and kidney function tests and reducing antioxidant markers. Either Aspirin or LUT gavages alone or combined produce a significant decrease in colon polyp number and size, significantly decreasing CEA, COX-2, and oxidative stress and increasing antioxidant markers. In conclusion, the supplementations of LUT adjacent to Aspirin in the treatment of DMH-induced carcinogenesis in rats reflect a better effect than the use of Aspirin alone. PMID:25342594

  15. Neocryptotanshinone inhibits lipopolysaccharide-induced inflammation in RAW264.7 macrophages by suppression of NF-κB and iNOS signaling pathways

    Directory of Open Access Journals (Sweden)

    Chuanhong Wu

    2015-07-01

    Full Text Available Neocryptotanshinone (NCTS is a natural product isolated from traditional Chinese herb Salvia miltiorrhiza Bunge. In this study, we investigated its anti-inflammatory effects in lipopolysaccharide (LPS-stimulated mouse macrophage (RAW264.7 cells. MTT results showed that NCTS partly reversed LPS-induced cytotoxicity. Real-time PCR results showed that NCTS suppressed LPS-induced mRNA expression of inflammatory cytokines, including tumor necrosis factor α (TNFα, interleukin-6 (IL-6 and interleukin-1β (IL-1β. Moreover, NCTS could decrease LPS-induced nitric oxide (NO production. Western blotting results showed that NCTS could down-regulate LPS-induced expression of inducible nitric oxide synthase (iNOS, p-IκBα, p-IKKβ and p-NF-κB p65 without affecting cyclooxygenase-2 (COX-2. In addition, NCTS inhibited LPS-induced p-NF-κB p65 nuclear translocation. In conclusion, these data demonstrated that NCTS showed anti-inflammatory effect by suppression of NF-κB and iNOS signaling pathways.

  16. Meloxicam inhibits fipronil-induced apoptosis via modulation of the oxidative stress and inflammatory response in SH-SY5Y cells.

    Science.gov (United States)

    Park, Jae Hyeon; Park, Youn Sun; Lee, Je-Bong; Park, Kyung-Hun; Paik, Min-kyoung; Jeong, Mihye; Koh, Hyun Chul

    2016-01-01

    Oxidative stress and inflammatory responses have been identified as key elements of neuronal cell apoptosis. In this study, we investigated the mechanisms by which inflammatory responses contribute to apoptosis in human neuroblastoma SH-SY5Y cells treated with fipronil (FPN). Based on the cytotoxic mechanism of FPN, we examined the neuroprotective effects of meloxicam against FPN-induced neuronal cell death. Treatment of SH-SY5Y cells with FPN induced apoptosis via activation of caspase-9 and -3, leading to nuclear condensation. In addition, FPN induced oxidative stress and increased expression of cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α) via inflammatory stimulation. Pretreatment of cells with meloxicam enhanced the viability of FPN-exposed cells through attenuation of oxidative stress and inflammatory response. FPN activated mitogen activated protein kinase (MAPK) and inhibitors of MAPK abolished FPN-induced COX-2 expression. Meloxicam also attenuated FPN-induced cell death by reducing MAPK-mediated pro-inflammatory factors. Furthermore, we observed both nuclear accumulation of p53 and enhanced levels of cytosolic p53 in a concentration-dependent manner after FPN treatment. Pretreatment of cells with meloxicam blocked the translocation of p53 from the cytosol to the nucleus. Together, these data suggest that meloxicam may exert anti-apoptotic effects against FPN-induced cytotoxicity by both attenuating oxidative stress and inhibiting the inflammatory cascade via inactivation of MAPK and p53 signaling.

  17. Adiponectin deficiency enhances colorectal carcinogenesis and liver tumor formation induced by azoxymethane in mice

    Institute of Scientific and Technical Information of China (English)

    Tamao Nishihara; Shinji Tamura; Norio Hayashi; Hiroyasu Iishi; Iichiro Shimornura; Miyako Baba; Morihiro Matsuda; Masahiro Inoue; Yasuko Nishizawa; Atsunori Fukuhara; Hiroshi Arald; Shinji Kihara; Tohru Funahashi

    2008-01-01

    AIM: To investigate the causal relationship between hypoadiponectinemia and colorectal carcinogenesis in in vivo experimental model, and to determine the con-tribution of adiponectin deficiency to colorectal cancer development and proliferation. METHODS: We examined the influence of adiponectin deficiency on colorectal carcinogenesis induced by the administration of azoxymethane (AOM) (7.5 mg/kg, in-traperitoneal injection once a week for 8 wk), by using adiponectin-knockout (KO) mice. RESULTS: At 53 wk after the first AOM treatment, KOmice developed larger and histologically more progres-sive colorectal tumors with greater frequency com-pared with wild-type (WT) mice, although the tumor incidence was not different between WT and KO mice. KO mice showed increased cell proliferation of colorec-tal tumor cells, which correlated with the expression levels of cyclooxygenase-2 (COX-2) in the colorectal tumors. In addition, KO mice showed higher incidence and frequency of liver tumors after AOI treatment. Thirteen percent of WT mice developed liver tumors, and these WT mice had only a single tumor. In contrast, 50% of K.O mice developed liver tumors, and 58% of these KO mice had multiple tumors. CONCLUSION: Adiponectin deficiency enhances colorectal carcinogenesis and liver tumor formation induced by AOM in mice. This study strongly suggests that hypoadiponectinemia could be involved in the pathogenesis for colorectal cancer and liver tumor in human subjects.

  18. Chemotherapy-induced hemorrhagic cystitis: pathogenesis, pharmacological approaches and new insights

    Directory of Open Access Journals (Sweden)

    Marcos V.A. Lima

    2012-04-01

    Full Text Available Chemotherapy-induced hemorrhagic cystitis (HC remains a common and life-threatening clinical complication, mainly due to the increasing usage of alkylating agents during conditioning regimen for hematopoietic cell transplantation. Currently, mesna and hyperhydration are the two more employed preventive measures. However, these prophylactic approaches have been proven not to be completely effective, since cystoscopic and histopathologic bladder damage are evidenced. Therefore, understanding the pathogenesis of HC must be the cornerstone for the development of novel therapeutic strategies. The purpose of this review is to examine the current knowledge regarding the pathogenesis of HC, describing the importance of transcription factors (nuclear factor kappaB, cytokines (tumor necrosis factor-α, interleukin-1β, -4, -6, and -8, enzymes (inducible nitric oxide synthase and cyclooxygenase-2, among other mediators, for the bladder injury. We also discuss the currently available animal models and future perspectives on the management of HC. [J Exp Integr Med 2012; 2(2.000: 95-112

  19. Acupuncture inhibits microglial activation and inflammatory events in the MPTP-induced mouse model.

    Science.gov (United States)

    Kang, Jun Mo; Park, Hi Joon; Choi, Yeong Gon; Choe, Il Hwan; Park, Jae Hyun; Kim, Yong Sik; Lim, Sabina

    2007-02-01

    Using a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD), this study investigated on the neuroprotective effects of acupuncture by examining whether acupuncture contributed to inhibiting microglial activation and inflammatory events. C57BL/6 mice were treated with MPTP (30 mg/kg, i.p.) for 5 consecutive days. Acupuncture was then applied to acupoints Yanglingquan (GB34) and Taichong (LR3) starting 2 h after the first MPTP administration and then at 48 h intervals until the mice were sacrificed for analyses at 1, 3, and 7 days after the last MPTP injection. These experiments demonstrated that acupuncture inhibited the decreased of the tyrosine hydroxylase (TH) immunoreactivity (IR) and generated a neuroprotective effects in the striatum (ST) and the substantia nigra (SN) on days 1, 3, and 7 post-MPTP injections. Acupuncture attenuated the increase of macrophage antigen complex-1 (MAC-1), a marker of microglial activation, at 1 and 3 days and reduced the increases in cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression on days 1, 3, and 7. In MPTP group, striatal dopamine (DA) was measured by 46% at 7 days, whereas DA in the acupuncture group was 78%. On the basis of these results, we suggest that acupuncture could be used as a neuroprotective intervention for the purpose of inhibiting microglial activation and inflammatory events in PD. PMID:17173870

  20. Dose-dependent effects of celecoxib on CB-1 agonist-induced antinociception in the mice

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Zarrindast

    2009-04-01

    Full Text Available "nObjective: Endocannabinoid produce analgesia that is comparable which of opioids. The mechanism of antinociceptive effects of (∆ - 9 tetrahydrocannabinol (THC is suggested to be through cyclooxygenase (COX pathway. In the present work, the effect of two extreme dose ranges of celecoxib (mg/kg and ng/kg, a cyclooxygenase-2 (COX-2 antagonist, on arachidonylcyclopropylamide (ACPA, a selective CB1 agonist induced antinociception in mice was examined. "nMethods: We have investigated the interaction between celecoxib, at the doses of mg/kg (50, 100, 200 and 400 i.p.  and ultra low dose (ULD (25 and 50 ng/kg, i.p., on the antinociceptive effect of intracerebroventricular (i.c.v. administration of ACPA (0.004, 0.0625 and 1 μg/mice, using formalin test in mice. "nResults: I.C.V. administration of ACPA induced antinociception. Intraperitoneal administration of celecoxib (mg/kg and its ULD (ng/kg attenuated and potentiated, ACPA antinociceptive effects, respectively. "nConclusion: It is concluded that the mg/kg doses of COX-2 antagonist showed opposite effects compare to the ultra-low dose of the drug.

  1. Docosahexaenoic acid suppresses arachidonic acid-induced proliferation of LS-174T human colon carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    Piet Habbel; Karsten H Weylandt; Katja Lichopoj; Johannes Nowak; Martin Purschke; Jing-Dong Wang; Cheng-Wei He; Daniel C Baumgart; Jing X Kang

    2009-01-01

    AIM: To investigate the impact of arachidonic acid (AA) and docosahexaenoic acid (DHA) and their combination on colon cancer cell growth.METHODS: The LS-174T colon cancer cell line was used to study the role of the prostaglandin precursor AA and the omega-3 polyunsaturated fatty acid DHA on cell growth. Cell viability was assessed in XTT assays. For analysis of cell cycle and cell death, flow cytometry and DAPI staining were applied. Expression of cyclooxygenase-2 (COX-2), p21 and bcl-2 in cells incubated with AA or DHA was examined by real-time RT-PCR. Prostaglandin E2 (PGE2) generation in the presence of AA and DHA was measured using a PGE2ELISA.RESULTS: AA increased cell growth, whereas DHA reduced viability of LS 174T cells in a time- and dosedependent manner. Furthermore, DHA down- regulated mRNA of bcl-2 and up-regulated p21. Interestingly,DHA was able to suppress AA-induced cell proliferation and significantly lowered AA-derived PGE2 formation.DHA also down-regulated COX-2 expression. In addition to the effect on PGE2 formation, DHA directly reduced PGE2-induced cell proliferation in a dosedependent manner.CONCLUSION: These results suggest that DHA can inhibit the pro-proliferative effect of abundant AA or PGE2.

  2. Progressive loss of nigrostriatal dopaminergic neurons induced by inflammatory responses to fipronil.

    Science.gov (United States)

    Park, Jae Hyeon; Park, Youn Sun; Koh, Hyun Chul

    2016-09-01

    Inflammatory responses are involved in mechanisms of neuronal cell damage in the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). We investigated the mechanisms whereby inflammatory responses contribute to loss of dopaminergic neurons in fipronil (FPN)-treated rats. After stereotaxic injection of FPN in the substantia nigra (SN), the number of tyrosine hydroxylase (TH)-positive neurons and the levels of TH expression in the SN decreased at 7days, and a significant decrease was observed at 14days with a subsequent reduction in striatal TH expression. Decreases in dopamine (DA) levels, however, began at 3days post-injection, preceding the changes in TH expression. In contrast, glial fibrillary acidic protein (GFAP) expression was significantly increased at 3days and persisted for up to 14days post-lesion; these changes in GFAP expression appeared to be inversely correlated with TH expression. Furthermore, we found that FPN administration induced an inflammatory response characterized by increased levels of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α), which was mediated by activated microglia following infusion of FPN unilaterally into the SN. Intranigral injection of FPN underwent an inflammatory response with a resultant ongoing loss of dopaminergic neurons, indicating that pesticides may have important implication for the study of PD. PMID:27313094

  3. Guggulsterone Attenuated Lipopolysaccharide-Induced Inflammatory Responses in Mouse Inner Medullary Collecting Duct-3 Cells.

    Science.gov (United States)

    Kim, Dong-Goo; Bae, Gi-Sang; Jo, Il-Joo; Choi, Sun-Bok; Kim, Myoung-Jin; Jeong, Jun-Hyeok; Kang, Dae-Gil; Lee, Ho-Sub; Song, Ho-Joon; Park, Sung-Joo

    2016-02-01

    Guggulsterone (GS) is a phytosterol that has been used to treat inflammatory diseases such as colitis, obesity, and thrombosis. Although many previous studies have examined activities of GS, the effect of GS on lipopolysaccharide (LPS)-induced inflammatory responses in mouse inner medullary collecting duct-3 (mIMCD-3) cells have not been examined. Therefore, here, we investigated the anti-inflammatory action of GS on mIMCD-3 cells exposed to LPS. LPS treatment on mIMCD-3 cells produced pro-inflammatory molecules such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) significantly; however, GS treatment significantly inhibited the production of pro-inflammatory molecules. In addition, GS inhibited the degradation of Iκ-Bα and translocation of NF-κB on mIMCD-3 cells. These results suggest that GS could inhibit inflammatory responses in collecting duct cells which could contribute to kidney injury during systemic infection. PMID:26260258

  4. Tartary buckwheat on nitric oxide-induced inflammation in RAW264.7 macrophage cells.

    Science.gov (United States)

    Choi, Soo Yeon; Choi, Ji Yeon; Lee, Jeong Min; Lee, Sanghyun; Cho, Eun Ju

    2015-08-01

    We investigated the effects of tartary buckwheat (TB, Fagopyrum tataricum) on the production of pro-inflammatory mediators in lipopolysaccharide (LPS)- and interferon (IFN)-γ-stimulated RAW264.7 cells. We evaluated the anti-inflammatory effects of TB against the LPS- and IFN-γ-stimulated inflammatory response in RAW264.7 macrophage cells. We fractionated TB to obtain 4 fractions including the n-hexane, methylene chloride, ethyl acetate (EtOAc), and n-butanol fractions. In addition, rutin was isolated and identified from the EtOAc fraction. The 4 fractions and rutin effectively inhibited the production of reactive oxygen species, nitric oxide (NO), and interleukin-6. In addition, the mRNA expression levels of pro-inflammatory factors including nuclear factor kappa B, cyclooxygenase-2, and inducible NO synthase were down-regulated in LPS- and IFN-γ-stimulated RAW264.7 cells following treatment with the 4 fractions and rutin. The present study suggests that TB could induce anti-inflammation by regulating the expression of inflammatory mediators. PMID:26134972

  5. Thymoquinone inhibits phorbol ester-induced activation of NF-κB and expression of COX-2, and induces expression of cytoprotective enzymes in mouse skin in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Kundu, Joydeb Kumar [College of Pharmacy, Keimyung University, Daegu 704-701 (Korea, Republic of); Liu, Lijia; Shin, Jun-Wan [Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 151-742 (Korea, Republic of); Surh, Young-Joon, E-mail: surh@plaza.snu.ac.kr [Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 151-742 (Korea, Republic of); Cancer Research Institute, Seoul National University, Seoul 110-799 (Korea, Republic of)

    2013-09-06

    Highlights: •Thymoquinone inhibits phorbol ester-induced COX-2 expression in mouse skin. •Thymoquinone attenuates phosphorylation of IκBα and DNA binding of NF-κB in mouse skin. •Thymoquinone inhibits phosphorylation of p38 MAP kinase, JNK and Akt in mouse skin. •Thymoquinone induces the expression of cytoprotective proteins in mouse skin. -- Abstract: Thymoquinone (TQ), the active ingredient of Nigella sativa, has been reported to possess anti-inflammatory and chemopreventive properties. The present study was aimed at elucidating the molecular mechanisms of anti-inflammatory and antioxidative activities of thymoquinone in mouse skin. Pretreatment of female HR-1 hairless mouse skin with TQ attenuated 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of cyclooxygenase-2 (COX-2). TQ diminished nuclear translocation and the DNA binding of nuclear factor-kappaB (NF-κB) via the blockade of phosphorylation and subsequent degradation of IκBα in TPA-treated mouse skin. Pretreatment with TQ attenuated the phosphorylation of Akt, c-Jun-N-terminal kinase and p38 mitogen-activated protein kinase, but not that of extracellular signal-regulated kinase-1/2. Moreover, topical application of TQ induced the expression of heme oxygenase-1, NAD(P)H-quinoneoxidoreductase-1, glutathione-S-transferase and glutamate cysteine ligase in mouse skin. Taken together, the inhibitory effects of TQ on TPA-induced COX-2 expression and NF-κB activation, and its ability to induce the expression of cytoprotective proteins provide a mechanistic basis of anti-inflammatory and antioxidative effects of TQ in hairless mouse skin.

  6. PUMA and survivin are involved in the apoptosis of HepG2 cells induced by microcystin-LR via mitochondria-mediated pathway.

    Science.gov (United States)

    Ma, Junguo; Feng, Yiyi; Liu, Yang; Li, Xiaoyu

    2016-08-01

    The present study aimed to determine the cytotoxicity of microcystin-LR (MC-LR) on the human hepatocellular carcinoma (HepG2) cells in order to elucidate the mechanism of apoptosis induced by MC-LR. Morphological evaluation results showed that MC-LR induced time- and concentration-dependent apoptosis in HepG2 cells. The biochemical assays revealed that MC-LR-exposure caused overproduction of reactive oxygen species (ROS), cyclooxygenase-2 activity alteration, cytochrome c release, and remarkable activation of caspase-3 and caspase-9 in HepG2 cells, indicating that MC-LR-induced apoptosis is mediated by mitochondrial pathway. Moreover, we also found that p53 and Bax might play an important role in MC-LR-induced apoptosis in HepG2 cells in which PUMA and survivin were involved. However, further studies are necessary to elucidate the possible functions of PUMA and survivin in MC-LR-induced apoptosis in HepG2 cells. PMID:27235693

  7. Mitigation of indomethacin-induced gastrointestinal damages in fat-1 transgenic mice via gate-keeper action of ω-3-polyunsaturated fatty acids

    Science.gov (United States)

    Han, Young-Min; Park, Jong-Min; Kang, Jing X.; Cha, Ji-Young; Lee, Ho-Jae; Jeong, Migeyong; Go, Eun-Jin; Hahm, Ki Baik

    2016-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) damage the gastrointestinal (GI) epithelial cell membranes by inducing several signals through lipid raft organization after membrane incorporation, whereas ω-3 polyunsaturated fatty acids (PUFAs) relieve inflammation, reduce oxidative stress, and provide cytoprotection, consequent to lipid raft disorganization. Therefore, we hypothesized that ω-3 PUFAs can protect the GI from NSAID-induced damages by initiating the gatekeeper action of cell membranes, subsequent to anti-inflammatory and anti-oxidative actions. Administration of indomethacin (IND) leads to the formation of lipid rafts and activation of caveolin-1; however, no such observations were made upon co-administration of eicosapentaenoic acid (EPA) and IND. In addition, the EPA-induced lipid raft disorganization, caveolin-1 inactivation, and cellular cytotoxicity were inhibited when target cells were knocked-out using G-protein coupled receptor 120 (GPR 120). EPA significantly attenuated IND-induced oxidative damage and apoptosis. IND administration induced significant ulceration, bleeding, and oedema in the stomach or small intestine of wild-type (WT) mice; however, such severe damages to the GI significantly decreased in fat-1 transgenic (TG) mice (P < 0.001), which exhibited decreased cyclooxygenase-2 expression and apoptosis, decreased interleukin-1β and FAS concentrations, and increased heme oxygenase-1 concentration. Our study indicates that the gatekeeper function of ω-3 PUFAs improves GI safety when administered with NSAID. PMID:27658533

  8. Therapeutic Effect of C-Phycocyanin Extracted from Blue Green Algae in a Rat Model of Acute Lung Injury Induced by Lipopolysaccharide

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    Pak-on Leung

    2013-01-01

    Full Text Available C-Phycocyanin (CPC, extracted from blue green algae, is a dietary nutritional supplement due to its several beneficial pharmacological effects. This study was conducted to evaluate whether CPC protects against lipopolysaccharide- (LPS- induced acute lung injury (ALI in rats. Rats were challenged with LPS (5 mg/kg body weight intratracheally to induce ALI. After 3 h LPS instillation, rats were administrated with CPC (50 mg/kg body weight, i.p. for another 3 h. Our results showed that posttreatment with CPC significantly inhibited LPS-induced elevation of protein concentration, nitrite/nitrate level, release of proinflammatory cytokines, the number of total polymorphonuclear cells in bronchoalveolar lavage fluid, and lung edema evidenced by decrease of lung wet/dry weight ratio accompanied by a remarkable improvement of lung histopathological alterations. Furthermore, CPC significantly attenuated LPS-induced myeloperoxidase activity, O2− formation, expression of inducible nitric oxide synthase, and cyclooxygenase-2 as well as nuclear factor-kappa B (NF-κB activation in lungs. Additionally, CPC significantly downregulated proapoptotic proteins such as caspase-3 and Bax, but upregulated antiapoptotic proteins such as Bcl-2 and Bcl-XL in lungs exposed to LPS. These findings indicate that CPC could be potentially useful for treatment of LPS-related ALI by inhibiting inflammatory responses and apoptosis in lung tissues.

  9. Cyclopamine and jervine induce COX-2 overexpression in human erythroleukemia cells but only cyclopamine has a pro-apoptotic effect

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    Ghezali, Lamia; Leger, David Yannick; Limami, Youness [Université de Limoges, FR 3503 GEIST, EA 1069 “Laboratoire de Chimie des Substances Naturelles”, GDR CNRS 3049, Faculté de Pharmacie, Laboratoire de Biochimie et Biologie Moléculaire, 2 rue du Docteur Marcland, 87025 Limoges Cedex (France); Cook-Moreau, Jeanne [Université de Limoges, FR 3503 GEIST, UMR CNRS 7276 “Contrôle de la réponse immune B et lymphoproliférations”, Faculté de Médecine, 2 rue du Docteur Marcland, 87025 Limoges Cedex (France); Beneytout, Jean-Louis [Université de Limoges, FR 3503 GEIST, EA 1069 “Laboratoire de Chimie des Substances Naturelles”, GDR CNRS 3049, Faculté de Pharmacie, Laboratoire de Biochimie et Biologie Moléculaire, 2 rue du Docteur Marcland, 87025 Limoges Cedex (France); Liagre, Bertrand, E-mail: bertrand.liagre@unilim.fr [Université de Limoges, FR 3503 GEIST, EA 1069 “Laboratoire de Chimie des Substances Naturelles”, GDR CNRS 3049, Faculté de Pharmacie, Laboratoire de Biochimie et Biologie Moléculaire, 2 rue du Docteur Marcland, 87025 Limoges Cedex (France)

    2013-04-15

    Erythroleukemia is generally associated with a very poor response and survival to current available therapeutic agents. Cyclooxygenase-2 (COX-2) has been described to play a crucial role in the proliferation and differentiation of leukemia cells, this enzyme seems to play an important role in chemoresistance in different cancer types. Previously, we demonstrated that diosgenin, a plant steroid, induced apoptosis in HEL cells with concomitant COX-2 overexpression. In this study, we investigated the antiproliferative and apoptotic effects of cyclopamine and jervine, two steroidal alkaloids with similar structures, on HEL and TF1a human erythroleukemia cell lines and, for the first time, their effect on COX-2 expression. Cyclopamine, but not jervine, inhibited cell proliferation and induced apoptosis in these cells. Both compounds induced COX-2 overexpression which was responsible for apoptosis resistance. In jervine-treated cells, COX-2 overexpression was NF-κB dependent. Inhibition of NF-κB reduced COX-2 overexpression and induced apoptosis. In addition, cyclopamine induced apoptosis and COX-2 overexpression via PKC activation. Inhibition of the PKC pathway reduced both apoptosis and COX-2 overexpression in both cell lines. Furthermore, we demonstrated that the p38/COX-2 pathway was involved in resistance to cyclopamine-induced apoptosis since p38 inhibition reduced COX-2 overexpression and increased apoptosis in both cell lines. - Highlights: ► Cyclopamine alone but not jervine induces apoptosis in human erythroleukemia cells. ► Cyclopamine and jervine induce COX-2 overexpression. ► COX-2 overexpression is implicated in resistance to cyclopamine-induced apoptosis. ► Apoptotic potential of jervine is restrained by NF-κB pathway activation. ► PKC is involved in cyclopamine-induced apoptosis and COX-2 overexpression.

  10. Eupafolin nanoparticles protect HaCaT keratinocytes from particulate matter-induced inflammation and oxidative stress

    Science.gov (United States)

    Lin, Zih-Chan; Lee, Chiang-Wen; Tsai, Ming-Horng; Ko, Horng-Huey; Fang, Jia-You; Chiang, Yao-Chang; Liang, Chan-Jung; Hsu, Lee-Fen; Hu, Stephen Chu-Sung; Yen, Feng-Lin

    2016-01-01

    Exposure to particulate matter (PM), a major form of air pollution, can induce oxidative stress and inflammation and may lead to many diseases in various organ systems including the skin. Eupafolin, a flavonoid compound derived from Phyla nodiflora, has been previously shown to exhibit various pharmacological activities, including antioxidant and anti-inflammatory effects. Unfortunately, eupafolin is characterized by poor water solubility and skin penetration, which limits its clinical applications. To address these issues, we successfully synthesized a eupafolin nanoparticle delivery system (ENDS). Our findings showed that ENDS could overcome the physicochemical drawbacks of raw eupafolin with respect to water solubility and skin penetration, through reduction of particle size and formation of an amorphous state with hydrogen bonding. Moreover, ENDS was superior to raw eupafolin in attenuating PM-induced oxidative stress and inflammation in HaCaT keratinocytes, by mediating the antioxidant pathway (decreased reactive oxygen species production and nicotinamide adenine dinucleotide phosphate oxidase activity) and anti-inflammation pathway (decreased cyclooxygenase-2 expression and prostaglandin E2 production through downregulation of mitogen-activated protein kinase and nuclear factor-κB signaling). In summary, ENDS shows better antioxidant and anti-inflammatory activities than raw eupafolin through improvement of water solubility and skin penetration. Therefore, ENDS may potentially be used as a medicinal drug and/or cosmeceutical product to prevent PM-induced skin inflammation.

  11. Sargachromenol from Sargassum micracanthum Inhibits the Lipopolysaccharide-Induced Production of Inflammatory Mediators in RAW 264.7 Macrophages

    Directory of Open Access Journals (Sweden)

    Eun-Jin Yang

    2013-01-01

    Full Text Available During our ongoing screening program designed to determine the anti-inflammatory potential of natural compounds, we isolated sargachromenol from Sargassum micracanthum. In the present study, we investigated the anti-inflammatory effects of sargachromenol on lipopolysaccharide (LPS-induced inflammation in murine RAW 264.7 macrophage cells and the underlying mechanisms. Sargachromenol significantly inhibited the LPS-induced production of nitric oxide (NO and prostaglandin E2 (PGE2 in a dose-dependent manner. It also significantly inhibited the protein expression of inducible NO synthase (iNOS and cyclooxygenase-2 (COX-2 in a dose-dependent manner in LPS-stimulated macrophage cells. Further analyses showed that sargachromenol decreased the cytoplasmic loss of inhibitor κBα (IκBα protein. These results suggest that sargachromenol may exert its anti-inflammatory effects on LPS-stimulated macrophage cells by inhibiting the activation of the NF-κB signaling pathway. In conclusion, to our knowledge, this is the first study to show that sargachromenol isolated from S. micracanthum has an effective anti-inflammatory activity. Therefore, sargachromenol might be useful for cosmetic, food, or medical applications requiring anti-inflammatory properties.

  12. Eupafolin nanoparticles protect HaCaT keratinocytes from particulate matter-induced inflammation and oxidative stress.

    Science.gov (United States)

    Lin, Zih-Chan; Lee, Chiang-Wen; Tsai, Ming-Horng; Ko, Horng-Huey; Fang, Jia-You; Chiang, Yao-Chang; Liang, Chan-Jung; Hsu, Lee-Fen; Hu, Stephen Chu-Sung; Yen, Feng-Lin

    2016-01-01

    Exposure to particulate matter (PM), a major form of air pollution, can induce oxidative stress and inflammation and may lead to many diseases in various organ systems including the skin. Eupafolin, a flavonoid compound derived from Phyla nodiflora, has been previously shown to exhibit various pharmacological activities, including antioxidant and anti-inflammatory effects. Unfortunately, eupafolin is characterized by poor water solubility and skin penetration, which limits its clinical applications. To address these issues, we successfully synthesized a eupafolin nanoparticle delivery system (ENDS). Our findings showed that ENDS could overcome the physicochemical drawbacks of raw eupafolin with respect to water solubility and skin penetration, through reduction of particle size and formation of an amorphous state with hydrogen bonding. Moreover, ENDS was superior to raw eupafolin in attenuating PM-induced oxidative stress and inflammation in HaCaT keratinocytes, by mediating the antioxidant pathway (decreased reactive oxygen species production and nicotinamide adenine dinucleotide phosphate oxidase activity) and anti-inflammation pathway (decreased cyclooxygenase-2 expression and prostaglandin E2 production through downregulation of mitogen-activated protein kinase and nuclear factor-κB signaling). In summary, ENDS shows better antioxidant and anti-inflammatory activities than raw eupafolin through improvement of water solubility and skin penetration. Therefore, ENDS may potentially be used as a medicinal drug and/or cosmeceutical product to prevent PM-induced skin inflammation.

  13. Inhibitory effects of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide-induced inflammatory responses in RAW264 macrophages.

    Science.gov (United States)

    Yasuda, Michiko; Kawabata, Kyuichi; Miyashita, Miki; Okumura, Mayu; Yamamoto, Norio; Takahashi, Masakazu; Ashida, Hitoshi; Ohigashi, Hajime

    2014-01-15

    The Japanese herb, Ashitaba (Angelica keiskei Koidzumi), contains two prenylated chalcones, 4-hydroxyderricin and xanthoangelol, which are considered to be the major active compounds of Ashitaba. However, their effects on inflammatory responses are poorly understood. In the present study, we investigated the effects and underlying molecular mechanisms of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264 mouse macrophages. LPS-mediated production of nitric oxide (NO) was markedly reduced by 4-hydroxyderricin (10 μM) and xanthoangelol (5 μM) compared with their parent compound, chalcone (25 μM). They also inhibited LPS-induced secretion of tumor necrosis factor-alpha (TNF-α) and expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Although chalcone decreased the DNA-binding activity of both activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB), 4-hydroxyderricin and xanthoangelol suppressed only AP-1 and had no effect on NF-κB. On the other hand, all of the tested chalcones reduced the phosphorylation (at serine 536) level of the p65 subunit of NF-κB. 4-Hydroxyderricin and xanthoangelol may be promising for the prevention of inflammatory diseases.

  14. Selenium Deficiency-Induced Inflammation and Increased Expression of Regulating Inflammatory Cytokines in the Chicken Gastrointestinal Tract.

    Science.gov (United States)

    Gao, Xuejiao; Zhang, Ziwei; Xing, Houjuan; Yu, Jiao; Zhang, Naisheng; Xu, Shiwen

    2016-09-01

    Selenium (Se), a nutritionally essential trace element, plays an important role in various aspects of health for a wide range of species, including birds. Se deficiency inhibits the growth of immune organs and decreases immune function, leading to many inflammatory diseases. The present study determined the effects and mechanism of dietary Se deficiency on gastrointestinal tract tissue inflammation. The histopathological changes showed that Se deficiency induced inflammatory lesions in the gastrointestinal tract tissues (glandular stomach, gizzard, duodenum, small intestine, and rectum). The expression levels of PTGE (prostagland E synthase), COX-2 (cyclooxygenase-2), TNF-α (tumor necrosis factor α), and NF-κB (nuclear transfer factor κB) in the gastrointestinal tract tissues (glandular stomach, gizzard, duodenum, small intestine, and rectum) were determined by qPCR on days 15, 25, 35, 45, and 55, respectively. The results showed that Se deficiency induced high expression levels of PTGE, COX-2, TNF-α, and NF-κB in the gastrointestinal tract tissues. The effects were more obvious in the duodenum and small intestine than those in the glandular stomach, gizzard, and rectum. In addition, the expression levels of these proteins in the gastrointestinal tract tissue increased in a time-dependent manner with Se deficiency feeding time. Furthermore, Se deficiency induced the production of pro-inflammatory factors, thus aggravating inflammatory lesions in the gastrointestinal tract. The effect of Se deficiency on inflammation and other gastrointestinal tract diseases should be further studied. PMID:26899319

  15. Eupafolin nanoparticles protect HaCaT keratinocytes from particulate matter-induced inflammation and oxidative stress

    Science.gov (United States)

    Lin, Zih-Chan; Lee, Chiang-Wen; Tsai, Ming-Horng; Ko, Horng-Huey; Fang, Jia-You; Chiang, Yao-Chang; Liang, Chan-Jung; Hsu, Lee-Fen; Hu, Stephen Chu-Sung; Yen, Feng-Lin

    2016-01-01

    Exposure to particulate matter (PM), a major form of air pollution, can induce oxidative stress and inflammation and may lead to many diseases in various organ systems including the skin. Eupafolin, a flavonoid compound derived from Phyla nodiflora, has been previously shown to exhibit various pharmacological activities, including antioxidant and anti-inflammatory effects. Unfortunately, eupafolin is characterized by poor water solubility and skin penetration, which limits its clinical applications. To address these issues, we successfully synthesized a eupafolin nanoparticle delivery system (ENDS). Our findings showed that ENDS could overcome the physicochemical drawbacks of raw eupafolin with respect to water solubility and skin penetration, through reduction of particle size and formation of an amorphous state with hydrogen bonding. Moreover, ENDS was superior to raw eupafolin in attenuating PM-induced oxidative stress and inflammation in HaCaT keratinocytes, by mediating the antioxidant pathway (decreased reactive oxygen species production and nicotinamide adenine dinucleotide phosphate oxidase activity) and anti-inflammation pathway (decreased cyclooxygenase-2 expression and prostaglandin E2 production through downregulation of mitogen-activated protein kinase and nuclear factor-κB signaling). In summary, ENDS shows better antioxidant and anti-inflammatory activities than raw eupafolin through improvement of water solubility and skin penetration. Therefore, ENDS may potentially be used as a medicinal drug and/or cosmeceutical product to prevent PM-induced skin inflammation. PMID:27570454

  16. BRP, a polysaccharide fraction isolated from Boschniakia rossica, protects against galactosamine and lipopolysaccharide induced hepatic failure in mice.

    Science.gov (United States)

    Quan, Jishu; Jin, Meihua; Xu, Huixian; Qiu, Delai; Yin, Xuezhe

    2014-05-01

    The aim of this study was to investigate the hepatoprotective effect of BRP, a polysaccharide fraction isolated from Boschniakia rossica, against galactosamine and lipopolysaccharide induced fulminant hepatic failure. Mice were injected with a single dose of galactosamine/lipopolysaccharide with or without pretreatment of BRP. Results showed marked reduction of hepatic necrosis, serum marker enzymes and levels of tumor necrosis factor-α and interleukin-6 in BRP pretreated mice when compared with galactosamine/lipopolysaccharide-challenged mice. Mice pretreated with BRP decreased the activation of caspases-3 and caspase-8, and showed a reduced level of DNA fragmentation of liver cells. BRP also reduced hepatic lipid peroxidation, increased potential of hepatic antioxidative defense system, and reduced hepatic nitric oxide level which was elevated by galactosamine/lipopolysaccharide injection. Immunoblot analysis showed down-regulation of inducible nitric oxide synthase and cyclooxygenase-2 proteins of liver tissues in BRP pretreated group when compared with galactosamine/lipopolysaccharide-challenged group. Furthermore, treatment with galactosamine/lipopolysaccharide markedly increased toll-like receptor 4, nuclear level of nuclear factor-κB, and phosphorylation of both extracellular signal-regulated kinase and c-Jun N-terminal kinase in liver tissues. However, these increases were attenuated by pretreatment with BRP. The results suggest that BRP alleviates galactosamine/lipopolysaccharide-induced liver injury by enhancing antioxidative defense system, suppressing inflammatory responses and reducing apoptotic signaling.

  17. Eupafolin nanoparticles protect HaCaT keratinocytes from particulate matter-induced inflammation and oxidative stress.

    Science.gov (United States)

    Lin, Zih-Chan; Lee, Chiang-Wen; Tsai, Ming-Horng; Ko, Horng-Huey; Fang, Jia-You; Chiang, Yao-Chang; Liang, Chan-Jung; Hsu, Lee-Fen; Hu, Stephen Chu-Sung; Yen, Feng-Lin

    2016-01-01

    Exposure to particulate matter (PM), a major form of air pollution, can induce oxidative stress and inflammation and may lead to many diseases in various organ systems including the skin. Eupafolin, a flavonoid compound derived from Phyla nodiflora, has been previously shown to exhibit various pharmacological activities, including antioxidant and anti-inflammatory effects. Unfortunately, eupafolin is characterized by poor water solubility and skin penetration, which limits its clinical applications. To address these issues, we successfully synthesized a eupafolin nanoparticle delivery system (ENDS). Our findings showed that ENDS could overcome the physicochemical drawbacks of raw eupafolin with respect to water solubility and skin penetration, through reduction of particle size and formation of an amorphous state with hydrogen bonding. Moreover, ENDS was superior to raw eupafolin in attenuating PM-induced oxidative stress and inflammation in HaCaT keratinocytes, by mediating the antioxidant pathway (decreased reactive oxygen species production and nicotinamide adenine dinucleotide phosphate oxidase activity) and anti-inflammation pathway (decreased cyclooxygenase-2 expression and prostaglandin E2 production through downregulation of mitogen-activated protein kinase and nuclear factor-κB signaling). In summary, ENDS shows better antioxidant and anti-inflammatory activities than raw eupafolin through improvement of water solubility and skin penetration. Therefore, ENDS may potentially be used as a medicinal drug and/or cosmeceutical product to prevent PM-induced skin inflammation. PMID:27570454

  18. Evidence that PGE2 in the dorsal and median raphe nuclei is involved in LPS-induced anorexia in rats.

    Science.gov (United States)

    Kopf, Brigitte S; Langhans, Wolfgang; Geary, Nori; Hrupka, Brian; Asarian, Lori

    2011-09-01

    Anorexia is an element of the acute-phase immune response. Its mechanisms remain poorly understood. Activation of inducible cyclooxygenase-2 (COX-2) in blood-brain-barrier endothelial cells and subsequent release of prostaglandins (e.g., prostaglandin E2, PGE2) may be involved. Therefore, we sought to relate the effects of prostaglandins on the anorexia following gram-negative bacterial lipopolysaccharide treatment (LPS) to neural activity in the dorsal and median raphe nuclei (DRN and MnR) in rats. COX-2 antagonist (NS-398, 10mg/kg; IP) administration prior to LPS (100μg/kg; IP) prevented anorexia and reduced c-Fos expression the DRN, MnR, nucleus tractus solitarii and several related forebrain areas. These data indicate that COX-2-mediated prostaglandin synthesis is necessary for LPS anorexia and much of the initial LPS-induced neural activation. Injection of NS-398 into the DRN and MnR (1ng/site) attenuated LPS-induced anorexia to nearly the same extent as IP NS-398, suggesting that prostaglandin signaling in these areas is necessary for LPS anorexia. Because the DRN and MnR are sources of major serotonergic projections to the forebrain, these data suggest that serotonergic neurons originating in the midbrain raphe play an important role in acute-phase response anorexia.

  19. Ibuprofen-loaded porous microspheres suppressed the progression of monosodium iodoacetate-induced osteoarthritis in a rat model.

    Science.gov (United States)

    Park, Jang Won; Yun, Young-Pil; Park, Kyeongsoon; Lee, Jae Yong; Kim, Hak-Jun; Kim, Sung Eun; Song, Hae-Ryong

    2016-11-01

    The objectives of this study were (1) to fabricate ibuprofen-loaded porous microspheres (IBU/PMSs), (2) to evaluate the in vitro anti-inflammatory effects of the microspheres using LPS-induced inflammation in cultured synoviocytes, and (3) to evaluate the in vivo effect of the IBU/PMSs on the progression of monosodium iodoacetate (MIA)-induced osteoarthritis (OA) in a rat model. A dose-dependent in vitro anti-inflammatory effect on pro-inflammatory cytokine markers (matrix metallopeptidase-3 (MMP-3), matrix metallopeptidase-13 (MMP-13), cyclooxygenase-2 (COX-2), a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5)), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α) was observed by confirming with real-time PCR analyses. In vivo, treatment with IBU/PMSs reduced MIA-stimulated mRNA expression of MMP-3, MMP-13, COX-2, ADAMTS-5, IL-6, and TNF-α in rat synoviocytes. In addition, we demonstrated that intra-articular IBU/PMSs suppressed the progression of MIA-induced OA in the rat model via anti-inflammatory mechanisms. In conclusion, IBU/PMSs are a promising therapeutic material to control the pain and progression of OA.

  20. Lansoprazole prevents experimental gastric injury induced by non-steroidal anti-inflammatory drugs through a reduction of mucosal oxidative damage

    Institute of Scientific and Technical Information of China (English)

    Corrado Blandizzi; Matteo Fornai; Rocchina Colucci; Gianfranco Natale; Valter Lubrano; Cristina Vassalle; Luca Antonioli; Gloria Lazzeri; Mario Del Tacca

    2005-01-01

    AIM: This study investigated the mechanisms of protection afforded by the proton pump inhibitor lansoprazole against gastric injury induced by different non-steroidal antiinflammatory drugs (NSAIDs) in rats.METHODS: Male Sprague-Dawley rats were orally treated with indomethacin (100 μmol/kg), diclofenac (60 μmol/kg),piroxicam (150 μmol/kg) or ketoprofen (150 μmol/kg).Thirty minutes before NSAIDs, animals were orally treated with lansoprazole 18 or 90 μmol/kg. Four hours after the end of treatments, the following parameters were assessed: gastric mucosal PGE2, malondialdehyde (MDA), myeloperoxidase (MPO) or non-proteic sulfhydryl compounds (GSH) levels; reverse transcription-polymerase chain reaction (RT-PCR) of mucosal COX-2 mRNA; gastric acid secretion in pylorus-ligated animals; in vitro effects of lansoprazole (1-300 μmol/L) on the oxidation of low density lipoproteins (LDLs) induced by copper sulphate.RESULTS: All NSAIDs elicited mucosal necrotic lesions which were associated with neutrophil infiltration and reduction of PGE2 levels. Increments of MPO and MDA contents, as well as a decrease in GSH levels were detected in the gastric mucosa of indomethacin- or piroxicam-treated animals. Indomethacin enhanced mucosal cyclooxygenase-2 expression, while not affecting cyclooxygenase-1. At the oral dose of 18 μmol/kg lansoprazole partly counteracted diclofenac-induced mucosal damage, whereas at 90 μmol/kg it markedly prevented injuries evoked by all test NSAIDs. Lansoprazole at 90 μmol/kg reversed also the effects of NSAIDs on MPO, MDA and GSH mucosal contents, without interfering with the decrease in PGE2 levels or indomethacin-induced cyclooxygenase-2 expression. However, both lansoprazole doses markedly inhibited acid secretion in pylorus-ligated rats. Lansoprazole concentration-dependently reduced the oxidation of LDLs in vitro.CONCLUSION: These results suggest that, besides the inhibition of acid secretion, lansoprazole protection against NSAID-induced

  1. Poly-γ-Glutamic Acid Induces Apoptosis via Reduction of COX-2 Expression in TPA-Induced HT-29 Human Colorectal Cancer Cells

    Directory of Open Access Journals (Sweden)

    Eun Ju Shin

    2015-04-01

    Full Text Available Poly-γ-glutamic acid (PGA is one of the bioactive compounds found in cheonggukjang, a fast-fermented soybean paste widely utilized in Korean cooking. PGA is reported to have a number of beneficial health effects, and interestingly, it has been identified as a possible anti-cancer compound through its ability to promote apoptosis in cancer cells, although the precise molecular mechanisms remain unclear. Our findings demonstrate that PGA inhibits the pro-proliferative functions of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA, a known chemical carcinogen in HT-29 human colorectal cancer cells. This inhibition was accompanied by hallmark apoptotic phenotypes, including DNA fragmentation and the cleavage of poly (ADP-ribose polymerase (PARP and caspase 3. In addition, PGA treatment reduced the expression of genes known to be overexpressed in colorectal cancer cells, including cyclooxygenase 2 (COX-2 and inducible nitric oxide synthase (iNOS. Lastly, PGA promoted activation of 5' adenosine monophosphate-activated protein (AMPK in HT-29 cells. Taken together, our results suggest that PGA treatment enhances apoptosis in colorectal cancer cells, in part by modulating the activity of the COX-2 and AMPK signaling pathways. These anti-cancer functions of PGA make it a promising compound for future study.

  2. Protective Effects of Resveratrol against UVA-Induced Damage in ARPE19 Cells

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    Chi-Ming Chan

    2015-03-01

    Full Text Available Ultraviolet radiation, especially UVA, can penetrate the lens, reach the retina, and induce oxidative stress to retinal pigment epithelial (RPE cells. Even though it is weakly absorbed by protein and DNA, it may trigger the production of reactive oxygen species (ROS and generate oxidative injury; oxidative injury to the retinal pigment epithelium has been implicated to play a contributory role in age-related macular degeneration (AMD. Studies showed that resveratrol, an abundant and active component of red grapes, can protect several cell types from oxidative stress. In this study, adult RPE cells being treated with different concentrations of resveratrol were used to evaluate the protective effect of resveratrol on RPE cells against UVA-induced damage. Cell viability assay showed that resveratrol reduced the UVA-induced decrease in RPE cell viability. Through flow cytometry analysis, we found that the generation of intracellular H2O2 induced by UVA irradiation in RPE cells could be suppressed by resveratrol in a concentration-dependent manner. Results of Western blot analysis demonstrated that resveratrol lowered the activation of UVA-induced extracellular signal-regulated kinase, c-jun-NH2 terminal kinase and p38 kinase in RPE cells. In addition, there was also a reduction in UVA-induced cyclooxygenase-2 (COX-2 expression in RPE cells pretreated with resveratrol. Our observations suggest that resveratrol is effective in preventing RPE cells from being damaged by UVA radiation, and is worth considering for further development as a chemoprotective agent for the prevention of early AMD.

  3. Protective Effect of Procyanidin B2 against CCl4-Induced Acute Liver Injury in Mice

    Directory of Open Access Journals (Sweden)

    Bing-Ya Yang

    2015-07-01

    Full Text Available Procyanidin B2 has demonstrated several health benefits and medical properties. However, its protective effects against CCl4-induced hepatotoxicity have not been clarified. The present study aimed to investigate the hepatoprotective effects of procyanidin B2 in CCl4-treated mice. Our data showed that procyanidin B2 significantly decreased the CCl4-induced elevation of serum alanine aminotransferase activities, as well as improved hepatic histopathological abnormalities. Procyanidin B2 also significantly decreased the content of MDA but enhanced the activities of antioxidant enzymes SOD, CAT and GSH-Px. Further research demonstrated that procyanidin B2 decreased the expression of TNF-α, IL-1β, cyclooxygenase-2 (COX-2 and inducible nitric oxide synthase (iNOS, as well as inhibited the translocation of nuclear factor-kappa B (NF-κB p65 from the cytosol to the nuclear fraction in mouse liver. Moreover, CCl4-induced apoptosis in mouse liver was measured by (terminal-deoxynucleotidyl transferase mediated nick end labeling TUNEL assay and the cleaved caspase-3. Meanwhile, the expression of apoptosis-related proteins Bax and Bcl-xL was analyzed by Western blot. Results showed that procyanidin B2 significantly inhibited CCl4-induced hepatocyte apoptosis, markedly suppressed the upregulation of Bax expression and restored the downregulation of Bcl-xL expression. Overall, the findings indicated that procyanidin B2 exhibited a protective effect on CCl4-induced hepatic injury by elevating the antioxidative defense potential and consequently suppressing the inflammatory response and apoptosis of liver tissues.

  4. Glycine inhibits ethanol-induced oxidative stress, neuroinflammation and apoptotic neurodegeneration in postnatal rat brain.

    Science.gov (United States)

    Amin, Faiz Ul; Shah, Shahid Ali; Kim, Myeong Ok

    2016-06-01

    Here we investigated for the first time the inhibitory potential of Glycine (Gly) against ethanol-induced oxidative stress, neuroinflammation and apoptotic neurodegeneration in human neuroblastoma SH-SY5Y cells and in the developing rat brain. The Gly co-treatment significantly increased the cell viability, inhibited the expression of phospho-Nuclear Factor kappa B (p-NF-kB) and caspase-3 and reduced the oxidative stress in ethanol-treated SH-SY5Y cells in a PI3K-dependent manner. Seven days old male rat pups were injected with ethanol (5 g/kg subcutaneously, prepared in a 20% saline solution) and Gly (1 g/kg). Gly co-treatment stimulated the PI3K/Akt signaling pathway to limit the ethanol induced reactive oxygen species (ROS) production in the developing rat brain. It lowered the ethanol-elevated levels of phospho-c Jun N terminal kinase (p-JNK) and its various downstream apoptotic markers, including Bax, cytochrome C, caspase-3 and PARP-1. Additionally, the Gly treatment upregulated antiapoptotic Bcl-2 proteins and prevented ethanol-induced neurodegeneration as assessed by Fluoro-Jade-B (FJB) and Nissl staining. Furthermore, the Gly administration caused significant reduction in the ethanol-induced neuroinflammation by inhibiting the expression of inflammatory markers such as p-NF-kB, cyclooxygenase 2 (COX2) and tumor necrosis factor-α (TNF-α) and reversed the ethanol-induced synaptic protein markers expression. The results suggest that acute Gly treatment reduces ethanol-induced oxidative stress and neuronal cell loss in SH-SY5Y cells and in the developing rat brain. Therefore, Gly may be considered as potential treatment in ethanol-intoxicated newborns and infants. PMID:27058626

  5. Magnolol Ameliorates Ligature-Induced Periodontitis in Rats and Osteoclastogenesis: In Vivo and In Vitro Study

    Directory of Open Access Journals (Sweden)

    Sheng-Hua Lu

    2013-01-01

    Full Text Available Periodontal disease characterized by alveolar bone resorption and bacterial pathogen-evoked inflammatory response has been believed to have an important impact on human oral health. The aim of this study was to evaluate whether magnolol, a main constituent of Magnolia officinalis, could inhibit the pathological features in ligature-induced periodontitis in rats and osteoclastogenesis. The sterile, 3–0 (diameter; 0.2 mm black braided silk thread, was placed around the cervix of the upper second molars bilaterally and knotted medially to induce periodontitis. The morphological changes around the ligated molars and alveolar bone were examined by micro-CT. The distances between the amelocemental junction and the alveolar crest of the upper second molars bilaterally were measured to evaluate the alveolar bone loss. Administration of magnolol (100 mg/kg, p.o. significantly inhibited alveolar bone resorption, the number of osteoclasts on bony surface, and protein expression of receptor activator of nuclear factor-κB ligand (RANKL, a key mediator promoting osteoclast differentiation, in ligated rats. Moreover, the ligature-induced neutrophil infiltration, expression of inducible nitric oxide synthase, cyclooxygenase-2, matrix metalloproteinase (MMP-1 and MMP-9, superoxide formation, and nuclear factor-κB activation in inflamed gingival tissues were all attenuated by magnolol. In the in vitro study, magnolol also inhibited the growth of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans that are key pathogens initiating periodontal disease. Furthermore, magnolol dose dependently reduced RANKL-induced osteoclast differentiation from RAW264.7 macrophages, tartrate-resistant acid phosphatase (TRAP activity of differentiated cells accompanied by a significant attenuation of resorption pit area caused by osteoclasts. Collectively, we demonstrated for the first time that magnolol significantly ameliorates the alveolar bone loss in

  6. Genistein inhibits phorbol ester-induced NF-κB transcriptional activity and COX-2 expression by blocking the phosphorylation of p65/RelA in human mammary epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Myung-Hoon; Kim, Do-Hee [Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul (Korea, Republic of); Na, Hye-Kyung [Department of Food and Nutrition, Sungshin Women' s University, Seoul (Korea, Republic of); Kim, Jung-Hwan; Kim, Ha-Na [Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul (Korea, Republic of); Haegeman, Guy [LEGEST, University of Gent (Belgium); Surh, Young-Joon, E-mail: surh@snu.ac.kr [Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul (Korea, Republic of); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul (Korea, Republic of); Cancer Research Institute, Seoul National University, Seoul (Korea, Republic of)

    2014-10-15

    Genistein, an isoflavone present in soy products, has chemopreventive effects on mammary carcinogenesis. In the present study, we have investigated the effects of genistein on phorbol ester-induced expression of cyclooxygenase-2 (COX-2) that plays an important role in the pathophysiology of inflammation-associated carcinogenesis. Pretreatment of cultured human breast epithelial (MCF10A) cells with genistein reduced COX-2 expression induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). There are multiple lines of evidence supporting that the induction of COX-2 is regulated by the eukaryotic transcription factor NF-κB. Genistein failed to inhibit TPA-induced nuclear translocation and DNA binding of NF-κB as well as degradation of IκB. However, genistein abrogated the TPA-induced transcriptional activity of NF-κB as determined by the luciferase reporter gene assay. Genistein inhibited phosphorylation of the p65 subunit of NF-κB and its interaction with cAMP regulatory element-binding protein-binding protein (CBP)/p300 and TATA-binding protein (TBP). TPA-induced NF-κB phosphorylation was abolished by pharmacological inhibition of extracellular signal-regulated kinase (ERK). Likewise, pharmacologic inhibition or dominant negative mutation of ERK suppressed phosphorylation of p65. The above findings, taken together, suggest that genistein inhibits TPA-induced COX-2 expression in MCF10A cells by blocking ERK-mediated phosphorylation of p65 and its subsequent interaction with CBP and TBP.

  7. Schisandrin B Ameliorates ICV-Infused Amyloid β Induced Oxidative Stress and Neuronal Dysfunction through Inhibiting RAGE/NF-κB/MAPK and Up-Regulating HSP/Beclin Expression.

    Directory of Open Access Journals (Sweden)

    Vijayasree V Giridharan

    Full Text Available Amyloid β (Aβ-induced neurotoxicity is a major pathological mechanism of Alzheimer's disease (AD. Our previous studies have demonstrated that schisandrin B (Sch B, an antioxidant lignan from Schisandra chinensis, could protect mouse brain against scopolamine- and cisplatin-induced neuronal dysfunction. In the present study, we examined the protective effect of Sch B against intracerebroventricular (ICV-infused Aβ-induced neuronal dysfunction in rat cortex and explored the potential mechanism of its action. Our results showed that 26 days co-administration of Sch B significantly improved the behavioral performance of Aβ (1-40-infused rats in step-through test. At the same time, Sch B attenuated Aβ-induced increases in oxidative and nitrosative stresses, inflammatory markers such as inducible nitric oxide syntheses, cyclooxygenase-2, interleukin-1β (IL-1β, IL-6, and tumor necrosis factor-α, and DNA damage. Several proteins such as receptor for advanced glycation end products (RAGE, nuclear factor-κB, mitogen-activated protein kinases, and apoptosis markers were over expressed in Aβ-infused rats but were significantly inhibited by Sch B treatment. Furthermore, Sch B negatively modulated the Aβ level with simultaneous up-regulation of HSP70 and beclin, autophagy markers in Aβ-infused rats. The aforementioned effects of Sch B suggest its protective role against Aβ-induced neurotoxicity through intervention in the negative cycle of RAGE-mediated Aβ accumulation during AD patho-physiology.

  8. Protective activity of salidroside against ethanol-induced gastric ulcer via the MAPK/NF-κB pathway in vivo and in vitro.

    Science.gov (United States)

    Chang, Xiayun; Luo, Fen; Jiang, Wenjiao; Zhu, Lingpeng; Gao, Jin; He, He; Wei, Tingting; Gong, Shilin; Yan, Tianhua

    2015-09-01

    Salidroside (Sal) is a traditional Chinese medicine with various pharmacological effects. The present study aimed to investigate the protective effect of Sal on ethanol-induced acute gastric ulcer and H2O2-induced gastric epithelial cell damage. 0.2 ml ethanol and 400 μM H2O2 were applied to establish a gastric ulcer model in vivo and in vitro respectively. The production of interleukin (IL)-6, interleukin (IL)-1β and tumor necrosis factor (TNF)-α was analyzed, as well as myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD). MTT assay was used to detect cell viability. In addition, MAPK/NF-κB signal pathway-related proteins p-ERK, p-JNK, p-p38, p-IκBα and p-NF-κBp65 were analyzed to determine the underlying protective mechanism. Downstream genes such as cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and leukotrienes B4 (LTB4) were also measured. Obtained data indicated that Sal inhibited the overproduction of pro-inflammatory cytokines and enhanced antioxidant activity. Collectively, it is assumed that Sal could alleviate ethanol-induced acute gastric ulcer and H2O2-induced gastric epithelial cell damage through the MAPK/NF-κB pathway.

  9. Hyaluronic acid as a rescue therapy for trinitrobenzene sulfonic acid-induced colitis through Cox-2 and PGE2 in a Toll-like receptor 4-dependent way

    Institute of Scientific and Technical Information of China (English)

    Huan CHEN; Mahesh MAHASETH; Yah ZHANG

    2011-01-01

    We hypothesized whether systemic administration of high-molecular-weight hyaluronic acid (HMW HA) could rescue trinitrobenzene sulfonic acid (TNBS)-induced colitis through Toll-like receptor 4 (TLR4) signal.C3H/HeN mice and C3H/HeJ mice were used.Mice were divided into four groups:control,50% ethanol treatment group,TNBS treatment group,and TNBS plus HA treatment group.The weight changes,clinical scores,macroscopic scores,and histological scores were recorded.Cyclooxygenase 2 (Cox-2) and prostaglandin E2 (PGE2) expressions were measured both in colons and peritoneal macrophages from these mice.HA was a rescue therapy for the colitis induced by TNBS only in C3H/HeN mice.The clinical score,macroscopic score,and histological score were much lower in C3H/HeN mice receiving TNBS plus HA treatment.Cox-2 and PGE2 expressions only increased in C3H/HeN mice.These Cox-2 expressing cells were macrophages.HA can also promote the production of Cox-2 and PGE2 in peritoneal macrophages from C3H/HeN mice.Our data demonstrated that HMW HA can rescue TNBS-induced colitis through inducing Cox-2 and PGE2 expressions in a TLR4-dependent way.Macrophages may be the effector cells of HMW HA.

  10. Honokiol, a phytochemical from the Magnolia plant, inhibits photocarcinogenesis by targeting UVB-induced inflammatory mediators and cell cycle regulators: development of topical formulation.

    Science.gov (United States)

    Vaid, Mudit; Sharma, Som D; Katiyar, Santosh K

    2010-11-01

    To develop newer and more effective chemopreventive agents for skin cancer, we assessed the effect of honokiol, a phytochemical from the Magnolia plant, on ultraviolet (UV) radiation-induced skin tumorigenesis using the SKH-1 hairless mouse model. Topical treatment of mice with honokiol in a hydrophilic cream-based topical formulation before or after UVB (180 mJ/cm(2)) irradiation resulted in a significant protection against photocarcinogenesis in terms of tumor multiplicity (28-60%, P skin samples from the tumor-bearing mice were analyzed for inflammatory mediators, cell cycle regulators and survival signals using immunostaining, western blotting and enzyme-linked immunosorbent assay. Treatment with honokiol significantly inhibited UVB-induced expression of cyclooxygenase-2, prostaglandin E(2) (P skin as well as in skin tumors. Western blot analysis revealed that honokiol: (i) inhibited the levels of cyclins D1, D2 and E and associated cyclin-dependent kinases (CDKs)2, CDK4 and CDK6, (ii) upregulated Cip/p21 and Kip/p27 and (iii) inhibited the levels of phosphatidylinositol 3-kinase and the phosphorylation of Akt at Ser(473) in UVB-induced skin tumors. Together, our results indicate that honokiol holds promise for the prevention of UVB-induced skin cancer by targeting inflammatory mediators, cell cycle regulators and cell survival signals in UVB-exposed skin. PMID:20823108

  11. α-Solanine Isolated From Solanum Tuberosum L. cv Jayoung Abrogates LPS-Induced Inflammatory Responses Via NF-κB Inactivation in RAW 264.7 Macrophages and Endotoxin-Induced Shock Model in Mice.

    Science.gov (United States)

    Shin, Ji-Sun; Lee, Kyoung-Goo; Lee, Hwi-Ho; Lee, Hae Jun; An, Hyo-Jin; Nam, Jung-Hwan; Jang, Dae Sik; Lee, Kyung-Tae

    2016-10-01

    α-Solanine, a trisaccharide glycoalkaloid, has been reported to possess anti-cancer effects. In this study, we investigated the anti-inflammatory effects of α-solanine isolated from "Jayoung" a dark purple-fleshed potato by examining its in vitro inhibitory effects on inducible nitric-oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines in LPS-induced RAW 264.7 macrophages and its in vivo effects on LPS-induced septic shock in a mouse model. α-Solanine suppressed the expression of iNOS and COX-2 both at protein and mRNA levels and consequently inhibited nitric oxide (NO) and prostaglandin E2 (PGE2 ) production in LPS-induced RAW 264.7 macrophages. α-Solanine also reduced the production and mRNA expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) induced by LPS. Furthermore, molecular mechanism studies indicated that α-solanine inhibited LPS-induced activation of nuclear factor-κB (NF-κB) by reducing nuclear translocation of p65, degradation of inhibitory κBα (IκBα), and phosphorylation of IκB kinaseα/β (IKKα/β). In an in vivo experiment of LPS-induced endotoxemia, treatment with α-solanine suppressed mRNA expressions of iNOS, COX-2, IL-6, TNF-α, and IL-1β, and the activation of NF-κB in liver. Importantly, α-solanine increased the survival rate of mice in LPS-induced endotoxemia and polymicrobial sepsis models. Taken together, our data suggest that the α-solanine may be a promising therapeutic against inflammatory diseases by inhibiting the NF-κB signaling pathway. J. Cell. Biochem. 117: 2327-2339, 2016. © 2016 Wiley Periodicals, Inc.

  12. Genome-Wide Expression Analysis of Human In Vivo Irritated Epidermis: Differential Profiles Induced by Sodium Lauryl Sulfate and Nonanoic Acid

    DEFF Research Database (Denmark)

    Clemmensen, Anders; Andersen, Klaus E; Clemmensen, Ole;

    2010-01-01

    -regulated kinase and growth factor receptor signaling, whereas SLS transiently downregulated cellular energy metabolism pathways. Differential expression of the cyclooxygenase-2 and matrix metalloproteinase 3 transcripts was confirmed immunohistochemically. After cumulative exposure, 883 genes were differentially...

  13. Eugenol suppressed the expression of lipopolysaccharide-induced proinflammatory mediators in human macrophages.

    Science.gov (United States)

    Lee, Ya-Yun; Hung, Shan-Ling; Pai, Sheng-Fang; Lee, Yuan-Ho; Yang, Shue-Fen

    2007-06-01

    Eugenol is commonly used as an analgesic agent during acute pulpitis and is a major component of root canal sealers. Despite the frequent applications of eugenol in the practice of dentistry, little is known about the role of eugenol under the status of inflammation. This study was aimed to investigate the influence of eugenol on human macrophages (U937) under the stimulation of lipopolysaccharide (LPS). Eugenol was shown to block the release of the bone resorbing mediators, including interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and prostaglandin E2 from LPS-stimulated macrophages. In contrast, eugenol alone did not alter the expression levels of these proinflammatory mediators in macrophages. Consistent with downregulation of bone-resorbing mediators, eugenol suppressed the messenger RNA expression of LPS-induced IL-1beta, TNF-alpha, and cyclooxygenase-2 in macrophages. The results suggest a potential anti-inflammatory effect of eugenol in the acute inflamed pulps and apical periodontitis.

  14. Isorhynchophylline improves learning and memory impairments induced by D-galactose in mice.

    Science.gov (United States)

    Xian, Yan-Fang; Su, Zi-Ren; Chen, Jian-Nan; Lai, Xiao-Ping; Mao, Qing-Qiu; Cheng, Christopher H K; Ip, Siu-Po; Lin, Zhi-Xiu

    2014-10-01

    Isorhynchophylline (IRN), an alkaloid isolated from Uncaria rhynchophylla, has been reported to improve cognitive impairment induced by beta-amyloid in rats. However, whether IRN could also ameliorate the D-galactose (D-gal)-induced mouse memory deficits is still not clear. In the present study, we aimed to investigate whether IRN had potential protective effect against the D-gal-induced cognitive deficits in mice. Mice were given a subcutaneous injection of D-gal (100mg/kg) and orally administered IRN (20 or 40mg/kg) daily for 8weeks, followed by assessing spatial learning and memory function by the Morris water maze test. The results showed that IRN significantly improved spatial learning and memory function in the D-gal-treated mice. In the mechanistic studies, IRN significantly increased the level of glutathione (GSH) and the activities of superoxide dismutase (SOD) and catalase (CAT), while decreased the level of malondialdehyde (MDA) in the brain tissues of the D-gal-treated mice. Moreover, IRN (20 or 40mg/kg) significantly inhibited the production of prostaglandin E 2 (PGE2) and nitric oxide (NO), and the mRNA expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), as well as the activation of nuclear factor kappa B (NF-κB) in the brain tissues of D-gal-treated mice. Our results amply demonstrated that IRN was able to ameliorate cognitive deficits induced by D-gal in mice, and the observed cognition-improving action may be mediated, at least in part, through enhancing the antioxidant status and anti-inflammatory effect of brain tissues via NFκB signaling. PMID:24984171

  15. Protective Effect of Areca catechu Leaf Ethanol Extract Against Ethanol-Induced Gastric Ulcers in ICR Mice.

    Science.gov (United States)

    Lee, Kang Pa; Choi, Nan Hee; Sudjarwo, Giftania Wardani; Ahn, Sang-Hyun; Park, In-Sik; Lee, Sang-Rak; Hong, Heeok

    2016-02-01

    Gastric ulcer is a common digestive disorder that results in considerable suffering. Hence, this digestive pathology has been the focus of a number of recent studies. Although numerous drugs have been developed to treat gastric ulcers, therapeutic approaches for many of the complications associated with these drugs remain to be identified. For this reason, many natural compounds have been explored as alternatives for these drugs. In this study, we have investigated the effectiveness of Areca catechu leaf ethanol extract (ACE) for treating ethanol-induced gastric ulcers in mice. We performed histological as well as immunohistochemical examinations to explore the therapeutic properties of ACE. We also examined the levels of inflammatory signaling molecules to confirm the anti-inflammatory effects of ACE. The histochemical data demonstrate that ACE can protect the mucosal epithelium as well as the vascular supply in the gastric tract. Furthermore, ACE significantly reduced the expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 receptor (IL-6R), inducible NO synthase (iNOS), cyclooxygenase 2 (COX2), and nuclear factor-kappa B (NF-κB). Taken together, these data suggest that ACE administration may have the potential as an alternative treatment for gastric ulcer because of its cytoprotective and anti-inflammatory effects and ability to promote the rejuvenation and revascularization of the damaged gastric epithelium. PMID:26540449

  16. The Algal Meroterpene 11-Hydroxy-1′-O-Methylamentadione Ameloriates Dextran Sulfate Sodium-Induced Colitis in Mice

    Science.gov (United States)

    Zbakh, Hanaa; Talero, Elena; Avila, Javier; Alcaide, Antonio; de los Reyes, Carolina; Zubía, Eva; Motilva, Virginia

    2016-01-01

    Inflammatory bowel disease (IBD) is a complex class of immune disorders. Unfortunately, a treatment for total remission has not yet been found, while the use of natural product-based therapies has emerged as a promising intervention. The present study was aimed to investigate the anti-inflammatory effects of the algal meroterpene 11-hydroxy-1′-O-methylamentadione (AMT-E) in a murine model of dextran sodium sulphate (DSS)-induced colitis. AMT-E was orally administered daily (1, 10, and 20 mg/kg animal) to DSS treated mice (3% w/v) for 7 days. AMT-E prevented body weight loss and colon shortening and effectively attenuated the extent of the colonic damage. Similarly, AMT-E increased mucus production and reduced myeloperoxidase activity (marker for anti-inflammatory activity). Moreover, the algal meroterpene decreased the tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-10 levels, and caused a significant reduction of the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Our results demonstrate the protective effects of AMT-E on experimental colitis, provide an insight of the underlying mechanisms of this compound, and suggest that this class of marine natural products might be an interesting candidate for further studies on the prevention/treatment of IBD. PMID:27527191

  17. Human iNKT Cells Promote Protective Inflammation by Inducing Oscillating Purinergic Signaling in Monocyte-Derived DCs.

    Science.gov (United States)

    Xu, Xuequn; Pocock, Ginger M; Sharma, Akshat; Peery, Stephen L; Fites, J Scott; Felley, Laura; Zarnowski, Robert; Stewart, Douglas; Berthier, Erwin; Klein, Bruce S; Sherer, Nathan M; Gumperz, Jenny E

    2016-09-20

    Invariant natural killer T (iNKT) cells are innate T lymphocytes that promote host defense against a variety of microbial pathogens. Whether microbial ligands are required for their protective effects remains unclear. Here, we show that iNKT cells stimulate human-monocyte-derived dendritic cells (DCs) to produce inflammatory mediators in a manner that does not require the presence of microbial compounds. Interleukin 2 (IL-2)-exposed iNKT cells selectively induced repeated cytoplasmic Ca(2+) fluxes in DCs that were dependent on signaling by the P2X7 purinergic receptor and mediated by ATP released during iNKT-DC interactions. Exposure to iNKT cells led to DC cyclooxygenase 2 (PTGS2) gene transcription, and release of PGE2 that was associated with vascular permeabilization in vivo. Additionally, soluble factors were released that induced neutrophil recruitment and activation and enhanced control of Candida albicans. These results suggest that sterile interactions between iNKT cells and monocyte-derived DCs lead to the production of non-redundant inflammatory mediators that promote neutrophil responses. PMID:27653689

  18. Curcumin Protects against UVB-Induced Skin Cancers in SKH-1 Hairless Mouse: Analysis of Early Molecular Markers in Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Kuen-Daw Tsai

    2012-01-01

    Full Text Available Curcumin (CUR has been shown to possess a preventive effect against various cancers and interfere with multiple-cell signaling pathways. We evaluated the protective effects of CUR in regression of UVB-induced skin tumor formation in SKH-1 hairless mice and its underlying early molecular biomarkers associated with carcinogenesis. Mice irradiated with UVB at 180 mJ/cm2 twice per week elicited 100% tumor incidence at 20 weeks. Topical application of CUR prior to UVB irradiation caused delay in tumor appearance, multiplicity, and size. Topical application of CUR prior to and immediately after a single UVB irradiation (180 mJ/cm2 resulted in a significant decrease in UVB-induced thymine dimer-positive cells, expression of proliferative cell nuclear antigen (PCNA, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and apoptotic sunburn cells together with an increase in p53 and p21/Cip1-positive cell population in epidermis. Simultaneously, CUR also significantly inhibited NF-κB, cyclooxygenase-2 (COX-2, prostaglandin E2 (PGE2, and nitric oxide (NO levels. The results suggest that the protective effect of CUR against photocarcinogenesis is accompanied by downregulation of cell proliferative controls, involving thymine dimer, PCNA, apoptosis, transcription factors NF-κB, and of inflammatory responses involving COX-2, PGE2, and NO, while upregulation of p53 and p21/Cip1 to prevent DNA damage and facilitate DNA repair.

  19. Quercetin Inhibits Peripheral and Spinal Cord Nociceptive Mechanisms to Reduce Intense Acute Swimming-Induced Muscle Pain in Mice

    Science.gov (United States)

    Borghi, Sergio M.; Pinho-Ribeiro, Felipe A.; Fattori, Victor; Bussmann, Allan J. C.; Vignoli, Josiane A.; Camilios-Neto, Doumit; Casagrande, Rubia; Verri, Waldiceu A.

    2016-01-01

    The present study aimed to evaluate the effects of the flavonoid quercetin (3,3´,4´,5,7-pentahydroxyflavone) in a mice model of intense acute swimming-induced muscle pain, which resembles delayed onset muscle soreness. Quercetin intraperitoneal (i.p.) treatment dose-dependently reduced muscle mechanical hyperalgesia. Quercetin inhibited myeloperoxidase (MPO) and N-acetyl-β-D- glucosaminidase (NAG) activities, cytokine production, oxidative stress, cyclooxygenase-2 (COX-2) and gp91phox mRNA expression and muscle injury (creatinine kinase [CK] blood levels and myoblast determination protein [MyoD] mRNA expression) as well as inhibited NFκB activation and induced Nrf2 and HO-1 mRNA expression in the soleus muscle. Beyond inhibiting those peripheral effects, quercetin also inhibited spinal cord cytokine production, oxidative stress and glial cells activation (glial fibrillary acidic protein [GFAP] and ionized calcium-binding adapter molecule 1 [Iba-1] mRNA expression). Concluding, the present data demonstrate that quercetin is a potential molecule for the treatment of muscle pain conditions related to unaccustomed exercise. PMID:27583449

  20. The Algal Meroterpene 11-Hydroxy-1'-O-Methylamentadione Ameloriates Dextran Sulfate Sodium-Induced Colitis in Mice.

    Science.gov (United States)

    Zbakh, Hanaa; Talero, Elena; Avila, Javier; Alcaide, Antonio; de Los Reyes, Carolina; Zubía, Eva; Motilva, Virginia

    2016-01-01

    Inflammatory bowel disease (IBD) is a complex class of immune disorders. Unfortunately, a treatment for total remission has not yet been found, while the use of natural product-based therapies has emerged as a promising intervention. The present study was aimed to investigate the anti-inflammatory effects of the algal meroterpene 11-hydroxy-1'-O-methylamentadione (AMT-E) in a murine model of dextran sodium sulphate (DSS)-induced colitis. AMT-E was orally administered daily (1, 10, and 20 mg/kg animal) to DSS treated mice (3% w/v) for 7 days. AMT-E prevented body weight loss and colon shortening and effectively attenuated the extent of the colonic damage. Similarly, AMT-E increased mucus production and reduced myeloperoxidase activity (marker for anti-inflammatory activity). Moreover, the algal meroterpene decreased the tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-10 levels, and caused a significant reduction of the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Our results demonstrate the protective effects of AMT-E on experimental colitis, provide an insight of the underlying mechanisms of this compound, and suggest that this class of marine natural products might be an interesting candidate for further studies on the prevention/treatment of IBD. PMID:27527191

  1. Monotropein isolated from the roots of Morinda officinalis ameliorates proinflammatory mediators in RAW 264.7 macrophages and dextran sulfate sodium (DSS)-induced colitis via NF-κB inactivation.

    Science.gov (United States)

    Shin, Ji-Sun; Yun, Kyung-Jin; Chung, Kyung-Sook; Seo, Kyeong-Hwa; Park, Hee-Juhn; Cho, Young-Wuk; Baek, Nam-In; Jang, Daesik; Lee, Kyung-Tae

    2013-03-01

    We previously demonstrated that monotropein isolated from the roots of Morinda officinalis (Rubiaceae) has anti-inflammatory effects in vivo. In the present study, we investigated the molecular mechanisms underlying the anti-inflammatory effects of monotropein in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and dextran sulfate sodium (DSS)-induced colitis mouse model. Monotropein was found to inhibit the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) mRNA in LPS-induced RAW 264.7 macrophages. Treatment with monotropein decreased the DNA binding activity of nuclear factor-κB (NF-κB). Consistent with these findings, monotropein also suppressed phosphorylation and degradation of inhibitory κB-α (IκB-α), and consequently the translocations of NF-κB. In the DSS-induced colitis model, monotropein reduced disease activity index (DAI), myeloperoxidase (MPO) activity, and inflammation-related protein expressions by suppressing NF-κB activation in colon mucosa. Taken together, these findings suggest that the anti-inflammatory effects of monotropein are mainly related to the inhibition of the expressions of inflammatory mediators via NF-κB inactivation, and support its possible therapeutic role in colitis. PMID:23261679

  2. Apocynin protects against ethanol-induced gastric ulcer in rats by attenuating the upregulation of NADPH oxidases 1 and 4.

    Science.gov (United States)

    El-Naga, Reem N

    2015-12-01

    Gastric ulcer is a common gastrointestinal disorder affecting many people all over the world. Absolute ethanol (5 ml/kg) was used to induce gastric ulceration in rats. Apocynin (50 mg/kg) was given orally one hour before the administration of absolute ethanol. Omeprazole (20 mg/kg) was used as a standard. Interestingly, apocynin pre-treatment provided 93.5% gastroprotection against ethanol-induced ulceration. Biochemically, gastric mucin content was significantly increased with apocynin pre-treatment. This finding was further supported by alcian blue staining of stomach sections obtained from the different treated groups. Also, gastric juice volume and acidity were significantly reduced. Apocynin significantly ameliorated ethanol-induced oxidative stress by replenishing reduced glutathione and superoxide dismutase levels as well as reducing elevated malondialdehyde levels in gastric tissues. Besides, ethanol-induced pro-inflammatory response was significantly decreased by apocynin pre-treatment via reducing elevated levels of pro-inflammatory markers; interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2 and inducible nitric oxide synthase. Additionally, caspase-3 tissue level was significantly reduced in apocynin pre-treated group. Interestingly, NADPH oxidase-1 (NOX-1) and NOX-4 up-regulation was shown to be partially involved in the pathogenesis of ethanol-induced gastric ulceration and was significantly reversed by apocynin pre-treatment. Gastroprotective properties of apocynin were confirmed by histopathological examination. It is worth mentioning that apocynin was superior in all aspects except gastric mucin content parameter where it was significantly increased by 13.5 folds in the omeprazole pre-treated group. This study was the first to show that apocynin is a promising gastroprotective agent against ethanol-induced gastric ulceration, partially via its anti-oxidant, anti-inflammatory, anti-apoptotic effects as well as down-regulating NOX-1 and NOX-4

  3. Anti-Inflammatory Effect of Apigenin on LPS-Induced Pro-Inflammatory Mediators and AP-1 Factors in Human Lung Epithelial Cells.

    Science.gov (United States)

    Patil, Rajeshwari H; Babu, R L; Naveen Kumar, M; Kiran Kumar, K M; Hegde, Shubha M; Nagesh, Rashmi; Ramesh, Govindarajan T; Sharma, S Chidananda

    2016-02-01

    Apigenin is one of the plant flavonoids present in fruits and vegetables, acting as an important nutraceutical component. It is recognized as a potential antioxidant, antimicrobial, and anti-inflammatory molecule. In the present study, the mechanism of anti-inflammatory action of apigenin on lipopolysaccharide (LPS)-induced pro-inflammatory cytokines and activator protein-1 (AP-1) factors in human lung A549 cells was investigated. The anti-inflammatory activity of apigenin on LPS-induced inflammation was determined by analyzing the expression of pro-inflammatory cytokines, nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and different AP-1 factors. Apigenin significantly inhibited the LPS-induced expression of iNOS, COX-2, expression of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8, and TNF-α), and AP-1 proteins (c-Jun, c-Fos, and JunB) including nitric oxide production. Study confirms the anti-inflammatory effect of apigenin by inhibiting the expression of inflammatory mediators and AP-1 factors involved in the inflammation and its importance in the treatment of lung inflammatory diseases. PMID:26276128

  4. Cucurbitane Triterpenoid from Momordica charantia Induces Apoptosis and Autophagy in Breast Cancer Cells, in Part, through Peroxisome Proliferator-Activated Receptor γ Activation

    Directory of Open Access Journals (Sweden)

    Jing-Ru Weng

    2013-01-01

    Full Text Available Although the antitumor activity of the crude extract of wild bitter gourd (Momordica charantia L. has been reported, its bioactive constituents and the underlying mechanism remain undefined. Here, we report that 3β,7β-dihydroxy-25-methoxycucurbita-5,23-diene-19-al (DMC, a cucurbitane-type triterpene isolated from wild bitter gourd, induced apoptotic death in breast cancer cells through peroxisome proliferator-activated receptor (PPAR γ activation. Luciferase reporter assays indicated the ability of DMC to activate PPARγ, and pharmacological inhibition of PPARγ protected cells from DMC's antiproliferative effect. Western blot analysis indicated that DMC suppressed the expression of many PPARγ-targeted signaling effectors, including cyclin D1, CDK6, Bcl-2, XIAP, cyclooxygenase-2, NF-κB, and estrogen receptor α, and induced endoplasmic reticulum stress, as manifested by the induction of GADD153 and GRP78 expression. Moreover, DMC inhibited mTOR-p70S6K signaling through Akt downregulation and AMPK activation. The ability of DMC to activate AMPK in liver kinase (LK B1-deficient MDA-MB-231 cells suggests that this activation was independent of LKB1-regulated cellular metabolic status. However, DMC induced a cytoprotective autophagy presumably through mTOR inhibition, which could be overcome by the cotreatment with the autophagy inhibitor chloroquine. Together, the ability of DMC to modulate multiple PPARγ-targeted signaling pathways provides a mechanistic basis to account for the antitumor activity of wild bitter gourd.

  5. Topical (+)-catechin emulsified gel prevents DMBA/TPA-induced squamous cell carcinoma of the skin by modulating antioxidants and inflammatory biomarkers in BALB/c mice.

    Science.gov (United States)

    Monga, Jitender; Aggarwal, Vaibhav; Suthar, Sharad Kumar; Monika; Nongalleima, Khumukcham; Sharma, Manu

    2014-12-01

    An emulsified gel of (+)-catechin was developed and evaluated topically against 7,12-dimethylbenz(a)anthracene-induced and 12-O-tetradecanoylphorbol-13-acetate-promoted (DMBA-induced and TPA-promoted) squamous cell carcinoma of the skin in BALB/c mice. The biological evaluation outcome indicated that the (+)-catechin emulsified gel increased the activity of oxidative stress biomarkers glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), glutathione reductase (GR), and glutathione peroxidase (GPx), whereas it decreased the level of malondialdehyde (MDA). The mechanistic study showed that genes implicated in the inflammation and cancer, such as cyclooxygenase-2 (COX-2), nuclear factor-kappa B (NF-κB), and inducible nitric-oxide synthase (iNOS), were down-regulated by (+)-catechin emulsified gel while inhibiting an inflammatory mediator prostaglandin E2 (PGE2). The (+)-catechin emulsified gel further suppressed the activity of pro-inflammatory cytokines, viz. tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). The in vitro permeation study revealed that release of (+)-catechin from an emulsified gel base reached a steady state after 6 h, while pH of the entire emulsified gel was found to be between 6.2 and 6.5 that falls well within the normal pH range of the skin.

  6. Essential oil from the heartwood of Taiwan fir ameliorates LPS-induced inflammatory response by inhibiting the activation of mitogen-activated protein kinase.

    Science.gov (United States)

    Liu, May-Lan; Hua, Kuo-Feng; Yang, Tzu-Jung; Chiu, Huan-Wen; Ho, Chen-Lung

    2014-10-01

    The essential oil from the heartwood of Taiwan fir (EOTC) was demonstrated to exhibit anti-inflammatory activity in lipopolysaccharide (LPS)-activated mouse macrophages. EOTC reduced nitrite oxide levels and inducible nitrite oxide synthase expression in, and tumor necrosis factor-α and interleukin-6 secretion by, LPS-activated macrophages without affecting cyclooxygenase-2 expression. EOTC reduced the levels of interleukin-lβ precursor induced by LPS and decreased the NLRP3 inflammasome-derived interleukin-lβ secretion induced by LPS and adenosine triphosphate. In addition, the phosphorylation levels of ERKI/2, JNK1/2, and p38 in LPS-activated macrophages were reduced by EOTC. Furthermore, EOTC was composed of oxygenated sesquiterpenes (68.4%), sesquiterpene hydrocarbons (28.9%) and diterpenes (0.9%). The major compounds of the oxygenated sesquiterpenes were τ-cadinol (23.9%), α-cadinol (21.1%) and cedrol (16.9%). These findings suggest that EOTC may be a candidate for the development of anti-inflammatory agents for preventing and ameliorating inflammation-related diseases. PMID:25522551

  7. (7R,8S)-Dehydrodiconiferyl Alcohol Suppresses Lipopolysaccharide-Induced Inflammatory Responses in BV2 Microglia by Inhibiting MAPK Signaling.

    Science.gov (United States)

    Liu, Si-Yu; Xu, Peng; Luo, Xiao-Ling; Hu, Jin-Feng; Liu, Xin-Hua

    2016-07-01

    (7R,8S)-Dehydrodiconiferyl alcohol (DDA), a lignan isolated from the dried stems of Clematis armandii, has been found to exert potential anti-inflammatory activity in vitro. In the present study, we investigated the effects and possible mechanisms of DDA on lipopolysaccharide (LPS)-mediated inflammatory response in murine BV2 microglia. Our results revealed that non-toxic concentrations (6.25-25 μM) of DDA markedly suppressed LPS-induced production of nitric oxide, expression of inducible nitric oxide synthase and cyclooxygenase-2, and release of inflammatory factors, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in a concentration dependent manner. In addition, DDA time- and concentration-dependently attenuated LPS-induced phosphorylation of c-Jun N-terminal kinase 1/2 (JNK), but not protein kinase B, p38, or extracellular signal-regulated kinase 1/2. Moreover, DDA significantly suppress LPS-mediated nuclear factor-κB (NF-κB) activation by inhibiting phosphorylation and nuclear translocation of NF-κB p65. Collectively, our results demonstrated that DDA inhibited LPS-stimulated inflammatory response in BV2 cell, at least in part, through inhibition of NF-κB activation and modulation of JNK signaling. PMID:26961887

  8. Purple Sweet Potato Color Ameliorates Cognition Deficits and Attenuates Oxidative Damage and Inflammation in Aging Mouse Brain Induced by D-Galactose

    Directory of Open Access Journals (Sweden)

    Qun Shan

    2009-01-01

    Full Text Available Purple sweet potato color (PSPC, a naturally occurring anthocyanin, has a powerful antioxidant activity in vitro and in vivo. This study explores whether PSPC has the neuroprotective effect on the aging mouse brain induced by D-galactose (D-gal. The mice administrated with PSPC (100 mg/kg.day, 4 weeks, from 9th week via oral gavage showed significantly improved behavior performance in the open field and passive avoidance test compared with D-gal-treated mice (500 mg/kg.day, 8 weeks. We further investigate the mechanism involved in neuroprotective effects of PSPC on mouse brain. Interestingly, we found, PSPC decreased the expression level of glial fibrillary acidic protein (GFAP, inducible nitric oxide synthase (iNOS, and cyclooxygenase-2 (COX-2, inhibited nuclear translocation of nuclear factor-kappaB (NF-κB, increased the activity of copper/zinc superoxide dismutase (Cu/Zn-SOD and catalase (CAT, and reduced the content of malondialdehyde (MDA, respectively. Our data suggested that PSPC attenuated D-gal-induced cognitive impairment partly via enhancing the antioxidant and anti-inflammatory capacity.

  9. Novel long chain fatty acid derivatives of quercetin-3-O-glucoside reduce cytotoxicity induced by cigarette smoke toxicants in human fetal lung fibroblasts.

    Science.gov (United States)

    Warnakulasuriya, Sumudu N; Ziaullah; Rupasinghe, H P Vasantha

    2016-06-15

    Smoking has become a global health concern due to its association with many disease conditions, such as chronic obstructive pulmonary disease (COPD), cardiovascular diseases (CVD) and cancer. Flavonoids are plant polyphenolic compounds, studied extensively for their antioxidant, anti-inflammatory, and anti-carcinogenic properties. Quercetin-3-O-glucoside (Q3G) is a flavonoid which is widely found in plants. Six novel long chain fatty acid [stearic acid, oleic acid, linoleic acid, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] derivatives of Q3G were evaluated for their potential in protecting human lung fibroblasts against cytotoxicity induced by selected cigarette smoke toxicants: 4-(methylnitrosoamino)-1-(3-pyridinyl)-1-butanone (NNK), benzo-α-pyrene (BaP), nicotine and chromium (Cr[VI]). Nicotine and Cr[VI] induced toxicity in fibroblasts and reduced the percentage of viable cells, while BaP and NNK did not affect cell viability. The fatty acid derivatives of Q3G provided protection against nicotine- and Cr[VI]-induced cell death and membrane lipid peroxidation. Based on the evaluation of inflammatory markers of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2), the fatty acid derivatives of Q3G were found to be effective in lowering the inflammatory response. Overall, these novel fatty acid esters of Q3G warrant further investigation as potential cytoprotective agents. PMID:27071958

  10. Protective mechanisms of thymoquinone on methotrexate-induced intestinal toxicity in rats

    Directory of Open Access Journals (Sweden)

    Azza A El-Sheikh

    2016-01-01

    Full Text Available Background: Intestinal toxicity is a serious side effect in methotrexate (MTX chemotherapy. Objective: To investigate the mechanisms by which the anticancer drug MTX-induced intestinal damage could be prevented by thymoquinone (TQ, an active ingredient of Nigella sativa. Materials and Methods: TQ was given orally for 10 days, and MTX toxicity was induced at the end of day 3 of the experiment, with or without TQ pretreatment. Results: MTX caused intestinal damage, represented by distortion in normal intestinal histological structure, with significant oxidative stress, exhibited as decrease in reduced glutathione concentration and catalase activity, along with significant increase in malondialdehyde level compared to control group. MTX also caused nitrosative stress evident by increased intestinal nitric oxide (NO level, with up-regulation of inducible NO synthase expression shown in immunohistochemical staining. Furthermore, MTX caused inflammatory effects as evident by up-regulation of intestinal necrosis factor-kappa beta and cyclooxygenase-2 expressions, which were confirmed by increased intestinal tumor necrosis factor-alpha level via enzyme-linked immunosorbent assay. Moreover, MTX caused apoptotic effect, as it up-regulated intestinal caspase 3 expression. Concomitant TQ significantly reversed the MTX-induced intestinal toxic effects by reversing intestinal microscopic damage, as well as significantly improving oxidative/nitrosative stress, inflammatory and apoptotic markers tested compared to MTX alone. Conclusion: TQ may possess beneficial intestinal protective effects as an adjuvant co-drug against MTX intestinal toxicity during cancer chemotherapy. TQ protection is conferred via antioxidant, anti-nitrosative, anti-inflammatory, and anti-apoptotic mechanisms.

  11. Growth Hormone Releasing Peptide-2 Attenuation of Protein Kinase C-Induced Inflammation in Human Ovarian Granulosa Cells

    Science.gov (United States)

    Chao, Yi-Ning; Sun, David; Peng, Yen-Chun; Wu, Yuh-Lin

    2016-01-01

    Cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) are two important inflammatory mediators in ovulation. Ghrelin may modulate inflammatory signaling via growth hormone secretagogue receptors. We investigated the role of ghrelin in KGN human ovarian granulosa cells using protein kinase C (PKC) activator phorbol 12, 13-didecanoate (PDD) and synthetic ghrelin analog growth hormone releasing peptide-2 (GHRP-2). GHRP-2 attenuated PDD-induced expression of protein and mRNA, the promoter activity of COX-2 and IL-8 genes, and the secretion of prostaglandin E2 (PGE2) and IL-8. GHRP-2 promoted the degradation of PDD-induced COX-2 and IL-8 proteins with the involvement of proteasomal and lysosomal pathways. PDD-mediated COX-2 production acts via the p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways; PDD-mediated IL-8 production acts via the p38, JNK and ERK pathways. GHRP-2 reduced the PDD-induced phosphorylation of p38 and JNK and activator protein 1 (AP-1) reporter activation and PDD-induced NF-κB nuclear translocation and reporter activation. The inhibitors of mitogen-activated protein kinase phosphatase-1 (MKP-1) and protein phosphatase 2 (PP2A) reduced the inhibitory effect of GHRP-2 on PDD-induced COX-2 and IL-8 expression. Our findings demonstrate an anti-inflammatory role for ghrelin (GHRP-2) in PKC-mediated inflammation of granulosa cells, at least in part, due to its inhibitory effect on PKC-induced activation of p38, JNK and NF-κB, possibly by targeting to MKP-1 and PP2A. PMID:27548147

  12. Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

    International Nuclear Information System (INIS)

    Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125 mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1 d–28 d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS+ and cyclooxygenase-2+) and alternatively activated profibrotic (YM-1+ and galectin-3+) macrophages appeared in the lung following NM administration; this was evident within 1 d, and persisted for 28 d. AG administration (50 mg/kg, 2 ×/day, 1 d–3 d) abrogated NM-induced injury, oxidative stress and inflammation at 1 d and 3 d post exposure, with no effects at 7 d or 28 d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis. -- Highlights: ► Nitrogen mustard (NM) induces acute lung injury and fibrosis. ► Pulmonary toxicity is associated with increased expression of iNOS. ► Transient inhibition of iNOS attenuates acute lung injury induced by

  13. Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Malaviya, Rama; Venosa, Alessandro [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Hall, LeRoy [Drug Safety Sciences, Johnson and Johnson, Raritan, NJ 08869 (United States); Gow, Andrew J. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Sinko, Patrick J. [Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854 (United States); Laskin, Debra L., E-mail: laskin@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States)

    2012-12-15

    Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125 mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1 d–28 d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS{sup +} and cyclooxygenase-2{sup +}) and alternatively activated profibrotic (YM-1{sup +} and galectin-3{sup +}) macrophages appeared in the lung following NM administration; this was evident within 1 d, and persisted for 28 d. AG administration (50 mg/kg, 2 ×/day, 1 d–3 d) abrogated NM-induced injury, oxidative stress and inflammation at 1 d and 3 d post exposure, with no effects at 7 d or 28 d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis. -- Highlights: ► Nitrogen mustard (NM) induces acute lung injury and fibrosis. ► Pulmonary toxicity is associated with increased expression of iNOS. ► Transient inhibition of iNOS attenuates acute

  14. Cyclooxygenase-2 mediated regulation of E-cadherin occurs in conventional but not early-onset gastric cancer cell lines

    NARCIS (Netherlands)

    R. Sitarz; R.J. Leguit; W.W.J. de Leng; F.H.M. Morsink; W.P. Polkowski; R. Maciejewski; G.J.A. Offerhaus; A.N. Milne

    2009-01-01

    Background: COX-2 and E-cadherin, involved in invasion and metastasis, are molecules critical for gastric carcinogenesis. A relationship between them is documented in non-small cell lung and prostate cancer. We present novel evidence of a relationship between COX-2 and E-cadherin expression in gastr

  15. Cyclooxygenase-2, multidrug resistance 1, and breast cancer resistance protein gene polymorphisms and inflammatory bowel disease in the Danish population

    DEFF Research Database (Denmark)

    Østergaard, Mette; Ernst, Anja; Labouriau, Rodrigo;

    2009-01-01

    Crohn's disease (CD) and ulcerative colitis (UC) are characterized by an impaired mucosal defence to normal constituents of the intestinal flora and a dysregulated inflammatory response. The purpose of the study was to investigate whether single nucleotide polymorphisms (SNPs) in genes involved...

  16. Cyclooxygenase-2 Mediated Regulation of E-Cadherin Occurs in Conventional But Not Early-Onset Gastric Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    R. Sitarz

    2009-01-01

    Full Text Available Background: COX-2 and E-cadherin, involved in invasion and metastasis, are molecules critical for gastric carcinogenesis. A relationship between them is documented in non-small cell lung and prostate cancer. We present novel evidence of a relationship between COX-2 and E-cadherin expression in gastric cancer.

  17. Role of cyclooxygenase-2 in the carcinogenesis of gastrointestinal tract cancers: A review and report of personal experience

    Institute of Scientific and Technical Information of China (English)

    Takashi Fujimura; Tetsuo Ohta; Katsunobu Oyama; Tomoharu Miyashita; Koichi Miwa

    2006-01-01

    Selective cyclooxygenase (COX)-2 inhibitors (coxibs)were developed as one of the anti-inflammatory drugs to avoid the various side effects of non-steroidal anti-inflammatory drugs (NSAIDs). However, coxibs also have an ability to inhibit tumor development of various kinds the same way that NSAIDs do. Many experimental studies using cell lines and animal models demonstrated an ability to prevent tumor proliferation of COX-2 inhibitors. After performing a randomized study for polyp chemoprevention study in patients with familial adenomatous polyposis (FAP),which showed that the treatment with celecoxib,one of the coxibs, significantly reduced the number of colorectal polyps in 2000, the U.S. Food and Drug Administration (FDA) immediately approved the clinicai use of celecoxib for FAP patients. However, some coxibs were recently reported to increase the risk of serious cardiovascular events including heart attack and stroke. In this article we review a role of COX-2in carcinogenesis of gastrointestinal tract, such as the esophagus, stomach and colorectum, and also analyze the prospect of coxibs for chemoprevention of gastrointestinal tract tumors.

  18. Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor α, cyclooxygenase 2, and inflammatory arthritis

    OpenAIRE

    Phillips, Kristine; Kedersha, Nancy; Shen, Lily; Blackshear, Perry J.; Anderson, Paul

    2004-01-01

    TIA-1 and TTP are AU-rich element-binding proteins that prevent the pathological overexpression of tumor necrosis factor α (TNF-α). TIA-1 inhibits the translation of TNF-α transcripts, whereas TTP promotes the degradation of TNF-α transcripts. Here we show that TIA-1 and TTP function as arthritis suppressor genes: TIA-1–/– mice develop mild arthritis, TTP–/– mice develop severe arthritis, and TIA-1–/–TTP–/– mice develop very severe arthritis. Peritoneal macrophages derived from all three geno...

  19. 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

  20. Cyclooxygenase-2 Pathway Correlates with VEGF Expression in Head and Neck Cancer. Implications for Tumor Angiogenesis and Metastasis

    Directory of Open Access Journals (Sweden)

    Oreste Gallo

    2001-01-01

    Full Text Available We evaluated the role of COX-2 pathway in 35 head and neck cancers (HNCs by analyzing COX-2 expression and prostaglandin E2 (PGE2 production in relation to tumor angiogenesis and lymph node metastasis. COX-2 activity was also correlated to vascular endothelial growth factor (VEGF mRNA and protein expression. COX-2 mRNA and protein expression was higher in tumor samples than in normal mucosa. PGE2 levels were higher in the tumor front zone in comparison with tumor core and normal mucosa (P<0001. Specimens from patients with lymph node metastasis exhibited higher COX-2 protein expression (P=.0074, PGEZ levels (P=.0011 and microvessel density (P<.0001 than specimens from patients without metastasis. A significant correlation between COX-2 and tumor vascularization (rs=0.450, P=.007 as well as between COX-2 and microvessel density with VEGF expression in tumor tissues was found (rs=0.450, P=.007; rs=0.620, P=.0001, respectively. The induction of COX-2 mRNA and PGE2 synthesis by EGF and Escherichia coli lipopolysaccharide (LPS in A-431 and SCC-9 cell lines, resulted in an increase in VEGF mRNA and protein production. Indomethacin and celecoxib reversed the EGF- and LPS-dependent COX-2, VEGF, and PGE2 increases. This study suggests a central role of COX-2 pathway in HNC angiogenesis by modulating VEGF production and indicates that COX-2 inhibitors may be useful in HNC treatment.

  1. Up-regulation of cyclooxygenase-2-derived prostaglandin E2 in colon cancer cells resistant to 5-fluorouracil

    OpenAIRE

    Choi, Cheol Hee; Lee, Tae Bum; Lee, Yeon Ah; Choi, Suk; Kim, Kyung Jong

    2011-01-01

    Purpose It has been suggested that constitutive up-regulation of cyclooxygenase (COX)-2 is associated with resistance to apoptosis, increased angiogenesis, and increased tumor invasiveness in various cancers including colon cancer. There are many factors involved in the resistance to 5-fluorouracil (5-FU) in colon cancer. However, little is known about the role of COX-2 in acquired resistance to 5-FU in colon cancer. Methods Hence we investigated whether COX-2 contribute to acquired resistanc...

  2. Cyclo-oxygenase-2 mediated prostaglandin release regulates blood flow in connective tissue during mechanical loading in humans

    DEFF Research Database (Denmark)

    Langberg, H; Boushel, Robert Christopher; Skovgaard, D;

    2003-01-01

    prior to the experiment) or COX unspecific (n = 8, indomethacin 100 mg (12 and 1 h pre-experiment) and acetyl salicylic acid 500 mg day-1 for 3 days pre-experiment). Prostaglandin E2 (PGE2) concentration was determined by microdialysis and blood flow by 133Xe washout. In C, interstitial PGE2 rose from...

  3. Aqueous extract of Gracilaria tenuistipitata suppresses LPS-induced NF-κB and MAPK activation in RAW 264.7 and rat peritoneal macrophages and exerts hepatoprotective effects on carbon tetrachloride-treated rat.

    Science.gov (United States)

    Tseng, Chin-Kai; Lin, Chun-Kuang; Chang, Hsueh-Wei; Wu, Yu-Hsuan; Yen, Feng-Lin; Chang, Fang-Rong; Chen, Wei-Chun; Yeh, Chi-Chen; Lee, Jin-Ching

    2014-01-01

    In addition to the previous investigations of bioactivity of aqueous extract of the edible Gracilaria tenuistipitata (AEGT) against H2O2-induced DNA damage and hepatitis C virus replication, the purpose of this study is to evaluate the potential therapeutic properties of AEGT against inflammation and hepatotoxicity using lipopolysaccharide (LPS)-stimulated mouse RAW 264.7 cells, primary rat peritoneal macrophages and carbon tetrachloride (CCl4)-induced acute hepatitis model in rats. AEGT concentration-dependently inhibited the elevated RNA and protein levels of inducible nitric oxide synthase and cyclooxygenase-2, thereby reducing nitric oxide and prostaglandin E2 levels, respectively. Moreover, AEGT significantly suppressed the production of LPS-induced proinflammatory cytokines, including interleukin (IL)-1β, IL-6 and tumor necrosis factor-α. These inhibitory effects were associated with the suppression of nuclear factor-kappa B activation and mitogen-activated protein kinase phosphorylation by AEGT in LPS-stimulated cells. In addition, we highlighted the hepatoprotective and curative effects of AEGT in a rat model of CCl4-intoxicated acute liver injury, which was evident from reduction in the elevated serum aspartate aminotransferase and alanine aminotransferase levels as well as amelioration of histological damage by pre-treatment or post-treatment of AEGT. In conclusion, the results demonstrate that AEGT may serve as a potential supplement in the prevention or amelioration of inflammatory diseases.

  4. Aqueous extract of Gracilaria tenuistipitata suppresses LPS-induced NF-κB and MAPK activation in RAW 264.7 and rat peritoneal macrophages and exerts hepatoprotective effects on carbon tetrachloride-treated rat.

    Directory of Open Access Journals (Sweden)

    Chin-Kai Tseng

    Full Text Available In addition to the previous investigations of bioactivity of aqueous extract of the edible Gracilaria tenuistipitata (AEGT against H2O2-induced DNA damage and hepatitis C virus replication, the purpose of this study is to evaluate the potential therapeutic properties of AEGT against inflammation and hepatotoxicity using lipopolysaccharide (LPS-stimulated mouse RAW 264.7 cells, primary rat peritoneal macrophages and carbon tetrachloride (CCl4-induced acute hepatitis model in rats. AEGT concentration-dependently inhibited the elevated RNA and protein levels of inducible nitric oxide synthase and cyclooxygenase-2, thereby reducing nitric oxide and prostaglandin E2 levels, respectively. Moreover, AEGT significantly suppressed the production of LPS-induced proinflammatory cytokines, including interleukin (IL-1β, IL-6 and tumor necrosis factor-α. These inhibitory effects were associated with the suppression of nuclear factor-kappa B activation and mitogen-activated protein kinase phosphorylation by AEGT in LPS-stimulated cells. In addition, we highlighted the hepatoprotective and curative effects of AEGT in a rat model of CCl4-intoxicated acute liver injury, which was evident from reduction in the elevated serum aspartate aminotransferase and alanine aminotransferase levels as well as amelioration of histological damage by pre-treatment or post-treatment of AEGT. In conclusion, the results demonstrate that AEGT may serve as a potential supplement in the prevention or amelioration of inflammatory diseases.

  5. Soft Coral-Derived Lemnalol Alleviates Monosodium Urate-Induced Gouty Arthritis in Rats by Inhibiting Leukocyte Infiltration and iNOS, COX-2 and c-Fos Protein Expression

    Directory of Open Access Journals (Sweden)

    Hsin-Pai Lee

    2013-01-01

    Full Text Available An acute gout attack manifests in the joint as dramatic inflammation. To date, the clinical use of medicinal agents has typically led to undesirable side effects. Numerous efforts have failed to create an effective and safe agent for the treatment of gout. Lemnalol — an extract from Formosan soft coral — has documented anti-inflammatory and anti-nociceptive properties. In the present study, we attempt to examine the therapeutic effects of lemnalol on intra-articular monosodium urate (MSU-induced gouty arthritis in rats. In the present study, we found that treatment with lemnalol (intramuscular [im], but not colchicine (oral [po], significantly attenuated MUS-induced mechanical allodynia, paw edema and knee swelling. Histomorphometric and immunohistochemistry analysis revealed that MSU-induced inflammatory cell infiltration, as well as the elevated expression of c-Fos and pro-inflammatory proteins (inducible nitric oxide synthase and cyclooxygenase-2 observed in synovial tissue, were significantly inhibited by treatment with lemnalol. We conclude that lemnalol may be a promising candidate for the development of a new treatment for gout and other acute neutrophil-driven inflammatory diseases.

  6. Anti-inflammatory and heme oxygenase-1 inducing activities of lanostane triterpenes isolated from mushroom Ganoderma lucidum in RAW264.7 cells.

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    Choi, Solip; Nguyen, Van Thu; Tae, Nara; Lee, Suhyun; Ryoo, Sungwoo; Min, Byung-Sun; Lee, Jeong-Hyung

    2014-11-01

    Ganoderma lucidum is a popular medicinal mushroom used in traditional medicine for preventing or treating a variety of diseases. In the present study, we investigated the anti-inflammatory and heme oxygenase (HO)-1 inducing effects of 12 lanostane triterpenes from G. lucidum in RAW264.7 cells. Of these, seven triterpenes, butyl lucidenateE2, butyl lucidenateD2 (GT-2), butyl lucidenate P, butyl lucidenateQ, Ganoderiol F, methyl ganodenate J and butyl lucidenate N induced HO-1 expression and suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO) production. Inhibiting HO-1 activity abrogated the inhibitory effects of these triterpenes on the production of NO in LPS-stimulated RAW264.7 cells, suggesting the involvement of HO-1 in the anti-inflammatory effects of these triterpenes. We further studied the anti-inflammatory and HO-1 inducing effects of GT-2. Mitogen-activated protein kinase inhibitors or N-acetylcysteine, an antioxidant, did not suppress GT-2-mediated HO-1 induction; however, LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, blocked GT-2-induced HO-1 mRNA and protein expression. GT-2 increased nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) and knockdown of Nrf2 by small interfering RNA blocked GT-2-mediated HO-1 induction, suggesting that GT-2 induced HO-1 expression via the PI3K/AKT-Nrf2 pathway. Consistent with the notion that HO-1 has anti-inflammatory properties, GT-2 inhibited the production of tumor necrosis factor-α and interleukin-6, as well as inducible nitric oxide synthase and cyclooxygenase-2 expression. These findings suggest that HO-1 inducing activities of these lanostane triterpenes may be important in the understanding of a novel mechanism for the anti-inflammatory activity of G. lucidum.

  7. Inhibitory effects of Chikusetsusaponin IVa on lipopolysaccharide-induced pro-inflammatory responses in THP-1 cells.

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    Wang, H; Qi, J; Li, L; Wu, T; Wang, Y; Wang, X; Ning, Q

    2015-09-01

    This study investigated anti-inflammatory effects and possible mechanisms of Chikusetsusaponin IVa (Chi IVa), one of the main bioactive components in saponins from Panacis japonica (SPJ), which is used in traditional Tujia and Hmong Chinese medicine. To this end, changes in the inflammatory profiles of lipopolysacchride (LPS)-stimulated phrobol 12-myristate 13-acetate(PMA)-differented THP-1 macrophages were evaluated following Chi IVa treatment. The results showed that Chi IVa markedly decreased the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) at both the mRNA and protein level, which proved to be dose-dependent. Further studies revealed that Chi IVa strongly suppressed NF-κB activation and downregulated the phosphorylation of ERK, p38, and JNK. Our present study demonstrates that Chi IVa suppresses the production of iNOS, COX-2, IL-1β, IL-6, and TNF-α in LPS-stimulated THP-1 cells likely by inhibiting NF-κB activation and ERK, JNK, and p38 signal pathway phosphorylation.

  8. Cyclooxygenase as a target in chemoprevention by probiotics during 1,2-dimethylhydrazine induced colon carcinogenesis in rats.

    Science.gov (United States)

    Walia, Sohini; Kamal, Rozy; Kanwar, Sarbjit Singh; Dhawan, Davinder Kumar

    2015-01-01

    The present study was undertaken to assess the effects of potential probiotics in regulating the activity of cyclooxygenase-2 (COX-2) along with other morphological and histological analysis during 1,2-dimethylhydrazine (DMH) induced colon carcinogenesis in rats. The rats were divided into 6 groups viz., normal control, Lactobacillus plantarum (AdF10) treated, Lactobacillus rhamnosus GG (LGG) treated, DMH treated, AdF10 + DMH treated and LGG + DMH treated. Probiotics were supplemented to rats at dose levels of 2 × 10(10) cells per day for 6 days in a week. All the treatments were continued for a period of 16 wk. DMH treatment resulted in a statistically significant increase in the levels of total sialic acid (TSA). However, on supplementation with probiotics, a significant reduction in TSA was observed. DMH treatment brought about a significant increase in the expression of COX-2. But, supplementation of probiotics brought down the protein expression to moderate level. Further, supplementation with probiotics was also able to reduce tumor incidence, tumor multiplicity and average tumor size. Therefore, treatment with probiotics has the potential of providing protection against colon cancer by suppressing the COX-2 expression as one of the protective mechanisms. PMID:25811420

  9. Honokiol improves learning and memory impairments induced by scopolamine in mice.

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    Xian, Yan-Fang; Ip, Siu-Po; Mao, Qing-Qiu; Su, Zi-Ren; Chen, Jian-Nan; Lai, Xiao-Ping; Lin, Zhi-Xiu

    2015-08-01

    Honokiol, a lignan isolated from the bark of Magnolia officinalis, has been reported to ameliorate the learning and memory impairments in senesed (SAMP8) mice. However, whether honokiol could improve scopolamine (SCOP)-induced learning and memory deficits in mice is still unknown. In this study, we aimed to investigate whether honokiol could reverse the SCOP-induced learning and memory impairments in mice and to elucidate its underlying mechanisms of action. Mice were given daily intraperitoneal injection of honokiol (10 and 20mg/kg) for 21 consecutive days. The results showed that honokiol significantly improved spatial learning and memory function (as assessed by the Morris water maze test) in the SCOP-treated mice. In addition, treatment with honokiol significantly decreased the protein and mRNA levels of interleukin (IL)-1β and the activity of acetylcholinesterase (AChE), while significantly increased the protein and mRNA levels of IL-10, and the level of acetylcholine (Ach) in the brain of the SCOP-treated mice. Moreover, honokiol also significantly suppressed the production of prostaglandin E 2 (PGE2) and mRNA expression of cyclooxygenase-2 (COX-2) in the brain of the SCOP-treated mice. Mechanistic investigations revealed that honokiol could markedly reverse the amount of phosphorylated Akt and extracellular regulated kinases 1/2 (ERK1/2) changes in the brain of the SCOP-treated mice. These results amply demonstrated that honokiol could improve learning and memory impairments induced by SCOP in mice, and the protective action may be mediated, at least in part, by inhibition of AChE activity, and amelioration of the neuroinflammatory processes in the SCOP-treated mice.

  10. Esculetin attenuates lipopolysaccharide (LPS)-induced neuroinflammatory processes and depressive-like behavior in mice.

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    Zhu, Lingpeng; Nang, Chen; Luo, Fen; Pan, Hong; Zhang, Kai; Liu, Jingyan; Zhou, Rui; Gao, Jin; Chang, Xiayun; He, He; Qiu, Yue; Wang, Jinglei; Long, Hongyan; Liu, Yu; Yan, Tianhua

    2016-09-01

    Esculetin is one of the major bioactive compounds of Cichorium intybus L. The main purpose of the present study was to investigate the effects and possible underlying mechanism of esculetin (Esc) on lipopolysaccharide (LPS)-induced neuroinflammatory processes and depressive-like behavior in mice. Mice were pretreatment with esculetin (Esc, 20, 40mg/kg, intragastric administration) and a positive control drug fluoxetine (Flu, 20mg/kg, intragastric administration) once daily for 7 consecutive days. At the 7th day, LPS (0.83mg/kg) was intraperitoneal injection 30min after drug administration. Higher dose (40mg/kg) of esculetin and fluoxetine significantly decreased immobility time in TST and FST. There was no significant effect on locomotor activity in mice by the drugs. Esculetin significantly reduced LPS-induced elevated levels of pro-inflammatory cytokines including interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum and hippocampus. Esculetin attenuated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression by inhibiting nuclear factor-κB (NF-κB) pathway in hippocampus. In addition, neuroprotection of esculetin was attributed to the upregulations of Brain derived neurotrophic factor (BDNF) and phosphorylated tyrosine kinase B (p-TrkB) protein expression in hippocampus. The obtained results demonstrated that esculetin exhibited antidepressant-like effects which might be related to the inhibition of NF-κB pathway and the activation of BDNF/TrkB signaling.

  11. Gastroprotective effect of andrographolide sodium bisulfite against indomethacin-induced gastric ulceration in rats.

    Science.gov (United States)

    Liu, Yu-Hong; Zhang, Zhen-Biao; Zheng, Yi-Feng; Chen, Hai-Ming; Yu, Xiu-Ting; Chen, Xiao-Ying; Zhang, Xie; Xie, Jian-Hui; Su, Zu-Qing; Feng, Xue-Xuan; Zeng, Hui-Fang; Su, Zi-Ren

    2015-06-01

    Andrographolide sodium bisulfite (ASB), a water-soluble sulfonate of andrographolide has been shown to possess anti-inflammatory, antipyretic and analgesic activities. However, there is no report on the gastroprotective effect of ASB against indomethacin-induced gastric ulcer. Here we investigated the possible anti-ulcerogenic potential of ASB and the underlying mechanism against indomethacin-induced gastric ulcer in rats. The ulcer area, histopathological assessment, contents of gastric mucosal glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), malonaldehyde (MDA) and prostaglandin E2 (PGE2) were examined. In addition, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) mRNA expression and immunohistochemical evaluation of HSP70, Bcl-2 and Bax proteins were also investigated. Results indicated that ASB pre-treatment significantly reduced the ulcer areas induced by indomethacin compared with the vehicle group. The gastric levels of GSH, CAT and SOD were markedly increased by ASB while the level of MDA was decreased. In addition, ASB pretreatment significantly promoted the gastric PGE2 levels and up-regulated the COX-1 and COX-2 mRNA expression in comparison with the vehicle group. Immunohistochemistry analysis showed obvious up-regulation of HSP70 and Bcl-2 protein expression while suppression of Bax protein in the gastric tissue of ASB-pretreated group. Taken together, these findings indicated that the gastroprotective effect of ASB might be associated with the improvement of antioxidative status, activation of COX-mediated PGE2 synthesis, down-regulation of Bax proteins and up-regulation of Bcl-2 and HSP70 proteins. ASB might have the potential for further development as a promising alternative for antiulcer treatment. PMID:25916678

  12. Repeated Predictable Stress Causes Resilience against Colitis-Induced Behavioral Changes in Mice

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    Ahmed M Hassan

    2014-11-01

    Full Text Available Inflammatory bowel disease is associated with an increased risk of mental disorders and can be exacerbated by stress. In this study which was performed with male 10-week old C57Bl/6N mice, we used dextran sulfate sodium (DSS-induced colitis to evaluate behavioral changes caused by intestinal inflammation, to assess the interaction between repeated psychological stress (water avoidance stress, WAS and colitis in modifying behavior, and to analyze neurochemical correlates of this interaction. A 7-day treatment with DSS (2 % in drinking water decreased locomotion and enhanced anxiety-like behavior in the open field test and reduced social interaction. Repeated exposure to WAS for 7 days had little influence on behavior but prevented the DSS-induced behavioral disturbances in the open field and social interaction tests. In contrast, repeated WAS did not modify colon length, colonic myeloperoxidase content and circulating proinflammatory cytokines, parameters used to assess colitis severity. DSS-induced colitis was associated with an increase in circulating neuropeptide Y (NPY, a rise in the hypothalamic expression of cyclooxygenase-2 mRNA and a decrease in the hippocampal expression of NPY mRNA, brain-derived neurotrophic factor mRNA and mineralocorticoid receptor mRNA. Repeated WAS significantly decreased the relative e